Indian Journal of Chemistry Vol. 40B, October 2001 , pp. 905-914

Enantiospecific synthesis of B-seco-C-aromatic taxanes t A Srikrishna,* T Jagadeeswar Reddy, P Praveen Kumar & Santosh J Gharpure Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India

Received 5 February 2001; accepted 23 May 2001

A simple and efficient methodology for the enantiospecific synthesis of B-seco-C-aromatic taxanes starting from monoterpene (R)-carvone is described. Coupling of 6,6-dimethylcarvone 5 with appropriate arylethyl bromides followed by oxidation generates the enones 7, 15, 25, which are transformed into the 20-nor-B-seco-C-aromatic taxane derivatives 1 1 , 17 and 8-seco-C-aromatic taxane derivative 29 via degradation of the isopropenyl group.

The search for new antitumor compounds using the bioassay-guided fractionation of plant extracts has led to the discovery of a number of novel active structures. Unfortunately, only a few of these substances have proved to be of sufficient pharmacological i nterest to reach clinical trials. Among these natural compounds, taxol® (paclitaxel) I .2

1 , isolated in minute quantities from a number of Taxus species and its analogue taxotere 2, appears today as two of the most promising drugs in the treatment of ovarian and breast cancers. In addition to its clinical interest, taxol is a powerful tool for biologists interested in the study of the tubulin­microtubule system, proteins which play a crucial role in the construction of the mitotic spindle during cell division and with which taxol interferes. A third area in which taxol has drawn interest is its partial and total synthesis. In addition to the challenge, which the synthesis of this complex molecule presents, the obtention of taxol by total or partial synthesis is one of the possible solutions to the serious problem of its limited availability from natural sources.3 During the last two decades, more than thirty-five research groups have been actively involved in the development of convenient approaches to taxane diterpenoids3.4. Recently, we have initiated an approach to taxanes starting from the readily available monoterpene, (R)-carvone 3, and developed an efficient route for the construction of functionalised chiral A-ring of taxanes, e.g. 4.5 It was anticipated that incorporation of a suitable C-ring component would result in the generation of B-seco taxanes en

. route to taxanes. Based on this concept, herein we

tDedicated to Prof. U. R. Ghatak on his 70lh birthday. Chiral synthons from carvone, part 49. For part 48, see Srikrishna A & Gharpure S J, J Org Chem, 66, 2001, 4379.

report synthesis of various functionalised chiral B­seco-C-aromatic taxane derivatives6.

Synthesis of chiral A-ring derivatives of taxanes has been extended to incorporate part of the C-ring of taxane. In this direction, first, synthesis of a C-ring aromatic taxane derivative was explored. It was contemplated that by opting phenethyl group as C­ring precursor, 6,6-dimethylcarvone 5 can be converted into a bis nor B-seco-C-aromatic taxane derivative, Scheme I. Thus, sequential two kinetic alkylations of (R)-carvone 3 with lithium diisopro­pylamide methyl iodide furnished 6,6-dimethyl­carvone 5.5 A Barbier reaction was opted for the addition of phenethyl group to dimethylcarvone 5. Reaction of dimethylcarvone 5 with phenethyl bromide in the presence of lithium, activated by ultrasonic irradiation, in THF furnished the Barbier product, the tertiary akohol 6, which on oxidation with PCC and silica gel in methylene chloride furnished the transposed product, the enone 7 in 92% yield. For the conversion of the enone 7 into a B-seco bisnortaxane, two carbons of the isopropenyl group needs to be degraded. Prior to the degradation of the isopropenyl group, the ketone group was masked. Thus, reduction of the enone 7 with LAH in ether furnished the syn allyl alcohol 8 in 99% yield. The hydroxy group in the alcohol 8 was protected as its methyl ether by treatment with sodium hydride and methyl iodide in THF in the presence of a catalytic amount of tetrabutylammonium iodide to furnish the methyl ether 9 in 99% yield. A two step strategy was opted for the degradation of the two carbons of the isopropenyl moiety. Thus, controlled ozonolysis of the methyl ether 9 in methylene chloride and methanol followed by reductive work-up with dimethyl sulfide furnished the ketone 10 in 76% yield.

906 INDIAN J CHEM, SEC B, ocrOBER 2001

AO 0 o Ph 0 -?'

J--- XJ-O'\"

A' N :. H OH

., H ' 0 HO 0 6AC

Ph� o

Taxanes 1 . A = Ac; A' = Ph (Taxor) 2. A = H; A' = tsuo (Taxotere)

F

H

2,3-seco-C-aromatic taxane

&O_ ... � �

� PO " ' � ;f,;\

� � H F

3 4 &0 � HO

a b �'fF) c 0 .- ..

IT: � 3

MeO' , ·

o

- -:;. �

5

1 1 . A=H 1 1 a. A=Me

g,h --

6

MeO' ' ' ' • f

10

� d,e

AO"'"

S. A=H 9. A=Me

Scheme I-(a) i . LOA, Mel; ii. LOA, Mel; (b) Li, PhCH2CH2Br, » ) ; (c) PCC, silica gel; (d) LiAIH4; (e) NaH, BU4NI, Mel; (f) 03/02; Me2S; (g) NaOH, Br2; (h) CH2N2.

� MeO\" 'hR�

o 1 0, R=Me 1 1 , R=OH 12. R=CI

x ..

x = O or H,OH

The acetyl group in 10 was oxidised to a carboxyl group employing a haloform reaction. Consequently, reaction of the ketone 10 with sodium hydroxide and bromine in dioxane and water furnished 1 3-methoxy-19,20-bisnor-C-aromatic-tax- l 1 -en-2-oic acid 11, which on esterification with an excess of ethereal diazomethane furnished the methyl ester 11a in 48% yield, whose structure was established from its spectral data. After preparing the B-seco-bisnortaxane derivatives, the ketone and acids 10 and 11, unsuccessful aLtempts were made to form the B-ring

of taxanes by employing intramolecular Friedel-Craft type reactions. Either intramolecular Friedel-Craft acylation of the acid chloride 12, obtained from the acid 11, with anhydrous aluminum chloride in methylene chloride or the acid catalysed intramolecular cyciisation of the acid 11 with polyphosphoric acid led only to a complex mixture. Similarly, acid catalysed cyciisation of the acetyl ether 10 using B F3.Et20 was also unsuccessful.

