Enantiospecific first total synthesis of (+)-cis,anti,cis-3-hydroxy-1,8,12,12-tetramethyl-4-oxatricyclo[6.4.0.0 2,6]-dodecan-9-yl senecioate, the optical antipode of a natural thapsane isolated from Thapsia villosa

Article abstract of DOI:10.1016/S0040-4039(02)02733-8

The enantiospecific first total synthesis of 10-hydroxy-10,11-epoxythapsan-5-yl senecioate (+)-1f, the enantiomer of the natural thapsane isolated from Thapsia villosa var minor, has been accomplished starting from (R)-carvone.

Full text of DOI:10.1016/S0040-4039(02)02733-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1031–1034
Enantiospecific first total synthesis of (+)-cis,anti,cis-
3-hydroxy-1,8,12,12-tetramethyl-4-oxatricyclo[6.4.0.02,6]-
dodecan-9-yl senecioate, the optical antipode of a natural
thapsane isolated from Thapsia villosaꢀ
A. Srikrishna* and K. Anebouselvy
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 1 October 2002; revised 21 November 2002; accepted 29 November 2002
Abstract—The enantiospecific first total synthesis of 10-hydroxy-10,11-epoxythapsan-5-yl senecioate (+)-1f, the enantiomer of the
natural thapsane isolated from Thapsia villosa var minor, has been accomplished starting from (R)-carvone. © 2003 Elsevier
Science Ltd. All rights reserved.
The medicinal properties of plants belonging to the
Mediterranean umbelliferous genus Thapsia were recog-
nised as early as 300 BC.1 Interest in the genus Thapsia
arose when the two guaianolides, thapsigargin and
thapsigargicin (the active principles present in Thapsia
garganica) were recognised as highly potent histamine
liberators, general stimulants of the immune system,
non-TPA tumour promoters and selective inhibitors of
the microsomal Ca2+-ATPases. Phytochemical investi-
gations on Thapsia villosa led to the isolation of a new
group of sesquiterpenes, thapsanes, which are unique to
the species. The research groups of Rasmussen,2
Grande3 and Christensen4 reported the isolation of
eight hemiacetalic 1a–g, 2, and six nonacetalic 3a–c, 4,
5a,b thapsanes, having novel carbon frameworks from
the extract of the roots of T. villosa var minor. The
structures of the thapsanes were assigned on the basis
of spectral data and were supported by the X-ray
crystal structure of 1a. Rasmussen et al. assigned the
absolute configuration of the thapsane 1a employing
the empirical method of Horeau, which is opposite to
that assigned5 to all thapsanes by Grande et al., on the
basis of the CD-curves of the ketones derived from the
thapsanes 1e,f. A characteristic of the structure of the
hemiacetalic thapsanes is the presence of a cis,anti,cis-
1,8,12,12-tetramethyl-4-oxatricyclo[6.4.0.02,6]dodecane
framework 6 (10,11-epoxythapsane), containing three
contiguous quaternary carbon atoms and five to six
chiral centres, which poses a significant synthetic chal-
lenge. So far, among the natural thapsanes, synthesis of
only the simplest member, 1g, has been reported.6
Herein, we report the first enantiospecific total synthesis
of the optical antipode of the thapsane 1f, which has an
ester group at the C-5 carbon, starting from the readily
and abundantly available monoterpene, (R)-carvone
(7).
ꢀ Chiral synthons from carvone, Part 58. For parts 56 and 57, see
Ref. 12.
