WO2003080567A2 - Intermediates for the synthesis of discodermolide and related analogues and methods for their preparation - Google Patents

Abstract

The invention relates to processes for preparing intermediates utilized in the synthesis of discodermolide and analogues thereof, to novel compounds utilized in the processes and to novel compounds prepared by the processes.

Description

INTERMEDIATES FOR THE SYNTHESIS OF DISCODERMOLIDE AND RELATED ANALOGUES AND METHODS FOR THEIR PREPARATION

FIELD OF INVENTION

The present invention relates to the area of scientific methodology and, more particularly, to processes for preparing intermediates utilized in the synthesis of discodermolide and analogues thereof, to novel compounds utilized in the processes and to novel compounds prepared by the processes.

BACKGROUND OF THE INVENTION

(+)-DISCODERMOLIDE

(+)-Discodermolide is a novel polyketide natural product that was isolated from extracts of the marine sponge Discodermia dissoluta by researchers at the Harbor Branch Oceanographic Institution (HBOI) (Gunasekera SP et al., "Discodermolide: A New Bioactive Polyhydroxylated Lactone From the Marine Sponge Discodermia Dissoluta", [published erratum appears in J. Org. Chem., Vol. 56, p. 1346 (1991)] J. Org. Chem., Vol. 55, pp. 4912- 4915 (1990)). Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. In fact, of the handful of compounds known to induce polymerization of purified tubulin, discodermolide is tl\e most potent. However, microtubules, the major structural component in cells, are not simple equilibrium polymers of tubulin. They exist as regulated GTP-driven dynamic assemblies of heterodimers of α- and β-tubulin. Although the dynamics are relatively slow in interphase cells, upon entering mitosis, the rate of growing and shortening increases 20- to 100-fold - the average microtubule turns over half the tubulin subunits every ten seconds. This change in rate allows the cytoskeletal microtubule network to dismantle and a bipolar spindle-shaped array of microtubules to assemble. The spindle attaches to chromosomes and moves them apart. The response to complete suppression of Case 4-32428A microtubule dynamics in cells is death. However, mitotic cells are more sensitive and the tolerance threshold appears to be cell-type specific. Molecules like paclitaxel that bind with high affinity to microtubules disrupt the dynamics process in tumor cells with lethal results even when the ratio of bound drug to tubulin is very low. Discodermolide binds to tubulin competitively with paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders.

Future development of discodermolide or structurally related analogues is hindered by the lack of a reliable natural source of the compound or a feasible synthetic route. Naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. There is an ever-growing need for improved syntheses that enable production of multi-gram amounts of discodermolide and structurally related analogues.

DESCRIPTION OF THE PRIOR ART

Smith et al., "Preparation of Intermediates For the Synthesis of Discodermolides and Their Polyhydroxy Dienyl Lactone Derivatives for Pharmaceutical Use", The Trustees of the University of Pennsylvania, USA, PCT Int. Appl., 201 pages (2000). CODEN: PIXXD2 WO 0004865 A2 20000203 Designated States W: AU, CA, JP. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE. Patent written in English. Application: W0 99-US16369 19990720. Priority: US 98-121551 19980723. CAN 132: 137207 AN 2000:84572

Paterson et al., Total Synthesis of the Antimicrotubule Agent (+)-Discodermolide Using Boron-Mediated Aldol Reactions of Chiral Ketones", Univ. Chem. Lab., Cambridge, UK, Angew. Chem., Int. Ed., Vol. 39, No. 2, pp. 377-380 (2000). CODEN: ACIEF5 ISSN: 1433-7851. Journal written in English. CAN 132:236926 AN 2000:76529

Smith et al., "Gram-Scale Synthesis of (+)-Discodermolide", Department of Chemistry Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, PA, USA, Org. Lett., Vol. 1, No. 11 , pp. 1823-1826 (1999). CODEN: ORLEF7 ISSN: 1523-7060. Journal written in English. CAN 132:35548 AN 1999:694867 Case 4-32428A

Halstead, "Total Synthesis of (+)-Miyakolide. I. Total Synthesis of (-)-Discodeιmolide. II. Total Synthesis of (+)-Discodermolide.", Harvard Univ., Cambridge, MA, USA. Avail. UMI, Order No. DA9921509, 199 pages (1999). From: Diss. Abstr. Int., B 1999, Vol. 60, No. 3, p. 1087. Dissertation written in English. CAN 132:194227 AN 1999:567611

Filla et al., "Synthesis of C1-C8 and C9-C24 Fragments of (-)-Discodermolide: Use of Asymmetric Alkylation and Stereoselective Aldol Reactions", Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA, Tetra. Lett., Vol. 40, No. 30, pp. 5449-5453 (1999). CODEN: TELEAY ISSN: 0040-4039. Journal written in English. CAN 131:271758 AN 1999:461996

Harried, "A Total Synthesis of (-)-Discodermolide", Univ. of California, Los Angeles, CA, USA. Avail. UMI, Order No. DA9913066, 189 pages (1998). From: Diss. Abstr. Int., B 1999, Vol. 59, No. 11, p. 5854. Dissertation written in English. CAN 131:199544 AN 1999:320599

Marshall et al., "Total Synthesis of (+)-Discodermolide", Department of Chemistry, University of Virginia, Charlottesville, VA, USA, J. Org. Chem., Vol. 63, No. 22, pp. 7885- 7892 (1998). CODEN: JOCEAH ISSN: 0022-3263. Journal written in English. CAN 130:38235 AN 1998:642722

Smith et al., "Synthetic Techniques and Intermediates for Polyhydroxy, Dienyllactones and Mimics Thereof, Trustees of the University of Pennsylvania, USA. PCT Int. Appl., 194 pages (1998). CODEN: PIXXD2 WO 9824429 A1 19980611 Designated States W: CA, JP. Designated States RW: AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE. Patent written in English. Application: WO 97-US21798 19971201. Priority: US 96-759817 19961203. CAN 129:67649 AN 1998:394202

Hung et al., "Syntheses of Discodermolides Useful for Investigating Microtubule Binding and Stabilization", Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA, J. Am. Chem. Soc, Vol. 118, No. 45, pp. 11054-11080 (1996). CODEN: JACSAT ISSN: 0002-7863. Journal written in English. CAN 126:31209 AN 1996:657111

Smith et al., "Total Synthesis of (-)-Discodermolide", Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA, USA, J. Am. Chem. Soc, Vol. 117, No. 48, pp. 12011-12012 (1995). CODEN: JACSAT ISSN: 0002-7863. Journal written in English. CAN 124:86679 AN 1995:938846 Case 4-32428A

Golec et al., "Total Synthesis of Discodermolide", Roussel Laboratories Ltd., UK, Brit. UK Pat. Appl., 57 pages (1995). CODEN: BAXXDU GB 2280677 A1 19950208 Patent written in English. Application: GB 94-15399 19940729. Priority: GB 93-15802 19930730. CAN 123:32864 AN 1995:615210

SUMMARY OF THE INVENTION

The present invention provides for new methods and intermediates for the synthesis of discodermolide and structurally related analogues. More particulariy, the present invention relates to novel synthetic intermediates useful for the preparation of discodermolide and structurally related analogues with modifications at positions 1-6 (see above Figure for discodermolide numbering). Furthermore, the present invention relates to processes for preparing intermediates in the synthesis of discodermolide and structurally related analogues.

DETAILED DESCRIPTION OF THE INVENTION

The essence of the instant invention is the discovery of more practical syntheses for intermediates to obtain discodemnolide and analogues thereof. More particularly, it has been discovered that certain intermediates useful for the preparation of discodermolide and structurally related analogues can be prepared using the following synthetic schemes.

Case 4-32428A Scheme 1

STEP B hydrolysis

IV III

As to the individual steps in Scheme 1 , STEP A involves the olefination of the aldehyde of formula I to obtain the compound of formula II. In a first part, the olefination is conducted in the presence of: 1) a premixed solution of transition metal complex in a polar solvent, preferably chromium halide in an ether, more preferably CrCI₂ in tetrahydrofuran; and 2) an allyl halide, preferably allyl bromide, at a temperature of between -20°C and 30°C, preferably between 0°C and 25°C, for a period of between 4 and 24 hours. In a second part, a base in a polar solvent, preferably KOH in methanol, is added to the mixture at a temperature of between -20°C and 30°C, preferably between 0°C and 25°C, for a period of between 30 minutes and 2 hours to complete the olefination.