In continuation of the synthesis of B -seco-taxanes, an electron rich aromatic ring was also considered. Accordingly, the sequence was carried out with 3,4-dimethoxyphenethyl bromide 13 as the C-ring precursor, Scheme II. The bromide 13 was obtained, in 70% yield, by the reaction of the alcohol 14 with triphenylphosphine and carbon tetrabromide. Addition of dimethylcarvone 5 and the bromide 13 in dry THF

SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF B-SECO-C-AROMATIC TAXANES 907

OH Br OMe

a b 0 •

� OMe

MeO

f OMe OMe 1 4 1 3

MeO

OMe d

OMe

.. 0 OMe OMe

1 7 1 6

Scheme II-(a) CBr4, PPh3; (b) i . Li, 5, ))); ii. PCC, silica gel; (c) Oy02; Me2S; (d) NaOH, Br2'

- I �OMe

o H " " " R O OMe o 16. R=Me 17. R=OH 1 8. R=CI

x • �(OMe)2 O� H X X = O or H,OH

to a sonochemically irradiated suspension of lithium in THF furnished the Barbier product, which on oxidation with PCC and silica gel in methylene chloride furnished the enone 15 in 75% yield. Controlled ozonolysis of the enone 15 in methylene chloride and methanol furnished the ketone 16 in 93% yield, After the synthesis of the ketone 16, one more unsuccessful attempt was made for the B-ring closure, Thus, adsorption of the dione 16 on montmorillonite K- lO and irradiation in a microwave oven failed to induce cyclisation, Treatment of the ketone 16 with sodium hydroxide and bromine in dioxane and water furnished the acid 17, which on treatment with oxalyl chloride in dry benzene furnished the corresponding acid chloride 18, Treatment of the acid chloride 18 with diethylaluminium chloride in methylene chloride, however, failed to produce any detectable amount of the cyclised product derived from intramolecular Friedal-Craft's acylation reaction,

The sequence was further extended to the synthesis of 2,3-seco-C-aromatic taxane by employing the bromide 19 as the C-ring precursor containing the C-20 carbon of taxanes also, The bromide 19 was obtained from o-cresol 20 via Claisen rearrangement as depicted in Scheme III. Thus, O-alkylation of o-cresol 20 with allyl bromide using anhydrous potassium carbonate in refluxing acetone furnished the allyl ether 21 in 85% yield. The \ Claisen rearrangement of the allyl ether 21 in a sealed tube at

1 80°C for 36 hours furnished the phenol 22 in 60% yield.s Protection of the hydroxy group in 22 using 50% aqueous potassium hydroxide and methyl iodide in methylene chloride in the presence of a catalytic amount of benzyltriethylammonium chloride at room temperature furnished the ether 23 in 90% yield. Ozonolysis of the allyl group in ether 23 in methanol followed by reductive work-up using sodium borohydride furnished the alcohol 24 in 97% yield. Treatment of the alcohol 24 with triphenylphosphine and carbon tetrabromide in methylene chloride at room temperature furnished the bromide 19 in 93% yield, whose structure was established on the basis of the spectral data. Addition of dimethylcarvone 5 and the bromide 19 in dry THF to a sonochemically irradiated suspension of lithium i n THF furnished the Barbier product, which on oxidation with PCC and silica gel in methylene chloride furnished the transposed enone 25. Conversion of the enone 25 into the B-seco-C-aromatic taxane derivative was uneventful. Thus, reduction of the enone 25 with LAH in ether furnished the alcohol 26 in 84% yield. The hydroxy group in 26 was protected as its methyl ether using sodium hydride, methyl iodide and a catalytic amount of tetrabutylammonium iodide in dry THF at room temperature to furnish the ether 27 in 72% yield. Controlled ozonolysis of the ether 27 in methanol and methylene chloride followed by reductive work-up with dimethyl sulfide furnished the ketone 28 in 60% yield. Reaction of the ketone 28 with sodium hydroxide and bromine in dioxane and water furnished the B-seco-C-aromatic taxane, namely 2,3-seco-3, 1 3-dimethoxy- I 9-nor-tax-3,5, 7 , 1 1 -tetraen-2-oic acid 29, which on esterification with an

908 INDIAN J CHEM, SEC B, OCTOBER 2001

�Me

�OH 20

a b

21 Me

Me �OH I �

� 22 i c Me e Cc:oMe

I " ..... i----

� Sr

Me �OMe

� Cc: OH

d ..

1 9 !f 24 23

g ,h RO" .

MeO' "

29. R=OH 29a. R=OMe

..

..

j , k MeO" ·

Me 1 26. R=H i + 27. R=Me

Scheme III-(a) K2C03, allyl bromide; (b) ll; (c) KOH. BnEt3NCI. Mel; (d) Of O2; NaBH4; (e) CBr4, PPh3; (f) i. Li, 5, »)) ; i i . PCC, silica gel ; (g) LiAlH4; (h) NaH, BU4NI, Mel; (i) Oi02; Me2S; (j) NaOH, Br2; (k) CH2N2.

excess of ethereal diazomethane furnished the methyl ester 29a in 76% yield, whose . structure was established from its spectral data.

In conclusion, an efficient and convenient general methodology was developed for the enantiospecific synthesis of B-seco-C-aromatic taxanes starting from the readily available monoterpene (R)-carvone.

Experimental Section Melting points were recorded using a Tempo

melting point apparatus in capillary tubes and are uncorrected. IR spectra were recorded on Perkin­Elmer 781 spectrophotometer. I H (90, 200, 270 and 300 MHz) and 1 3C NMR (22.5, 50, 75 MHz) spectra were recorded on Jeol FX-90Q and JNM A-300, Brucker ACF-200 and WH-270 spectrometers. The chemical shifts (8 ppm) and the coupling constants (Hz) are reported with reference to either internal tetramethylsilane (for ' H) or the central line (77 . 1 ppm) of CDCh (for 1 3C). In the 13C NMR spectra the nature of the carbons were determined by either off­resonance decoupling or DEPT- 135 spectra, and are

given in parentheses. Low and High resolution mass measurements were carried out using a Jeol JMS-DX 303 GC-MS instrument using a direct inlet mode. Relative intensities of the ions are given in parentheses. Elemental analyses were carried out using a Carlo Erba 1 106 CHN analyser. Optical rotations were measured using a Jasco DIP-370 digital polarimeter and [a]o values are given in the units of 1 O-' .deg.cm

2.g-l . Ozonolysis experiments were

carried out using either a Penwalt Wallace and Tierman ozonator or Fischer 502 ozone generator. Sonochemical experiments were carried out using a lulabo USR-3 ultrasonic cleaning bath. All solvent evaporations were carried out using either a steam bath or a Buchi rotary evaporator. Analytical thin­layer chromatographies (TLC) were performed on glass plates coated with Acme's silica gel G containing 1 3% calcium sulphate as binder and various combinations of ethyl acetate and hexane were used as eluents. Visualisatation of spots was accomplished by exposure to iodine vapour. Acme's silica gel ( 100-200 mesh) was used, appoximately 15-

SRIKRISHNA et al. : ENANTIOSPECIFIC SYNTHESIS OF B-SECO-C-AROMATIC TAXANES 909

20 g per 1 g of the crude product, for column chromatography. All small-scale dry reactions were carried out using standard syringe-septum technique. Low temperature reactions were conducted in a bath made of alcohol and liquid nitrogen.

