Enantioselective total synthesis of the novel tricyclic sesquiterpene (-)-sulcatine G. absolute configuration of the natural product

Article abstract of DOI:10.1016/S0040-4039(02)00534-8

An enantioselective total synthesis of (-)-sulcatine G 4 from the readily available (+)-diquinane diol 6 has been accomplished. This leads to the establishment of the absolute configuration of the natural product (+)-sulcatine G as 1.

Full text of DOI:10.1016/S0040-4039(02)00534-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3319–3321
Enantioselective total synthesis of the novel tricyclic
sesquiterpene (−)-sulcatine G. Absolute configuration of the
natural product
Goverdhan Mehta* and K. Sreenivas
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 January 2002; revised 12 February 2002; accepted 15 March 2002
Abstract—An enantioselective total synthesis of (−)-sulcatine G 4 from the readily available (+)-diquinane diol 6 has been
accomplished. This leads to the establishment of the absolute configuration of the natural product (+)-sulcatine G as 1. © 2002
Published by Elsevier Science Ltd.
During the past decade, novel terpene skeleta embody-
ing the 4-5-5 ring fused tricarbocyclic core have been
encountered in Nature from diverse sources. Among
the very few known examples of terpenoid natural
products bearing this ring system are sulcatine G 1
from a Basidiomycetes fungi,1 kelsoene 2 from a tropi-
cal marine sponge Cymbastela hooperi,2a liverworts
Ptychanthus striatus,2b,c Calypogeia muelleriana2d and
Tritomaria quinquedentata2e and poduran 3 from the
springtail Podura aquatica.3 The structural novelty and
interesting biosynthetic origin of these natural products
have aroused considerable synthetic interest in the past
few years.4,5 We too have been enticed by these natural
products and have accomplished the total synthesis of
racemic, (+)- and (−)-kelsoene 2.4a–c Continuing our
efforts in the area, a total synthesis of racemic sulcatine
G 1 has been reported recently by us,5 fully securing its
formulation which had been earlier deduced1 mainly
from the analysis of the NMR data. However, the
absolute configuration of sulcatine G remains unknown
as the functionality profile of the natural product does
not permit ready recourse to chiro-optical methods of
absolute configuration determination. Herein, we wish
to describe an enantioselective synthesis of (−)-sulcatine
G 4, which establishes the absolute configuration of the
naturally occurring (+)- sulcatine G as 1.
We have recently shown that endo,endo-cis-bicy-
clo[3.3.0]octane-2,6-diol rac-6, obtained in two steps
from commercially available 1,5-cyclooctadiene 5 via
Pd2+-mediated transannular diacetoxylation and
hydrolysis,6 on lipase-catalyzed enantiomer selective
transesterification in an organic medium furnished diol
(+)-6 (>98% ee) and diacetate (+)-7 (>99% ee) in
preparatively useful yields (Scheme 1).4c For our pro-
jected enantioselective synthesis of sulcatine G, diol
(+)-6 was employed and elaborated to diquinane ketone
(−)-9, through the intermediacy of (−)-8, as described
by us recently5 (Scheme 2).7 This is the first enantio-
selective preparation of (−)-9, which in racemic form has
been previously employed in the synthesis of triquinane
natural products8 and may find further applications in
chiral synthesis of terpenoid natural products.
Diquinane (−)-9 was further elaborated to the a-car-
bomethoxycyclopentenone (−)-10 as shown in Scheme
3.7 Further evolution of (−)-10 to the tricyclic bridge-
head vinyl compound (−)-11, involved [2+2]-photocy-
cloaddition as a pivotal step to append the cyclobutane
ring and generate the desired 4-5-5 fused tricyclic
framework. With tricyclic (−)-11 having all the 15-car-
bons of the natural product in hand, the remaining task
was to harness the vinyl group to access the oxy-func-
HO
O
H
OH
H
O
H
H
HO
OH
H
H
5
H
H
H
H
(+)-Sulcatine G 1
(-)-Sulcatine G 4
(+)-Kelsoene 2
Poduran 3
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00534-8

