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Title:
DISORAZOLES AND THEIR ANALOGUES AND METHODS FOR THEIR PRODUCTION
Document Type and Number:
WIPO Patent Application WO/2022/074068
Kind Code:
A1
Abstract:
The present invention describes disorazoles and their analogues as described in formula III wherein the variables are defined in the description, or pharmaceutically acceptable salts thereof. Described is also a novel synthetic pathway for the production of disorazoles and their analogues, using two precursors twice in coupling reactions and a final cyclisation for a compound of formula III. The compounds of the present invention are useful as anti-cancer drugs.

Inventors:
SCHINZER DIETER (DE)
SPIESS OLIVER (DE)
LIZZADRO LUCA (DE)
Application Number:
PCT/EP2021/077602
Publication Date:
April 14, 2022
Filing Date:
October 06, 2021
Export Citation:
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Assignee:
OTTO VON GUERICKE UNIVERSTIY MAGDEBURG (DE)
International Classes:
A61P35/00; A61K31/424; C07C21/17; C07D263/32; C07D498/22
Domestic Patent References:
WO2018237178A12018-12-27
Other References:
HARTUNG I V ET AL: "Toward the Total Synthesis of Disorazole A1 and C1: Asymmetric Synthesis of a Masked Southern Segment", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 4, no. 19, 1 January 2002 (2002-01-01), pages 3239 - 3242, XP002265585, ISSN: 1523-7060, DOI: 10.1021/OL026468J
WIPF PETER ET AL: "Total Synthesis of ()-Disorazole C 1", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 126, no. 47, 1 December 2004 (2004-12-01), pages 15346 - 15347, XP055795096, ISSN: 0002-7863, DOI: 10.1021/ja0443068
NIESS BARBARA ET AL: "Synthesis of a Tetradehydro-Disorazole C1", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2006, no. 5, 1 March 2006 (2006-03-01), DE, pages 1132 - 1143, XP055795209, ISSN: 1434-193X, DOI: 10.1002/ejoc.200500675
HILLIER M C ET AL: "The synthesis of the monomeric moiety of disorazole C"1", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 41, no. 16, 1 April 2000 (2000-04-01), pages 2821 - 2824, XP004195679, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)00271-9
WIPF P. ET AL., J. AM. CHEM. SOC., vol. 126, no. 47, 2004, pages 15346 - 15347
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Claims:
Claims 1. Compound of the formula III III wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), alkinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; as well as the individual stereoisomers of this compound and/or a pharmaceutically acceptable salt thereof. 2. Compound of the Formula III according to claim 1, namely (4R)-Disorazole C1 of formula 31r

Bis(thiazolyl)-Disorazole C1 of formula 60t 3. Method for the production of a compound of formula III according to claim 1

(III) wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; comprising the following steps: (a) reacting a compound of formula I wherein R and R1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product obtained in step (a) with a compound of formula I, wherein the coupling of the obtained product and compound of for- mula I is performed via the carboxyl ester of compound I and the X group of the obtained product; (c) reacting the product obtained in step (b) with a compound of formula II in the same way as in step (a); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. 4. Method for the production of a compound of formula III according to claim 1

wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; comprising the following steps: (a) reacting a compound of formula I wherein R and R1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product of step (a) in two different steps, namely step (b1) and step (b2), wherein in step (b1) the compound obtained in step (a) is modified, in a way that PG from X is removed to obtain a compound wherein X is OH, SH, or NH2, and wherein in step (b2) the compound obtained in step (a) is modified, in a way that residue R of the carboxy group is removed and replaced with H; (c) reacting the product obtained in step (b1) with the product obtained in step (b2); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. 5. Method for the production of disorazole-C1 of formula 37

comprising the following steps: (a) reacting a compound of formula 30a wherein R is methyl or hydrogen with a compound of formula 18 wherein PG1 is MOM obtaining a compound of formula 31

(b) reacting the compound of formula 31 with a compound of formula 30a, obtaining a compound of formula 32 (c) reacting the compound of formula 32 with a compound of formula 18, obtaining a compound of formula 33

(d) reacting compound of formula 33 into disorazole-C1 of formula 37. 6. Method, according to claim 5, wherein step (a) is a coupling reaction combining compounds of formula 18 and of formula 30a, wherein R is methyl. 7. Method, according to claim 5 or 6, wherein step (b) is an esterification. 8. Method, according to at least one of preceding claims 5 to 7, wherein step (c) is a coupling reaction combining compounds of formula 31 and of formula 30a, wherein R is hydrogen. 9. Method, according to at least one of preceding claims 5 to 8, wherein step (d) comprises the following steps: (d1) saponification of methyl ester from compound of formula 33 to a compound of formula 34

(d2) macrolactonisation of open-chained compound 34 into compound of formula 35 (d3) reduction of the triple bonds of compound of formula 35 forming compound of formula 36

(d4) removing the protection groups to obtain compound of formula 37. 10. Method for the production of disorazole-C1 of formula 37 comprising the following steps: (a) reacting a compound of formula 30a wherein R and Ry are methyl; with a compound of formula 17a wherein PG1 is methyl and PG2 is MOM; obtaining a compound of formula 40 wherein Rx is PG1 and Ry is methyl as defined above; (b) reacting the compound of formula 40 partially in a step (b1) into a compound of formula 41 and partially in a step (b2) into a compound of formula 42

(c) reacting the compound of formula 41 with the compound of formula 42, obtaining a compound of formula 43 (d) removing Rx and Ry and replacing with hydrogen, obtaining a com- pound of formula 44

(e) reacting compound of formula 44 into disorazole-C1 of formula 37 as described in claim 8, wherein the starting compound is the com- pound of formula 44 instead of formula 34. 11. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula 30a wherein R is methyl or hydrogen. 12. Intermediate product, for the production according to at least one of the claims 3 to 9, according to formula 18 wherein PG1 is MOM. 13. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula 33 wherein PG1 is MOM. 14. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula I wherein R and R1 is as defined above. 15. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS. . 16. Pharmaceutical preparation for the treatment of cancer diseases, com- prising at least one compound according to claim 1 and other accepta- ble excipients, adjuvants and /or additives.
Description:
Disorazoles and their Analogues and Methods for their Production Technical Field The present invention relates to disorazoles and their analogues and meth- ods for their production. These compounds can be used as medicaments, in particular for the treatment of various tumors. Background Art Disorazoles are potent anti-cancer drugs and are natural substances. It is known that natural substances of the group consisting of the disorazoles are isolated from the bacterium of the strain Sorangium cellulosum. Synthetic methods for the preparation of disorazoles are described, for exam- ple, in WO 2018/237178 A1 or Wipf P. et al., J. Am. Chem. Soc.2004, 126, 47, 15346–15347. Therefore, it is an object of the present invention to provide a production method resulting in a high yield of disorazoles and their analogues, especially disorazole C1. Summary of Invention In some aspects, the present invention discloses new disorazoles and their analogues and new synthetic methods for the up-scaled production of disora- zoles and their analogues. One aspect is, that the disorazoles and their analogues may be produced by using two main substructures, also named as precursors, that can be pro- duced in large scales. These two main substructures are used to produce an open-chained precursor for the final cyclisation of disorazoles and their ana- logues. One preferred embodiment of the present invention is a compound of the formula III wherein: X is O, S, or NR;

R is H, or alkyl (c≤8) ;

R 1 is H, alkyl (c≤8) , or cycloalkyl (c≤8) ;

R 2 and R 3 are each independently H, alkyl (c≤8) , (CH 2 ) n (n = 1 -5);

R 4 is independently H, alkyl (c≤8) , cycloalkyl (c≤8) , alkenyl (c≤8) , alkinyl (c≤8) , allyl, propargyl, phenyl, or benzyl;

Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;

* indicate the stereoisomeric centers of the compound; as well as the individual stereoisomers of this compound and/or a pharmaceutically acceptable salt thereof.

A further preferred embodiment aspect of the present invention are com- pounds of the Formula III, namely

(4R)-Disorazole C1 of formula 31 r

Bis(thiazolyl)-Disorazole C1 of formula 60t Another aspect of the present invention is a method for the production of a compound of formula III

wherein:

X is O, S, or NR;

R is H, or alkyl (c≤8) ;

R 1 is H, alkyl (c≤8) , or cycloalkyl (c≤8) ;

R 2 and R 3 are each independently H, alkyl (c≤8) , (CH 2 ) n (n = 1-5);

R 4 is independently H, alkyl (c≤8) , cycloalkyl (c≤8) , alkenyl (c≤8) , al- kinyl (c≤8) , allyl, propargyl, phenyl, or benzyl;

Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl;

* indicate the stereoisomeric centers of the compound; comprising the following steps:

(a) reacting a compound of formula I wherein R and R 1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c≤8) ; or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product obtained in step (a) with a compound of formula I, wherein the coupling of the obtained product and compound of for- mula I is performed via the carboxyl ester of compound I and the X group of the obtained product; (c) reacting the product obtained in step (b) with a compound of formula II in the same way as in step (a); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. The main feature of this aspect is that two precursors as disclosed, as com- pounds of formula I and of formula II, are used to produce an open chained precursor of disorazols and their analogues. This open chained precursor is then cyclized and the final products as described as compounds of formula III, namely disorazoles and their analogues, are produced in a high yield and in a great purity. Another aspect of the present invention is a method for the production of a compound of formula III according to claim 1 wherein: X is O, S, or NR;

R is H, or alkyl (c≤8) ;

R 1 is H, alkyl (c≤8) , or cycloalkyl (c≤8) ;

R 2 and R 3 are each independently H, alkyl (c≤8) , (CH 2 ) n (n = 1 -5);

R 4 is independently H, alkyl (c≤8) , cycloalkyl (c≤8) , alkenyl (c≤8) , al- kinyl (c≤8) , allyl, propargyl, phenyl, or benzyl;

Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;

* indicate the stereoisomeric centers of the compound; comprising the following steps:

(a) reacting a compound of formula I

wherein R and R 1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c≤8) ; or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product of step (a) in two different steps, namely step (b1) and step (b2), wherein in step (b1) the compound obtained in step (a) is modified, in a way that PG from X is removed to obtain a compound wherein X is OH, SH, or NH 2 , and wherein in step (b2) the compound obtained in step (a) is modified, in a way that residue R of the carboxy group is removed and replaced with H; (c) reacting the product obtained in step (b1) with the product obtained in step (b2); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. An especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37 comprising the following steps: (a) reacting a compound of formula 30a wherein R is methyl or hydrogen with a compound of formula 18 wherein PG1 is MOM obtaining a compound of formula 31 (b) reacting the compound of formula 31 with a compound of formula 30a, obtaining a compound of formula 32 (c) reacting the compound of formula 32 with a compound of formula 18, obtaining a compound of formula 33

(d) reacting compound of formula 33 into disorazole-C1 of formula 37. Especially preferred herein is the method, wherein step (a) is a coupling re- action combining compounds of formula 18 and of formula 30a, wherein R is methyl. Especially preferred herein is also the method, wherein step (b) is an esterifi- cation. Further especially preferred herein is the method, wherein step (c) is a cou- pling reaction combining compounds of formula 31 and of formula 30a, wherein R is hydrogen. Preferred herein is also the method, wherein step (d) comprises the following steps: (d1) saponification of methyl ester from compound of formula 33 to a com- pound of formula 34

(d2) macrolactonisation of open-chained compound 34 into compound of for- mula 35 (d3) reduction of the triple bonds of compound of formula 35 forming com- pound of formula 36

(d4) removing the protection groups to obtain compound of formula 37. Another especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37 comprising the following steps: (a) reacting a compound of formula 30a wherein R and R y are methyl; with a compound of formula 17a wherein PG 1 is methyl and PG 2 is MOM; obtaining a compound of formula 40 wherein R x is PG 1 and R y is methyl as defined above; (b) reacting the compound of formula 40 partially in a step (b1) into a compound of formula 41

and partially in a step (b2) into a compound of formula 42 (c) reacting the compound of formula 41 with the compound of formula 42, obtaining a compound of formula 43 (d) removing R x and R y and replacing with hydrogen, obtaining a com- pound of formula 44 (e) reacting compound of formula 44 into disorazole-C1 of formula 37 as described above, wherein the starting compound is the compound of formula 44 instead of formula 34. A great advantage of this embodiment is that the yield of the reaction and the purity of the products is much higher. The reason is, that the complete reac- tion is more effective, as the coupled compounds 41 and 42 from precursors 17a and 30a differ in the protective groups. The different compounds 41 and 42 can easily be produced from the same precursors 17a and 30a. The fur- ther details are described below in reaction scheme 6. A further preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 30a wherein R is methyl or hydrogen. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 18 wherein PG1 is MOM. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 33 wherein PG1 is MOM. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula I

wherein R and R 1 is as defined above. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR com- prise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c≤8) ; or a protective group selected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS. A great advantage of the present invention is that only two precursors are needed to synthesize disorazoles and their analogues, namely compounds of formula I, formula II, formula 18, formula 30a, formula 29, or formula 30. Another great advantage of the present invention is to combine also com- pound of formula 17a with compound of formula 30a with different protective groups or substituents as described below in scheme 6. Another great advantage is that the precursors used can be selected accord- ing to their stereospecific properties. The compounds of formula I comprises one asymmetric carbon atom. The compounds of formula II comprise up to three asymmetric carbon atoms. For the person skilled in the art it is there therefore clear that the asymmetric centres in the final disorazoles can be produced easily by selecting the re- spective precursors as indicated above. The final product of formula III con- tains up to eight asymmetric centres and all possible combinations of the dia- stereomers can be produced easily. This option is one of the greatest ad- vantages of the present invention.

One preferred embodiment of the present invention is the production of diso- razole C1 . A high yield in the production of the final product is also a great advantage.

A further object of the present invention is a pharmaceutical preparation for the treatment of cancer diseases, comprising at least one compound accord- ing to the invention and other acceptable excipients, adjuvants and /or addi- tives.

It is known in the state of the art how to produce pharmaceutical prepara- tions, especially when using disorazols as known in the art.

Description of Embodiments The process for the production of disorazole and their analogues according to the invention will now be described in great detail. The following reaction schemes describe the synthesis of disorazoles and their analogues in gen- eral. One preferred embodiment of the synthesis in described in the exam- ples as given below in greater details. These examples are one preferred synthetic pathway for the production of disorazole C1. One compound for the production of disorazole is (S)-HYTRA ((S)-(-)-2-Hy- droxy-1,2,2-triphenylethylacetate), which is a protective group. The synthetic pathway is described in Scheme 1. In order to produce the important precursor of formula 18, which is described as lateral chain, a first fragment is synthesized as described in Scheme 2.

Using (S)-HYTRA of formula 3 and the aldehyde of formula 7 (as shown in Scheme 2) the synthesis of precursor of formula 18 is described in Scheme 3. Aldehyde 7 is reacted with compound of formula 3, then reacted with lith- ium aluminium hydride. An addition of protection groups, preferably with TES, is performed in the next step. The next step is an by ozonolysis, followed by a chiral allylation (preferably with Leighton reagent). In the next step the addi- tion of a protection group for the new hydroxy group is performed. A double bond isomerisation is performed (Grubbs reaction), followed by a Swern oxi- dation. Furthermore, a Wittig reaction is performed and a Z-vinyl iodide is ob- tained which is finally selectively deprotected. Now, precursor of formula 18 is prepared, as shown in Scheme 3. In the following Scheme 4 the synthesis of the second precursor for the syn- thetic method for the disorazole according to the present invention is de- scribed. The second precursor, named as oxazole fragment, is synthesized starting with ß-hydroxy ester of formula 19. The first step is an O-methylation reaction, followed by ozonolysis. The next step is performed as a Wittig reac- tion, followed by a hydrolysation of the ester obtaining product of formula 25. In the next step, L-serin methyl ester is reacted with compound of formula 25 to form the respective amide. In the following step, a cyclisation of the amide according to formula 26 is performed and this results to an oxazoline deriva- tive. In the next step, the oxazoline is oxidized in order to obtain the oxazole derivative according to formula 28. The protective group in the compound of formula 28 is then removed and compound of formula 29 is obtained. This compound will be used for the final reaction as one of the starting materials indicated as compound of Formula 30a. The compound of formula 30a is a combination of compounds of formula 29 and 30, which differ from each other in the ester function of the carboxyl group. Finally, compound of formula 29 is saponificated to remove the methyl group from the ester group in the compound of formula 29. Now is final product of formula 30 is obtained. According to the invention, compounds of formula 29 and formula 30 will be used in combination with the compound of formula 18 for the final reaction steps to obtain the final product disorazole of formula 37.

Now, the two precursors, namely the compounds of formula 30 and formula 29 are obtained and will be used in the final strategy for the production of dis- orazole named as compound of formula 37. Now, in Scheme 5 the final strategy is described in detail.

The total synthesis of disorazole of the formula 37 is performed in the follow- ing steps. The compounds of formula 18 and formula 29 are coupled. Especially pre- ferred is the use of a Sonogashira reaction. Compound of formula 31 is pro- duced and an esterification with compound of formula 30 is performed in the next step, wherein compound of formula 32 is obtained. In the next step, compound of formula 32 and compound of formula 18 are coupled, especially preferred also with a Sonogashira reaction. The reaction produces the open- chained compound of formula 33. The next steps of the reactions according to Scheme 5 perform the cyclisa- tion of compound of formula 33, forming the final product, disorazole of for- mula 37. In the first step, a saponification of the methyl ester in compound of formula 33 is performed and compound of formula 34 is obtained. With compound of formula 34 a macrolactonisation is performed, wherein the Yamaguchi reac- tion is preferred. With the obtained compound of formula 35 a hydrogenation of the triple bonds is performed and compound of formula 36 is obtained. In the final step, the protective groups are removed and the final product ac- cording to the invention, disorazole C1 of formula 37 is obtained. Now in Scheme 6 a further advantageous strategy for the production of diso- razoles according to the present invention is described in detail. The precur- sor 17a, comprising protective groups PG 1 and PG 2 is described already in the complete description. This precursor is also named as general formula II. The same applies to precursor 30a, which is also described herein as com- pound of formula I. In reaction Scheme 6 the carboxyl group is methylated. All reactive groups are protected so that the step a), as indicated in Scheme 6, is performed as a Sonogashira reaction, as described in Scheme 5. In con- trast to Scheme 5, the product 40 is now reacted in two different steps in or- der to obtain the products 41 and 42. The products 41 and 42 differ from each other only in one reactive group. In step b) , as indicated in Scheme 6, which is a simple demethylation step, Rx, the methyl group is removed and changed into hydrogen, so that a free hydroxyl group is present in the com- pound of formula 41. In step c) , as indicated in Scheme 6, compound of for- mula 40 is demethylated in a simple saponification step and results in a free carboxylic group as indicated in the compound of formula 42. Now in step d), as indicated in Scheme 6, a Yamaguchi reaction is performed as a lactoniza- tion of compounds of formula 41 and 42 into compound of formula 43. In the final steps e) and f), as indicated in Scheme 6, the protective groups are re- moved as already shown in steps b) and c) , as indicated in Scheme 6. The final cyclization reaction to obtain the disorazole according to the present in- vention is performed, for example, in the same way as shown in Scheme 5 , as indicated above. For a person skilled in the art it is clear that all possible diastereomers of dis- orazoles according to general formula III of formula 37 can be obtained, when starting the reactions with the respective diastereomeric precursors of formula I and formula II, as described above. In the presented Schemes 1 to 6 different protective groups are indicated. It is clear for a person skilled in the art that other protective groups may be used. Especially preferred are the following protective groups: MOM (meth- oxymethyl), MEM ((2-methoxyethoxy)phenyl), THP (tetrahydropyranyl), TMS (trimethylsilyl), TES (triethylsilyl), TIPS(triisopropylsilyl), TBS (tert-butyldime- thylsilyl), TBDPS (tert-butyldiphenylsilyl), OAc (O-Acyl). Furthermore, in the Schemes 1 to 6 name reactions are mentioned. It is also clear for persons skilled in the art that other reactions or name reactions may be used according to the invention. Details of the performed reactions are disclosed in the examples as pre- sented herein. Complete chemical names of the compounds of the given for- mulas are also disclosed in the examples as given herein. It has to be pointed out that the above described synthetic pathways can be modified by persons skilled in the art to produce all disorazoles and their ana- logues according to the present invention. The most important feature of the present invention is the use of two precursors as described as compounds of formula I and II. These compounds are each used twice in different steps.

Examples The following examples disclose the preferred embodiments of the present invention. It should be appreciated by those of skill in the art that the tech- niques disclosed in the examples which follow represent techniques discov- ered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are dis- closed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Synthesis of compounds of the invention General: Solvents were dried by standard procedures and redistilled under N 2 atmosphere prior to use. All organometallic reactions were run under nitro- gen. The products were purified by flash chromatography on Merck silica gel 60 (40-63 µm). Mass spectra were recorded on Finnigan MAT 95 and Waters Xevo G2-TOF spectrometers. NMR spectra were recorded on Brucker AVIII 400 and Brucker AVI 600 spectrometers. Optical rotations were recorded with a Perkin-Elmer 341 polarimeter.

Example 1: (S)-(+)-Mandelic acid methyl ester (1) To a solution of (S)-(+)-Mandelic acid (57.13 g, 376 mmol, 1 eq) in MeOH (300 mL), concentrated sulfuric acid (600 µL, 11.3 mmol, 0.03 eq) was added and the mixture was refluxed for 4 h. The reaction was quenched with K 2 CO 3 (1.04 g, 7.52 mmol, 0.02 eq) in 1.2 mL of water and the MeOH was evapo- rated in vacuo. Then Et 2 O (300 mL) was added and the solid was filtered off; the mixture was concentrated and crystallized from hexane (75 mL) to furnish ester 1 (54.9 g, 330.72 mmol, 88%) as a white solid. General Data: C 9 H 10 O 3 ; FW: 166.06; Mp: 56-58°C; TLC: R f = 0.35 (Pen- tane/Et 2 O 1:1); UV (+); Vanillin: yellow. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.36-7.34 (d, 2H); 7.31-7.30 (d, 2H); 7.27-7.26 (dd, 1H); 5.11 (s, 1H), 3.69 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 174.17; 138.22; 128.65; 128.55; 126.65; 126.61; 72.89 (C-2); 53.09.

