WO2000056732A2

WO2000056732A2 - Synthesis of epoxy-thf compounds

Info

Publication number: WO2000056732A2
Application number: PCT/US2000/007302
Authority: WO
Inventors: Fatih M. Uckun; Keqiang Li
Original assignee: Parker Hughes Institute
Current assignee: Parker Hughes Institute
Priority date: 1999-03-19
Filing date: 2000-03-17
Publication date: 2000-09-28
Anticipated expiration: 2001-09-19
Also published as: WO2000056732A3; AU4015900A

Abstract

A stereoselective process for preparing novel compounds, particularly a tetrahydrofuran (THF) epoxide, which can be used to prepare therapeutically active mono-THF and bis-THF acetogenins. The process starts with a commercially available aldehyde and affords the desired THF epoxide in 11 steps.

Description

SYNTHESIS OF EPOXY-THF COMPOUNDS

Field of the Invention

The invention relates to a stereocontrolled process for preparing novel compounds, particularly a tetrahydrofuran (THF) epoxide, which can be used to prepare therapeutically active mono-THF and bis-THF acetogenins

Background of the Invention

Since the first discovery of uvaπcm in 1982¹, more than 230 annonaceous acetogenins have been isolated and identified from vaπous acetogenm species ² Considerable attention has been paid to this class of naturally occurring polyketide- deπved fatty acids due to their pleiotropic biological activities³, including their immunosuppressive and anti-neoplastic properties Acetogenins are optically pure compounds frequently containing a long hydrocarbon chain featuring a terminal γ- lactone, a center unit containing 1 to 3 THF πngs and several hydroxylated setereogenic centers The stereochemistry of the THF rings may affect the activity of acetogenins since it has been noticed that different stereoisomers of acetogenins display strikingly different biological activity profiles However, very little is known about the structure-activity relationships contributing to these differences The presence of multiple stereogemc centers m annonaceous acetogenins presents a great challenge for their synthesis and characterization Earlier reports described schemes for total synthesis of mono-THF and bis-THF acetogenins ⁴ However, very few synthetic strategies yielding the central core THF-umt of mono-

¹ Jolad, S D , Hoffman, J J , Schram, K H , Tempesta, M S , Kriek, G R , Bates, R B , Cole, J R J Org Chem 1982, 47, 3151

² a) Cave, A , Figadere, B , Laurens, A , Cortes D , Acetogenins from Annonaceae In Herz W , ed , Prog) ess in the Chemistry of Organic Natwal Products Acetogenins from Annonaceae New York Springer- Verlag, 1997 81-228 b) Rupprecht, Y K , Hui, J H ,McLaughlιn, J L , J Nat Prod , 1990, 53, 237 C) Gu, Z M , Zhao, G X , Ober es, N H , Zeng, L , McLaughlin, J L , Annonaceous Acetogenins In Amason, J T , Mata, R , Romeo, J T , ed , Recent Advances In Phytochemistry New York Plenum Press, 1995 249-310

³ a) Zeng, L , Ye, Q , Oberhes, N H , Shi, G , Gu, Z -M , He, K , McLaughlin, J L Natwal Pwduct Repoi ts, 1996, 275 and references cited therein b) Fang, X P , Rieser, M J , Gu, Z M , Zhao, G X , McLaughlin, J L , Phytochem Anal 1993, 4, 27-48 a) Figadere, B , Peyrat, J -F , Cave, A J Oig Chem 1997, 62, 3248 and references cited therein b) Hoye, T R , Ye, Z J Am Chem Soc 1996, 1 18, 1801 c) Figadere, B Ace Chem Res 1995, 28 359 and references cited therein THF containing acetogenins are stereoselective and therefore require chromatographic separation of the key intermediates ⁵

Summary of the Invention The present invention includes a process for preparing the compound of formula I

wherein Alk is alkyl which includes the steps of

(a) contacting a stereoisomeπc compound of the formula

Alk' II under asymmetric epoxidation conditions with a chiral auxiliary to form a stereoisomeπc compound of the formula

(b) contacting the resulting epoxide of Formula III with an alkyl sulfonyl hahde or aryl-sulfonyl hahde in the presence of a base to form a stereoisomeπc compound of the formula

