Total synthesis of (±)-kalihinol C

Article abstract of DOI:10.1021/ol049918b

The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated from Acanthella sp., is reported. The decalin framework was established via an intramolecular Diels-Alder cycloaddition and subsequently functionalized through a series of substrate-controlled diastereoselective transformations to install the tertiary isonitrile, β-hydroxy isonitrile, and pendant tetrahydrofuranyl ring.

Full text of DOI:10.1021/ol049918b

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1123-1126
Total Synthesis of (±)-Kalihinol C
Ryan D. White, Gregg F. Keaney, Corin D. Slown, and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
john.wood@yale.edu
Received January 13, 2004
ABSTRACT
The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated from Acanthella sp., is reported. The decalin framework was
established via an intramolecular Diels−Alder cycloaddition and subsequently functionalized through a series of substrate-controlled
diastereoselective transformations to install the tertiary isonitrile, â-hydroxy isonitrile, and pendant tetrahydrofuranyl ring.
Kalihinol C (1), isolated by Scheuer and co-workers in 1984
from the sponge Acanthella sp., is a member of a richly
functionalized family of marine diterpenoids known as the
kalihinanes.1 This class of natural products includes more
than 40 members and is characterized by a highly function-
alized tricyclic core containing isonitrile, isothiocyanate,
formamide, and/or chlorine moieties. Several kalihinanes
have demonstrated anthelmintic,1,2 antifouling,1,3 antimicro-
bial,1 antifungal,1,4 and, mostly notably, potent antimalarial
activity.5 While the antimalarial activity of kalihinol C has
yet to be determined, the isonitrile-containing kalihinanes
that have been tested for in vitro antimalarial activity were
found to be nanomolar inhibitors of the malaria parasite,
Plasmodium falciparum.5,6
The initial retrosynthetic analysis of kalihinol C was
centered upon three major structural features: the pendant
tetrahydrofuran, the isonitriles, and the trans-decalin core
(Figure 1). On the basis of previous model studies and the
(1) (a) Chang, C. W. J.; Patra, A.; Roll, D. M.; Scheuer, P. J.; Matsumoto,
G. K.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 4644. (b) Chang, C. W. J.;
Patra, A.; Baker, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1987, 109, 6119.
(c) Shimomura, M.; Miyaoka, H.; Yamada, Y. Tetrahedron Lett. 1999, 40,
8015. (d) Fusetani, N.; Yasumuro, K.; Kawai, H.; Natori, T.; Brinen, L.;
Clardy, J. Tetrahedron Lett. 1990, 31, 3599. (e) Rodriguez, J.; Nieto, R.
M.; Hunter, L. M.; Diaz, M. C.; Crews, P.; Lobkovsky, E.; Clardy, J.
Tetrahedron 1994, 50, 11079. (f) Okino, T.; Yoshimura, E.; Hirota, H.;
Fusetani, N. J. Nat. Prod. 1996, 59, 1081. (g) Patra, A.; Chang, C. W. J.;
Scheuer, P. J.; Vanduyne, G. D.; Matsumoto, G. K.; Clardy, J. J. Am. Chem.
Soc. 1984, 106, 7981.
(2) Alvi, K. A.; Tenenbaum, L.; Crews, P. J. Nat. Prod. 1991, 54, 71.
(3) (a) Hirota, H.; Tomono, Y.; Fusetani, N. Tetrahedron 1996, 52, 2359.
(b) Fusetani, N. J. Nat. Toxins 1996, 5, 249.
(4) Trimurtulu, G.; Faulkner, D. J. J. Nat. Prod. 1994, 57, 501.
(5) Miyaoka, H.; Shimomura, M.; Kimura, H.; Yamada, Y.; Kim, H. S.;
Wataya, Y. Tetrahedron 1998, 54, 13467.
Figure 1. Retrosynthetic analysis.
conformationally rigid nature of trans-decalins, the topology
enforced by the decalin carbocycle was expected to influence
introduction of the remaining functionality through a series
of substrate-controlled, diastereoselective reactions.7 The
pendant tetrahydrofuran was envisioned as arising from
10.1021/ol049918b CCC: $27.50 © 2004 American Chemical Society
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addition to a methyl ketone (3) and subsequent 5-exo cycli-
zation of bishomoallylic alcohol 2. The C(4)/C(5) functional-
ity would derive from a trans diaxial opening of an epoxide
with a nucleophilic nitrogen source. The equatorial nitrogen
at C(10) would be installed by aziridination of exo-methylene
3. An intramolecular Diels-Alder cycloaddition was ex-
pected to deliver the decalin core, and triene 4 could be
derived from the coupling of â-hydroxy ester 5 and alkyl
bromide 6.
Scheme 2
To set the relative stereochemistry between C(7) and
C(11), â-hydroxy ester (()-5 was treated with lithium
diisopropylamide followed by alkyl bromide 6 (Scheme 1).8,9
Scheme 1
