The first enantiospecific synthesis of (+)-10,11-epoxythapsan-10-ol: Revision of the absolute stereochemistry of thapsanes

Article abstract of DOI:10.1016/S0040-4039(02)01051-1

The first enantiospecific synthesis of (+)-cis,anti,cis-1,8,12,12-tetramethyl-4-oxatricyclo[6.4.0.0^2,6] dodecan-3-ol (+)-1g, an enantiomer of natural thapsane isolated from Thapsia villosa var minor, is accomplished starting from (R)-carvone, w

Full text of DOI:10.1016/S0040-4039(02)01051-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5261–5264
The first enantiospecific synthesis of
(+)-10,11-epoxythapsan-10-ol: revision of the absolute
stereochemistry of thapsanes†
A. Srikrishna* and K. Anebouselvy
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 21 May 2002; accepted 31 May 2002
Abstract—The first enantiospecific synthesis of (+)-cis,anti,cis-1,8,12,12-tetramethyl-4-oxatricyclo[6.4.0.02,6]dodecan-3-ol (+)-1g, an
enantiomer of natural thapsane isolated from Thapsia villosa var minor, is accomplished starting from (R)-carvone, which revises
the absolute stereochemistry of natural thapsanes. © 2002 Elsevier Science Ltd. All rights reserved.
Rasmussen and co-workers reported1 the isolation of the
sesquiterpene 1a from the ethanolic extract of the roots
of the Mediterranean umbelliferous plant, Thapsia villosa
L. Simultaneously, Grande and co-workers reported2 the
isolation of the corresponding senicioate ester 1b from
the benzene extract of the roots of T. villosa var minor,
along with five other hemiacetalic 1c–f, 2, and four
nonacetalic 3a, 4a,b, 5 minor components, having the
same carbon framework. The trivial name ‘thapsane’ was
suggested for the bicyclic carbon framework cis-
1,2,2,6,8,9-hexamethylbicyclo[4.3.0]nonane 6 containing
the three contiguous quaternary carbon atoms which are
present in these sesquiterpenes. Later Christensen and
co-workers reported3 the isolation of three more thap-
sanes, two nonacetalic 3b,c and one hemiacetalic 1g, from
T. villosa var minor. The structures of the thapsanes were
established from their spectroscopic data in conjunction
with chemical transformations, and were further sup-
ported by the single crystal X-ray analysis of 1a. Ras-
mussen et al.1 have assigned the absolute stereochemistry
of (−)-1a as 1R,6R,8R,9R,10S by employing Horeau’s
empirical method for secondary alcohols. Grande and
co-workers have also assigned2 the same configuration
for all the thapsanes, on the basis of the CD curves of
the ketones derived from thapsanes 1e and 1f. A charac-
teristic of the structure of the hemiacetalic thapsanes is
the presence of a cis,anti,cis-1,8,12,12-tetramethyl-4-oxa-
tricyclo[6.4.0.02,6]dodecane framework containing three
contiguous quaternary carbon atoms, which poses a
significant synthetic challenge. Earlier we have reported4a
the synthesis of the racemic thapsane ( )-1g. So far there
is no report on the synthesis of any natural thapsane in
an optically active form, which would confirm the
absolute stereochemistry.5 Herein, we report the first
enantiospecific synthesis of (+)-1g, starting from (R)-
carvone 7, which establishes that the absolute con-
figuration of thapsanes is opposite to that assigned1,2
earlier.
R"
OSen
X
SenO
O
R'
Ang =
Sen =
O
O
Y
OR
O
R
O
OH
O
3a X=OSen;Y=OAc
b X=H;Y=OH
c X=H;Y=OFer
a R=R'=H;R"=OAng;
b R=R'=H;R"=OSen;
c R=R'=H;R"=OCoum;
d R=R'=H;R"=OFer;
e R=OAng;R'=R"=H;
f R'=OSen;R=R"=H;
g R=R'=R"=H;
4a R=H
1
O
2
b R=Ac
O
12
Coum =
OAng
13
6
15
O
OH
7
1
OAc
CHO
OMe
3
Fer =
9
11
14
10
6
OH
5
* Corresponding author. Fax: 91-80-3600683; 3600529; e-mail: ask@orgchem.iisc.ernet.in
† Chiral synthons from carvone, Part 55. For part 54, see reference 5b.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01051-1

