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Title:
PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2010/024762
Kind Code:
A1
Abstract:
A process for stereoselective synthesis of a β-phenylisoserine comprises reacting a carbonyl imine R-C=N-CO-OR1 with a protected α- oxyaldehyde X1O-CH2CHO in the presence of a chiral amine catalyst and oxidizing aldehyde so obtained.

Inventors:
CORDOVA ARMANDO (SE)
DZIEDZIC PAWEL (SE)
VESELY JAN (CZ)
Application Number:
PCT/SE2009/050962
Publication Date:
March 04, 2010
Filing Date:
August 26, 2009
Export Citation:
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Assignee:
ORGANOCLICK AKTIEBOLAG (SE)
CORDOVA ARMANDO (SE)
DZIEDZIC PAWEL (SE)
VESELY JAN (CZ)
International Classes:
C07C269/06; C07C51/235; C07C271/22
Foreign References:
US6114550A2000-09-05
Other References:
SUNG-GON KIM ET AL: "An efficient synthesis of (+)-epi-cytoxazone via asymmetric organocatalysis", TETRAHEDRON: ASYMMETRY, vol. 19, July 2008 (2008-07-01), pages 1626 - 1629, XP023172282
CORDOVA A. ET AL: "A highly enantioselective route to either enantiomerer of both alpha- and beta-amino acid derivatives", JACS, vol. 124, no. 9, 2002, pages 1866 - 1867, XP002420049
DZIEDZIC, PAWEL ET AL: "Highly enantioselective organocatalytic addition of aldehydes to N-(Phenylmethylene)benzamides: asymmetric synthesis of the paclitaxel side chain and its analogues", CHEM. EUR. JOURNAL, vol. 15, no. 16, April 2009 (2009-04-01), pages 4044 - 4048, XP003026094
DZIEDZIC, PAWEL ET AL.: "Catalytic asymmetric synthesis of the docetaxel (Taxotere) side chain: organocatalytic highly enantioselective synthesis of esterification-ready alpha-hydroxy-beta-amino acids", TETRAHEDRON LETTERS, vol. 49, no. 47, September 2008 (2008-09-01), pages 6631 - 6634, XP026234580
VESELY J. ET AL: "Highly enantioselective organocatalytic addition of unmodified aldehydes to N-Boc protected imines: one-pot asymmetric synthesis of beta-amino acids", TETRAHEDRON LETTERS, vol. 48, no. 3, 2007, pages 421 - 425, XP005730750
VESELY J. ET AL: "Aza-Morita-Baylis-Hillman-type reactions: highly enantioselective organocatalytic addition of unmodified alpha,beta-unsaturated aldehydes to N-Boc protected imines", TETRAHEDRON LETTERS, vol. 48, no. 39, 2007, pages 6900 - 6904, XP022218617
Attorney, Agent or Firm:
IPQ IP SPECIALIST AB (Stockholm, SE)
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Claims:
C l a i m s

1. A process for stereoselective synthesis of a β-phenylisoserine derivative of the general formula I:

O JJ R1-O^NH O

R-^OH (l) OX1

wherein

R is aryl (Ar) or R2; R1 is C1-C10 non-branched or branched alkyl, C2-C8 alkynyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C4-C5 cycloalkenyl, or C7-Cn bicycloalkyl, R1 being optionally substituted with one or more of the group consisting of: halogen, hydroxyl, alkoxy, aryl such as phenyl, cyano, carboxyl, CrC7 alkyloxycarbonyl; X1 is H or a hydroxyl-protecting group selected from methoxymethyl, 1 - ethoxyethyl, bexyloxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl and β-(thmethylsilyl)ethoxymethyl, trialkylsilyl in which the alkyl contains from 1 to 4 carbon atoms, alkyldiphenylsilyl, -CH2-Ph in which Ph represents phenyl optionally substituted with one or more same or different atoms or groups chosen from halogen, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms; the process comprising a first step comprising the reaction between a N- carbonyl imine of the general formula II, R-C=N-CO-OR1 (II), in which Ar and R1 have the same meaning as above, with a protected α-oxyaldehyde of the general formula III, X1O-CH2CHO (III), in which X1 has the same meaning as above, in the presence of a chiral amine catalyst of the general formula IV

and a consecutive second step, in which the β-amino-α-hydroxyaldehyde of the general formula V,

o

R1-O^NH O

(V)

R

OX1

formed in the first step, in which R, R1 and X1 have the same meaning as above, is oxidized to the corresponding carboxylic acid of the general formula I.

2. The process of claim 1 , wherein the intermediate β-amino-α-hydroxy- aldehyde of the general formula V is oxidized without purification to the carboxylic acid of the general formula I.

3. The process of claim 1 or 2, wherein the oxidant comprises NaCIO2.

4. The process of claim 3, wherein the oxidant further comprises isobutene.

5. The process of any of claims 1 to 4, wherein Y2 is any of CO2H, Ar2OSiR3, tetrazole, O=C-NHR, O=C-NH-SO2R.

6. The process of any of claims 1 to 4, wherein the catalyst is (R)-proline.

7. The process of any of claims 1 to 6, wherein, if R is aryl, it is any of: phenyl or α- or β-naphthyl optionally substituted with one or more of halogen (fluorine, chlorine, bromine, iodine); alkyl, alkenyl, akynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro; trifluoromethyl; and wherein alkyl or an alkyl portion of a substituent is any of CrC4 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and wherein aryl comprises any of phenyl, α- or β-naphthyl, 2- or

3-furfuryl, thiophenyl, 2- or 3-pyridyl, indolyl, 2- or 3-pyridyl, imidazolyl.

8. The process of any of claims 1 to 6, wherein R2 is branched or non- branched C1-C10 alkyl, C2-C8 alkynyl, C2-C8 alkenyl; C3-C6 cycloalkyl; C4- Cβ cycloalkenyl; C7-Cn bicycloalkyl; optionally substituted with one or more of halogen; hydroxy; alkoxy; aryl, in particular phenyl; cyano; carboxyl; alkyloxycarbonyl in which alkyl is CrC7, for instance benzyl; a carbon atom substituted by three halogen atoms, such as CF3, wherein aryl is optionally phenyl or phenyl substituted with one or more same or different substituents selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl.

9. The method of any of claims 1 to 8, further comprising transforming the compound of general formula 1 to an ester of the general formula Vl,

0

Jl

R1-O^NH O

(Vl)

R' OMe

OX1

wherein R, R1 and X1 are defined as above and Me is straight or branched CrCβ alkyl, in particular methyl or ethyl.