STEP B involves the hydrolysis of the para-methoxy benzyl ether group of the compound of formula II to obtain the compound of formula III. The hydrolysis is conducted in the presence of: 1) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); 2) water; and 3) a non-polar solvent, preferably dichloromethane (DCM), at a temperature between -20°C and 30°C, preferably between 10°C and 25°C, for a period of between 20 minutes and 4 hours, preferably between 30 minutes and 3 hours.

STEP C involves the oxidation of the hydroxyl group of the compound of formula III to obtain the compound of formula IV. The hydrolysis is conducted in the presence of: 1) a mild oxidizing agent, preferably Dess-Martin periodinane; and 2) a non-polar solvent, Case 4-32428A preferably DCM, at a temperature between -20°C and 30°C, preferably between 10^βC and

25°C, for a period of between 1 and 12 hours, preferably between 2 and 6 hours.

Scheme 2

IX

where R_t is Si((C₁-_β)alkyl)₃ or an acid labile hydroxyl protecting group.

As to the individual steps in Scheme 2, STEP A involves the alkylboration of the aldehyde of formula I to obtain the alcohol of formula VI. The alkylboration is conducted in the presence of: 1 ) a drying agent, preferably molecular sieves; 2) an unsaturated alkylboronate, preferably a chiral unsaturated alkylboronate; and 3) a non-polar solvent, preferably toluene, at a temperature between -120°C and 20°C, preferably between -85°C and 0°C, for a period of between 6 and 48 hours, preferably between 12 and 24 hours. Case 4-32428A

STEP B involves the protection of the hydroxy group of the alcohol of formula VI to obtain an olefin of formula VII. The protection is conducted in the presence of: 1) a base, preferably an amine, more preferably 2,6-lutidine; 2) an acid labile hydroxyl protection reagent, preferably a trialkylsilyl reagent, more preferably tert-butyldimethylsilyl trifluoromethanesulfonate; and 3) a non-polar solvent, preferably DCM, or an ether, more preferably tetrahydrofuran (THF), at a temperature between -60°C and 20°C, preferably between -10°C and 10°C, for a period of between 30 minutes and 12 hours, preferably between 1 and 4 hours.

STEP C involves the oxidation of an olefin of formula VII to obtain an aldehyde of formula VIII. In a first part, the oxidation is conducted in the presence of: 1 ) Os0 ;

2) 4-methylmorpholine N-oxide; and 3) one or more of the following solvents: acetone, tert- butyl alcohol and water, at a temperature between -10°C and 30°C, preferably between 10°C and 25°C, for a period of between 6 and 48 hours, preferably between 12 and

24 hours. In a second part, after concentration of the previous mixture by vacuum, the oxidation is completed in the presence of: 1) Nal0₄; and 2) a polar solvent, preferably an ether, more preferably THF, at a temperature between -10°C and 30°C, preferably between 10°C and 25°C, for a period of between 1 and 4 hours.

STEP D involves the oxidation of an aldehyde of formula VIII to obtain a carboxylic acid of formula IX. The oxidation is conducted in the presence of: 1)NaCIO₂; 2) NaH₂P0₄;

3) tert-butyl alcohol; 4) dimethyl-2-butene; and 5) water, at a temperature between -10°C and 30°C, preferably between 10°C and 25°C, for a period of between 30 minutes and 12 hours, preferably between 30 minutes and 4 hours.

STEP E involves the amidation of a carboxylic acid of formula IX to obtain an amide of formula X. The amidation is conducted in the presence of: 1 ) a base, preferably an amine, more preferably 4-methylmorpholine; 2) N.O-dimethylhydroxylamine hydrochloride; and 3) a polar solvent, preferably an ether, more preferably THF, at a temperature between -10°C and 30°C, preferably between 0°C and 25°C, for a period of between 6 and 48 hours, preferably between 12 and 24 hours. Case 4-32428A Scheme 3

Case 4-32428A

XVIII

XIX

where X is bromide or iodide; each of R^ and R₃, independently, is Si((C₁-₆)alkyl)₃ or an acid labile hydroxyl protecting group; and each of R₂ and R₄, independently, is (C₁-₆)alkyl or benzyl.

As to the individual steps in Scheme 3, STEP A involves the Pd(0) coupling of an alkyl halide of formula XI to obtain an ester of formula XII. The coupling is conducted in the presence of: 1 ) a Pd(0) catalyst, preferably Pd(PPh₃)₄; 2) a propylzinc halide ester, preferably a propylzinc bromine ester; and 3) a polar solvent, preferably an ether, more preferably THF, at a temperature between -10°C and 30°C, preferably between 10°C and 25°C, for a period of between 6 and 48 hours, preferably between 12 and 24 hours. Case 4-32428A

STEP B involves the amidation of an ester of formula XII to obtain an amide of formula XIII. The amidation is conducted in the presence of a premixed solution of:

1) N.O-dimethylhydroxylamine hydrochloride; 2) a Lewis acid, preferably trimethylaluminum; and 3) non-polar solvent, preferably toluene, at a temperature, of the premixed solution, between -10°C and 10°C and for a period between 15 and 60 minutes, and a temperature, for the combination of the ester and the premixed solution, between 20°C and 120^βC, preferably between 70°C and 90°C, for a period of between 1 and 8 hours.

STEP C involves the conversion of an amide of formula XIII to a ketone of formula XIV. The conversion is conducted in the presence of: 1) a Grignard reagent, preferably an alkylmagnesium bromide; and 2) a polar solvent, preferably an ether, more preferably THF, at a temperature between -10°C and 40°C, preferably between -10°C and 10°C, for a period of 30 minutes to 24 hours, preferably between 1 and 4 hours.

STEP D (preferred to the combination of STEP B and STEP C) involves the conversion of an ester of formula XII to a ketone of formula XIV. The conversion is conducted in the presence of: 1) N.O-dimethylhydroxylamine hydrochloride; 2) a Grignard reagent, preferably an alkylmagnesium bromide, in an amount between 4-12 equivalents of N.O-dimethylhydroxylamiπe hydrochloride; and 3) a polar solvent, preferably an ether, more preferably THF, at a temperature between -10°C and 40°C, for a period of between 1 and 48 hours, preferably between 1 and 4 hours.

STEP E involves the aldol coupling of a ketone of formula XIV to obtain an alcohol of formula XV. In a first part, the coupling is conducted in the presence of: 1) a base, preferably an amine salt, more preferably lithium diisoproplamide (LDA); and 2) a polar solvent, preferably an ether, more preferably THF, at a temperature between -120°C and 0^βC, preferably between -100°C and -60°C, for a period of between 1 and 24 hours, preferably between 1 and 4 hours. In a second part, the coupling is completed in the presence of: 1) a chelating agent, preferably a magnesium salt, more preferably MgBr₂; and

2) an aldehyde, preferably of formula IV, at a temperature between -120°C and 0°C, preferably between -100°C and -60°C, for a period of between 1 and 24 hours, preferably between 6 and 24 hours.

STEP F involves the carbamoylation of an alcohol of formula XV to obtain a compound of formula XVI. The carbamoylation is conducted in the presence of: 1) trichloroacetyl isocyanate; 2) neutral alumina; and 3) a non-polar solvent, preferably DCM, Case 4-32428A at a temperature between -20°C and 30°C, preferably between 10^βC and 25°C, for a period of between 20 minutes and 4 hours after trichloroacetyl isocyanate addition, preferably between 30 minutes and 3 hours, and for a period of between 1 and 24 hours after addition of neutral alumina, preferably between 2 and 6 hours.

STEP G involves the reduction of the carbonyl group of the compound of formula XVI to obtain an alcohol of formula XVII. The reduction is conducted in the presence of: 1 ) a hydride donating agent, preferably an aluminium hydride complex, more preferably lithium tri-tert-butoxyaluminohydride (LiAIH(0-t-Bu)₃); and 2) a polar solvent, preferably an ether, more preferably THF, at a temperature between -120°C and 0^βC, preferably between -100°C and -60°C, for a period of between 1-24 hours, preferably between 1 and 4 hours.

STEP H involves the hydroxy protection of an alcohol of formula XVII to obtain a compound of formula XVIII. The hydroxy protection is conducted in the presence of: 1 ) a base, preferably an amine, more preferably 2,6-lutidine; 2) an acid labile hydroxyl protection reagent, preferably a trialkylsilyl reagent, more preferably tert-butyldimethylsilyl trifluoromethanesulfonate; and 3) a polar solvent, preferably DCM, or an ether, preferably THF, at a temperature between -60°C and 30°C, preferably between 0°C and 30°C, for a period of between 30 minutes and 12 hours, preferably between 1 and 4 hours.

