Enantiospecific first total synthesis and assignment of absolute configuration of the sesquiterpene (-)-cucumin H

Article abstract of DOI:10.1021/ol034635p

(Matrix presented) The first total synthesis of the sesquiterpene (-)-cucumin H, a linear triquinane isolated from Macrocystidia cucumis, has been accomplished starting from (R)-limonene employing two different cyclopentannulation methodologies, which in

Full text of DOI:10.1021/ol034635p

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2295-2298
Enantiospecific First Total Synthesis
and Assignment of Absolute
Configuration of the Sesquiterpene
†
(−)-Cucumin H
A. Srikrishna* and Dattatraya H. Dethe
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
ask@orgchem.iisc.ernet.in
Received April 14, 2003
ABSTRACT
The first total synthesis of the sesquiterpene (−)-cucumin H, a linear triquinane isolated from Macrocystidia cucumis, has been accomplished
starting from (R)-limonene employing two different cyclopentannulation methodologies, which in addition to confirming the structure also
established the absolute configuration of the natural product.
Among the cyclopentanoid natural products, linearly fused
triquinane sesquiterpenes have been encountered in increas-
ing numbers from diverse natural sources. The presence of
an interesting tricyclic carbon framework coupled with the
functional group diversity, stereochemical intricacies, and
promising biological activities have sustained a high level
of synthetic interest in this family of natural products.1 In
1998, research groups of Steglich and Anke reported2 the
isolation of eight new linear triquinane sesquiterpenes from
mycelial cultures of the agaric Macrocystidia cucumis, four
belonging to the hirsutane group (cucumins A-D, 1-4),
three to the cucumane group (cucumins E-G, 5-7), and
one to the ceratopicane group (cucumin H, 8). Cucumin H
A-C were found to exhibit high cytotoxic and antimicrobial
(8) is the second member of the ceratopicane group to be
activities. The structure of cucumin H (8) was determined
isolated from Nature, whose first member ceratopicanol (9)
through incisive high-field NMR studies. However, due to
was reported in 19883 by Hanssen and Abraham from the
agar cultures of ascomycete Ceratosystis piceae. Cucumins
(3) Isolation of ceratopicanol: Hanssen, H.-P.; Abraham, W.-R. Tetra-
hedron 1988, 44, 2175. For synthesis, see: Mehta, G.; Karra, S. R. J. Chem.
Soc., Chem. Commun. 1991, 1367. Clive, D. L. J.; Magnuson, S. R.
Tetrahedron Lett. 1995, 36, 15. Baralotto, C.; Chanon, M.; Julliard, M. J.
Org. Chem. 1996, 61, 3576. Paquette, L. A.; Geng, F. J. Am. Chem. Soc.
2002, 124, 9199. Anger, T.; Graalmann, O.; Schroder, H.; Gerke, R.; Kaiser,
U.; Fitjer, L.; Noltemeyer, M. Tetrahedron 1998, 54, 10713. Mukai, C.;
Kobayashi, M.; Kim, I. J.; Hanaoka, M. Tetrahedron 2002, 58, 5225.
† Dedicated with respect and affection to Professor Goverdhan Mehta
on his 60th birthday.
(1) Recent reviews: (a) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97,
671. (b) Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647.
(2) Hellwig, V.; Dasenbrock, J.; Schumann, S.; Steglich, W.; Leonhardt,
K.; Anke, T. Eur. J. Org. Chem. 1998, 73.
10.1021/ol034635p CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/04/2003

the paucity of the material, assignment of the absolute con-
figuration and evaluation of the biological profile were not
addressed. Herein, we report the enantiospecific first total
synthesis of (-)-cucumin H ((-)-8) along with three other
regio- and stereoisomers, which not only confirmed the
stereostructure but also established the absolute configuration
of the sesquiterpene.