10. The method of claim 9, comprising selective removal of the protecting group X1 from a compound of the general formula Vl for preparing a β- amino-α-hydroxy carboxylic ester derivative of the general formula VII

wherein R and R1 are defined as above.

11. The method of claim 9, comprising selective removal of the protecting group R1 from a compound of the general formula Vl for preparing a β- amino-α-hydroxy carboxylic ester derivative of the general formula VIII

NH2 O

(VIM)

R OMe

OX1

wherein R is defined as above and X1 is H.

12. The process of claim 1 , wherein the aldehyde of the general formula V is obtained in an enantiomeric purity of at least 99 %.

Description:
PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to a method of preparing β-isoserine derivatives. In particular, the present invention relates to a catalytic asymmetric method for preparing carbamate-protected (BOC- or Cbz-protected) α-oxy-β-amino aldehydes and their transformation to corresponding carboxylic acids. Most particularly, the present invention relates to the preparation of α-hydroxy-β- amino-acids useful in the selective esterification of the hydroxyl group at position 15 of baccatin III.

BACKGROUND OF THE INVENTION

The β-amino-α-hydroxy acid moiety is a common structural component in a vast group of naturally occurring pharmaceutically active molecules. Docetaxel (Taxotere™), a synthetic derivative of paclitaxel (Taxol™), is an important anticancer agent. It is an ester of (2R,3S)-phenylisoserine with the hydroxyl group at position 15 of the tetracyclic heptadecane skeleton common to docetaxel, paclitaxel, and their derivatives.

Paclitaxel and docetaxel are used in the treatment of various cancer forms. Paclitaxel and analogues thereof modified in the phenylisoserine side chain can be obtained by esterification of the corresponding (2R,3S)-phenylisoserine derivative with a protected baccatin III derivative: esterifi cation; deprotection paclitaxel Baccatin III derivative

PG = Protective Group Baccatin III is obtained from Pacific yew (Taxus brevifolia).

Paclitaxel derivatives are modified in their isoserine side chain. They are of considerable interest since chemical modification of the side chain is a way to change the biological activity and/or other properties of paclitaxel with the aim to find better anti-cancer agents.

The synthesis of paclitaxel and derivatives thereof on an industrial scale employs chiral auxiliaries or toxic metal catalysts (see, for instance, U.S. Patents Nos. 6,114,550 and 6,307,064; A. M. Kanazawa, J.-N. Denis, A. E. Greene, J. Org. Chem. 59 (1994) 1238; references cited therein).

Thus, the provision of an improved method for the synthesis of paclitaxel derivatives is highly desirable.

Compounds of the general formula (I), especially those in which X 1 is -CH 2 -Ph, are useful in the preparation of paclitaxel and its derivatives by direct estehfication with a 10-deacetyl baccatin III derivative comprising suitably protected hydroxyl groups, such as a 10-deacetyl baccatin III derivative disclosed in European Patents Nos. EP 0 336 840 and EP 0414 610.

Compounds of the general formula (I) in which X 1 is H can be converted to the corresponding acetonide derivatives, which are useful in the preparation of paclitaxel and its analogues by esterification with a 10-deacetyl baccatin III derivative having suitably protected hydroxyl groups (A. M. Kanazawa, J.-N. Denis, A. E. Greene, J. Org. Chem. 1994, 59, 1238). Compounds of the general formula (I) can be prepared by using chiral technology described in U.S. Patent No. 6,114,550.

SHORT DESCRIPTION OF THE INVENTION

The present invention relates to a process for stereoselective synthesis of β-phenylisosehne derivatives of the general formula I:

O

Jl

R 1 -O^NH O

(I)

R" >^ OH

OX 1

wherein

R is aryl or R 2 ;

R 1 is C1-C10 non-branched or branched alkyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, C3-C6 cycloalkyl, C 4 -Cβ cycloalkenyl, C 4 -C 5 cycloalkenyl, or C 7 -Cn bicycloalkyl, R 1 being optionally substituted with one or more of the group consisting of: halogen, hydroxyl, alkoxy, aryl such as phenyl, cyano, carboxyl, CrC 7 alkyloxycarbonyl;

X 1 is H or a hydroxyl-protecting group selected from methoxymethyl, 1 - ethoxyethyl, bexyloxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl and β-(thmethylsilyl)ethoxymethyl, trialkylsilyl in which the alkyl contains from 1 to 4 carbon atoms, alkyldiphenylsilyl, -CH 2 -Ph in which Ph represents phenyl optionally substituted with one or more same or different atoms or groups chosen from halogen, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms.

If R is aryl, it is preferably phenyl or α- or β-naphthyl optionally substituted with one or more of halogen (fluorine, chlorine, bromine, iodine); alkyl, alkenyl, akynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro; trifluoromethyl; wherein alkyl or an alkyl portion of a substituent is any of CrC 4 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and wherein aryl comprises any of phenyl, α- or β-naphthyl, 2- or 3-furfuryl, thiophenyl, 2- or 3-pyridyl, indolyl, 2- or 3-pyridyl, imidazolyl.

If R is R 2 , it is preferably branched or non-branched C1-C10 alkyl, C2-C8 alkynyl, C 2 -C 8 alkenyl; C 3 -C 6 cycloalkyl; C 4 -C 6 cycloalkenyl; C 7 -Cn bicycloalkyl; optionally substituted with one or more of halogen; hydroxy; alkoxy; aryl, in particular phenyl; cyano; carboxyl; alkyloxycarbonyl in which alkyl is CrC 7, for instance benzyl; a carbon atom substituted by three halogen atoms, such as CF 3 , wherein aryl is optionally phenyl or phenyl substituted with one or more same or different substituents selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl.

Particularly preferred is a compound of the general formula (I) in which R is phenyl, R 1 is te/t-butoxy, and X 1 is benzyl or p-methoxybenzyl.

According to the present invention the β-phenylisosehne derivatives of the general formula I can be advantageously obtained directly by the process of the invention with excellent enantio- and diastereoselectivity. The process of the invention comprises fewer steps than the non-catalytic processes known in the art. The process of the invention includes a step similar to one described in WO2008/043798 directed to the preparation of precursors of compounds of general formula (I).