STEP I involves the hydrolysis of a compound of formula XVIII to obtain a compound of formula XIX. The hydrolysis is^' conducted in the presence of: 1) DDQ; 2) water; and 3) a non-polar solvent, preferably DCM, at a temperature between -20°C and 30°C, preferably between 10°C and 25°C, for a period of between 20 minutes and 4 hours, preferably between 30 minutes and 3 hours.

STEP J involves the oxidation of an alcohol of formula XIX to obtain an aldehyde of formula XX. The oxidation is conducted in the presence of: 1) 2,2,6,6-tetramethyM- piperidinyloxy free radical (TEMPO); 2) iodobenzene diacetate (BAIB); and 3) a non-polar solvent, preferably non-anhydrous DCM, at a temperature between -20°C and 30°C, preferably between 10^βC and 25°C, for a period of between 20 minutes and 4 hours, preferably between 30 minutes and 3 hours.

STEP K involves the Wittig coupling of an aldehyde of formula XX to obtain a compound of formula XXI. The Wittig coupling is conducted in the presence of: 1) a base, preferably K₂C0₃; 2) 18-crown-6; 3) a methylphosphate ester, preferably bis(2,2,2- trifluoroethyl)methoxycarbonylmethyl)phosphate; and 4) a non-polar solvent, preferably Case 4-32428A toluene, at a temperature between -60°C and 30°C, preferably between -30^CC and 0°C, for a period of between 30 minutes and 12 hours, preferably between 1 and 4 hours.

The compounds of formulae I and XI are known and have previously been disclosed in the literature, e.g., in 1) Smith et al., J. Am. Chem. Soc, Vol. 122, pp. 8654-8664 (2000); and 2) U.S. Patent No. 6,031,133.

As is evident to those skilled in the art, compounds of formulae l-IV and VI-XXI contain asymmetric carbon atoms. It should be understood, therefore, that the individual stereoisomers are contemplated as being included within the scope of this invention.

In the above definitions: the term "(Chalky!" as used herein refers to a straight or branched chain consisting solely of carbon and hydrogen and having from 1-6 carbons atoms. Examples of "alkyl" groups include methyl, ethyl, propyl, butyl, pentyl, 3-methylpentyl, etc.

The term "acid labile hydroxy protecting group" as used herein refers to any oxygen bound group that can be removed upon exposure to an acid. Numerous examples of these groups are known by those skilled in the art and can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2^nd edition, John Wiley & Sons, New York, 1991. Specific examples include, but are not limited to, t-butyldimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl and tetrahydropyranyl.

The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be clearly understood that they are for purposes of illustration only.

Example 1 (2S,3R,4S)-1-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5-hexen-3-ol

Case 4-32428A

A solution of (4S,5S)-2-[(2Z)-2-butenyl]-1 ,3,2-dioxaborolane-4,5-dicarboxylic acid bis(l-methylethyl) ester (32.2 g, 108.0 mmol), anhydrous toluene (450 mL), and 4 A molecular sieves (3.22 g) was stirred at room temperature for 30 minutes under nitrogen. The solution is cooled to -78°C, and a mixture of (2S)-3-[(4-methoxyphenyl)methoxy]-2- methyl-propanal (15.0 g, 72.0 mmol) in anhydrous toluene (50 mL) is slowly added, while maintaining a temperature of -78°C. The stirring is maintained at -78°C overnight for 18 hours. The reaction is carefully quenched with a suspension of NaBH₄ (1 g) in absolute ethanol (100 mL). The mixture is warmed to 0°C, diluted with aqueous NaOH (1 N, 500 mL) solution, and stirred vigorously for 2 hours. The layers are separated, and the aqueous layer extracted with diethyl ether (Et₂0) (3 x 100 mL). The organic layers are combined, dried over K₂C0₃, and concentrated. The crude product is purified by flash chromatography (Si0₂, 10% ethyl acetate (EtOAc) in hexane) to give the desired compound as a clear oil (11 g, 58% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.85 (m, 1H), 5.05 (d, J = 6.0 Hz, 1H), 5.00 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.63 (dd, J = 9.4, 4.1, Hz, 1 H), 3.43 (m, 2 H), 3.27 (d, J = 4.1 Hz, 1H), 2.30 (m, 1H), 1.92 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 159.3, 142.4, 129.9, 129.4, 114.0, 113.8, 79.1, 74.6, 73.2, 55.3, 41.0, 35.6, 14.4, 13.2; HSMS m/z calcd for C₁₆H₂5θ₆ (M+H) 265.180, found 265.175.

Example 2

(1,1-dimethylethyl)[[(1R,2S)-1-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2-methyl- 3-butenyl]oxy]dimethylsilane

Case 4-32428A

A solution of (2S,3R,4S)-1-[(4-methoxyphenyI)methoxy]-2,4-dimethyl-5-hexen-3-ol (6.41 g, 24.2 mmol), 2,6-lutidine (5.7 mL, 48.9 mmol), and anhydrous THF (40 mL) is cooled to 0°C and stirred under nitrogen. Tert-butyldimethylsilyl trifluoromethanesulfonate (8.4 mL, 36.6 mmol) is slowly added while maintaining a temperature of 0°C. After 1.5 hours, the reaction is quenched with saturated aqueous NH₄CI (200mL), and extracted with DCM (3 x 100 mL). The organic layers are combined, dried over Na₂S0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 2.5% EtOAc in hexane) to give the desired compound as a clear oil (8.7 g, 95% yield).

H NMR (300 MHz, CDCI₃) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.78 (ddd, J = 17.4, 7.4, 10.3 Hz, 1H), 4.96 (m, 2H), 4.40 (s, 2H), 3.81 (s, 3H), 3.56 (dd, J = 9.2, 4.7 Hz, 1H), 3.49 (t, J = 4.9 Hz, 1H), 3.24 (dd, J = 9.2, 8.1 Hz, 1H), 2.36 (m, 1H), 1.98 (m, 1H), 0.97 (d, J= 6.8 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 6H); ¹³C NMR (75 MHz, CDCI₃) δ 142.5, 130.9, 129.0, 127.8, 113.7, 112.9, 78.0, 72.5, 72.2, 55.2, 41.6, 37.8, 26.1 , 18.3, 15.5, 15.2, -3.7, -4.2; (ESI+) m/z 379.

Example 3

2,4-dideoxy-3-0-[(1,1-dimethylethyl)dimethylsilyl]-5-0-[(4-methoxyphenyl)methyl]-2,4- dimethyl-L-arabinose

(1,1-dimethylethyl)[[(1R,2S)-1-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2- methyl-3-butenyl]oxy]dimethylsilane (7.90 g, 20.9 mmol), 4-methylmorpholine N-oxide (2.93 g, 25.0 mmol), Os0₄ (0.54 g, 2.1 mmol), acetone (300 mL), tert-butyl alcohol (45 mL), and water (15 mL) are combined and stirred at room temperature overnight. After 18 hours, the mixture is concentrated under vacuum. To the resultant paste is added a solution of Nal0₄ (8.92 g, 41.7 mmol), THF (525 mL), and water (175 mL), and the resultant mixture is Case 4-32428A stirred at room temperature for 2 hours. The mixture is concentrated, and the crude product purified by flash chromatography (Si0₂, 2.5% EtOAc in hexane) to give the desired compound as a clear oil (5.63 g, 71% yield). IR (KBr) 1725 cm^'1.

¹H NMR (300 MHz, CDCI₃) δ 9.69 (s, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.38 (ABq, J_AB = 11.7 Hz, Δv_AB = 18.1 Hz, 2H), 4.19 (dd, J = 6.2, 3.6, 1H), 3.81 (s, 3H), 3.43 (dd, J= 9.0, 5.7, 1H), 3.32 (dd, J = 9.0, 6.0, 1H), 2.39 (dq, J = 6.8, 3.6, 1H), 2.00 (m, 1H), 1.09 (d, J = 6.8, 3 H), 0.95 (d, J = 6.8, 3H), 0.85 (s, 9H), 0.05 (s, 3H), -0.01 (s, 3H).

