Total synthesis of (+)-kuhistaferone

Article abstract of DOI:10.1016/j.tetlet.2004.12.129

The first, enantiocontrolled total synthesis of (+)-kuhistaferone was achieved using an aluminum-based Lewis acid mediated rearrangement for the construction of a quaternary stereogenic center, an ene-reaction and an intramolecular Horner-Emmons reaction

Full text of DOI:10.1016/j.tetlet.2004.12.129

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1269–1271
Total synthesis of (+)-kuhistaferone
Mari Fujita, Mitsuru Shindo and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Received 2 December 2004; revised 20 December 2004; accepted 24 December 2004
Abstract—The first, enantiocontrolled total synthesis of (+)-kuhistaferone was achieved using an aluminum-based Lewis acid medi-
ated rearrangement for the construction of a quaternary stereogenic center, an ene-reaction and an intramolecular Horner–Emmons
reaction as the key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
Kuhistaferone (1), an unusual sesquiterpene isolated
from extracts of the fruit of the Uzbekistan medicinal
plant Ferula kuistanica by Takaishi and co-workers,1
was discovered to have moderate cytotoxicity against
the human colon tumor cell line HCT116. The entire
structure of kuhistaferone was inferred from spectral
properties, mainly extensive NMR studies, and pro-
posed to have a bicyclic lactol structure with five contig-
uous stereogenic centers, including two quaternary
carbons. However, the absolute structure of 1 has
yet to be confirmed. The intriguing structural features
coupled with the promising biological profile of this
compound inspired us to develop an efficient and
enantioselective strategy for the synthesis of the natural
product. We report here the first, enantiocontrolled total
synthesis of (+)-kuhistaferone, thereby establishing its
absolute stereochemistry (Fig. 1).
We thought that kuhistaferone (1) could be derived
from the bicyclic lactone 2 via diastereoselective intro-
duction of the oxygen functionality at C-6 because of
the convex structure of the bicyclic system. The lactone
2 could be assembled by way of an intramolecular Hor-
ner–Emmons reaction starting from the cyclopentanone
3, which could be prepared from the alkenyl aldehyde 4
by an intramolecular ene-reaction followed by oxida-
tion. The crucial quaternary stereogenic center at the
future C-1 with the S configuration in aldehyde 4 could
be constructed by Lewis acid mediated rearrangement2,3
of the epoxide 5 prepared from geraniol (Scheme 1).
Reaction of the epoxy silyl ether 5, prepared by Kat-
suki–Sharpless asymmetric epoxidation of geraniol fol-
lowed by silylation, with 2 equiv of methylaluminum
bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) in
methylene chloride (CH2Cl2) at ꢀ78 °C for 1 h, pro-
ceeded via configuration inversion to provide the alde-
hyde 62 with the S configuration in 98% yield (>95%
ee). The quaternary stereogenic center of 1 was thus con-
structed. Horner–Emmons reaction using diethyl (2-
oxopropyl)phosphonate4 followed by selective reduction
of the unsaturated double bond with triethylsilane and a
catalytic tris(triphenylphosphine) rhodium chloride
(WilkinsonÕs catalyst)5 cleanly provided the ketone 7.
After protection of the ketone, desilylation followed
by Dess–Martin oxidation of 8 gave the aldehyde 4,
which was subjected to an intramolecular ene-reaction6
using a variety of Lewis acid catalysts. Of these, trimeth-
ylaluminum provided the best results. Thus, treatment
of a solution of 4 in CH2Cl2 with 1.5 equiv of Me3Al
at ꢀ78 °C–0 °C for 8 h produced the cyclopentanol 9
in 77% yield as a mixture of diastereoisomers along with
the methylation product 10 in 19% yield. To prevent the
Figure 1.
Keywords: Terpene; Kuhistaferone; Quaternary carbon; Ene-reaction;
Intramolecular Horner–Emmons reaction.
*
Corresponding author. Tel.: +81 88 633 7287; fax: +81 88 633 9575;
e-mail: shishido@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.129