(+ )-(SS)-S-Isopropenyl-2,6,6-trimethylcyclohex-2-enone 5. To a cold (- 1 0°C), magnetically stirred solution of diisopropylamine ( 17.6 mL, 1 24.8 mmole) in anhydrous THF (90 mL) was slowly added n-BuLi (78 mL of a 1 .6 M solution in hexane, 1 24.8 mmole) over a period of 20 min. To the LDA thus formed was added dropwise a solution of R-carvone (3, 14.4 g, 95.7 mmole) in anhyd. THF ( 1 35 mL) and stirred for 2 hr at the same temperature. The enol ate was then treated with an excess of methyl iodide (30 mL, 482 mmole) and stirred overnight at RT. The reaction mixture was then diluted with water and extracted with ether (3 x 30 mL). The combined organic extract was washed with 3 N aq. HCI, saturated aq. NaHC03 solution and brine, and dried (Na2S04). Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :40 to I :20) as eluent furnished a 3 :2 epimeric mixture of 6-methy\carvone ( 1 5.4 g, 98%). Second alkylation of 6-methylcarvone ( 15.4 g, 93.8 mmole) employing the same procedure as above, using 1 .3 equiv. of LDA and 10 equiv. of methyl iodide furnished dimethyl­carvone 5 ( 15.9 g, 95% yield) as an oil, [a]0

26 + 1 .8 (c

3.8, CHCh); IR (neat): 1 660, 1 640, 890 cm· l ; IH NMR (200 MHz, CDCI3): 8 6.62 ( 1 H, m, H-3), 4.86 ( 1 H, quintet, J=1 .0 Hz) and 4.75 ( 1 H, quintet, J=1 .0 Hz) [C=CH2], 2.35-2.6 (3 H, m), 1 .78 (3 H, q, J=1 .6 Hz) and 1 .7 1 (3 H, s) [2 x olefinic CI-h], 1 . 14 (3 H, s) and 1 .04 (3 H, s) [CH3CCH3] ; 1 3C NMR (22.5 MHz, CDCh): 8 202.8 (s, C=O), 145.0 (s, C=CH2), 1 4 1 .3 (d, C-3), 1 32.7 (s, C-2), 1 1 3.0 (t, C=CH2), 5 1 .3 (d, C-5), 43.7 (s, C-6), 28.3 (t, C-4), 23.7 (q), 22.5 (q), 19.6 (q) and 1 5 .6 (q) [4 x CH3] ; Mass: rnIz 178 (M+, 10%), 163 (20), 1 35 (20), 1 23 ( 15), 108 (40), 1 07 (90), 106 (45), 96 ( 100), 82 ( 100). HRMS: rnIz Calcd. for C 12HI 80: 178. 1 357. Found: 1 78. 1 354.

( + )-( SS)-S-Isopropenyl-3-(2-phenylethyl)-2,4,4-tri­methylcyclohex-2-enone 7. To a sonochemically irradiated, suspension of lithium (2 1 0 mg, 30 mmole) in dry THF (25 mL) in a round bottom flask, placed in an ultrasonic cleaning bath, was added a mixture of dimethy\carvone (5, 890 mg, 5 mmole) and phenethyl bromide ( 1 .85 g, 1 .35 mL, 1 0 mmole) at 15-20°C over

a period of 40 min. The reaction mixture was then decanted from the excess lithium, quenched with saturated aq. N�CI solution and extracted with ether (3 x 45 mL). The ether extract was washed with brine and dried (Na2S04). Evaporation of the solvent furnished the tertiary alcohol 6. To a magnetically stirred solution of the tertiary alcohol 6 (2.3 g) in 25 mL of dry CH2Ch was added a homogenous mixture of PCC (3.0 g, 1 3 .9 mmole) and silica gel (3.0 g), and stirred vigorously for 36 hr at RT. The mixture was then filtered through a small silica gel column and eluted the column with excess CH2Ch. Evaporation of the solvent and purification of the residue on a silica gel column using ethyl acetate-hexane ( 1 :40 to 1 :20) as eluent furnished phenethylcarvone 7 ( 1 .29 g, 9 1 .5% overall in two steps) as an oil, which solidified on cooling in a refrigerator, m.p. 52-53°C; [a]D

26

+36.4 (c 3.3, CHCh); IR (neat): 1 665, 1605, 895 em- I ; I H NMR (200 MHz, CDCh): 8 7. 15-7.40 (5 H, m, Ar­H), 4.95 ( 1 H, s) and 4.8 ( 1 H, s) [C=CH2], 2.4-2.85 (7 H, m), 1 .9 (3 H, s) and 1 .74 (3 H, s) [2 x olefinic CH3], 1 .29 (3 H, s) and 1 . 15 (3 H, s) [CH3CCH3] ; l 3C NMR (22.5 MHz, CDCh): 8 1 98. 1 (s, C=O), 1 62.9 (s, C-3), 1 45.4 (C=CH2), 1 30.9 (s, C-2), 14 1 .3 (s), 1 28.4 (2 C, d), 1 27.9 (2 C, d), 1 26. 1 (d), 1 14.9 (t, C=CH2), 5 1 .8 (d, C-5), 39.6 (2 C, t and s, C-4 and 6), 34.5 (t), 33. 1 (t), 27. 1 (q), 22.9 (q), 22.0 (q), 1 1 .4 (q); Mass: rnIz 282 (M+, 1 3%), 267 (39), 1 9 1 (49), 1 05 (37), 9 1 ( 1 00); Anal. Calcd. for C2oH260: C, 85 .06; H , 9.28. Found: C, 85.38; H, 9.5%.

