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Title:
ANALOGUES OF ANGIOPTERLACTONE B AND A PROCESS FOR THE SYNTHESIS THEREOF
Document Type and Number:
WIPO Patent Application WO/2017/077549
Kind Code:
A1
Abstract:
The invention discloses a novel analogues of Angiopterlactone B of formula (I) and process for the synthesis thereof. Further the present invention discloses a total synthetic one pot process for the synthesis of Angiopterlactone B and its analogues comprises the reaction of the dihydro pyronones with Tetra-n-butylammonium fluoride (TBAF) in dry solvent for the time period ranging from 1-2 hours at the temperature ranging from 20-30°C, working up and subjecting the residue to column chromatography to obtain the product.

Inventors:
BHATTACHARYA ASISH KUMAR (IN)
KOTAMMAGARI THARUN KUMAR (IN)
Application Number:
IN2016/050376
Publication Date:
May 11, 2017
Filing Date:
November 02, 2016
Export Citation:
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Assignee:
COUNCIL SCIENT IND RES (IN)
International Classes:
C07D315/00; C07D325/00
Other References:
YONG-MING YU, JUN-SHAN YANG, CHAO-ZHONG PENG, VALERIE CAER, PU-ZHU CONG, ZHONG-MEI ZOU, YANG LU, SHI-YING YANG, YU-CHENG GU: "Lactones from Angiopteris caudatiformis", JOURNAL OF NATURAL PRODUCTS, vol. 72, no. 5, 22 May 2009 (2009-05-22), pages 921 - 924, XP002768141, DOI: 10.1021/np900027m
ROBERT A. HILL AND ANDREW SUTHERLAND: "Hot off the press", NATURAL PRODUCT REPORTS, vol. 26, 2009, pages 973 - 976, XP002768144
K.H. HOLLENBEAK; M.E. KUEHNE: "The Isolation and Structure Determination of the Fern Glycoside Osmundalin and the Synthesis of its Aglycone Osmundalactone", TETRAHEDRON, vol. 30, 1974, pages 2307 - 2316, XP002768142
J. NAT. PROD., vol. 72, 2009, pages 921 - 924
YUYONGMING, STUDIES ON THE CHEMICAL CONSTITUENTS AND BIOLOGICAL ACTIVITIES OF ANGIOPTERIS I CAUDATIFORMIS AND ASPLENIUM UNILATERALE, 2009
Attorney, Agent or Firm:
REMFRY & SAGAR (Sector 27 Gurgaon, Haryana 9, IN)
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Claims:
CLAIMS

1. A compound analogues of Angiopterlactone of formula (I).

Formula I

Wherein

R = hydrogen, alkyl, substituted alkyl, substituted aryl or substituted hetero aryl, O- alkyl, substituted alkyl, substituted aryl or substituted hetero aryl.

The compound of formula (I) as claimed in claim 1, wherein said compound is selected from (3S,3aS,4aR,5R,8aS,8bR)-3-((R)-l-hydroxyethyl)-5-methylhexahydro- lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione, (3S,3aR,4aR,5S,8aS,8bS)-3-((S)-l- hydroxyethyl)- 5 -methylhexahydro

-lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione, (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-

1- hydroxyethyl)-5-methylhexahydro-lH-furo[3',4':4,5]-furo[2,3-c]pyran-l,7(3H)- dione, (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-methoxyethyl)-5- (methoxymethyl)hexahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione, (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-2-(benzyloxy)-l-hydroxyethyl)-5-((benzyloxy) methyl)-hexahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran- 1,7(3 H)-dione,(R)-2-

((3S,3aS,4aS,5R,8aR,8bR)-l,7-dioxo-5-((((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6- methoxytetrahydro-2H-pyran-2-carbonyl)oxy)methyl) octahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-3-yl)-2-hydroxyethyl (2R,3S,4S,5R,6S)- 3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-carboxylate, (R)-2-hydroxy-

2- ((3S,3aS,4aS,5R,8aR,8bR)-5-((nicotinoyloxy) methyl)- l,7-dioxooctahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-3-yl)ethyl nicotinate, ((3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-((2-iodobenzoyl) oxy)ethyl)-l,7-dioxooctahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-5-yl)methyl2- iodobenzoate.