Example 4

(2 ?,3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-5-(4-methoxy-benzyloxy)-2,4-dimethyl- pentanoic acid

To a solution of 2,4-dideoxy-3-0-[(1,1-dimethylethyl)dimethylsilyl]-5-0-[(4- methoxyphenyl)methyl]-2,4-dimethyl-L-arabinose (61 mg, 0.16 mmol), tert-butyl alcohol (3.5 mL), 2,3-dimethyl-2-butene (3.5 mL) and water (0.5 mL) is added NaCI0₂ (80%, 74 mg, 0.65 mmol) and NaH P0 (74 mg, 0.62 mmol) at room temperature. The resultant mixture is stirred for 1 hour. The mixture is then diluted with DCM (33 mL) and water (17 mL), and acidified with one drop of trifluoro acetic acid. The layers are separated, and the aqueous layer is extracted with DCM (50 mL). The organic layers are combined, dried over MgS0₄, and concentrated. The crude product is purified by flash chromatography (SiO₂, 30% EtOAc in hexane) to give the desired compound as a clear oil (58 mg, 91% yield).

¹H NMR (300 MHz, CDCI₃) δ 10.98 (s, 1H), 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.42 (s, 2H), 4.00 (apparent t, J = 5.27 Hz, 1H), 3.80 (s, 3H), 3.54 (dd, J = 9.0, 5.7 Hz, 1H), 3.28 (dd, J = 9.0, 6.0 Hz, 1H), 2.75-2.66 (m, 1H), 2.04-1.95 (m, 1H), 1.16 (d, J = 7.2 Case 4-32428A

Hz, 3H), 0.96 (d, J = 7.2 Hz, 3H), 0.88 (m, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 179.5, 159.6, 130.7, 129.7, 114.2, 75.6, 73.1, 71.9, 55.7, 43.8, 38.5, 26.4, 18.7, 15.4, 12.3, -3.7, -3.9.

Example 5

(2R,3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-5-(4-methoxy-benzyloxy)-2,4-dimethyl- pentanoic acid methoxy-methyl-amide

To a mixture of (2R,3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-5-(4-methoxy- benzyloxy)-2,4-dimethyl-pentanoic acid (29 mg, 0.073 mmol) in anhydrous THF (2 mL) at a temperature of 0°C is added 2-chloro-4,6-dimethoxy-1,3,5-triazine (14.1 mg, 0.080 mmol) and 4-methylmorpholine (0.009 mL, 0.082 mmol) under nitrogen. After one hour of stirring, N.O-dimethylhydroxylamine hydrochloride (14.3 mg, 0.147 mmol) and 4-methylmorpholine (0.016 mL, 0.145 mmol) is added to the reaction mixture. After one hour of stirring at 0°C, the reaction mixture is warmed to room temperature and stirred overnight (18 hours). The mixture is washed with saturated aqueous NH₄CI. The organic layer is dried over Na₂S0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 20% EtOAc in hexane) to give the desired compound as a clear oil (28 mg, 87% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7, 2H), 4.39 (ABq, J_AB = 11.7 Hz, Δv = 13.9 Hz, 2H), 3.93 (dd, J = 8.1, 2.8 Hz, 1H), 3.80 (s, 3H), 3.59-3.54 (m, 4H), 3.19-3.11 (m, 5H), 1.97-1.83 (m, 1H), 1.11 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 7.2 Hz, 3H), 0.98 (s, 9H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCI₃) δ 176.8, 159.0, 130.9, 129.3, 113.6, 76.1, 72.7, 71.9, 61.2, 55.3, 39.3, 38.8, 26.2, 18.4, 15.4, 15.1, -3.8, -3.9. (ESI+) m/z 440. Case 4-32428A

Example 6

(1,1 -dimethylethyl)[[(1 R,2S,3Z)-4-iodo-1 -[(1 S)-2-[(4-methoxyphenyl)methoxy]-1 -methylethyl]- 2-methyl-3-pentenyl]oxy]dimethylsilane

To a stirred solution of (ethyl)triphenylphosphonium iodide (10.33 g, 24.7 mmol) in anhydrous THF (95 mL) is added butyllithium (BuLi) (2.5 M in hexanes, 9.4 mL, 23.5 mmol), while maintaining a temperature of 25°C under nitrogen. After stirring for 10 minutes, the mixture is cooled to -78°C. A pre-cooled (-78°C) solution of l₂ (6.27 g, 24.7 mmol) in anhydrous THF (210 mL) is added to the stirring mixture by cannula. The resultant mixture is allowed to stir for 15 minutes at -70°C, and then warmed to -23^βC. Sodium bis(trimethylsilyl)amide (NaHMDS) (1.0 M in THF, 22.0 mL, 22.0 mmol) is slowly added over a 15-minute period (maintaining -23°C). The reaction mixture is stirred for an additional 10 minutes at -23°C, then cooled to -33^βC. A solution of 2,4-dideoxy-3-0-[(1 ,1- dimethylethyl)dimethylsilyl]-5-0-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinose (4.95 g, 13.0 mmol) in anhydrous THF (20 mL) is added dropwise to the mixture, while maintaining a temperature of -33°C. The reaction mixture is stirred for 30 minutes, then warmed to room temperature. The reaction is quenched with MeOH (10 mL) and concentrated. The brown residue is filtered through a silica column (50% EtOAc in hexane), and the filtrate is washed with saturated aqueous Na₂S₂0₃ and brine (300 mL each), dried over MgS0 , filtered, and concentrated. The crude product is purified by flash chromatography (Si0₂, 5% EtOAc in hexane) to give the desired compound as a clear oil (2.42 g, 36% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.28 (apparent dd, J = 8.9, 1.3 Hz, 1H), 4.41 (s, 2H), 3.80 (s, 3H), 3.58 (apparent t, J = 5.3 Hz, 1H), 3.51 (dd, J = 9.0, 4.9 Hz, 1H), 3.23 (dd, J = 8.7, 8.3 Hz, 1H), 2.50 (m, 1H), 2.44 (d, J = Case 4-32428A

1.5, H), 2.33 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.02 (s,

3H), 0.01 (s, 3H).

Example 7 1-methoxy-4-[β(2S,3Z)-2-methyl-3,5-hexadienyl]oxy]methyl]benzene

A solution of CrCI₂ (4.36 g, 35.5 mmol) and anhydrous THF (150 mL) is allowed to stir at room temperature under N₂ for 30 minutes. The reaction mixture is cooled to 0°C, and (2R)-3-[(4-methoxyphenyl)methoxy]-2-methyl-propanal (3.12 g, 15.0 mmol) and (1-bromo-2- propenyl)trimethylsilane (6.85 g, 35.5 mmol) are added neat, respectively. The mixture is allowed to stir for one hour at 0°C, and then warmed to room temperature and stirred overnight (18 hours). A solution of aqueous 6 M KOH (150 mL) and methanol (MeOH) (75 mL) is slowly added to the reaction mixture, maintaining 25^CC with an ice bath. After one hour of stirring, the mixture is carefully extracted with DCM (5 x 150 mL). The organic layers are combined, dried over Na₂S0 , and gently concentrated. The crude product is purified by flash chromatography (Si0₂, 25% DCM in hexane, then 100% DCM) to give the desired compound as a clear oil (1.98 g, 57% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.64 (apparent dt, J = 16.6, 10.4 Hz, 1 H), 6.02 (apparent t, J = 10.9, 1H), 5.31-5.09 (m, 3H), 4.44 (ABq, J_AB = 11.7, Δv = 13.2 Hz, 2H), 3.81 (s, 3H), 3.30 (m, 2H), 1.02 (d, J = 6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 159.1, 135.2, 132.4, 130.7, 129.4, 129.2, 117.5, 113.7, 74.8, 72.6, 55.3, 32.9, 17.8.

Example 8

(2S,32)-2-methyl-3,5-hexadien-1-ol

Case 4-32428A

To a stirring mixture of 1-methoxy-4-[[[(2S,3Z)-2-methyl-3,5- hexadienyl]oxy]methyl]benzene (2.30 g, 9.90 mmol), DCM (70 mL), and water (2 mL) is added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.00 g, 13.2 mmol) at room temperature. After one hour, the reaction mixture is washed with saturated aqueous NaHC0₃ (2 x 200 mL) and 1 M aqueous NaHS0₃ (2 x 200 mL), dried over Na₂S0₄, and carefully concentrated. The crude product is purified by flash chromatography (Si0₂, 50% DCM in hexane, then 100% DCM) to give the desired compound as a clear oil (0.90 g, 81% yield).