Scheme 2a
The presence of an interesting triquinane carbon frame-
work comprised of six quaternary carbon atoms (three sp3
and three sp2) and a γ-hydroxyenone moiety coupled with
its low natural abundance has made cucumin H (8) an
important synthetic target. Retrosynthetically it was envi-
sioned that the Nazarov cyclization based cyclopentannula-
tion of bicyclic ketone 10 provides a convenient route for
cucumin H (Scheme 1). For the enantiospecific synthesis of
Scheme 1
bicyclic ketone 10 containing two vicinal ring junction
quaternary carbon atoms, allyl alcohol 11, derived from
readily and abundantly available monoterpene (R)-limonene,
was chosen as the chiral starting material visualizing the
isopropenyl group as a masked ketone as well as a disposable
chiral director.
a Reagents, conditions, and yields: (a) ref 4; (b) MeC(OEt)3,
EtCO2H, sealed tube, 180 °C, 5 days, 80%; (c) 10% aq NaOH,
MeOH, reflux, 8 h, 94%; (d) (i) (COCl)2, C6H6, rt, 2 h; (ii) CH2N2,
Et2O, rt, 2 h; (e) Cu-CuSO4, c-C6H12, W-lamp, reflux, 5 h, 70%
(from the acid 14); (f) Li, liquid NH3, -33 °C, 15 min, 85%; (g)
pTSA, CH2Cl2, rt, 2 days, 99%; (h) O3/O2, CH2Cl2-MeOH (5:1),
-70 °C; Me2S, rt, 5 h; 90%; (i) (CH2SH)2, BF3‚Et2O, C6H6, 0 °C,
1 h, 80%; (j) Raney Ni, EtOH, reflux, 100%; (k) (i) HCtC-
CH2OTHP, n-BuLi, THF, -78 °C, 6 h, 80%; (ii) PPTS, MeOH,
rt, 6 h, 90%; (l) P2O5, MsOH (4 equiv), rt, CH2Cl2, 1 h, 70%; (m)
NaH, THF, rt, 1 h, MeI, 17 h, 75%; (n) di-tert-butyl chromate,
CCl4, reflux, 9 h, 80%.
The synthetic sequence starting from (R)-limonene (12)
is depicted in Scheme 2. To begin with, (R)-limonene (12)
was converted into allyl alcohol 11 in three steps.4 A Claisen
rearrangement-intramolecular cyclopropanation-regiospe-
cific cyclopropane ring cleavage sequence was contemplated
for the simultaneous creation of the two quaternary carbon
atoms and annulation of the second cyclopentane ring on
cyclopentenylmethanol 11. Thus, Johnson’s ortho ester
Claisen rearrangement5 of allyl alcohol 11 with triethyl
orthoacetate and propionic acid generated the γ,δ-unsaturated
ester 13 in a highly stereoselective manner, which on hy-
drolysis furnished acid 14. Anhydrous copper sulfate-copper
catalyzed decomposition6 of diazo ketone 15, obtained from
acid 14, in refluxing cyclohexane resulted in the intramo-
lecular cyclopropanation leading to stereo- and regiospecific
two new chiral centers, the original chiral center was disposed
of by converting it into a ketone group. Thus, isomerization
of the isopropenyl to isopropylidene group with p-toluene-
sulfonic acid (pTSA) converted compound 17 into 18, [R]25
D
+68 (c 1.9, CHCl3), which on ozonolytic cleavage generated
the diquinane dione 19, mp 108-110 °C, [R]26D -42 (c 1.2,
CHCl3). Controlled thioketalization8 of dione 19 with
formation of the tricyclic ketone 16, [R]25 -115 (c 1.65,
D
CHCl3). Treatment of tricyclic ketone 16 with lithium in
liquid ammonia, predictably,7 furnished bicyclic ketone 17,
[R]27 +140 (c 3, CHCl3), mp 41-43 °C, via selective
D
cleavage of the C-2-C-3 bond. After successfully creating
(4) Srikrishna, A.; Babu, N. C. Tetrahedron Lett. 2001, 42, 4913.
(5) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741.
(6) Stork, G.; Ficini, J. J. Am. Chem. Soc. 1961, 83, 4678. Burke, S. D.;
Grieco, P. A. Org. React. 1979, 26, 361.
ethanedithiol in the presence of boron trifluoride etherate
followed by Raney nickel mediated desulfurization of the
resultant monothioketal 20 furnished bicyclic ketone 10,
(7) Norin, T. Acta Chem. Scand. 1963, 17, 738. Dauben, W. G.; Wolf,
R. E. J. Org. Chem. 1970, 35, 374 and 2361. Srikrishna, A.; Krishnan, K.;
Yelamaggad, C. V. Tetrahedron 1992, 48, 9725.
(8) In addition, a small amount (<5%) of the corresponding bis-thioketal
(easily separable) was also formed.