Example 2: (S)-(-)-1,1,2-Triphenyl-1,2-ethandiol (2) To a solution of Phenyl magnesium bromide 3 M in Et 2 O (200 mL, 600 mmol, 5.0 eq), ester 1 (20 g, 120.36 mmol, 1 eq) in Et 2 O (120 mL) and THF (12 mL) was added dropwise at 0°C at such a rate that the temperature does not rise above 10°C (90 min required). The mixture was allowed to slowly warm to room temperature overnight and then refluxed for 1 h. After cooling to room temperature, the mixture was carefully poured into ice (200 g) and HCl 2 M was added dropwise to adjust the pH value to 4. The mixture was stirred for 1 h at room temperature and then the organic layer was separated. The aque- ous phase was extracted with CH 2 Cl 2 (3x200 mL) and the combined organic extracts were washed with NaHCO 3 , dried over MgSO 4 and concentrated in vacuo. Crystallization of the residue from methanol (70 mL) afforded diol 2 (24.1 g, 83 mmol, 69%) as a white needle-shaped solid. General Data: C 20 H 18 O 2 ; FW: 290.13; Mp: 123-127°C; [α] = -125.5 (c = 1.0, CHCl 3 ); TLC: R f = 0.25 (Pentane/Et 2 O 2:1); UV (+); Vanillin: yellow. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.65-7.61 (m, 2H); 7.40-7.00 (m, 13H); 5.55 (s, 1H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 145.12; 143.36; 138.81; 128.47; 128.09; 127.72; 127.64; 127.63; 127.48; 127.40; 127.30; 127.12; 127.02; 126.74; 126.19; 80.77; 50.89. Example 3: (S)-(-)-2-Hydroxy-1,2,2-triphenylethylacetate [(S)-HYTRA] (3) Acetyl chloride (7.85 mL, 110.39, 1.33 eq) in CH 2 Cl 2 (20 mL) was added dropwise at 0°C to a solution of diol 2 (24.1 g, 83 mmol, 1 eq) in CH 2 Cl 2 (220 mL) and Pyridine (10.74 mL, 132.8 mmol, 1.6 eq), at such a rate that the temperature does not rise above 5°C. The mixture was stirred for 16 h at room temperature. Then water (100 mL) was added and the mixture was stirred for 10 min. The mixture was concentrated in vacuo until second phase CH 2 Cl 2 was no longer observed. The white precipitate was filtered by suction, washed with water and HCl and dried by suction for 2-3 h. Then the solid was dissolved in hot toluene and the azeotrope was removed by atmospheric dis- tillation. The mixture was allowed to cool to room temperature over several hours and then cooled to 0°C for 1 h. The precipitate was collected on a filter and recrystallized from acetone to furnish (S)-HYTRA 3 (23.2 g, 69.8 mmol, 84 %) as a white solid. General Data: C 22 H 20 O 3 ; FW: 332.14; Mp: 249-251°C; [α] = -215.5 (c = 1.0, Pyridine); TLC: R f = 0.50 (Pentane/Et 2 O 2:1); UV (+). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.50-7.48 (m, 2H); 7.31-6.98 (m, 13H); 6.61 (s, 1H); 2.76 (s, 1H); 1.92 (s, 3H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 169.73; 144.82; 142.64; 135.82; 128.44; 128.38; 127.93; 127.79; 127.47; 127.35; 127.01; 126.41; 126.30; 126.17; 126.12; 125.03; 80.30; 78.50; 21.14. Example 4: Ethyl 3-hydroxy-2,2-dimethylpentanoate (4) n-BuLi (133 mL, 332.38 mmol, 1.1 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (46.5 mL, 332.37 mmol, 1.1 eq) in THF (300 mL). This LDA solution was stirred for 30 min at 0°C and then cooled to -78°C. Ethyl isobutyrate (40.6 mL, 302.16 mmol, 1 eq) dis- solved in THF (58 mL) was added dropwise and the mixture was stirred for 1 h at -78°C. Propionaldehyde (23.8 mL, 332.38 mmol, 1.1 eq) was added dropwise at -78°C and then the bath was removed and the mixture was stirred for 30 min between -50°C and -10°C. The reaction was quenched by dropwise addition of saturated aqueous NH 4 Cl solution (300 mL) and the or- ganic layer was separated and the aqueous phase was extracted with Et 2 O (3x200 mL). The combined organic extracts were dried over MgSO 4 and con- centrated in vacuo. Purification of the residue by vacuum distillation through a short Vigreux column afforded β-hydroxy ester 4 (48.97 g, 281.25 mmol, 93%) as a colorless liquid. General Data: C 9 H 18 O 3 ; FW: 174.13; Bp: 105°C (5 mbar); TLC: R f = 0.35 (Pentane/Et 2 O 2:1); UV (-); Vanillin: light blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 4.16 (q, J = 7.27 Hz, J = 21.46 Hz, 2H); 3.45 (dd, J = 10.68, J = 2.02, 1H); 1.54-1.48 (m, 2H); 1.25 (t, J = 7.34 Hz, 3H); 1.17 (s, 3H,); 1.15 (s, 3H); 0.95 (t, J = 7.77 Hz, 3H). 1 3 C-NMR (151MHz, CDCl 3 ): δ (ppm): 177.80; 78.39; 60.62; 47.02; 24.58; 20.42; 14.15; 11.29. MS (EI): m/z (%): 175.07 (100) [M+H] + , 173.06 (68), 170.05 (26), 169.04 (22). HR-MS: calculated: 174.1329, found: 175.1329 [M+H] + , 197.1152 [M+Na + ] + . Example 5: Ethyl (E)-2,2-dimethyl-3-pentenoate (5) Hydroxy ester 4 (48.97 g, 281.25 mmol) was refluxed with Sicapent (70 g) in Cyclohexane (250 mL) for 30 min. The solvent was removed by atmospheric distillation and vacuum distillation of the residue afforded ester 5 (29.85 g, 191.25 mmol, 68%) as a colorless liquid. General Data: C 9 H 16 O 2 ; FW: 156.12; Bp: 55-60°C (10 mbar); TLC: R f = 0.75 (Pentane/Et 2 O 2:1); UV (-); Vanillin: blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.64 (dq, J = 15.72 Hz, J = 1.6 Hz 1H); 5.53-5.47 (m, 1H); 4.14 (qd, J = 7.09 Hz, J = 1.18 Hz, 2H); 1.68 (dd, J = 6.24 Hz, J = 1.58 Hz 3H), 1.27 (s, 6H); 1.25 (t, J = 7.15 Hz, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 176.83; 135.61; 123.33; 60.54; 44.02; 25.13; 18.03; 14.15. MS (EI): m/z (%): 156.07 (100) [M] + , 141.05 (77), 116.03 (54), 110.02 (21). HR-MS: calculated: 156.1145, found: 156.1145. Example 6: (E)- 2,2-dimethyl-3-penten-1-ol (6) To a solution of ester 5 (16.37 g, 104.94 mmol, 1 eq) in THF (150 mL), LiAlH 4 (7.98 g, 209.87 mmol, 2 eq) was added and the mixture was refluxed for 2 h. After cooling to 0°C, Et 2 O (100 mL) was added and the reaction was quenched by dropwise addition of water (10 mL). The mixture was stirred for 30 min at room temperature until a white precipitate was formed, which was filtered off by suction through Celite and washed with Et 2 O (3x200 mL). The filtrate and the washings were combined and concentrated in vacuo to furnish crude alcohol 6 (8.97 g, 78.7 mmol, 75%) as a colorless liquid, which was used for the preparation of aldehyde 7 without further purification. General Data: C 7 H 14 O; FW: 114.10; Bp: 152-160°C; TLC: R f = 0.35 (Pen- tane/Et 2 O 2:1); UV (-); dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.50-5.44 (m, 1H); 5.35 (dq, J = 15.68 Hz, J = 1.29 Hz, 1H); 3.28 (s, 2H); 1.69 (d, J = 6.22 Hz, 3H); 1.65 (s, 1H); 0.977 (s, 6H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.76; 124.14; 71.6; 38.33; 46.21; 23.92; 18.23. HR-MS: calculated: 114.10, found: 115.11 [M+H] + . Example 7: (E)-2,2-dimethyl-3-pentenal (7) DMSO (11.2 mL, 157.4 mmol, 2.0 eq) in CH 2 Cl 2 (45 mL) was added drop- wise at -78°C to a stirred solution of (COCl)2 (8.1 mL, 94.44 mmol, 1.2 eq) in CH 2 Cl 2 (210 mL). The mixture was stirred for 10 min at -78°C. The crude (E)- 2,2-dimethyl-3-penten-1-ol 6 (8.97 g, 78.7 mmol, 1 eq) dissolved in CH 2 Cl 2 (60 mL) was added dropwise at -78°C and the mixture was stirred for 1 h at - 78°C. The reaction was quenched by dropwise addition of NEt 3 (54.6 mL, 393.5 mmol, 5.0 eq) and the mixture was warmed to room temperature over 45 min. Water was added (250 mL) and the mixture was stirred for 10 min. The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (3x150 mL). The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. Vacuum distillation of the residue afforded alde- hyde 7 (6.6 g, 79.02 mmol, 75%) as a colorless liquid. General Data: C 7 H 14 O; FW: 112.09; Bp: 127-128°C; TLC: R f = 0.80 (Pen- tane/Et 2 O 5:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 9.32 (s, 1 H); 5.58-5.48 (m, 1H); 5.36 (dq, J = 15.76 Hz, J = 1.69 Hz, 1H); 1.71 (dd, J = 6.41 Hz, J = 1.61 Hz, 3H); 1.14 (s, 6H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 202.92; 132.46; 127.06; 46.21; 21.49; 18.3. Example 8: (1S)-2-Hydoxy-1,2,2-triphenylethl (3S,5E)-3hydoxy-4,4-dimethyl-5-hep- tenoate (8) n-BuLi (22.5 mL, 56.32 mmol, 2.2 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (7.9 mL, 56.32 mmol, 2.2 eq) in THF (80 mL). This LDA solution was stirred for 30 min at 0°C and then added dropwise to a solution of (S)-HYTRA 3 (8.5 g, 25.6 mmol, 1 eq) in THF (150 mL) at -78°C. The mixture was stirred for 1 h at 0°C. The resulting or- ange-red solution was cooled to -78°C and a solution of aldehyde 7 (3.44 mg, 30.7 mmol, 1.2 eq) in THF (7 mL) was added dropwise. The mixture was stirred for 2h30min at -78°C. The reaction was quenched by dropwise addi- tion of saturated aqueous NH 4 Cl solution (150 mL) and the mixture was al- lowed to warm to room temperature over 30 min. The organic layer was sep- arated and the aqueous phase was extracted with CH 2 Cl 2 (3x100 mL). The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. Purification of the residue by flash chromatography (pentane/Et 2 O 3:1) afforded β-hydroxy ester 8 (8.75 g, 19.71 mmol, 77%) as a colorless solid. General Data: C29H32O 4 ; FW: 444.23; Melting point: 120 - 126°C; [α] = - 167.8 (c = 1.0, CHCl 3 ); TLC: R f = 0.45 (Pentane/Et 2 O 2:1); UV (+); Vanillin: green. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.61-7.53 (m, 2H); 7.39-7.33 (m, 2H); 7.31-7.26 (m, 1H); 7.22-7.03 (m, 10H); 6.71 (s, 1H); 5.43-5.45 (m, 1H); 5.26 (dd, J = 15.72, J = 1.31 Hz, 1H); 3.51 (dd, J = 10.38 Hz, J = 2.18 Hz, 1H); 2.79 (s, 1H); 2.36 (dd, J = 15.81, Hz, J = 2.07 Hz, 1H); 2.24 (dd, J = 16.29 Hz, J = 10.35 Hz, 1H); 1.98 (s, 1H); 1.65 (dd, J = 6.08 Hz, J = 1.28 Hz, 3H); 0.92 (s, 3H); 0.91 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 172.23; 144.61; 142.58; 137.02; 135.42; 128.41; 128.35; 127.99; 127.83; 127.54; 127.36; 127.11; 127.28; 127.20; 123.86; 80.33; 78.96; 74.86; 40.03; 37.35; 23.62; 22.68; 18.26. MS (EI): m/z (%): 911.45 (40) [2M+Na + ] + , 467.22 (97) [M+Na + ] + , (77), 444.23 (˂0.4), 273.13 (100), 255.12 (18), 195.08 (31). HR-MS: calculated: 444.2298, found: 467.2198 [M+Na + ] + . Example 9: (3S,5E)-4,4-dimethyl-5-heptene-1,3-diol (9) 8 LiAlH 4 (5.2 g, 137.97 mmol, 7.0 eq) was added portionwise to a refluxing so- lution of β-hydroxy ester 13 (8.75 g, 19.71 mmol, 1 eq) in Et 2 O (210 mL), dur- ing a period of 2 h. Reflux was continued for 30 min. After cooling to 0°C, the reaction was quenched by dropwise addition of water (10 mL). Then Et 2 O (150 mL) and water (0.95 mL) was and the mixture was stirred for 30 min at room temperature until a white precipitate was formed. The precipitate was filtered off by suction through Celite and washed with Et 2 O (4x100 mL). The filtrate and the washings were combined and concentrated in vacuo. Purifica- tion of the residue by flash chromatography (pentane/Et 2 O 2:1 to pure Et 2 O) afforded diol 9 (2.5 g, 15.77 mmol, 80%) as a colorless oil and (S)-(-)-1,1,2- triphenyl-1,2-ethandiol 2 (5.1 g, 17.74 mmol, 90 %) General Data: C 9 H 18 O 2 ; FW: 158.13; [α] = -7.28 (c = 0.7, CHCl 3 ); TLC: R f = 0.30 (Et 2 O); UV (-); Vanillin: dark blue. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.52-5.43 (m, 1 H); 5.35 (dq, J = 15.69 Hz, J = 1.29 Hz, 1H); 3.86-3.76 (m, 2H); 3.48 (dd, J = 10.49 Hz, J = 2.16 Hz, 1H); 2.39 (s, 1H); 1.68 (dd, J = 5.96 Hz, J = 1.23 Hz, 3H); 1.74-1.66 (m, 1H); 1.74-1.66 (m, 1H); 1.62-1.52 (m, 1H); 0.98 (s, 6H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.55; 124.51; 78.88; 62.56; 40.71; 32.62; 23.67; 22.16; 18.30. MS (EI): m/z (%): 181.1207 (100), 158.13 (˂0.4), 123.12 (42). HR-MS: calculated: 158.1307, found: 181.1207 [M+Na + ] + . Example 10: (S,E)-3,3,9,9-tetraethyl-5-(2-methylpent-3-en-2-yl)-4,8-diox a-3,9-disilaun- decane (10) To a solution of diol 9 (1.96 g, 12.4 mmol, 1 eq) in CH 2 Cl 2 (120 mL), 2,6- Lutidine (5.8 mL, 49.6 mmol, 4 eq) and TESOTf (8.4 mL, 37.18 mmol, 3 eq) were sequentially added dropwise at -78°C. The mixture was stirred for 30 min at -78°C and for 1 h at 0°C. Saturated aqueous NaHCO 3 solution (100 mL) was added and the layers were separated. The aqueous phase was ex- tracted with CH 2 Cl 2 (3x80 mL) and the combined organic extracts were dried over MgSO 4 and concentrated in vacuo. Purification of the residue by flash chromatography (pure pentane) furnished compound 9 (4.74 g, 12.28 mmol, 99%) as a colorless liquid. General Data: C 21 H 46 O 2 Si 2 ; FW: 386.3; [α] = -7.25 (c = 0.4, CHCl 3 ); TLC: R f = 0.20 (pentane); UV (-); Vanillin: black. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.43 (dq, J = 15.67 Hz, J = 1.22 Hz, 1H); 5.38-5.29 (m, 1H); 3.71-3.63 (m, 1H); 3.61-3.53 (m, 1H); 3.46 (dd, , J = 8.17 Hz, J = 2.7 Hz); 1.65 (dd, J = 5.93 Hz, J = 1.19, 3H); 1.77-1.68 (m, 1H); 1.53-1.43 (m, 1H); 1.00-0.89 (m, 18H); 0.96 (s, 3H); 0.92 (s, 3H); 0.66-0.47 (m, 12H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 139.29; 121.46; 76.87; 60.87; 41.12; 36.71; 24.63; 22.90; 18.30; 7.14; 6.81; 6.79; 6.41; 5.47; 4.46. Example 11: (S)-2,2-dimethyl-3,5-bis((triethylsilyl)oxy)pentanal (11) A stream of ozone in oxygen was bubbled through a solution of compound 10 (4.74 g, 12.28 mmol, 1 eq) in CH 2 Cl 2 (400 mL) at -78°C until the blue color of the solution persisted. Then PPh3 (3.86 g, 14.73 mmol, 1.2 eq) was added at -78°C and the mixture was allowed to slowly warm to room temperature over 4 h. The crude was concentrated in vacuo and purified by flash chromatog- raphy (pentane/Et 2 O 200:1 to 50:1) to furnish aldehyde 11 (2.75 g, 7.36 mmol, 60 %) as a colorless liquid. General Data: C 19 H 42 O 3 Si 2 ; FW: 374.27; [α] = +10.11 (c = 0.9, CHCl 3 ); TLC: R f = 0.35 (Pentane/Et 2 O 50:1); UV (-); Vanillin: violet. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 9.57 (s, 1H); 3.99 (dd, J = 8.13 Hz, J = 3.02 Hz, 1H); 3.71-3.58 (m, 2H); 1.74-1.64 (m, 1H); 1.62-1.52 (m, 1H); 1.04 (s, 3H); 1.00 (s, 3H); 0.98-0.908 (m, 18H); 0.65-0.54 (m, 12H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 206.6; 73.21; 59.53; 51.09; 36.33; 18.88; 17.34; 6.97; 6.78; 5.35; 4.43.

Example 12: (4S,6S)-5,5-dimethyl-6,8-bis((triethylsilyl)oxy)oct-1-en-4-o l (12) A solution of Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH 2 Cl 2 (50 mL). Then Sc(OTf) 3 (175 mg, 0.375 mmol, 0.05 eq) was added and the mixture was stirred for 24 h at room temperature. TBAF trihydrate (2.26 g, 7.15 mmol, 1 eq) was added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (pentane/Et 2 O 50:1, then pentane/EtOAc/NEt 3 1:1:0.1) to furnish the allylic alcohol (2.36 g, 5.65 mmol, 80%) as a colorless liquid and the recovered diamine (3.64 g, 8.08 mmol, 87 %) as a yellow paste. General Data: C 22 H 48 O 3 Si 2 ; FW: 416.31; [α] 0 = -4.2 (c = 0.5, CHCl 3 ); TLC: R f = 0.2 (Pentane/Et 2 O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.94-5.86 (m, 1H); 5.13-5.05 (m, 2H); 3.79 (dd, J = 6.76 Hz, J = 2.79 Hz, 1H); 3.74 (m, 1H); 3.65 (m, 1H); 3.51 (d, J = 10.49 Hz, 1H); 2.73 (s, 1H); 2.31-2.25 (m, 1H); 2.1-2.02 (m, 1H); 2.01-1.93 (m, 1H); 1.54-1.48 (m, 1H); 0.993-0.923 (m, 18H); 0.897 (s, 3H); 0.781 (s, 3H); 0.65-0.54 (m, 12H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.22; 116.51; 75.64; 75.41; 61.24; 42.44; 36.46; 36.37; 18.72; 18.49; 7.08; 6.72; 5.51; 4.28.

Example 13: (5S,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl )oxy)-2,4,10-tri- oxa-11-silatridecane (13) MOMCl (1.3 mL, 17 mmol, 3 eq) was added dropwise at 0°C to a solution of allylic alcohol 12 (2.36 g, 5.67 mmol, 1 eq), DIPEA (3 mL, 17 mmol, 3 eq) and DMAP (207 mg, 1.7 mmol, 0.3 eq) in CH 2 Cl 2 (60 mL). The mixture was stirred overnight at 45°C. Evaporation of the solvent and purification of the residue by flash chromatography (Pen/Et 2 O 60:1) afforded the protected al- cohol (2.4 g, 5.21 mmol, 92 %) as a colorless liquid. General Data: C 24 H 52 O 4 Si 2 ; FW: 460.34; [α] = -10.67 (c = 0.75, CHCl 3 ); TLC: R f = 0.5 (Pentane/Et 2 O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.95-5.87 (m, 1H); 5.09-4.98 (m, 2H); 4.61 (q, J = 6.61 Hz, 2H); 3.74-3.68 (m, 2H); 3.63.3.57 (m, 1H); 3.48 (dd, J = 8.59 Hz, J = 2.85, Hz 1H); 2.48-2.41 (m, 1H); 2.23-2.14 (m, 1H); 1.91-1.83 (m, 1H); 1.55-1.48 (m, 1H); 1.00-0.923 (m, 18H); 0.917 (s, 3H); 0.811 (s, 3H); 0.655-0.565 (m, 12H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.22; 115.95; 98.09; 83.46; 74.54; 60.86; 56.11; 43.39; 36.17; 20.78; 19.26; 7.14; 6.79; 5.63; 4.43.

Example 14: (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl) oxy)non-7- en-1-ol (15) A solution of protected triol 13 (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred overnight at 60°C. The mixture was then concentrated in vacuo and the residue was filtered on a pad of sil- ica gel (Pen/Et 2 O 1:1). The filtrate was concentrated in vacuo affording a mix- ture of 15 (80%) and 14 (15%) as a colorless liquid, which was used in the next step without further purification. General Data (14): C 25 H 52 O 4 Si 2 ; FW: 460.34; [α] 2 = -44.0 (c = 0.2, CHCl 3 ); TLC: R f = 0.5 (Pentane/Et 2 O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (14) (600 MHz, CDCl 3 ): δ (ppm): 5.64-5.54 (m, 1H); 5.31 (qd, J = 7.79 Hz, J = 1.69 Hz, 1H); 4.66 (d, J = 6.58 Hz, 1H); 4.43 (d, J = 6.58 Hz, 1H); 3.86 (d, J = 8.85 Hz, 1H); 3.75 (dd, J = 8.62 Hz, J = 2.38 Hz, 1H); 3.73.3.55 (m, 2H); 3.35 (s, 3H); 1.94-1.82 (m, 1H); 1.71 (dd, J = 6.37 Hz, J = 1.54 Hz, 3H) 1.63-1.53 (m, 1H); 1.01-0.878 (m, 18H); 0.948 (s, 3H); 0.939 (s, 3H); 0.668-0.540 (m, 12H). 1 3 C-NMR (14) (151 MHz, CDCl 3 ): δ (ppm): 130.63; 127.94; 93.43; 81.11; 74.3; 61.09; 55.74; 42.18; 35.74; 20.10; 19.35; 17.79; 7.14; 6.77; 5.63; 4.37. General Data (15): C 18 H 38 O 4 Si; FW: 346.25; [α] = -69.0 (c = 0.8, CHCl 3 ); TLC: R f = 0.3 (Pentane/Et 2 O 3:1); UV (-); Vanillin: dark blue. 1H-NMR (15) (600 MHz, CDCl 3 ): δ (ppm): 5.64-5.54 (m, 1H); 5.31 (qd, J = 6.70 Hz, J = 1.64 Hz, 1H); 4.62 (d, J = 6.46 Hz, 1H); 4.43 (d, J = 6.46 Hz, 1H); 3.87 (dd, J = 8.68 Hz, J = 2.59 Hz, 2H); 3.81 (d, J = 8.50 Hz, 1H); 3.79- 3.72 (m, 1H); 3.71-3.62 (m, 1H); 3.33 (s, 3H); 1.95-1.84 (m, 1H); 1.71 (dd, J = 6.48 Hz, J = 1.53 Hz, 3H); 1.67-1.57 (m, 1H); 1.00-0.932 (m, 9H); 0.923 (s, 3H); 0.736 (s, 3H); 0.678-0.583 (m, 6H). 13 C-NMR (15) (151 MHz, CDCl 3 ): δ (ppm): 130.84; 127.77; 93.64; 81.75; 74.46; 60.85; 55.67; 42.06; 35.34; 20.10; 19.10; 17.82; 7.11; 5.60. Example 15: (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl) oxy)oct-6- enal (16) DMSO (0.780 mL, 11 mmol, 2 eq) in CH 2 Cl 2 (5 mL) was added dropwise to a solution of oxalyl chloride (0.644 mL, 7.5 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) at - 78°C. The mixture was stirred for 10 min at -78°C and then the crude 14 + 15 dissolved in CH 2 Cl 2 (5 mL) was added dropwise. The reaction was stirred for 1 h at -78°C, quenched by dropwise addition of NEt 3 (3.5 mL, 25 mmol, 5 eq) and then warmed to room temperature over 45 min. H 2 O (30 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x20 mL) and the combined organic extracts were dried over Na2SO 4 , filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Pen/Et 2 O 10:1) afforded aldehyde 16 (1.33 g, 3.86 mmol, 77%) as a colorless liquid. General Data: C 18 H 36 O 4 Si 2 ; FW: 344.24; [α] = -54.87 (c = 0.8, CHCl 3 ); TLC: R f = 0.3 (Pentane/Et 2 O 10:1); UV (-); Vanillin: grey. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 9.83 (dd, J = 3.00 Hz, J = 1.21 Hz, 1H); 5.66-5.56 (m, 1H); 5.29 (qd, J = 7.60 Hz, J = 1.66 Hz, 1H); 4.64 (d, J = 6.71 Hz, 1H); 4.41 (d, J = 6.71 Hz, 1H); 4.31 (dd, J = 7.05 Hz, J = 3.59 Hz, 1H); 3.78 (d, J = 8.70 Hz, 1H); 3.33 (s, 3H); 2.75 (qd, J = 16.71, Hz, J = 1.33 Hz, 1H); 2.58 (qd, J = 16.23, Hz, J = 3.01 Hz, 1H); 1.72 (dd, J = 6.48 Hz, J = 1.67 Hz, 3H); 0.965 (s, 3H); 0.957-0.907 (m, 9H); 0.767 (s, 3H); 0.640-0.545 (m, 6H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 202.75; 131.42; 127.20; 93.26; 81.37; 72.01; 55.87; 47.82; 42.06; 20.05; 19.74; 6.99; 5.35. Example 16: (5S,7S)-9,9-diethyl-7-((Z)-3-iodoallyl)-6,6-dimethyl-5-((E)- prop-1-en-1-yl)- 2,4,8-trioxa-9-silaundecane (17) NaHMDS (1 M in THF, 4.2 mL, 4.2 mmol, 1.5 eq) was added dropwise at 0°C to a solution of IMePPh3I (2.22 g, 4.2 mmol, 1.5 eq) in THF (30 mL). The red solution was stirred for 10 min at room temperature and then cooled to -78°C. DMPU (2.5 mL, 20.93 mmol, 7.5 eq) was added dropwise, followed by alde- hyde 16 (960 mg, 2.79 mmol, 1 eq) in THF (7 mL). The mixture was stirred for 1 h at -78°C and 30 min at room temperature. Saturated NH 4 Cl solution was added and the aqueous phase was extracted with Et 2 O (3x25 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Pen/Et 2 O 100:1) giving the Z Iodide 17 (875 mg, 1.87 mmol, 67%) as a slightly yellow liquid. General Data: C 19 H 37 IO 3 Si; FW: 468.16; [α] = -30.133 (c = 0.75, CHCl 3 ); TLC: R f = 0.25 (Pentane/Et 2 O 100:1); UV (-); Vanillin: black. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.36 (q, J = 7.43 Hz, 1H); 6.21 (dt, J = 7.36 Hz, J = 1.67 Hz, 1H); 5.69-5.56 (m, 1H); 5.33 (qd, J = 6.69 Hz, J = 1.62 Hz, 1H); 4.68 (d, J = 6.60 Hz, 1H); 4.45 (d, J = 6.60 Hz, 1H); 3.88 (t, J = 5.03 Hz, 1H); 3.86 (d, J = 3.80 Hz, 1H); 3.36 (s, 3H); 2.44-2.38 (m, 2H); 1.73 (dd, J = 6.52 Hz, J = 1.57 Hz, 3H); 1.02-0.922 (m, 9H); 0.941 (s, 3H); 0.769 (s, 3H); 0.658-0.559 (m, 6H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 140.20; 131.02; 127.77; 93.49; 82.57; 81.41; 75.63; 55.90; 42.65; 38.61; 20.16; 19.60; 17.85; 7.12; 5.57. Example 17: (1Z,4S,6S,7E)-1-iodo-6-(methoxymethoxy)-5,5-dimethylnona-1,7 -dien-4- ol (18) CSA (93 mg, 0.4 mmol, 0.2 eq) was added at 0°C to a solution of Z Iodide 17 (940 mg, 2 mmol, 1 eq) in CH 2 Cl 2 (50 mL) and MeOH (50 mL). The mixture was stirred for 1 h at 0°C without N2. Saturated NaHCO 3 solution (100 mL) was added and the layers were separated. The aqueous phase was ex- tracted with CH 2 Cl 2 (3x100 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was puri- fied by flash chromatography (Pen/Et 2 O 3:1) giving deprotected Iodide 18 (601 mg, 1.7 mmol, 85%) as a slightly yellow liquid. General Data: C 13 H 23 IO 3 ; FW: 354.07; [α] = -52.7 (c = 1.00, CHCl 3 ); TLC: R f = 0.3 (Pentane/Et 2 O 3:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.39 (q, J = 6.68 Hz, 1H); 6.28 (dt, J = 7.24 Hz, J = 1.18 Hz, 1H); 5.74-5.60 (m, 1H); 5.32 (qd, J = 6.34 Hz, J = 1.49 Hz, 1H); 4.72 (d, J = 6.65 Hz, 1H); 4.46 (d, J = 6.65 Hz, 1H); 3.89 (d, J = 9.12 Hz, 1H); 3.66 (dd, J = 10.22 Hz, J = 2.74 Hz, 1H); 3.38 (s, 3H); 2.42-2.32 (m, 1H); 2.30-2.16 (m, 1H); 1.74 (dd, J = 6.46 Hz, J = 1.42 Hz, 3H); 0.980 (s, 3H); 0.826 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 139.48; 132.59; 126.83; 93.01; 84.89; 83.50; 77.43; 56.03; 40.94; 37.31; 21.62; 17.87; 15.85. Example 18: tert-Butyl (R)-3-hydroxypent-4-enoate (19) Vinyl acetate (16 mL, 174.18 mmol, 3 eq) was added to a solution of racemic tert-Butyl 3-hydroxypent-4-enoate (10 g, 58.06 mmol, 1 eq) in pentane (200 mL). Then Amano Lipase PS (6 g) and 4Â molecular sieves (9.5 g) were added and the mixture was stirred for 24 h at 30°C. The solids were filtered on paper and washed with Et 2 O; the filtrate was concentrated in vacuo and the residue purified by flash chromatography (Pen/Et 2 O 6:1 to 2:1) to afford (R)-19 (4.71 g, 27.35 mmol, 47%) as a colorless liquid and (S)-Acetate (6.04 g, 28.22 mmol, 48%). General Data: C 9 H 16 O 3 ; FW: 172.11; [α] = +8.9 (c = 0.55, CHCl 3 ); TLC: R f = 0.35 (Pentane/Et 2 O 2:1); UV (-); Vanillin: light blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.89-5.80 (m, 1H); 5.27 (dt, J = 17.19 Hz, J = 1.43 Hz, 1H); 5.11 (dt, J = 10.53 Hz, J = 1.29 Hz, 1H); 4.49-4.43 (m, 1H); 2.47 (dd, J = 16.14 Hz, J = 4.1 Hz, 1H); 2.47 (dd, J = 16.02 Hz, J = 8.35 Hz, 1H); 1.43 (s, 9H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 171.64; 138.94; 115.05; 81.34; 68.98; 42.11; 28.05. Example 19: tert-Butyl (R)-3-Methoxypent-4-enoate (21) Proton Sponge (17.5 g, 81.86 mmol, 3 eq) and trimethyl oxonium tetra- fluoroborate (8.08 g, 54.58 mmol, 2 eq) were added to a solution of (R)-19 (4.7 g, 27.29 mmol, 1 eq) in CH 2 Cl 2 (115 mL) and the mixture was stirred for 3 h at room temperature. The reaction mixture was then filtered through a pad of Celite and the filtrate was washed with saturated aqueous solution of NaHSO 4 to remove Proton Sponge. The aqueous phase was extracted with CH 2 Cl 2 and the organic extracts were dried over Na 2 SO 4 , filtered and concen- trated in vacuo. The residue was purified by silica gel chromatography (Pen/Et 2 O 20:1, then 2:1) to give 21 (3.91 g, 21.03 mmol, 77%) as a color- less liquid and unreacted alcohol (517 mg, 3.00 mmol, 11%). General Data: C 10 H 18 O 3 ; FW: 186.13; [α] 0 = +1.1 (c = 0.55, CHCl 3 ); TLC: R f = 0.30 (Pentane/Et 2 O 20:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.72-5.65 (m, 1H); 5.27 (dt, J = 17.17 Hz, J = 1.43 Hz, 1H); 5.21 (dt, J = 10.53 Hz, J = 1.29 Hz, 1H); 4.00-3.93 (m, 1H); 3.28 (s, 3H); 2.51 (dd, J = 14.85 Hz, J = 8.09 Hz, 1H); 2.36 (dd, J = 14.75 Hz, J = 5.68 Hz, 1H); 1.44 (s, 9H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 170.16; 137.22; 117.65; 80.60; 79.40; 56.49; 42.06; 28.09.