¹H NMR (300 MHz, CDCI₃) δ 6.66 (apparent dt, J = 17.0, 10.1 Hz, 1H), 6.13 (apparent t, J = 10.9 Hz, 1H), 5.30-5.13 (m, 3H), 3.58-3.50 (m, 1H), 3.42-3.35 (m, 1H), 2.96-2.82 (m, 1 H), 1.44-1.39 (m, 1 H), 1.00 (d, J = 6.4, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 135.0, 132.6, 131.5, 118.8, 68.1 , 35.7, 17.3.

Example 9

(2S,3Z)-2-methyl-3,5-hexadienal

(2S,3Z)-2-methyl-3,5-hexadien-1-ol (0.53 g, 4.72 mmol), anhydrous DCM (40 mL), and Dess-Martin periodinane are combined and stirred at room temperature for 4 hours. Et₂O (40 mL), saturated aqueous NaHC0₃ (20 mL) and Na₂S₂0₃ (20 mL) are added and allowed to vigorously stir for 15 minutes. The organic layer is separated and washed a second time with NaHC0₃ and Na₂S₂0₃. The organic layer is separated, dried over Na S0₄, and carefully concentrated. The crude product is quickly passed through a plug of silica gel with DCM as the eluent. The filtrate is carefully concentrated to give the desired compound as a clear oil (0.38 g, 73% yield).

¹H NMR (300 MHz, CDCI₃) δ 9.55 (d, J = 1.5 Hz, 1H), 6.61 (dddd, J = 16.8, 10.6, 10.6, 0.7, 1H), 6.25 (apparent t, J = 10.7 Hz, 1H), 5.36-5.23 (m, 3H), 3.58-3.47 (m, 1H), 1.22 (d, J = 6.8, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 201.1, 133.3, 131.8, 127.6, 120.4, 46.5, 14.6. Case 4-32428A

Example 10

(2S,4Z,6S,7 ?,8S)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-9-[(4-methoxyphenyl)methoxy]- 2,4,6,8-tetramethyl-4-nonenoic acid methyl ester

To a solution of (1,1-dimethylethyl)[[(1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4- methoxyphenyl)methoxy]-1 -methylethyl]-2-methyl-3-pentenyl]oxy]dimethylsilane (0.209 g, 0.403 mmol), anhydrous THF (2 mL), and Pd(PPh₃)₄ (0.047 g, 0.041 mmole) is added (R)-(+)-3-methoxy-2-methyl-3-oxo-propylzinc bromide (0.5 M in THF, 0.85 mL, 0.425 mmol), stirring at room temperature under N₂. After 18 hours, the reaction is quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The organic layers are combined, dried over MgS0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 5% EtOAc in hexane) to give the desired compound as a clear oil (0.173 g, 87% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.10 (d, J = 10.1 Hz, 1H), 4.39 (s, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.49 (dd, J = 9.0, 4.9 Hz, 1H), 3.38 (apparent t, J = 5.3 Hz, 1H), 3.20 (apparent t, J = 8.9 Hz, 1H), 2.65-2.49 (m, 2H), 2.34-2.17 (m, 2H), 1.99-1.88 (m, 1H), 1.60 (d, J = 1.1 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3H), 0.91-0.88 (m, 12 H), 0.02 (s, 6H).

Case 4-32428A

Example 11

(2S,4Z,6S,7R,8S)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-Λ/-methoxy-9-[(4- methoxyphenyl)methoxy]-Λ/,2,4,6,8-pentamethyl-4-nonenamide

To a stirring solution of N.O-dimethylhydroxylamine hydrochloride (0.104 g, 1.06 mmol) in anhydrous toluene (3 mL) at 0°C under N₂ is added trimethylaluminum (2.0 M in hexanes, 0.53 mL, 1.06 mmol), while maintaining the temperature at 0°C. The resultant mixture is warmed to room temperature and stirred for 30 minutes. A solution of (2S,4Z,6S,7R,8S)-7-[[(1 ,1-dimethylethyl)dimethylsilyl]oxy]-9-[(4-methoxyphenyl)methoxy]- 2,4,6,8-tetramethyl-4-nonenoic acid methyl ester (0.173 g, 0.351 mmol) in anhydrous toluene (2 mL, plus 1 mL rinse) is added to the reaction mixture. The reaction mixture is then stirred at 80°C for two hours. The reaction is quenched with 1 M aqueous tartaric acid solution (100 mL) and stirred vigorously for 1 hour. The mixture is extracted with DCM (3 x 50 mL). The organic layers are combined, dried over NaS0 , and concentrated. The crude product is purified by flash chromatography (Si0₂, 30% EtOAc in hexane) to give the desired compound as a clear oil (0.167 g, 91% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.09 (d, J = 10.2 Hz, 1H), 4.38 (s, 2H), 3.80 (s, 3H), 3.68 (s, 3H), 3.49 (dd, J = 9.0, 4.9 Hz, 1H), 3.40-3.36 (m, 1H), 3.22-3.15 (m, 4H), 2.65-2.53 (m, 1H), 2.32 (dd, J = 13.4, 8.9 Hz, 1H), 2.11 (dd, J = 13.4, 5.5 Hz, 1H), 1.99-1.88 (m, 1H), 1.62 (d, J = 1.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H) 0.96 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.01 (s, 6H); ¹³C NMR (75 MHz, CDCI₃) δ 171.9, 159.4, 133.0, 131.5, 131.1, 129.5, 114.1, 78.8, 73.0 (2 signals), 61.8, 55.7, 38.9, 36.1, 35.8, 33.8, 32.8, 26.6, 23.7, 18.8, 17.2, 17.0, 15,2, -3.4, -3.5. Case 4-32428A

Example 12

(4S,6Z,8S,9 ?,10S)-9-[[(1 ,1 -dimethylethyl)dimethylsilyl]oxy]-11 -[(4-methoxyphenyl)methoxy]- 4,6,8,10-tetramethyl-6-undecen-3-one

Method A (preferred): To a stirring solution of (2S,4Z,6S,7R,8S)-7-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-9-[(4-methoxyphenyl)methoxy]-2,4,6,8-tetramethyl-4- nonenoic acid methyl ester (1.21 g, 2.46 mmol), N.O-dimethylhydroxylamine hydrochloride (0.300 g, 3.08 mmol), and THF (50 mL) at a temperature of -10°C under nitrogen is added ethylmagnesium bromide (EtMgBr) (1.0 M in THF, 2.1 mL, 2.10 mmol) dropwise, while maintaining a temperature of -10°C. The mixture is slowly warmed to room temperature over the course of an hour, and then maintained at room temperature for an additional hour. The mixture is quenched with saturated aqueous NH₄CI solution (500 mL), and extracted with DCM (3 x 300 mL). The organic layers are combined, dried over NaS0 , and concentrated. The crude product is purified by flash chromatography (Si0₂, 5% EtOAc in hexane) to give the desired compound as a clear oil (1.09 g, 90% yield).

Method B: To a solution of (2S,4Z,6S,7R,8S)-7-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-Λ/-methoxy-9-[(4-methoxyphenyl)methoxy]-Λ/,2,4,6,8- pentamethyl-4-nonenamide (0.167 g, 0.320 mmol) in anhydrous THF (5 mL) at 0°C under N₂ is slowly added EtMgBr (1.0 M in THF, 0.62 mL, 0.62 mmol). The resultant mixture is stirred for one hour at 0°C. The reaction is quenched with saturated aqueous NH₄CI (25 mL), and extracted with DCM (3 x 25 mL). The organic layers are combined, dried over MgS0₄, and concentrated. The crude product is purified by flash chromatography (Si0_2l 10% EtOAc in hexane) to give the desired compound as a clear oil (0.119 g, 75% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.09 (d, J = 10.5 Hz, 1H), 4.39 (s, 2H), 3.80 (3, 3H), 3.49 (dd, J = 9.0, 4.5 Hz, 1H), 3.36 (apparent t, J = 5.3 Hz, 1H), 3.19 (apparent t, J = 8.7 Hz, 1H), 2.72-2.51 (m, 2H), 2.46 (q, J = 7.4 Hz, Case 4-32428A

2H), 2.21 (dd, J = 13.4, 9.2 Hz, 1 H), 2.08 (dd, J = 13.2, 5.7 Hz, 1 H), 1.99-1.83 (m, 1H), 1.61

(d, J = 1.1 Hz, 3H), 1.04 (t. J = 7.2 Hz. 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H),

0.91-0.84 (m, 12H), 0.02 (s. 6H); ¹³C NMR (75 MHz, CDCI₃) δ 213.6, 157.6, 131.2, 129.5,

129.0, 127.7, 112.3, 77.0, 71.2, 71.1, 53.9, 42.6, 36.9, 34.1, 33.7, 33.1, 24.8, 21.9, 17.0,

15.4, 14.3, 13.5, 6.4, -1.4.