The process of the present invention comprises a first step comprising the reaction between a N-carbonyl imine of the general formula II, R-C=N-CO-OR 1 , in which Ar and R 1 have the same meaning as above, with a protected α- oxyaldehyde of the general formula III, X 1 O-CH 2 CHO, in which X 1 has the same meaning as above, in the presence of a chiral amine catalyst of the general formula IV R 2

O ,γ2

N " o w r ι H 2 .N} ' Ύ ' 2 ( IV )

H 2

wherein Y 2 is any Of CO 2 H, Ar 2 OSiR 3 , tetrazole, O=C-NHR, O=C-NH-SO 2 R, and the most preferred catalysts is (R)-proline,

and a second step, in which the β-amino-α-hydroxyaldhyde of the general formula V formed in the first step,

OX 1

in which R, R 1 and X 1 have the same meaning as above, is oxidized to the corresponding carboxylic acid of the general formula I. Suitable oxidants comprise NaCIO 2 , in particular in combination with butene. In a preferred embodiment the aldehyde of the general formula V is oxidized directly, that is, without purification, to the carboxylic acid of the general formula 1.

The process according to the invention is generally carried out by reaction the N-carbamate imine of the general formula Il with the protected α-oxyaldehyde of general formula III in the presence of a chiral amino acid or a derivative thereof of the general formula IV. Suitable amino acids and derivatives thereof comprise (R)-proline, (R)-proline tetrazoles, (R)-proline amides, (R)-proline sulfoneamides. (R)-proline is particularly preferred. In the process of the invention the desired enantiomeric form of the aldehyde of the general formula V is obtained in an enantiomeric excess of 99 % or more, that is, in essentially pure enantiomeric form.

The process of the invention is preferably carried out in a polar aprotic solvent, for instance acetonitrile, dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or /V-methyl pyrrolidone (NMP), at a temperature from -20 to 30 0 C, preferably at about room temperature (20-25 0 C). A catalyst loading of 5-30 mol-%, in particular of about 20 mol%, is preferred.

The product of general formula (V) can be oxidized in, for instance, te/t-butanol:H 2 O 2:1 (v/v) at a concentration of from about 0.05 to about 0.5 M, preferably at about room temperature (20-25 0 C). To the stirred solution isobutene (6-7 eqvivalents), KH 2 PO 4 (1 ,5-2 eq), and NaCIO 2 (3-4 eq) are added sequentially. The resulting mixture is stirred at room temperature to form the desired product of the general formula (I) for a time sufficient to consume 95 % or more of compound V..

According to a preferred aspect of the invention, the compound of general formula I is used to prepare a methyl or other aliphatic or aromatic carboxylic ester of the general formula Vl

wherein R, R 1 and X 1 are defined as above and Me is straight or branched CrCβ alkyl, in particular methyl and ethyl.

Another preferred aspect of the invention comprises selective removal of the protecting group X 1 from a compound of the general formula Vl for preparing a β-amino-α-hydroxy carboxylic acid derivative of the general formula VII

wherein R and R 1 are defined as above. Still another preferred aspect of the invention comprises selective removal of the protecting group R 1 from a compound of the general formula Vl to prepare a β- amino-α-hydroxy carboxylic acid derivative of the general formula VIII

NH 2 O

(VIM)

R OMe

OX 1

wherein R is defined as above and X 1 is H.

The invention will now be explained in greater detail by reference to a number of preferred embodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS

A. Stereoselective preparation of aldehyde derivatives of β-isosehne

Example 1. (2R,3S)-2-fert-Butyldimethylsilyloxy-3-fert-butoxycarbonyl- amino-3-phenylpropanal (10). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in DMF (10 ml_) at 4 0 C was added (R)-proline (20 mol%), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 10 were combined, and the solvent evaporated under reduced pressure. The title compound 10 was recovered in form of a colourless oil; yield 12%, diastereomeric ratio (dr) >19:1 , enantiomeric excess (ee), 99%. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, - 5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The ratio of enantiomers was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = + 10.5 (c=1.0, CHCI 3 ). Example 2. (2/?,3S)-2-fert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (11). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 4 0 C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. Next, the reaction was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 11 were combined, and the solvent evaporated under reduced pressure. The title compound 11 was obtained as a colourless oil in 36% yield; dr >19:1 ; ee >99%l. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = + 10.5 (c=1.0, CHCI 3 ).

Example 3: (2/?,3S)-2-fert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (12). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in NMP (10 ml_) at 4 0 C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 12 were combined, and the solvent evaporated under reduced pressure. The title compound 12 was obtained as a colourless oil in 24 % yield; dr >19:1 ; ee 99 %. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), - 0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /- PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = + 10.5 (c=1.0, CHCI 3 ).

Example 4. (2R,3S)-2-tert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (13). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyl-oxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 13 were combined, and the solvent evaporated under reduced pressure. The title compound 13 was obtained as a colourless oil in 56% yield; dr >19:1 ; ee 99%. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = + 10.5 (c=1.0, CHCI 3 ).

Example 5. (2S,3/?)-2-tert-Butyldimethylsilyloxy-3-fert-butoxy-carbonyl - amino-3-phenylpropanal (14). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (S)-proline (20 mol %), and the reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc). Fractions containing pure aldehyde 14 were combined, and the solvent removed under reduced pressure. The title compound 14 was obtained in 49% yield as a colourless oil; dr >19:1 dr; ee 99%. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = -10.5 (c=1.0, CHCI 3 ).

Example 6. (2S,3/?)-2-fert-Butyldimethylsilyloxy-3-tert-butoxy- carbonylamino-3-phenylpropanal (15). To a stirred solution of N-tert- butoxycarbonylbenzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyl- oxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added frans-hydroxy-(S)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 15 were combined, and the solvent evaporated. The title compound 15 was obtained as a colourless oil in 6 % yield: dr >19:1 ; ee 99 %. 1 H NMR (400 MHz, CDCI 3 ): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d,

J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), - 0.14 (s, 3H), -0.34 (s, 3H); 13 C NMR (100 MHz, CDCI 3 ): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C 20 H 33 NO 4 Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /- PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 16.6 min; minor enantiomer, t R = 24.1 min; [α] D 25 = -10.5 (c=1.0, CHCI 3 ).

Example 7. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanal (16). To a stirred solution of /V-te/t-butoxycarbonylbenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 mL) at 23 0 C was added (R)-proline (20 mol%), and the reaction mixture vigorously stirred for 7 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 16 were combined, and the solvent evaporated. The title compound 16 was obtained as a colourless oil in 60% yield; dr >19:1 dr; ee 99%. 1 H NMR (400 MHz): δ = 9.73-9.72 (m, 1 H), 7.37-7.23 (m, 8H), 7.10-7.06 (m, 2H), 5.52 (bs, 1 H), 5.24 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.39 (d, J=11.6Hz, 1 H), 4.04 (bs, 1 H), 1.40 (s, 9H); 13 C NMR (100 MHz): 201.2, 155.2, 139.4, 136.7, 128.8, 128.7, 128.4, 128.3, 127.9, 126.8, 86.0, 80.3, 73.6, 54.3, 28.5; HRMS (ESI): calcd for [M+Na] (C 2 IH 25 NO 4 ) requires m/z 378.1676, found 378.1671. The enantiomeric excess was determined by HPLC with an AD column (n-hexane: /-PrOH = 90:10, λ = 220 nm), 0.5 ml/min; major enantiomer, t R = 15.9 min; minor enantiomer, t R = 28.2 min; [α] D 25 = + 29.0 (c=1.0, CHCI 3 ).