A total synthetic one pot process for the synthesis of compound of formula (II) as claimed in claim 1 comprises reacting the dihydro pyronones with Tetra-n- butylammonium fluoride (TBAF) in dry solvent for the time period ranging from 1-2 hours at the temperature ranging from 20 to 30 °C to obtain the desired product.

The process as claimed in claim 1, wherein said dihydro pyronones is selected from Lactone 1 to Lactone 9.

Lactone 1 Lactone 2 Lactone 3 Lactone 4

Lactone 5 Lactone 6 Lactone 7

Lactone 8 Lactone 9 The process as claimed in claim 1, wherein said solvent is selected from cyclic ethers or alkyl ethers.

The process as claimed in claim 1, wherein said solvent is dry tetrahydrofuran, 1-4- dioxane, diethyl ether.

The process as claimed in claim 1, wherein the yield of said process is 60-65%.

Description:
ANGIOPTERLACTONE B, ANALOGUES AND PROCESS FOR SYNTHESIS

THEREOF

FIELD OF THE INVENTION:

The invention relates to a novel analogues of Angiopterlactone B of formula (I) and process for the synthesis thereof.

BACKGROUND AND PRIOR ART:

Angiopteris caudatiformis Hieron (Angiopteridaceae) is an ancient fern species that grows mainly in Asia. Its rhizome is known as "ji ma" in Dai folk medicine in China, and it is used to treat infectious diseases such as enteritis, dysentery, and tuberculosis. The rhizomes and fibrous roots of A. caudatiformis are also used as ingredients in treatments of cough with lung heat, venomous snake bite, furuncle, and bleeding wounds in Tu folk medicine in China. Angiopterlactone B (1), a unique lactone having a tricyclic system was isolated J. Nat. Prod. 2009, 72, 921-924) from the rhizome of Angiopteris caudatiformis. The structure of 1 was determined by NMR and MS methods, and confirmed by X-ray crystallography. The absolute configuration of 1 was assigned by application of the CD excitation chirality method and the modified Mosher's method and is represented herein.

Angiopterlactone B (1)

Thesis entitled "Radical cyclization routes to the synthesis of a-methylene cis-fused bicyclic systems, synthesis of (-)-osmundalactone, it's epimer and butyro-lactone moiety of Angiopterlactone A" discloses Angiopterlactone A is unique metabolite possessing dual- lactone skeleton, isolated from rhizome of Angiopteris caudatiformis and having insect antifeeding activity against Plutella xylostella and Heliothis virescens and slightly cytotoxic against HeLa cells, with an IC50 value of 68.8 μΜ. Thesis titled "Studies on the chemical constituents and biological activities of angiopteris caudatiformis and asplenium unilaterale" by YuYongMing, 2009 discloses the chemical constituents of Angiopteris caudatiformis were investigated for the first time in this thesis and 21 compounds were isolated and identified by modern chromatography and spectral analysis. Considering the importance of the compound Angiopterlactone B, and it various uses, it would be advantageous to have a completely synthetic approach for the preparation of the compound. Further, the molecule has not been explored for providing active analogues, derivatives, isomers and so on. OBJECTIVE OF THE INVENTION:

The main objective of the present invention is to provide a total synthetic one pot process of synthesis of Angiopterlactone B (1) and its various analogues.

Another objective of the present invention is to provide novel analogues of Angiopterlactone. SUMMARY OF THE INVENTION:

Accordingly, the present invention provide a novel analogues of Angiopterlactone of formula

(I).

Formula I

Wherein

R = hydrogen, alkyl, substituted alkyl, substituted aryl or substituted hetero aryl, O-alkyl, substituted alkyl, substituted aryl or substituted hetero aryl.

In an embodiment, the present invention provides a total synthetic one pot process for the synthesis of Angiopterlactone B and its analogues by base-catalyzed tandem Michael addition.

In another embodiment, the present invention provides comprises a total synthetic one pot process for the synthesis of Angiopterlactone B and its analogues comprises the reaction of the dihydro pyronones with tetra-n-butylammonium fluoride (TBAF) in dry solvent for the time period ranging from 1-2 hours at the temperature ranging from 20-30°C, working up and subjecting the residue to column chromatography to obtain the desired product.

In a preferred embodiment, said dihydro pyrones is selected from Lactone 1 to Lactone 9 as shown below.