(+ )-(1S, SS)-S-Isopropenyl-3-(2-phenylethyl)-2,4,4-trimethylcyclohex-2-enol 8. To a cold (-90°C), magnetically stirred solution of the enone 7 ( 1 .0 g, 3.55 mmole) in 40 mL of dry ether was added LiAlH4 ( 1 35 mg, 3.55 mmole) and stirred for 2 hr. The reaction mixture was then diluted with ether ( 1 5 mL) and carefully quenched with water (5 mL). The organic layer was separated and the aq. phase was extracted with ether (2 x 20 mL). The combined organic phase was washed with brine and dried (Na2S04). Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :20 to 1 : 1 0) as eluent furnished the alcohol 8 ( 1 .0 g, 99.2%), which was recrystallised from a mixture of hexane and CH2Ch, m.p. 106-108°C; [a]D

26 + 44.6 (c 3 .7, CHCI3); IR (nujol): 3365, 1 635, 1 600, 895 cm- I ; IH NMR (270 MHz, CDCh): 8 7 . 1 5-7.4 (5 H, m, Ar-H), 4.95 ( 1 H, s) and 4.74 ( 1 H,

9 1 0 INDIAN J CHEM. SEC B . OCTOBER 2001 s) [C=CH2]. 4. l 3 ( l H. m, CHOH), 2.69 (2 H, t, J=8.7 Hz, ArCH2), 2.2-2.35 (2 H, m), 2. 1 7 (l H, dd, J=l 3 . 1 and 1 .9 Hz), 1 .99 ( l H, ddd, J=1 2.4, 6 . 1 and 2.3 Hz), 1 .84 (3 H, s) and 1 .79 (3 H, s) [2 x olefinic CH3], 1 .7-1 .9 ( l H, m), 1 . 1 2 (3H, s) and 1 .0 (3H, s) [CH3CCH3]; ' 3C NMR (22.5 MHz, CDCh): 8 1 46.7 (s, C=CH2), 142.7 (s), 140.8 (s), l 30.3 (s), 1 28.3 (2 C, d), 128.0 (2 C, d), 125 .9 (d), 1 14.3 (t, C=CH2), 7 1 .4 (d, CHOH), 50.2 (d, C-5), 39.6 (s, C-4), 36.0 (t), 34.8 (t), 3 1 .7 (t), 27.2 (q), 23. 1 (q), 22.8 (q), 1 5 .0 (q); Anal. Calcd. for C2oH2SO: C, 84.45; H, 9.92. Found: C, 84.73; H, 10.05%.

(+ )-(1S, 5S)-5-lsopropenyJ-3-(2-phenyJethyJ)-2,4,4-trimethylcyclohex-2-enyJ methyl ether 9. To a magnetically stirred suspension of NaH (295 mg, 55% dispersion in oil, 6.76 mmole, washed with dry hexanes) and tetrabutylammonium iodide (catalytic) in THF (4 mL) was added a solution of the alcohol 8 ( 1 .0 g, 3.52 mmole) in THF ( l mL) and DMF (0.7 mL), and stirred for 1 hr at RT. To the reaction mixture was then added methyl iodide (2.8 mL) and stirred for 8 hr. It was then quenched with water (2 mL) and extracted with ether (3 x 1 0 mL). The combined ether extract was washed with brine and dried (Na2S04). Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( l :50) as eluent furnished the methyl ether 9 (839 mg, 98.7% based on the consumed starting material) as an oil, [a]D

24 +58.0 (c

2. 1 2, CHCh); IR (neat): 1 635, 1 600, 895 cm· ' ; 'H NMR (270 MHz, CDCh): 8 7. 15-7.4 (5 H, m, Ar-H) , 4.94 ( 1 H, s) and 4.72 ( 1 H, s) [C=CH2], 3 .76 ( 1 H, dd, J=9.2 and 6.4 Hz, CHOMe), 3.38 (3 H, s, OCH3), 2.68 (2 H, t, J=8.8 Hz, ArCH2), 1 .65-2.4 (5 H, m), 1 .79 (3 H, s) and 1 .78 (3 H, s) [2 x olefinic CH3] , 1 . 12 (3 H, s) and 0.97 (3 H, s) [CH3CCH3] ; I 3C NMR (22.5 MHz, CDCh): 8 1 46.5 (C=CH2), 142.6, 1 4 1 .7 , 1 29.0, 128.3 (2 C), 1 27.8 (2 C), 1 25 .6, 1 14.2 (C=CH2], 80.0 (CHOMe), 55.4 (OCH)), 49.9 (C-5), 39.5, 35.9, 3 1 .7, 30.0, 26.8, 22.9, 22.5, 14.8; Mass: rnIz 298 (M+, 12%), 225 (60), 202 (37), 1 87 (29), 175 (34), 1 1 1 (55), 105 (90), 9 1 ( 100). Further elution of the column with ethyl acetate-hexane ( 1 :20) furnished the unreacted starting material 8 ( 1 90 mg, 19%).

(+ )-(1S, 5R)- 5-Acetyl-3-(2-phenyJethyl)-2,4,4-tri­methylcyclohex-2-enyl methyl ether 10. Through a cold (-90°C) solution of the ether 9 (370 mg, 1 .24 mmole) and a catalytic amount of NaHC03 in

methanol (0.09 mL, 2.2 mmole) and CH2Ch (7 mL) was passed a precooled (-80°C) mixture of ozone in oxygen ca 5 min . The excess ozone was flushed off with oxygen. Dimethyl sulfide (0.8 mL) was added to the reaction mixture, it was then slowly warmed up to RT and magnetically stirred for 8 hr. Evaporation of the solvent under reduced pressure and purification of the residue on a silica gel column using ethyl acetate­hexane ( 1 :5) as eluent first furnished the starting material 9 (2 1 5 mg, 58. 1 % yield). Further elution of the column with ethyl acetate-hexane ( 1 :5) furnished the keto ether 10 ( 1 1 9 mg, 76.2% based on starting material consumed), [a]D

24 +45.0 (c 2.0, CHCh); IR (neat): 1 700, 1600 cm· ' ; 'H NMR (90 MHz, CDCh): 8 7.00-7.40 (5 H, m, Ar-H), 3.73 ( 1 H, dd, J=8.0 and 6.5 Hz, CHOMe), 3.38 (3 H, s, OCH3), 2.22 (3 H, s, CH3C=O), 1 .85-2.35 (7 H, m), 1 .78 (3 H, s, olefinic CH3), 1 .20 (3 H, s) and 1 .09 (3 H, s) [CH3CCH3] ; I3C NMR (22.5 MHz, CDCh): 8 209.6 (s, C=O), 1 4 1 .7 (s), 140. 1 (s), 128.5 (s), 127.7 (2 C, d), 127.3 (2 C, d), 125.2 (d), 78.0 (d, CHOMe), 55. 1 (q, OCH3), 54.8 (d, C-5), 37.6 (s, C-4), 35.3 (t), 30.7 (2 C, t), 26.6 (q), 26.2 (q), 22.0 (q), 14.5 (q); Mass: rnIz 300 (M+, 10%), 202 (52), 1 95 ( 1 7), 1 87 (23), 1 1 1 (35), 1 05 (47), 9 1 ( l 00).