Example 20: tert-butyl (R)-3-methoxy-4-oxobutanoate (22) A stream of O 3 in O 2 was bubbled through a solution of (R)-21 (3.23 g, 17.37 mmol, 1 eq) in CH 2 Cl 2 (75 mL) and MeOH (15 mL) at -78°C until the blue color of the solution persisted. Then O 2 was bubbled for 10 min and PPh3 (5.47 g, 20.84 mmol, 1.2 eq) was added. The mixture was warmed to room temperature and stirred for 2 h. The solvents were removed in vacuo and the residue was purified by flash chromatography (Pen/Et 2 O 2:1) to afford alde- hyde 22 (2.91 g, 15.5 mmol, 89%) as a colorless liquid. General Data: C 9 H 16 O 4 ; FW: 188.10; = +30.08 (c = 1.25, CHCl 3 ); TLC: R f = 0.25 (Pentane/Et 2 O 2:1); UV (-); Vanillin: yellow. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 9.76 (s, 1H); 3.93-3.89 (m, 1H); 3.50 (s, 3H); 2.69 (dd, J = 16.06 Hz, J = 4.86 Hz, 1H); 2.60 (dd, J = 16.41 Hz, J = 6.68 Hz, 1H); 1.44 (s, 9H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 202.38; 169.14; 82.06; 81.62; 58.65; 36.99; 28.01. Example 21: tert-Butyl (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoate (24) nBuLi 2.5 M in hexane (8 mL, 20.05 mmol, 1.3 eq) was added dropwise to a suspension of Phosphonium Bromide 23 (9.96 g, 18.5 mmol, 1.2 eq) in THF (100 mL) at -78°C. The red solution was stirred at 0°C for 30 min and then aldehyde 22 (2.9 g, 15.42 mmol, 1 eq) in THF (20 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 30 min. The re- action was quenched by addition of saturated NH 4 Cl aqueous solution (100 mL) and the layers were separated. The aqueous phase was extracted with Et 2 O (3x80 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the residue by flash chro- matography (Pen/Et 2 O 40:1 to 30:1) gave E-24 (3.38 g, 9.25 mmol, 60%) and Z-24 (1.25 g, 3.42 mmol, 22%) E/Z 2.7:1. General Data: C 21 H 38 O 3 Si; FW: 366.26; = +8.2 (c = 0.5, CHCl 3 ); TLC: R f = 0.45 (Pentane/Et 2 O 20:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.01 (dd, J = 15.86 Hz, J = 7.29 Hz, 1H); 5.76 (dd, J = 15.87 Hz, J = 1.05 Hz, 1H); 4.04-3.98 (m, 1H); 3.30 (s, 3H); 2.50 (dd, J = 14.53 Hz, J = 7.94 Hz, 1H); 2.37 (dd, J = 14.98 Hz, J = 5.67 Hz, 1H); 1.44 (s, 9H); 1.07 (s, 20H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 169.81; 142.32; 112.79; 104.44; 92.03; 80.86; 78.39; 56.98; 41.89; 28.06; 18.59; 11.24. Example 22: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoic acid (25) A solution of 24 (3.2 g, 8.74 mmol) in formic acid (13 mL) was stirred over- night at room temperature. The mixture was then concentrated in vacuo and azeotropically dried with toluene for 3 times to remove formic acid. Car- bossilic acid 25 was obtained (2.68 g, 8.65 mmol, 99%) as a slightly yellow liquid. General Data: C 17 H 30 O 3 Si; FW: 310.20; = +10.22 (c = 0.45, CHCl 3 ); TLC: R f = 0.3 (Pentane/Et 2 O 5:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.02 (dd, J = 15.86 Hz, J = 7.29 Hz, 1H); 5.76 (dd, J = 15.87 Hz, J = 1.05 Hz, 1H); 4.04-3.98 (m, 1H); 3.30 (s, 3H); 2.50 (dd, J = 14.53 Hz, J = 7.94 Hz, 1H); 2.37 (dd, J = 14.98 Hz, J = 5.67 Hz, 1H); 1.07 (s, 20H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 175.91; 141.40; 113.50; 104.04; 92.69; 77.71; 57.03; 40.34; 18.60; 11.24. Example 23: methyl ((R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoyl)-L-s eri- nate (26) DIPEA (3.5 mL, 20.1 mmol, 2.3 eq) and TFFH (2.54 g, 9.61 mmol, 1.1 eq) were added to a solution of carboxylic acid 26 (2.7 g, 8.74 mmol, 1 eq) in THF (30 mL) and the mixture was stirred for 2 h at room temperature. L-ser- ine methyl ester hydrochloride (1.63 g, 10.49 mmol, 1.2 eq) was added and the mixture was stirred for 3 h. Et 2 O (20mL) was added and the solution was washed with HCl 1 M (40 mL). The aqueous phase was extracted with Et 2 O (3x40 mL) and the organic layers were dried over Na 2 SO 4 , filtered and con- centrated in vacuo. Purification of the residue by flash chromatography (Et 2 O) afforded the serinate 26 (3.22 g, 7.82 mmol, 90%) as a yellow oil. General Data: C 21 H 37 NO 5 Si; FW: 411.24; = +28.42 (c = 1.2, CHCl 3 ); TLC: R f = 0.25 (Et 2 O); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.32-7.29 (br, 1H); 6.01 (dd, J = 15.79 Hz, J = 7.33 Hz, 1H); 5.79 (d, J = 16.01 Hz, 1H); 4.71-4.61 (m, 1H); 4.09-4.00 (m, 1H); 3.99-3.89 (m, 1H); 3.79 (s, 3H); 3.35 (s, 3H); 2.55 (dd, J = 15.45 Hz, J = 8.28 Hz, 1H); 2.46 (dd, J = 14.90 Hz, J = 3.31 Hz, 1H); 1.07 (s, 20H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 170.79; 141.43; 113.26; 103.98; 92.85; 78.39; 63.24; 56.97; 54.87; 52.76; 41.98; 18.60; 11.23. Example 24: Methyl 2-((R,E)-2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)- 4,5- dihydrooxazole-4-carboxylate (27) DAST (1.13 mL, 8.56 mmol, 1.1 eq) was added dropwise to a solution of serinate 26 (3.2 g, 7.78 mmol, 1 eq) in CH 2 Cl 2 (60 mL) at -78°C and the mix- ture was stirred for 2 h at -78°C. K2CO 3 (2.15 g, 15.56 mmol, 2 eq) was added and the mixture was warmed to room temperature and stirred for 1 h. A saturated solution of NH 4 Cl (50 mL) was carefully added and, after the gas evolution ceased, the layers were separated. The aqueous phase was ex- tracted with CH 2 Cl 2 (3x50 mL) and the combined organic extracts were washed with Brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford the crude product 27 as a yellow oil, which was used for the next step without further purification. General Data: C 21 H 35 NO 4 Si; FW: 393.23; = +58.59 (c = 0.85, CHCl 3 ); TLC: R f = 0.4 (Et 2 O); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.03 (dd, J = 15.83 Hz, J = 7.39 Hz, 1H); 5.77 (dd, J = 16.01 Hz, J = 0.965 Hz, 1H); 4.76-4.72 (m, 1H); 4.50 (dd, J = 9.26 Hz, J = 8.02 Hz, 1H); 4.38 (dd, J = 11.18 Hz, J = 8.69 Hz, 1H); 4.07- 3.99 (m, 1H); 3.77 (s, 3H); 3.29 (s, 3H); 2.66 (dd, J = 14.63 Hz, J = 7.66 Hz, 1H); 2.49 (dd, J = 14.99 Hz, J = 5.87 Hz, 1H); 1.06 (s, 20H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 171.49; 167.42; 141.96; 113.14; 104.28; 92.31; 78.41; 69.40; 68.10; 56.95; 52.64; 34.30; 18.60; 11.24.

Example 25: Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1- yl)oxazole-4-carboxylate (28) The crude material 27 was dissolved in CH 2 Cl 2 (60 mL), cooled to 0°C and protected from light with aluminium foil. DBU (2.24 mL, 15.56 mmol, 2 eq) and BrCCl 3 (1.53 mL, 15.56 mmol, 2 eq) were sequentially added dropwise, then the bath was removed and the mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NH 4 Cl solution (100 mL) and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x100 mL) and the organic layers were dried over Na 2 SO 4 , fil- tered and concentrated in vacuo. Purification of the residue by flash chroma- tography (Pen/Et 2 O 2:1) afforded oxazole 28 (1.77 g, 4.51 mmol, 58% from 27) as a yellow oil. General Data: C 21 H 33 NO 4 Si; FW: 391.22; = -17.4 (c = 0.5, CHCl 3 ); TLC: R f = 0.35 (Pentane/Et 2 O 2:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.16 (s, 1H); 6.04 (dd, J = 16.10 Hz, J = 7.51 Hz, 1H); 5.77 (dd, J = 15.93 Hz, J = 0.991 Hz, 1H); 4.18-4.11 (m, 1H); 3.90 (s, 3H); 3.26 (s, 3H); 3.08 (dd, J = 15.63 Hz, J = 8.13 Hz, 1H); 2.99 (dd, J = 15.05 Hz, J = 5.31 Hz, 1H); 1.07 (s, 20H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.47; 161.68; 143.99; 141.58; 133.35; 113.72; 103.98; 92.81; 79.14; 56.97; 52.16; 34.51; 18.59; 11.22.

Example 26: Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (29) TBAF (1 M in THF, 4.6 mL, 4.6 mmol, 1.2 eq) was added dropwise at 0°C to a solution of TIPS oxazole 28 (1.5 g, 3.83 mmol, 1 eq) in THF (10 mL). The mixture was stirred for 1 h at room temperature and then quenched with wa- ter. The aqueous phase was extracted with Et 2 O and the organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the res- idue by flash chromatography (Pen/Et 2 O 2:1 to 1:1) afforded oxazole 29 (675 mg, 2.87 mmol, 75%) as a yellow oil. General Data: C 12 H 13 NO 4 ; FW: 235.08; = -26.89 (c = 0.45, CHCl 3 ); TLC: R f = 0.30 (Pentane/Et 2 O 1:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.16 (s, 1H); 6.10 (ddd, J = 16.19 Hz, J = 7.42 Hz, J = 0.434 Hz, 1H); 5.70 (ddd, J = 16.01 Hz, J = 2.15 Hz, J = 0.908 Hz, 1H); 4.19-4.12 (m, 1H); 3.89 (s, 3H); 3.26 (s, 3H); 3.08 (dd, J = 14.47 Hz, J = 7.89 Hz, 1H); 2.98 (dd, J = 14.74 Hz, J = 5.79 Hz, 1H); 2.92 (d, J = 2.30 Hz, 1H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.24; 161.59; 144.00; 142.99; 133.34; 112.29; 80.80; 78.91; 78.89; 56.95; 52.13; 34.35.

Example 27: (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylic acid (30) LiOH (1 M in H 2 O, 3.9 mL, 3.9 mmol, 2.5 eq) was added to a solution of the oxazole 29 (367 mg, 1.56 mmol, 1 eq) in THF (1 mL) at room temperature. The mixture was stirred for 2 h and then quenched with 1 M HCl. The aque- ous phase was extracted with Et 2 O and the organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford the acid 30 (326 mg, 1.54 mmol, 99%) as a yellow solid. General Data: C 11 H 11 NO 4 ; FW: 221.07; = -26.4 (c = 0.5, CHCl 3 ); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.25 (s, 1H); 6.13 (ddd, J = 15.97 Hz, J = 7.36 Hz, J = 0.566 Hz, 1H); 5.73 (ddd, J = 16.02 Hz, J = 2.38 Hz, J = 0.977 Hz, 1H); 4.23-4.15 (m, 1H); 3.27 (s, 3H); 3.14 (dd, J = 15.14 Hz, J = 7.66 Hz, 1H); 3.05 (dd, J = 15.02 Hz, J = 5.57 Hz, 1H); 2.93 (d, J = 3.31 Hz, 1H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 164.80; 162.73; 145.01; 142.88; 132.94; 112.43; 80.81; 78.96; 78.90; 56.98; 52.13; 34.22.

Example 28: Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxa zole-4- carboxylate (30) The vinyl iodide 18 (300 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl 2 (PPh3)2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -20°C. NEt 3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29 (240 mg, 1.02 mmol, 1.2 eq) in degassed CH 3 CN (3 mL). The solution became red and af- ter 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with NH 4 Cl solution. The aqueous phase was ex- tracted with Et 2 O and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (Et 2 O/Pen 2:1) to give the monomer 31 (360 mg, 0.781 mmol, 92 %) as a yellow oil. General Data: C 25 H 35 NO 7 ; FW: 461.24; TLC: R f = 0.25 (Et 2 O/Pentane 2:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.16 (s, 1H); 6.19-6.08 (m, 1H); 5.96 (dd, J = 8.56 Hz, J = 7.30 Hz, 1H); 5.82 (dd, J = 15.9 Hz, J = 2.07 Hz, 1H); 5.73-5.61 (m, 2H); 5.33 (qd, J = 6.42 Hz, J = 1.71 Hz, 1H); 4.71 (d, J = 6.67 Hz, 1H); 4.46 (d, J = 6.67 Hz, 1H); 4.16 (q, J = 7.48 Hz, 1H); 3.90 (s, 3H); 3.89 (app dd, J = 8.46 Hz, J = 4.55 Hz, 1H); 3.62 (dd, J = 10.16, J = 2.80, 1H); 3.37 (s, 3H); 3.26 (s, 3H); 3.10 (dd, J = 7.75 Hz, J = 6.97 Hz, 1H); 2.99 (dd, J = 9.30 Hz, J = 5.62 Hz, 1H); 2.61-2.50 (m, 1H); 1.65 (s, 1H); 2.48-2.32 (m, 1H); 1.74 (dd, J = 6.50 Hz, J = 1.70 Hz, 3H); 0.976 (s, 3H); 0.809 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.41; 161.63; 143.99; 142.54; 140.27; 133.33; 132.38; 126.93; 113.78; 110.11; 93.04; 91.10; 88.02; 84.69; 79.22; 77.87; 56.83; 55.99; 52.15; 41.08; 34.55; 32.88; 21.39; 17.87; 16.02. Example 29: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxaz ol-2-yl)- 4-(methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn- 6-yl 2- ((R,E)-2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (32) The monomer 31 (320 mg, 0.694 mmol, 1 eq) and the acid 30 (291 mg, 1.32 mmol, 1.5 eq) and DMAP (85 mg, 0.694 mmol, 1 eq) were dissolved in CH 2 Cl 2 (10 mL) and cooled to 0°C. DCC (716 mg, 3.47 mmol, 5 eq) was added and the mixture was stirred overnight at room temperature. The solu- tion was directly chromatographed (CH 2 Cl 2 /MeOH 99:1) to afford ester 32 (460 mg, 0.692 mmol, 99%) as a yellow wax, containing DCU impurity. General Data: C 36 H 44 N 2 O 10 ; FW: 664.30; = +23.16 (c = 0.6, CHCl 3 ); TLC: R f = 0.25 (CH 2 Cl 2 /MeOH 99:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.17 (s, 1H); 8.06 (s, 1H); 6.13 (dd, J = 16.38 Hz, J = 7.39 Hz, 1H); 5.98 (dd, J = 15.5 Hz, J = 7.39 Hz, 1H); 5.98- 5.92 (m, 1H); 5.87 (dd, J = 15.92 Hz, J = 2.03 Hz, 1H); 5.73 (ddd, J = 16.25 Hz, J = 2.33 Hz, J = 1.09 Hz, 1H); 5.63-5.53 (m, 2H); 5.34 (app dd, J = 9.86 Hz, J = 3.28 Hz, 1H); 5.31 (app qd, J = 7.63 Hz, J = 1.74 Hz, 1H); 4.68 (d, J = 6.78 Hz, 1H); 4.45 (d, J = 6.68 Hz, 1H); 4.18 (q, J = 6.06 Hz, 2H); 3.90 (s, 3H); 3.82 (d, J = 8.69 Hz, 1H); 3.62 (dd, J = 10.16 Hz, J = 2.80 Hz, 1H); 3.37 (s, 3H); 3.28 (s, 6H); 3.14-3.05 (m, 2H); 3.03-2.96 (m, 2H); 2.92 (d, J = 2.15 Hz, 1H); 2.79-2.64 (m, 2H); 1.72 (dd, J = 6.59 Hz, J = 1.46 Hz, 3H); 1.02 (s, 3H); 0.948 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.37; 162.25; 161.63; 160.62; 144.03; 143.53; 143.13; 140.49; 140.40; 133.45; 133.38; 132.19; 126.76; 113.61; 112.20; 111.11; 93.35; 91.26; 87.96; 81.37; 80.91; 79.20; 78.87; 78.83; 56.98; 55.75; 52.14; 41.61; 34.55; 34.37; 31.08; 25.45; 19.93; 19.46; 17.92. Example 30: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxaz ol-2-yl)- 4-(methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn- 6-yl 2- ((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methoxymeth oxy)- 11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-car boxylate (33) The vinyl iodide 18 (120 mg, 0.339 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (15 mg, 0.102 mmol, 0.3 eq) and PdCl 2 (PPh 3 ) 2 (24 mg, 0.0339 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -20°C. NEt 3 (0.283 mL, 2.03 mmol, 6 eq) was added, followed by a slow addition of the enyne 32 (300 mg, 0.452 mmol, 1.33 eq) in degassed CH 3 CN (3 mL). The solution became red and af- ter 30 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with NH 4 Cl solution. The aqueous phase was ex- tracted with Et 2 O and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (CH 2 Cl 2 /MeOH 99:1) to give 33 (246 mg, 0.276 mmol, 82%) as a yellow oil. General Data: C 49 H 66 N 2 O 13 ; FW: 890.46; = -22.83 (c = 0.6, CHCl 3 ); TLC: R f = 0.20 (CH 2 Cl 2 /MeOH 99:1); UV (+); Vanillin: black. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.17 (s, 1H); 8.05 (s, 1H); 6.19-6.09 (m, 1H); 6.03-5.83 (m, 5H); 5.70-5.51 (m, 4H); 5.37-5.25 (m, 3H); 4.70 (dd, J = 15.62 Hz, J = 6.57 Hz, 1H); 4.45 (t, J = 6.86 Hz, 1H); 4.22-4.13 (m, 2H); 3.90 (s, 3H); 3.89 (d, J = 9.06 Hz, 1H); 3.82 (d, J = 8.55 Hz, 1H); 3.56 (dt, J = 10.20 Hz, J = 3.26 Hz, 1H); 3.37 (s, 6H); 3.28 (s, 3H); 3.27 (s, 3H); 3.15-2.96 (m, 4H); 2.78-2.64 (m, 2H); 2.61-2.49 (m, 1H); 2.47-2.32 (m, 1H); 1.74 (dd, J = 6.43 Hz, J = 1.58 Hz, 3H); 1.72 (dd, J = 6.49 Hz, J = 1.40 Hz, 3H); 1.02 (s, 3H); 0.977 (s, 3H); 0.944 (s, 3H); 0.813 (s, 3H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.45; 162.37; 161.62; 160.63; 144.03; 143.51; 142.52; 140.49; 140.42; 133.41; 133.36; 132.39; 132.19; 126.93; 126.76; 125.51; 113.67; 113.61; 111.09; 110.13; 93.34; 93.05; 91.27; 91.16; 87.99; 87.96; 84.71; 81.36; 79.20; 77.85; 77.23; 56.87; 56.85; 56.01; 52.15; 41.63; 41.07; 34.50; 34.39; 32.87; 31.13; 21.41; 19.88; 19.36; 17.93; 17.86; 16.02. Example 31: 2-((2R,3E,7Z,10S,12S,13E)-10-((2-((2R,3E,7Z,10S,12S,13E)-10- hydroxy-2- methoxy-12-(methoxymethoxy)-11,11-dimethylpentadeca-3,7,13-t rien-5-