* Corresponding author. Fax: 91-80-3600683; 3600529; e-mail:
ask@orgchem.iisc.ernet.in
For the enantiospecific synthesis of the thapsane 1f, we
conceived a combination of our earlier approach to
racemic thapsane6a 1g and the recently developed7
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02733-8

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A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 44 (2003) 1031–1034
described earlier,7 (R)-carvone (7) was converted into
the ketoester 11, via trimethylcarvone 12 and bicy-
clo[2.2.2]octanone 13, employing a regio-, stereo- and
enantiospecific translocation of the isopropenyl side
chain of trimethylcarvone from the C-5 carbon to the
C-2 carbon (as an acetate side chain) strategy. The
keto-ester 11 was transformed into the silyloxy ester 10
employing an intramolecular hydride reduction of the
ketone as the key step.7 The ester 10 was transformed
into the b-ketoester 8 via the aldehyde 14. Thus, lithium
aluminium hydride (LAH) reduction of the ester 10
followed by PCC oxidation of the resultant alcohol
generated the aldehyde 14, [h]2D4 −8.5 (c 4, CHCl3).
Stannous chloride catalysed coupling8 of the aldehyde
14 with ethyl diazoacetate furnished the b-ketoester 8,
[h]2D6 −34 (c 1, CHCl3), in 92% yield. Diazo transfer
reaction with tosyl azide and triethylamine converted
the ketoester 8 into the a-diazo-b-ketoester 15 in 90%
enantiospecific synthesis of a thapsenol. It was antici-
pated that intramolecular cyclopropanation of the dia-
zoketone derived from the b-ketoester 8 would generate
the tricyclic ketone 9, which could be further elaborated
into thapsane 1f. It was contemplated that the ester 10,
which could be obtained from (R)-carvone (7) in opti-
cally active form,7 would serve as an ideal precursor for
the generation of the b-ketoester 8 (Scheme 1).
The synthetic sequence starting from (R)-carvone (7) is
depicted in Schemes 2 and 3. To begin with, as
yield.
A rhodium acetate catalysed stereospecific
intramolecular cyclopropanation9 reaction of the diazo
compound 15 resulted in the formation of the tricyclic
compound† 9, in 45% yield, along with 9% of the
unexpected byproduct† 16. The formation of the
byproduct 16 can be rationalised via CꢀH insertion of
the intermediate rhodium carbenoid through the oxy-
gen of the ketone.10 On the other hand, treatment of
Scheme 1.
† All compounds exhibited spectral data consistent with their structures. Yields refer to isolated and chromatographically pure compounds.
Spectral data for the tricyclic compound 9: [h]D25: −27.86 (c 1.4, CHCl3). IR (neat): wmax 1742, 1722 cm−1 1H NMR (300 MHz, CDCl3+CCl4):
.
l 4.17 (2H, q, J=7.0 Hz), 3.35 (1H, dd, J=11.1 and 4.2 Hz), 2.22 and 1.83 (2H, 2×d, J=18.0 Hz), 1.85–1.50 (4H, m), 1.46 (1H, t of d, J=13.5
and 3.6 Hz), 1.33–1.26 (1H, m), 1.28 (3H, t, J=7.0 Hz), 1.13 (3H, s), 1.11 (3H, s), 0.60 (3H, s), 0.85 (9H, s), 0.05 (6H, s). 13C NMR (75 MHz,
CDCl3+CCl4): l 207.0 (C), 167.9 (C), 76.5 (CH), 61.2 (CH2), 53.5 (C), 49.0 (C), 45.3 (CH2), 44.8 (C), 37.0 (CH2), 33.0 (C), 28.2 (CH3), 27.5
(CH2), 27.0 (CH3), 25.8 (3C, CH3), 18.05 (CH3), 18.0 (C), 17.6 (CH2), 14.0 (CH3), −3.7 (CH3), −5.0 (CH3). For the compound 16: [h]2D5: +31.7
(c 1.2, CHCl3). IR (neat): wmax 1718, 1700, 1663, 891 cm−1 1H NMR (300 MHz, CDCl3+CCl4): l 5.06 (1H, s), 5.00 (1H, s), 4.72 (1H, d, J=1.1
.