Alk' O- P

O" IV wherein P is an alkyl sulfonyl hahde or aryl-sulfonyl hahde,

⁵ a) Gesson, J -P , Bertrand, P Tetrahedron Lett 1992, 33, 5177 b) Harmange J -C Figadere, B Cave, A Teti ahedron Lett 1992, 33, 5749 c) Makabe, H , Tanaks, A Oπtani, T J Chem Soc Peikin Trans 1, 1994, 1975 d) Wu, Y -L , Yao, Z -J Teti ahedron Lett 1994, 35, 157 e) Wu, Y -L Yao, Z -J J Org Chem 1995, 60, 1170 (c) contacting a compound of Formula IV under asymmetric dihydroxylation conditions with a chiral auxiliary to form a stereoisomeric compound of the formula

V (d) contacting a compound of Formula V with acid followed by followed by an alkali metal alkoxide or carbonate in an alcohol solvent to afford the product of the above Formula I.

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The

Figures and the detailed description which follow more particularly exemplify these embodiments.

Detailed Description of the Preferred Embodiment

The following terms used throughout the present application have the following meanings:

The term "stereoisomeric" compound means the compound depicted by its respective formula existing in any of 2" possible optical isomers, where n is the number of asymmetric carbon atoms. The compounds of Formulae I have 4 asymmetric carbon atoms or chiral centers and each center containing the asymmetric carbon atoms connected to four different groups exist either in the R configuration or S configuration.

By way of illustration the asymmetric carbon atoms or chiral centers of the compound of Formula I is designed with an asterisk as follows:

The term "alkyl" (designated as Alk) denotes a straight or branched hydrocarbon chain. Typically, the term alkyl includes such straight or branched hydrocarbon chains having from 1 to 15 carbon atoms. As a preferred embodiment, chains from 1 to 12 carbon atoms are included. These include as examples, methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. A most preferred embodiment includes a dodecyl hydrocarbon chain.

The term "hydroxyl activating" group means any group capable of protecting a hydroxyl group and capable of being easily removed under basic or acidic conditions without affecting other functional groups in the compound. These include, for example, mesylates, benzylsulfonates, alkyl alkyl carbonates, alkyl vinyl carbonates and tosylates. Preferred hydroxyl activating groups include, for example, mesylates and tosylates. A most preferred hydroxyl activating group includes tosylates. The term "alkoxy" refers to an alkyl moiety connected to an oxygen atom depicted by the formula OR, where R is an alkyl chain as defined above. Preferred alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the corresponding branched chain alkoxy groups of the propoxy and butoxy groups.

The term "asymmetric epoxidation conditions" means the reaction conditions used to introduce an epoxide moiety into a molecule with stereospecificity as disclosed in Hanson, R.M.; Sharpless, K.B. J. Org. Chem. 1986, 51, 1922 herein incorporated by reference.

The term "asymmetric dihydroxylation" means the reaction conditions used to introduce a vicinal diol moiety into a molecule with stereospecificity as disclosed in Kolb, H. C; VanNieuwenhze, M. S.; Sharpless, K. B.; Chem. Rev. 1994, 94, 2483-2547 herein incorporated by reference.

The synthesis of the novel compounds of the present invention by a stereocontrolled method is illustrated by way of example in Scheme 1 and begins with a commercially available tridecanal. The synthesis shown in the scheme and described below is for a particular stereoisomer but the synthesis can be used to prepare all possible stereoisomers. The tridecanal 1 is first extended to a γ, δ-unsaturated ethyl ester 3 by a two step reaction sequence⁶ including contacting the tridecanal with vinylmagnesium bromide to form an allylic alcohol, followed by contact with triethyl orthoacetate and a catalytic amount of propionic acid.⁷ The carbon chain of the γ, δ-unsaturated ethyl ester is further extended by a four-step reaction sequence to form 7 (as described in Rossiter, B. E.; Synthetic Aspects and Applications of Asymmetric

Epoxidation. In: Morrison, J., ed.; Asymmetric Synthesis. Orlando: Academic Press,

