The enantioselective syntheses of bisabolane sesquiterpenes Lepistirone and Cheimonophyllon E

Article abstract of DOI:10.1016/j.tetlet.2005.02.058

The synthetic approach to the bisabolane sesquiterpenes Lepistirone 1 and Cheimonophyllon E 2 involves the transformation of (+)-2-carene (5) into the p-menthane furans 8 and 11. Regio- and stereoselective alkylation, and standard reactions complete the e

Full text of DOI:10.1016/j.tetlet.2005.02.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2397–2398
The enantioselective syntheses of bisabolane sesquiterpenes
Lepistirone and Cheimonophyllon E
Timothy John Brocksom,* Paulo R. Zanotto and Ursula Brocksom
´
Departamento de Quımica, Universidade Federal de Sa˜o Carlos, 13565-905, Sa˜o Carlos-SP, Brazil
Received 31 January 2005; accepted 10 February 2005
Abstract—The synthetic approach to the bisabolane sesquiterpenes Lepistirone 1 and Cheimonophyllon E 2 involves the transfor-
mation of (+)-2-carene (5) into the p-menthane furans 8 and 11. Regio- and stereoselective alkylation, and standard reactions
complete the enantioselective syntheses.
Ó 2005 Elsevier Ltd. All rights reserved.
The bisabolane sesquiterpene Lepistirone (1) is the ma-
jor volatile metabolite isolated from liquid cultures of
Lepista irina (Basidiomycotina), an edible fungal species
with an odor reminiscent of orange blossoms.1 The clo-
sely related Cheimonophyllon E (2) is an antimicrobial
and nematicidal bisabolane isolated from cultures of
the basidiomycete Cheimonophyllum candidissimum.2,3
prenyl side chain, and functional group modifications
via 3 (FG = functional groups) and 4 leading to com-
mercially available (+)-2-carene (5) (Scheme 1).
2-Carene epoxide (6),4,5 obtained from (+)-2-carene (5),6
underwent an isomerization reaction catalyzed by ZrO2–
7
TiO2
generating 2,8-para-menthadienol-1 (4)5,7,8
(Scheme 2, 50% yield for two steps). Allylic chlori-
nation9 with Ca(OCl)2 furnished the chloride 710 in
40–55% yield. Simultaneous hydrolysis11 and cyclization
The structures and relative stereochemistries of 1 and 2
were determined by conventional spectroscopic analy-
ses, and NOESY experiments. The structure of Lepisti-
rone (1) is proposed with its absolute configuration as
depicted, by application of the octant rule, whereas the
structure of Cheimonophyllon E (2) is proposed as the
relative configuration.
HO
HO
O
a
b
c
Cl
We report herein enantioselective syntheses of sesquiter-
penes 1 and 2, based upon disconnection of the a-keto-
5
6
4
7
d
HO
HO
FG
HO
e
O
O
f
O
O
O
O
O
HO
O
O
1
9
8
1
2
3
4
5
Scheme 2. Reagents and conditions: (a) MCPBA, NaHCO3, CH2Cl2,
rt, 4 h; (b) ZrO2–TiO2, dry toluene, 80 °C, 10 min (50% for two steps);
(c) Ca(OCl)2 70%, H2O, dry ice, CH2Cl2, 15 min, 40–55%; (d) HMPA/
H2O, 60 °C, 18 h, 70%; (e) À65 °C, (2 equiv) t-BuLi (0.78 M), (2 equiv)
ZnCl2, 10 min, (CH3)2CHCH2CHO, 10 min, 52%; (f) PDC, CH2Cl2,
rt, 24 h, 67%.
Scheme 1.
Keywords: Lepistirone; Cheimonophyllon; Bisabolane; 2-Carene.
*
Corresponding author. Tel.: +55 16 3351 8213; fax: +55 16 3351
8350; e-mail: brocksom@terra.com.br
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.058

