CN100389123C - Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds - Google Patents

Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds Download PDF

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CN100389123C
CN100389123C CNB2006100292522A CN200610029252A CN100389123C CN 100389123 C CN100389123 C CN 100389123C CN B2006100292522 A CNB2006100292522 A CN B2006100292522A CN 200610029252 A CN200610029252 A CN 200610029252A CN 100389123 C CN100389123 C CN 100389123C
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acetic acid
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hydrogen bromide
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CN1887900A (en
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田伟生
王静
许启海
林静容
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Normal University
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Normal University
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Abstract

The present invention relates to the synthesis process of 26-bromo-16, 22-dioxy-cholesterol compounds. Under the action of hydrogen bromide-acetic solution, steroid E/F ketal spiro compound is ring opening reacted and has its 26 site bromized to obtain 26-bromo-16, 22-dioxy-cholesterol compounds. The 26-bromo-16, 22-dioxy-cholesterol compounds may be debrominated to obtain cholest compounds, which may be further synthesized into OSW-1 aglycones and their analogs. The synthesis process of the present invention has convenient operation and is suitable for industrial production.

Description

Synthesis method of 26-bromo-16, 22-dioxo-cholesterol compound
Technical Field
The invention relates to a synthetic method of 26-bromo-16, 22-dioxo-cholesterol compound, namely, a 16-bit oxidation product of steroid sapogenin or derivatives thereof reacts with hydrogen bromide-acetic acid solution to obtain a series of steroid E/F ring-opened 26-bromo compounds; the compound is debrominated to obtain 16, 22-dioxo-cholesterol compound which can be further synthesized into OSW-1 and analogues thereof.
Technical Field
The star-of-Bethlehem saponin (OSW-1) is a saponin with cholesterol skeleton separated from the underground bulb of Ornithogalum saunderside, which is a very green ornamental plant native to south Africa, and has strong killing power to various malignant tumor cells, and the efficacy is 10-100 times higher than that of several anticancer drugs such as Mitomycin (Mitomycin), Adriamycin (Adriamycin), Taxol (Taxol) and the like which are clinically used at present. More importantly, although OSW-1 has good activity against many malignant tumor cells, it has little toxicity to normal lung cells (IC)501500nM) (see Phytochemistry, 1992, 31, 3969; bioorg.&Med.chem.lett.1997, 7, 633) with the following specific structure:
Figure C20061002925200041
because OSW-1 has extremely strong anticancer activity and a unique chemical structure, and plant resources containing the compound are few, chemical synthesis of the compound has attracted extensive attention. However, most groups have synthesized OSW-1 aglycone starting from dehydroepiandrosterone (see tetra. Lett.1998, 39, 1099; J. org.chem.1999, 64, 202; J. arm.chem.Soc.2002, 124, 6576; CarbohydrateRes.2002, 337), whereas dehydroepiandrosterone is obtained by six-step degradation of natural Diosgenin (Diosgenin) with a total yield of 25-50% (see J.am.chem.Soc.1940, 62, 3350; J.org.chem.1956, 21, 520).
Tabanese et al, using diosgenin (diosgenin) as a starting material, fully utilize the complete carbon skeleton of steroidal sapogenin to synthesize rhodea ornata saponin (OSW-1) (CN 02145066.8; tetra. Lett.2003, 44, 9375; CN 200610026473.4) and pennogenin (CN 02150907.7; Chinese Science in China Ser.B Chemistry, 2004, 47, 142), respectively, and reported synthetic routes are as follows:
synthesis of OSW-1:
Figure C20061002925200051
as can be seen from the above synthetic routes, the synthesis of the diketone compound A from diosgenin requires reduction to open the F ring and then oxidation to open the E ring, while the synthesis of the diketone compound B requires oxidation to open only the E/F ring; the operation for synthesizing the diketone compound A is complicated, the transformation can be complete only by repeated oxidation and separation, and the diketone compound B can be obtained from the diosgenin with the total yield of more than 70 percent; in order to synthesize both natural products OSW-1 and pennogenin more efficiently, Tianweisheng et al have integrated two synthetic routes to convert a derivative compound D of diketone B, which is easy to prepare in large quantities, into a derivative compound C of diketone A, which is difficult to prepare in large quantities (see CN 200610025917.2):
Figure C20061002925200061
however, the above route is long, the operation is complicated, the total yield is low, and the method is not favorable for mass production of the compound C.
