Method for preparing 6-alkylated steroidal derivatives and corresponding alkylated 5,6,7,8-tetrahydronaphthalene-2(4 alpha.H)-ones

Abstract

The present invention concerns a method for preparing certain steroidal derivatives alkylated in position 6, comprising a step of alkylating the corresponding compound halogenated in position 6 with an organometallic alkylating agent.

Claims

1. A process for the preparation of a compound of formula (I): ##STR00028## wherein for the compound of formula (I): R.sub.1 and R.sub.2 together form C and D rings of a steroidal carbon-based backbone, wherein said C and D rings optionally comprise one or more double bonds and are optionally substituted by one or more moieties selected from the group consisting of: linear or branched alkyl groups comprising from 1 to 12 carbon atoms, acyl groups comprising from 1 to 12 carbon atoms and optionally substituted by one or more hydroxyl groups, carboxyl, hydroxyl or oxo groups, and halogen atoms, wherein the acyl, carboxyl, hydroxyl, and oxo groups are in free or protected form, and wherein each position of said C and D rings is optionally substituted with one or, where possible, two said moieties; R′.sub.1 is a hydrogen or halogen atom, and R.sub.1 and R′.sub.1 are located on either side of the plane of the A and B rings; R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; is a single bond or a double bond; and is a single bond in the α or β position of the A and B rings, or a double bond in the plane of the A and B rings, wherein said process comprises alkylation of a compound of formula (II): ##STR00029## wherein for the compound of formula (II), R.sub.1, R′.sub.1, R.sub.2, and are as defined for the compound of formula (I), and X is a halogen atom; with an organometallic alkylating agent, optionally in the presence of a metal catalyst, wherein the group R.sub.3, present in the organometallic alkylating agent, replaces group X of the compound of formula (II), to obtain the compound of formula (I).

2. The process according to claim 1, wherein the organometallic alkylating agent is selected from the group consisting of organolithium compounds of formula R.sub.3Li, organomagnesium compounds of formula R.sub.3MgX′, organozinc compounds of formula R.sub.3ZnX′, where X′ is a halogen atom, organocopper compounds of formula R.sub.3Cu, lithium organocuprates of formula (R.sub.3).sub.2CuLi, organocyanocuprates of formula R.sub.3CuCNLi or (R.sub.3).sub.2CuCN(Li).sub.2, halocuprates of formula R.sub.3CuLiX″, where X″ is a halogen atom, organoboron compounds of formula R.sub.3B(OH).sub.2 and organotrifluoroborates of formula R.sub.3BF.sub.3K.

3. The process according to claim 2, wherein the organometallic alkylating agent is selected from the group consisting of organomagnesium compounds of formula R.sub.3MgX′, where X′ is a halogen atom, organocopper compounds of formula R.sub.3Cu, lithium organocuprates of formula (R.sub.3).sub.2CuLi, organocyanocuprates of formula R.sub.3CuCNLi or (R.sub.3).sub.2CuCN(Li).sub.2, and halocuprates of formula R.sub.3CuLiX″, where X″ is a halogen atom.

4. The process according to claim 3, wherein the organometallic alkylating agent is an organomagnesium compound of formula R.sub.3MgX′, where X′ is a halogen atom, and wherein the alkylation is carried out in the presence of a copper catalyst.

5. The process according to claim 3, wherein the organometallic alkylating agent is a halocuprate of formula R.sub.3CuLiX″, where X″ is a halogen atom.

6. The process according to claim 3, wherein the organometallic alkylating agent is a lithium organocuprate of formula (R.sub.3).sub.2CuLi or an organocyanocuprate of formula (R.sub.3).sub.2CuCN(Li).sub.2.

7. The process according to claim 3, wherein the organometallic alkylating agent is a lithium organocuprate of formula (R.sub.3).sub.2CuLi, and wherein the alkylation comprises reaction of the compound of formula (II) with said lithium organocuprate, followed by reaction of the resulting compound with a second alkylating agent of formula R.sub.3X′″, where X′″ is a halogen atom.

8. The process according to claim 1, wherein the compound of formula (II) is obtained by halogenation of a compound of formula (III): ##STR00030## wherein for the compound of formula (III), R.sub.1, R′.sub.1, R.sub.2, and are as defined in claim 1.

9. The process according to claim 1, wherein X is a bromine atom.

10. The process according to claim 9, wherein the compound of formula (II) is obtained by reaction of the compound of formula (III) with an N-bromoimide in the presence of a radical initiator.