2398
T. J. Brocksom et al. / Tetrahedron Letters 46 (2005) 2397–2398
Finally, PDC oxidation (70% yield) of 13 followed by
deprotection (78% yield) of the acetonide group com-
pleted the synthesis of Cheimonophyllon E (2).
HO
HO
O
HO
O
O
O
a,b
c
d
O
4
The syn epoxidation of 4 is completely stereoselective as
expected by the reaction conditions, and confirmed by
the subsequent reactions of cyclization and specially of
the cis-diol protection. Once again we predict the stereo-
selectivity of the alkylation as being from the convex
face of 12 leading to 13, and thus this synthetic sequence
leads with complete stereoselectivity to the creation of
the four new stereogenic centres of 2.
Cl
10
11
12
e
HO
O
HO
O
O
f,g
O
O
The relative stereochemistries depicted for synthetic 1
and 2 were confirmed by 1H NMR, 13C NMR, IR,
MS and differential NOE spectroscopy, and the spectral
data are identical with those reported in the literature1–3
for the two natural products Lepistirone and Cheimono-
phyllon E.
HO
2
13
Scheme 3. Reagents and conditions: (a) t-BuOOH (90%), VO(acac)2,
benzene, rt, 20 h, 60%; (b) Ca(OCl)2 70%, H2O, dry ice, CH2Cl2, 1 h,
57%; (c) HMPA/H2O, 60 °C, 22 h, 75%; (d) Me2C(OMe)2, PTSA (cat),
acetone, rt, 3 h, 85%; (e) À65 °C (1 equiv) sec-BuLi (0.52 M), (1 equiv)
ZnCl2, 10 min, (CH3)2CHCH2CHO, 10 min, 72%; (f) PDC, CH2Cl2,
rt, 24 h, 70%; (g) PPTS, MeOH, 50 °C, 48 h, 78%.
In conclusion, we have developed short, efficient and
enantioselective syntheses of bioactive sesquiterpenes
Lepistirone (1) (six steps; overall yield 6.7%) and Chei-
monophyllon E (2) (nine steps; overall yield 4.3%) start-
ing from readily available (+)-2-carene.
using water/HMPA produced the cis-fused tetrahydro-
furan 8 in 70% yield.
Acknowledgements
The proposed stereochemistry for 8 is based upon anal-
ysis of the ring junction carbinolic hydrogen being a
broad singlet at d 4.24 ppm (slightly hidden beneath
the AB quartet of the tetrahydrofuran methylene hydro-
gens), and also is expected for mechanistic and stereo-
electronic reasons.
We thank FAPESP, CNPq and CAPES for a fellowship
and financial support.
References and notes
The crucial alkylation of 8 with isovaleraldehyde was
then tested using a modification of EvansÕ procedure12
by exchange of the first formed lithium carbanion to
the organo-zinc species. Thus, reaction of 8 at À65 °C
with 2 equiv of t-butyllithium, 10 min reaction then
addition of 2 equiv of zinc chloride, a further 10 min
reaction time, and then addition of isovaleraldehyde
led to the desired product 9 in 52% yield. The stereo-
chemistry proposed is based upon the expected convex
face approach of the aldehyde to the cis-fused bicyclic
carbanion of 8. Oxidation of the alcohol 9 with PDC
(67% yield) completed the synthesis of Lepistirone (1)
(Scheme 2).
1. Abraham, W.-R.; Hanssen, H.-P.; Urbasch, I. Z. Natur-
forsch 1991, 46c, 169–171.
2. Stadler, M.; Anke, H.; Sterner, O. J. Antibiotics 1994, 47,
1284–1289.
3. Stadler, M.; Anke, H.; Sterner, O. Tetrahedron 1994, 50,
12649–12654.
4. Clark, B. C., Jr.; Chafin, T. C.; Lee, P. L.; Hunter, G. L.
K. J. Org. Chem. 1978, 43, 519–520.
5. Prasad, R. S.; Dev, S. Tetrahedron 1976, 32, 1437–
1441.
6. 2-Carene, 97%, Aldrich product 23,238-6, used without
any purification.
7. Arata, K.; Bledsoe, J. O., Jr.; Tanabe, K. J. Org. Chem.
1978, 43, 1660–1664.
8. Ohloff, G.; Giersch, W. Helv. Chim. Acta 1980, 63, 76–94.
9. Hegde, S. G.; Wolinsky, J. J. Org. Chem. 1982, 47, 3148–
3150.
10. All new compounds gave satisfactory micro-analytical or
high resolution mass spectrum data, and the expected
spectroscopic data.
11. Hutchins, R. O.; Taffer, I. M. J. Org. Chem. 1983, 48,
1360–1362.
12. Evans, D. A.; Andrews, G. C.; Buckwalter, B. J. Am.
Chem. Soc. 1974, 96, 5560–5561.
In the synthesis of Cheimonophyllon E (Scheme 3), ster-
eoselective syn-epoxidation13 of 4 gave an epoxide in
60% yield, which was subjected to allylic chlorination9
with Ca(OCl)2 leading to compound 10 in 57% yield.
The simultaneous hydrolysis11 and cyclization of 10
using water/HMPA furnished tetrahydrofuran 11 in
75% yield, and subsequent protection of the diol func-
tion with 2,2-dimethoxypropane (85% yield) provided
12. Metallation at À65 °C with 1 equiv of sec-butyl-
lithium, exchange to the organozinc species,12 and reac-
tion with isovaleraldehyde led to 13 in 72% yield.
13. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136–6137.