2296
Org. Lett., Vol. 5, No. 13, 2003

[R]26D -104 (c 2.3, CHCl3). A modified Nazarov cyclization
was contemplated for the annulation of the third cyclopentane
ring.9 Thus, reaction of ketone 10 with the lithium salt of
propargyl THP ether followed by hydrolysis of the THP
Scheme 3
group furnished diol 21, mp 98-100 °C, [R]24 -12.3 (c
D
1.9, CHCl3). After experimenting with different conditions,
it was found that treatment of diol 21 directly with Eaton’s
reagent (15% P2O5 in MsOH)10 in a 0.01 M solution of
methylene chloride furnishes triquinane 22.11 However, when
the reaction was stopped prior to completion, formation of
varying amounts of rearranged dehydrated alcohol 23 was
observed, in addition to triquinane 22. The structure of
alcohol 23 was deduced from its spectral data.12 On the other
hand, dehydration of mono-THP ether 21a with pyridine and
phosphorus oxychloride followed by hydrolysis of the THP
ether generated enynol 24. Reaction of diol 21 with meth-
anesulfonic acid for a short time resulted in the formation
of a 3:1 mixture of alcohols 23 and 24. Formation of the
rearranged alcohol 23 can be readily explained via a series
of bond migrations as depicted in Scheme 3.
Treatment of enynol 24 with Eaton’s reagent furnished
triquinane 22, which is quite expected as it is well established
that enynol 24 will be the first intermediate in the 21 f 22
cyclization sequence. But interestingly, even alcohol 23 on
treatment with Eaton’s reagent furnished triquinane 22.
Formation of triquinane 22 from rearranged alcohol 23 is
surprising, as alcohol 23 has to be converted first into enynol
24 for the cyclization to proceed to furnish triquinane enone
22.
(9) Ramaiah, M. Synthesis 1984, 529.
(10) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38,
4071.
(11) All the compounds exhibited spectral data consistent with their
structures. Yields refer to isolated and chromatographically pure compounds.
Selected spectral data for triquinane 22: [R]26 -54 (c 1.3, CHCl3). IR
D
(neat) νmax/cm-1 1697, 1646. 1H NMR (300 MHz, CDCl3 + CCl4) δ 2.70-
2.60 (2 H, m), 2.50-2.30 (4 H, m), 2.05-1.97 (1 H, m), 1.70-1.20 (5 H,
m), 1.14 (3 H, s), and 1.10 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4)
δ 202.7 (C), 181.3 (C), 153.3 (C), 56.5 (C), 52.2 (C), 47.6 (CH2), 44.0
(CH2), 40.7 (CH2), 38.2 (CH2), 25.3 (CH2), 24.6 (CH3), 24.0 (CH2), 20.5
(CH3). For alcohol 23: [R]26D +11.8 (c 0.85, CHCl3). IR (neat) νmax/cm-1
Introduction of the gem-dimethyl group by one-step double
alkylation transformed enone 22 into enone 25 containing
the complete carbon framework of ceratopicanes. Allylic
oxidation of enone 25 with di-tert-butyl chromate furnished
enedione 26 in a highly regioselective manner.13,14 Regio-
1
3340, 1654. H NMR (300 MHz, CDCl3 + CCl4) δ 5.10 (1 H, br s), 4.25
(2 H, s), 2.63 (1 H, quintet of d, J ) 16.5 and 2 Hz), 2.34 (1 H, quintet of
d, J ) 16.5 and 2 Hz), 2.10-1.90 (1 H, m), 1.82-1.20 (6 H, m), 1.59 (3
H, q, J ) 2 Hz), 1.14 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4) δ
144.7 (C), 121.1 (CH), 92.7 (C), 80.9 (C), 61.2 (C), 51.5 (CH2), 49.7 (C),
46.5 (CH2), 44.0 (CH2), 37.5 (CH2), 24.6 (CH2), 22.9 (CH3), 13.1 (CH3).