by oxidation with pyridinium chlorochromate afforded cis-
decalin 10 in 65% overall yield from 9 with 5:1 diastereo-
selectivity.12 In the course of screening oxidants, a clear
correlation was observed between the Lewis acidity of the
reagent and diastereoselectivity of the reaction.13
Epoxidation of cis-decalin 10 with dimethyl dioxirane
proceeded with 94:6 diastereoselectivity. Subsequent epimer-
ization afforded a 3:2 mixture of decalins favoring the trans-
decalin, which, upon Wittig methylenation, gave almost
exclusively trans-decalin 11.14 Benzyl deprotection of 11
with sodium metal afforded alcohol 12, which was oxidized
using Dess-Martin periodinane to provide the corresponding
methyl ketone 3.15
Alcohol mixture 7 was obtained in 79% yield, diastereomeric
only at the silyl ether (vide infra). The free alcohol was
protected as its benzyl ether 8, and the substrate was
subjected to diisobutylaluminum hydride reduction and
Swern oxidation to provide aldehyde 9.
Homologation of 9 under Horner-Wadsworth-Emmons
conditions produced the desired triene (4) as a single olefin
isomer (Scheme 2). With the intramolecular Diels-Alder
precursor in hand, initial efforts were focused upon a one-
step deprotection-oxidation-cyclization sequence to obtain
cis-decalin 10 via the anticipated endo-boat transition state.10
Indeed, treatment of 4 with Jones reagent gave 10 as the
major stereoisomer. However, due to the delicate nature of
4, the optimized yield of this reaction was only 30%. Less
acidic conditions were explored, and it was found that
deprotection of 4 with catalytic fluorosilicic acid11 followed
With the ketone at C(11) serving as a handle for in-
corporation of the tetrahydrofuran, selectivity of nucleophilic
addition to ketone 3 was examined (Scheme 3). Reduction
of 3 with sodium borohydride provided a mixture of alcohols
with 91:9 diastereoselectivity. The stereochemistry of the
1
major product differed from that of 12, as observed by H
NMR (see Scheme 2), and thus was assigned as its C(11)
epimer (13). If a homoprenyl carbon nucleophile added with
the same facial selectivity as hydride, the desired C(11)
epimer would be obtained. Interestingly, the desired stere-
oisomer corresponds to the anti-Felkin product.16,17
In an effort to obtain alcohol 14, methyl ketone 3 was
exposed to homoprenylmagnesium bromide (15) under a
(6) For antimalarial activity of other isonitrile-containing compounds,
see: (a) Wright, A. D.; Konig, G. M.; Angerhofer, C. K.; Greenidge, P.;
Linden, A.; Desqueyroux-Faundez, R. J. Nat. Prod. 1996, 59, 710. (b)
Wright, A. D.; Wang, H. Q.; Gurrath, M.; Konig, G. M.; Kocak, G.;
Neumann, G.; Loria, P.; Foley, M.; Tilley, L. J. Med. Chem. 2001, 44,
873. (c) Schwartz, O.; Brun, R.; Bats, J. W.; Schmalz, H. Tetrahedron Lett.
2002, 43, 1009.
(12) Minor component in this ratio represents the combined yield of the
three undesired decalin stereoisomers as determined by GC.
(13) See Supporting Information.
(14) Direct methylenation of the pure cis-decalin led to a variable ratio
of trans- to cis-decalin olefinated product.
(7) White, R. D.; Wood, J. L. Org. Lett. 2001, 3, 1825.
(15) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(16) (a) Fieser, L. F.; Huang, W. Y.; Goto, T. J. Am. Chem. Soc. 1960,
82, 1688. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61. (c)
Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (d) Eliel,
E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds;
Wiley & Sons: New York, 1994.
(8) ()-5 was prepared from reduction of tert-butyl acetoacetate with
sodium borohydride; see: Mohrig, J. R.; Rosenberg, R. E.; Apostol, J. W.
et al. J. Am. Chem. Soc. 1997, 119, 479. Alternatively, (-)-5 can be accessed
by Noyori hydrogenation of tert-butyl acetoacetate. For preparation of alkyl
bromide 6, see Supporting Information.
(9) Frater, G.; Wulf, G.; Mueller, U. HelV. Chim. Acta 1989, 72, 1846.
(10) Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979, 101, 3992.
(11) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.;
DeShong, P. J. Org. Chem. 1992, 57, 2492.
(17) Methine is the “large” group, the methylene is the “medium” group,
and the hydrogen is the “small” group, as defined by ref 16a. The anti-
Felkin selectivity of hydride addition was also observed in related substrates
with varying functionality at C(4) and C(5).
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Org. Lett., Vol. 6, No. 7, 2004

