An enantiospecific approach to thapsanes from R-carvone: Synthesis of (-)-thaps-8-en-5-ol

Article abstract of DOI:10.1016/S0040-4039(00)01107-2

The first enantiospecific synthesis of a thapsane, containing three contiguous quaternary carbon atoms, is accomplished starting from R-carvone. An intramolecular alkylation and an intramolecular diazoketone cyclopropanation reaction were employed for the

Full text of DOI:10.1016/S0040-4039(00)01107-2

Tetrahedron Letters 41 (2000) 6643±6647
An enantiospeci®c approach to thapsanes from R-carvone:
synthesis of (^)-thaps-8-en-5-oly
A. Srikrishna,* K. Anebouselvy and T. Jagadeeshwar Reddy
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 5 June 2000; accepted 29 June 2000
Abstract
The ®rst enantiospeci®c synthesis of a thapsane, containing three contiguous quaternary carbon atoms,
is accomplished starting from R-carvone. An intramolecular alkylation and an intramolecular diazoketone
cyclopropanation reaction were employed for the stereo- and regiospeci®c generation of three contiguous
quaternary carbon atoms present in the thapsane framework. # 2000 Published by Elsevier Science Ltd.
Thapsanes 1±4 are a small group of sesquiterpenes isolated from the Mediterranean umbelliferous
plant Thapsia villosa.1 A characteristic of the structure of the thapsanes is the presence of a cis-
1,2,2,6,8,9-hexamethylbicyclo[4.3.0]nonane carbon framework 5 incorporating three contiguous
quaternary carbon atoms, posing a signi®cant synthetic challenge. Even though the synthesis of
the thapsane carbon framework and subsequently one of the natural thapsanes 1g in racemic
form were achieved,2 there is no report on the synthesis of thapsanes in optically active form.
Herein we report an enantiospeci®c approach to the thapsane carbon framework containing an
oxygen functionality at the C-5 carbon, starting from R-carvone 6.
Retrosynthetic analysis on the basis of an intramolecular diazoketone cyclopropanation
reaction is depicted in Scheme 1. It was anticipated that intramolecular cyclopropanation of the
* Corresponding author. Tel: +91-80-3092215; fax: +91-80-3600529; e-mail: ask@orgchem.iisc.ernet.in
y
Chiral Synthons from Carvone, Part 42. For Part 41, see: Srikrishna, A.; Dinesh, C. Indian J. Chem. 2000, 39B, in press.
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01107-2

6644
diazoketone derived from the acid 7 would generate the tricyclic ketone 8, which can be further
elaborated to thapsane 9. Alkylation at the a-position of the enone with an equivalent of
CH2COOH suggested the enone 10 as the appropriate precursor for the acid 7. Identifying the
isopropenyl group as a masked hydroxy group, R-carvone 6 was chosen as the chiral precursor
for the generation of a chiral analogue of the enone 10. The synthetic sequence starting from
R-carvone 6 is depicted in Scheme 2. To begin with, R-carvone 6 was transformed into R-3,4,4-
trimethylcarvone 11. Sequential kinetic alkylation of carvone 6 with LDA and methyl iodide
furnished the 6,6-dimethylcarvone 12,3 which was transformed into the enone 11 via an alkylative
enone transposition strategy.
Scheme 1.
Scheme 2. Reagents and conditions: (a) Ref. 3; (b) i. MeMgI, Et2O, 0ꢀC to rt, 12 h; ii. PCC, silica gel, CH2Cl2, rt, 6 h,
60%; (c) NBS, CH2Cl2:MeOH (3:2), 0ꢀC to rt, 6 h, 90%; (d) tBuOK, tBuOH±THF, ^5ꢀC to rt, 12 h, 70%; (e) i. O3/O2,
MeOH:CH2Cl2 (1:4), NaHCO3, ^70ꢀC; ii. Ac2O, NEt3, DMAP, C6H6, re¯ux, 6 h; 67% (60% conversion); (f) 5% Pd/
C, H2, EtOAc, 30 min, 90%; (g) Scheme 3; (h) TBDMSCl, DMAP, DMF, rt, 48 h, 95%; (i) 5% NaOH in MeOH:H2O
(1:1), re¯ux, 12 h, 95%; (j) i. (COCl)2, py, C6H6, rt, 3 h; ii. CH3CHN2, Et2O, 0ꢀC, 2 h; (k) Cu±CuSO4, c-C6H12, W-lamp,
re¯ux, 5 h, 47% (from the acid 23); (l) Li, liq. NH3, tBuOH, ^33ꢀC, 2 h, 82% (85% conversion); (m) tBuOK, Ph3PCH3Br,
C6H6, 70ꢀC, 4 h, 75% (82% conversion); (n) p-TSA, CH2Cl2, rt, 6 h, 62%; (o) TBAF, THF, re¯ux, 24 h, 90%