yn-1-yl)oxazole-4-carbonyl)oxy)-2-methoxy-12-(methoxymeth oxy)-11,11- dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-carboxyli c acid (34) 33 (48 mg, 0.0539 mmol, 1 eq) was dissolved in THF (1 mL) and treated at room temperature with LiOH (1 M in H 2 O, 0.108 mL, 0.108 mmol, 2 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl. The aqueous phase was extracted with Et 2 O and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give seco-acid 34 (44 mg, 0.0502 mmol, 93%) as a yellow wax, which was used without fur- ther purification. General Data: C 48 H 64 N 2 O 13 ; FW: 876.44; = -26.4 (c = 0.5, CHCl 3 ); UV (+); Vanillin: grey. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.20 (s, 1H); 8.10 (s, 1H); 6.18-6.09 (m, 1H); 6.04-5.80 (m, 5H); 5.73-5.52 (m, 4H); 5.38-5.26 (m, 3H); 4.71 (dd, J = 13.08 Hz, J = 6.64 Hz, 1H); 4.46 (dd, J = 7.04 Hz, J = 4.02 Hz, 1H); 4.24- 4.13 (m, 2H); 3.90 (d, J = 9.19 Hz, 1H); 3.83 (d, J = 8.68 Hz, 1H); 3.64 (dd, J = 10.12 Hz, J = 2.74 Hz, 1H); 3.39 (s, 3H); 3.38 (s, 3H); 3.30 (s, 3H); 3.28 (s, 3H); 3.18-2.94 (m, 4H); 2.82-2.51 (m, 3H); 2.47-2.33 (m, 1H); 1.74 (dd, J = 6.48 Hz, J = 1.52 Hz, 3H); 1.71 (dd, J = 6.38 Hz, J = 1.16 Hz, 3H); 1.03 (s, 3H); 0.983 (s, 3H); 0.950 (s, 3H); 0.815 (s, 3H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.42; 162.36; 162.10; 160.61; 144.36; 143.74; 142.44; 140.44; 140.35; 133.46; 133.34; 132.47; 132.22; 126.86; 126.70; 125.51; 113.72; 113.64; 111.25; 110.20; 93.39; 93.03; 91.24; 91.20; 88.00; 87.92; 84.77; 81.54; 79.14; 77.98; 77.22; 56.85; 56.02; 55.99; 49.54; 41.63; 41.07; 34.59; 34.54; 33.94; 31.06; 21.39; 19.92; 19.45; 17.93; 17.86; 16.02. Example 32: (16,16’)-Bis(methoxymethyl)-(9,10,9’,10’)-tetradehydri dodisorazole C1 (35) The crude seco-acid 34 (28 mg, 0.0319 mmol, 1 eq) was dissolved in THF (2.5 mL) and NEt 3 (89 µL, 0.638 mmol, 20 eq) and TCBC (50 µL, 0.319 mmol, 10 eq) were added at room temperature. The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (1.5 mL) and added dropwise to a solution of DMAP (156 mg, 1.28 mmol, 40 eq) in toluene (45 mL). The mixture was stirred overnight at room temperature and then quenched with NH 4 Cl solution (10 mL) and water (10 mL) and the aqueous phase was extracted with EtOAc. The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (CH 2 Cl 2 /MeOH 99:1) to afford the macrocycle 35 (22 mg, 0.0255, 80%) as a colorless wax. General Data: C 48 H 62 N 2 O 12 ; FW: 858.43; UV (+); TLC: R f = 0.55 (CH 2 Cl 2 /MeOH 50:1 Vanillin: black. 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.04 (s, 2H); 6.03-5.88 (m, 4H); 5.70- 5.47 (m, 6H); 5.44-5.23 (m, 4H); 4.69 (d, J = 7.18 Hz, 1H); 4.45 (d, J = 6.68 Hz, 1H); 4.17-3.99 (m, 2H); 3.81 (d, J = 9.36 Hz, 2H); 3.38 (s, 6H); 3.36 (s, 6H); 3.32-3.25 (m, 2H); 3.07-2.83 (m, 4H); 2.53-2.43 (m, 2H); 1.73 (dd, J = 6.48 Hz, J = 1.52 Hz, 6H); 1.71 (dd, J = 6.36 Hz, J = 1.27 Hz, 3H); 1.03 (s, 6H); 0.962 (s, 6H). 1 3 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 161.64; 160.52; 144.36; 143.33; 141.14; 140.31; 133.60; 132.38; 126.65; 125.51; 113.51; 112.08; 93.37; 90.80; 87.75; 81.47; 79.56; 77.22; 56.85; 56.07; 41.43; 33.96; 25.59; 19.84; 19.29; 17.94. Example 33: (16,16’)-Bis(methoxymethyl)-disorazole C1 (36) Nitrogen is bubbled for 15 min through a suspension of Zinc (3 g, 45.88 mmol) in H 2 O (18 mL) and then Cu(OAc) 2 ·H 2 O (300 mg, 1.50 mmol) was added at room temperature and after 15 min AgNO 3 (300 mg, 1.77 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H 2 O (30 mL), MeOH (20 mL), acetone (20 mL) and Et 2 O (20 mL). This activated zinc solids were added to a solution of 35 (20 mg, 0.0233 mmol) in MeOH/H 2 O 1:1 (5 mL). The mixture was stirred overnight at 50°C and then filtered on a pad of silica and washed with MeOH. The filtrate was concentrated in vacuo and the resi- due was purified by flash chromatography (CH 2 Cl 2 /MeOH 60:1) to afford 36 (12 mg, 0.0139, 60%) as a colorless oil. General Data: C 48 H 66 N 2 O 12 ; FW: 862.46; UV (+); TLC: R f = 0.40 (CH 2 Cl 2 /MeOH 50:1) Vanillin: dark blue. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.89 (s, 2H); 6.44 (dd, J = 14.93 Hz, J = 11.38 Hz, 2H); 6.34 (t, J = 11.38 Hz, 2H); 6.21 (t, J = 11.64 Hz, 2H); 5.90 (t, J = 11.04 Hz, 2H); 5.63-5.58 (m, 2H); 5.56-5.51 (m, 2H); 5.38 (dd, J = 10.91 Hz, J = 2.48 Hz, 1H); 5.34-5.27 (m, 4H); 4.68 (d, J = 6.67 Hz, 1H); 4.43 (d, J = 6.67 Hz, 1H); 4.15-4.10 (m, 2H); 3.81 (d, J = 8.73 Hz, 2H); 3.36 (s, 6H); 3.26 (s, 6H); 3.12 (dd, J = 14.66 Hz, J = 6.03 Hz, 2H); 2.97-2.86 (m, 2H); 2.78 (dd, J = 14.83 Hz, J = 7.27 Hz, 2H); 2.63-2.50 (m, 2H); 1.73 (dd, J = 6.48 Hz, J = 1.52 Hz, 6H); 1.73 (dd, J = 6.59 Hz, J = 1.22 Hz, 3H); 0.984 (s, 6H); 0.919 (s, 6H). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.23; 160.59; 143.20; 133.34; 133.03; 132.28; 130.13; 128.98; 127.95; 126.73; 125.59; 125.55; 93.26; 81.30; 79.79; 56.55; 56.13; 41.44; 35.06; 29.70; 19.95; 19.45; 17.94. Example 34: Disorazole C1 (37) MOM protected disorazole C136 (1 mg, 1.16 µmol) was dissolved in MeOH (0.3 mL) and cooled to 0°C. HCl 6 M (0.6 mL) was added dropwise and then the mixture was stirred for 4 days at 0°C. The reaction was quenched with saturated aqueous NaHCO 3 solution and the aqueous phase was extracted with Et 2 O. The organic extracts were dried over MgSO 4 , filtered and concen- trated in vacuo. The residue was purified by flash chromatography (CH 2 Cl 2 /MeOH 50:1) to give Disorazole C137(0.6 mg, 0.7 µmol, 60%) as a colorless wax. General Data: C 44 H 58 N 2 O 10 ; FW: 774.41; UV (+); TLC: R f = 0.20 (CH 2 Cl 2 /MeOH 50:1) Vanillin: dark blue. 1H-NMR (600 MHz, CD 3 OD): δ (ppm): δ 8.23 (s, 2 H); 6.50 (dd, J = 15.2 Hz, J = 11.5 Hz, 2H); 6.40 (app t, J = 11.2 Hz, 2 H); 6.28 (dd, 2 H, J = 11.4 Hz, J = 11.1 Hz, 2 H); 5.91 (dd, J = 11.2 Hz, J = 10.9 Hz, 2 H); 5.66 (dq, J = 15.2 Hz, J = 6.6 Hz, 2 H); 5.57 (ddd, J = 15.2 Hz, J = 7.8 Hz, J = 1.4 Hz, 2H); 5.54 (dd, J = 15.0 Hz, J = 8.3 Hz, 2 H); 5.48 (app dt, J = 10.0 Hz, J = 6.7 Hz, 2 H); 5.25 (dd, J = 11.3 Hz, J = 2.2 Hz, 2 H); 4.13 (ddd, J = 7.8 Hz, 7.2 Hz, 5.5 Hz, 2 H); 3.84 (d, 2 H, J = 7.8 Hz); 3.21 (s, 6 H), 2.99 (dd, 2 H, J = 15.5, J = 7.4 Hz); 2.76 (dd, J = 15.5 Hz, J = 5.4 Hz, 2 H); 2.69 (ddd, J = 13.8 Hz, J = 10.9 Hz, J = 10.2 Hz, 2 H); 2.38 (dd, J = 13.8 Hz, J = 6.1 Hz, 2 H); 1.69 (dd, J = 6.4 Hz, J = 1.3 Hz, 6 H); 1.00 (s, 6 H); 0.95 (s, 6 H). 13 C-NMR (151 MHz, CD 3 OD) δ 164.12; 162.26; 145.83; 134.15; 134.09; 131.68; 130.88; 129.96; 129.63; 129.30; 127.36; 126.79; 80.57; 78.75; 77.84; 56.83; 42.70; 35.97; 29.24; 19.41; 19.32; 18.03. Example 35: Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)ox- azole-4-carboxylate (40) The vinyl iodide 17 (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl 2 (PPh 3 ) 2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -15°C (ice/acetone bath). NEt 3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29 (240 mg, 1.02 mmol, 1.2 eq) in degassed CH 3 CN (3 mL). The solution became red and after 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH 4 Cl solution (10 mL). The aqueous phase was extracted with Et 2 O (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et 2 O 2:1) to give the monomer 40 (414 mg, 0.720 mmol, 85%) as a yellow oil. General Data: C 31 H 49 NO 7 Si; FW: 575.33; TLC: R f = 0.20 (pentane/Et 2 O 2:1); UV (+); Vanillin: black; = -28.4 (c = 0.5, CHCl 3 ). 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.16 (s, 1H, NC=CH); 6.10-6.02 (m, 1H, CH 2 CH=CH); 5.99 (dd, J = 15.9, 7.5 Hz, 1H, CCH=CHCH); 5.89 (dd, J = 15.9, 2.2 Hz, 1H, CCH=CHCH 2 ); 5.66- 5.54 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.37-5.28 (m, 1H, CH=CHCH 3 ); 4.66 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.46 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.21-4.13 (m, 1H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.84 (d, J = 9.3 Hz, 1H, CH 2 CHOTES); 3.67 (dd, J = 7.1, 3.8 Hz, 1H, CH 2 CHOTES); 3.35 (s, 3H, CHOCH 3 ); 3.27 (s, 3H, CHOCH 2 OCH 3 ); 3.10 (dd, J = 12.6, 5.6 Hz, 1H, 1CH 2 CHOCH 3 ); 2.99 (dd, J = 15.0, 5.5 Hz, 1H, 1CH 2 CHOCH 3 ); 2.62-2.53 (m, 1H, 1CH 2 CH=CH); 2.45-2.37 (m, 1H, 1CH 2 CH=CH); 1.71 (dd, J = 6.4, 1.6 Hz, 3H, CH=CHCH 3 ); 0.952 (app t, J = 8.0 Hz, 9H, OSi(CH 2 CH 3 )3); 0.922 (s, 3H, CCH 3 ); 0.849 (s, 3H, CCH 3 ); 0.599 (q, J = 8.0 Hz, 6H, OSi(CH 2 CH 3 )3). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.6 (C=O); 161.8 (C=N); 144.1 (CH); 143.2 (CH); 140.4 (CH); 133.5 (C); 131.0 (CH); 128.0 (CH); 113.9 (CH); 109.5 (CH); 93.6 (CH 2 ); 91.2 (C); 88.5 (C); 81.6 (CH); 79.4 (CH); 76.5 (CH); 56.9 (CH 3 ); 55.7 (CH 3 ); 52.3 (CH 3 ); 43.1 (C); 34.7 (CH 2 ); 34.5 (CH 2 ); 19.8 (CH 3 ); 19.4 (CH 3 ); 18.0 (CH 3 ); 7.3 (CH 3 ); 5.7 (CH 2 ). IR(neat): 3656 (w); 2980 (s); 2884 (m); 1749 (m); 1585 (m); 1461 (m); 1382 (m); 1238 (m); 1142 (m); 1091 (s); 1036 (s); 1004 (s); 956 (s); 923 (m); 727 (s); 678 (m); 604 (w) cm -1 . MS (ESI): m/z (%): 418.20 (100), 514.29 (81), 598.31 (22), 593.36 (18) [M+NH 4 ] + , 350.17 (8), 482.27 (6), 576.33 (<1) [M+H] + . HRMS (ESI) m/z: [M+H] + Calcd for C 31 H 50 NO 7 Si: 576.3357; found: 576.3363. Example 36: Methyl-2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(me thox- ymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxa zole-4- carboxylate (31) CSA (10 mg, 0.0444 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 40 (128 mg, 0.222 mmol, 1 eq) in CH 2 Cl 2 (6 mL) and MeOH (6 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Saturated aqueous NaHCO 3 solution (15 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , fil- tered and concentrated in vacuo. The residue was purified by flash chroma- tography (Et 2 O/pentane 2:1) giving deprotected monomer 31 (97 mg, 0.210 mmol, 95%) as a slightly yellow oil. General Data: C 25 H 35 NO 7 ; FW: 461.24; TLC: R f = 0.25 (Et 2 O/Pentane 2:1); UV (+); Vanillin: black; [ = -36.11 (c = 1.75, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.16 (s, 1H, NC=CH); 6.24-6.15 (m, 1H, CH 2 CH=CH); 5.96 (dd, J = 15.8, 7.5 Hz, 1H, CCH=CHCH); 5.87 (d, J = 15.9 Hz, 1H, CCH=CHCH 2 ); 5.71-5.61 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.43-5.36 (m, 1H, CH=CHCH3); 4.65 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 4.47 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 4.21-4.12 (m, 1H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (1H, CH2CHOH); 3.68 (d, J = 10.0 Hz, 1H, CHOCH2OCH3); 3.38 (s, 3H, CHOCH3); 3.26 (s, 3H, CHOCH2OCH3); 3.09 (dd, J = 15.1, 7.9 Hz, 1H, 1CH2CHOCH3); 2.99 (dd, J = 14.9, 5.3 Hz, 1H, 1CH2CHOCH3); 2.54 (dd, J = 14.3, 7.6 Hz, 1H, 1CH2CH=CH); 2.37- 2.28 (m, 1H, 1CH2CH=CH); 1.75 (d, J = 6.3 Hz, 3H, CH=CHCH3); 0.917 (s, 3H, CCH3); 0.867 (s, 3H, CCH3). 13 C-NMR (151 MHz, CDCl3): δ (ppm): 162.6 (C=O); 161.8 (C=N); 144.1 (CH); 143.3 (CH); 140.3 (CH); 133.5 (C); 132.0 (CH); 126.9 (CH); 114.0 (CH); 109.8 (CH); 93.8 (CH2); 91.1 (C); 88.3 (C); 84.7 (CH); 79.4 (CH); 76.1 (CH); 56.9 (CH3); 56.2 (CH3); 52.3 (CH3); 41.0 (C); 34.7 (CH2); 32.8 (CH2); 21.1 (CH3); 17.7 (CH3); 18.0 (CH3). IR(neat): 3483 (br); 3164 (w); 2934 (m); 2826 (w); 2249 (w); 1734 (m); 1585 (m); 1438 (m); 1322 (m); 1166 (m); 1101 (s); 1030 (s); 927 (m); 917 (m); 731 (s) cm -1 . MS (ESI): m/z (%): 304.11 (100), 400.21 (48), 479.27 (20) [M+NH4] + , 272.09 (19), 430.22 (15), 462.24 (12) [M+H] + , 209.13 (3). HRMS (ESI) m/z: [M+H] + Calcd for C25H36NO7: 462.2492; found: 462.2473. Example 37: 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,1 1-di- methyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole -4- carboxylic acid (42)