11. The process according to claim 1, wherein the compound of formula (I) is a steroidal compound of formula (IA): ##STR00031## wherein for the compound of formula (IA): R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; R.sub.4 is hydrogen, or a hydroxyl or oxo group, wherein the hydroxyl or oxo group is in free or protected form; R.sub.5 is hydrogen or a halogen atom; R.sub.6 is hydrogen or a hydroxyl group, in free or protected form; R.sub.7 is hydrogen or a —C(O)R.sub.7′ or —C(OR).sub.2R.sub.7′ group, where R is a protective group for the carbonyl functional group and where R.sub.7′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form, or R.sub.6 and R.sub.7 together form an oxo group in the 17 position of the steroidal backbone of the compound of formula (IA); R.sub.8 is hydrogen or an alkyl group comprising from 1 to 3 carbon atoms; wherein the R.sub.6 and R.sub.7 groups are located on either side of the plane of the A, B, C and D rings; is a single bond or a double bond; is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and wherein the compound of formula (II) is a compound of formula (IIA): ##STR00032##  wherein for the compound of formula (IIA), R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and are as defined for the compound of formula (IA), and X is a halogen atom.

12. The process according to claim 11, wherein the compound of formula (I) is a steroidal compound of formula (IA): ##STR00033## wherein for the compound of formula (IA): R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; R.sub.4 is hydrogen, or a hydroxyl or oxo group, wherein the hydroxyl or oxo group is in free or protected form; R.sub.5 is hydrogen or a halogen atom; R.sub.6 is hydrogen, or a hydroxyl group, in free or protected form; R.sub.7′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form; R.sub.8 is hydrogen or an alkyl group comprising from 1 to 3 carbon atoms; wherein the R.sub.6 and —C(O)R.sub.7′ groups are located on either side of the plane of the A, B, C and D rings; the oxo group located on the carbon in the 20 position of the steroidal backbone is in free or protected form; is a single bond or a double bond; is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and wherein the compound of formula (II) is a compound of formula (IIA): ##STR00034## wherein for the compound of formula (IIA): R.sub.4, R.sub.5, R.sub.6, R.sub.7′, R.sub.8, and are as defined for the compound of formula (IA); the oxo group located on the 20 carbon of the steroidal backbone is in free or protected form; and X is a halogen atom.

13. The process according to claim 12, wherein the compound of formula (I) is a compound of formula (IB): ##STR00035## wherein for the compound of formula (IB): R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; R.sub.4 is selected from the group consisting of hydrogen, a β-hydroxyl group, in free or protected form, and an oxo group, in free or protected form; R.sub.5 is hydrogen or a halogen atom; R.sub.6 is hydrogen, or a hydroxyl group, in free or protected form; R.sub.7′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form; R.sub.8 is hydrogen or an α-alkyl group comprising from 1 to 3 carbon atoms; the oxo group located on the 20 carbon of the steroidal backbone is in free or protected form; is a single bond or a double bond; is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and wherein the compound of formula (II) is a compound of formula (IIB): ##STR00036## wherein for the compound of formula (IIB): R.sub.4, R.sub.5, R.sub.6, R.sub.7′, R.sub.8, and are as defined for the compound of formula (IB); the oxo group located on the 20 carbon of the steroidal backbone is in free or protected form; and X is a halogen atom.

14. The process according to claim 13, wherein the compound of formula (I) is a compound of formula (IC): ##STR00037## wherein for the compound of formula (IC): R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; R.sub.4 is hydrogen, or a hydroxyl group, in free or protected form; R.sub.5 is hydrogen or a halogen atom; R.sub.6 is hydrogen, or a hydroxyl group, in free or protected form; R.sub.7′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form; and wherein the compound of formula (II) is a compound of formula (IIC): ##STR00038## wherein for the compound of formula (IIC), R.sub.4, R.sub.5, R.sub.6 and R.sub.7′ are as defined for the compound of formula (IC), and X is a halogen atom.

15. The process according to claim 14, wherein for the compounds of formulae (IC) and (IIC), R.sub.7′ is a methyl group or a hydroxymethyl group, in free or protected form.

16. The process according to claim 14, wherein for the compounds of formulae (IC) and (IIC), R.sub.6 is a hydroxyl group, in free or protected form.

17. The process according to claim 14, wherein for the compounds of formulae (IC) and (IIC), R.sub.4 is a hydroxyl group in protected form and R.sub.7′ is a hydroxymethyl group in protected form.