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Reaction of the enone 12 with methylmagnesium iodide followed by oxidation of the resulting
allyllic tertiary alcohol with pyridinium chlorochromate and silica gel furnished the enone 11.
Instead of the degradation of the isopropenyl group and introduction of an acetic acid side chain
at the C-2 position, translocation of the isopropenyl group from C-5 to the C-2 position as the
acetic acid side chain was envisaged. An intramolecular alkylation methodology was adopted for
joining the C-2 carbon of the enone 11 with the isopropenyl group.4 Thus, reaction of
trimethylcarvone 11 with N-bromosuccinimide (NBS) in a methanol±methylene chloride medium
furnished the allyl bromide 13 in 90% yield.5 Treatment of the allyl bromide 13 with potassium
tert-butoxide in tert-butanol±THF furnished the bicyclo[2.2.2]octanone 14{ via regioselective
intramolecular alkylation of the intermediate dienolate. The steric hindrance of the C-6 methyl-
ene group was exploited for the regioselective cleavage of the C-8 methylene group in the ketone
14. Thus, controlled ozonolysis of the bicyclic ketone 14 in methylene chloride±methanol
followed by treatment of the intermediate methoxyhydroperoxide with acetic anhydride,
triethylamine and a catalytic amount of 4-N,N-dimethylaminopyridine (DMAP) in re¯uxing
benzene furnished the keto ester 15{ via the Criegee fragmentation,6,7 along with varying amounts
(10±15%) of the simple ozonolysis product. Regioselective hydrogenation using 5% Pd/C as the
catalyst in ethyl acetate transformed the enone ester 15 into the saturated ketone 16. For further
elaboration, it was anticipated that the ketone could be converted into the corresponding alcohol
and protected. Sodium borohydride reduction of the keto ester 16 in methanol, quite expectedly,
generated the cis-lactone 17, m.p. 39±40ꢀC (Scheme 3). The problem was circumvented via the
Scheme 3. Reagents and conditions: (a) NaBH4, MeOH, 0ꢀC, 30 min; (b) 5% NaOH in MeOH:H2O (1:1), re¯ux, 12 h;
(c) NaBH4, THF, 0ꢀC, 3 h; (d) CH2N2, Et2O, 0ꢀC, 10 min
{
All the compounds exhibited spectral data consistent with their structures. Yields refer to isolated and chromato-
26
graphically pure compounds. Spectral data for the bicyclic ketone 14: ‰ꢀŠ ^4.9 (c 7.32; CHCl3). IR (neat): ꢁmax 1720,
D
1650, 1630, 890 cm^1. 1H NMR (200 MHz, CDCl3): ꢂ 5.0 (2H, s), 4.93 (1H, br s), 4.79 (1H, br s), 2.68 (1H, dd, J 20.4
and 3.9 Hz), 2.41 (2H, t, J 2.3 Hz), 2.31 (1H, br s), 2.26 (1H, dd, J 20.4 and 2.9 Hz), 1.18 (3H, s), 1.15 (3H, s), 1.14 (3H,
s). 13C NMR (22.5 MHz, CDCl3): ꢂ 211.3 (s), 156.4 (s), 145.4 (s), 108.6 (t), 108.4 (t), 52.4 (s), 50.1 (d), 40.6 (t), 38.4 (t),
25
D
37.4 (s), 31.0 (q), 28.2 (q), 16.2 (q). For the keto ester 15: ‰aŠ +38 (c 1.1; CHCl3). IR (neat): ꢁmax 1740, 1680, 1622, 902
cm^1. H NMR (300 MHz, CDCl3): ꢂ 6.53 (1H, d, J 10.2 Hz), 5.99 (1H, d, J 10.2 Hz), 5.16 (1H, s), 5.11 (1H, s), 3.56
1
(3H, s), 3.35 and 2.76 (2H, 2Âd, J 16.7 Hz), 1.38 (3H, s, CH3), 1.34 (3H, s, CH3), 1.30 (3H, s, CH3). 13C NMR (75
MHz, DEPT): ꢂ 200.1 (C), 171.2 (C), 157.2 (C), 155.8 (CH), 123.9 (CH), 110.4 (CH2), 51.4 (CH3), 49.3 (C), 42.7 (CH2),
25
D
37.5 (C), 33.0 (CH3), 31.2 (CH3), 30.8 (CH3). For the tricyclic ketone 25: m.p. 73±75ꢀC. ‰ꢀŠ ^25 (c 1.0; CHCl3). IR
(neat): ꢁmax 1715, 889 cm^1. 1H NMR (300 MHz, CDCl3): ꢂ 3.15 (1H, dd, J 11.3 and 4.4 Hz), 2.12 and 1.74 (2H, 2Âd, J
18.0 Hz), 1.90±1.40 (5H, m), 1.37 (3H, s), 1.15 (3H, s), 1.11 (3H, s), 1.03 (1H, d, J 4.8 Hz), 0.86 (9H, s), 0.82 (3H, s),
0.03 (6H, s). 13C NMR (75 MHz, DEPT): ꢂ 213.2 (C), 76.9 (CH), 48.5 (C), 44.7 (CH2), 44.2 (C), 41.4 (C), 38.3 (CH2),
33.6 (C), 28.9 (CH3), 28.6 (CH3), 27.7 (CH2), 25.8 (3 C, CH3), 21.3 (CH2), 18.5 (CH3), 18.0 (C), 14.2 (CH3), ^3.7 (CH3),
25
D
^5.0 (CH3). For the thapsenyl TBDMS ether 27: ‰ꢀŠ +27 (c 1.2; CHCl3). IR (neat): ꢁmax 1652, 888 cm^1. 1H NMR (300
MHz, CDCl3): ꢂ 4.84 (1H, s), 4.79 (1H, s), 3.42 (1H, dd, J 11.2 and 4.4 Hz), 2.70 (1H, m), 2.35 and 2.15 (2H, 2Âd, J
16.2 Hz), 1.66±1.55 (3H, m), 1.20 (1H, dd, J 10.2 and 3.6 Hz), 1.07 (3H, d, J 7.0 Hz), 0.98 (3H, s), 0.96 (3H, s), 0.88
(9H, s), 0.86 (3H, s), 0.82 (3H, s), 0.01 (6H, s). 13C NMR (75 MHz, DEPT): ꢂ 156.5 (C), 106.3 (CH2), 73.0 (CH), 50.9
(C), 49.3 (C), 44.4 (CH2), 42.6 (CH), 37.1 (CH2), 36.2 (C), 29.9 (CH3), 27.9 (CH2), 26.1 (3 C, CH3), 25.5 (CH3), 18.5
(CH3), 18.2 (CH3), 15.9 (CH3), 13.8 (CH3), ^3.7 (CH3), ^4.7 (CH3).