1985:193-246). This four-step reaction sequence includes reduction of the ethyl ester of 3 to the corresponding alcohol with lithium aluminum hydride (LAH) followed by oxidation to the aldehyde 5 with dimethyl sulfoxide, oxalyl chloride and triethyl amine. The aldehyde 5 is extended by contacting it with triethyl phosphonoacetate to form the ethyl ester 6, followed by diisobutylaluminum hydride (DIBAL) reduction to afford the allylic alcohol 7. The allylic alcohol 7 is then converted to the epoxy alcohol 8 as a single isomer by Sharpless asymmetric epoxidation (as described in Hanson, R.M.; Sharpless, K.B. J. Org. Chem. 1986, 51, 1922) using diisopropyl L-tartrate (L-(+)-DIPT) as a chiral auxiliary. Formation of the tetrahydrofuran (THF) moiety is then accomplished by first converting the primary alcohol in 8 to an alkyl sulfonyl halide or aryl-sulfonyl halide, such as a mesylate or tosylate, using, for example, mesyl chloride or tosyl chloride in the presence of an amine, such as triethylamine or pyridine. The resulting tosylate or mesylate is then subjected to Sharpless asymmetric dihydroxylation (as described in Kolb, H. C; VanNieuwenhze, M. S.; Sharpless, K. B.; Chem. Rev. 1994, 94, 2483- 2547) using AD mix-β to form 10. The next step, one of the key steps in the overall process, is the one-step epoxide ring opening and 5-exo cyclization of 10 using an acid, such as camphor sulfonic acid (CSA), as the catalyst to form 11 as a single isomer. The THF species 11 is then contacted with an alkali metal alkoxide or in an alcohol solvent, particularly, for example, sodium methoxide or potassium carbonate in methanol to yield the THF-epoxide compound 12, which corresponds to the C₁₆- C₃₄ unit of C₃₇ acetogenins or the C₁₄-C₃₂ unit of C₃₅ acetogenins and is versatile synthetic precursor for mono-THF and bis-THF containing acetogenins.

⁶ Wang, Z. M.; Zhang, X. L.; Sharpless, K. B.: Smha, S. C; Sinha-Bagchi, A., Keinan, E. Tetrahedron Lett. 1992, 3, 6407-6410. H₂₅Cι₂

OEt

(94%)

H₇ 25<C 2 OTs (62%) H, 2₅5CM2

O"^" O""

(97%)

12

Conditions, (a) Allyl MgBr; (b) H₃CC(OEt)₃; (c) LAH; (d) DMSO, (COC1),, Et₃N; (e) (EtO)₂P(0)CH₂C0₂Et, (f) DIBAL; (g) Asymmetric epoxidation, L-(+)-DIPT; (h) TsCl, pyπdme, (1) Asymmetric dihydroxylation, AD mix- β; 0) Camphor sulfomc acid, (k) K₂C0₃, MeOH

Scheme 1

Trust, R I , Ireland, R E ; Organic Synth Coll Vol 6 1988, 606 The compound 12 is used as a key intermediate as the epoxide can be easily opened by different nucleophiles to lead to structures with a fixed stereochemical relationship around the THF-ring unit. For example, as shown in Scheme 2, compound 13 has been prepared using allyl magnesium bromide as a nucleophile. Compound 13 possesses anti-cancer properties as disclosed in United States Patent

Application Serial No. 09/352, 649 herein incorporated by reference.

Thus, the present invention provides an efficient procedure for the stereocontrolled synthesis of THF-epoxides. This synthetic approach offers several advantages over previously described strategies. First, the stereochemical outcome in the Sharpless asymmetric epoxidation step can be selected by the use of either enantiomer of diisopropyl tartrate. Second, the stereochemical outcome for the formation of the THF moiety can also be varied by through the use of different chiral auxiliaries during asymmetric dihydroxylation. This approach can yield a variety of stereoisomeric THF-epoxides and thereby provide the opportunity to generate large chemical libraries of mono-THF containing acetogenins.

Examples

Compound 2.