Lactone 1 Lactone 2 Lactone 3 Lactone 4

Lactone 5 Lactone 6 Lactone 7

Lactone 8 Lactone 9

In another preferred embodiment, said solvent is selected from cyclic ethers or alkyl ethers. Still in another preferred embodiment, said solvent is dry tetrahydrofuran, 1-4-dioxane, diethyl ether.

Yet in another preferred embodiment, the yield of said process is 60-65% of the desired product.

Still yet in another preferred embodiment, corresponding ketones are used as starting materials to obtain different analogues of Angiopterlactones. The compound of formula I, Angiopterlactone B and its analogues find use as antibacterial agents and as antifeedant.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1: Circular Dichroism (CD) spectra of (3S,3aS,4aR,5R,8aS,8bR)-3-((R)-l- hydroxyethyl)-5-methylhexahydro-lH-furo[3',4':4,5]furo[2,3-c ]pyran-l,7(3H)-dione and (3R,3aR,4aS,5S,8aR,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro

-lHfuro[3',4':4,5]-furo-[2,3-c]pyran-l,7(3H)-dione (Angiopterlactone B)

Fig. 2: Circular Dichroism (CD) spectra of enantiomers (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l- hydroxyethyl)-5-methylhexahydro-lH-furo[3',4':4,5]-furo[2,3- c]pyran-l,7(3H)-dione and (3S,3aR,4aR,5S,8aS,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro-lH- furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provide a novel compound analogues of Angiopterlactone of formula (I).

Formula I Wherein

R = hydrogen, alkyl, substituted alkyl, substituted aryl or substituted hetero aryl, O-alkyl, substituted alkyl, substituted aryl or substituted hetero aryl. In a preferred embodiment, said analogues of Angiopterlactone of formula (I) are selected from (3R,3aR,4aS,5S,8aR,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro

-lHfuro[3',4':4,5]-furo-[2,3-c]pyran-l,7(3H)-dione[Angiop terlactoneB(l)],

(3S,3aS,4aR,5R,8aS,8bR)-3-((R)-l-hydroxyethyl)-5-methylhe xahydro-lH- furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione[Compound (2)], (3S,3aR,4aR,5S,8aS,8bS)-3- ((S)-l-hydroxyethyl)-5-methylhexahydro-lH-furo[3',4':4,5]fur o[2,3-c]pyran-l,7(3H)-dione [Compound (3)], (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxyethyl)-5-methyl hexahydro-lH-furo[3',4':4,5]-furo[2,3-c]pyran-l,7(3H)-dione[ Compound(4)],

(3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-methoxyethyl)- 5-(methoxymethyl)hexahydro- lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione [Compound (5)],

(3R,3aS,4aS,5R,8aR,8bR)-3-((R)-2-(benzyloxy)-l-hydroxyeth yl)-5-((benzyloxy)methyl)- hexahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione [Compound (6)], (R)-2- ((3S,3aS,4aS,5R,8aR,8bR)-l,7-dioxo-5-((((2R,3S,4S,5R,6S)-3,4 ,5-tris(benzyloxy)-6- methoxytetrahydro-2H-pyran-2-carbonyl)oxy)methyl) octahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-3-yl)-2-hydroxy ethyl (2R,3S,4S,5R,6S)-3,4,5- tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-carboxylate [Compound (7)], (R)-2- hydroxy-2-((3S,3aS,4aS,5R,8aR,8bR)-5-((nicotinoyloxy)methyl) -l,7-dioxooctahydro-lH- furo[3',4':4,5]furo[2,3-c]pyran-3-yl)ethyl nicotinate [Compound (8)],

((3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-((2-iodobenzo yl)oxy)ethyl)- l,7-dioxooctahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-5-yl)m ethyl2-iodobenzoate

[Compound (9)].

In an embodiment, the present invention provides a total synthetic one pot process for the synthesis of Angiopterlactone B and its analogues by base-catalyzed tandem Michael addition.

Table 1 : Analogues of Angiopterlactone B from corresponding dihydropyrones

In another embodiment, the present invention provides comprises a total synthetic one pot process for the synthesis of Angiopterlactone B and its analogues comprises the reaction of the dihydro pyronones with Tetra-n-butylammonium fluoride (TBAF) in dry solvent for the time period ranging from 1-2 hours at the temperature ranging from 20-30°C, working up and subjecting the residue to column chromatography to obtain the product.

In a preferred embodiment, said dihydro pyronones is selected from Lactone 1 to Lactone 9 as shown below.