Scheme 3
Scheme 4
variety of conditions. However, addition was not observed.
Furthermore, a range of sp3- and sp2-hybridized nucleophiles,
including Grignard reagents, dithianes, sulfones, alkyllithium
reagents, and enolates, failed to undergo addition to 3.
Deuterium-quenching experiments revealed that enolization
of the methyl ketone was occurring under the reaction
conditions. Attempts to modulate the nucleophile basicity
by transmetalation did not promote addition. Ultimately, less
basic and less sterically demanding sp-hybridized nucleo-
philes were examined. It was found that the lithium anion
of ethyl propiolate efficiently added to 3, affording propargyl
alcohol 16 with excellent diastereoselectivity (98:2).
Due to functional group incompatibilities encountered
while attempting to advance 16, we turned to a strategy that
installed the C(10) nitrogen prior to propiolate addition to
the methyl ketone (Scheme 4). Toward this end, aziridination
of 3 led to the desired aziridine (17) with 5:1 diastereose-
lectivity. Treatment of 17 with propiolate anion gave 18 in
89% yield and thus demonstrated that the propiolate addition
was both highly diastereoselective and chemoselective.
Alkyne reduction using catalytic hydrogenation conditions
provided ester 19. Lactonization with lithium hydroxide gave
lactone 20, a crystalline solid for which an X-ray structure
was obtained. X-ray crystallography revealed that 20 pos-
sessed the correct C(11) stereochemistry and confirmed that
the propiolate addition had indeed occurred in the desired,
anti-Felkin mode.
Scheme 5
With the trans-decalin and tetrahydrofuran in place, the
endgame strategy required incorporation of the isonitriles.
To this end, it was found that nucleophiles consistently added
to the terminal aziridine in preference to the epoxide. As a
result, aziridine 22 was treated with Super-Hydride to give
the corresponding tertiary amine, which was then exposed
to ammonium azide to afford azido-alcohol 23 (Scheme 6).
Tosyl deprotection and simultaneous azide reduction with
sodium metal19 provided bisamine 24, which upon formy-
lation with acetic formic anhydride and subsequent dehydra-
tion afforded kalihinol C (1). The spectroscopic and chro-
matographic properties of 1 were identical to those reported
for the natural product.20
Reduction of ester 19 with diisobutylaluminum hydride
provided lactol mixture 21, which was converted to bisho-
moallylic alcohol 2 in 62% yield over two steps (Scheme
5). Seleno-etherification of 2 followed by elimination
provided exclusively the tetrahydrofuran regioisomer with
modest preference (3:2) for the desired C(14) epimer (22).18
(19) An unexpected side product of this reduction was the corresponding
bishomoallylic alcohol, resulting from fragmentation of the tetrahydrofuran
ring. For a similar example, see: Sakai, K.; Ohtsuka, T.; Misumi, S.;
Shirahama, H.; Matsumoto, T. Chem. Lett. 1981, 355.
(18) Stereochemical assignments were based upon the 13C NMR shifts
of the C(11) and C(14) ether carbons; see Supporting Information.
Org. Lett., Vol. 6, No. 7, 2004
1125

Diels-Alder cycloaddition, and facial bias of this core is
utilized throughout the synthesis to direct functionalization
with high fidelity. Our continued work toward other members
of the kalihinane family will be reported in due course.
Scheme 6
Acknowledgment. We thank Christopher Incarvito for
X-ray crystallographic analysis. We thank Bristol-Myers
Squibb, Amgen, Yamanouchi, Pfizer, and Merck for funding,
and the Camille and Henry Dreyfus Foundation for a
Teacher-Scholar Award. J.L.W. is a fellow of the Alfred
P. Sloan Foundation.
Supporting Information Available: Experimental and
spectral data for compounds 1-23. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL049918B
In summary, the first total synthesis of the marine
diterpenoid kalihinol C has been accomplished. The decalin
core is constructed via diastereoselective intramolecular
(20) See refs 1a and 1b.
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Org. Lett., Vol. 6, No. 7, 2004