3320
G. Mehta, K. Sreeni6as / Tetrahedron Letters 43 (2002) 3319–3321
HO
H
HO
H
AcO
H
H
a
b
+
H
OH
H
OH
OAc
(±)-6
(1R,2S,5R,6S)-(+)-6
(1S,2R,5S,6R)-(+)-7
5
>98%ee
>99%ee
Scheme 1. Reagents and conditions: (a) i. PdCl2, Pb(OAc)4, AcOH, rt, 72 h, 70%; ii. KOH, MeOH, rt, 3 h, 95%; (b) vinyl acetate,
t
Amano lipase PS-30, BuOMe, rt, 6 days, 82%.
BnO
HO
BnO
H
H
H
H
a
b
H
H
O
O
OH
(+)-6
(-)-8
c
BnO
HO
O
H
H
H
H
e
d
S
H
H
S
(-)-9
t
Scheme 2. Reagents and conditions: (a) i. NaH, BnBr, Bu4N+I−, THF, rt, 12 h, 87%; ii. PCC, DCM, rt, 94%; (b) KOtBu, BuOH,
MeI, 0°C–rt, 8 h, 91%; (c) i. (CH2SH)2, PTSA, benzene, 96%; (d) Raney-Ni, EtOH, reflux, 6 h, 92%; (e) PCC, DCM, rt, 3 h, 90%.
O
H
O
H
O
H
H
a
b
MeO2C
MeO2C
H
H
(-)-9
(-)-10
c
O
AcO
HO
H
H
H
H
H
MeO2C
Cl
HO
e
HO
d
H
Cl
f
AcO
AcO
HO
H
H
H
H
H
O
O
g
h
AcO
HO
H
(-)-11
(-)-12
(-)-Sulcatine G 4
Scheme 3. Reagents and conditions: (a) i. NaH, (MeO)2CO, benzene, reflux, 5 h, 85%; ii. NaH, PhSeCl, THF, 0°C, 15 min; iii. 30%
H2O2, DCM, 0°C, 15 min, 82% (two steps); (b) i. MeMgI, CuI, Et2O, −10°C, 2 h, 96%; ii. NaH, PhSeCl, THF, 0°C, 15 min; iii.
30% H2O2, DCM, 0°C, 15 min, 50%, (two steps); (c) trans-1,2-dichloroethylene, C6H12, hw, Pyrex, rt, 6 h, 95%; (d) i. DIBAL-H,
t
DCM, rt, 3 h, ii. sodium naphthalenide, DME, rt, 1 h; iii. H2, PtO2, EtOAc, 1 h, 60% (three steps); (e) i. BDMS-Cl, imidazole,
DMAP, DCM, 8 h, rt, 92%; ii. Ac2O, DMAP, DCM, rt, 20 h, 100%; iii. 2N H2SO4, MeOH–H2O (4:1), rt, 2 h, 90%; (f) i. PCC,
DCM, rt, 2 h, 91%; ii. MePPh3I, KOtBu, THF, 0°C, 10 min, 92%; (g) i. OsO4, NMMO, Me2CO–H2O (4:1), rt, 2 h, 86%; ii. Ac2O,
DMAP, DCM, 0°C, 30 min, 100%; iii. PCC, DCM, rt, 6 h, 77%; (h) i. Sc(OTf)3, MeOH–H2O (4:1), 47°C, 8 h; ii. 8%
KOH–MeOH, −10°C, 3 h, 61% (two steps).

G. Mehta, K. Sreeni6as / Tetrahedron Letters 43 (2002) 3319–3321
Soc., Perkin Trans. 1 1993, 2723.
3321
tionalization present in the natural product and sulcatine
G diacetate (−)-12 was readily realized, Scheme 3.7
Finally, acetate hydrolysis as reported previously5 fur-
nished (−)-sulcatine G 4, [h]D −40 (c 0.25, CHCl3), which
was spectroscopically identical with the natural product
but had opposite specific rotation to that reported for the
naturally occurring sulcatine G 1 [h]D +44.5 (c 0.15,
CHCl3).1 This established the absolute configuration of
the natural product as 1.
2. (a) Konig, G.; Wright, A. D. J. Org. Chem. 1997, 62,
3837; (b) Nabeta, K.; Yamamoto, K.; Hashimoto, M.;
Koshino, H.; Funatsuki, K.; Katoh, K. Chem. Commun.
1998, 1485; (c) Hashimoto, T.; Ikeda, H.; Takaoka,
S.; Tanaka, M.; Asakawa, Y. Phytochemistry 1999, 52,
501; (d) Warmers, U.; Wihstutz, K.; Bulow, N.; Fricke,
C.; Konig, W. A. Phytochemistry 1998, 49, 1723; (e)
Warmers, U.; Konig, W. A. Phytochemistry 1999, 52,
1519.
In summary, we have outlined a stereo- and enantiocon-
trolled synthesis of the sesquiterpene (−)-sulcatine G 4
from a readily available chiral diquinane diol (+)-6, which
unambiguously establishes the absolute configuration of
the natural product as depicted in 1. Since, sulcatine G
(+)-1 is biogenetically related to illudins and related
sesquiterpenoids which are also found in Basidiomycetes
fungi, determination of the absolute configuration of 1
has a bearing on the absolute configuration of other
members of this group.
3. Schulz, S.; Messer, C.; Dettner, K. Tetrahedron Lett.
1997, 38, 2077.
4. (a) Mehta, G.; Sreenivas, K. Tetrahedron Lett. 1999, 40,
4877; (b) Mehta, G.; Sreenivas, K. Synlett 1999, 555; (c)
Mehta, G.; Sreenivas, K. Tetrahedron Lett. 2001, 42,
2855; (d) Piers, E.; Orellana, A. Synthesis 2001, 2138; (e)
Fietz-Razavian, S.; Schulz, S.; Dix, I.; Jones, P. G.
Chem. Commun. 2001, 2154.
5. Mehta, G.; Sreenivas, K. Chem. Commun. 2001, 1892.
6. (a) Henry, P. M.; Davies, M.; Ferguson, G.; Philips, S.;
Restivo, R. Chem. Commun. 1974, 112; (b) Mehta, G.;
Rao, K. V. Ind. J. Chem. 1991, 30B, 457.
Acknowledgements
7. All new compounds reported here were duly character-
ized on the basis of spectroscopic (IR, 1H and 13C
NMR) and analytical data and their specific rotations
were determined.
We thank JNCASR for the financial support. One of us
(K.S.) thanks UGC for the award of a research fellowship.
8. Cossy, J.; Belotti, D.; Pete, J. P. Tetrahedron Lett. 1987,
28, 4547. For
polyquinane natural products, see: Mehta, G.; Srikr-
a recent review on the synthesis of
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