40 (150 mg, 0.261 mmol, 1 eq) was dissolved in THF (5 mL) and treated at room temperature with LiOH (1 M in H2O, 0.783 mL, 0.783 mmol, 3 eq). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the or- ganic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give acid 42 (146 mg, 0.259 mmol, 99%) as a yellow oil, which was used for the next step without further purification. General Data: C 30 H 47 NO 7 Si; FW: 561.31; TLC: UV (+); Vanillin: black; = -36.9 (c = 1.0, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.24 (s, 1H, NC=CH); 6.09-6.02 (m, 1H, CH2CH=CH); 6.00 (dd, J = 15.6, 7.5 Hz, 1H, CCH=CHCH); 5.89 (d, J = 15.9 Hz, 1H, CCH=CHCH2); 5.69-5.55 (m, 2H, CH(OCH3)CH=CH, CH=CHCH 3 ); 5.37-5.28 (m, 1H, CH=CHCH 3 ); 4.68 (d, J = 6.4 Hz, 1H,1OCH2OCH 3 ); 4.48 (d, J = 6.4 Hz, 1H, 1OCH2OCH 3 ); 4.23-4.13 (m, 1H, CHOCH 3 ); 3.84 (d, J = 9.0 Hz, 1H, CHOCH2OCH 3 ); 3.65 (dd, J = 6.8, 3.5 Hz, 1H, CHOTES); 3.36 (s, 3H, CHOCH 3 ); 3.28 (s, 3H, CHOCH2OCH 3 ); 3.13 (dd, J = 15.0, 7.4 Hz, 1H, 1CH2CHOCH3); 3.03 (dd, J = 15.0, 4.2 Hz, 1H, 1CH2CHOCH 3 ); 2.59-2.51 (m, 1H, 1CH2CH=CH); 2.45-2.36 (m, 1H, 1CH2CH=CH); 1.72 (d, J = 5.9, Hz, 3H, CH=CHCH 3 ); 0.951 (t, J = 7.8 Hz, 9H, OSi(CH2CH 3 )3); 0.925 (s, 3H, CCH 3 ); 0.853 (s, 3H, CCH 3 ); 0.598 (q, J = 7.9 Hz, 6H, OSi(CH2CH 3 )3). 1 3C-NMR (151 MHz, CDCl3): δ (ppm): 164.4 (C=O); 162.8 (C=N); 145.0 (CH); 143.2 (CH); 140.2 (CH); 133.0 (C); 131.1 (CH); 127.9 (CH); 114.0 (CH); 109.5 (CH); 93.6 (CH2); 91.2 (C); 88.5 (C); 81.8 (CH); 79.3 (CH); 76.5 (CH); 56.9 (CH 3 ); 55.7 (CH 3 ); 43.2 (C); 34.4 (CH2); 30.5 (CH2); 19.8 (CH 3 ); 19.4 (CH 3 ); 18.0 (CH 3 ); 7.3 (CH 3 ); 5.7 (CH2). IR(neat): 2953 (m); 2912 (m); 2877 (m); 1716 (m); 1587 (m); 1440 (m); 1359 (w); 1234 (w); 1144 (m); 1090 (s); 1036 (s); 957 (m); 921 (m); 826 (m); 726 (s); 542 (w) cm-1. MS (ESI): m/z (%): 404.18 (100), 579.34 (78) [M+NH4]+, 500.28 (51), 372.16 (27), 468.25 (10), 336.15 (8), 562.32 (3) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C30H48NO7Si: 562.3200; found: 562.3188. Example 38: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxaz ol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6- yl 2- ((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11- dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole -4-car- boxylate (43) The crude acid 42 (91 mg, 0.162 mmol, 1.5 eq) was dissolved in THF (5 mL) and treated at room temperature with NEt3 (90 µL, 0.648 mmol, 6 eq) and 2,4,6-trichlorobenzoyl chloride (68 µL, 0.432 mmol, 4 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of alcohol 31 (50 mg, 0.108 mmol, 1 eq) and DMAP (79 mg, 0.648 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH 4 Cl solution (15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the dimer 43 (81 mg, 0.0813 mmol, 75%) as a slightly yellow oil. General Data: C 55 H 80 N 2 O 13 Si; FW: 1004.54; TLC: Rf = 0.30 (Et2O/pentane 2:1); UV (+); Vanillin: black; = +29.65 (c = 1.75, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.18 (s, 1H, NC=CH); 8.06 (s, 1H, NC=CH); 6.10-5.94 (m, 4H, CH=CH); 5.93-5.84 (m, 2H, CH=CH); 5.70-5.52 (m, 4H, CH=CH); 5.42-5.28 (m, 2H, CH=CH); 5.25 (app dd, J = 7.6, 5.5 Hz, 1H, CHOC=O); 4.65 (dd, J = 6.5, 3.0 Hz, 2H, OCH 2 OCH 3 ); 4.46 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.39 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.23-4.13 (m, 2H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.84 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.76 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.66 (dd, J = 7.0, 3.8 Hz, 1H, CH 2 CHOTES); 3.34 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 3 ); 3.28 (s, 3H, CHOCH 2 OCH 3 ); 3.27 (s, 3H, CHOCH 2 OCH 3 ); 3.15-2.93 (m, 4H, CH 2 CHOCH 3 ); 2.72-2.62 (m, 2H, CH 2 CH=CH); 2.60-2.51 (m, 1H, 1CH 2 CH=CH); 2.46-2.36 (m, 1H, 1CH 2 CH=CH); 1.71 (dt, J = 6.4, 1.5 Hz, 6H, CH=CHCH 3 ); 1.03 (s, 3H, CCH 3 ); 0.966 (s, 3H, CCH 3 ); 0.945 (app t, J = 7.9 Hz, 9H, OSi(CH 2 CH 3 ) 3 ); 0.918 (s, 3H, CCH 3 ); 0.844 (s, 3H, CCH 3 ); 0.591 (q, J = 8.0 Hz, 6H, OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 162.6 (C=O); 162.5 (C=O); 161.8 (C=N); 160.8 (C=N); 144.2 (CH); 143.6 (CH); 143.2 (CH); 140.6 (CH); 140.5 (CH); 133.6 (C); 133.5 (C); 132.1 (CH); 131.0 (CH); 128.0 (CH); 127.1 (CH); 125.6 (CH); 113.8 (CH); 113.7 (CH); 111.1 (CH); 109.5 (CH); 93.6 (CH 2 ); 93.6 (CH 2 ); 91.4 (C); 91.2 (C); 88.4 (C); 88.0 (C); 81.6 (CH); 81.6 (CH); 79.3 (CH); 77.4 (CH); 77.0 (CH); 76.4 (CH); 57.0 (CH 3 ); 56.9 (CH 3 ); 56.1 (CH 3 ); 55.7 (CH 3 ); 52.3 (CH 3 ); 43.2 (C); 41.8 (C); 34.7 (CH 2 ); 34.5 (CH 2 ); 31.4 (CH 2 ); 30.4 (CH 2 ); 19.9 (CH 3 ); 19.8 (CH 3 ); 19.5 (CH 3 ); 19.4 (CH 3 ); 18.1 (CH 3 ); 18.0 (CH 3 ); 7.3 (CH 3 ); 5.7 (CH 2 ). IR(neat): 2953 (m); 2879 (m); 2284 (w); 1737 (m); 1583 (m); 1439 (m); 1318 (m); 1168 (m); 1099 (s); 1033 (s); 911 (s); 807 (m); 728 (s); 647 (m); 551 (w) cm -1 . MS (ESI): m/z (%): 1005.55 (100) [M+H] + , 1022.56 (760) [M+NH 4 ] + , 943.52 (45), 973.53 (28), 847.43 (8). HRMS ( ESI) m/z: [M+H]+ Calcd for C55H81N2O13Si: 1005.5508; found: 1005.5594 Example 39: (16,16’)-Bis(methoxymethyl)-(9,10,9’,10’)-tetradehydri dodisorazole C1 (35) CSA (3 mg, 0.0132 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 43 (67 mg, 0.0661 mmol, 1 eq) in CH2Cl 2 (2 mL) and MeOH (2 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO 3 solution (10 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl 2 (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo giving the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C 49 H 66 N 2 O 13 ; FW: 890.46; TLC: R f = 0.30 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: black; = +24.93 (c = 1.4, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.18 (s, 1H, NC=CH); 8.06 (s, 1H, NC=CH); 6.24-6.14 (m, 1H, CH 2 CH=CH); 6.03-6.92 (m, 3H, CH=CH); 5.88 (ddd, J = 15.9, 4.8, 2.0 Hz, 2H, CH=CH); 5.72-5.60 (m, 3H, CH=CH); 5.56 (d, J = 10.1 H, 1H, CH=CH); 5.44-5.32 (m, 2H, CH=CH); 5.25 (dd, J = 8.0, 5.2 Hz, 1H, CHOC=O); 4.70 (dd, J = 15.0, 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.45 (t, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.65 (dd, J = 6.5, 1.8 Hz, 1H, CHOCH 2 OCH 3 ); 4.47 (d, J = 6.6 Hz, 1H, CHOCH 2 OCH 3 ); 4.39 (d, J = 6.6 Hz, 1H, CHOCH 2 OCH 3 ); 4.23-4.13 (m, 2H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.89 (m, 1H, CHOCH 2 OCH 3 ); 3.76 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.68 (dd, J = 10.3, 2.4 Hz, 1H, CHOH); 3.38 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 3 ); 3.28 (s, 3H, CHOCH 2 OCH 3 ); 3.27 (s, 3H, CHOCH 2 OCH 3 ); 3.15-2.94 (m, 4H, CH 2 CHOCH 3 ); 2.72-2.62 (m, 2H, CH 2 CH=CH); 2.58-2.48 (m, 1H, 1CH 2 CH=CH); 2.39-2.28 (m, 1H, 1CH 2 CH=CH); 1.74 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH 3 ); 1.71 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH 3 ); 1.03 (s, 3H, CCH 3 ); 0.968 (s, 3H, CCH 3 ); 0.921 (s, 3H, CCH 3 ); 0.868 (s, 3H, CCH 3 ). 13 C-NMR (100 MHz, CDCl3): δ (ppm): 162.6 (C=O); 162.5 (C=O); 161.8 (C=N); 160.8 (C=N); 144.2 (CH); 143.6 (CH); 143.2 (CH); 140.6 (CH); 140.4 (CH); 140.4 (CH); 133.6 (C); 133.5 (C); 132.1 (CH); 132.0 (CH); 127.1 (CH); 126.8 (CH); 113.9 (CH); 113.7 (CH); 111.1 (CH); 109.8 (CH); 93.8 (CH 2 ); 93.6 (CH 2 ); 91.4 (C); 91.2 (C); 88.3 (C); 88.0 (C); 84.7 (CH); 81.4 (CH); 79.3 (CH); 77.4 (CH); 77.0 (CH); 76.1 (CH); 57.0 (CH 3 ); 56.9 (CH 3 ); 56.2 (CH 3 ); 56.1 (CH 3 ); 52.3 (CH 3 ); 41.8 (C); 41.0 (C); 34.7 (CH 2 ); 34.7 (CH 2 ); 32.8 (CH 2 ); 31.4 (CH 2 ); 21.1 (CH 3 ); 19.9 (CH 3 ); 19.8 (CH 3 ); 19.5 (CH 3 ); 18.1 (CH 3 ); 18.0 (CH 3 ). IR(neat): 3658 (br); 2980 (s); 2890 (m); 1737 (m); 1584 (m); 1463 (m); 1380 (m); 1258 (m); 1143 (s); 1098 (s); 1031 (s); 969 (m); 919 (m); 805 (m); 732 (m); 542 (w) cm -1 . MS (ESI): m/z (%): 908.49 (100) [M+NH 4 ] + , 891.46 (98) [M+H] + , 859.44 (35), 733.33 (7), 829.43 (5). HRMS (ESI) m/z: [M+H] + Calcd for C 49 H 67 N 2 O 13 : 891.4643; found: 891.4768. The crude deprotected alcohol was dissolved in THF (1.5 mL) and treated at room temperature with LiOH (1 M in H 2 O, 0.165 mL, 0.165 mmol, 2.5 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (1 mL). The aqueous phase was extracted with Et 2 O (3x3 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purifi- cation. General Data: C 48 H 64 N 2 O 13 ; FW: 876.44; TLC: UV (+); Vanillin: grey; = +17.4 (c = 1.3, CHCl 3 ). 1 H-NMR (400 MHz, CDCl3): δ (ppm): 8.24 (s, 1H, NC=CH); 8.07 (s, 1H, NC=CH); 6.24-6.14 (m, 1H, CH2CH=CH); 6.04-5.93 (m, 3H, CH=CH); 5.93-5.81 (m, 2H, CH=CH); 5.73-5.60 (m, 3H, CH=CH); 5.55 (d, J = 10.5 Hz, 1H, CH=CH); 5.44-5.32 (m, 2H, CH=CH); 5.25 (dd, J = 8.6, 4.3 Hz, 1H, CHOC=O); 4.67 (d, J = 6.6 Hz, 2H, OCH2OCH3); 4.49 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.41 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.23-4.14 (m, 2H, CHOCH3); 3.92 (d, J = 8.8 Hz, 1H, CHOCH2OCH3); 3.76 (d, J = 9.1 Hz, 1H, CHOCH2OCH3); 3.70 (dd, J = 10.3, 2.6 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH3); 3.34 (s, 3H, CHOCH3); 3.30 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.19-2.94 (m, 4H, CH2CHOCH3); 2.75-2.61 (m, 2H, CH2CH=CH); 2.59-2.49 (m, 1H, 1CH2CH=CH); 2.42-2.29 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.03 (s, 3H, CCH3); 0.975 (s, 3H, CCH3); 0.927 (s, 3H, CCH3); 0.877 (s, 3H, CCH3). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 163.7 (C=O); 162.6 (C=O); 162.5 (C=N); 160.7 (C=N); 144.8 (CH); 143.7 (CH); 143.1 (CH); 140.5 (CH); 140.3 (CH); 133.5 (C); 133.2 (C); 132.2 (CH); 132.1 (CH); 127.1 (CH); 126.8 (CH); 125.7 (CH); 113.9 (CH); 113.8 (CH); 111.2 (CH); 109.9 (CH); 93.8 (CH3); 93.5 (CH 3 ); 91.4 (C); 91.2 (C); 88.3 (C); 88.0 (C); 84.7 (CH); 81.6 (CH); 79.4 (CH); 79.3 (CH); 77.4 (CH); 76.3 (CH); 57.0 (CH 3 ); 56.9 (CH 3 ); 56.2 (CH 3 ); 6.1 (CH 3 ); 41.8 (C); 41.0 (C); 34.6 (CH2); 34.5 (CH2); 30.5 (CH2); 29.8 (CH2); 21.1 (CH 3 ); 19.9 (CH 3 ); 19.9 (CH 3 ); 19.4 (CH 3 ); 18.1 (CH 3 ); 18.1 (CH 3 ). IR(neat): 3658 (br); 2980 (s); 2923 (s); 2328 (w); 1719 (m); 1584 (m); 1461 (m); 1377 (m); 1251 (m); 1146 (m); 1098 (s); 1032 (s); 969 (s); 909 (m); 818 ( w); 734 (s); 542 (w) cm -1 . MS (ESI): m/z (%): 877.44 (100) [M+H] + , 894.47 (77) [M+NH4] + , 845.42 (49), 719.31 (30), 783.38 (23). HRMS (ESI) m/z: [M+H] + Calcd for C 48 H 65 N 2 O 13 : 877.4487; found: 877.4473. The crude seco-acid was dissolved in THF (5 mL) and treated at room tem- perature with NEt 3 (184 µL, 1.32 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chloride (103 µL, 0.661 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added drop- wise to a solution of DMAP (323 mg, 2.64 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH 4 Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the macrocycle 35 (40 mg, 0.0462 mmol, 70% from 43) as a slightly yellow oil. General Data: C 48 H 62 N 2 O 12 ; FW: 858.43; TLC: R f = 0.50 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: black; = +140.2 (c = 0.5, CHCl3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.04 (s, 2H, NC=CH); 6.02-5.90 (m, 4H, CH=CH); 5.70- 5.60 (m, 4H, CH=CH); 5.51 (d, J = 10.3 Hz, 2H, CH=CH); 5.44-5.36 (m, 2H, CH=CH); 5.34 (dd, J = 11.0, 2.3 Hz, 2H, CHOC=O); 4.67 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.42 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.17- 4.08 (m, 2H, CHOCH 3 ); 3.73 (d, J = 9.2 Hz, 2H, CHOCH 2 OCH 3 ); 3.36 (s, 6H, CHOCH 3 ); 3.34 (s, 6H, CHOCH 2 OCH 3 ); 3.32-3.26 (m, 2H, CH 2 CH=CH); 3.06-2.88 (m, 4H, CH 2 CHOCH 3 ); 2.43-2.35 (m, 2H, CH 2 CH=CH); 1.74 (dd, J = 6.1, 1.2 Hz, 6H, CH=CHCH 3 ); 1.04 (s, 6H, CCH 3 ); 1.00 (s, 6H, CCH 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 161.8 (C=O); 160.7 (C=N); 143.4 (CH); 141.3 (CH); 140.4 (CH); 133.8 (C); 132.0 (CH); 127.2 (CH); 113.7 (CH); 112.2 (CH); 93.8 (CH 2 ); 91.0 (C); 87.9 (C); 81.5 (CH); 79.7 (CH); 76.4 (CH); 57.0 (CH 3 ); 56.2 (CH 3 ); 41.6 (C); 34.5 (CH 2 ); 31.5 (CH 2 ); 19.9 (CH 3 ); 19.6 (CH 3 ); 18.1 (CH 3 ). IR(neat): 3172 (w); 3180 (w); 2930 (m); 2855 (m); 1736 (m); 1649 (m); 1584 (m); 1450 (m); 1368 (m); 1216 (m); 1140 (m); 1103 (s); 1031 (s); 973 (m); 921 (m); 830 (m); 752 (s) cm -1 . MS (ESI): m/z (%): 859.44 (100) [M+H] + , 876.46 (42) [M+NH 4 ] + , 797.40 (16), 735.36 (3). HRMS (ESI) m/z: [M+H] + Calcd for C 48 H 65 N 2 O 13 : 859.4381; found: 859.4464. Example 40: Disorazole C1 (37) The intermediate product from Example 39 can be reacted according to the sequence of Example 33 followed by Example 34, as indicated above. The following Examples 41 to 52 disclose the synthesis of (4R)-Disorazole C1 (37r) Example 41: (4R,6S)-5,5-dimethyl-6,8-bis((triethylsilyl)oxy)oct-1-en-4-o l (12r) A solution of (S,S)-Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH 2 Cl 2 (50 mL). Then Sc(OTf) 3 (175 mg, 0.375 mmol, 0.05 eq) was added and the mixture was stirred for 24 h at room temperature. TBAF trihydrate (2.26 g, 7.15 mmol, 1 eq) was added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (pentane/Et 2 O 50:1, then pentane/EtOAc/NEt 3 1:1:0.1) to furnish the allylic alcohol 12r (2.53 g, 6.08 mmol, 85%) as a colorless liquid and the recovered diamine of the Leighton reagent (3.64 g, 8.08 mmol, 87 %) as a yellow paste. Analysis by 1 H and 13 C NMR showed a 13:1 mixture syn and anti diastereoisomers. General Data: C 22 H 48 O 3 Si 2 ; FW: 416.31; TLC: R f = 0.2 (Pentane/Et 2 O 50:1); UV (-); Vanillin: dark blue; = -4.2 (c = 0.5, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.94-5.86 (m, 1H, CH=CH 2 ); 5.13-5.05 (m, 2H, CH=CH 2 ); 3.79 (dd, J = 6.5, 2.7 Hz, 1H, CHOH); 3.73 (m, 1H, 1CH 2 OSi); 3.65 (m, 1H, 1CH 2 OSi); 3.51 (dt, J = 10.5, 2.3 Hz, 1H, CHOSi); 2.74 (s, 1H, CHOH); 2.31-2.25 (m, 1H, 1CH 2 CH); 2.1-2.02 (m, 1H, 1CH 2 CH); 2.01-1.93 (m, 1H, 1CH 2 CH 2 O); 1.54-1.48 (m, 1H, 1CH 2 CH 2 O); 0.990-0.931 (m, 18H, 2OSi(CH 2 CH 3 ) 3 ); 0.897 (s, 3H, 1CCH 3 ); 0.781 (s, 3H, 1CCH 3 ); 0.650-0.570 (m, 12H, 2OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.26 (CH); 116.74 (CH2); 75.78 (CH); 75.55 (CH); 61.24 (CH 2 ); 42.57 (C); 36.60 (CH 2 ); 36.51 (CH 2 ); 18.86 (CH 3 ); 18.64 (CH 3 ); 7.22 (CH 3 ); 6.88 (CH 3 ); 5.64 (CH 2 ); 4.42 (CH 2 ). IR(neat): 3335 (br); 2955 (s); 2913 (s); 2877 (s); 1670 (w); 1642 (w); 1461 (m); 1415 (m); 1381 (m); 1238 (m); 1093 (s); 1056 (s); 1004 (s); 910 (m); 842 (m); 726 (s); 675 (m) cm -1 . MS (ESI): m/z (%): 303.24 (100), 417.32 (23), 153.13 (16), 418.32 (8). HR-MS (ESI): calculated for C 22 H 48 O 3 Si 2 [M+H] + : 417.3220, found: 417.3227. Example 42: (5R,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl )oxy)-2,4,10- trioxa-11- silatridecane (13r) MOMCl (1.3 mL, 17 mmol, 3 eq) was added dropwise at 0°C to a solution of allylic alcohol 12r (2.36 g, 5.67 mmol, 1 eq), DIPEA (3 mL, 17 mmol, 3 eq) and DMAP (207 mg, 1.7 mmol, 0.3 eq) in CH 2 Cl 2 (60 mL). The mixture was stirred overnight at 45°C. Evaporation of the solvent and purification of the residue by flash chromatography (Pen/Et 2 O 60:1) afforded the protected triol 13r (2.4 g, 5.21 mmol, 92 %) as a colorless liquid. General Data: C 24 H 52 O 4 Si 2 ; FW: 460.34; TLC: Rf= 0.5 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue; = -10.67 (c = 0.75, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 5.95-5.87 (m, 1H, CH=CH 2 ); 5.09-4.98 (m, 2H, CH=CH 2 ); 4.61 (q, J = 6.7 Hz, 2H, OCH 2 OCH 3 ); 3.74-3.68 (m, 1H, 1CH 2 OSi); 3.71 (dd, J = 8.6, 1.8 Hz, 1H, CHOCH 2 OCH 3 ); 3.63.3.57 (m, 1H, 1CH 2 OSi); 3.47 (dd, J = 8.6, 2.9 Hz 1H, CHOSi); 3.36 (s, 3H, OCH 3 ); 2.48- 2.41 (m, 1H, 1CH 2 CH); 2.23-2.14 (m, 1H, 1CH 2 CH); 1.91-1.83 (m, 1H, 1CH 2 CH 2 O); 1.55-1.48 (m, 1H, 1CH 2 CH 2 O); 1.00-0.923 (m, 18H, 2OSi(CH 2 CH 3 ) 3 ); 0.917 (s, 3H, 1CCH 3 ); 0.811 (s, 3H, 1CCH 3 ); 0.655-0.565 (m, 12H, 2OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 137.44 (CH); 116.09 (CH 2 ); 98.19 (CH 2 ); 83.58 (CH); 74.63 (CH); 60.94 (CH 2 ); 56.19 (CH 3 ); 43.44 (C); 36.37 (CH2); 36.33 (CH2); 21.00 (CH3); 19.39 (CH3); 7.29 (CH3); 6.95 (CH3); 5.77 (CH2); 4.58 (CH2). IR(neat): 2954 (m); 2914 (m); 2877 (m); 1641 (w); 1461 (m); 1382 (m); 1238 (m); 1093 (s); 1035 (s); 1006 (s); 912 (m); 725 (s); 674 (m) cm -1 . MS (EI, 70eV): m/z (%): 116.02 (100), 58.54 (64), 86.32 (50), 300.21 (45), 436.80 (9), 313.7 (6). HRMS (ESI) m/z: [M+H] + Calcd for C 24 H 52 O 4 Si 2 : 461.3438; found: 461.3460. Example 43: (3S,5R,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl) oxy)non-7- en-1-ol (14r) A solution of protected triol 13r (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred for 20 h at 60°C. The mixture was then concentrated in vacuo and the residue was filtered on a pad of silica gel (Pen/Et 2 O 1:1). The filtrate was concentrated in vacuo affording a mixture of 14r (80%) and 15r (15%) as a colorless liquid, which was used in the next step without further purification. A small amount was further purified by flash chromatography(Pen/Et 2 O 60:1 to 3:1) for analytical purpose. Analysis by 1H and 13 C NMR showed a 14:1 mixture of E and Z isomers. General Data (15r): C 24 H 52 O 4 Si 2 ; FW: 460.34; TLC: R f = 0.5 (Pen- tane/Et 2 O 50:1); UV (-); Vanillin: dark blue; = -44.0 (c = 0.2, CHCl 3 ). 1 H-NMR (15r) (400 MHz, CDCl 3 ): δ (ppm): 5.64-5.54 (m, 1H, CH=CH); 5.31 (m, 1H, CH=CH); 4.66 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.43 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 3.86 (d, J = 8.7 Hz, 1H, CHOCH 2 OCH 3 ); 3.75 (dd, J = 8.8, 2.4 Hz, 1H, CHOSi); 3.73-3.67 (m, 1H, 1CH 2 OSi); 3.64-3.55 (m, 1H, 1CH 2 OSi); 3.35 (s, 3H, OCH 3 ); 1.94-1.82 (m, 1H, 1CH 2 CH 2 O); 1.71 (dd, J = 6.4, 1.4 Hz, 3H, CHCH 3 ); 1.63-1.53 (m, 1H, 1CH 2 CH 2 O); 1.01-0.878 (m, 18H, 2OSi(CH 2 CH 3 ) 3 ); 0.922 (s, 3H, 1CCH 3 ); 0.746 (s, 3H, 1CCH 3 ); 0.668-0.540 (m, 12H, 2OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (15r) (100 MHz, CDCl 3 ): δ (ppm): 130.84 (CH); 128.07 (CH); 93.53 (CH 2 ); 81.31 (CH); 74.48 (CH); 61.29 (CH 2 ); 55.91 (CH 3 ); 42.38 (C); 35.92 (CH 2 ); 20.31 (CH 3 ); 19.54 (CH 3 ); 17.98 (CH 3 ); 7.31 (CH 3 ); 6.95 (CH 3 ); 5.83 (CH 2 ); 4.56 (CH 2 ). IR(neat) (15r): 2954 (m); 2918 (m); 2877 (m); 1730 (w); 1671 (w); 1632 (w); 1461 (m); 1415 (m); 1379 (m); 1239 (m); 1095 (s); 1033 (s); 973 (m); 922 (m); 823 (m); 726 (s) cm -1 . MS (EI, 70eV): m/z (%): 116.02 (100), 58.54 (64), 86.32 (50), 300.21 (45), 436.80 (9), 313.7 (6). HRMS (ESI) m/z (15r): [M+H] + Calcd for C 24 H 53 O 4 Si 2 : 461.3482; found: 461.3445. General Data (14r): C 18 H 38 O 4 Si; FW: 346.25; TLC: R f = 0.3 (Pentane/Et 2 O 3:1); UV (-); Vanillin: dark blue; = -69.0 (c = 0.8, CHCl 3 ). 1 H-NMR (12r) (400 MHz, CDCl 3 ): δ (ppm): 5.64-5.54 (m, 1H, CH=CH); 5.31 (m, 1H, CH=CH); 4.62 (d, J = 6.5 Hz, 1H, 1OCH 2 OCH 3 ); 4.43 (d, J = 6.5 Hz, 1H, 1OCH 2 OCH 3 ); 3.87 (dd, J = 8.7, 2.4 Hz, 1H, CHOSi); 3.81 (d, J = 8.5 Hz, 1H, CHOCH 2 OCH 3 ); 3.79-3.72 (m, 1H, 1CH 2 OSi); 3.71-3.62 (m, 1H, 1CH2OSi); 3.33 (s, 3H, OCH 3 ); 1.95-1.84 (m, 1H, 1CH2CH2O); 1.71 (dd, J = 6.4, 1.5 Hz, 3H, CHCH 3 ); 1.67-1.57 (m, 1H, 1CH2CH2O); 1.00-0.932 (m, 9H, OSi(CH 2 CH 3 ) 3 ); 0.923 (s, 3H, 1CCH3); 0.736 (s, 3H, 1CCH3); 0.678-0.583 (m, 6H, OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (12r) (100 MHz, CDCl 3 ): δ (ppm): 131.02 (CH); 127.85 (CH); 93.71 (CH 2 ); 81.89 (CH); 74.64 (CH); 61.02 (CH 2 ); 55.85 (CH 3 ); 42.23 (C); 35.43 (CH 2 ); 20.25 (CH 3 ); 19.24 (CH3); 17.96 (CH 3 ); 7.25 (CH 3 ); 5.74 (CH 2 ). IR(neat) (12r): 3386 (br); 2954 (m); 2877 (m); 1669 (w); 1465 (m); 1415 (m); 1382 (m); 1238 (m); 1146 (m); 1091 (m); 1033 (s); 972 (m); 921 (m); 840 (m); 727 (s) cm -1 . MS (ESI): m/z (%): 347.26 (100) [M+H] + , 317.25 (31), 348.26 (28), 369.24 (16) [M+Na] + , 285.22 (7). HR-MS (ESI): calculated for C 18 H 39 O 4 Si [M+H] + : 347.2618, found: 347.2620, 369.2435 [M+Na] + . Example 44: (3S,5R,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl) oxy)oct-6- enal (16r) DMSO (0.780 mL, 11 mmol, 2 eq) in CH 2 Cl 2 (5 mL) was added dropwise to a solution of oxalyl chloride (0.644 mL, 7.5 mmol, 1.5 eq) in CH 2 Cl 2 (20 mL) at - 78°C. The mixture was stirred for 10 min at -78°C and then the crude 15r + 14r dissolved in CH 2 Cl 2 (5 mL) was added dropwise. The reaction was stirred for 1 h at -78°C, quenched by dropwise addition of NEt 3 (3.5 mL, 25 mmol, 5 eq) and then warmed to room temperature over 45 min. H 2 O (30 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x20 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Pen/Et2O 10:1) afforded aldehyde 16r (1.33 g, 3.86 mmol, 77% from 13r) as a colorless liquid. General Data: C 18 H 36 O 4 Si; FW: 344.24; TLC: R f = 0.3 (Pentane/Et 2 O 10:1); UV (-); Vanillin: grey; = -54.87 (c = 0.8, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 9.84 (dd, J = 3.0, 1.2 Hz, 1H, CHO); 5.66-5.56 (m, 1H, CH=CH); 5.35-5.25 (m, 1H, CH=CH); 4.64 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.41 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.31 (dd, J = 7.2, 3.7 Hz, 1H, CHOSi); 3.78 (d, J = 8.7 Hz, 1H, CHOCH 2 OCH 3 ); 3.33 (s, 3H, OCH 3 ); 2.75 (ddd, J = 16.7, 3.7, 1.3 Hz, 1H, 1CH 2 CO); 2.58 (ddd, J = 16.7, 7.2, 3.0 Hz, 1H, 1CH 2 CO); 1.72 (dd, J = 6.5, 1.6 Hz, 3H, CHCH 3 ); 0.973 (s, 3H, 1CCH 3 ); 0.986-0.912 (m, 9H, OSi(CH 2 CH 3 )3); 0.777 (s, 3H, 1CCH 3 ); 0.651-0.545 (m, 6H, OSi(CH 2 CH 3 )3). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 202.90 (C=O); 131.62 (CH); 127.42 (CH); 93.43 (CH 2 ); 81.50 (CH); 72.15 (CH); 56.10 (CH 3 ); 47.95 (CH 2 ); 42.27 (C); 20.19 (CH 3 ); 19.89 (CH 3 ); 17.97 (CH 3 ); 7.14 (CH 3 ); 5.50 (CH 2 ). IR(neat): 3017 (w); 2952 (m); 2877 (m); 2716 (w); 1727 (s); 1464 (m); 1381 (w); 1238 (w); 1096 (s); 1074 (s); 1030 (s); 972 (m); 921 (m); 823 (m); 726 (s) cm -1 . MS (ESI): m/z (%): 362.27 (100) [M+Na] + , 367.22 (76), 345.24 (28) [M+H] + , 369.24 (16), 285.22 (7). HR-MS (ESI): calculated for C 18 H 36 O 4 Si [M+H] + : 345.2461, found: 345.2460, 362.2727 [M+NH 4 ] + . Example 45: (5R,7S)-9,9-diethyl-7-((Z)-3-iodoallyl)-6,6-dimethyl-5-((E)- prop-1-en-1- yl)-2,4,8-trioxa-9-silaundecane (17r) NaHMDS (1 M in THF, 4.2 mL, 4.2 mmol, 1.5 eq) was added dropwise at 0°C to a solution of IMePPh3I (2.22 g, 4.2 mmol, 1.5 eq) in THF (30 mL). The red solution was stirred for 10 min at room temperature and then cooled to -78°C. DMPU (2.5 mL, 20.93 mmol, 7.5 eq) was added dropwise, followed by alde- hyde 16r (960 mg, 2.79 mmol, 1 eq) in THF (7 mL). The mixture was stirred for 1 h at -78°C and 30 min at room temperature. Saturated NH 4 Cl solution was added and the aqueous phase was extracted with Et 2 O (3x25 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Pen/Et 2 O 100:1) giving the Z Iodide 17r (875 mg, 1.87 mmol, 67%) as a slightly yellow liquid. General Data: C 19 H 37 IO 3 Si; FW: 468.16; TLC: R f = 0.25 (Pentane/Et 2 O 100:1); UV (-); Vanillin: black; = -30.133 (c = 0.75, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 6.36 (q, J = 7.3 Hz, 1H, CH=CHI); 6.21 (dt, J = 7.4, 1.7 Hz, 1H, CH=CHI); 5.69-5.58 (m, 1H, CH=CH); 5.33 (m, 1H, CH=CH); 4.68 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.45 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 3.90-3.84 (m, 2H, 2CHOR); 3.36 (s, 3H, OCH 3 ); 2.44-2.38 (m, 2H, CH 2 CH); 1.73 (dd, J = 6.5, 1.6 Hz, 3H, CHCH 3 ); 1.02-0.922 (m, 9H, OSi(CH 2 CH 3 )3); 0.944 (s, 3H, 1CCH 3 ); 0.769 (s, 3H, 1CCH 3 ); 0.658-0.559 (m, 6H, OSi(CH 2 CH 3 )3). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 140.30 (CH); 131.17 (CH); 127.88 (CH); 93.59 (CH 2 ); 82.72 (CH); 81.56 (CH); 75.77 (CH); 56.04 (CH 3 ); 42.81 (C); 38.76 (CH 2 ); 20.32 (CH 3 ); 19.75 (CH 3 ); 17.99 (CH 3 ); 7.27 (CH 3 ); 5.72 (CH 2 ). IR(neat): 3016 (w); 2919 (m); 2876 (m); 1665 (w); 1465 (m); 1415 (m); 1381 (w); 1238 (m); 1093 (s); 1033 (s); 972 (m); 922 (m); 822 (w); 724 (s) cm-1. MS (ESI): m/z (%): 506.53 (100), 507.53 (45), 504.51 (22), 469.16 (8) [M+H]+, 457.16 (5), 396.31 (4). HR-MS (ESI): calculated for C 19 H 38 IO 3 Si [M+H]+: 469.1635, found: 469.1631. Example 46: Methyl 2-((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1- yl)oxazole-4-carboxylate (40r) The vinyl iodide 17r (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl 2 (PPh 3 ) 2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -10°C. NEt 3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29r (240 mg, 1.02 mmol, 1.2 eq) in degassed CH 3 CN (3 mL). The solution became red and af- ter 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH 4 Cl solution (10 mL). The aqueous phase was extracted with Et 2 O (3x10 mL) and the combined or- ganic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et 2 O 2:1) to give the monomer 40r (448 mg, 0.779 mmol, 92 %) as a slightly yellow oil. General Data: C31H 4 9NO7Si; FW: 575.33; TLC: R f = 0.20 (pentane/Et 2 O 2:1); UV (+); Vanillin: black; = -13.00 (c = 0.8, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.15 (s, 1H, NC=CH); 6.14-6.05 (m, 1H, CH 2 CH=CH); 5.99 (dd, J = 15.8, 7.4 Hz, 1H, CCH=CHCH); 5.88 (dd, J = 15.9, 2.1 Hz, 1H, CCH=CHCH 2 ); 5.66- 5.54 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.36-5.27 (m, 1H, CH=CHCH 3 ); 4.66 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.43 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.20-4.13 (m, 1H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.89 (app t, J = 6.2 Hz, 1H, CHOCH 2 OCH 3 ); 3.82 (t, J = 5.3 Hz, 1H, CH 2 CHOTES); 3.33 (s, 3H, CHOCH 3 ); 3.26 (s, 3H, CHOCH 2 OCH 3 ); 3.10 (dd, J = 15.0, 7.9 Hz, 1H, 1CH 2 CHOCH 3 ); 2.98 (dd, J = 15.0, 5.5 Hz, 1H, 1CH 2 CHOCH 3 ); 2.62-2.54 (m, 2H, CH 2 CH=CH); 1.71 (dd, J = 6.4, 1.5 Hz, 3H, CH=CHCH 3 ); 0.957 (app t, J = 8.0 Hz, 9H, OSi(CH 2 CH 3 ) 3 ); 0.938 (s, 3H, CCH 3 ); 0.765 (s, 3H, CCH 3 ); 0.600 (q, J = 7.8 Hz, 6H, OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 162.61 (C=O); 161.79 (C=N); 144.11 (CH); 143.47 (CH); 140.30 (CH); 133.50 (C); 130.96 (CH); 128.03 (CH); 113.98 (CH); 109.39 (CH); 93.56 (CH 2 ); 91.27 (C); 88.53 (C); 81.48 (CH); 79.42 (CH); 76.51 (CH); 56.92 (CH3); 55.92 (CH3); 52.26 (CH3); 42.87 (C); 34.74 (CH 2 ); 34.40 (CH 2 ); 20.22 (CH 3 ); 19.67 (CH 3 ); 17.98 (CH 3 ); 7.25 (CH 3 ); 5.72 (CH 2 ). IR(neat): 3237 (m); 2954 (m); 2878 (m); 1750 (m); 1583 (m); 1536 (m); 1397 (s); 1238 (m); 1140 (m); 1093 (s); 1033 (s); 1006 (s); 956 (m); 922 (m); 725 (m); 670 (m); 609 (w) cm -1 . MS (ESI): m/z (%): 593.36 (100) [M+NH 4 ] + , 418.20 (54), 514.30 (48), 350.17 (8), 482.27 (6), 576.33 (2) [M+H]+. HR-MS (ESI): calculated for C31H50NO7Si [M+H] + : 576.3357, found: 576.3365, 593.3646 [M+NH 4 ] + . Example 47: Methyl 2-((2R,3E,7Z,10S,12R,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11- dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylate (31r)