(lR,13S)-13-Methoxy-20-nor-(2, 3)-seco-C-aromatic­tax-1 1-en-2-oic acid methyJ ester 11a. To a cold (5°C) magnetically stirred solution of the ketone 10 ( 1 20 mg, 0.4 mmole) in dioxane (5.5 mL) and water ( 1 .6 mL) was added a cold (O°C) solution of sodium hypobromide [prepared by adding bromine (2 17 mg, 0.07 mL, 1 .32 mmole) to a cold (-5°C) solution of NaOH (2 10 mg, 5 .25 mmole) in water ( 1 .8 mL) and diluted with dioxane ( 1 .2 mL) at the same temperature] and stirred for 3 hr at 1 O- 15°C. The excess sodium hypobromide was decomposed by addition of a solution of sodium sulfite (50 mg) in water (0.5 mL). The reaction mixture was acidified with conc. HCI, stirred for 5 min and extracted with CH2Ch. The combined CH2Ch extract was washed with water (3 x 5 mL) and brine, and dried (Na2S04). Evaporation of the solvent furnished the acid 11. To a magnetically stirred solution of the acid 11 was added a cold ethereal diazomethane solution ( 10 mL) and stirred for 2 hr. Careful evaporation of the excess diazomethane and solvent, and purification of the residue over a silica gel column using ethyl acetate­hexane ( l :20 to 1 : 1 5) as eluent furnished the ester 113

SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF B-SECO-C-AROMA TIC TAXANES 9 1 1

(60 mg, 47.5%) as an oil, IR (neat): 1 725 cm- I ; IH NMR (90 MHz, CDCh): 8 7.29 (5 H, br s, Ar-H), 3.72 (4 H, triplet merged with singlet, CHOMe and COOCH3), 3.35 (3 H, s, OCH3), 1 .80-2.80 (7 H, m), 1 .78 (3 H, olefinic CH3), 1 .2 1 (3 H, s) and 1 .06 (3 H, s) [CH3CCH3] ; Mass: mJz 3 1 6 (M+, 9%), 2 1 1 (27), 202 (27), 1 86 ( 1 8), 1 1 1 (20), 1 05 (22), 9 1 ( 1 00).

1,2-Dimethoxy-4-(2-bromoethyl)benzene 13. To a cold (O°C), magnetically stirred solution of the alcohol 14 ( 1 . 1 2 g, 6. 1 5 mmole) i n dry CH2Ch (30 mL) was simultaneously added CBr4 (2.65 g, 8.0 mmole) and PPh3 (2. 1 g, 8.0 mmole). The reaction mixture was slowly warmed-up to RT and then solvent was evaporated under reduced pressure. Purification of the residue over a neutral alumina column using hexane as eluent furnished the bromide 13 ( 1 .2 g, 80%), IR (neat): 1 590, 1 5 1 5, 800, 770 cm-I ; IH NMR (300 MHz, CDCh): 8 6.80-6.60 (3 H, m, Ar­H), 3.82 (3 H, s) and 3 .78 (3 H, s) [2 x OCH3], 3 .44 (2 H, t, J=7.8 Hz, CH2Br), 3.02 (2 H, t, J=7.8 Hz,); l 3C NMR (75 MHz, CDCI3) : 8 149 . 1 , 148. 1 , 1 3 1 .5, 120.7, 1 1 1 .9, 1 1 1 .4, 55.83 and 55 .79 [2 x OCH3], 39.2 and 32.9 [2 x CH2] ; Mass: mJz 244 (M+, 52%), 246 (M++2, 52%), 1 5 1 ( 1 00).

(+)-(5 S)-5-Isopropenyl-3-[2-(3, 4-dimetboxyphenyl)­ethyl]-2,4,4-trimethylcyclohex-2-enone 15. To a suspension of lithium (23 mg, 3 .3 mmole) i n dry THF (2 mL) in a round bottom flask, placed in an ultrasonic cleaning bath, was added a mixture of dimethylcarvone 5 (97 mg, 0.544 mmole) and 3,4-dimethoxyphenethyl bromide (13, 200 mg, 0.8 1 8 mmole) in THF (3 mL) at 1 5-20°C and sono­chemically irradiated for 40 min. The reaction mixture was decanted from the excess lithium, quenched with saturated aq. N14CI solution and extracted with ether (5 x 5 mL). The ether extract was washed with brine and dried (Na2S04)' Evaporation of the solvent furnished the tertiary alcohol [IR (neat): 3540, 3460 cm- I ; IH NMR (300 MHz, CDCh): 8 6.85-6.70 (3 H, m, Ar-H),' 5 .54 ( 1 H, s, olefinic H), 4.94 ( 1 H, s) and 4.79 (1 H, s) [C=CH2], 3.89 (3 H, s) and 3.86 (3 H, s) [2 x OCH3], 2.80-2.50 (4 H, m), 2.20- 1 .80 (4 H, m), 1 .80 (6 H, s, 2 x olefinic CH3), 0.96 (3 H, s) and 0.94 (3 H, s) [CH3CCH3], which was oxidised using PCC ( 1 76 mg, 0.8 1 7- mmole) and silica gel ( 176 mg) for 8 hr in CH2Ch (3 mL) as described for 7, and purification of the product over a silica gel column using ethyl acetate-hexane ( 1 : 1 0) as eluent

furnished the transposed enone 15 ( 140 mg, 75% overall in two steps); [a]D

27 34.5 (c 2.0, CHCh); IR (neat): 1660, 1600, 1580, 890 cm- I ; IH NMR (300 MHz, CDCh): 8 6.83 and 6.78 (2 H, AB quartet, J=8.2 Hz), 6.74 ( 1 H, s), 4.94 ( 1 H, s) and 4.78 ( 1 H, s) [C=CH2], 3.90 (3 H, s) and 3 .87 (3 H, s) [2 x OCH3] , 2.70-2.50 (7 H, m), 1 .89 (3 H, s) and 1 .73 (3 H, s) [2 x olefinic CH3], 1 .28 (3 H, s) and 1 . 14 (3 H, s) [CH3CCH3]; l 3C NMR (75 MHz, CDCh): 8 1 98.8 (C=O), 163.4, 148.9, 147.5, 145.5, 134. 1 , 1 3 1 . 1 , 1 19.8, 1 15.0 (C=CH2), 1 1 1 .4 (2 C), 55 .9, 55.8, 52.0, 39.7, 39.6, 34.2, 33.4, 27.2, 23.0, 22. 1 , 1 1 .6; Mass: mJz 342 (M+, 5%), 1 5 1 ( 100), 1 07 (5).