For enynol 24: [R]24D -36.5 (c 2.6, CHCl3). IR (neat) νmax/cm-1 3341. 1H
NMR (300 MHz, CDCl3 + CCl4) δ 5.84 (1 H, s), 4.37 (2 H, s), 2.30 (2 H,
ABq, J ) 17.7 Hz), 2.10-1.90 (1 H, m), 1.70-1.20 (6 H, m), 1.04 (3 H,
s), 1.03 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4) δ 134.9 (CH), 132.7
(C), 88.3 (C), 82.6 (C), 59.7 (C), 51.7 (CH2), 49.2 (C), 48.5 (CH2), 44.3
Scheme 4a
(CH2), 38.9 (CH2), 24.8 (CH3), 23.6 (CH2), 21.6 (CH3). For enone 25: [R]27
D
1
-57 (c 1, CHCl3). IR (neat) νmax/cm-1 1698, 1648. H NMR (300 MHz,
CDCl3 + CCl4) δ 2.36 (2 H, s), 2.27 (2 H, s), 2.05-1.95 (1 H, m), 1.70-
1.20 (5 H, m), 1.14 (3 H, s), 1.11 (6 H, s), and 1.10 (3 H, s). 13C NMR (75
MHz, CDCl3 + CCl4) δ 207.7 (C), 177.9 (C), 150.7 (C), 56.2 (C), 52.5
(C), 50.3 (C), 48.0 (CH2), 44.3 (CH2), 42.3 (CH2), 38.2 (CH2), 25.7 (CH3),
25.3 (CH3), 24.8 (CH3), 24.3 (CH2), 20.7 (CH3). For enedione 26: [R]24
D
-5.3 (c 0.95, CHCl3). Mp 88-90 °C. IR (neat) νmax/cm-1 1704. 1H NMR
(300 MHz, CDCl3 + CCl4) δ 2.45 (2 H, s), 2.00 (2 H, dd, J ) 12.9 and 6.3
Hz), 1.65-1.30 (3 H, m), 1.27 (3 H, s), 1.20 (3 H, s), 1.18 (3 H, s), 1.13
(3 H, s), 1.20-0.90 (1 H, m). 13C NMR (75 MHz, CDCl3 + CCl4) δ 210.3
(C), 209.0 (C), 173.5(C), 167.6 (C), 64.7 (C), 51.4 (C), 49.7 (C), 39.7 (CH2),
36.8 (CH2), 36.7 (CH2), 25.5 (CH3), 25.2 (CH3), 23.4 (CH2), 20.1 (CH3),
19.2 (CH3). For hydroxyenone 27: [R]25 -67 (c 0.7, CHCl3). IR (neat)
D
ν
max/cm-1 3402, 1680, 1644. 1H NMR (300 MHz, CDCl3 + CCl4): δ 4.51
a Reagents, conditions, and yields: (a) NaBH4, CeCl3‚7H2O,
MeOH, 0 °C, 1 h, 95%; (b) PPh3, EtOOCNdNCOOEt, p-nitro-
benzoic acid, THF, rt, 8 h, 85%; (c) K2CO3, MeOH, rt, 6 h, 95%;
(d) LiAlH4, THF, 0 °C, 5 min, 70%.
(1 H, br s), 2.45 and 2.26 (2 H, 2 × d, J ) 18.3 Hz), 2.16-2.00 (2 H, m),
1.70-1.00 (5 H, m), 1.12 (12 H, s). 13C NMR (75 MHz, CDCl3 + CCl4)
δ 208.2 (C), 177.3 (C), 150.1 (C), 82.0 (CH), 60.2 (C), 52.3 (C), 50.2 (C),
39.8 (CH2), 37.8 (CH2), 34.9 (CH2), 25.8 (CH3), 25.0 (CH3), 24.5 (CH2),
23.1 (CH3), 20.6 (CH3). For epicucumin H 30: [R]25 +17 (c 1, CHCl3).
D
IR (neat) νmax/cm-1 3421, 1681, 1636. 1H NMR (300 MHz, CDCl3) δ 4.35
(1 H, s), 2.27 and 2.13 (2 H, 2 × d, J ) 15.9 Hz), 1.96 (1 H, dd, J ) 12.6
and 5.4 Hz), 1.87 (1 H, dd, J ) 11.7 and 5.3 Hz), 1.70-0.90 (5 H, m),
1.27 (3 H, s), 1.12 (3 H, s), 1.11 (3 H, s), and 1.09 (3 H, s). 13C NMR (75
MHz, CDCl3) δ 212.9 (C), 185.4 (C), 146.7 (C), 80.6 (CH), 62.9 (C), 51.3
(C), 47.8 (C), 39.1 (CH2), 37.8 (CH2), 36.5 (CH2), 27.8 (CH3), 22.9 (CH2),
22.2 (CH3), 21.1 (CH3), 19.3 (CH3).
and stereoselective reduction of enedione 26 with sodium
borohydride-cerium chloride heptahydrate furnished alcohol
(13) Kent, G. J.; Wallis, E. S. J. Org. Chem. 1959, 24, 1235.
(14) A reduction-protection-allylic oxidation-deprotection protocol
was also explored for the regiocontrolled conversion of the enone 25 into
cucumin H, but was unsuccessful.