Example 8. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-

(naphthalene-2-yl)propanal (17). To a stirred solution of N-tert- butoxycarbonylnaphthylimine (1.0 equiv, 2.5 mmol) and 2- benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 17 were combined, and the solvent evaporated under reduced pressure. The title compound 17 was obtained as a yellow oil in 60% yield; dr 95:5 dr; ee 99%. 1 H NMR (400MHz, CDCI 3 ): δ - 9.79 (s, 1 H), 7.87-7.77 (m, 4H), 7.54-7.44 (m, 3H), 7.26-7.14 (m, 3H), 7.05 (d, J=7.6Hz, 2H), 5.78 (d, J=8.8Hz, 1 H), 5.48 (d, J=8.8Hz, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.37 (d, J=11.6Hz, 1 H), 4.15 (bs, 1 H), 1.42 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 201.3, 155.4, 136.9, 136.7, 133,5, 133.1 , 128.7, 128.6, 128.4, 128.4, 128.3, 127.9, 126.6, 126.3, 125.8, 124.9, 86.0, 80.4, 73.7, 54.5, 28.5; HRMS (ESI): calcd. for [M+Na] (C 25 H 27 NO 4 ) requires m/z 428.1832, found 428.1842. The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 254 nm) 1.0 ml/min, syn-diastereomer: t R major enantiomer = 9.4 min, t R minor enantiomer = 19.3 min; [α] D = + 40.0 (c=1.0, CHCI 3 ).

Example 9. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanal (18). To a stirred solution of /V-te/t-butoxycarbonylbenzylimine (1.0 equiv, 50 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 55 mmol) in CH 3 CN (200 mL) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 10 h. The reaction was quenched by extraction with EtOAc and H 2 O. The combined organic layers were dried with Na 2 SO 4 , concentrated under reduced pressure, loaded on a silica-gel column, and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 18 were combined, and the solvent evaporated under reduced pressure. The title compound 18 was obtained as a colourless oil in 61 % yield; dr >19:1 ; ee 99%. 1 H NMR (400 MHz): δ = 9.73-9.72 (m, 1 H), 7.37-7.23 (m, 8H), 7.10-7.06 (m, 2H), 5.52 (bs, 1 H), 5.24 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.39 (d, J=11.6Hz, 1 H), 4.04 (bs, 1 H), 1.40 (s, 9H); 13 C NMR (100 MHz): 201.2, 155.2, 139.4, 136.7, 128.8, 128.7, 128.4, 128.3, 127.9, 126.8, 86.0, 80.3, 73.6, 54.3, 28.5; HRMS (ESI): calcd for [M+Na] (C 2 iH 25 NO 4 ) requires m/z 378.1676, found 378.1671. The enantiomeric excess was determined by HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 220 nm), 0.5 mL/min; major enantiomer, t R = 15.9 min; minor enantiomer, t R = 28.2 min; [α] D 25 = + 29.0 (c=1.0, CHCI 3 ).

Example 10. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methylphenyl)propanal (19). To a stirred solution of /V-te/t-butoxycarbonyl-4- methylbenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 19 were combined, and the solvent evaporated. The title compound 19 was obtained as a colourless oil in 56% yield; dr 3:1 ; ee 99 %. 1 H NMR (400 MHz, CDCI 3 ): δ(antf) = 9.70 (s, 1 H), 9.48 * (bs, 0.3H), 7.36-7.08 (m, 12H), 5.50 (bs, 1 H), 5.20 (bs, 0.3H), 5.14 * (bs, 0.3H), 5.04 * (bs, 0.3H), 4.70 * (d, J=11.6 hz, 0.3H), 4.60 (d, J=11.2Hz, 1 H), 4.52 * (d, J=12Hz, 0.3H), 4.42 (d, J=12Hz, 1 H), 4.10 * (m, 0.3H), 4.02 (bs, 1 H), 2.36 (s, 3H), 2.33 * (s, 1 H), 1.40(s, 12H); 13 C (100MHz, CDCI 3 ): 21.3, 28.5, 54.1 , 73.6, 80.2, 86.1 , 126.7, 127.9, 128.3, 128.4, 128.7, 128.8, 129.4, 136.8, 137.5, 155.2, 201.3; HRMS (ESI): calcd for [M+Na] (C 22 H 27 NO 4 ) requires m/z 392.1839, found 392.1832; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 220 nm) 0.5 ml/min; syn-diastereomer: major enantiomer, t R = 14.60 min; minor enantiomer, t R = 23.25 min; [α] D = +22.0 for dr 3:1 (symanti) (c=1.0, CHCI 3 ).

Example 11. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methoxyphenyl)propanal (20). To a stirred solution of /V-te/t-butoxycarbonyl-4- methoxybenzyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 20 were combined, and the solvent evaporated under reduced pressure. The title compound 20 was obtained as a colourless oil in 52% yield; dr 9:1 ; ee 99%. 1 H NMR (400 MHz, CDCI 3 ): δ= 9.70 (s, 1 H), 7.40-7.20 (m, 6H), 7.16-7.11 (m, 1 H), 6.89-6.86 (d, J=8.4Hz, 2H), 5.48 (bs, 1 H), 5.18 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.42 (d, J=11.6Hz, 1 H), 4.00 (bs, 1 H), 3.82 (s, 3H),1.40 (s, 9H); 13 C NMR (100 MHz, CDCI 3 ): 28.3, 35.5, 73.4, 80.0, 85.9, 113.9, 127.8, 128.0, 128.1 , 128.2, 128.2, 128.5, 128.6, 136.6, 155.0, 201.3; HRMS (ESI): calcd for [M+Na] (C 22 H 27 NO 5 ) requires m/z 408.1781 , found 408.1785; The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 220 nm) 0.5 ml/min. Syn-diastereomer: major enantiomer, t R = 20.34 min; minor enantiomer, t R = 36.04 min; [α] D = +28.0 (c=1.0, CHCI 3 ).