CSA (13 mg, 0.0521 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 40r (150 mg, 0.261 mmol, 1 eq) in CH 2 Cl 2 (7 mL) and MeOH (7 mL). The mixture was stirred for 1 h at 0°C under normal atmos- phere. Saturated aqueous NaHCO 3 solution (15 mL) was added and the lay- ers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et 2 O/pentane 2:1) giving deprotected monomer 31r (102 mg, 0.222 mmol, 85%) as a slightly yellow oil. General Data: C 25 H 35 NO 7 ; FW: 461.24; TLC: R f = 0.25 (Et 2 O/Pentane 2:1); UV (+); Vanillin: black; = -81.07 (c = 0.75, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.15 (s, 1H, NC=CH); 6.19-6.08 (m, 1H, CH 2 CH=CH); 5.96 (dd, J = 15.8, 7.3 Hz, 1H, CCH=CHCH); 5.86 (dd, J = 15.9, 2.0 Hz, 1H, CCH=CHCH 2 ); 5.73- 5.61 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.37-5.27 (m, 1H, CH=CHCH 3 ); 4.71 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.46 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.21-4.11 (m, 1H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.89 (app dd, J = 6.7, 2.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.62 (dd, J = 10.1, 2.8 Hz, 1H, CH 2 CHOH); 3.37 (s, 3H, CHOCH 3 ); 3.26 (s, 3H, CHOCH 2 OCH 3 ); 3.10 (dd, J = 14.9, 7.8 Hz, 1H, 1CH 2 CHOCH 3 ); 2.99 (dd, J = 14.9, 5.6 Hz, 1H, 1CH 2 CHOCH 3 ); 2.61- 2.50 (m, 1H, 1CH 2 CH=CH); 2.43-2.33 (m, 1H, 1CH 2 CH=CH); 1.74 (dd, J = 6.5, 1.7 Hz, 3H, CH=CHCH 3 ); 0.973 (s, 3H, CCH 3 ); 0.807 (s, 3H, CCH 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 162.54 (C=O); 161.76 (C=N); 144.12 (CH); 142.67 (CH); 140.41 (CH); 133.49 (C); 132.47 (CH); 127.08 (CH); 113.88 (CH); 110.26 (CH); 93.21 (CH 2 ); 91.23 (C); 88.17 (C); 84.83 (CH); 79.37 (CH); 77.97 (CH); 56.96 (CH 3 ); 56.15 (CH 3 ); 52.26 (CH 3 ); 41.23 (C); 34.70 (CH 2 ); 33.04 (CH 2 ); 21.50 (CH 3 ); 17.98 (CH 3 ); 16.20 (CH 3 ). IR(neat): 3489 (br); 3159 (w); 3020 (m); 2937 (m); 2826 (w); 2246 (w); 1737 (m); 1585 (m); 1438 (m); 1322 (m); 1221 (m); 1167 (m); 1098 (s); 1032 (s); 913 (s); 806 (m); 730 (s); 646 (m); 542 (w) cm -1 . MS (ESI): m/z (%): 304.11 (100), 479.27 (80) [M+NH 4 ] + , 272.09 (77), 400.21 (48), 430.22 (30), 462.24 (28) [M+H] + , 368.18 (27), 209.13 (3). HR-MS (ESI): calculated for C 25 H 36 NO 7 [M+H] + : 462.2492, found: 462.2482, 479.2748 [M+NH 4 ] + . Example 48: 2-((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)-11,1 1-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole -4-car- boxylic acid (42r) 31r (150 mg, 0.261 mmol, 1 eq) was dissolved in THF (5 mL) and treated at r oom temperature with LiOH (1 M in H 2 O, 0.783 mL, 0.783 mmol, 3 eq). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et 2 O (3x3 mL) and the or- ganic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give acid 42r (146 mg, 0.259 mmol, 99%) as a slightly yellow oil, which was used for the next step without further purification. General Data: C 30 H 47 NO 7 Si; FW: 561.31; TLC: UV (+); Vanillin: black. 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.23 (s, 1H, NC=CH); 6.16-6.07 (m, 1H, CH 2 CH=CH); 6.00 (dd, J = 15.7, 7.4 Hz, 1H, CCH=CHCH); 5.89 (dd, J = 15.8, 1.9 Hz, 1H, CCH=CHCH 2 ); 5.64- 5.56 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.35-5.29 (m, 1H, CH=CHCH 3 ); 4.67 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.44 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.20-4.15 (m, 1H, CHOCH 3 ); 3.89 (d, J = 8.9 Hz, 1H, CHOCH 2 OCH 3 ); 3.82 (t, J = 5.2 Hz, 1H, CHOTES); 3.35 (s, 3H, CHOCH 3 ); 3.28 (s, 3H, CHOCH 2 OCH 3 ); 3.12 (dd, J = 15.0, 7.8 Hz, 1H, 1CH 2 CHOCH 3 ); 3.02 (dd, J = 15.1, 5.6 Hz, 1H, 1CH 2 CHOCH 3 ); 2.62-2.54 (m, 2H, 1CH 2 CH=CH); 1.72 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH 3 ); 0.959 (t, J = 8.0 Hz, 9H, OSi(CH 2 CH 3 ) 3 ); 0.943 (s, 3H, CCH 3 ); 0.771 (s, 3H, CCH 3 ); 0.604 (q, J = 7.9 Hz, 6H, OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 164.0 (C=O); 162.8 (C=N); 144.9 (CH); 143.5 (CH); 140.1 (CH); 132.9 (C); 131.0 (CH); 128.0 (CH); 114.1 (CH); 109.4 (CH); 93.5 (CH 2 ); 91.2 (C); 88.6 (C); 81.6 (CH); 79.3 (CH); 76.6 (CH); 56.9 (CH 3 ); 55.9 (CH 3 ); 42.9 (C); 34.4 (CH 2 ); 30.5 (CH 2 ); 20.3 (CH 3 ); 19.7 (CH 3 ); 18.0 (CH 3 ); 7.3 (CH 3 ); 5.7 (CH 2 ). IR(neat): 3026 (w); 2934 (br); 2876 (m); 1723 (m); 1586 (m); 1463 (m); 1360 (w); 1214 (w); 1143 (m); 1095 (s); 1033 (s); 973 (m); 921 (m); 766 (m); 6728 (s); 546 (w) cm -1 . MS (ESI): m/z (%): 404.18 (100), 579.34 (78) [M+NH 4 ] + , 500.28 (51), 372.16 (27), 468.25 (10), 336.15 (8), 562.32 (3) [M+H] + . HR-MS (ESI): calculated for C 30 H 48 NO 7 Si [M+H]+: 562.3200, found: 562.3199, 579.3453 [M+NH 4 ] + . Example 49: (2E,4R,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxaz ol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6- yl 2- ((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)-11,11- dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole -4-car- boxylate (43r)

The crude acid 42r (91 mg, 0.162 mmol, 1.5 eq) was dissolved in THF (5 mL) treated at room temperature with NEt3 (90 µL, 0.648 mmol, 6 eq) and 2,4,6- trichlorobenzoyl chloride (68 µL,0.432 mmol, 4 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of alcohol 31r (50 mg, 0.108 mmol, 1 eq) and DMAP (79 mg, 0.648 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH 4 Cl solution (15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et 2 O/pentane 2:1) to afford the dimer 43r (81 mg, 0.0813 mmol, 75%) as a slightly yellow oil. General Data: C 55 H 80 N 2 O 13 Si; FW: 1004.54; TLC: R f = 0.30 (Et 2 O/pentane 2:1); UV (+); Vanillin: black. 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.18 (s, 1H, NC=CH); 8.07 (s, 1H, NC=CH); 6.15-6.05 (m, 1H, CH 2 CH=CH); 6.05-5.84 (m, 5H, CH=CH); 5.66- 5.53 (m, 4H, CH=CH); 5.38-5.29 (m, 2H, CH=CH); 5.28 (app dd, J = 5.3, 1.7 Hz, 1H, CHOC=O); 4.68 (dd, J = 7.0, 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.45 (dd, J = 6.9, 4.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.24-4.14 (m, 2H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.89 (app d, J = 7.8 Hz, 1H, CH 2 CHOTES); 3.82 (m, 2H, CHOCH 2 OCH 3 ); 3.38 (s, 3H, CHOCH 3 ); 3.34 (s, 3H, CHOCH 3 ); 3.29 (s, 3H, CHOCH 2 OCH 3 ); 3.28 (s, 3H, CHOCH 2 OCH 3 ); 3.17-2.98 (m, 4H, CH 2 CHOCH 3 ); 2.76-2.69 (m, 2H, CH 2 CH=CH); 2.62-2.56 (m, 2H, CH 2 CH=CH); 1.71 (dd, J = 6.4, 1.3 Hz, 6H, CH=CHCH 3 ); 1.02 (s, 3H, CCH 3 ); 0.977 (s, 3H, CCH 3 ); 0.951 (app t, J = 5.6 Hz, 9H, OSi(CH 2 CH 3 ) 3 ); 0.938 (s, 3H, CCH 3 ); 0.771 (s, 3H, CCH 3 ); 0.602 (q, J = 7.7 Hz, 6H, OSi(CH 2 CH 3 ) 3 ). IR(neat): 2953 (m); 2879 (m); 2284 (w); 1737 (m); 1583 (m); 1439 (m); 1318 (m); 1168 (m); 1099 (s); 1033 (s); 911 (s); 807 (m); 728 (s); 647 (m); 551 (w) cm -1 . MS (ESI): m/z (%): 1005.55 (100) [M+H] + , 1022.56 (760) [M+NH 4 ] + , 943.52 (45), 973.53 (28), 847.43 (8). HRMS (ESI) m/z: [M+H] + Calcd for C 55 H 81 N 2 O 13 Si: 1005.5508; found: 1005.5594. Example 50: (16,16’)-(4R-bis(methoxymethyl))-(9,10,9’,10’)-tetrade hydridodisorazole C1 (35r) CSA (3 mg, 0.0132 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 43r (67 mg, 0.0661 mmol, 1 eq) in CH 2 Cl 2 (2 mL) and MeOH (2 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO 3 solution (10 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo giving the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C 49 H 66 N 2 O 13 ; FW: 890.46; TLC: R f = 0.20 (CH 2 Cl 2 /MeOH 100:1); UV (+); Vanillin: black; = -22.83 (c = 0.6, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.17 (s, 1H, NC=CH); 8.05 (s, 1H, NC=CH); 6.19-6.09 (m, 1H, CH 2 CH=CH); 6.03-5.83 (m, 5H, CH=CH); 5.70- 5.51 (m, 4H, CH=CH); 5.37-5.25 (m, 2H, CH=CH); 5.28 (app dd, J = 5.3, 1.7 Hz, 1H, CHOC=O); 4.70 (dd, J = 15.0, 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.45 (t, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.22-4.13 (m, 2H, CHOCH 3 ); 3.90 (s, 3H, COOCH 3 ); 3.89 (app d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.82 (d, J = 8.7 Hz, 1H, CHOCH 2 OCH 3 ); 3.62 (dt, J = 10.0, 2.7 Hz, 1H, CHOH); 3.37 (s, 6H, CHOCH 3 ); 3.28 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.15-2.96 (m, 4H, CH 2 CHOCH 3 ); 2.78-2.64 (m, 2H, CH 2 CH=CH); 2.61-2.51 (m, 1H, 1CH 2 CH=CH); 2.45-2.33 (m, 1H, 1CH 2 CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH 3 ); 1.71 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH 3 ); 1.02 (s, 3H, CCH 3 ); 0.977 (s, 3H, CCH 3 ); 0.944 (s, 3H, CCH 3 ); 0.813 (s, 3H, CCH 3 ). 13 C-NMR (151 MHz, CDCl3): δ (ppm): 162.59 (C=O); 162.50 (C=O); 161.76 (C=N); 160.77 (C=N); 144.17 (CH); 143.64 (CH); 142.65 (CH); 140.62 (CH); 140.55 (CH); 133.55 (C); 133.49 (C); 132.52 (CH); 132.32 (CH); 127.06 (CH); 126.90 (CH); 125.65 (CH); 113.81 (CH); 113.75 (CH); 111.23 (CH); 110.27 (CH); 93.48 (CH 2 ); 93.19 (CH 2 ); 91.41 (C); 91.30 (C); 88.13 (C); 88.09 (C); 84.86 (CH); 81.50 (CH); 79.33 (CH); 78.00 (CH); 77.37 (CH); 57.01 (CH 3 ); 56.99 (CH 3 ); 56.16 (CH 3 ); 52.28 (CH 3 ); 41.76 (C); 41.22 (C); 34.69 (CH 2 ); 34.09 (CH 2 ); 33.03 (CH 2 ); 31.21 (CH 2 ); 21.53 (CH 3 ); 20.07 (CH 3 ); 19.60 (CH 3 ); 18.07 (CH 3 ); 18.00 (CH 3 ); 16.17 (CH 3 ). IR(neat): 3327 (br); 3165 (w); 2928 (m); 2853 (m); 1736 (s); 1583 (m); 1439 (m); 1370 (m); 1314 (m); 1241 (m); 1143 (m); 1099 (s); 1031 (s); 972 (m); 920 (m); 883 (w); 762 (m); 724 (m); 542 (m) cm -1 . MS (ESI): m/z (%): 908.49 (100) [M+NH 4 ] + , 891.46 (83) [M+H] + , 733.33 (41), 797.40 (25), 671.29 (7). HR-MS (ESI): calculated for C 49 H 67 N 2 O 13 [M+H] + : 891.4643, found: 891.4648, 908.4911 [M+NH 4 ] + . The crude deprotected alcohol was dissolved in THF (1.5 mL) and treated at room temperature with LiOH (1 M in H 2 O, 0.165 mL, 0.165 mmol, 2.5 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (1 mL). The aqueous phase was extracted with Et 2 O (3x3 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purifi- cation. General Data: C 48 H 64 N 2 O 13 ; FW: 876.44; TLC: UV (+); Vanillin: grey; -26.4 (c = 0.5,CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.20 (s, 1H, NC=CH); 8.10 (s, 1H, NC=CH); 6.18-6.09 (m, 1H, CH 2 CH=CH); 6.04-5.80 (m, 5H, CH=CH); 5.73- 5.52 (m, 4H, CH=CH); 5.38-5.26 (m, 3H, CH=CH, CHOC=O); 4.71 (dd, J = 13.5, 6.8 Hz, 1H, 1OCH 2 OCH 3 ); 4.46 (dd, J = 6.7, 3.8 Hz, 1H, 1OCH 2 OCH 3 ); 4.24-4.13 (m, 2H, CHOCH 3 ); 3.90 (d, J = 9.1 Hz, 1H, CHOCH 2 OCH 3 ); 3.83 (d, J = 8.7 Hz, 1H, CHOCH 2 OCH 3 ); 3.64 (dd, J = 9.8, 2.8 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH 3 ); 3.38 (s, 3H, CHOCH 3 ); 3.30 (s, 3H, CHOCH 2 OCH 3 ); 3.28 (s, 3H, CHOCH 2 OCH 3 ); 3.18-2.94 (m, 4H, CH 2 CHOCH 3 ); 2.82-2.51 (m, 3H, 3CH 2 CH=CH); 2.47-2.33 (m, 1H, 1CH 2 CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH 3 ); 1.71 (dd, J = 6.4, 1.3 Hz, 3H, CH=CHCH 3 ); 1.03 (s, 3H, CCH 3 ); 0.983 (s, 3H, CCH 3 ); 0.950 (s, 3H, CCH 3 ); 0.815 (s, 3H, CCH 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.56 (C=O); 162.23 (C=O); 160.74 (C=N); 157.69 (C=N); 144.49 (CH); 143.88 (CH); 142.58 (CH); 140.58 (CH); 140.50 (CH); 133.60 (C); 133.47 (C); 132.61 (CH); 132.36 (CH); 126.99 (CH); 126.84 (CH); 125.65 (CH); 113.86 (CH); 113.78 (CH); 111.38 (CH); 110.33 (CH); 93.53 (CH 3 ); 93.17 (CH 3 ); 91.38 (C); 91.33 (C); 88.14 (C); 88.05 (C); 84.91 (CH); 81.67 (CH); 79.46 (CH); 79.28 (CH); 78.12 (CH); 77.36 (CH); 56.99 (CH 3 ); 56.98 (CH 3 ); 56.16 (CH 3 ); 56.13 (CH 3 ); 41.77 (C); 41.21 (C); 34.64 (CH 2 ); 33.01 (CH 2 ); 31.28 (CH 2 ); 29.84 (CH 2 ); 21.56 (CH 3 ); 20.02 (CH 3 ); 19.50 (CH 3 ); 18.09 (CH 3 ); 18.01 (CH 3 ); 16.16 (CH 3 ). IR(neat): 3323 (br); 2929 (m); 2851 (m); 2249 (w); 1731 (m); 1583 (m); 1438 (m); 1364 (m); 1310 (m); 1143 (m); 1100 (s); 1030 (s); 972 (m); 910 (m); 837 (w); 730 (s); 646 (m) cm -1 . MS (ESI): m/z (%): 877.44 (100) [M+H] + , 894.47 (77) [M+NH 4 ] + , 845.42 (49), 719.31 (30), 783.38 (23). HR-MS (ESI): calculated for C 48 H 65 N 2 O 13 [M+H]+: 877.4487, found: 877.4478, 894.4744 [M+NH 4 ] + . The crude seco-acid was dissolved in THF (5 mL) and treated at room tem- perature with NEt 3 (184 µL, 1.32 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chloride (103 µL, 0.661 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of DMAP (323 mg, 2.64 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quen- ched with saturated aqueous NH 4 Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the macrocycle 35r (40 mg, 0.0462 mmol, 70% from 43r) as a slightly yellow oil. General Data: C 48 H 62 N 2 O 12 ; FW: 858.43; TLC: R f = 0.50 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: black; = +53.7 (c = 1.00, CHCl 3 ). 1H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.04 (s, 2H, NC=CH); 6.03-5.88 (m, 4H, CH=CH); 5.70-5.47 (m, 6H, CH=CH); 5.44-5.23 (m, 2H, CH=CH); 5.40 (dd, J = 11.2, 2.4 Hz, 2H, CHOC=O); 4.69 (d, J = 7.0 Hz, 1H, 1OCH 2 OCH 3 ); 4.45 (d, J = 7.0 Hz, 1H, 1OCH 2 OCH 3 ); 4.17-3.99 (m, 2H, CHOCH 3 ); 3.81 (d, J = 8.8 Hz, 2H, CHOCH 2 OCH 3 ); 3.38 (s, 6H, CHOCH 3 ); 3.36 (s, 6H, CHOCH 2 OCH 3 ); 3.34-3.25 (m, 2H, CH 2 CH=CH); 3.07-2.83 (m, 4H, CH 2 CHOCH 3 ); 2.53-2.43 (m, 2H, CH 2 CH=CH); 1.73 (dd, J = 6.3, 1.3 Hz, 6H, CH=CHCH 3 ); 1.03 (s, 6H, CCH 3 ); 0.962 (s, 6H, CCH 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 161.77 (C=O); 160.66 (C=N); 143.46 (CH); 141.27 (CH); 140.44 (CH); 133.74 (C); 132.51 (CH); 126.79 (CH); 113.64 (CH); 112.21 (CH); 93.51 (CH 2 ); 90.94 (C); 87.89 (C); 81.61 (CH); 79.71 (CH); 77.36 (CH); 56.99 (CH 3 ); 56.21 (CH 3 ); 41.57 (C); 34.51 (CH 2 ); 31.09 (CH 2 ); 19.99 (CH 3 ); 19.44 (CH 3 ); 18.08 (CH 3 ). IR(neat): 3168 (w); 2933 (m); 2855 (m); 2249 (w); 1736 (m); 1690 (m); 1582 (m); 1441 (m); 1365 (m); 1308 (m); 1141 (m); 1099 (s); 1028 (s); 988 (m); 914 (m); 805 (m); 730 (s) cm -1 . MS (ESI): m/z (%): 859.43 (100) [M+H] + , 876.46 (32) [M+NH 4 ] + , 797.40 (20), 735.36 (3). HR-MS (ESI): calculated for C 48 H 65 N 2 O 13 [M+H] + : 859.4381, found: 859.4366, 876.4633 [M+NH 4 ] + . Example 51 (16,16’)-(4R-bis(methoxymethyl))-disorazole C1 (36r)