Lactone 1 Lactone 2 Lactone 3 Lactone 4

Lactone 5 Lactone 6 Lactone 7

Lactone 8 Lactone 9

In another preferred embodiment, said solvent is selected from cyclic ethers or alkyl ethers. Still in another preferred embodiment, said solvent is dry tetra hydro furan, 1-4-dioxane, diethyl ether.

Yet in another preferred embodiment, the yield of said process is 60-65% of the desired product.

The one pot process for the synthesis of Angiopterlactone B and its analogues of formula (I) is depicted in Scheme 1.

= H, Angiopterlactone B (1 )

R = O^lkyl sutelftutedalkyl/ai^substrtuted aryl

R = O-COR-,, Ft, = aikyl/substitutedalk l/aryl/substituted aryl Scheme 1. Synthesis of angiopterlactone B (1) and its analogues.

The compound of formula I, Angiopterlactone B and its analogues find use as antibacterial agents and as antifeedant. To obtain different analogues of Angiopterlactone s, corresponding dihydropyrones are used as starting materials, refer Table 1.

Fig. 1 shows Circular dichroism (CD) spectra are recorded on a JASCO model type J-815 spectropolarimeter. In the figure 1 one of the enantiomers (3S,3aS,4aR,5R,8aS,8bR)-3-((R)- l-hydroxyethyl)-5-methylhexahydro-lH-furo[3',4':4,5]furo[2,3 -c]pyran-l,7(3H)-dione shows positive sign and other enantiomer (3R,3aR,4aS,5S,8aR,8bS)-3-((S)-l-hydroxyethyl)-5- methylhexahydro-lHfuro[3',4':4,5]-furo-[2,3-c]pyran-l,7(3H)- dione (Angiopterlactone B) showed negative as shown in the graph. In the figure 2 one of the enantiomers (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxyethyl)-5- methyl hexahydro-lH-furo[3',4':4,5]-furo[2,3-c]pyran-l,7(3H)-dione shows positive sign and the other enatiomer (3S,3aR,4aR,5S,8aS,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro- lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione showed negative sign as shown in the graph. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Example 1: General procedure for the preparation of Angiopterlactone B and its analogues

To a solution of 5,6-dihydropyron-2-ones (0.45 mmol) in dry THF at room temperature, tetrabutyl ammonium fluoride (TBAF) in THF was added (0.9 mmol, 1.0 M) and the resulting solution was stirred further for 1.5-2h. The reaction mixture was diluted with ethyl acetate and water was added. Organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3x10 mL), and the combined organic fractions dried over anhydrous Na 2 S0 4 , evaporated and the residue was subjected to column chromatography to furnish the desired products in 60-65% yield. A. Synthesis of (3R,3aR,4aS,5S,8aR,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro -lHfuro[3',4':4,5]-furo-[2,3-c]pyran-l,7(3H)-dione [Angiopterlactone B (1)]:

TLC: R f = 0.35 (50% Acetone/ CHC1 3 ).

m.p.: 199-201° C.

[a] D 25 = -24 (c = 0.04, EtOAc).

Yield: 24.8 mg (62%). 1H NMR ((CD 3 ) 2 CO, 400 MHz): δ Η = 4.65 (dd, J = 5.5, 4.1 Hz, 1 H), 4.46 (dd, J = 6.4, 1.4 Hz, 1 H), 4.25 - 4.19 (m, 2 H), 4.11 (d, J = 4.1 Hz, 1 H), 4.08 - 4.00 (m, 1 H), 3.55 (dd, J = 11.0, 5.5 Hz, 1 H), 3.44-3.37 (m, 1 H), 3.07 (d, J = 16.5 Hz, 1 H), 2.68 - 2.61 (m, 1 H), 1.35 (d, = 6.4 Hz, 3 H), 1.23 (d, = 6.4 Hz, 3 H).

13 C NMR ((CD 3 ) 2 CO, 100 MHz): 0 C = 173.9, 169.8, 85.0, 79.2, 78.7, 72.8, 65.9, 48.8, 36.5, 27.6, 17.9, 16.2.

HRMS (ESI) m/z calcd. For Ci 2 Hi 6 0 6 Na [M + Na] + : 279.0839, found: 279.0835.