The synthesis of 26-bromo-16, 22-dioxo-cholesterol compounds was also reported by agravin et al, but with a relatively low efficiency (see CN 02150907.7):
26-bromo-16, 22-dioxo-cholesterol compounds 26-bromine can be removed by literature methods to obtain cholesteric compound A and its analogues (see J.Med.chem.1984, 27, 1690; tetra.Lett.1994, 35, 935).
The invention starts from the 16-site oxidation product of the steroid sapogenin or the derivative thereof, and can conveniently prepare the 26-bromo-16, 22-dioxo-cholesterol compound which can be further used for synthesizing the compound A and the analogue thereof, thereby realizing the accumulation of the amount of key compounds in the route for synthesizing the OSW-1.
Disclosure of Invention
The invention aims to provide a method for synthesizing 26-bromo-16, 22-dioxo-cholesterol compounds.
The synthesis method of the 26-bromo-16, 22-dioxo-cholesterol compound comprises the following steps:
dissolving a 16-site oxidation product 1 of the steroid sapogenin or the derivative thereof in an aprotic solvent, acetic acid or a mixed solvent of the aprotic solvent and the acetic acid, adding a hydrogen bromide-acetic acid solution, and stirring the mixture at a reflux temperature of-20 ℃ for 0.5-24 h to obtain a 26-bromo-16, 22-dioxo-cholesterol compound 2, wherein the molar ratio of the compound 1 to the hydrogen bromide is 1: 1-10; the hydrogen bromide-acetic acid solution is an acetic acid solution containing 1-50% of hydrogen bromide; the aprotic solvent is dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane (dioxane), benzene, toluene, acetonitrile or a mixed solvent thereof;
the structural formulas of the compounds 1 and 2 are shown as follows:
Figure C20061002925200071
Figure C20061002925200072
represents upward or downward; r1Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R2To form a carbonyl group; r2Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R1To form a carbonyl group; r3Is H or C1~4A hydrocarbon group of (a); r4OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r5H, OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r6Is H, OH, OAc, OTMS, X or with R7To form a 5, 6-double bond or a 5, 6-epoxy; r7Is H, OH, OAc, OTMS, X or with R6To form a 5, 6-double bond or a 5, 6-epoxy;
wherein MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is t-butyldimethylsilyl, TBDPS is t-butyldiphenylsilyl, and X is halogen.
Compound 2 cholesteric Compound A and its analogues can be synthesized by literature methods (see J.Med.chem.1984, 27, 1690; tetra.Lett.1994, 35, 935) to achieve accumulation of the amount of key compounds in the synthetic OSW-1 route. .
The invention starts from the 16-position oxidation product of the steroid sapogenin or the derivative thereof, and conveniently prepares the 26-bromo-16, 22-dioxo-cholesterol compound, thereby not only having simple and convenient operation, but also being suitable for industrial production and having great superiority compared with the prior method. OSW-1 aglycone and analogues thereof can be conveniently synthesized by the methods of the literature references (see CN 02145066.8; CN 200610025917.2; CN 200610026473.4).
Detailed description of the invention
The following detailed description will help to understand the present invention, but does not limit the content of the present invention.
Compounds 1a, 1d, 1e, 1f, 1g of the invention were synthesized according to the methods described in the references (see CN 02150907.7; tetra. Lett.1994, 35, 935).
EXAMPLE 1 Synthesis of Compounds 1b and 1c
Figure C20061002925200081
1.861g of Compound 1a are dissolved in 50ml of absolute ethanol, 0.411g of NH are added4Cl (2.6eq.) and 0.966g zinc powder (5.0eq.) were refluxed for 0.5h, the fluorescence spot disappeared and the reaction was good. Filtering with diatomite, washing the filter cake with anhydrous ethanol, spin-drying the filtrate, and separating by flash column chromatography (PE: EA is 40: 1-10: 1) to obtain 1b0.139g (10.0%) of compound and 1c 1.314g (89.0%).
Compound 1 b: c29H44O4;FW 472;mp 150℃;
1H-NMR(CDCl3,300 MHz)δ:5.39(1H,d,J=4.8Hz,6-H),4.63-4.57(1H,m,3-H),3.61-3.56(3H,m,26-H and 16-OH),1.03(3H,s,19-Me),1.01(3H,d,J=6.9Hz,21-Me),0.83(3H,d,J=6.3Hz,27-Me),0.76(3H,s,18-Me);
MS(EI):454(M+-18,11.1%),43(100%).