Example 12. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4-chloro - phenyl)propanal (21). To a stirred solution of /V-te/t-butoxycarbonyl-4- chlorobenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a colourless oil in 22 % yield; dr 3:1 ; ee 99%. 1 H NMR (400 MHz, CDCI 3 ): δ(antι ) - 9.71 (s, 1 H), 9.46 * (bs, 1 H), 7.40-7.20 (m, 16H), 7.10-7.06 (m, 2H), 5.56 (bs, 1 H), 5.20 (bs, 1 H), 5.16 * (d, J=11.2Hz, 1 H), 5.04 * (bs, 1 H), 4.72 * (d, J=12Hz, 1 H), 4.63 (d, J=12Hz, 1 H), 4.52 * (d, J=12Hz, 1 H), 4.40 (d, J=12Hz, 1 H), 4.06 * (bs, 1 H), 3.98 (bs, 1 H), 1.40 (s, 18H); 13 C NMR (100MHz, CDCI 3 )(syn- diastereomer): 200.9, 154.9, 136.2, 133.5, 129.3, 128.7, 128.5, 128.3, 128.2, 128.0, 127.0, 85.3, 80.3, 73.4, 53.7, 28.3; HRMS (ESI): calcd for [M+Na] (C 2 iH 24 NO 4 CI) requires m/z 412.1286, found 412.1290; The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 93:7, λ = 220 nm) 0.5 mL/min; syn-diastereomer: major enantiomer, t R = 18.60 min; minor enantiomer, t R = 41.88 min. [a] D = +31.0 for dr 2:1 (syrr.anti) (c=1.0, CHCI 3 ).

Example 13. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(2-nitro- phenyl)propanal (22). To a stirred solution of /V-te/t-butoxycarbonyl-2- nitrobenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a yellow oil in 45 % yield; dr 95:5; ee 99%. 1 H NMR (400MHz, CDCI 3 ): δ - 9.81 (s, 1 H), 8.04 (d, J=7.6Hz, 1 H), 7.67-7.57 (m, 2H), 7.51 -7.45 (m, 1 H), 7.25-7.16 (m, 3H), 6.97 (d, J=6.4Hz, 2H), 6.00 (d, J=8.0Hz, 1 H), 5.70 (d, J=8.0Hz, 1 H), 4.70 (d, J=11.6Hz, 1 H), 4.34 (s, 1 H), 4.27 (d, J=7.2Hz, 1 H), 1.37 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 199.0, 154.9, 147.8, 136.4, 136.0, 133.6, 129.6, 128.8, 128.7, 128.5, 128.4, 125.5, 90.0, 80.7, 73.7, 49.9, 28.4; HRMS (ESI): calcd. for [M+Na] (C2iH 24 N 2 O6) requires m/z 423.1527, found 423.1525. The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 92:8, λ = 254 nm) 0.5 ml/min, syn-diastereomer: t R major enantiomer = 21.2 min, t R minor enantiomer = 25.8 min; [ά\o = - 13.0 (c=1.0, CHCI 3 ).

Example 14. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanal (23). To a stirred solution of /V-te/t-butoxycarbonyl-3- methoxybenzyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 23 were combined, and the solvent evaporated under reduced pressure. The title compound 23 was obtained as a colourless oil in 67% yield; dr 93:7; ee 99%. 1 H NMR (400MHz, CDCI 3 ): δ - 9.71 (s, 1 H), 7.28-7.23 (m, 4H), 7.11 -7.07 (m, 2H), 6.91 -6.88 (m, 1 H), 6.86-6.82 (m, 2H), 5.50 (d, J=7.6Hz, 1 H), 5.22 (d, J=7.6Hz, 1 H), 4.04 (s, 1 H), 3.77 (s, 3H), 1.40 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 201.2, 160.0, 155.2, 141.1 , 136.7, 129.8, 128.7, 128.4, 128.3, 119.0, 113.4, 112.5, 86.0, 80.3, 73.7, 55.4, 28.5; HRMS (ESI): calcd. for [M+Na] (C 22 H 27 NO 5 ) requires m/z 408.1781 , found 408.1790; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 254 nm) 1.0 ml/min, syn- diastereomer: t R major enantiomer = 10.1 min, t R minor enantiomer = 17.9 min; [α] D = + 24.0 (c=1.0, CHCI 3 ).

Example 15. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- (naphthalene-2-yl)propanal (24). To a stirred solution of N- benzyloxycarbonylnaphthylimine (1.0 equiv, 2.5 mmol) and 2- benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 24 were combined, and the solvent evaporated under reduced pressure. The title compound 24 was obtained as a colourless oil in 48% yield; dr 98:2 dr; ee 93%.[CC]D 25 = + 30.7 (c = 1.0, CHCI 3 ); 1 H NMR (400 MHz, CDCI 3 ) δ 9.76 (d, J = 1.2 Hz, 1 H), 7.83-7.76 (m, 5H), 7.52-7.15 (m, 10H), 7.06-7.04 (m, 2H), 5.90 (d, J = 8.4 Hz, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 5.11 -5.08 (m, 2H),4.61 -4.58 (m, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 4.14 (br s, 1 H); 13 C NMR (100 MHz, CDCI 3 ) δ 201.3, 155.7, 136.4, 136.2, 133.3, 133.1 , 128.7, 128.67, 128.65, 128.62, 128.57, 128.4, 128.3, 128.1 , 127.8, 126.5, 126.3, 125.7, 124.6, 116.2, 85.6, 73.8, 67.3, 55.0; The enantiomeric excess was determined by HPLC with an Ad column, (n- hexane: /-PrOH = 80:20, λ =220 nm), 1.0 mL/min; t R = major enantiomer 23.5 min, minor enantiomer 13.6 min. HRMS (ESI): calcd. for

[M+Na] + (C 28 H 25 NO 4 Na) requires m/z 462.1676, found 462.1689.