Nitrogen was bubbled for 15 min through a suspension of Zinc (3 g, 45.88 mmol) in H 2 O (18 mL) and then Cu(OAc) 2 ·H 2 O (300 mg, 1.50 mmol) was ad- ded at room temperature and after 15 min AgNO 3 (300 mg, 1.77 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room tem- perature, filtered by suction and washed with H 2 O (30 mL), MeOH (20 mL), acetone (20 mL) and Et 2 O (20 mL). This activated zinc solids were added to a solution of 35r (20 mg, 0.0233 mmol) in MeOH/H2O 1:1 (5 mL). The mix- ture was stirred for 24 h at 50°C and then filtered on a pad of silica and washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (CH 2 Cl 2 /MeOH 60:1) to afford 36r (13 mg, 0.0151, 65%) as a colorless oil. General Data: C 48 H 66 N 2 O 12 ; FW: 862.46; TLC: Rf= 0.40 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: dark green; = -43.3 (c = 0.35, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 7.89 (s, 2H, NC=CH); 6.44 (dd, J = 15.2, 11.3 Hz, 2H, CH(OCH 3 )CH=CH); 6.34 (app t, J = 11.3 Hz, 2H, CH2CH=CH); 6.21 (dd, J = 11.5, 11.0 Hz, 2H, CHCH=CHCH); 5.90 (dd, J = 11.2, 11.0 Hz, 2H, CHCH=CHCH); 5.61 (dd, J = 15.4, 6.5 Hz, 2H, CH 3 CH=CH); 5.54 (dd, J = 15.1, 8.6 Hz, 2H, CH 3 CH=CH); 5.38 (dd, J = 10.8, 2.5 Hz, 2H, CHOC=O); 5.32 (dd, J = 8.8, 1.7 Hz, 2H, CH(OCH 3 )CH=CH); 5.29 (dd, J = 8.6, 1.5 Hz, 2H, CH2CH=CH); 4.68 (d, J = 6.9 Hz, 1H, 1OCH 2 OCH 3 ); 4.43 (d, J = 6.9 Hz, 1H, 1OCH 2 OCH 3 ); 4.15-4.10 (app q, J = 14.9, 6.7 Hz, 2H, CHOCH 3 ); 3.81 (d, J = 8.7 Hz, 2H, CHOH); 3.36 (s, 6H, CHOCH 2 OCH 3 ); 3.26 (s, 6H, CHOCH 3 ); 3.12 (dd, J = 14.8, 6.0 Hz, 2H, CH 2 CHOCH 3 ); 2.78 (dd, J = 14.8, 7.2 Hz, 2H, CH 2 CHOCH 3 ); 2.63-2.50 (m, 4H, CH 2 CH=CH); 1.73 (dd, J = 6.5, 1.3 Hz, 3H, CH=CHCH 3 ); 0.984 (s, 6H, CCH 3 ); 0.919 (s, 6H, CCH 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 162.36 (C=O); 160.73 (C=N); 143.34 (CH); 133.47 (C); 133.18 (CH); 132.41 (CH); 130.27 (CH); 129.11 (CH); 128.09 (CH); 126.87 (CH); 125.73 (CH);125.68 (CH); 93.40 (CH 2 ); 81.44 (CH); 79.94 (CH); 77.58 (CH); 56.69 (CH 3 ); 56.27 (CH 3 ); 41.59 (C); 35.21 (CH 2 ); 28.07 (CH 2 ); 20.10 (CH 3 ); 19.60 (CH 3 ); 18.09 (CH 3 ). MS (ESI): m/z (%): 861.46 (100) [M+H] + , 282.28 (70), 880.49 (32) [M+NH 4 ] + . HR-MS (ESI): calculated for C 48 H 67 N 2 O 12 [M+H]+: 863.4694, found 863.4672, 880.4945 [M+NH4]+. Example 52: (4R)-Disorazole C1 (31r) MOM protected 36r (16 mg, 18.45 µmol) was dissolved in CH 3 CN (2 mL) and cooled to 0°C.3 drops of HBr (48% in H 2 O) were slowly added and then the mixture was stirred for 1 h at 0°C. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO 3 solution (5 mL). The aqueous phase was extracted with EtOAc (3x5 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was puri- fied by flash chromatography (CH 2 Cl 2 /MeOH 50:1) to give (4R)-Disorazole C 1 31r (8 mg, 12.9, 10.33µmol, 56%) as a colorless wax. General Data: C 44 H 58 N 2 O 10 ; FW: 774.41; TLC: R f = 0.20 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: dark green; = -128.00 (c = 0.1, MeOH). 1 H-NMR (600 MHz, CD 3 OD): δ (ppm): 8.23 (s, 2H, NC=CH); 6.51 (dd, J = 14.9, 11.3 Hz, 2H, CH(OCH 3 )CH=CH); 6.41 (app t, J = 11.2 Hz, 2H, CH2CH=CH); 6.29 (dd, J = 11.3, 11.1 Hz, 2H, CHCH=CHCH); 5.91 (dd, J = 11.3, 11.0 Hz, 2H, CHCH=CHCH); 5.64 (dq, J = 15.1, 6.3 Hz, 2H, CH 3 CH=CH); 5.57 (ddd, J = 15.4, 7.6, 1.5 Hz, 2H, CH 3 CH=CH); 5.53 (dd, J = 15.1, 8.3 Hz, 2H, CH(OCH 3 )CH=CH); 5.48 (app dt, J = 10.0, 6.7 Hz, 2H, CH2CH=CH); 5.29 (dd, J = 11.3, 2.1 Hz, 2H, CHOC=O); 4.13 (ddd, J = 7.9, 7.2, 5.1 Hz, 2H, CHOCH 3 ); 3.91 (d, J = 7.3 Hz, 2H, CHOH); 3.21 (s, 6H, CHOCH 3 ); 2.99 (dd, J = 15.5, 7.3 Hz, 2H, CH 2 CHOCH 3 ); 2.75 (dd, J = 15.6, 5.0 Hz, 2H, CH 2 CHOCH 3 ); 2.71 (ddd, J = 13.8, 10.9, 10.1 Hz, 2H, CH 2 CH=CH); 2.45 (dd, J = 13.1, 6.1 Hz, 2H, CH 2 CH=CH); 1.71 (dd, J = 6.1, 1.1 Hz, 6H, CH=CHCH 3 ); 0.991 (s, 6H, CCH 3 ); 0.953 (s, 6H, CCH 3 ). 13 C-NMR (151 MHz, CD 3 OD): δ (ppm): 164.13 (C=O); 162.25 (C=N); 145.79 (CH); 134.07 (C); 134.05 (CH); 131.49 (CH); 131.04 (CH); 129.98 (CH); 129.55 (CH); 129.20 (CH); 127.42 (CH); 126.89 (CH); 80.45 (CH); 79.19 (CH); 78.00 (CH); 56.82 (CH 3 ); 42.74 (C); 36.02 (CH 2 ); 29.16 (CH 2 ); 19.71 (CH 3 ); 19.69 (CH 3 ); 18.02 (CH 3 ). MS (ESI): m/z (%): 775.41 (100) [M+H] + , 792.44 (48) [M+NH 4 ] + , 757.40 (11), 771.36 (8), 693.35 (4). HR-MS (ESI): calculated for C 44 H 59 N 2 O 10 [M+H]+: 775.4170, found 775.4175, 792.4445 [M+NH 4 ] +. The following Examples 53 to 63 disclose the synthesis of Bis(thiazolyl)-Diso- razole C1 (60t) . Example 53: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynamide (21t) Carboxylic acid 25 (2.3 g, 7.41 mmol, 1 eq) was dissolved in THF (40 mL), cooled to 0°C and ethyl chloroformate (0.917 mL, 9.63 mmol, 1.3 eq) was ad- ded dropwise, followed by NEt 3 (1.44 mL, 10.37 mmol, 1.4 eq). The mixture was stirred for 30 min at 0°C and then 25% aqueous NH 4 OH solution (3 mL) was added. The mixture was stirred for 30 min at 0°C and 1h at room tempe- rature. The solution was washed with H 2 O (30 mL) and the aqueous phase was extracted with EtOAc (3x25 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford the crude amide 50t as a yellow oil, which was used for the next step without further purification. General Data: C 17 H 31 NO 2 Si; FW: 309.21; TLC: R f = 0.2 (Et 2 O); UV (+); Vanil- lin: brown; = +24.4 (c = 0.75, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 6.01 (dd, J = 16.0, 7.4 Hz, 1H, CH=CH); 5.80 (dd, J = 15.9, 1.0 Hz, 1H, CH=CH); 4.06-4.01 (m, 1H, CHOCH 3 ); 3.33 (s, 3H, OCH 3 ); 2.49-2.44 (m, 2H, CH 2 CH); 1.07 (s, 21H, Si(CH(CH 3 ))3). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 173.4 (C=O); 141.4 (CH); 113.6 (CH); 104.1 (C); 93.0 (C); 78.3 (CH); 57.1 (CH 3 ); 41.8 (CH 2 ); 18.7 (CH 3 ); 11.4 (CH). IR(neat): 2921 (s); 3339 (br); 2942 (s); 2865 (s); 2134 (w); 1667 (s); 1462 (m); 1385 (m); 1241 (w); 1093 (s); 996 (m); 957 (m); 882 (s); 662 (s) cm -1 . MS (ESI): m/z (%): 278.19 (100), 332.20 (10) [M+Na] + ., 619.43 (8), 310.22 (4) [M+H] + . HRMS (ESI) m/z: [M+H] + Calcd for C 17 H 32 NO 2 Si: 310.2202; found: 310.2206. Example 53: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynethioamid e (51t) 51t Lawesson‘s reagent (2.1 g, 5.19 mmol, 0.7 eq) was added to a solution of crude 50t in THF (65 mL) and the mixture was stirred for 30 min at room temperature. The solution was washed with Brine (100 mL) and the aqueous phase was extracted with Et 2 O (3x70 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the residue by flash chromatography (hexane/EtOAc 4:1) afforded 51t (1.76 g, 5.41 mmol, 73%) as an orange oil. General Data: C 17 H 31 NOSSi; FW: 325.19; TLC: R f = 0.25 (pentane/Et 2 O 3:2); UV (+); = +7.0 (c = 1.0, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 6.00 (dd, J = 15.9, 7.2 Hz, 1H, CH=CH); 5.81 (dd, J = 15.9, 0.9 Hz, 1H, CH=CH); 4.11-4.03 (m, 1H, CHOCH 3 ); 3.34 (s, 3H, OCH 3 ); 2.97 (dd, J = 15.1, 3.1 Hz, 1H, 1CH 2 CH); 2.87 (dd, J = 15.1, 8.1 Hz, 1H, 1CH 2 CH); 1.07 (s, 21H, Si(CH(CH 3 ))3). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 206.3 (C=S); 140.8 (CH); 113.9 (CH); 104.0 (C); 93.2 (C); 80.4 (CH); 57.2 (CH 3 ); 50.4 (CH 2 ); 18.7 (CH 3 ); 11.4 (CH). IR(neat): 3658 (m); 3313 (m); 3173 (m); 2970 (s); 2865 (s); 2327 (w); 1626 (m); 1461 (m); 1384 (m); 1256 (m); 1073 (s); 951 (s); 882 (m); 664 (s) cm -1 . MS (ESI): m/z (%): 294.17 (100), 112.02 (9), 638.42 (23), 326.19 (7) [M+H] + ,250.10 (6). HRMS (ESI) m/z: [M+H] + Calcd for C 17 H 32 NOSSi: 326.1974; found: 326.1943. Example 55: Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)t hia- zole-4-carboxylate (52t) NaHCO 3 (2.3 g, 27.05 mmol, 5 eq) was added portionwise to a solution of 51t (1.76 g, 5.41 mmol, 1 eq) in THF (45 mL) at 0°C, followed by a dropwise addition of methyl bromopyruvate (1.73 mL, 16.23 mmol, 3 eq). The mixture was stirred for 1h at 0°C, then the reaction was cooled to -30°C and pyridine (3.06 mL, 37.87 mmol, 7 eq) and TFAA (3 mL, 21.64 mmol, 4 eq) were sequentially added dropwise. The mixture was stirred for 1h at -30°C and then qunched with Brine (50 mL). The layers were separated and the aqueous phase was extracted with Et 2 O (3x40 mL). The organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (hexane/EtOAc 5.1 to 4:1) to give thiazole 52t (1.83 g, 4.49 mmol, 83%) as a yellow oil. General Data: C 21 H 33 NO 3 SSi; FW: 407.20; TLC: Rf= 0.35 (pentane/Et 2 O 2:1); UV (+); Vanillin: brown; = +1.76 (c = 0.85, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.11 (s, 1H, C=CH); 6.04 (dd, J = 16.0, 7.2 Hz, 1H,CH=CH); 5.78 (dd, J = 16.0, 0.9 Hz, 1H, CH=CH); 4.02-3.92 (m, 1H, CHOCH 3 ); 3.97-3.88 (m, 1H, 1CH 2 CH); 3.95 (s, 3H, COOCH 3 ); 3.31 (s, 3H, CHOCH 3 ); 3.20 (dd, J = 15.0, 8.8 Hz, 1H, 1CH 2 CH); 1.08 (s, 21H, Si(CH(CH 3 )) 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 167.8 (C=O); 162.0 (C=N); 145.9 (C); 141.6 (CH); 128.5 (CH); 113.7 (CH); 104.2 (C); 93.0 (C); 80.3 (CH); 57.1 (CH 3 ); 52.6 (CH 3 ); 39.5 (CH 2 ); 18.7 (CH 3 ); 11.4 (CH). IR(neat): 3118 (w); 2926 (m); 2325 (m); 2130 (w); 1725 (s); 1462 (m); 1324 (m); 1238 (s); 1093 (s); 995 (m); 883 (m); 754 (m); 675 (s) cm -1 . MS (ESI): m/z (%): 376.18 (100), 408.21 (88) [M+H] + , 430.18 (22), 194.02 (6). HRMS (ESI) m/z: [M+H] + Calcd for C 21 H 34 NO 3 SSi: 408.2029; found: 408.2067. Example 56: Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)thiazole-4-carboxylate (53t) TIPS thiazole 52t (1.4 g, 3.44 mmol, 1 eq) was carefully dried under high vac- uum, dissoved in THF (35 mL) and cooled to 0°C. TBAF (1 M in THF, 3.78 mL, 3.78 mmol, 1.1 eq) was added dropwise and the mixture was stirred for 30 min at room temperature and then quenched with water (30 mL). The aqueous phase was extracted with Et 2 O (3x20 mL) and the organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the residue by flash chromatography (pentane/Et 2 O 2:1 to 1:1) afforded thiazole 53t (691 mg, 2.75 mmol, 80%) as a yellow oil. General Data: C 12 H 13 NO 3 S; FW: 251.06; TLC: R f = 0.30 (pentane/Et 2 O 1:1); UV (+); Vanillin: brown; = +12.2 (c = 1.0, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.11 (s, 1H, NC=CH); 6.12 (dd, J = 16.1, 7.1, 1H, CH=CH); 5.72 (ddd, J = 15.9, 2.1, 0.9 Hz, 1H, CH=CH); 4.04-3.96 (m, 1H, CHOCH 3 ); 3.95 (s, 3H, COOCH 3 ); 3.36-2.27 (m, 1H, 1CH 2 CH); 3.31 (s, 3H, CHOCH 3 ); 3.21 (dd, J = 15.1, 8.5 Hz, 1H, 1CH 2 CH); 2.94 (d, J = 2.2 Hz, 1H, CCH). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 167.4 (C=O); 162.0 (C=N); 146.1 (C); 143.1 (CH); 128.5 (CH); 112.3 (CH); 81.1 (C); 80.1 (CH); 79.0 (CH); 57.1 (CH 3 ); 52.6 (CH 3 ); 39.4 (CH 2 ). IR(neat): 3626 (w); 3219 (m); 3126 (m); 2953 (m); 2836 (w); 1719 (s); 1482 (s); 1319 (m); 1236 (s); 1194 (s); 1091 (s); 983 (s); 915 (m); 782 (m); 672 (m) cm -1 . MS (ESI): m/z (%): 252.07 (100) [M+H] + , 220.04 (95), 274.05 (34) [M+Na] + , 206.03 (13), 194.03 (8). HRMS (ESI) m/z: [M+H] + Calcd for C 12 H 14 NO 3 S: 252.0694; found: 252.0711. Example 57: Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10-((triethylsilyl)oxy)pentadeca-3,7,13-trien -5-yn-1-yl)thi- azole-4-carboxylate (54t)

The vinyl iodide 17 (595 mg, 1.27 mmol, 1 eq) was dissolved in degassed CH 3 CN (12 mL) and CuI (57 mg, 0.381 mmol, 0.3 eq) and PdCl 2 (PPh3)2 (89 mg, 0.127 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -15°C (ice/acetone bath). NEt 3 (1.06 mL, 7.62 mmol, 6 eq) was added, followed by a slow addition of the enyne 53t (383 mg, 1.52 mmol, 1.2 eq) in degassed CH 3 CN (3 mL). The solution became green and after 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH 4 Cl solution (15 mL). The aqueous phase was extracted with Et 2 O (3x10 mL) and the com- bined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et 2 O 2:1) to give the monomer 54t (563 mg, 0.952 mmol, 75%) as a yellow oil. General Data: C 31 H 49 NO 6 SSi; FW: 591.31; TLC: R f = 0.20 (pentane/Et 2 O 2:1); UV (+); Vanillin: black; = -8.5 (c = 0.85, CHCl 3 ). 1 H-NMR (600 MHz, CD 3 OD): δ (ppm): 8.29 (s, 1H, NC=CH); 6.11-6.04 (m, 1H, CH 2 CH=CH); 6.03-5.94 (m, 2H, CH=CH); 5.71-5.60 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.40-5.33 (m, 1H, CH=CHCH 3 ); 4.65 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.46 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.11-4.06 (m, 1H, CHOCH 3 ); 3.91 (s, 3H, COOCH 3 ); 3.89 (d, J = 9.2 Hz, 1H, CH 2 CHOTES); 3.71 (dd, J = 7.2, 3.8 Hz, 1H, CH 2 CHOTES); 3.34 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 2 OCH 3 ); 3.26 (dd, J = 14.5, 4.6 Hz, 2H, CH 2 CHOCH 3 ); 2.63-2.56 (m, 1H, 1CH 2 CH=CH); 2.46-2.38 (m, 1H, 1CH 2 CH=CH); 1.72 (dd, J = 6.6, 1.7 Hz, 3H, CH=CHCH 3 ); 0.984 (app t, J = 7.9 Hz, 9H, OSi(CH 2 CH 3 )3); 0.934 (s, 3H, CCH 3 ); 0.871 (s, 3H, CCH 3 ); 0.638 (q, J = 8.0 Hz, 6H, OSi(CH 2 CH 3 )3). 13 C-NMR (151 MHz, CD 3 OD): δ (ppm): 169.7 (C=O); 163.0 (C=N); 146.6 (C); 143.6 (CH); 141.7 (CH); 132.3 (CH); 129.9 (CH); 129.2 (CH); 114.7 (CH); 110.8 (CH); 94.5 (CH 2 ); 92.5 (C); 88.9 (C); 82.7 (CH); 81.3 (CH); 77.9 (CH); 57.1 (CH 3 ); 55.9 (CH 3 ); 52.7 (CH 3 ); 44.2 (C); 39.8 (CH 2 ); 35.5 (CH 2 ); 20.4 (CH 3 ); 19.9 (CH 3 ); 18.0 (CH 3 ); 7.5 (CH 3 ); 6.5 (CH 2 ). IR(neat): 3120 (w); 2953 (m); 2877 (m); 1724 (m); 1464 (m); 1325 (m); 1238 (m); 1210 (m); 1089 (s); 1036 (s); 957 (m); 919 (m); 739 (s) cm -1 . MS (ESI): m/z (%): 530.28 (100), 434.18 (97), 614.29 (22), 366.15 (16), 498.25 (18), 592.31 (<1) [M+H] + . HRMS (ESI) m/z: [M+H] + Calcd for C 31 H 50 NO 6 SSi: 592.3128; found: 592.3130. Example 58: Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methoxy- methoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)thia zole-4-car- boxylate (55t) CSA (18 mg, 0.0744 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 54t (220 mg, 0.372 mmol, 1 eq) in CH 2 Cl 2 (9 mL) and MeOH (9 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Saturated aqueous NaHCO 3 solution (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x15 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et 2 O/pentane 2:1) giving deprotected monomer 55t (168 mg, 0.353 mmol, 95%) as a slightly yellow oil. General Data: C 25 H 35 NO 6 S; FW: 477.22; TLC: R f = 0.25 (Et 2 O/Pentane 2:1); UV (+); Vanillin: black; = -18.0 (c = 1.8, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.10 (s, 1H, NC=CH); 6.22-6.16 (m, 1H, CH 2 CH=CH); 5.96 (dd, J = 15.9, 7.1 Hz, 1H, CCH=CHCH); 5.87 (dd, J = 15.8, 1.8 Hz, 1H, CCH=CHCH 2 ); 5.70-5.62 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.42-5.35 (m, 1H, CH=CHCH 3 ); 4.65 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.47 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.02-3.95 (m, 1H, CHOCH 3 ); 3.93 (s, 3H, COOCH 3 ); 3.90 (d, J = 8.7 Hz, 1H, CH 2 CHOH); 3.67 (dd, J = 10.2, 2.5 Hz, 1H, CHOCH 2 OCH 3 ); 3.37 (s, 3H, CHOCH 3 ); 3.32-3.27 (m, 1H, 1CH 2 CHOCH 3 ); 3.29 (s, 3H, CHOCH 2 OCH 3 ); 3.21 (dd, J = 15.1, 8.7 Hz, 1H, 1CH 2 CHOCH 3 ); 2.59-2.51 (m, 1H, 1CH 2 CH=CH); 2.37-2.28 (m, 1H, 1CH 2 CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH 3 ); 0.913 (s, 3H, CCH 3 ); 0.863 (s, 3H, CCH 3 ). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 167.6 (C=O); 162.0 (C=N); 146.0 (C); 143.2 (CH); 140.2 (CH); 132.0 (CH); 128.4 (CH); 126.9 (CH); 113.8 (CH); 109.8 (CH); 93.8 (CH 2 ); 91.2 (C); 88.3 (C); 84.7 (CH); 80.4 (CH); 76.1 (CH); 56.9 (CH 3 ); 56.2 (CH 3 ); 52.5 (CH 3 ); 41.0 (C); 39.6 (CH 2 ); 32.8 (CH 2 ); 21.1 (CH 3 ); 19.7 (CH 3 ); 18.0 (CH 3 ). IR(neat): 3657 (w); 3452 (br); 2972 (s); 2888 (m); 2326 (w); 1722 (s); 1603 (m); 1440 (m); 1339 (m); 1256 (m); 1146 (m); 1091 (s); 1033 (s); 954 (s); 922 (m); 753 (m) cm -1 . MS (ESI): m/z (%): 320.10 (100), 384.16 (56), 416.19 (52), 446.20 (45), 228.07 (29), 500.20 (22), 478.23 (12) [M+H] + . HRMS (ESI) m/z: [M+H] + Calcd for C 25 H 36 NO 6 S: 478.2263; found: 478.2257. Example 59: 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,1 1-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)thiazol e-4- carboxylic acid (56t)