B. Synthesis of (3S,3aS,4aR,5R,8aS,8bR)-3-((R)-l-hydroxyethyl)-5-methylhexah ydro- lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione [Compound (2)]:

TLC: R f = 0.34 (50% Acetone/ CHC1 3 ).

m.p.: 199-200° C.

[«] D 25 = +33 (c = 0.04, EtOAc).

Yield: 30 mg (60%).

1H NMR ((CD 3 ) 2 CO, 400 MHz): δ Η = 4.67 (dd, = 5.4, 3.9 Hz, 1 H), 4.47 (dd, = 6.6, 1.7 Hz, 1 H), 4.27 - 4.21 (m, 2 H), 4.15 (d, = 4.2 Hz, 1 H), 4.10 - 4.01 (m, 1 H), 3.59 - 3.54 (m, 1 H), 3.46 - 3.38 (m, 1 H), 3.08 (d, J = 16.4 Hz, 1 H), 2.66 (dd, J = 16.4, 9.0 Hz, 1 H), 1.37 (d, J = 6.6 Hz, 3 H), 1.25 (d, J = 6.4 Hz, 3 H).

13 C NMR ((CD 3 ) 2 CO, 100 MHz): 0 C = 173.9, 169.8, 84.9, 79.2, 78.6, 72.7, 65.8, 48.8, 36.5, 27.5, 17.9, 16.1.

HRMS (ESI) m/z calcd. for Ci 2 Hi 7 0 6 [M + H] + : 257.1020, found: 257.1017.

C. Synthesis of (3S,3aR,4aR,5S,8aS,8bS)-3-((S)-l-hydroxyethyl)-5-methylhexah ydro -lH-furo[3',4':4,5]furo[2,3-c]pyran-l,7(3H)-dione [Compound (3)]:

TLC: R f = 0.60 (50% Acetone/ CHC1 3 ).

m.p.: 208-209° C.

[a] D 25 = -106 (c = 0.1, Acetone).

Yield: 34.8 mg (60%).

1H NMR (C 5 D 5 N, 400 MHz): <5 H = 5.30 (d, = 4.9 Hz, 1 H), 5.05 - 5.14 (m, 1 H), 4.69 (d, = 3.4 Hz, 1 H), 4.50 (dd, = 8.3, 6.4 Hz, 1 H), 4.28 (dd, = 6.6, 3.2 Hz, 1 H), 4.17 (t, = 8.3 Hz, 1 H), 3.73 (d, = 5.4 Hz, 1 H), 3.43 - 3.37 (m, 1 H), 2.96 - 2.92 (m, 2 H), 1.40 (d, = 6.4 Hz, 3 H), 1.36 (d, = 6.4 Hz, 3 H).

13 C NMR (C 5 D 5 N, 100 MHz): 0 C = 177.3, 171.0, 88.2, 81.0, 79.3, 74.2, 66.2, 52.9, 39.4, 33.3, 19.0, 18.4.

HRMS (ESI) m/z calcd. for Ci 2 Hi 6 0 6 Na [M + Na] + : 279.0839, found: 279.0838.

D. Synthesis of (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxyethyl)-5-methyl

hexahydro-lH-furo[3',4':4,5]-fur -c]pyran-l,7(3H)-dione [Compound (4)]:

TLC: R f = 0.61 (50% Acetone/ CHC1 3 ).

m.p.: 208-209° C.

[a] D 25 = +105 (c = 0.7, Acetone).

Yield: 23.1 mg (61%).

1H NMR (DMSO-d 6 , 400 MHz): <5 H = 5.52 (d, J = 5.5 Hz, 1 H), 4.75 (d, J = 5.5 Hz, 1 H), 3.76 (m, 2 H), 3.16 (d, J = 5.0 Hz, 1 H), 2.88 (d, J = 9.2 Hz, 1 H), 2.65 (dd, J = 8.9, 3.9 Hz, 2 H), 2.49 (d, J = 14.7 Hz, 2 H), 1.25 (d, J = 6.4 Hz, 3 H), 1.08 (d, J = 6.9 Hz, 3 H) "C NMR (DMSO-d 6 , 100 MHz): 0 C = 178.0, 172.7, 87.8, 80.4, 78.8, 74.2, 66.1, 52.3, 38.4, 32.9, 18.9, 18.4. HRMS (ESI) m/z calcd. for Ci 2 Hi 6 0 6 Na [M + Na] + : 279.0839, found: 279.0835.