6646
intramolecular reduction of the ketone group. Consequently, hydrolysis of the keto ester 16
generated the keto acid 18. Treatment of the keto acid 18 with sodium borohydride in THF
delivered the hydride in an intramolecular fashion via the carboxyborohydride and generated the
hydroxy acid 19, which on esteri®cation with diazomethane furnished the hydroxy ester 20, along
with trace amounts of the cis- and trans-lactones 17 and 21. The alcohol group in the hydroxy
ester 20 was protected as its tert-butyldimethylsilyl (TBDMS) ether 22 by treatment with
TBDMSCl and DMAP in DMF. The third quaternary carbon atom was created employing an
intramolecular diazoketone cyclopropanation reaction. Base-catalysed hydrolysis of the ester
moiety in 22 furnished the acid 23. To introduce simultaneously a methyl group at the C-9
position of thapsane, it was intended to convert the acid 23 into the diazoketone 24.
Consequently, reaction of the acid 23 with oxalyl chloride in benzene and pyridine followed by
treatment of the resulting acid chloride with an excess of ethereal diazoethane furnished the
diazoketone 24. Anhydrous copper sulfate±copper-catalysed decomposition of the diazoketone
24 in re¯uxing cyclohexane under irradiation with a tungsten lamp followed by stereospeci®c
insertion of the resulting keto carbenoid furnished the tricyclic ketone 25,{ containing four qua-
ternary centres. Regiospeci®c cleavage of the cyclopropane ring2,8 employing lithium in liquid
ammonia reduction conditions transformed the tricyclic ketone 25 into northapsanone 26 in a
stereoselective manner. The ®fteenth carbon atom of thapsane was introduced employing a Wit-
tig olꢀe®nation. Thus, reaction of the ketone 26 with methylenetriphenylphosphorane in benzene
at 70 C furnished the TBDMS ether of thaps-8(11)-en-5-ol (+)-27.{ Isomerisation of the double
bond with p-TSA transformed 27 into the TBDMS ether of thaps-8-en-5-ol (^)-28. Finally, clea-
vage of the TBDMS ether 28 with tetrabutylammonium ¯uoride (TBAF) in re¯uxing THF furn-
26
ished (^)-thaps-8-en-5-ol 29, m.p. 77±79ꢀC, ‰ꢀŠ ^15.2 (c 1.2; CHCl3).
D
In conclusion, we have developed the ®rst enantiospeci®c approach to chiral thapsanes. A
combination of an intramolecular alkylation and a facile Crigee fragmentation reaction were
exploited for the translocation of the isopropenyl group of carvone from C-5 to the C-2 position,
thereby incorporating nine of the 10 carbons of carvone in thapsane. An intramolecular
diazoketone cyclopropanation reaction was employed for the generation of three contiguous
quaternary carbon atoms. Currently, we are investigating extension of this methodology to
natural thapsanes.
Acknowledgements
We thank the DST for ®nancial support, and the CSIR and UGC for providing the research
fellowships to K.A.S. and T.J.R., respectively.
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6647
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