(+ )-(5S)-5-Acetyl-3-[2-(3,4-dimethoxyphenyl)ethyIJ-2,4,4-trimethylcyclohex-2-enone 16. Selective ozono­lysis of the enone 15 (42 mg, 0. 123 mmole) in methanol (0.3 mL) and CH2Ch (2.0 mL) for 40 sec and reductive work-up with dimethyl sulfide (0.8 mL) as described for the compound 10, fol lowed by purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :5) as eluent first furnished the unreacted starting material 15 ( 1 2 mg). Further elution of the column with ethyl acetate­hexane ( 1 :2.5) as eluent furnished the endione 16 (28 mg, 93%) as an oil, [a]D

27 9.4 (c 1 .06, CHCh); IR (neat): 1700, 1660, 1 605, 1 590 cm- I ; IH NMR (300 MHz, CDCh): 8 6.83 and 6.77 (2 H, AB quartet, J=8.2 Hz), 6.74 ( 1 H, s), 3 .90 (3 H, s) and 3.87 (3 H, s) [2 x OCH3], 3 . 1 0 (1 H, dd, J=1 0.2 and 4.8 Hz, H-5), 2.75-2.40 (6 H, m), 2.23 (3 H, s, COCH3), 1 .87 (3 H, s, olefinic CH3), 1 .34 (3 H, s) and 1 .24 (3 H, s) [CH3CCH3J; l 3C NMR (75 MHz, CDCh): 8 209.2 (C=O), 1 96.7, 1 62.3, 149.0, 147.6, 1 34.0, 1 3 1 .0, 1 19 .8, 1 1 1 .4 (2 C), 56.7, 55.97, 55.93, 39. 1 , 36.4, 34.3, 32.9, 32.0, 27.0, 22.2, 1 1 .7 ; Mass: mJz 344 (M+, 30%), 1 52 ( 13), 1 5 1 ( 100), 1 07 (20).

2-Allyl-6-methylanisole 23. To a magnetically stirred solution of the phenol 228 (3 1 2 mg, 2. 1 mmole) in CH2Ch ( 1 0 mL) was added 50% aq. KOH solution (25 mL), benzyltriethylammonium chloride (228 mg, 1 mmole) and methyl iodide (0.7 mL) and stirred for 24 hr at RT. It was then extracted with CH2Ch (2 x 5 mL). The combined organic extract was washed with brine and dried (Na2S04)' Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :20) as eluent furnished the methyl ether 23 (307 mg, 90%) as an oil, IR (neat): 1630, 905 cm-I ; IH NMR (300 MHz,

9 12 INDIAN J CHEM, SEC B , OCTOBER 2001 CDCb +CCI4): 8 7.05-6.95 (3 H, m, Ar-H), 6.00 ( 1 H, t of dd, J=17.0, 1 1 .0 and 6.6 Hz, CH2CH=CH2), 5 . 15-5 .05 (2 H, m, CH=CH2), 3.74 (3 H, s, ArOCH3), 3 .45 (2 H, d, J=6.6 Hz, CH2CH=CH2), 2.32 (3 H, s, ArCH3).

2-(2-Methoxy-3-methylphenyl)ethanol 24. A pre­cooled (-90°C) mixture of ozone in oxygen was passed through a solution of the ether 23 (3 10 mg, 1 .9 1 mmole) in MeOH (3 mL) for 1 2 min. The excess ozone was removed by flushing the solution with oxygen gas and sodium borohydride (200 mg, 5.26 mmole) was added maintaining the temperature at -20°C to -50°C. The reaction mixture was slowly warmed up to RT and stirred for 1 0 hr. Evaporation of methanol afforded a solid residue, which was neutralised with 1 0% aq. HCI and extracted with methylene chloride (2 x 5 mL). The organic extract was washed with NaHC03 solution and dried (Na2S04). Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( I :20 to 1 : 1 0) as eluent furnished the alcohol 24 (3 1 5 mg, 97%) as an oil, IR (neat): 3360, 1 590 cm·' ; 'H NMR (300 MHz, CDCI3) : 8 7 . 1 0-6.85 (3 H, m, Ar-H), 3 .80 (2 H, t, J=6.6 Hz, CH20H), 3 .73 (3 H, s, ArOCH3), 2.86 (2 H, t, J=6.6 Hz, ArCH2), 2.29 (3 H, s, ArCH3) 2.05 (1 H, br s, OH).

2-(2-Bromoethyl)-6-methylanisole 19. To a cold (O°C), magnetically stirred solution of the alcohol 24 (3 15 mg, 1 .9 mmole) in dry CH2Ch (4 mL) were added, simultaneously CBr4 (756 mg, 2.28 mmole) and PPh3 (598 mg, 2.3 mmole). The reaction mixture was stirred at RT for 20 hr and the solvent was evaporated under reduced pressure. Purification of the residue over a neutral alumina column using hexane as eluent furnished the bromide 19 (400 mg, 93%) as an oil, IR (neat): 1 590 cm- ' ; 'H NMR (300 MHz, CDCI3 + CCl4) : 8 7. 1 0-6.95 (3 H, m, Ar-H), 3 .75 (3 H, s, OCH3), 3 .61 (2 H, t, J=7.5 Hz, CH2Br), 3. 1 8 (2 H, t, J=7.5 Hz), 2.3 1 (3 H, s, ArCH3); I3C NMR (75 MHz, DEPT, CDCl3 + CCI4): 8 1 56.9 (C), 1 3 1 .7 (C), 1 3 1 .3 (C), 1 30.4 (CH), 128 . 1 (CH), 124. 1 (CH), 60.5 (CH3, OCH3), 34.2 (CH2), 32.2 (CH2), 1 6.2 (CH3, ArCH3); Mass: mlz 228 (M+, 55%), 230 (M + 2, 55%), 149 (55), 1 35 ( 1 00), 1 05 (96), 9 1 (35).

(+)-(5 S)-5-Isopropenyl-3-[2-(2-methoxy-3-methyl­phenyl)ethyJJ-2,4,4-trimethylcyclohex-2-enone 25. To a suspension of lithium (55 mg, 7.8 mmole) in dry THF (3 mL) in a round bottom flask, placed in an ultrasonic cleaning bath, was added a mixture of

dimethylcarvone 5 (35 mg, 0.2 mmole) and the bromide 19 ( 1 80 mg, 0.78 mmole) at 1 5 -20°C and sonochemically irradiated for 40 min. The reaction mixture was decanted from the excess lithium, quenched with saturated aq. NH4CI solution and extracted with ether (2 x 5 mL). The ether extract was washed with brine and dried (Na2S04). Evaporation of the solvent furnished the tertiary alcohol, which was oxidised using PCC (400 mg, 1 .86 mmole) and silica gel (400 mg) in CH2Ch ( 1 mL) for 6 hr as described for 7, and purification of the product over a silica gel column using ethyl acetate-hexane ( 1 :20 to 1 : 1 0) as eluent furnished the transposed enone 25 (27 mg, 42% overall in two steps), [a]D

2 ' 36.4 (c 2.72, CHCh); IR (neat): 1 660, 1 600, 1 0 10, 890 cm- ' ; 'H NMR (300 MHz, CDCh): 8 7.07 (2 H, d, J=7.2 Hz), 6.99 (1 H, t, J=7.2 Hz), 4.95 ( 1 H, s) and 4.79 ( 1 H, s) [C=CH2], 3.77 (3 H, s, OCH3), 2.80-2.45 (7 H, m), 2.33 (3 H, s, ArCH3), 1 .94 (3 H, s) and 1 .75 (3 H, s) [2 x olefinic CH3], 1 .3 1 (3 H, s) and 1 . 1 5 (3 H, s) [CH3CCH3]; I