18. The process according to claim 14, wherein for the compounds of formulae (IC) and (TIC), R.sub.5 is a hydrogen or fluorine atom.

19. The process according to claim 12, wherein the compound of formula (I) is a compound of formula (ID): ##STR00039## wherein for the compound of formula (ID): R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms; R.sub.4 is selected from the group consisting of hydrogen, a β-hydroxyl group, in free or protected form, and an oxo group, in free or protected form; R.sub.5 is hydrogen or a halogen atom; R.sub.6 is hydrogen, or a hydroxyl group, in free or protected form; R.sub.7′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form; R.sub.8 is hydrogen or an α-alkyl group comprising from 1 to 3 carbon atoms; the oxo group located on the 20 carbon of the steroidal backbone is in free or protected form; is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and wherein the compound of formula (II) is a compound of formula (IID): ##STR00040## wherein for the compound of formula (IID): R.sub.4, R.sub.5, R.sub.6, R.sub.7′, R.sub.8 and are as defined for the compound of formula (ID); the oxo group located on the 20 carbon of the steroidal backbone is in free or protected form, in the same way as it is present in the compound of formula (ID); and X is a halogen atom.

20. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.4 is a β-hydroxyl group, in free or protected form, or an oxo group, in free or protected form.

21. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.7′ is a methyl group or a hydroxymethyl group, in free or protected form.

22. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.6 is a hydroxyl group, in free or protected form.

23. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.5 is a hydrogen atom.

24. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.7′ is a hydroxymethyl group, in free or protected form.

25. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.8 is an α-methyl group.

26. The process according to claim 19, wherein for the compounds of formulae (ID) and (IID), R.sub.6 is a hydroxyl group, R.sub.7′ is a hydroxymethyl group, and R.sub.6, R.sub.7′ and the oxo group of the 20 carbon of the steroidal backbone are jointly protected in the form of an oxaspirane group.

27. The process according to claim 26, wherein the compounds of formulae (ID) and (IID) are the compounds of formulae (Id′) and (IId′), respectively: ##STR00041## wherein for the compound of formula (IId′), X is a halogen atom.

Description

EXAMPLES

Example 1: (4αS,8R)-8-bromo-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one

(1) 1 g (6.17 mmol) of (S)-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one was charged to 60 ml of tetrachloromethane in a round-bottomed flask equipped with a magnetic stirrer. 1.65 g (9.25 mmol) of N-bromosuccinimide and 0.30 g (1.23 mmol) of benzoyl peroxide were then added. The resulting suspension was stirred under reflux for one hour. The resulting orange-colored solution was subsequently cooled to ambient temperature and 100 ml of dichloromethane were added. The reaction mixture was subsequently washed with a saturated aqueous sodium bicarbonate solution. The organic phases were subsequently washed with water, dried with sodium sulfate and filtered, and the solvent was evaporated; the product was subsequently purified on a chromatography column on silica gel in order to obtain the (4αS,8R)-8-bromo-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one (0.6 g, 99% purity).

(2) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ (ppm), 6.73 (d, J=9.94 Hz, 1H), 6.27 (d, J=1.95 Hz, 1H), 6.20 (dd, J=9.94 and 1.75 Hz, 1H), 5.07-5.01 (m, 1H), 2.35 (ddd, J=15.01, 3.02 and 2.83 Hz, 1H), 2.30-2.17 (m, 1H), 2.02-1.92 (m, 1H), 1.92-1.71 (m, 2H), 1.62 (s, 3H), 1.41 (td, J=13.45 and 4.09 Hz, 1H).

(3) .sup.13C NMR (CDCl.sub.3, 100 MHz): δ (ppm), 186.44, 160.67, 158.08, 127.02, 125.62, 50.97, 40.42, 36.44, 36.05, 27.74, 16.51.

Example 2: (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one

(4) 104 mg of copper iodide were charged to dry tetrahydrofuran (3 ml) in a 10 ml dried Schlenk flask purged under argon and equipped with a magnetic stirrer and with a septum, and the gray mixture was cooled to 0° C. 1.09 mmol of MeLi were subsequently added dropwise, still at 0° C., and the yellow mixture was stirred at this temperature until a colorless solution was obtained. The lithium dimethylcuprate is thus formed in situ. The solution was cooled to −40° C. and a solution of 110 mg (0.45 mmol) of (4αS,8R)-8-bromo-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one in dry tetrahydrofuran was added dropwise. After stirring at −40° C., 1.36 mmol of methyl iodide are added and the orange mixture is stirred for a further 30 minutes at this temperature; the reaction is subsequently halted with a 25% aqueous ammonium chloride solution and the reaction products are extracted with ethyl acetate; the organic phases are subsequently washed with aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated under vacuum. The residue is subsequently purified on a chromatography column on silica gel in order to obtain the (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one (27 mg, 98% purity).