Example 16. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- phenylpropanal (25). To a stirred solution of /V-benzyloxycarbonyl benzyl imine (1.0 equiv, 50 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 55 mmol) in CH 3 CN (200 mL) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 10 h. The reaction was quenched by extraction with EtOAc and H 2 O. The combined organic layers were dried with Na 2 SO 4 , concentrated under reduced pressure, loaded on a silica-gel column, and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 25 were combined, and the solvent evaporated under reduced pressure. The title compound 25 was obtained as a colourless oil in 72% yield; dr 75:25; ee 98%.[CC]D 25 = + 16.6 (c = 1.0, CHCI 3 ); 1 H NMR (400 MHz, CDCI 3 ) δ 9.72 (s, 1 H), 7.73-7.08 (m, 15H), 5.80 (d, J = 8.8 Hz, 1 H), 5.30 (d, J = 8.8 Hz, 1 H), 5.11 -5.07 (m, 2H),4.61 -4.58 (m, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 4.05 (br s, 1 H); 13 C NMR (100 MHz, CDCI 3 ) δ 201.3, 155.7, 136.4, 133.3, 128.7, 128.6, 128.5, 128.3, 127.8, 126.5, 126.3, 125.7, 124.6, 116.2, 85.6, 73.8, 67.3, 55.0; The enantiomeric excess was determined by HPLC with an Ad column, (n-hexane: /- PrOH = 80:20, λ =220 nm), 1.0 mL/min; t R = major enantiomer 11.4 min, minor enantiomer 24.9 min. HRMS (ESI): calcd. for [M+Na] + (C 24 H 23 NO 4 Na) requires m/z 412.1519, found 412.1518.

Example 17. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- (cinnamoyl)propanal (26). To a stirred solution of /V-te/t-butoxycarbonyl-3- cinnamoyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH 3 CN (10 ml_) at 23 0 C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 26 were combined, and the solvent evaporated under reduced pressure. The title compound 26 was obtained as a colourless oil in 52% yield; dr 67:33; ee 98%. Compound 26 was reduced to the corresponding alcohol 26a with NaBH 4 . Data for compound 26a: white solid. 1 H NMR (400MHz, CDCI 3 ): δ - 7.36-7.26 (m, 10H), 6.59 (dd, J=1.2Hz, J ' =15.6Hz, J " =2.0Hz, 1 H), 6.19 (dd, J=6.4Hz, J ' =12Hz, J " =6.0Hz, 1 H), 5.0 (d, J=8.8Hz, 1 H), 4.60 (ddd, J=11.6Hz, J ' =9.6Hz, J " =11.2Hz, 2H), 3.78-3.66 (m, 1 H), 3.58- 3.48 (m, 1 H), 3.18 (bs, 1 H), 1.47 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 156.9, 138.1 , 136.9, 131.4, 128.8, 128.7, 128.3, 128.2, 127.9, 126.6, 81.4, 80.5, 73.6, 61.2, 52.6, 28.6; HRMS (ESI): calcd. for [M+Na] (C 23 H 29 NO 4 ) requires m/z 406.1989, found 406.1979; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 254 nm) 0.5 ml/min, syn-diastereomer: t R minor enantiomer = 14.3 min, t R major enantiomer = 16.9 min; anf/ ' -diastereomer: t R minor enantiomer = 21.8 min, t R major enantiomer = 30.4 min [α] D = +19.5 (c=1.0, CHCI 3 ).

B. Oxidation of β-isoserine aldehydes to carboxylic acids

Example 18. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanoic acid (27). To a mixture of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal (16; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 ml_) and H 2 O (2.0 ml_) was added sequentially KH 2 PO 4 (54.4 mg, 4.0 mmol) and NaCIO 2 (36 mg, 4.0 mmol) at 23 0 C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford 320 mg (85%) of the title compound 27 as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ = 7.37- 7.19 (m, 8H), 7.04-7.00 (m, 2H), 5.80 (d, J=8Hz, 1 H), 5.30 (d, J=8.8Hz, 1 H), 4.70 (d, J=1 OHz, 1 H), 4.32 (d, J=1 OHz, 1 H), 4.20 (bs, 1 H), 1.42 (s, 9H); 13 C NMR (100 MHz, CDCI 3 ): 173.4, 155.9, 139.5, 136.6, 128.8, 128.6, 128.2, 128.0, 127.8, 126.9, 80.6, 80.1 , 73.2, 56.0, 28.5; HRMS (ESI): calcd for [M+Na] (C 2 IH 25 NO 5 ) requires m/z 394.1625, found 394.1635. [α] D 25 = +19.0 (c=1.0, CHCI 3 ).

Example 19. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanoic acid (28). To a mixture of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal (16; 5 mmol), isobutene (0.5 ml_), te/t-butanol (20.0 ml_) and H 2 O (10.0 ml_) was added sequentially KH 2 PO 4 (272 mg, 20.0 mmol) and NaCIO 2 (180 mg, 20.0 mmol) at 23 0 C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford 1.5g (80%) of the title compound 28 as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ = 7.37- 7.19 (m, 8H), 7.04-7.00 (m, 2H), 5.80 (d, J=8Hz, 1 H), 5.30 (d, J=8.8Hz, 1 H), 4.70 (d, J=1 OHz, 1 H), 4.32 (d, J=1 OHz, 1 H), 4.20 (bs, 1 H), 1.42 (s, 9H); 13 C NMR (100 MHz, CDCI 3 ): 173.4, 155.9, 139.5, 136.6, 128.8, 128.6, 128.2, 128.0, 127.8, 126.9, 80.6, 80.1 , 73.2, 56.0, 28.5; HRMS (ESI): calcd for [M+Na] (C 2 IH 25 NO 5 ) requires m/z 394.1625, found 394.1635. [α] D 25 = +19.0 (c=1.0, CHCI 3 ). Example 20. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methylphenyl)propanoic acid (29). To a mixture of (2R,3S)-2-Benzyloxy-3-te/t- butoxy-carbonylamino-3-(4-nnethylphenyl)propanal (19; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 mL) and H 2 O (2.0 ml_) was added sequentially KH 2 PO 4 (54.4 mg, 4.0 mmol) and NaCIO 2 (36 mg, 4.0 mmol) at 23 0 C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 29 as a colorless oil in 64% yield. 1 H NMR (400MHz, CDCI 3 ): δ - 10.0 (bs, 1 H), 7.25-7.20 (m, 5H), 7.15 (d, J=11.6Hz, 2H), 7.07 (d, J=5.2Hz, 2H), 5.80 (d, J=8.8Hz, 1 H), 5.28 (d, J=9.2Hz, 1 H), 4.70 (d, J=10.8Hz, 1 H), 4.34 (d, J=8.0Hz, 1 H), 4.20 (s, 1 H), 2.36 (s, 3H), 1.43 (s, 9H); 13 C NMR

(100MHz, CDCI 3 ): 173.5, 155.9, 137.4, 136.8, 136.6, 129.3, 128.5, 128.3, 128.2, 126.8, 80.6, 80.2, 73.2, 55.8, 28.5, 21.3; HRMS (ESI): calcd. for [M+Na] (C 22 H 27 NO 5 ) requires m/z 408.1781 , found 408.1778; [α] D = + 17.0 (c=1.0, CHCI 3 ).