Compound 1 c: c31H48O5;FW 500;mp 145-148℃;
1H-NMR(CDCl3,300 MHz)δ:5.38(1H,d,J=4.8Hz,6-H),4.62-4.50(1H,m,3-H),3.70-3.36(4H,m,26-H and 16-OCH 2 CH3),2.03(3H,s,OAc),1.21(3H,t,J=7.2Hz,16-OCH2 CH 3 ),1.03(3H,s,19-Me),1.01(3H,d,J=6.6Hz,21-Me),0.81(3H,d,J=7.8Hz,27-Me),0.78(3H,s,18-Me).
EXAMPLE 2 Synthesis of Compound 2a
Figure C20061002925200082
0.5g of Compound 1a is taken in 5ml of CH2Cl2Dissolving, adding 0.2ml 30% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is completed, taking about 2h, and adding saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain 0.415g of compound 2a (76% yield).
Compound 2 a: c29H43Br3O4;FW 692;
1H-NMR(CDCl3,300 MHz)δ:5.50(1H,t,J=5.4Hz,6-H),4.83(1H,m,3-H),3.43(2H,d,J=5.2Hz,26-H),2.03(3H,s,OAc),1.04(6H,S,18,19-CH3);
IR v:2946,1736,1377,1242,1029 cm-1.
EXAMPLE 3 Synthesis of Compound 2b
The method comprises the following steps: synthesis of Compound 2b from Compound 1b
Figure C20061002925200091
0.299g Compound 1b in 5ml CH2C12Adding 0.20ml of 33% hydrogen bromide-acetic acid solution, reacting at room temperature for 1.5h, and completing the reaction to obtain saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4The crude product obtained by drying, filtration and concentration was isolated by column chromatography to give 0.314g of compound 2b (92.8% yield).
The second method comprises the following steps: synthesis of Compound 2b from Compound 1c
Figure C20061002925200092
0.316g of Compound 1c are dissolved in 5ml of CH2Cl2Adding 0.30ml of 33% hydrogen bromide-acetic acid solution, reacting at room temperature for 3.0h, and completing the reaction, wherein the saturated NaHCO is3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4The crude product obtained by drying, filtration and concentration was isolated by column chromatography to give 0.295g of compound 2b (87.4% yield).
Compound 2 b: c29H43BrO4;FW 534;
1H-NMR(CDCl3,300 MHz)δ:5.38(1H,t,J=4.4Hz,6-H),4.62(1H,m,3-H),3.45(2H,d,J=5.2Hz,26-H),2.17(3H,s,OAc),1.04(6H,s,18,19-CH3);
MS(ESI):536(M++2);
IR v:2960,1728,1456,1375,1247,1021cm-1
Theoretical values of elemental analysis C65.04%, H8.09%,
measured C65.46%, H8.42%.
EXAMPLE 4 Synthesis of Compound 2d
Figure C20061002925200101
0.3g of compound 1d is taken up in 10ml of CH2Cl2Dissolving, adding 0.22ml 33% hydrogen bromide-acetic acid solution (2.0eq.), reacting at room temperature, tracking by TLC until the reaction is completed, and taking 1.5h, and adding saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product obtained was isolated by column chromatography (PE: EA: 16: 1) to yield 0.306g of compound 2d (89% yield).
Compound 2 d: c29H45BrO4;FW 536;
1HNMR(CDCl3,300 MHz)δ:4.67(1H,m,3-H),3.34(1H,m,26-H),2.77(1H,m,20-H),2.03(3H,s,OAc),1.13(3H,d,J=6.4 Hz,21-CH3),0.91(3H,d,J=6.8 Hz,27-CH3),0.85(3H,s,19-CH3),0.77(3H,s,18-CH3);
MS(ESI):538(M++2);
IR v:2960,1728,1020cm-1
Theoretical values of elemental analysis C64.79%, H8.44%,
measurement C64.76%, H8.49%.
EXAMPLE 5 Synthesis of Compound 2e
Figure C20061002925200102
0.433g of Compound 1e in 5ml CH2Cl2Adding 0.15ml of 37% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is finished, and saturating by NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain 0.357g of compound 2e (75.6% yield).
Compound 2 e: c43H59BrO4Si;FW 746;
1HNMR(CDCl3,300 MHz)δ:7.69-7.65 and 7.40-7.36(10H,m,Ar),3.49(1H,m,3-H),3.31(m,2H,26-H),1.06(9H,s,t-Bu),1.10(d,3H,J=6.9Hz,21-H),0.96(d,3H,J=5.4Hz,27-Me),0.86(s,3H,18-Me),0.85(s,3H,19-Me);
MS(ESI):748(M++2);
Theoretical values of elemental analysis C69.05%, H7.95%,
measurement C68.83%, H8.07%.