3C

NMR (75 MHz, DEPT, CDCI3): 8 1 99.0 (C, C=O), 1 63.8 (C, C-3), 1 56.7 (C), 145 .6 (C, C=CH2), 1 34.3 (C), 1 3 1 .2 (2 C, C), 1 29.7 (CH), 1 27.5 (CH), 124.2 (CH), 1 1 5 .0 (CH2, C=CH2), 60.4 (CH3, OCH3), 52.0 (CH), 39.9 (C), 39.7 (CH2), 32.6 (CH2), 29.6 (CH2), 27.0 (CH3), 23. 1 (CH3), 22.0 (CH3), 1 6.2 (CH3), 1 1 .4 (CH3); Mass: mlz 326 (M+, 7%), 3 1 1 ( 1 5), 1 35 ( 100).

(+ )-(lS,5S)-5-IsopropenyJ-3-[2-(2-methoxy-3-methyl­phenyl)ethyIJ-2,4,4-trimethylcyclohex-2-enol 26. Reduction of the enone 25 (220 mg, 0.67 mmole) in ether ( 1 0 mL) using LiAIHt ( 1 3 mg, 0.34 mmole ) at -90°C for 2 hr as described for the alcohol 8 and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 : 1 0) as eluent furnished the alcohol 26 ( 1 50 mg, 84%) as an oil, [a]D25 54.4 (c 1 . 14, CHCh); I R (neat): 3330, 890 cm- ' ; 'H NMR (300 MHz, CDCl3 + CCI4) : 8 7.04 ( 1 H, d, J=7.2 Hz), 7.01 ( 1 H, d, J=7.2 Hz), 6.94 ( l H, t, J=7.2 Hz), 4.94 ( 1 H, s) and 4.73 ( l H, s) [C=CH2], 4. 10 ( 1 H, dd, J=9.0 and 7.0 Hz, CHOH), 3.75 (3 H, s, OCH3), 2.70-2.60 (2 H, m, ArCH2), 2.3 1 (3 H, s, ArCH3), 2.35- 1 .65 (5 H, m), 1 .87 (3 H, s) and 1 .80 (3 H, s) [2 x olefinic CH3] , 1 . 1 5 (3 H, s) and 1;00 (3 H, s) [CH3CCH3] ; I 3C NMR (75 MHz, DEPT, CDCh + CCI4) : 8 1 56.8 (C), 146.7 (C), 14 1 . 1 (C), 1 35 .4 (C), 1 30.9 (C), 1 30.4 (C), 1 29.3 (CH), 1 27.7 (CH), 1 24. 1 (CH), 1 14.5 (CH2), 7 1 .6 (CH), 60.3 (CH3), 50.3 (CH), 39.8 (C), 35.0 (CH2, C-6), 3 1 .2 (CH2). 30.7 (CH2), 27. 1 (CH3), 23.3

SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF B-SECO-C-AROMATIC T AXANES 9 1 3

(CH3), 22.8 (CH3), 1 6.3 (CH3), 14.9 (CH3) ; Mass: m1z 328 (M+, 3%), 3 1 1 ( 1 0), 1 75 ( 1 5), 1 49 (30), 1 35 ( 1 00), 1 2 1 ( 1 5) .

( + )-(IS,5S)-5-lsopropenyl-3-[2-(2-metboxy-3-methyl­phenyl)ethyIJ-2,4,4-trimethylcyclohex-2-enyl methyl ether 27. To a magnetically stirred solution of NaH (30 mg, 55% dispersion in oil, 0.58 mmole, washed with dry hexanes) and terabutylammonium iodide (catalytic) in THF ( 1 mL) was added a solution of the alcohol 26 (94 mg, 0.29 mmole) in dry THF (2 mL) and DMF (0. 1 mL), and stirred for 1 hr at RT. Methyl iodide (0. 1 mL) was added to the reaction mixture and stirred for 8 hr. It was then quenched with water (2 mL) and extracted with ether (2 x 4 mL). The combined ether extract was washed with brine and dried (Na2S04) ' Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :20) as eluent furnished the methyl ether 27 (52 mg, 72% based on the consumed starting material) as an oil, [aJo25 52.3 (c 1 .3, CHCI3) ; IR (neat): 1 640, 890 cm- ' ; 'H NMR (300 MHz, CDCI3) : 0 7.00 (I H, d, 1=7.2 Hz), 6.96 ( l H, d, 1=7.2 Hz), 6.89 ( 1 H, t, 1=7.2 Hz), 4.9 1 ( 1 H, s) and 4.70 ( l H, s) [C=CH2] , 3 .72 (3 H, s, ArOCH3), 3.35 (3 H, s, OCH3), 3 .75-3 .65 ( 1 H, m, CHOMe), 2.65-2.55 (2 H, m, ArCH2), 2.30- 1 .65 (5 H, m), 2.29 (3 H, s, ArCH3), 1 .78 (6 H, s, 2 x olefinic CH3), 1 . 1 2 (3 H, s) and 0.98 (3 H, s) [CH3CCH3] ; I 3C NMR (75 MHz, DEPT, CDCh + CCI4) : 0 1 56.9 (C), 1 46.8 (C), 141 .9 (C), 1 35 .5 (C), 1 30.9 (C), 1 29.5 (C), 1 29.3 (CH), 127.7 (CH), 1 24.2 (CH), 1 14.6 (CH2), 80.2 (CH), 60.3 (CH3) , 55.7 (CH3), 50.3 (CH), 39.9 (C), 3 1 .3 (CH2), 30.8 (CH2), 30.2 (CH2), 27.0 (CH3), 23.3 (CH3), 22.7 (CH3), 1 6.4 (CH3), 1 5 .0 (CH3) ; Mass: m1z 342 (M+, 8%), 327 ( 1 8), 326 ( 1 8), 3 1 1 (40), 1 9 1 (40), 1 82 (40), 1 49 (80), 1 36 ( 1 00), 1 35 ( 1 00), 1 05 ( 1 00).