Hz, CꢁCH), 4.14 and 4.06 (2H, q of AB q, J=10.6 and 7.0 Hz, OCH2CH3), 2.95 (1H, d, J=16.2 Hz), 2.76 (1H, dd, J=16.2 Hz and 1.6 Hz),
2.15 (1H, t of d, J=14.3 and 4.0 Hz), 1.98 (1H, d of t, J=14.0 and 4.0 Hz), 1.63 (1H, d of t, J=13.2 and 4.0 Hz), 1.36 (1H, t of d, J=14.0
and 4.0 Hz), 1.24 (3H, t, J=7.0 Hz), 1.30 (3H, s), 1.15 (3H, s), 1.11 (3H, s), 0.88 (9H, s), 0.25 (3H, s), 0.10 (3H, s). 13C NMR (75 MHz,
CDCl3+CCl4): l 168.8 (C), 165.2 (C), 157.8 (C), 112.6 (C), 110.1 (CH2), 89.2 (CH, O-CꢁCH), 58.9 (CH2), 50.2 (C), 45.9 (CH2), 35.4 (C), 35.2
(CH2), 31.3 (CH3), 30.1 (2 C, CH3 and CH2), 25.9 (3C, CH3), 25.5 (CH3), 18.1 (C), 14.6 (CH3), −2.9 (CH3), −3.8 (CH3). For the compound 19:
[h]2D4: +20.5 (c 4.0, CHCl3). IR (neat): wmax 1745, 1717, 1653, 883 cm−1. 1H NMR (300 MHz, CDCl3+CCl4): l 4.91 (1H, s), 4.83 (1H, s), 4.22–4.02
(2H, m), 3.63 (1H, br s), 3.41 (1H, dd, J=10.5 and 4.2 Hz), 2.44 and 2.28 (2H, 2×d, J=16.2 Hz), 1.75–1.35 (4H, m), 1.27 (3H, t, J=6.9 Hz),
1.12 (3H, s), 1.00 (3H, s), 0.98 (3H, s), 0.81 (3H, s), 0.88 (9H, s), 0.02 (6H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 173.4 (C), 148.9 (C), 108.5
(CH2), 72.9 (CH), 59.9 (CH2), 54.7 (CH), 54.3 (C), 49.9 (C), 44.0 (CH2), 36.7 (CH2), 36.2 (C), 28.6 (CH3), 27.9 (CH2), 26.1 (3C, CH3), 25.3
(CH3), 18.2 (C), 15.5 (CH3), 14.9 (CH3), 14.5 (CH3), −3.6 (CH3), −4.7 (CH3). For the ethoxy lactone 21: [h]2D5: −40.0 (c 0.6, CHCl3). IR (neat):
wmax 1772 cm−1 1H NMR (300 MHz, CDCl3): l 5.14 (1H, s), 3.87 (1H, q of d, J=9.3 and 6.9 Hz), 3.56 (1H, q of d, J=9.3 and 6.9 Hz), 3.39
.
(1H, dd, J=10.8 and 3.6 Hz), 3.30 (1H, d, J=11.1 Hz), 2.75 (1H, q, J=9.9 Hz), 2.23 (1H, dd, J=12.9 and 9.3 Hz), 1.70–1.20 (5H, m), 1.23
(3H, t, J=6.9 Hz), 1.07 (3H, s), 1.01 (3H, s), 0.97 (3H, s), 0.94 (3H, s), 0.89 (9H, s), 0.06 (3H, s), 0.055 (3H, s). 13C NMR (75 MHz, CDCl3):
l 176.6 (C), 107.9 (CH), 73.0 (CH), 64.9 (CH2), 53.8 (C), 53.3 (C), 51.6 (CH), 44.2 (CH), 40.3 (CH2), 36.9 (CH2), 35.7 (C), 30.3 (CH3), 27.6
(CH2), 25.8 (3C, CH3), 24.5 (CH3), 18.0 (C), 15.8 (CH3), 15.3 (CH3), 14.9 (CH3), −3.7 (CH3), −4.9 (CH3). For the trifluoroacetate 23: mp
100–102°C. [h]2D3: +34.28 (c 1.4, CHCl3). IR (neat): wmax 1776 cm−1 1H NMR (300 MHz, CDCl3): l 4.99 (1H, dd, J=12.2 and 4.4 Hz), 4.44
.