To the solution of vinyl magnesium bromide (230 mL of 1M solution in THF) in anhydrous ether (151 mL) at 0 °C was added dropwise a solution of tridecanal (31.70 g, 159.8 mmol) in anhydrous THF (75 mL). After being stirred at 0 °C for lh, the reaction was quenched by saturated NH₄C1 and diluted with ether (700 mL). The organic phase was washed with water (3 x 160 mL) and brine (200 mL), dried over anhydrous MgSO , filtered and concentrated to give compound 2 (33.23 g, 97%). H NMR (300 MHz, CDC1₃) δ 5.85 (m, IH), 5.16 (m, 2H), 4.08 (ddd, J = 6.5, 6.5, 6.5, IH), 1.51 (m, 4H), 1.23 (m, 18H), 0.86 (t, J = 6.5, 3H); ¹³C NMR (75 MHz, CDC1₃) δ 141.27, 114.52, 73.31, 37.06, 31.94, 29.67, 29.61, 29.38, 25.36, 22.72, 14.16; IR 3347, 2926, 2856, 1468, 992, 923 cm^"1.

Compound 3.

A mixture of the allylic alcohol 2 (32.08 g, 141.1 mmol), triethyl orthoacetate (130 mL, 709 mmol) and propionic acid (1.1 mL, 15 mmol) was heated at 138-142 °C for 4 hours. After cooling the reaction mixture to room temperature, propionic acid and the excess triethyl orthoacetate were removed under reduced pressure to give ester 3 with a quantitative yield (41.67 g). Η NMR (300 MHz, CDC1₃) δ 5.40 (m, 2H), 4.11 (q, J = 7.5 Hz, 2H), 2.31 (m, 4H), 1.94 (m, 2H), 1.23 (m, 3H), 0.86 (t, J = 6.5

Hz, 3H); 1¹3^JC NMR (75 MHz, CDC1₃) δ 173.23, 131.82, 127.84, 60.22, 34.46, 32.52, 31.94, 29.67, 29.53, 29.48, 29.38, 29.15, 27.98, 22.71, 14.28, 14.14.

Compound 4.

To the solution of ester 3 (39.59 g, 133.5 mmol) in ether (900 mL) was added LAH (7.60 g, 200 mmol) slowly at 0 °C. The reaction mixture was stirred for 3h at 0 °C and then quenched with water (8 mL) at 0 °C. The mixture was partitioned between ether (900 mL) and water (800 mL). The organic layer was washed with saturated NH₄C1 (400 mL), dried over anhydrous MgSO₄, and concentrated. The crude product was purified by flash column chromatography (hexane/ethylacetate 4:1) to afford pure alcohol 4 (31.29 g, 92%) as a white solid. Η NMR (300 MHz, CDC1₃) δ 5.41 (m, 2H), 3.63 (t, J = 6.5 Hz, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.61 (m, 2H), 1.57 (m, 21H), 0.86 (t, J = 6.5 Hz, 3H); ¹³C NMR (75 MHz, CDC1₃) δ 131.24, 129.27, 62.57, 32.58, 32.46, 31.94, 29.68, 29.58, 29.38, 29.21, 28.94, 22.72, 14.16; IR (neat) 3301-3207 (br), 2998, 2954, 2917, 2848, 1461, 1367, 1060, 962 cm^"1.

Compound 5.

To a solution of oxalyl chloride (46 mL, 520 mmol) in anhydrous dichloromethane (800 mL) at -78 °C under nitrogen was added dimethyl sulfoxide (75 mL, 1.1 mol) dropwise. After stirring at -78 °C for 30 min, a solution of alcohol 5 (33.33 g, 131.0 mmol) in dichloromethane (200 mL) was added at -78 °C. The resulting mixture was stirred at -78 °C for 1 h, followed by addition of triethylamine (156 mL, 1.12 mol).