E. Synthesis of (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-methoxyethyl)-5- (methoxymethyl)hexahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran- l,7(3H)-dione

[Compound (5)]:

TLC: R f = 0.28 (60% EtOAc-petroleum ether).

[a] D 25 = +60 (c = 2.2, CHC1 3 ). Colourless liquid.

Yield: 26 mg (64%). 1H NMR (400 MHz, CDCI3): <¾ = 4.92 (d, J = 5.5 Hz, IH), 4.53 (d, J = 4.1 Hz, IH), 4.33 - 4.31 (m, 2H), 3.95-3.93 (m, IH), 3.74-3.71 (m, IH), 3.65-3.61 (m, IH), 3.57-3.49 (m, 2H), 3.42 (s, 3H), 3.41 (s, 3H), 3.19 (d, J = 5.5Hz, IH), 3.15-3.12 (m, IH), 2.91-2.86 (m, IH), 2.49-2.42 (m, IH), 1.83 (brs, IH). 13 C NMR (100 MHz, CDCI3,): 0 C = 176.4, 170.3, 84.9, 79.1, 78.1, 75.5, 72.5, 71.9, 69.8, 59.5, 59.4, 52.2, 39.0, 32.9.

HRMS (ESI) m/z calcd. for Ci 4 H 20 O 8 Na [M + Na] + : 339.1050, found: 339.1046.

F. Synthesis of (3R,3aS,4aS,5R,8aR,8bR)-3-((R)-2-(benzyloxy)-l-hydroxyethyl) -5- ((benzyloxy)methyl)-hexahydro-lH-furo[3',4':4,5]furo[2,3-c]p yran-l,7(3H)-dione

[Compound (6)]:

TLC: R f = 0.30 (60% EtOAc-petroleum ether).

[a] D 25 = +41 (c = 1.0, CHC1 3 ).

Yield: 21 mg (60%).

1H NMR (CDCI 3 ,200 MHz): ¾ = 7.38- 7.28 (m, 10H), 4.87 (d, =5.6 Hz, 1H), 4.55 - 4.60 (m, 4H), 4.52 (d, = 4.4 Hz, 1H), 4.32 (d, = 5.2 Hz, 2H), 3.88 - 4.00 (m, 1H), 3.78 (d, = 2.3 Hz, 1H), 3.72 - 3.70 (m, 1H), 3.61 - 3.57 (m, 2H), 3.11 (d, = 5.2 Hz, 2H), 2.92 - 2.71 (m, 2H), 2.37 (dd, = 15.8, 10.6 Hz, 1H).

13 C NMR (CDCI 3 , 50MHz): S c = 176.0, 170.0, 137.3, 128.6, 128.6, 128.2, 128.0, 127.8, 84.7, 79.0, 78.3,75.6, 73.9, 73.7, 70.1, 70.0, 69.5, 52.2, 39.0, 32.9, 29.7. HRMS (ESI) m/z calcd. for CieHigOgNa [M + Na] + : 491.1676, found: 491.1671.

G. Synthesis of (R)-2-((3S,3aS,4aS,5R,8aR,8bR)-l,7-dioxo-5-((((2R,3S,4S,5R,6 S)-3,4,5- tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-carbonyl)oxy) methyl) octahydro-lH-furo[3',4':4,5]furo[2,3-c]pyran-3-yl)-2-hydroxy ethyl (2R,3S,4S,5R,6S)-

3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-carb oxylate [Compound (7)] :

TLC: R f = 0.22 (50% EtOAc-petroleum ether).

[a] D 25 = +30 (c = 1.1, CHC1 3 ). Yield: 24.7 mg (65%).

1H NMR ((CD 3 ) 2 CO, 400 MHz): <5 H = 7.44 - 7.24 (m, 30H), 5.23 (d, 7=4.9 Hz, 1H), 5.14 (d, 7=4.9 Hz, 1H), 4.98 - 4.89 (m, 4H), 4.86 - 4.73 (m, 9H), 4.70 - 4.57 (m, 4H), 4.53 - 4.44 (m, 2H), 4.41 (br. s., 1H), 4.31 (d, 7=5.4 Hz, 1H), 4.18 - 4.08 (m, 3H), 3.90 (dt, 7=9.3, 4.6 Hz, 3H), 3.82 - 3.72 (m, 2H), 3.61 (dt, 7=6.6, 3.1 Hz, 2H), 3.41 (s, 6H), 3.35 (d, 7=4.9 Hz, 1H), 2.82 ppm (d, 7=9.3 Hz, 2H).