(1H, t, J=9.2 Hz), 3.96 (1H, dd, J=9.6 and 3.9 Hz), 3.30–3.10 (2H, m), 2.00–1.40 (6H, m), 1.17 (3H, s), 1.15 (3H, s), 1.05 (3H, s), 1.04 (3H,
s). 13C NMR (75 MHz, CDCl3): l 176.8 (C), 157.5 (C, q, 2JCꢀF=42 Hz), 114.5 (C, q, 1JCꢀF=284 Hz), 80.3 (CH), 72.7 (CH2), 54.4 (C), 52.6
(C), 50.7 (CH, C-2), 43.8 (CH2), 36.3 (CH2), 35.9 (C), 35.6 (CH), 30.2 (CH3), 24.5 (CH3), 23.6 (CH2), 16.0 (CH3), 15.1 (CH3). For the
(+)-hydroxyacetal 26: mp 110–112°C (lit.:3b 112–114°C). [h]D24: +64.3 (c 0.7, CHCl3) [lit.3b for (−)-26: −67.5 (c 2.4, CHCl3)]. IR (thin film): wmax
3479 cm−1 1H NMR (300 MHz, CDCl3): l 4.79 (1H, s), 3.96 (1H, t, J=7.8 Hz), 3.63 (1H, d, J=7.8 Hz), 3.64–3.58 (1H, m), 3.27 (3H, s),
.
2.85–2.74 (2H, m), 2.25–2.10 (1H, m), 1.80–1.50 (4H, m), 1.35–1.20 (2H, m), 0.96 (6H, s), 0.88 (6H, s). 13C NMR (75 MHz, CDCl3): l 107.3
(CH), 72.5 (CH2), 72.4 (CH), 57.7 (CH), 54.3 (CH3), 53.4 (C), 50.1 (C), 43.4 (CH2), 38.0 (CH), 36.5 (CH2), 35.8 (C), 28.0 (CH3), 27.6 (CH2),
24.6 (CH3), 14.7 (CH3), 13.4 (CH3). For the thapsane 1f: [h]D23: +37.3 (c 1.1, CHCl3) [lit.3b for (−)-1f: −35.7 (c 4.7, CHCl3)]. IR (neat): wmax 3408,
1714, 1650 cm−1 1H NMR (300 MHz, CDCl3): l 5.67 (1H, s), 5.36 (1H, s), 4.99 (1H, dd, J=11.4 and 4.5 Hz), 4.14 (1H, t, J=8.0 Hz), 3.62
.
(1H, d, J=8.0 Hz), 3.05–2.85 (2H, m), 2.21 (1H, br s), 2.17 (3H, s), 1.89 (3H, s), 1.95–1.50 (4H, m) 1.35–1.20 (2H, m), 1.05 (3H, s), 0.99 (3H,
s), 0.94 (3H, s), 0.89 (3H, s). 13C NMR (75 MHz, CDCl3): l 166.6 (C), 156.3 (C), 116.4 (CH), 100.7 (CH), 73.5 (CH), 72.8 (CH2), 58.3 (CH),
52.3 (C), 50.6 (C), 43.5 (CH2), 38.0 (CH), 36.2 (CH2), 35.8 (C), 28.1 (CH3), 27.4 (CH3), 24.6 (CH3), 24.3 (CH2), 20.2 (CH3), 16.0 (CH3), 13.2
(CH3).