(12) The structure of alcohol 23 was further confirmed by the single-
crystal X-ray diffraction analysis of the p-nitrobenzoate ester of alcohol 23
(CCDC deposition number CCDC 201351)
Org. Lett., Vol. 5, No. 13, 2003
2297

27, which is isomeric to cucumin H (8). To unambiguously
establish the stereochemistry of alcohol in 27, it was
converted into p-nitrobenzoate 28 employing a Mitsunobu
inversion.15 The single-crystal X-ray structure16 of 28
unambiguously established not only the structure of 28 but
also the regioselectivity in the allylic oxidation (25 f 26)
and sodium borohydride (26 f 27) reactions. Hydrolysis of
chromatography on silica gel. The stereochemistry of the
alcohol group in 8 and 30 was ascertained on the basis of
the chemical shift due to the CHOH signal (δ 4.51 for 8
1
and δ 4.35 for 30) in the H NMR spectrum in analogy to
that in alcohols 27 and 29 (δ 4.51 for 27 and δ 4.33 for 29).
The synthetic sample (-)-8, [R]23 -26 (c 1, CHCl3) {lit.2
D
[R]18D -25 (c 1.03, CHCl3)}, exhibited the UV, IR, 1H and
13C NMR (in methanol-d4), and mass spectra, as well as the
sign of the CD curves identical with those of the natural
cucumin H, thus confirming the stereostructure of the natural
product as well as establishing its absolute configuration.
In conclusion, we have accomplished the first total
synthesis of the sesquiterpene (-)-cucumin H (8) along with
three other regio- and stereoisomers 27, 29, and 30, which
in addition to confirming the structure of the molecule also
established its absolute configuration. In the process we have
observed an interesting reversal in the regioselectivity in the
reduction17 of enedione 26 (C 7 vs C 3 ketones) using sodium
borohydride-cerium chloride vs lithium aluminum hydride.
Figure 1. X-ray crystal structure of p-nitrobenzoate 28.
Acknowledgment. We thank Professor Steglich for pro-
viding the copies of the spectra (UV, IR, 1H and 13C NMR,
mass, and CD) of the natural cucumin H for comparison
purposes. We thank the CCD facility of I.I.Sc., Mr. U. Singh
for help in the determination of the structure of the p-ni-
trobenzoate of alcohol 23, and Dr. G. N. Sastry for carrying
out the theoretical calculations.
the ester in p-nitrobenzoate 28 furnished the corresponding
alcohol 29. Finally, controlled reduction of enedione 26 with
lithium aluminum hydride furnished a 4:1 mixture of
cucumin H (8) and epicucumin H (30) via regioselective
reduction of the C-3 ketone, which were separated by column
Supporting Information Available: X-ray crystallo-
graphic data for compound 28. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) Hughes, D. L. Org. React. 1992, 42, 335.
(16) Crystal data for the p-nitrobenzoate 28: Structure was solved by
direct methods (SIR92). Refinement was by full-matrix least-squares
procedures on F2 with use of SHELXL-97. Crystal system monoclinic, space
group P2(1). Cell parameters: a ) 17.449(5) Å, b ) 11.559(3) Å, c )
17.582(5) Å, â ) 117.88°, V ) 3134.85 Å3, Z ) 6, F(calcd) ) 1.22 g
cm-3, F(000) ) 1236, µ ) 0.09 mm-1, λ ) 0.7107 Å. R1 ) 0.0524 for
4912 Fo > 4σ(Fo) and 0.0875 for all 7649 data. wR2 ) 0.1228, GOF )
0.878. There are three independent molecules in the asymmetric unit. An
ORTEP drawing of compound 28 with a 50% ellipsoidal probability level
is shown in Figure 1 (only one molecule is shown and hydrogen atoms are
removed for clarity). Crystallographic data are being deposited with the
Cambridge Crystallographic Data Center (CCDC 201351)
OL034635P
(17) Theoretical calculations (MNDO and AM1 level) indicated that exo
sides of both the C 3 and C 7 ketones in 26 are equally preferred for the
hydride attack, which is followed by the endo face of the C 3 ketone,
whereas the endo face of the C 7 ketone is hindered for the hydride attack.
However, the origin of the total difference in regioselectivity between the
sodium borohydride-cerium chloride and lithium aluminum hydride in the
reduction of 26 is not clear.
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Org. Lett., Vol. 5, No. 13, 2003