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A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 43 (2002) 5261–5264
For the enantiospecific synthesis of thapsane 1g, we
have conceived a combination of our earlier approach
towards racemic thapsane4a 1g and the recently
developed5a enantiospecific synthesis of a thapsenol. It
was anticipated that intramolecular cyclopropanation
of the diazoketone derived from the b-ketoester 8 could
generate the tricyclic ketone 9, which could be further
elaborated into thapsane 1g. It was contemplated that
the aldehyde 10, which could be obtained from (R)-car-
vone 7 in optically active form, 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 Scheme 2. To begin with, (R)-carvone 7 was
converted into the ketoester 11, via trimethylcarvone 12
and bicyclo[2.2.2]octanone 13, employing a regio-,
stereo- and enantiospecific translocation of the isopro-
penyl side chain of trimethylcarvone from the C-5
carbon to the C-2 carbon (as an acetate side chain)
strategy as described earlier.5a Wolff–Kishner reduction
of the ketoester 11 with hydrazine hydrate and potas-
sium hydroxide in digol followed by esterification of the
resultant acid with diazomethane furnished the ester 14,
[h]2D6 −3.7 (c 3, CHCl3), in 53% yield, along with a
O
O
CHO
O
1g
COOEt
COOEt
9
8
10
7
Scheme 1.
O
O
O
R
O
X
a
a
a
COOMe
H
R
7
R = H
7a R = Me
12 X = H
12a X = Br
13
11
b
N
O
N
O
c
d
CHO
COOMe
+
COOEt
8
10
14
15
e
COOEt
N2
O
g
f
O
O
+
COOEt
O
H
COOEt
COOEt
( 5 : 3 )
16
9
18
17
h
OEt
j
i
O
CHO
+
O
COOEt
COOEt
COOEt
O
( 4 : 5 )
22
21
20
19
l
k
m
O
O
OH
COOEt
OH
O
(+)-24
(+)-1g
23
Scheme 2. Reagents, conditions and yields: (a) Ref. 5a; (b) i. N2H4·H2O, KOH, digol, 180°C, 12 h; ii. CH2N2, Et2O, 0°C, 10 min;
75%, 14:15 5:2; (c) i. LAH, Et2O, 0°C–rt, 2.5 h, 91%; ii. PCC, silica gel, CH2Cl2, rt, 1 h, 83%; (d) N2CHCO2Et, SnCl2·2H2O,
CH2Cl2, rt, 6 h, 88%; (e) p-TsN3, NEt3, CH3CN, rt, 12 h, 89%; (f) Rh2(OAc)4, C6H6, rt, 20 h, 69%; (g) Li, liq. NH3, THF, −33°C,
5 min, 86%; (h) Ph3P+CH3 Br−, K+ tAmO−, C6H6, reflux, 12 h, 98%; (i) MMPPA, EtOH, rt, 36 h, 83%; (j) BF3·Et2O, CH2Cl2,
rt, 2 h, 70%; (k) Et3SiH, CF3COOH, reflux, 5 h, 74%; (l) NaBH4, MeOH, 0°C, 0.5 h, 91%; (m) DIBAL-H, hexane, −78°C, 75 min,
87%.