A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 44 (2003) 1031–1034
1033
groups,11 respectively. Wittig reaction of the ketoester
17 with methyltriphenylphosphonium bromide and
potassium tert-amylate in refluxing benzene generated
the ester† 19 in quantitative yield. Epoxidation of the
exomethylene in 19 with m-chloroperbenzoic acid
(MCPBA) in methylene chloride generated a :2:1
epimeric mixture of the epoxides 20 in 80% yield.
Treatment of the epimeric mixture of the epoxides 20
with a catalytic amount of boron trifluoride diethyl
etherate in methylene chloride furnished a :1:1 mix-
ture of the ethoxylactone† 21 and the desilylated lactone
22, [h]2D3 −59.4 (c 1.6, CHCl3), in 70% yield, which were
separated by silica gel column chromatography. For-
mation of the ethoxylactones 21 and 22 can be ratio-
nalised via the boron trifluoride diethyl etherate-
catalysed rearrangement of the epoxide in 20 followed
by intramolecular transacetalisation of the resultant
ester aldehyde. Ionic hydrogenation of either of the
ethoxylactones 21 or 22 using a combination of tri-
fluoroacetic acid and triethylsilane furnished the tri-
fluoroacetoxy lactonec 23, which on hydrolysis with
potassium carbonate in methanol furnished the hydroxy-
lactone 24, [h]2D3 +40 (c 0.9, CHCl3), mp 177–179°C
(lit.3b 184–186°C), a degradation product of the thap-
sane 1f, which exhibited IR and 1H NMR spectra
identical to those of the authentic sample.3 Controlled
reduction of the lactone moiety in 24 with diisobutyl-
aluminum hydride (DIBAL-H) furnished an epimeric
mixture of the hydroxy hemiacetal 25, which on acetal-
isation with methanol in the presence of PTSA fur-
nished the hydroxyacetal† 26. Coupling of the
hydroxyacetal 26 with senecioic acid in the presence of
1,3-dicyclohexylcarbodiimide (DCC) and a catalytic
amount of 4-N,N-dimethylaminopyridine (DMAP)
generated a mixture of the senecioate 27 and the decon-
jugated ester 28, which was quantitatively equilibrated
Scheme 2. Reagents, conditions and yields: (a) Ref. 7; (b) i.
LAH, Et2O, 0°C–rt, 2 h, 91%; ii, PCC, silica gel, CH2Cl2, rt,
3 h, 90%; (c) N2CHCO2Et, SnCl2·2H2O, CH2Cl2, rt, 6 h, 92%;
(d) p-TsN3, NEt3, CH3CN, rt, 12 h, 90%; (e) Rh2(OAc)4,
C6H6, rt, 20 h, 45% of 9 and 9% of 16; (f) Cu, CuSO4,
c-C6H12, W-lamp, 24 h, 60% of 9.
the a-diazo-b-ketoester 15 with copper and anhydrous
copper sulfate in refluxing cyclohexane in the presence
of a tungsten lamp furnished, exclusively, the tricyclic
b-keto ester 9, in 60% yield. Reductive cleavage of the
cyclopropane ring in 9 employing lithium in liquid
ammonia furnished a 3:4 mixture of the hydrindanone
17, mp 85–87°C, [h]D22 +67.5 (c 1.2, CHCl3), and the
decalinone 18, [h]2D2 −38 (c 1.3, CHCl3), in 78% yield,
via electron transfer to the ketone and ester carbonyl
Scheme 3. Reagents, conditions and yields: (g) Li, liq. NH3, THF, −33°C, 10 min, 78%; (h) Ph3P+CH3 Br−, K+tAmO−, C6H6, reflux,
12 h, 99%; (i) MCPBA, CH2Cl2, rt, 24 h, 80%; (j) BF3·Et2O, CH2Cl2, rt, 0.5 h, 70%; (k) Et3SiH, CF3COOH, reflux, 4–5 h, 70%;
(l) K2CO3, MeOH, rt, 6 h, 95%; (m) DIBAL-H, PhMe, −78°C, 1 h, 89%; (n) MeOH, p-TSA, 10 min, rt, 84%; (o)
Me2CꢁCHCOOH, DCC, DMAP, PhMe, rt, 24 h, 99%; (p) DBU, CH2Cl2, rt, 9 h, 100%; (q) 3N HCl, THF, rt, 0.8 h, 96%.