Example 13

(3Z,5S,6S,7R,9S,11Z,13S,14R,15S)-14-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-hydroxy-16- [(4-methoxyphenyl)methoxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-one

A batch of 0.11 M LDA in THF is freshly made by slowly adding BuLi (2.5 M in hexanes, 9 mL, 22.5 mmol) to a stirring solution of diisopropylamine (3.5 mL, 25.0 mmol) and anhydrous THF (187.5 mL) at room temperature under nitrogen, and allowing the mixture to stir for 30 minutes.

A stirring mixture of (4S,6Z,8S,9R,10S)-9-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11- [(4-methoxyphenyl)methoxy]-4,6,8,10-tetramethyl-6-undecen-3-one (0.100 g, 0.204 mmol) and anhydrous THF (3 mL) is cooled to -78°C under N₂. The 0.11 M LDA in THF solution (1.90 mL, 0.214 mmol) is slowly added to the reaction mixture, while maintaining the temperature at -78°C. After stirring for 1.5 hours, anhydrous MgBr₂ and (2S,3Z)-2-methyl- 3,5-hexadienal (0.110 g, 0.998 mmol, added neat) are added. The resultant mixture is allowed to stir for 18 hours at a temperature of -78°C. The reaction is quenched with saturated aqueous NH₄CI (50 mL), and then extracted with DCM (3 x 50 mL). The organic layers are combined, dried over NaS0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 5% EtOAc in hexane) to give the desired compound as a clear oil (35% yield, after 74% recovered starting material). Case 4-32428A

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7, 2 H), 6.59 (apparent dt, J = 16.6, 10.5 Hz, 1H), 6.11 (apparent t, J = 11.1 Hz, 1H), 5.42 (apparent t, J = 10.9 Hz, 1H), 5.25 (d, J = 17.0 Hz, 1H), 5.15-5.08 (m, 2H), 4.39 (s, 2H), 3.80 (s, 3H), 3.73-3.68 (m, 1H), 3.49 (dd, J = 9.0, 4.9 Hz, 1H), 3.37 (apparent t, J = 5.3 Hz, 1H), 3.19 (apparent t, J = 8.7 Hz, 1 H), 2.86-2.71 (m, 3H), 2.65 (d, J = 2.6 Hz, 1 H), 2.54 (apparent dt, J = 10.0, 6.2 Hz, 1H), 2.24 (dd, J = 13.4, 9.6 Hz, 1H), 2.03 (dd, J = 13.6, 4.9 Hz, 1H), 1.98-1.89 (m, 1H), 1.98 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.00-0.88 (m, 21H), 0.02 (s, 6H).

Example 14

(3Z,5S,6S,7R,9S, 11 Z,13S, 14R, 15S)-6-[(aminocarbonyl)oxy]-14-[[(1 , 1 - dimethylethyl)dimethylsilyl]oxy]-16-[(4-methoxyphenyl)methoxy]-5,7,9,11,13,15-hexamethyl- 1 ,3,11-hexadecatrien-8-one

To a room temperature solution of (3Z,5S,6S,7R,9S,11Z,13S,14R,15S)-14-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-6-hydroxy-16-[(4-methoxyphenyl)methoxy]-5,7,9,11,13,15- hexamethyl-1,3,11-hexadecatrien-8-one (11 mg, 0.018 mmol) in anhydrous DCM (1 mL) is added trichloroacetyl isocyanate (3 drops) under nitrogen. After one hour of stirring, neutral alumina (300 mg) was added. After stirring for an additional 4 hours, the reaction mixture is concentrated. The crude product (adsorbed on the alumina) is placed on the top of a column, and is purified by flash chromatography (Si0₂, 25% EtOAc in hexane) to give the desired compound as a clear oil (11 mg, 93% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.47 (apparent dt, J = 16.6, 10.5 Hz, 1H), 6.05 (t, J = 11.1 Hz, 1H), 5.41 (apparent t, J = 10.4 Hz, 1H), 5.19 (d, J = 16.2 Hz, 1H), 5.12-5.05 (m, 3H), 4.84 (s, 2H), 4.40 (s, 2H), 3.81 (s, 3H), 3.49 (dd. J = 9.0, 4.5 Hz, 1H), 3.36 (apparent t, J = 5.1 Hz, 1H), 3.20 (apparent t, J = 8.7 Hz, Case 4-32428A

1H), 3.00-2.70 (m, 3H), 2.60-2.46 (m, 1H), 2.33-2.21 (m, 1H), 2.06-1.91 (m, 2H), 1.71 (s,

3H), 1.13 (d, J = 7.2 Hz, 3H), 1.05-1.00 (m, 6H), 0.97-0.86 (m, 15H), 0.03-0.01 (m, 6H).

Example 15

(3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-6-carbamate-14-[[(1 ,1- dimethylethyl)dimethylsilyl]oxy]-16-[(4-methoxyphenyl)methoxy]-5,7,9,11 ,13,15-hexamethyl- 1 ,3,11-hexadecatriene-6,8-diol

To a -78°C stirring solution of (3Z,5S,6S,7R,9S,11Z,13S,14R,15S)-6- [(aminocarbonyl)oxy]-14-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-16-[(4- methoxyphenyl)methoxy]-5,7,9,11 ,13,15-hexamethyl-1 ,3,11-hexadecatrien-8-one (11 mg, 0.017 mmol) in anhydrous THF (1 mL) is added lithium tri-tert-butoxyaluminohydride (1 M in THF, 0.10 mL, 0.100 mmol) dropwise. After stirring for 1 hour at -78°C, the reaction is quenched with saturated aqueous NH CI solution (30 mL) and extracted with DCM (3 x 30 mL). The organic layers are combined, dried over Na S0 , and concentrated. The crude product is purified by flash chromatography (SiO_∑, 30% EtOAc in hexane) to give the desired compound as a clear oil (10 mg, 91% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.61 (apparent dt, J = 16.3, 10.7 Hz, 1H), 6.02 (apparent t, J = 10.7 Hz, 1H), 5.33 (apparent t, J = 10.4 Hz, 1H), 5.22 (d, J = 17.0 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 5.00 (d, J = 10.5 Hz, 1H), 4.74 (dd, J = 7.0, 4.7 Hz, 1H), 4.52 (s, 2H), 4.40 (Abq, J_AB = 11.5 Hz, V_AB = 15.6 Hz, 2H), 3.81 (s, 3H), 3.51 (dd, J = 9.2, 5.1 Hz, 1H), 3.38 (dd, J = 6.0, 4.1 Hz, 1H), 3.24-3.17 (m, 2H), 3.04-2.96 (m, 1H), 2.62-2.53 (m, 1H), 2.05-1.87 (m, 6H), 1.59 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.96-0.81 (m, 21 H), 0.03-0.01 (m, 6H). Case 4-32428A

Example 16

(3Z,5S,6S,7R,8R,9S,11Z,13S,14R,15S)-8,14-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-16- -methoxyphenylJmethoxyl-S .Θ.I I.IS.Iδ-hexamethyl-I.S.H-hexadecatrien-e-ol carbamate

To a stirring solution of (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-6-carbamate-14- [[(1 ,1 -dimethylethyl)dimethylsilyl]oxy]-16-[(4-methoxyphenyl)methoxy]- 5,7,9,11,13,15-hexamethyl-1, 3,11-hexadecatriene-6,8-diol (10 mg, 0.015 mmol), 2,6-lutidine (0.02 mL, 0.1717 mmol) and anhydrous DCM (2 mL) is added tert- butyldimethylsilyltrifluoromethanesulfonate (0.02 mL, 0.087 mmol) at room temperature under N₂. The resultant mixture is stirred at room temperature for one hour and quenched with saturated aqueous NH₄CI solution (30 mL) and extracted with DCM (3 x 30 mL). The organic layers are combined, concentrated and methanol (5 mL) and K₂C0₃ (300 mg) is added. After 30 minutes of stirring, the suspension is concentrated, and the white paste partitioned between water (50 mL) and DCM (30 mL). The organic layer is separated, and the aqueous layer is extracted with DCM (2 x 25 mL). The organic layers are combined, dried over Na₂SO , and concentrated. The crude product is purified by flash chromatography (Si0₂, 30% EtOAc in hexane) to give the desired compound as a clear oil (11 mg, 93% yield).