(+ )-(IR,13S)-3,13-Dimethoxy-2-methyl-2,3-seco-19-nor-tax-3,5,7,II-tetraene-2-one 28. Controlled ozonolysis of the methyl ether 27 (40 mg, 0. 1 2 mmole) i n methanol ( 1 drop) and CH2Ch (3 mL) for ca 30 sec at -70°C followed by reductive work-up using dimethyl sulfide (0.05 mL) as described for the keto ether 10 and purification of the residue on a silica gel column using ethyl acetate-hexane ( 1 :20) as eluent first furnished the starting material methyl ether 27 ( 1 2 mg, 29%). Further elution of the column with ethyl acetate-hexane ( 1 : 1 0) furnished the ketone 28 (20 mg, 49%) as an oil, [a]o25 4 1 .9 (c 1 .6, CHCh);

IR (neat): 1 700 cm- ' ; 'H NMR (300 MHz, CDCh): 0 7.00-6.85 (3 H, m), 3.7 1 (3 H, s, ArOMe), 3 .67 ( 1 H, t, 1=6.6 Hz), 3.32 (3 H, s), 2.65-2.60 (2 H, m), 2.50 ( I H, dd, 1=1 3 .2 and ca. 5 .0 Hz), 2.30- 1 .75 (4 H , m), 2.28 (3 H, s, H-20), 2. 1 7 (3 H, s, COCH3) 1 .77 (3 H, s), 1 .20 (3 H, s), 1 .08 (3 H, s); I 3C NMR (75 MHz, CDCh): 0 2 10.0 (C, C=O), 1 56.9 (C), 1 4 1 .3 (C), 1 35 .2 (C), 1 30.9 (C), 1 29.4 (C), 1 29.3 (CH), 127.7 (CH), 1 24.2 (CH), 78.9 (CH), 60.3 (CH3), 56.3 (CH3), 55.5 (CH), 38.7 (C), 3 1 .5 (CH3) , 30.8 (CH2), 30.7 (CH2), 27.4 (CH3), 27.2 (CH2), 22.8 (CH3), 1 6.4 (CH3), 1 5 .2 (CH3) ; Mass: m1z 344 (M+, 5%), 246 (25), 1 49 (20), 1 35 ( 1 00), 1 05 (50).

(lR,13S)-3,13-Dimethoxy-2,3-seco-19-nortax-3,5, 7,1 l-tetraene-2-oic acid methyl ester 29a. To a cold (5°C) magnetically stirred solution of the ketone 28 (60 mg, 0. 1 7 mmole) in dioxane (2.4 mL) and water (0.7 mL) was added a cold (O°C) solution of the sodium hypobromide solution [prepared by adding bromine (93 mg, 0.03 mL, 0.56 mmole) to a cold (-5°C) solution of NaOH (90 mg, 2.23 mmole) in water (0.8 mL) and diluted with dioxane (0.5 mL) at the same temperature] and the reaction mixture stirred for 3 hr at 1 O- 15°C. The excess sodium hypobromide was decomposed by the addition of a solution of sodium sulfite (30 mg) in water (0.5 mL). It was then acidified with conc. HC1, stirred for 5 min and extracted with CH2Ch (2x5 mL). The combined CH2Ch extract was washed with water (3x5 mL) and brine, and dried (Na2S04)' Evaporation of the solvent furnished the acid 29. Esterification of the acid 29 using cold ethereal diazomethane solution (5 mL) stirred for 2 hr as described for the ester l la, and purification of the residue over a silica gel column using ethyl acetate-hexane ( 1 :20 to 1 : 1 5) as eluent furnished the ester 29a (45 mg, 76%) as an oil, [a]o25

38.5 (c 1 .48, CHCh); IR (neat) : 1 730 cm-' ; 'H NMR (300 MHz, CDCh + CCI4): 0 7.00-6.80 (3 H, m, Ar­H), 3 .65 (3 H, s, COOCH3), 3 .70-3 .60 (1 H, m, CHOMe), 3 .62 (3 H, s, ArOCH3), 3 .28 (3 H, s, CHOCH3), 2.65-2.50 (2 H, m), 2.40- 1 .75 (5 H, m), 2.23 (3 H, s, ArCH3), 1 .73 (3 H, s, olefinic CH3), 1 . 1 6 (3 H , s) and 1 .00 (3 H , s) [2 x tert. CH3] ; I 3C NMR (75 MHz, CDCh): 0 1 74.0 (C, OC=O), 1 56.9 (C), 1 40.8 (C), 1 35.2 (C), 1 30.9 (C), 1 29.6 (C), 129.3 (CH), 1 27.7 (CH), 1 24.2 (CH), 78.7 (CH), 60.2 (CH3), 55.5 (CH3), 5 1 .2 (CH), 49.5 (CH3), 38.4 (C), 3 1 .0 (CH2), 30.8 (CH2), 27.3 (CH2), 27.2 (CH3), 22.8

9 14 INDIAN J CHEM, SEC B , OCTOBER 2001

(CH3), 1 6.4 (CH3), 1 5. 1 (CH3) ; Mass : rnJz 360 (M+, 1 0%), 246 (20), 2 1 1 (30), 1 35 ( 1 00), 1 05 (60).

Acknowledgement We thank the Department of Science and

Technology for the financial support, and UGC and CSIR, New Delhi for providing research fellowships to TJR, PPK and SJG.

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2 Taxol is the registered trademark for the molecule with the generic name paclitaxel.

3 For reviews on various aspects of taxanes, see: Swindell C S, Org Prep Proced lilt, 23, 1991, 465; Tetrahedron Symposia in Print, edited by J 0 Winkler, Tetrahedron, 1992, 6953; Kingston 0 G J, Molinero A A & Rimoldi J M, Progress ill the Chemistry of Organic Natural Products (Springer-Verlag, New York), 1993, 6 1 ; Guenard 0, Gueritte-Voegelein F & Potier P, Acc Chem Res. 26, 1993, 1 60; Boa A N, Jenkins P R & Lawrence N J, Contemp Org Sylllh, 1 , 1994, 47; Nicolaou K C, Dai W-M & Guy R K, Angew Chem Int Ed Engl, 33, 1994, 15 ; Georg G J, Chen T T, Ojima I & 0 M. Vyas, Eds., Taxane Anticancer Agellts: Basic Science and O!rrellt Status, ACS Symposium Series 583; American Chemical Society: Washington, DC, 1995; Taxol Symposium series 583; American Chemical Society; Washillgton, DC. 1995; Taxol Science and Applications, edited by M Suffness, CRC, Boca Raton, FL, 1995; Wender P A, Natchus M G & Shuker A J In TaxolR Sciellce alld Applications, edited by M Suffness, CRC Press, New York, 1995, 1 23.

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5 Srikrishna A , Reddy T J & Kumar P P , Chem CommulI, 1996, 1 369.

6 Srikrishna A, Reddy T J & Kumar P P, J Chem Soc. Perkin Trans J, 1998, 3 143.

7 Garver L, van Eikeren P & Byrd J E, J Org Chem, 41 , 1976, 2773.

8 Segal C L & Faurote P 0, U. S. patent 3,422,062, Chemical abstracts 70: P58641 w.