Example 3: (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one

(5) 104 mg of copper iodide were charged to dry tetrahydrofuran (3 ml) in a 10 ml dried Schlenk flask purged under argon and equipped with a magnetic stirrer and with a septum, and the gray mixture was cooled to 0° C. 1.09 mmol of MeLi were subsequently added dropwise, still at 0° C., and the yellow mixture was stirred at this temperature until a colorless solution was obtained. The lithium dimethylcuprate is thus formed in situ. The solution was cooled to −40° C. and a solution of 110 mg (0.45 mmol) of (4αS,8R)-8-bromo-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one in dry tetrahydrofuran was added dropwise. After stirring at −40° C. for 10 minutes, the reaction is subsequently halted with a 25% aqueous ammonium chloride solution and the reaction products are extracted with ethyl acetate; the organic phases are subsequently washed with aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated under vacuum. The residue is subsequently purified on a chromatography column on silica gel in order to obtain the (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one (28 mg, 98% purity).

Example 4: (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one

(6) 104 mg of copper iodide were charged to dry tetrahydrofuran (3 ml) in a 10 ml dried Schlenk flask purged under argon and equipped with a magnetic stirrer and with a septum, and the gray mixture was cooled to 0° C. 0.55 mmol of MeLi were subsequently added dropwise, still at 0° C., and the yellow mixture was stirred at this temperature until a colorless solution was obtained. The lithium monomethylcuprate is thus formed in situ. The solution was cooled to −40° C. and a solution of 110 mg (0.45 mmol) of (4αS,8R)-8-bromo-4α-methyl-5,6,7,8-tetrahydronaphth-2(4αH)-one in dry tetrahydrofuran was added dropwise. After stirring at −40° C. for 10 minutes, the reaction is subsequently halted with a 25% aqueous ammonium chloride solution and the reaction products are extracted with ethyl acetate; the organic phases are subsequently washed with aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated under vacuum. The residue is subsequently purified on a chromatography column on silica gel in order to obtain the (4αS,8R)-4α,8-dimethyl-5,6,7,8-tetrahydronaphth-2(4αH)-one (36 mg, 98% purity).

(7) .sup.1H NMR (CDCl.sub.3, 300 MHz): δ (ppm), 6.78 (d, J=9.95 Hz, 1H), 6.21 (dd, J=9.81 and 1.80 Hz, 1H), 6.11 (t, J=1.66 Hz, 1H), 2.58-2.43 (m, 1H), 2.04-1.93 (m, 1H), 1.89-1.63 (m, 3H), 1.36-1.28 (m, 1H), 1.25 (s, 3H), 1.13 (d, J=6.63 Hz, 3H), 1.03 (dd, J=12.72 and 4.42 Hz, 1H).

(8) .sup.13C NMR (CDCl.sub.3, 75 MHz): δ (ppm), 187.41, 171.09, 158.08, 126.28, 121.41, 41.20, 38.55, 36.96, 34.09, 23.35, 20.98, 17.63.

Example 5: Diacetylation of Prednisolone, in Order to Protect the Hydroxyls in the 11 and 21 Positions

(9) ##STR00026##

(10) Prednisolone (21.60 g, 60 mmol) is introduced into and dissolved in dichloromethane (300 ml) in a 500 ml round-bottomed flask. DMAP (1.5 g, 12 mmol, 0.2 equiv.), triethylamine (24.2 ml, 180 mmol, 3 equiv.) and acetic anhydride (17.0 ml, 180 mmol, 3.0 equiv.) are successively added to the reaction medium and then the latter is stirred at 25° C. The progress of the reaction is monitored by HPLC. After stirring for 17 h, the conversion of the prednisolone is complete. The reaction medium is quenched with a saturated ammonium chloride solution and then the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (dichloromethane/methanol 99:1) to give the compound 2 with a yield of 90% (purity 98%).