EXAMPLE 6 Synthesis of Compound 2f
Figure C20061002925200111
0.339g of compound 1f is taken and 5ml of CH is used2Cl2Dissolving, adding 0.35ml of 33% hydrogen bromide-acetic acid solution,reaction at room temperature, TLC tracing to completion of reaction, saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering and concentrating the crude product, and separating by column chromatography to obtain compound 2f0.194g (51.3% yield).
Compound 2 f: c31H51BrO6;FW 598;
1HNMR(CDCl3,300 MHz)δ:4.75-4.71(m,2H,12-OCH 2 OCH3),4.68(s,2H,3-OCH 2 OCH3),3.75(m,2H,3-H,12-H),3.37(s,3H,12-OCH2OCH 3 ),3.35(s,3H,3-OCH2OCH 3 ),3.30(m,2H,26-H),1.04(d,J=6.6Hz,3H,21-CH3),0.96(d,3H,J=5.4Hz,27-Me),0.87(s,3H,18-CH3),0.85(s,3H,19-CH3);
MS(ESI):600(M++2);
Theoretical values of elemental analysis C62.09%, H8.57%,
measurement C62.40%, H8.49%.
EXAMPLE 7 Synthesis of Compound 2g
0.424g of compound 1g is taken, 5ml of CH2Cl2Dissolving, adding 0.20ml 30% hydrogen bromide-acetic acid solution, reacting at room temperature, tracking by TLC until the reaction is completed, and collecting saturated NaHCO3Quenching the solution, aqueous phase with CH2Cl2Extracting, washing the combined organic phase with saturated brine, anhydrous Na2SO4Drying, filtering, and concentratingThe crude product was isolated by column chromatography to give 2g of compound 0.187g (40.4% yield).
Compound 2 g: c41H49BrO7;FW 732;
1HNMR(CDCl3,300MHz)δ:8.03-7.46(10H,m,Ar),3.99(m,2H,1-H and 3-H),3.44(1H,m,26-H),3.04(m,1H,6-H),1.18(d,3H,J=6.9Hz,21-H),1.00(3H,s,19-Me),0.95(3H,s,18-Me),0.89(3H,d,J=6.3Hz,27-Me);
MS(ESI):734(M++2);
Theoretical values of elemental analysis C67.11%, H6.73%,
measurement C67.02%, H6.54%.
EXAMPLE 8 Synthesis of Compound 3a
Figure C20061002925200122
200mg of Compound 2a was dissolved in 5ml of ethanol, and 180mg (10.0eq.) of zinc powder and 38mg of NH were added4Cl (2.5eq.), reflux heating for 10h, complete reaction, filtration to remove solids, spin-drying ethanol, dissolving the residue with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration to obtain crude reaction product, and flash column chromatography to obtain compound 3a 90mg (68.3% yield).
Compound 3 a: c29H44O4;FW 456;
1H-NMR(CDCl3,300 MHz)δ:5.37(1H,d,J=5.1Hz,6-H),4.62(1H,m,3-H),2.04(3H,s,OAc),1.06(3H,d,J=6.0Hz,21-Me),1.05(3H,s,19-Me),0.91(6H,d,J=6.0Hz,26,27-Me),0.81(3H,s,18-Me);
MS(EI):441(M+-15,5.4%),397(11.5%),340(100%);
IR v:1732,1712cm-1.
EXAMPLE 9 Synthesis of Compound 3d
Figure C20061002925200131
1.072g of Compound 2d are dissolved in 50mL of ethanol, 0.65g (5.0eq) of zinc dust and 0.268g of NH are added4Cl (2.5eq), reflux-heating for 4h to complete the reaction, filtering to remove solids, spin-drying ethanol, dissolving the residue with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating to obtain crude reaction product, and flash column chromatography to obtain compound 3d 0.805mg (87.9% yield).
Compound 3 d: c29H46O4;FW 458;
1H-NMR(CDCl3,300 MHz)δ:4.61(1H,m,3-H),2.04(3H,s,OAc),1.06(3H,d,J=6.0Hz,21-Me),0.91(6H,d,J=6.0Hz,26,27-Me),0.85(3H,s,19-Me)),0.79(3H,s,18-Me);
Theoretical values of elemental analysis C75.94%, H10.11%,
measured C75.82%, H9.87%.