A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 43 (2002) 5261–5264
5263
varying amount of the hexahydrocinnoline 15, mp 119–
121°C, [h]2D3 −85.5 (c 2, CHCl3). Lithium aluminium
hydride (LAH) reduction followed by PCC oxidation of
the resultant alcohol transformed the ester 14 into the
key intermediate of the sequence, aldehyde 10, [h]D23
+3.8 (c 4, CHCl3). Stannous chloride catalysed
reaction6 of the aldehyde 10 with ethyl diazoacetate
furnished the b-ketoester 8, [h]2D5 −10 (c 5.2, CHCl3), in
88% yield. A diazo transfer reaction with tosyl azide
and triethylamine converted the ketoester 8 into the
a-diazo-b-ketoester 16 in 89% yield. A rhodium acetate
catalysed stereospecific intramolecular cyclopropana-
tion7 reaction of the diazo compound 16 resulted in the
formation of the tricyclic compound 9,† in 69% yield.
Reductive cleavage of the cyclopropane ring in 9
employing lithium in liquid ammonia furnished a 3:5
mixture of the hydrindanone† 17 and the decalinone 18,
[h]2D4 −52 (c 2.5, CHCl3), in 86% yield, via electron
transfer to the ketone and ester carbonyl groups,8
respectively. A Wittig reaction of the ketoester 17 with
methyltriphenylphosphonium bromide and potassium
tert-amylate in refluxing benzene generated the ester†
19 in 98% yield. Epoxidation of the exomethylene in 19
with magnesium monoperoxyphthalate (MMPPA) in
ethanol generated a :1:1 epimeric mixture of the epox-
ide 20 in 83% yield. Treatment of the epimeric mixture
of the epoxide 20 with a catalytic amount of boron
trifluoride diethyl etherate in methylene chloride fur-
nished a 5:4 mixture of the ethoxylactone† 21 and the
aldehyde-ester 22, [h]2D5 +8.6 (c 1.4, CHCl3), in 70%
yield, which were separated by silica gel column chro-
matography. Formation of the ethoxylactone 21 could
be rationalised via the boron trifluoride diethyl etherate
catalysed rearrangement of the epoxide in 20 followed
by intramolecular transacetalisation of the cis-isomer of
the resultant ester aldehyde. Reduction of the aldehyde
group in 22 with sodium borohydride in methanol
furnished the hydroxy-ester 23 confirming the trans-
relationship of the ester and aldehyde groups in 22.
Ionic hydrogenation of the ethoxylactone 21 using a
combination of trifluoroacetic acid and triethylsilane
furnished the lactone 24, mp 120–123°C (lit.2b 123–
125°C), [h]2D5 +43.3 (c 1, CHCl3) {lit.2b −41 (c 1.4,
CHCl3)}, a degradation product of a number of thap-
sanes.2 Finally, reduction of the lactone 24 with
diisobutylaluminium hydride furnished the thapsane 1g,
mp 85–87°C (lit.3 85.5–87°C), [h]D25 +40 (c 0.5, CHCl3)
{lit.3 −47 (c 0.16, CHCl3)}. The lactone 24 and the
1
thapsane 1g exhibited H and 13C NMR spectra identi-
cal to those of the compounds derived from Nature,
but exhibited the opposite optical rotation, establishing
the configuration of the natural thapsanes to be oppo-
site from that originally assigned.1,2
In conclusion, we have developed the first enantiospe-
cific approach to an ent-thapsane, which unambigu-
ously established the absolute configuration of the
natural thapsanes as 1S,6S,8S,9S, which is the opposite
to that assigned earlier by the research groups of Ras-
mussen and Grande. Currently, we are investigating the
extension of this methodology to other natural
thapsanes.
† All the compounds exhibited spectroscopic data consistent with their
structures. Yields refer to isolated and chromatographically pure
compounds. Spectral data for the tricyclic compound 9: mp: 68°C.
1
[h]D24 −37.5 (c 1.2, CHCl3). IR (thin film): wmax 1720 cm−1. H NMR
(300 MHz, CDCl3+CCl4): l 4.19 (2H, q, J=7.5 Hz), 2.08 (1H, d,
J=17.5 Hz), 1.82 (1H, d, J=5.7 Hz), 1.75 (1H, d, J=17.5 Hz),
1.80–1.35 (7H, m), 1.31 (3H, t, J=7.2 Hz), 1.22 (3H, s), 1.17 (3H,
s), 0.64 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 206.8 (C), 168.0
(C), 61.2 (CH2), 54.4 (C), 49.9 (CH2), 49.4 (C), 39.5 (CH2), 39.2
(CH2), 38.7 (C), 33.6 (C), 28.3 (CH3), 27.5 (CH3), 23.2 (CH3), 18.7
(CH2), 18.3 (CH2), 14.2 (CH3). For the ketoester 17: [h]2D4 +70.0 (c
Acknowledgements
We thank the DST for financial support, and the CSIR
for the award of a research fellowship to K.A.S.
1.4, CHCl3). IR (thin film): wmax 1753, 1726 cm−1 1H NMR (300
.
MHz, CDCl3+CCl4): l 4.15 (2H, q of AB q, J=10.5 and 7.0 Hz),
3.70 (1H, s), 2.40 and 1.97 (2H, 2×d, J=18.5 Hz, H-9), 1.75–1.35 (6H,
m), 1.27 (3H, t, J=7.0 Hz), 1.24 (3H, s), 1.21 (3H, s), 1.07 (3H, s),
0.86 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 210.8 (C), 169.6
(C), 61.6 (CH), 60.6 (CH2), 53.6 (CH2), 51.2 (C), 40.5 (C), 37.4 (CH2),
37.2 (CH2), 36.4 (C), 28.8 (CH3), 25.4 (CH3), 22.8 (CH3), 18.6 (CH2),
14.5 (CH3), 14.2 (CH3). For the ester 19: [h]2D5 23.6 (c 2.8, CHCl3).
IR (neat): wmax 1745 cm−1. 1H NMR (300 MHz, CDCl3+CCl4): l 4.83
(1H, s), 4.75 (1H, s), 4.08 and 4.04 (2H, q of AB q, J=11.7 and 7.0
Hz), 3.71 (1H, m), 2.47 (1H, q of d, J=16.5 and 3.0 Hz), 1.91 (1H,
d, J=16.5 Hz), 1.60–1.10 (6H, m), 1.21 (3H, t, J=7.0 Hz), 1.03 (6H,
s), 0.92 (3H, s), 0.76 (3H, s). 13C NMR (22.5 MHz, CDCl3): l 174.2
(s), 149.3 (s), 107.9 (t), 59.9 (t), 54.7 (d), 52.5 (s), 48.7 (t), 43.0 (s),
37.6 (t), 36.3 (t), 36.1 (s), 28.6 (q), 25.0 (q), 22.6 (q), 18.8 (t), 14.3 (q),
13.9 (q). For the ethoxylactone 21: mp: 98–100°C. [h]2D5 −71.7 (c 1.66,
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A. Srikrishna, K. Anebousel6y / Tetrahedron Letters 43 (2002) 5261–5264
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