Example 6: Bromination at the 6 Position of Prednisolone Diacetate

(11) ##STR00027##

(12) NBS (3.56 g, 20 mmol, 2.0 equiv.) and benzoyl peroxide (0.48 g, 2 mmol, 0.2 equiv.) are added to a solution of diacetylated prednisolone 2 (4.44 g, 10 mmol) in carbon tetrachloride (500 ml). The reaction medium is brought to reflux and stirred for approximately 3 h. The progress of the reaction is monitored by HPLC. After 3 h, the reaction mixture no longer changes. The reaction medium is cooled to ambient temperature and then filtered. The round-bottomed flask is rinsed 3 times with carbon tetrachloride.

(13) The filtrate is subsequently concentrated under vacuum. The crude product is extracted with dichloromethane and washed with a 10% sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (dichloromethane/methanol 99:1) to give the compound 3 with a yield of 84% (purity 93%).

(14) It should be noted that it is also possible to use chlorobenzene as solvent for this synthesis.

Example 7: 6α-Methylprednisolone Diacetate

(15) 228 mg of copper iodide were charged to dry tetrahydrofuran (6 ml) in a 10 ml dried Schlenk flask purged under argon and equipped with a magnetic stirrer and with a septum, and the gray mixture was cooled to 0° C. 2.4 mmol of MeLi were subsequently added dropwise, still at 0° C., and the yellow mixture was stirred at this temperature until a colorless solution was obtained. The lithium dimethylcuprate is thus formed in situ. The solution was cooled to −40° C. and a solution of 523 mg (1.0 mmol) of 6β-bromoprednisolone diacetate in dry tetrahydrofuran (2 ml) was added dropwise.

(16) After stirring at −40° C. for 10 minutes, the reaction is subsequently halted with a 25% aqueous ammonium chloride solution and the reaction products are extracted with ethyl acetate; the organic phases are subsequently washed with aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated under vacuum. The residue is subsequently purified on a chromatography column on silica gel in order to obtain the 6α-methylprednisolone diacetate (120 mg, purity 85%).

Example 8: 6α-Methylprednisolone Diacetate

(17) 228 mg (1.2 mmol) of copper iodide were charged to dry tetrahydrofuran (6 ml) in a 10 ml dried Schlenk flask purged under argon and equipped with a magnetic stirrer and with a septum, and the gray mixture was cooled to 0° C. 1.2 mmol of MeLi were subsequently added dropwise, still at 0° C., and the yellow mixture was stirred at this temperature until an orange suspension was obtained. The monomethylcuprate is thus formed in situ. The solution was cooled to −40° C. and a solution of 523 mg (1.0 mmol) of 6β-bromoprednisolone diacetate in dry tetrahydrofuran (2 ml) was added dropwise.

(18) After stirring at −40° C. for 10 minutes, the reaction is subsequently halted with a 25% aqueous ammonium chloride solution and the reaction products are extracted with ethyl acetate; the organic phases are subsequently washed with aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated under vacuum. The residue is subsequently purified on a chromatography column on silica gel in order to obtain the 6α-methylprednisolone diacetate (160 mg, purity 98%).

(19) .sup.1H NMR (CDCl.sub.3, 600 MHz): δ (ppm), 6.96 (d, J=9.98 Hz, 1H), 6.27 (dd, J=9.98 and 1.76 Hz, 1H), 6.03 (d, J=1.76 Hz, 1H), 5.54 (d, J=2.93 Hz, 1H), 5.09 (d, J=17.02 Hz, 1H), 4.68 (d, J=17.61 Hz, 1H), 2.79-2.73 (m, 1H), 2.64-2.57 (m, 1H), 2.21 (qd, J=11.25 and 4.40 Hz, 1H), 2.15 (s, 3H), 2.09 (s, 3H), 2.06-2.01 (m, 2H), 1.85-1.80 (m, 2H), 1.77-1.71 (m, 1H), 1.54-1.41 (m, 2H), 1.27 (s, 3H), 1.21-1.15 (m, 1H), 1.13 (d, J=6.46 Hz, 3H), 0.94-0.85 (m, 2H), 0.84 (s, 3H).

(20) .sup.13C NMR (CDCl.sub.3, 150 MHz): δ (ppm), 204.64, 186.05, 171.99, 170.30, 169.66, 155.19, 127.67, 119.74, 89.07, 71.12, 67.45, 54.04, 50.81, 47.18, 43.06, 42.30, 35.24, 34.37, 32.86, 31.39, 23.50, 21.57, 20.90, 20.27, 17.47, 16.36.