After being stirred for an additional 10 min at -78 °C, the reaction mixture was slowly warmed to room temperature and then water (350 mL) was added. The organic layer was separated and then washed with water (2 x 400 mL), brine (400 mL), dried over MgSO₄, and concentrated to give 5 (25.62 g, 70%). Η NMR (300

MHz, CDC1₃) δ 9.74 (t, J = 1.8 Hz, IH), 5.41 (m, 2H), 2.47 (m, 2H), 2.31 (m, 2H),

1.95 (m, 2H), 1.24 (m, 19H), 0.86 (t, J = 6.53 Hz, 3H); ¹³C NMR (75 MHz, CDC1₃) δ 202.47, 132.10, 127.98, 127.51, 66.49, 43.55, 32.52, 31.94, 29.68, 29.52, 29.38,

29.17, 28.61, 28.07, 25.21, 22.72, 14.16; IR 2921, 2856, 2710, 1772, 1728, 1463,

1170, 964, 720 cm^"1

Compound 6. Triethyl phosphonoacetate (29.36 mL, 147.95 mmol) was added dropwise to a mixture of NaH (5.918 g of 60% dispersion in mineral oil; 147.95 mmol) in dry dimethoxy ethane (200 mL) at 0 °C under nitrogen. The resulting solution was stirred for 30 min at 0 °C and then transferred via cannula to a solution of crude aldehyde 5 (31.12 g; 123.28 mmol) in dry benzene (200 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 1 hr before being quenched with aqueous NH₄C1 (100 mL) and extracted with ether (700 mL). The organic layer was washed with water (200 mL), brine (200 mL) and dried over anhydrous MgSO₄, filtered, concentrated and further purified by flash column chromatography (hexane/ethylacetate 50:1) to provide pure ester 6 (35.39 g, 89%). 1H NMR (300 MHz, CDC1₃) δ 6.93 (dt, J = 15.6, 6.6 Hz, IH), 5.79 (dt, J = 15.6, 1.5 Hz, IH), 5.39 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 2.23 (m, 2H), 2.13 (m, 2H), 1.95 (m, 2H), 1.23 (m, 20H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDC1₃) δ 166.66, 148.69, 131.81, 128.26, 121.44, 60.14, 32.55, 32.30, 31.94, 31.01, 29.70, 29.52, 29.38,

29.17, 22.72, 14.30, 14.16; IR 2927, 2851, 2357, 5336, 1718, 1652, 1468, 1365, 1311, 1262, 1170, 1045, 969 cm^"1

Compound 7. A solution of ester 6 (20.10 g, 60.45 mmol) in anhydrous dichloromethane (400 mL) was cooled to -78 °C and DIBAL-H (23.70 mL, 132.99 mmol) was added dropwise. After stirring the reaction mixture for 1 hr, the reaction was quenched with MeOH (10 ml), warmed to ambient temperature and treated with NH₄C1 (150 ml) for 30 min at 0 °C. The mixture was then filtered through a pad of celite and the solid fraction was rinsed with dichloromethane (250 mL). The filtrate was washed with water (200mL), brine (200 mL), dried over MgSO₄, filtered and concentrated. Flash column chromatography (hexane/ethylacetate 4:1) furnished the alcohol 7 (16.25 g, 93%) as a white solid. IR (neat) 3286-3206 (br), 3000, 2954, 2917, 2848, 1471, 1442, 1080, 963 cm^"1; Η NMR (300 MHz, CDC1₃) δ 5.65 (m, 2H), 5.38 (m, 2H), 4.07 (m, 2H), 2.07 (m, 4H), 1.95 (m, 2H), 1.55 (bs, IH), 1.24 (m, 20H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (CDC1₃) δ 132.84, 131.10, 129.13, 63.81, 32.58, 32.32,

32.18, 31.93, 29.67, 29.54, 29.38, 29.18, 22.71, 14.15.