LiOH (1 M in H 2 O, 0.777 mL, 0.777 mmol, 3 eq) was added to a solution of 54t (153 mg, 0.259 mmol, 1 eq) in THF (3.5 mL). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et 2 O (3x3 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give acid 56t (148 mg, 0.256 mmol, 99%) as a yellow oil, which was used for the next step without further purification. General Data: C 30 H 47 NO 6 SSi; FW: 577.29; TLC: UV (+); Vanillin: black; = +36.9 (c = 0.55, CHCl 3 ). 1 H-NMR (600 MHz, CDCl 3 ): δ (ppm): 8.25 (s, 1H, NC=CH); 6.11-6.04 (m, 1H, CH 2 CH=CH); 6.03-5.94 (m, 2H, CCH=CHCH); 5.72-5.60 (m, 2H, CH(OCH 3 )CH=CH, CH=CHCH 3 ); 5.40-5.33 (m, 1H, CH=CHCH 3 ); 4.65 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.46 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.13-4.04 (m, 1H, CHOCH 3 ); 3.92-3.87 (m, 1H, CHOTES); 3.71 (dd, J = 7.2, 3.7 Hz, 1H, CHOCH 2 OCH 3 ); 3.34 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 2 OCH 3 ); 3.26 (dd, J = 13.7, 4.6 Hz, 2H, CH 2 CHOCH 3 ); 2.63-2.56 (m, 1H, 1CH 2 CH=CH); 2.46- 2.38 (m, 1H, 1CH 2 CH=CH); 1.72 (dd, J = 6.4, 1.6 Hz, 3H, CH=CHCH 3 ); 1.01-0.959 (m, 9H, OSi(CH 2 CH 3 )3); 0.937 (s, 3H, CCH 3 ); 0.873 (s, 3H, CCH 3 ); 0.638 (q, J = 8.0 Hz, 6H, OSi(CH 2 CH 3 )3). 13 C-NMR (151 MHz, CDCl 3 ): δ (ppm): 164.4 (C=O); 162.8 (C=N); 145.0 (CH); 143.2 (CH); 140.2 (CH); 133.0 (C); 131.1 (CH); 127.9 (CH); 114.0 (CH); 109.5 (CH); 93.6 (CH 2 ); 91.2 (C); 88.5 (C); 81.8 (CH); 79.3 (CH); 76.5 (CH); 56.9 (CH 3 ); 55.7 (CH 3 ); 43.2 (C); 34.4 (CH 2 ); 30.5 (CH 2 ); 19.8 (CH 3 ); 19.4 (CH 3 ); 18.0 (CH 3 ); 7.3 (CH 3 ); 5.7 (CH 2 ). IR(neat): 3495 (w); 2952 (m); 2877 (m); 1715 (m); 1468 (m); 1415 (w); 1192 (m); 1091 (s); 1033 (s); 956 (m); 921 (m); 825 (m); 723 (s); 542 (w) cm -1 . MS (ESI): m/z (%): 420.17 (100), 516.26 (77), 600.28 (49), 546.27 (24), 388.14 (17), 352.14 (8), 306.08 (4), 578.27 (<1) [M+H] + . HRMS (ESI) m/z: [M+H] + Calcd for C 30 H 48 NO 6 SSi: 578.2972; found: 578.2963. Example 60: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)thia zol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6- yl 2- ((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11- dime- thyl-10-((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl )thiazole-4-car- boxylate (57t) The crude acid 56t (140 mg, 0.243 mmol, 1.2 eq) was dissolved in THF (4 mL) and treated at room temperature with NEt 3 (0.175 mL, 1.25 mmol, 6 eq) and 2,4,6-trichlorobenzoyl chloride (0.130 mL, 0.836 mmol, 4 eq). The turbid solu- tion was stirred for 2 h at room temperature and then diluted with toluene (2 mL) and added dropwise to a solution of alcohol 55t (100 mg, 0.209 mmol, 1 eq) and DMAP (153 mg, 1.25 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aque- ous NH 4 Cl solution (20 mL). The aqueous phase was extracted with EtOAc (3x15 mL) and the organic layers were dried over Na 2 SO 4 , filtered and con- centrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1) to afford 57t (168 mg, 0.162 mmol, 77%) as a slightly yellow oil. General Data: C 55 H 80 N 2 O 11 S 2 Si; FW: 1036.50; TLC: R f = 0.45 (hexane/EtOAc 1:1); UV (+); Vanillin: black; 0 = +26.7 (c = 1.25, CHCl 3 ). 1 H-NMR (400 MHz, CD 3 OD): δ (ppm): 8.30 (s, 1H, NC=CH); 8.23 (s, 1H, NC=CH); 6.12-6.03 (m, 2H, CH=CH); 6.025.92 (m, 4H, CH=CH); 5.76-5.55 (m, 4H, CH=CH); 5.48-5.31 (m, 2H, CH=CH); 5.24 (app dd, J = 6.7, 6.0 Hz, 1H, CHOC=O); 4.64 (dd, J = 8.9, 6.5 Hz, 2H, OCH 2 OCH 3 ); 4.46 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.40 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.14-4.06 (m, 2H, CHOCH 3 ); 3.91-3.87 (m, 1H, CHOCH 2 OCH 3 );3.90 (s, 3H, COOCH 3 ); 3.83 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.71 (dd, J = 7.0, 3.7 Hz, 1H, CH 2 CHOTES); 3.34 (s, 3H, CHOCH 3 ); 3.33 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 2 OCH 3 ); 3.29 (s, 3H, CHOCH 2 OCH 3 ); 3.28-3.23 (m, 4H, CH 2 CHOCH 3 ); 2.73 (app dd, J = 6.9, 7.2 Hz, 2H, CH 2 CH=CH); 2.65-2.55 (m, 1H, 1CH 2 CH=CH); 2.47-2.37 (m, 1H, 1CH 2 CH=CH); 1.712 (app d, J = 6.2 Hz, 6H, CH=CHCH 3 ); 1.06 (s, 3H, CCH 3 ); 1.01 (s, 3H, CCH 3 ); 0.982 (app t, J = 7.8 Hz, 9H, OSi(CH 2 CH 3 ) 3 ); 0.935 (s, 3H, CCH 3 ); 0.871 (s, 3H, CCH 3 ); 0.637 (q, J = 8.0 Hz, 6H, OSi(CH 2 CH 3 ) 3 ). 13 C-NMR (100 MHz, CD 3 OD): δ (ppm): 169.6 (C=O); 169.5 (C=O); 163.0 (C=N); 162.2 (C=N); 147.1 (CH); 146.6 (CH); 143.6 (CH); 141.9 (CH); 141.8 (CH); 141.2 (C); 133.1 (C); 132.3 (CH); 130.0 (CH); 129.8 (CH); 129.2 (CH); 128.5 (CH); 114.7 (CH); 114.6 (CH); 112.1 (CH); 110.8 (CH); 94.6 (CH 2 ); 94.5 (CH 2 ); 92.6 (C); 92.5 (C); 88.9 (C); 88.5 (C); 82.8 (CH); 82.7 (CH); 81.4 (CH); 81.2 (CH); 78.6 (CH); 77.9 (CH); 57.1 (CH 3 ); 57.0 (CH 3 ); 56.3 (CH 3 ); 56.0 (CH3); 52.7 (CH 3 ); 44.2 (C); 42.8 (C); 39.8 (CH 2 ); 39.7 (CH 2 ); 35.5 (CH 2 ); 32.4 (CH 2 ); 20.4 (CH 3 ); 20.3 (CH 3 ); 19.9 (CH 3 ); 19.7 (CH 3 ); 18.1 (CH 3 ); 18.0 (CH 3 ); 7.5 (CH 3 ); 6.5 (CH 2 ). IR(neat): 2952 (m); 2879 (m); 2224 (w); 1736 (s); 1468 (m); 1371 (m); 1238 (s); 1206 (s); 1091 (s); 1033 (s); 956 (s); 918 (m); 736 (s) cm -1 . MS (ESI): m/z (%): 1005.55 (100) [M+H] + , 1022.56 (760) [M+NH 4 ] + , 943.52 (45), 973.53 (28), 847.43 (8). HRMS (ESI) m/z: [M+H] + Calcd for C 55 H 81 N 2 O 11 S 2 Si: 1036.4973; found: 1036.4981. Example 61: Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-(9,10,9’,10†™)-tetradehydrido- disorazole C1 (58t) CSA (8 mg, 0.0324 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 57t (168 mg, 0.162 mmol, 1 eq) in CH 2 Cl 2 (8 mL) and MeOH (8 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO 3 solution (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x15 mL) and the combined or- ganic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo giv- ing the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C 49 H 66 N 2 O 11 S2; FW: 922.41; TLC: R f = 0.30 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: black; = +36.9 (c = 0.55, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.11 (s, 1H, NC=CH); 7.99 (s, 1H, NC=CH); 6.27-6.12 (m, 1H, CH 2 CH=CH); 6.05-6.93 (m, 3H, CH=CH); 5.89 (ddd, J = 16.0, 4.8, 2.5 Hz, 2H, CH=CH); 5.73-5.61 (m, 3H, CH=CH); 5.56 (d, J = 10.3 Hz, 1H, CH=CH); 5.45-5.33 (m, 2H, CH=CH); 5.28 (dd, J = 8.0, 4.8 Hz, 1H, CHOC=O); 4.66 (d, J = 6.6 Hz, 2H, 1OCH 2 OCH 3 ); 4.48 (d, J = 6.7 Hz, 1H, 1OCH 2 OCH 3 ); 4.40 (d, J = 6.7 Hz, 1H, CHOCH 2 OCH 3 ); .4.06-3.96 (m, 2H, CHOCH 3 ); 3.94 (s, 3H, COOCH 3 ); 3.92 (m, 1H, CHOCH 2 OCH 3 ); 3.79 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.69 (dd, J = 10.1, 2.2 Hz, 1H, CHOH); 3.38 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 3 ); 3.31 (s, 3H, CHOCH 2 OCH 3 ); 3.35-2.29 (m, 2H, CH 2 CHOCH 3 ); 23.30 (s, 3H, CHOCH 2 OCH 3 ); 3.26-2.18 (m, 2H, CH 2 CHOCH 3 ); 2.80-2.66 (m, 2H, CH 2 CH=CH); 2.61-2.50 (m, 1H, 1CH 2 CH=CH); 2.40-2.28 (m, 1H, 1CH 2 CH=CH); 1.75 (dd, J = 6.3, 1.3 Hz, 3H, CH=CHCH 3 ); 1.71 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH 3 ); 1.05 (s, 3H, CCH 3 ); 1.00 (s, 3H, CCH 3 ); 0.927 (s, 3H, CCH 3 ); 0.878 (s, 3H, CCH 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 167.5 (C=O); 167.4 (C=O); 162.1 (C=N); 160.9 (C=N); 146.6 (CH); 146.1 (CH); 143.2 (CH); 140.5 (CH); 140.4 (CH); 132.0 (CH); 131.9 (CH); 128.5 (CH); 127.6 (C); 127.3 (C); 126.9 (CH); 125.7 (CH); 113.7 (CH); 113.6 (CH); 111.1 (CH); 109.8 (CH); 93.8 (CH 2 ); 93.7 (CH 2 ); 91.5 (C); 91.3 (C); 88.3 (C); 88.1 (C); 84.7 (CH); 81.6 (CH); 80.4 (CH); 80.4 (CH); 77.4 (CH); 76.2 (CH); 57.0 (CH 3 ); 56.9 (CH 3 ); 56.2 (CH 3 ); 56.1 (CH 3 ); 52.6 (CH 3 ); 41.9 (C); 41.0 (C); 39.7 (CH 2 ); 32.9 (CH 2 ); 31.6 (CH 2 ); 30.4 (CH 2 ); 21.1 (CH 3 ); 20.0 (CH 3 ); 19.8 (CH 3 ); 19.6 (CH 3 ); 18.1 (CH 3 ); 18.0 (CH 3 ). IR(neat): 3500 (br); 2934 (m); 2886 (m); 1723 (m); 1468 (m); 1345 (m); 1205 (s); 1092 (s); 1032 (s); 971 (s); 919 (m); 749 (m); 540 (w) cm -1 . MS (ESI): m/z (%): 923.42 (100) [M+H] + , 891.39 (10), 945.40 (6) [M+Na] + , 765.29 (5). HRMS (ESI) m/z: [M+H] + Calcd for C 49 H 67 N 2 O 11 S2: 923.4186; found: 923.4194. The crude deprotected alcohol was dissolved in THF (6 mL) and treated at room temperature with LiOH (1 M in H 2 O, 0.486 mL, 0.486 mmol, 3 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et 2 O (3x3 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purification. General Data: C 48 H 64 N 2 O 11 S 2 ; FW: 908.40; TLC: UV (+); Vanillin: grey; = +28.5 (c = 1.0, CHCl3). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 8.18 (s, 1H, NC=CH); 8.00 (s, 1H, NC=CH); 6.26-6.14 (m, 1H, CH 2 CH=CH); 6.03-5.93 (m, 3H, CH=CH); 5.93- 5.83 (m, 2H, CH=CH); 5.71-5.61 (m, 3H, CH=CH); 5.56 (d, J = 10.1 Hz, 1H, CH=CH); 5.44-5.33 (m, 2H, CH=CH); 5.28 (dd, J = 7.5, 5.8 Hz, 1H, CHOC=O); 4.67 (d, J = 6.6 Hz, 2H, OCH 2 OCH 3 ); 4.48 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.41 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.08-3.97 (m, 2H, CHOCH 3 ); 3.91 (d, J = 8.6 Hz, 1H, CHOCH 2 OCH 3 ); 3.79 (d, J = 9.0 Hz, 1H, CHOCH 2 OCH 3 ); 3.70 (dd, J = 10.2, 2.0 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH 3 ); 3.35-3.28 (m, 2H, CH 2 CHOCH 3 ); 3.33 (s, 3H, CHOCH 3 ); 3.32 (s, 3H, CHOCH 2 OCH 3 ); 3.31 (s, 3H, CHOCH 2 OCH 3 ); 3.27-3.16 (m, 2H, CH 2 CHOCH 3 ); 2.76-2.66 (m, 2H, CH 2 CH=CH); 2.60-2.50 (m, 1H, 1CH 2 CH=CH); 2.41-2.30 (m, 1H, 1CH 2 CH=CH); 1.75 (d, J = 6.3 Hz, 3H, CH=CHCH 3 ); 1.71 (d, J = 6.3, 1.4 Hz, 3H, CH=CHCH 3 ); 1.05 (s, 3H, CCH 3 ); 0.999 (s, 3H, CCH 3 ); 0.928 (s, 3H, CCH 3 ); 0.879 (s, 3H, CCH 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 167.6 (C=O); 167.5 (C=O); 163.2 (C=N); 160.8 (C=N); 146.4 (CH); 145.8 (CH); 143.1 (CH); 140.6 (CH); 140.4 (C); 132.1 (CH); 129.2 (C); 129.1 (CH); 127.8 (CH); 127.2 (CH); 126.8 (CH); 125.6 (CH); 113.7 (CH); 111.0 (CH); 109.9 (CH); 109.8 (CH); 93.8 (CH 3 ); 93.6 (CH 3 ); 91.5 ( C); 91.3 (C); 88.3 (C); 88.1 (C); 84.7 (CH); 81.6 (CH); 80.4 (CH); 80.2 (CH); 77.4 (CH); 76.3 (CH); 57.0 (CH 3 ); 56.9 (CH 3 ); 56.2 (CH 3 ); 56.1 (CH 3 ); 41.9 (C); 41.0 (C); 32.8 (CH 2 ); 31.6 (CH 2 ); 30.5 (CH 2 ); 29.8 (CH 2 ); 21.1 (CH 3 ); 20.0 (CH 3 ); 19.8 (CH 3 ); 19.5 (CH 3 ); 18.1 (CH 3 ); 18.0 (CH 3 ). IR(neat): 3507 (br); 2924 (m); 2826 (w); 1722 (s); 1469 (m); 1337 (m); 1200 (s); 1146 (m); 1093 (s); 1030 (s); 956 (s); 911 (s); 730 (s); 576 (w) cm -1 . MS (ESI): m/z (%): 909.40 (100) [M+H] + , 931.39 (18) [M+Na] + , 897.40 (12), 847.36 (9). HRMS (ESI) m/z: [M+H] + Calcd for C 48 H 65 N 2 O 11 S 2 : 909.4030; found: 909.4003. The crude seco-acid was dissolved in THF (10 mL) and treated at room tem- perature with NEt 3 (506 µL, 3.24 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chlo- ride (225 µL, 1.62 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a so- lution of DMAP (791 mg, 6.48 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH 4 Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et 2 O/pentane 2:1 to 1:1) to afford the macrocycle 58t (65 mg, 0.0729 mmol, 45% from 57t) as a slightly yellow wax. General Data: C 48 H 62 N 2 O 10 S2; FW: 890.38; TLC: R f = 0.50 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: black; = +98.2 (c = 0.5, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 7.98 (s, 2H, NC=CH); 6.02-5.90 (m, 4H, CH=CH); 5.79 (dd, J = 15.8, 2.0 Hz, 2H, CH=CH); 5.66 (dd, J = 15.4, 6.5 Hz, 2H, CH=CH); 5.54 (d, J = 10.8 Hz, 2H, CH=CH); 5.46-5.37 (m, 2H, CH=CH); 5.32 (dd, J = 10.6, 2.8 Hz, 2H, CHOC=O); 4.67 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.42 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.15-4.07 (m, 2H, CHOCH 3 ); 3.77 (d, J = 8.9 Hz, 2H, CHOCH 2 OCH 3 ); 3.53-3.46 (m, 2H, CH 2 CH=CH); 3.37 (s, 6H, CHOCH 3 ); 3.34 (s, 6H, CHOCH 2 OCH 3 ); 3.31-3.22 (m, 2H, CH 2 CH=CH); 3.05- 2.90 (m, 2H, CH 2 CHOCH 3 ); 2.50-2.41 (m, 2H, CH 2 CH=CH); 1.73 (dd, J = 6.4, 1.4 Hz, 6H, CH=CHCH 3 ); 1.07 (s, 6H, CCH 3 ); 1.03 (s, 6H, CCH 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 165.8 (C=O); 160.6 (C=N); 147.0 (CH); 140.5 (CH); 140.4 (CH); 131.9 (C); 128.4 (CH); 127.4 (CH); 114.5 (CH); 112.1 (CH); 93.8 (CH 2 ); 91.2 (C); 88.2 (C); 81.7 (CH); 79.9 (CH); 77.4 (CH); 56.9 (CH 3 ); 56.2 (CH 3 ); 41.7 (C); 39.1 (CH 2 ); 30.5 (CH 2 ); 20.1 (CH 3 ); 19.8 (CH 3 ); 18.1 (CH 3 ). IR(neat): 3115 (w); 2925 (m); 2854 (m); 1730 (m); 1468 (m); 1368 (m); 1236 (s); 1192 (s); 1092 (s); 1031 (s); 960 (s); 921 (m); 824 (m); 747 (m) cm -1 . MS (ESI): m/z (%): 891.39 (100) [M+H] + , 829.35 (15), 913.37 (12) [M+Na] + , 879.39 (9). HRMS (ESI) m/z: [M+H] + Calcd for C 48 H 63 N 2 O 10 S 2 : 891.3924; found: 891.3915. Example 62: Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-disorazole C1 (59t) Nitrogen was bubbled for 15 min through a suspension of Zinc (6 g, 91.77 mmol) in H 2 O (30 mL) and then Cu(OAc)2·H 2 O (600 mg, 3.00 mmol) was added at room temperature and after 15 min AgNO 3 (600 mg, 3.53 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H 2 O (40 mL), MeOH (30 mL), acetone (30 mL) and Et 2 O (30 mL). This activated zinc solids were added to a solution of 58t (50 mg, 0.0562 mmol) in MeOH/H 2 O 1:1 (25 mL). The mixture was stirred for 24 h at 50°C, then filtered on a pad of silica with MeOH washes. The filtrate was concentrated in vacuo and the residue was purified by flash chromatog- raphy (CH 2 Cl 2 /MeOH 70:1) to afford 59t (30 mg, 0.0335, 60%) as a colorless wax. General Data: C 48 H 66 N 2 O 10 S 2 ; FW: 894.42; TLC: R f = 0.40 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: dark green; = -52.8 (c = 0.5, CHCl 3 ). 1 H-NMR (400 MHz, CDCl 3 ): δ (ppm): 7.82 (s, 2H, NC=CH); 6.43 (dd, J = 15.3, 11.6 Hz, 2H, CH(OCH 3 )CH=CH); 6.33 (app t, J = 11.3 Hz, 2H, CH2CH=CH); 6.19 (dd, J = 11.7, 11.0 Hz, 2H, CHCH=CHCH); 5.89 (dd, J = 11.2, 10.9 Hz, 2H, CHCH=CHCH); 5.63 (dd, J = 15.3, 6.5 Hz, 2H, CH 3 CH=CH); 5.50 (dd, J = 15.1, 8.7 Hz, 2H, CH 3 CH=CH); 5.40 (ddd, J = 15.2, 9.0, 1.5 Hz, 2H, CH(OCH 3 )CH=CH); 5.31 (dd, J = 11.2, 2.5 Hz, 2H, CHOC=O); 5.26 (dd, J = 11.2, 2.2 Hz, 2H, CH2CH=CH); 4.66 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.39 (d, J = 6.6 Hz, 1H, 1OCH 2 OCH 3 ); 4.10 (ddd, J = 12.8, 7.0, 5.0 Hz, 2H, CHOCH 3 ); 3.74 (d, J = 9.0 Hz, 2H, CHOH); 3.43 (dd, J = 14.2, 5.3 Hz, 2H, CH 2 CHOCH 3 ); 3.33 (s, 6H, CHOCH 2 OCH 3 ); 3.28 (s, 6H, CHOCH 3 ); 3.01 (dd, J = 14.2, 8.0 Hz, 2H, CH 2 CHOCH 3 ); 2.65-2.55 (m, 2H, CH 2 CH=CH); 2.50 (dd, J = 15.3, 6.1 Hz, 2H, CH 2 CH=CH); 1.72 (d, J = 6.1 Hz, 3H, CH=CHCH 3 ); 1.03 (s, 6H, CCH 3 ); 0.979 (s, 6H, CCH 3 ). 13 C-NMR (100 MHz, CDCl 3 ): δ (ppm): 166.6 (C=O); 160.8 (C=N); 147.1 (CH); 132.9 (C); 132.0 (CH); 129.9 (CH); 128.1 (CH); 127.2 (CH); 126.8 (CH); 125.7 (CH); 125.6 (CH); 125.5 (CH); 93.6 (CH 2 ); 81.9 (CH); 81.2 (CH); 77.4 (CH); 56.6 (CH 3 ); 56.1 (CH 3 ); 41.8 (C); 30.5 (CH 2 ); 29.8 (CH 2 ); 20.3 (CH 3 ); 19.9 (CH 3 ); 18.1 (CH 3 ). IR(neat): 2923 (s); 2853 (m); 1731 (m); 1466 (m); 1365 (w); 1194 (m); 1092 (s); 1032 (s); 973 (m); 920 (m); 731 (m) cm -1 . MS (ESI): m/z (%): 895.42 (100) [M+H] + , 917.40 (12) [M+Na] + , 863.39 (5), 833.38 (4). HRMS (ESI) m/z: [M+H] + Calcd for C 48 H 67 N 2 O 10 S 2 : 895.4237; found 895.4210. Example 63: Bis(thiazolyl)-Disorazole C1 (60t) MOM protected 59t (12 mg, 13.4 µmol) was dissolved in CH 3 CN (1.5 mL) and cooled to 0°C. 2 drops of HBr (48% in H 2 O) were slowly added and then the mixture was stirred for 1 h at 0°C. The mixture was diluted with EtOAc (4 mL) and washed with saturated aqueous NaHCO 3 solution (3 mL). The aqueous phase was extracted with EtOAc (3x5 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (CH 2 Cl 2 /MeOH 50:1) to give Bis(thiazolyl)-disorazole C 160t (6 mg, 7.44 µmol, 56%) as a colorless wax. General Data: C44H58N2O8S2; FW: 806.36; TLC: R f = 0.20 (CH 2 Cl 2 /MeOH 50:1); UV (+); Vanillin: dark green; = -113.33 (c = 0.15, MeOH). 1 H-NMR (600 MHz, CD 3 OD): δ (ppm): 8.11 (s, 2H, NC=CH); 6.49 (dd, J = 15.2, 11.4 Hz, 2H, CH(OCH 3 )CH=CH); 6.39 (app t, J = 11.1 Hz, 2H, CH2CH=CH); 6.27 (dd, J = 11.2, 11.0 Hz, 2H, CHCH=CHCH); 5.85 (dd, J = 11.2, 11.1 Hz, 2H, CHCH=CHCH); 5.67 (dq, J = 15.3, 6.4 Hz, 2H, CH 3 CH=CH); 5.59 (ddd, J = 15.3, 7.9, 1.5 Hz, 2H, CH 3 CH=CH); 5.51 (dd, J = 15.4, 8.0 Hz, 4H, CH(OCH 3 )CH=CH); 5.26 (dd, J = 11.1, 2.2 Hz, 2H, CHOC=O); 4.13 (ddd, J = 7.9, 7.2, 5.3 Hz, 2H, CHOCH 3 ); 3.86 (d, J = 7.9 Hz, 2H, CHOH); 3.25 (s, 6H, CHOCH 3 ); 3.20 (dd, J = 12.4, 7.3 Hz, 2H, CH 2 CHOCH 3 ); 3.01 (dd, J = 14.9, 5.6 Hz, 2H, CH 2 CHOCH 3 ); 2.69 (ddd, J = 13.8, 10.9, 10.2 Hz, 2H, CH 2 CH=CH); 2.46 (dd, J = 14.1, 6.5 Hz, 2H, CH 2 CH=CH); 1.69 (dd, J = 6.1, 1.1 Hz, 6H, CH=CHCH 3 ); 1.03 (s, 6H, CCH 3 ); 0.972 (s, 6H, CCH 3 ). 13 C-NMR (151 MHz, CD 3 OD): δ (ppm): 169.0 (C=O); 162.3 (C=N); 147.5 (CH); 133.9 (C); 131.7 (CH); 130.6 (CH); 130.1 (CH); 129.7 (CH); 129.3 (CH); 129.0 (CH); 127.2 (CH); 126.6 (CH); 81.8 (CH); 79.2 (CH); 77.9 (CH); 56.9 (CH 3 ); 42.8 (C); 40.5 (CH 2 ); 29.2 (CH 2 ); 19.5 (CH 3 ); 19.4 (CH 3 ); 18.0 (CH 3 ). IR(neat): 3419 (br); 2924 (m); 2854 (m); 1723 (m); 1583 (m); 1447 (w); 1367 (w); 1312 (w); 1261 (w); 1101 (s); 1010 (m); 803 (m); 758 (m); 729 (m) cm -1 . MS (ESI): m/z (%): 807.37 (100) [M+H] + , 829.35 (34) [M+Na] + , 172.13 (33); 155.11 (28), 659.52 (14), 798.36 (13). HRMS (ESI) m/z: [M+H] + Calcd for C44H59N2O8S2: 807.3713; found 807.3704.




 
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