¹H NMR (300 MHz, CDCI₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.60 (apparent dt, J = 17.0, 10.5 Hz, 1 H), 6.02 (apparent t, J = 10.9 Hz, 1 H), 5.35 (apparent t, J = 10.5 Hz, 1H), 5.22 (d. J = 17.0 Hz, 1H), 5.13 (d, J = 9.8 Hz, 1H), 4.98 (d, J = 10.2 Hz, 1H), 4.76-4.70 (m, 3H), 4.38 (ABq, J_AB = 11.7 Hz, v_AB = 15.4 Hz, 2H), 3.79 (s, 3 H), 3.50-3.35 (m, 3 H), 3.21 (apparent t, J = 8.9 Hz, 1H), 3.06-2.93 (m, 1H), 2.54-2.42 (m, 1H), 2.15-1.81 (m, 4H), 1.68 (d, J = 12.1 Hz, 1H), 1.58 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.95-0.86 (m, 27H), Case 4-32428A

0.74 (d, J = 6.8 Hz, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.03 (s, 6H); ¹³C NMR (75 MHz, CDCI₃) δ

158.9, 157.1, 133.5, 132.0, 131.1 , 129.7, 129.0, 118.0, 113.7, 78.7, 78.5, 76.9, 72.6, 72.4,

55.2, 38.7, 37.9, 36.0, 35.6, 35.1, 34.4, 26.2, 26.1, 22.9, 18.5, 18.4, 17.5, 17.3, 14.6, 14.2,

13.8, 10.1, -3.4 (2), -3.9 (2); HSMS m/z calcd for C₄₃H₇₈N0₆Si₂ (M+H) 760.537, found

760.539.

Example 17

(ΣS.SR^S.δZ.βS.gR.IO .HS.^S.ISZJ-H-carbamate-S.g-bisIKI.I- dimethylethyl)dimethylsilyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol

(3Z,5S,6S,7R,8R,9S,11Z,13S,14R,15S)-8,14-bis[[(1,1- dimethylethyl)dimethylsilyl]oxy]-16-[(4-methoxyphenyl)methoxy]-5,7,9,11,13,15-hexamethyl- 1,3,11-hexadecatrien-6-ol carbamate (40 mg, 0.053 mmol), DCM (10 mL), water (0.10 mL), and 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (400 mg, 1.762 mmol) are combined and stirred at room temperature for one hour. To the reaction mixture is added DCM (150 mL), saturated aqueous NaHC0₃ (150 mL), and saturated aqueous NaHS0₄ (150 mL), and the resultant mixture is stirred vigorously for 15 minutes. The organic layer is separated, and the aqueous layer is extracted with DCM (50 mL). The organic layers are combined and stirred vigorously again for 15 minutes with saturated aqueous NaHC0₃ (150 mL) and saturated aqueous NaHS0₄ (150 mL). The organic layer is separated, and the aqueous layer extracted with DCM (50 mL). The organic layers are combined, dried over Na₂S0 , and concentrated. The crude product is purified by flash chromatography (Si0₂, 30% EtOAc in hexane) to give the desired compound as a clear oil (31 mg, 92% yield). Case 4-32428A

¹H NMR (300 MHz, CDCI₃) δ 6.61 (apparent dt, J = 17.0, 10.7 Hz, 1H), 6.06 (apparent t, J = 11.1 Hz, 1H), 5.38 (apparent t, J = 10.5 Hz, 1H), 5.24 (d, J = 17.0 Hz, 1H), 5.14 (d, J = 10.2 Hz, 1H), 4.98 (d, J = 10.2 Hz, 1H), 4.74 (apparent t, J = 6.0 Hz, 1H), 4.53 (s, 2H), 3.72-3.65 (m, 1H), 3.54-3.38 (m, 3H), 3.06-2.94 (m, 1H), 2.63-2.51 (m, 1H), 2.42 (apparent t, J = 5.8 Hz, 1H), 2.14 (apparent t, J = 12.2 Hz, 1H), 1.94-1.69 (m, 4H), 1.61 (s, 3H), 1.00 (d, J = 7.2 Hz, 6H), 0.95-0.91 (m, 24H), 0.74 (d, J = 6.8 Hz, 3H), 0.11 (s, 6H), 0.10 (s, 3H), 0.08 (s, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 157.3, 134.0, 133.4, 132.6, 130.7, 130.2, 118.3, 82.3, 79.2, 77.2, 65.7, 38.6, 38.4, 37.4, 36.6, 35.5, 34.8, 26.6, 23.4, 18.9, 18.7, 18.1 , 17.9, 16.3, 14.1, 10.5, -3.1, -3.5.

Example 18

(2R,3R,4S,5Z,8S,9R, 10R, 11 S,12S, 13Z)-11 -[(aminocarbonyl)oxy]-3,9-bis[[(1 , 1 - dimethylethyl)dimethylsilyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13, 15-hexadecatrienal

To a solution of (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-11-carbamate-3,9-bis[[(1,1- dimethylethyl)dimethylsilyl]oxy]-2,4,6 ,8, 10, 12-hexamethyl-5, 13, 15-hexadecatriene-1 , 11 -diol (31 mg, 0.048 mmol) in DCM (3 mL) is added 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) (1 mg, 0.006 mmol) and iodobenzene diacetate (23 mg, 0.071 mmol) at room temperature. After two hours of stirring, the reaction is quenched with saturated aqueous Na₂S₂0₃ (50 mL). DCM (50 mL) is added, and the organic layer is separated and washed with saturated aqueous NaHC0₃ (50 mL). The organic layer is separated, dried over NaS0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 30% EtOAc in hexane) to give the desired compound as a clear oil (30 mg, 97% yield). Case 4-32428A

¹H NMR (300 MHz, CDCI₃) δ 9.61 (s, 1H), 6.60 (apparent dt, J = 16.8, 10.6 Hz, 1H), 6.04 (apparent t, J = 10.9, 1H), 5.38 (apparent t, J = 10.4, 1H), 5.23 (d, J = 17.0 Hz, 1H), 5.14 (d, J = 9.8, 1H), 4.82-4.72 (m, 2H), 4.52 (s, 2H), 3.75 (dd, J = 8.1, 3.6 Hz, 1H), 3.42 (apparent t, J = 4.5 Hz, 1H), 3.06-2.94 (m, 1H), 2.58-2.45 (m, 2H), 2.07 (apparent t, J = 12.0, 1H), 1.93-1.80 (m, 2H), 1.66 (d, J = 12.4 Hz, 1H) 1.57 (s, 3H), 1.07 (d, J = 7.2 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.95-0.89 (m, 24H), 0.71 (d, J = 6.8 Hz, 3H), 0.12 (s, 3H), 0.09 (s, 6H), 0.06 (s, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 203.5, 157.3, 135.9, 134.0, 132.5, 130.2, 129.4, 118.4, 79.1, 78.7, 77.3, 52.5, 38.4, 36.9, 35.3, 34.8, 26.6, 26.3, 23.3, 19.0, 18.6, 18.4, 17.9, 14.3, 10.4, 10.2, -2.9, -3.1 , -3.8, -3.9; HSMS m/z calcd for CssHe/NNaOgSiz (M+Na) 660.446, found 660.443.

Example 19

(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1- dimethylethyl)dimethylsilyl]oxy]-4,6,8, 10,12,14-hexamethyl-2,7, 15,17-octadecatetraenoic acid methyl ester

A mixture of anhydrous toluene (2 mL), 18-crown-6 (285 mg, 1.08 mmol) and K₂C0₃ (150 mg, 1.09 mmol) is stirred at room temperature under nitrogen for one hour. The mixture is cooled to a temperature of -20°C, and a solution of toluene (2 mL), (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-11-[(aminocarbonyl)oxy]-3,9-bis[[(1 ,1- dimethylethylJdimethylsilyOoxyl^^.β.S.IO.IΣ-hexamethyl-S.IS.IS-hexadecatrienaUSO mg, 0.05 mmol) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphate (0.10 mL, 0.47 mmol) is added slowly to the mixture. The resultant mixture is stirred for two hours at a temperature of -20°C, slowly warmed to 0°C and quenched with saturated aqueous NH₄CI. The resultant mixture is extracted with EtOAc (3 x 20 mL). The organic layers are combined, Case 4-32428A dried over Na₂S0₄, and concentrated. The crude product is purified by flash chromatography (Si0₂, 20% EtOAc in hexane) to give the desired compound as a clear oil (27 mg, 83% yield).