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A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 44 (2003) 1031–1034
to 27, [h]2D4 +48.5 (c 1.3, CHCl3), with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in methylene chloride.
Finally, hydrolysis of the acetal moiety in 27 furnished
the thapsane† 1f. The thapsane 1f exhibited IR, 1H
NMR and mass spectra identical to those of the natural
product, but the opposite optical rotation.3b,5
curves of the ketones i and ii (containing cyclohexanone
part structure) derived from the thapsanes 1e and 1f, but
Grande et al. accidentally depicted the opposite absolute
stereochemistry for all the thapsanes in Refs. 3a–c
(Grande, M., personal communication).
In conclusion, we have accomplished the first enan-
tiospecific total synthesis of the optical antipode of the
hemiacetalic thapsane 1f containing a senecioate moiety
at the C-5 position. Currently, we are investigating the
extension of this methodology to other natural
thapsanes.
6. (a) Srikrishna, A.; Krishnan, K. J. Org. Chem. 1993, 58,
7751. For enantiospecific synthesis of (+)-1g, see: (b)
Srikrishna, A.; Anebouselvy, K. Tetrahedron Lett. 2002,
43, 5261.
Acknowledgements
7. Srikrishna, A.; Anebouselvy, K.; Reddy, T. J. Tetra-
hedron Lett. 2000, 41, 6643.
8. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989,
54, 3258.
9. (a) Stork, G.; Ficini, J. J. Am. Chem. Soc. 1961, 83, 4678;
(b) Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361;
(c) Mander, L. N. Synlett 1991, 134; (d) Padwa, A.;
Krumpe, K. E. Tetrahedron 1992, 48, 5385.
We thank Professor M. Grande, Universidad de Sala-
manca, for providing the copies of the spectra of the
compounds 24, 27 and 1f. We are grateful to D.S.T. for
financial support, and the C.S.I.R. for the award of a
research fellowship to KAS.
References
10. Insertion of the rhodium carbenoid through the oxygen
of the ketone group, instead of the a-carbon, is unusual
and there are only a few examples in the literature, see:
Wardrop, D. J.; Forslund, R. E. Tetrahedron Lett. 2002,
43, 737 and references cited therein. TBAF-mediated
desilylation of 16 resulted in the formation of the
hydrindanone iii via intra-molecular aldol condensation
of the intermediate dione, confirming the structure of 16.
1. Christensen, S. B.; Andersen, A.; Smitt, U. W. Prog.
Chem. Org. Nat. Prod. 1997, 71, 129.
2. Lemmich, E.; Jensen, B.; Rasmussen, U. Phytochemistry
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3. (a) Teresa, J. P.; Moran, J. R.; Grande, M. Chem. Lett.
1985, 865; (b) Teresa, J. P.; Moran, J. R.; Fernandez, A.;
Grande, M. Phytochemistry 1986, 25, 703; (c) Teresa, J.
P.; Moran, J. R.; Fernandez, A.; Grande, M. Phytochem-
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11. (a) Norin, T. Acta Chem. Scand. 1963, 17, 738; (b) Norin,
T. Acta Chem. Scand. 1965, 19, 1289; (c) Dauben, W. G.;
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Phytochemistry 1990, 29, 873.
5. The absolute configuration given by Rasmussen et al. for
1a needs to be revised.6b The absolute configuration of
the natural thapsanes was assigned based on the CD
12. For Part 56, see: Srikrishna, A.; Gharpure, S. J. Arkivoc
2002, (vii) 52. For Part 57, see: Srikrishna, A.; Kumar, P.
R.; Padmavathi, V. Synlett 2002, 1907.