EXAMPLE 10 Synthesis of Compound 4
Figure C20061002925200132
2.290g of Compound 3a are dissolved in 35ml of HOAc, and 1.06ml of HSCH are added2CH2SH (2.5eq.), then 1.3ml BF was added dropwise3·Et2O (2.0eq.) and reacting at room temperature for 2.5h, the raw material disappears. Further 20ml of Ac were added2O, the mixture immediately turns from white turbidity to orange-red transparent, and the reaction is finished after 20 min. Adding saturated NaHCO3Solution, then solid NaHCO3Until no bubble emerges, extracting with ethyl acetate, and separating the organic phase with NaHCO3The solution was washed with saturated NaCl solution, MgSO4Drying, filtering, evaporating the solvent under reduced pressure and flash column chromatography (PE: EA: 40: 1) gave compound 4 as a pale yellow viscous oil, 1.830g (63.5%).
Compound 4: c33H50O4S2;FW 574;[α]D28=2 1.4°(C=0.433,CHCl3);
1H-NMR(CDCl3,300 MHz)δ:5.40(1H,d,J=3.9Hz,6-H),4.61(1H,m,3-H),3.68(1H,q,J=6.9Hz,20-H),2.98 and 2.81(4H,m,SCH2CH2S),2.35(3H,s,SAc),2.04(3H,s,OAc),1.22(3H,d,J=7.2Hz,21-Me),1.05(3H,s,19-Me),0.98(3H,s,18-Me),0.87(6H,d,J=5.7Hz,26,27-Me);
13C-NMR(CDCl3,75MHz)δ:210.98,195.10,170.51,153.39,139.92,131.03,122.11,73.79,56.49,50.09,48.87,46.84,38.58,38.04,36.74,36.71,35.07,34.39,32.98,31.25,30.59,30.07,29.75,27.62,22.43,22.35,21.39,20.42,19.15,17.14,14.34;
MS(EI):574(M+,1.2%),475(M+-99,100%);
Hrms (maldi): calculated value C33H50O4S2Na: 597.3040, respectively; measurement values: 597.3043, respectively;
IR v:1734,1713,1696cm-1.
EXAMPLE 11 Synthesis of Compound 5
Figure C20061002925200141
930mg of compound 4 is dissolved in 30ml of absolute ethanol, about 3.5g of W-2 type Raney nickel is added, reaction is carried out at room temperature for 0.5h, the raw material disappears, filtration is carried out, the residue is fully washed by the absolute ethanol, the filtrate is dried by spinning, and flash column chromatography separation is carried out (PE: EA is 20: 1), thus obtaining 641mg (90%) of compound 5 white solid.
Compound 5: c29H44O3;FW 440;
1H-NMR(CDCl3,300 MHz)δ:5.37(2H,br s,6-H and 16-H),4.61(1H,m,3-H),3.20(1H,q,J=6.9Hz,20-H),2.04(3H,s,OAc),1.16(3H,d,J=6.6Hz,21-Me),1.06(3H,s,19-Me),0.87(6H,d,J=6.0Hz,26,27-Me),0.85(3H,s,18-Me);
MS(ESI):441(M++1,100%);
IR v:1735,1714,1244 cm-1.

Claims (2)

1. A synthetic method of 26-bromo-16, 22-dioxo-cholesterol compounds is characterized by comprising the following steps:
in an aprotic solvent, acetic acid or a mixed solvent of the aprotic solvent and the acetic acid, stirring a steroid sapogenin 16-site oxidation product 1 and a hydrogen bromide-acetic acid solution at a temperature of-20 ℃ to reflux temperature for 0.5 to 24 hours to obtain a 26-bromo-16, 22-dioxo-cholesterol compound 2, wherein the molar ratio of the compound 1 to the hydrogen bromide is 1: 1-10; the hydrogen bromide-acetic acid solution is an acetic acid solution containing 1-50% by weight of hydrogen bromide;
the structural formulas of the compound 1 and the compound 2 are shown as follows:
Figure C2006100292520002C1
wherein,
Figure C2006100292520002C2
represents upward or downward; r1Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R2To form a carbonyl group; r2Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R1To form a carbonyl group; r3Is H or C1-4A hydrocarbon group of (a); r4OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r5H, OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r6Is H, OH, OAc, OTMS, X or with R7To form a 5, 6-double bond or a 5, 6-epoxy; r7Is H, OH, OAc, OTMS, X or with R6To form a 5, 6-double bond or a 5, 6-epoxy;
MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, and X is halogen.
2. A method according to claim 1, characterised in that the aprotic solvent is dichloromethane, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, acetonitrile or mixtures thereof.
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