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M. Fujita et al. / Tetrahedron Letters 46 (2005) 1269–1271
Scheme 1. Retrosynthetic analysis.
formation of 10, the reaction was conducted with Et3Al;
however, reduction of the formyl group occurred to give
the corresponding alcohol 8 in 95% yield. Dess–Martin
oxidation of 9 followed by reduction provided the cyclo-
pentanone 3. Since direct a-hydroxylation using stan-
dard procedures gave unsatisfactory results, we
decided to use a two-step sequence. Treatment of 3 with
LDA and TMSCl produced the silyl enol ether, which
was reacted with m-CPBA to give the a-hydroxy ketone
11 as a 3:2 mixture of diastereoisomers quantitatively
from 3. Fortunately, the isomers could be separated
by silica gel column chromatography; however, their
stereochemistry could not be determined at this stage.
The slightly predominant isomer 11a was then con-
densed with diethyl phosphonoacetic acid and DCC
using catalytic 4-dimethylaminopyridine (4-DMAP) to
give the phosphonate, which was subjected to the intra-
molecular Horner–Emmons reaction7 with lithium bro-
mide and triethylamine in refluxing THF to provide
cleanly the bicyclic butenolide 12 in 80% yield for the
two steps. Catalytic hydrogenation produced the lactone
2, whose structure was established by NOESY experi-
ments as shown in Scheme 2. The major isomer of 11
turned out to be the desired one. The minor isomer
11b was recycled into the ketone 3 in 98% yield by
sequential dehydration (thionyl chloride and pyridine)
and catalytic reduction of the resulting enone 13.
With the desired bicyclic lactone 2 in hand, we next
examined the introduction of the oxygen functionality
at the C-6 position. Exposure of 2 to a-hydroxylation
conditions using ( )-trans-2-(phenylsulfonyl)-3-phenyl-
oxaziridine8 and KHMDS in THF at ꢀ78 °C resulted
in the formation of 14 as the single product. The stereo-
chemistry at C-6 was determined to be S, the undesired
isomer, by an NOE correlation between the C-6 methine
and the C-13 methyl protons. For the inversion of the
configuration at C-6, an oxidation–reduction sequence
turned out to be the best choice. Thus, Dess–Martin oxi-
dation of 14 followed by reduction with NaBH4 pro-
vided the a-hydroxylactone 15 as the single product
with the desired R configuration at C-6 (NOE between
C6-H and C5-H) in 90% yield. Reduction of 15 with di-
isobutylaluminum hydride followed by immediate treat-
ment with p-toluenesulfonic acid in MeOH afforded
the hydroxy acetal 16 as a mixture of diastereoisomers,
which was condensed with p-methoxymethyloxybenzoic
acid9 in the presence of DCC and 4-DMAP to provide
Scheme 2. Reagents and conditions: (a) CH3COCH2P(O)(OEt)2, NaH, DME, reflux, 8 h, 80%; (b) Et3SiH, ClRh(Ph3P)3, CH2Cl2, reflux, 4 h, 94%;
(c) ethylene glycol, p-TsOH, benzene, reflux, 4 h, 93%; (d) n-Bu4NF, THF, reflux, 8 h; (e) Dess–Martin periodinane, CH2Cl2, rt, 15 min, 93% for the
two steps; (f) Me3Al, CH2Cl2, ꢀ78 to 0 °C, 8 h, 77%: (g) Dess–Martin periodinane, CH2Cl2, rt, 15 min; (h) HCO2NH2, 10% Pd–C, MeOH, rt, 4 h,
88% for the two steps; (i) LDA, TMSCl, THF, ꢀ78 °C, 0.5 h; (j) m-CPBA, CH2Cl2, rt, 4 h, quant. for the two steps; (k) (EtO)2P(O)CH2CO2H, DCC,
4-DMAP, CH2Cl2, reflux, 24 h; (l) LiBr, Et3N, THF, reflux, 2 h, 80% for the two steps; (m) H2, 10% Pd–C, EtOH, rt, 2 h, quant.; (n) SOCl2, pyridine,
rt, 4 h; (o) H2, 10% Pd–C, EtOH, rt, 3 h, 98% for the two steps.

M. Fujita et al. / Tetrahedron Letters 46 (2005) 1269–1271
1271
Scheme 3. Reagents and conditions: (a) ( )-trans-2-(phenylsulfonyl)-3-phenyloxaziridine, KHMDS, THF, ꢀ78 °C, 1 h; (b) Dess–Martin
periodinane, CH2Cl2, rt, 15 min, 70% for the two steps; (c) NaBH4, MeOH, rt, 5 min, 90%; (d) i-Bu2AlH, hexane, Et2O, ꢀ78 °C, 1 h then p-
TsOH, MeOH, rt, 4 h, 70%; (e) p-methoxymethyloxybenzoic acid, DCC, 4-DMAP, CH2Cl2, rt, 24 h; (f) 6 N-HCl, THF, reflux, 2 h, 82% for the two
steps.
the penultimate ester 17. Finally, acidic hydrolysis of
17 in refluxing THF produced (+)-kuhistaferone (1),
16209001) from the Japan Society for the Promotion
of Science.
25
D
25
D
½aꢁ +12.5 (c 0.81, MeOH) {lit.1 ½aꢁ +10.1 (c 0.77,
MeOH)}, in 82% yield for the two steps after separation
of the C-7 epimer (11% yield). The spectral data as well
as TLC behavior were in agreement with those for the
natural kuhistaferone (Scheme 3).
References and notes
1. Tamemoto, K.; Takaishi, Y.; Kawazoe, K.; Honda, G.; Ito,
M.; Kikuchi, F.; Takeda, Y.; Kodzhimatov, O. K.;
Ashurmotov, O.; Shimizu, K.; Nagasawa, H.; Uto, Y.;
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1998, 9, 356–361.
3. Omodani, T.; Shishido, K. J. Chem. Soc., Chem. Commun.
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3133.
5. Ojima, I.; Kogure, T. Tetrahedron Lett. 1972, 49, 5035–
5038.
In summary, we have completed the first enantioselec-
tive total synthesis of the optically pure, natural enantio-
mer of (+)-kuhistaferone. The key steps include Lewis
acid mediated rearrangement of the epoxide for the
construction of the quaternary stereogenic center and
intramolecular ene-reaction and Horner–Emmons cycli-
zation. Because of the convex nature of the substrate
molecule 2, the C-6 stereogenic center was created using
an oxidation–reduction sequence. In addition, the abso-
lute configuration was established to be (1R,4R,5S,
6R,7R) by the present total synthesis. The synthetic
route developed here is general and efficient and would
be applicable to other related molecules.
6. Andersen, N. H.; Hadley, S. W.; Kelly, J. D.; Bacon, E. R.
J. Org. Chem. 1985, 50, 4144–4151.
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Acknowledgements
9. Lampe, J. W.; Biggers, C. K.; Defauw, J. M.; Foglesong, R.
J.; Hall, S. E.; Heerding, J. M.; Hollinshead, S. P.; Hu, H.;
Hughes, P. F.; Jagdmann, G. E., Jr.; Johnson, M. G.; Lai,
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We thank Professor Yoshihisa Takaishi and Dr.
Kazuyoshi Kawazoe of our Department for providing
us with the sample of natural kuhistaferone and its spec-
tral data. This work was supported financially by a
Grant-in-Aid for Scientific Research (A) (No.