Example 21. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanoic acid (30). To a mixture of (2R,3S)-2-Benzyloxy-3- te/t-butoxy-carbonylamino-3-(3-methoxyphenyl)propanal (23; 1 mmol), isobutene (0.1 mL), te/t-butanol (4.0 mL) and H 2 O (2.0 mL) was added sequentially KH 2 PO 4 (54.4 mg, 4.0 mmol) and NaCIO 2 (36 mg, 4.0 mmol) at 23 0 C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 30 as a colorless oil in 74% yield. 1 H NMR (400MHz, CDCI 3 ): δ - 9.00 (bs, 1 H), 7.25-7.19 (m, 4H), 7.04 (d, J=2.8Hz, 2H), 6.92 (d, J=7.6Hz, 1 H), 6.88-6.81 (m, 2H), 5.80 (d, J=9.2Hz, 1 H), 5.28 (d, J=8.8Hz, 1 H), 4.70 (d, J=7.6Hz, 1 H), 4.32 (d, J=7.6Hz, 1 H), 4.20 (s, 1 H), 3.76 (s, 3H), 1.43 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 173.5, 159.9, 155.9, 136.8, 129.6, 128.5, 128.5, 128.3, 128.2, 119.2, 113.4, 112.4, 80.1 , 73.1 , 55.4, 28.5; HRMS (ESI): calcd. for [M+Na] (C 22 H 27 NO 6 ) requires m/z 424.1731 , found 424.1726; [α] D = + 36.7 (c=1.0, CHCI 3 ).

Example 22. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- (naphthalene-2-yl)propanoic acid (31). To a mixture of (2R,3S)-2-Benzyloxy- 3-benzyloxy-carbonylamino-3-(naphthalene-2-yl)propanal (24; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 ml_) and H 2 O (2.0 ml_) was added sequentially KH 2 PO 4 (54.4 mg, 4.0 mmol) and NaCIO 2 (36 mg, 4.0 mmol) at 23 0 C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 31 as a yellow oil in 80% yield. 1 H NMR (400MHz, CDCI 3 ): δ - 8.80-8.20 (bs, 1 H), 7.86-7.76 (m, 4H), 7.52-7.42 (m, 3H), 7.20-7.04 (m, 3H), 6.98 (d, J=7.6Hz, 2H), 5.91 (d, J=9.6Hz, 1 H), 5.48 (d, J=9.2Hz, 1 H), 4.70 (d, J=7.6Hz, 1 H), 4.30 (d, J=8.8Hz, 1 H), 1.44 (s, 9H); 13 C NMR (100MHz, CDCI 3 ): 173.4, 156.0, 137.0, 136.5, 133.4, 133.1 , 128.9, 128.5, 128.4, 128.3, 127.8, 126.4, 126.2, 125.8, 125.0, 79.9, 73.3, 56.2, 28.5; HRMS (ESI):calcd for [M+Na] (C 25 H 27 NO 5 ) requires m/z 444.1781 , found 444.1790. [α] D = + 37.5 (c=1.0, CHCI 3 ) .

C. Esterification of β-isoserine derivatives

Example 23. Methyl (2R,3S)-2-benzyloxy-3-tert-butoxy-carbonylamino-3- phenylpropanoate (32). To a solution of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanoic acid (26; 80 mg, 0.22 mmol) in toluene:MeOH (4:1 , 2.5 ml_) was added slowly thmethylsilyldiazometane (2.0 M in ether, 0.117 ml_, 0.23 mmol). After 30 min of vigorous stirring the reaction was quenched with acetic acid, and the solution evaporated. The residue was purified by silica-gel chromatography, eluant pentane/EtOAc (3:1 ). The title compound 32 was obtained as yellow oil in 95% yield (80 mg). 1 H NMR (400 MHz, CDCI 3 ): δ = 7.36-7.18 (m, 8H), 7.02-6.98 (m, 2H), 4.68 (d, J= 11.6Hz, 1 H), 4.26 (d, J= 12Hz, 1 H), 4.14 (bs, 1 H), 3.78 (s, 3H), 1.40 (s, 9H); 13 C NMR (100 MHz, CDCI 3 ): 170.9, 155.4, 139.7, 136.9, 128.6, 128.5, 128.1 , 127.7, 126.9, 80.4, 80.2, 73.0, 56.3, 52.5, 28.5; HRMS (ESI): calcd. for [M+Na] (C 22 H 27 NO 5 ) requires m/z 408.1781 , found 408.1788; [α] D = +25.0 (c=1.0, CHCI 3 ).

D. Selective removal of protective groups from β-isoserine esters

Example 24. Methyl (2/?,3S)-2-hydroxy-3-fert-butoxy-carbonylamino-3- phenylpropanoate (33).To a solution of methyl (2R,3S)-2-benzyloxy-3-te/t- butoxy-carbonylamino-3-phenylpropanoate (32; 55 mg, 0.14 mmol) in MeOH (4 ml_), palladium on carbon (5 mg) was added. The reaction mixture was stirred under H 2 (90 psi) atmosphere. When the starting material could no longer be detected by TLC, the solution was filtered through celite and concentrated to give the title compound as white crystals in 99% yield (42 mg). 1 H NMR (400 MHz, CDCI 3 ): δ = 7.38-7.18 (m, 5H), 5.44 (d, J=9.6Hz, 1 H), 5.22 (d, J=8.8Hz, 1 H), 4.46 (bs, 1 H), 3.83 (s, 3H), 1.40 (s, 9H); 13 C NMR (100 MHz, CDCI 3 ): 173.6, 155.4, 139.3, 128.8, 128.0, 126.9, 80.2, 73.8, 56.3, 53.3, 28.5; HRMS (ESI): calcd for [M+Na] (Ci 5 H 2 iNO 5 ) requires m/z 318.1312, found 318.1313; [α] D = + 13.2 (c=1.0, CHCI 3 ).

Example 25. Methyl (2R,3S)-2-benzyloxy-3-amino-3-phenyl-propanoate (32).