13 C NMR (CDC1 3 , 100 MHz): 0 C = 175.9, 169.5, 168.9, 168.8, 139.1, 138.8, 138.5, 128.2, 128.1, 128.1, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4, 127.3, 98.4, 98.3, 83.2, 81.0, 79.9, 79.8, 79.6, 79.5, 79.4, 79.3, 75.4, 75.1, 74.9, 74.6, 74.5, 72.2, 70.4, 70.3, 68.5, 65.4, 64.0, 55.0, 54.9, 54.6, 51.8, 38.8, 32.7, 31.1, 29.5, 29.3, 29.1, 28.9, 28.8, 28.6, 28.4.

HRMS (ESI) m/z calcd for C 68 H 72 0 2 oNa [M + Na] + : 1231.4509, found: 1231.4509.

H. Synthesis of (R)-2-hydroxy-2-((3S,3aS,4aS,5R,8aR,8bR)-5-((nicotinoyloxy)

methyl)- 1,7-dioxooctahydro- lH-furo[3 ' ,4' : 4,5]furo[2,3-c]pyran-3-yl)ethyl nicotinate

[Compound (8)]:

TLC: R f = 0.38 (80% EtOAc-petroleum ether).

[«] D 25 = +90 (c = 0.8, CHCI 3 ).

Yield: 18 mg (60%).

1H NMR (CDCI 3 , 500 MHz): S H = 9.28 - 9.13 (m, 2H), 8.79 - 8.69 (m, 2H), 8.33 (m, 2H), 7.50 - 7.37 (m, 2H), 5.09 (d, 7 =5.49 Hz, 1H), 4.80 (d, 7 = 9.77 Hz, 1H), 4.72 - 4.60 (m, 2H), 4.58 - 4.44 (m, 4H), 4.33 - 4.22 (m, 1H), 3.37 (d, 7 = 5.49 Hz, 1H), 3.28 (brs, 1H), 2.91 (d, 7 =5.80 Hz, 1H), 2.73 - 2.58 (m, 1 H). "C NMR (CDCI3, 125 MHz): 0 C = 176.2, 170.1, 164.8, 164.5, 153.3, 153.2, 150.5, 150.3, 138.0, 137.7, 125.8, 125.7, 123.9, 123.8, 84.5, 79.6, 75.9, 75.7, 68.8, 65.5, 63.8, 52.1, 39.1, 33.1. HRMS (ESI) m/z calcd for C 24 H 23 0ioN 2 [M + H] + : 499.1347, found: 499.1342.

I. Synthesis of ((3R,3aS,4aS,5R,8aR,8bR)-3-((R)-l-hydroxy-2-((2-iodobenzoyl) oxy)ethyl)- 1,7-dioxooctahydro- lH-furo[3 ' ,4' : 4,5]furo[2,3-c]pyran-5-yl)methyl2- iodobenzoate [Compound (9)

TLC: R f = 0.40 (60% EtOAc-petroleum ether).

[a] D 25 = +32 (c = 3.1, CHCl 3 ).

Yield: 32 mg (64%). 1H NMR ((CD 3 ) 2 CO, 200 MHz): ¾ = 8.06 (dt, / = 8.0, 1.1 Hz, 2H), 7.91-7.83 (m, 2H), 7.59- 7.48 (m, 2H), 7.34 - 7.24 (m, 2H), 5.25 (d, = 5.2 Hz, 2H), 4.75-4.48 (m, 7H), 4.33-4.22 (m, 1H), 3.42 (d, = 5.1 Hz, 1H), 3.28 - 3.12 (m, 1H), 2.91-2.65 (m, 2H).

13 C NMR ((CD 3 ) 2 CO, 50 MHz): 0 C = 177.0, 170.7, 166.8, 166.7, 142.2, 136.3, 136.2, 134.0, 133.9, 131.9, 131.8, 129.2, 94.3, 94.3, 84.4, 80.6, 76.7, 76.0, 69.6, 66.7, 65.1, 52.8, 39.9,

33.7.

HRMS (ESI) m/z calcd for C 26 H 22 Oi 0 I 2 Na [M + Na] + : 770.9195, found: 770.9191

Advantages of invention:

• Complete synthetic route proposed

• Novel analogues synthesized