¹H NMR (300 MHz, CDCI₃) δ 6.60 (apparent dt, J = 16.7, 10.6 Hz, 1H), 6.38 (dd, J = 11.5, 10.0 Hz, 1 H), 6.04 (apparent t, J = 10.9, 1 H), 5.71 (d, J = 11.7, 1 H), 5.39 (apparent t, J = 10.5, 1H), 5.22 (d, J = 16.6 Hz, 1H), 5.14 (d, J = 10.2, 1H), 4.89 (d, J = 10.2, 1H), 4.73 (apparent t, J = 6.0 Hz, 1H), 4.52 (s, 2H), 3.71-3.63 (m, 4H), 3.41 (apparent t, J = 4.3 Hz, 1H), 3.35 (dd, J = 7.7, 2.4 Hz, 1H), 3.03-2.95 (m, 1H), 2.33-2.25 (m, 1H), 2.01 (apparent t, J = 12.4, 1H), 1.92-1.75 (m, 2H), 1.62-1.54 (m, 4H), 1.04-0.98 (m, 6H), 0.95-0.85 (m, 24H), 0.69 (d, J = 6.4 Hz, 3H), 0.11 (s, 3H), 0.09-0.05 (m, 9H); ¹³C NMR (75 MHz, CDCI₃) δ 166.5, 157.0, 152.5, 133.6, 132.8, 132.1 , 130.2, 129.8, 118.5, 117.9, 80.7 (2 signals), 78.9, 50.9, 37.9, 37.8, 37.5, 35.8, 35.2, 34.5, 26.2, 25.9, 22.8, 18.5 (2 signals), 18.3, 18.2, 17.5, 13.9, 10.1, -3.4, -3.5 (2 signals), -3.6; HSMS m/z calcd for C₃8H₇₂N0₆Si₂ (M+H) 694.490, found 694.491.

Claims

Case 4-32428ACLAIMS

1. A process for preparing the compound of formula IV

which comprises oxidizing the hydroxy group of an alcohol of formula

by treating it with a mild oxidizing agent in a non-polar solvent to obtain the compound of formula IV.

2. A process for preparing the compound of formula III

which comprises, in a first step, olefinating the compound of formula

initially in the presence of a transition metal complex, an allyl halide and a polar solvent and then in the presence of a base in a polar solvent to obtain the diene of formula II

in a second step, hydrolyzing the para-methoxy benzyl ether moiety of the diene obtained in the first step by treating it with 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone and water in a non-polar solvent to obtain the alcohol of formula III Case 4-32428A

3. A compound which is 1-methoxy-4-[[[(3Z)-2-methyl-3,5- hexadienyl]oxy]methyl]benzene of formula II

4. A compound which is (3Z)-2-methyl-3,5-hexadien-1-ol of formula III

5. A compound which is (3Z)-2-methyl-3,5-hexadienal of formula IV

6. A process for preparing a compound of formula X

where Ri is Si((Cι^)alkyl)₃ or an acid labile hydroxyl protecting group, which comprises, amidating the carboxylic acid of formula IX Case 4-32428A

where Ri is as defined above, by treating it with a base and N.O-dimethylhydroxylamine hydrochloride in a polar solvent to obtain a compound of formula X.

7. A process for preparing a compound of formula IX

where Ri is Si((Cι-6)alkyl)₃ or an acid labile hydroxyl protecting group, which comprises, in a first step, alkylborating the compound of formula I

in the presence of a drying agent and an unsaturated alkylboronate in a non-polar solvent to obtain the alcohol of formula VI

Case 4-32428A in a second step, protecting the hydroxy group of the alcohol obtained in the first step by treating it with a base and an acid labile hydroxyl protecting reagent in a non-polar solvent to obtain an olefin of formula VII

where Ri is as defined above, in a third step, oxidizing the olefin obtained in the second step by initially treating it with osmium tetroxide and 4-methylmorpholine N-oxide in a mixture of acetone, tert-butyl alcohol and water, and then treating the resulting product with sodium periodate in a polar solvent, to obtain an aldehyde of formula VIII

where R, is as defined above, in a fourth step, oxidizing the aldehyde obtained in the third step by treating it with sodium chlorite and sodium hydrogenphosphate in a mixture of tert- butyl alcohol, dimethyl-2-butene and water to obtain a carboxylic acid of formula IX.

8. A compound of formula VIII

where Ri is Si((C₁^)alkyl)₃ or an acid labile hydroxyl protecting group. Case 4-32428A

9. A compound of formula IX

where R_t is Si((C₁^)alkyl)₃ or an acid labile hydroxyl protecting group.

10. A process for preparing a compound of formula XXI

where each of Ri and R₃, independently, is Si((C₁-₆)alky!)₃ or an acid labile hydroxyl protecting group, and R₄ is (C^alkyl or benzyl, which comprises a Wittig coupling of a compound of formula XX

Case 4-32428A where Ri and R₃ are as defined above, by treating it with a base, 18-crown-6 and a methylphosphate ester in a non-polar solvent to obtain a compound of formula XXI.

11. A process for preparing a compound of formula XX

where each of Ri and R₃, independently, is Si((C₁-6)alkyl)₃ or an acid labile hydroxyl protecting group, which comprises, in a first step, a Pd(0) coupling of a compound of formula XI

where R, is as defined above and X is bromide or iodide, in the presence of a Pd(0) catalyst and a propylzinc halide ester in a polar solvent to obtain an ester of formula XII

Case 4-32428A where Ri is as defined above and R₂ is (Cι^)alkyl or benzyl, in a second step, converting the ester obtained in the first step to a ketone by treating it with N.O-dimethylhydroxylamine hydrochloride and a Grignard reagent in a polar solvent to obtain a compound of formula XIV

where Ri is as defined above, in a third step, an aldol coupling with the ketone obtained in the second step by initially treating it with a base in a polar solvent, and then with a chelating agent and an aldehyde in a polar solvent to obtain a compound of formula XV

where Ri is as defined above, in a fourth step, carbamoylating the alcohol obtained in the third step by treating it with trichloroacetyl isocyanate and neutral alumina in a non-polar solvent to obtain a compound of formula XVI

where Ri is as defined above, in a fifth step, reducing the compound obtained in the fourth step by treating it with a hydride donating agent in a polar solvent to obtain an alcohol of formula XVII Case 4-32428A

where Ri is as defined above, in a sixth step, protecting the hydroxy group of the alcohol obtained in the fifth step by treating it with a base and an acid labile hydroxyl protecting reagent in a polar solvent to obtain a compound of formula XVIII

XVIII ,

where Ri and R₃ are as defined above, in a seventh step, hydrolyzing the compound obtained in the sixth step by treating it with 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone and water in a non-polar solvent to obtain a compound of formula XIX

where Ri and R₃ are as defined above, and, in a eighth step, oxidizing the compound obtained in the seventh step by treating it with 2,2,6,6-tetramethyM-piperidinyloxy free radical and iodobenzene diacetate in a non-polar solvent to obtain a compound of formula XX.

12. A compound of formula XII Case 4-32428A

where Ri is Si((Cι-₆)alkyl)₃ or an acid labile hydroxyl protecting group, and R₂ is (Cι^)alkyl or benzyl.

13. A compound of formula XIII

where Ri is Si((C₁.₆)alkyl)₃ or an acid labile hydroxyl protecting group.

14. A compound of formula XIV

where Ri is Si((Cι.₆)alkyl)₃ or an acid labile hydroxyl protecting group.

15. A compound of formula XV Case 4-32428A

where Ri is Si((Cι--€)alkyl)₃ or an acid labile hydroxyl protecting group.

16. A compound of formula XVI

where Ri is Si((Cι-₆)alkyl)₃ or an acid labile hydroxyl protecting group.

17. A compound of formula XVII

where Ri is Si((C₁^)alkyl)₃ or an acid labile hydroxyl protecting group.

18. A compound of formula XVIII Case 4-32428A

where each of Ri and R₃, independently, is Si((Cι^)alkyl)₃ or an acid labile hydroxyl protecting group.

19. A compound of formula XIX

where each of R and R₃, independently, is Si((Cι-6)alkyl)₃ or an acid labile hydroxyl protecting group.

20. A compound of formula XX

where each of Ri and R₃, independently, is Si((Cι^)alkyl)₃ or an acid labile hydroxyl protecting group.