A solution of methyl (2R,3S)-2-benzyloxy-3-te/t-butoxy-carbonylamino-3- phenylpropanoate (32; 35 mg, 0.9 mmol) in CH 2 CI 2 /HCOOH (1 :1 ;1 ml_) was stirred overnight. The reaction mixture was neutralized with aqueous NaHCO 3 , and the aqueous phase extracted with CH 2 CI 2 . The organic phase was dried with Na 2 SO 4 and evaporated. The residue was purified by silica-gel chromatography to give 20 mg (78 %) of the title compound 32 in form of white crystals. 1 H NMR (400 MHz, CDCI 3 ): δ = 7.35-7.25 (m, 8H), 7.20-7.16 (m, 2H), 4.65 (d, J= 11.6Hz, 1 H), 4.44 (d, J= 11.6Hz, 1 H), 4.32 (d, J=5.2Hz, 1 H), 4.06 (d, J=5.2Hz, 1 H), 3.61 (s, 3H), 2.25 (bs, 2H); 13 C NMR (100 MHz, CDCI 3 ): 171.7, 141.3, 137.2, 128.6, 128.6, 128.3, 128.1 , 128.0, 127.4, 83.5, 73.2, 58.4, 52.1 ; HRMS (ESI): calcd for [M+H] (Ci 7 Hi 9 NO 3 ) requires m/z 286.1438, found 286.1439; [α] D = + 78.4 (c=1.0, CHCI 3 ).

E. Preparation of protected docetaxel derivative 33.

33 Example 26. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo - 7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)-11 -taxen-13α-yl (2R, 3S)-3- (fert-butoxycarbonylamino)-3-phenyl-2-(benzyloxy)-propionate (33). (2R, 3S)-2-(Benzyloxy)-3-(fe/t-butoxycarbonylamino)-3-phenylpropa noic acid 28 (1.40 g, 3.77 mmol) was dissolved in dry toluene (35 ml_) under nitrogen atmosphere in a single necked 100 ml round bottomed flask equipped with magnetic stirrer. Dicyclohexylcarbodiimide (0.778 g, 3.77 mmol) is added to the mixture which is left under stirring for 5 minutes at room temperature. Then 4- (N,N-dimethylamino)pyhdine (0.087 g, 0.71 mmol) and 4-acetoxy-2α- benzoyloxy-5β,20-epoxy-1 ,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2- trichloroethoxycarbonyloxy)-11-taxene (0.650 g, 0.73 mmol) are added at once. The mixture is left under stirring for 26 hours at room temperature. Then ethyl acetate (200 ml) is added and the organic phase is washed with water (30 ml), sodium hydrogen carbonate (2x30 ml), and saturated sodium chloride solution (30 ml) and finally dried with anhydrous sodium sulphate. The organic phase is filtered and evaporated to give a residue which is purified by silica gel chromatography to give 0.660 g (73% yield) of 4-acetoxy-2α-benzoyloxy-5β,20- epoxy-1 ,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-thchloroethoxycarbo nyloxy)-11 - taxen-13α-yl (2R, 3S)-3-(te/t-butoxycarbonylamino)-3-phenyl-2-(benzyloxy)- propionate 33.

E. Preparation of protected docetaxel derivative 34.

34

Example 27. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy- 9- oxo-11 -taxen-13α-y I {2R, 3S)-3-terf-butoxycarbonylamino-3-phenyl-2- (benzyloxy)propionate (34). Docetaxel derivative 33 (0.590 g, 0.471 mmol) was dissolved in glacial acetic acid (30 ml) under nitrogen atmosphere in a 100 ml single-necked flask equipped with magnetic stirrer. Methanol (30 ml) is then added followed by zinc/copper mixture (2.60 g, 2.2Og of zinc and 0.40 g of copper). The solution is heated for 2 hours at 65 0 C then cooled to room temperature, diluted with ethyl acetate (40 ml) and filtered through Celite which is washed afterwards with ethyl acetate (4x40ml). The solvent is evaporated and the residue is purified by silica gel chromatography to give 0.230 g (55 % yield) of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1 ,7β,10β-thhydroxy-9-oxo-11 -taxen- 13α-yl (2R, 3S)-3-terf-butoxycarbonylamino-3-phenyl-2-(benzyloxy)propion ate 34. 1 H NMR (400 MHz, CDCI 3 ): δ - 8.10-8.04 (d, J=8.0Hz, 2H), 7.62-7.57 (m, 1 H), 7.51-7.45 (m, 2H), 7.40-7.20 (m, 10H), 7.04 (bs, 1 H), 6.26 (m, 1 H), 5.66 (d, J=7.2Hz, 1 H), 5.58 (d, J=9.2Hz, 1 H), 5.24 (s, 1 H), 4.92 (d, J=8.8Hz, 1 H), 4.68 (d, J=7.6Hz, 1 H), 4.34-4.10 (m, 5H), 3.90 (d, J=6.8Hz, 1 H), 2.60-2.45 (m, 1 H), 2.23 (s, 3H), 1.89 (s, 3H), 1.88-1.80 (m, 3H), 1.72 (s, 3H), 1.33 (s, 9H), 1.25 (s, 3H), 1.11 (s, 3H); 13 C NMR (I OOMHz, CDCI 3 ): 211.6, 170.7, 170.1 , 167.3, 138.9, 136.3, 136.0, 133.9, 130.4, 129.5, 128.9, 128.8, 128.5, 128.1 , 128.0, 126.8, 84.5, 81.2, 80.2, 79.1 , 76.8, 75.3, 74.7, 72.9, 72.1 , 71.8, 57.8, 56.1 , 46.6, 43.4, 37.0, 35.8, 28.5, 28.4, 26.6, 22.7, 21.2, 14.7, 10.2; HRMS (ESI): calcd. for [M+Na] (C50H59NO14) requires 920.3828, found 920.3805; [α] D = -36.0 (c=1.0, CHCI 3 ).

F. Preparation of protected docetaxel

docetaxel

Example 28. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy- 9- oxo-11-taxen-13α-yl (2R, 3S)-3-tert-butoxycarbonylamino-3-phenyl-2- hydroxypropionate (docetaxel). 4-acetoxy-2α-benzoyloxy-5β,20-epoxy- 1 ,7β,10β-thhydroxy-9-oxo-11-taxen-13α-yl (2R, 3S)-3-te/t-butoxycarbonylamino- 3-phenyl-2-(benzyloxy)propionate 34 (0.03 g, 0.037 mmol) was dissolved in methanol (3 ml) in a 10 ml single-necked round bottomed flask equipped with magnetic stirrer. Then palladium hydroxide (0.03 g, 0.21 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere (100 psi) at room temperature for 66 hours. The solution was then filtered through Celite and the solids were washed with methanol (5x1 OmI). Evaporation of the solvent gave white solid purified by silica gel chromatography to give 0.025 g (84% yield) of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1 ,7β,10β-thhydroxy-9-oxo-11-taxen-13α- yl (2R, 3S)-3-fe/t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (docetaxel).