Compound 8. L-(+)-diisopropyl tartrate (1.21 mL, 5.75 mmol), titanium isopropoxide (0.67 mL, 2.30 mmol), and tert-butyl hydroperoxide (14.38 mL of 5 M solution in decane, 71.94 mmol) were successively added to a suspension of molecular sieves 4 A (5g) in 200 mL of anhydrous dichloromethane and the reaction mixture was stirred at -20 °C for 25 minutes. A solution of 7 (8.07g, 28.77 mmol) in anhydrous dichloromethane (65 mL) was added to the above mixture at -30 to -25 °C. The resulting mixture was stirred for 17 hours and then filtered through a celite pad. The organic phase was washed with 10 % tartaric acid (180 mL), water and brine, dried over anhydrous MgSO₄, filtered and concentrated. Flash column chromatography (hexane/ethylacetate 1 :1) provided pure compound 8 (8.02 g, 94% yield). [α]_D 23 - 20.9° (c .085, CHC1₃); 1H NMR (300 MHz, CDC1₃) δ 5.41 (m, 2H), 3.88 (m, IH), 3.60 (m, IH), 2.93 (m, 2H), 2.13 (m, 2H), 1.95 (m, 2H), 1.65 - 1.53 (m, 5H), 1.23 (m, 18H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (CDC1₃) δ 131.61, 128.52, 61.65, 58.47, 55.52, 32.57, 31.94, 31.60, 29.69, 29.54, 29.38, 29.21, 28.99, 22.72, 14.16;

IR (neat) 3191-3131(br), 2985, 2952, 2917, 2846, 1457, 1242, 1026, 985, 962, 873 cm -i .

Compound 9. TsCl (11.30 g, 59.32 mmol) was added to the solution of alcohol 8 (15.99 g, 53.93 mmol) and DMAP (65 mg, 5.32 mmol) in pyridine (150 mL) at 0 °C in one portion. The reaction mixture was stirred for 16 hr at 0 °C and then was quenched by pouring into a mixture of ethylacetate and water (1 :1, 400 mL). The organic phase was washed with brine (40 mL), dried over MgSO₄, filtered and concentrated. Flash column chromatography (hexane/ethylacetate 9:1) provided the tosylate 9 (15.06 g, 62% yield). [α]_D ²³ -24.0° (c 0.75, CHC1₃); 1H NMR (300 MHz, CDC1₃) δ 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.37 (m, 2H), 4.16 (dd, J = 11.4, 4.2 Hz, IH), 3.93 (dd, J = 11.4, 6.0 Hz, IH), 2.94 (m, IH), 2.78 (m, IH), 2.43 (s, 3H), 2.07 (m, 2H), 1.93 (m, 2H), 1.55 (m, 3H), 1.23 (m, 19H), 0.86 (t, J - 6.5 Hz, 3H); ¹³C NMR (CDC1₃) δ 131.80, 129.85, 128.15, 127.91, 70.13, 56.30, 54.66, 32.53, 31.93, 31.33, 29.68, 29.52, 29.38, 29.21, 28.77, 22.71, 21.69, 14.16. IR (neat) 2932, 2852, 1598, 1465, 1367,1178, 1097, 968 cm^"1.

Compound 10. A solution of AD mix-β (15.48 g) in t-BuOH (50 mL) and H₂O (50 mL) was stirred at ambient temperature for 10 min to produce two clear phases. Methanesulfonamide (950 mg, 9.98 mmol) was added and the mixture was cooled to 0 °C. Compound 9 (4.98 g, 11.05 mmol) was added at once and the reaction was stirred for 20 h at 0 °C. Sodium sulfite (15 g) was added and the mixture was allowed to warm to room temperature and stirred for lh. The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO₄, filtered and concentrated to give 10 (5.20 g, 97%). Compound 11 was used for the next step without further purification. Η NMR (300 MHz, CDC1₃) δ 7.77 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.17 (dd, J = 1 1.4, 3.9 Hz, IH), 3.95 (dd, J = 11.4, 5.7 Hz, IH), 3.39 (m, 2H), 2.98 (m, IH), 2.84 (m, lH), 2.43 (s, 3H), 1.84 (m, IH), 1.65 - 1.16 (m, 17H), 0.85 (t, J = 6.3, 3H). Compound 11.

To the solution of diol-epoxide 10 (7.29 g, 15.05 mmol) in anhydrous dichloromethane (175 mL) was added camphor sulfonic acid ( 250 mg, l.lmmol ) at 0 °C. The reaction mixture was stirred for 30 min. The mixture was neutralized with triethylamine and partitioned between dichloromethane and water. The organic phase was washed with brine, dried over MgSO₄, filtered, concentrated to afford 11. 1H NMR (300 MHz, CDC1₃) δ 7.79 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.16 (dd, J = 10.0, 3.0 Hz, IH), 4.04 (dd, J = 10.0, 6.0 Hz, IH), 3.88 - 3.70 (m, 3H), 3.32 (m, IH), 2.44 (s, 3H), 2.30 (m, IH), 2.15 (bs, IH), 2.03 - 1.76 (m, 3H), 1.62 (m, IH), 1.45 - 1.16 (m, 22H), 0.86 (t, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDC1₃) δ 144.99, 132.41, 129.83, 127.89, 83.20, 78.40, 73.99, 71.38, 71.01, 33.16, 31.87, 29.61, 29.31, 28.14, 17.99, 25.50, 22.64, 21.62, 14.10; IR 3360, 2920, 2845, 1354, 1180 cm^"1.

Compound 12.

A solution of crude 11 in anhydrous methanol (170 ml) was treated with potassium carbonate (18.72g, 135.46 mmol). The heterogenous mixture was stirred at ambient temperature for 1 h and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO₄, filtered and concentrated. Flash column chromatography (hexane/ethylacetate 4:1) provided pure compound 12 (3.85g, 82%o in two steps) as a white solid. [α]_D ²³ +71.0° (c 0.25,

CHC1₃); Η NMR (300 MHz, CDC1₃) δ 3.92 (m, IH), 3.83 (m, IH), 3.37 (m, IH), 2.99 (m, IH), 2.78 (m, IH), 2.60 (m, IH), 2.25 (d, J - 3.5 Hz, IH), 2.1 1-1.94 (m, 2H), 1.84-1.63 (m, 2H), 1.50-1.16 (m, 22H), 0.86 (t, J = 6.5 Hz, 3H); ¹³C NMR (300 MHz, CDC1₃) δ 83.13, 78.50, 73.99, 53.26, 45.20, 33.52, 31.90, 29.64, 29.35, 28.40, 28.06, 25.62, 22.69, 14.13; GC/MS m z 312 (M⁺), 269, 199, 143, 125, 113; IR (neat) 3473, 2923, 2854, 1466, 1070 cm^"1.

The present invention should not be considered limited to the particular examples described above, but rather should be understood to cover all aspects of the invention as fairly set out in the attached claims. Various modifications, equivalent processes, as well as numerous structures to which the present invention may be applicable will be readily apparent to those of skill in the art to which the present invention is directed upon review of the instant specification. The content of all publications, patents, and patent documents described and cited herein is incorporated by reference as if fully set forth. The invention described herein may be modified to include alternative embodiments. All such obvious alternatives are within the spirit and scope of the invention, as claimed below.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a stereoisomeric compound of the formula

wherein Alk is alkyl comprising the steps of:

(a) contacting a stereoisomeric compound of the formula

Alk" "^ ^ ^^ ^{^}OH _π under asymmetric epoxidation conditions with a chiral auxiliary to form a stereoisomeric compound of the formula

Alk' OH

0""^' III

(b) contacting the resulting epoxide of Formula III with an alkyl sulfonyl halide or aryl-sulfonyl halide in the presence of a base to form a stereoisomeric compound of the formula

A11T ^^ ^^ i ^ O- P

°" IV wherein P is selected from the group consisting of alkyl sulfonyl halide and aryl-sulfonyl halide;

(c) contacting a compound of Formula IV under asymmetric dihydroxylation conditions with a chiral auxiliary to form a stereoisomeric compound of the formula

(d) contacting a compound of Formula V with acid followed by an alkali metal alkoxide or carbonate in an alcohol solvent to afford the product of the above formula I.

2. The process of claim 1, wherein the chiral auxiliary in step (a) is diisopropyl L-tartrate.

3. The process of claim 1, wherein in step (b) the alkyl sulfonyl halide or aryl- sulfonyl halide is tosyl chloride and the base is pyridine.

4. The process of claim 1, wherein the chiral auxiliary in step (c) is AD mix-β.

5. The process of claim 1, wherein in step (d) the acid is camphor sulfonic acid and the alkali metal carbonate is potassium carbonate and the alcohol is methanol.