An enantioselective biomimetic total synthesis of (-)-siccanin

Article abstract of DOI:10.1002/anie.200351868

A convergent asymmetric synthesis of the clinically important antifungal agent (-)-siccanin (1) mimics the proposed biosynthetic pathway. A Pd-catalyzed asymmetric allylic alkylation was used to establish the stereochemistry, and sequential radical proces

Full text of DOI:10.1002/anie.200351868

Angewandte
Chemie
Biomimetic Total Synthesis
An Enantioselective Biomimetic Total Synthesis
of (À)-Siccanin**
Barry M. Trost,* Hong C. Shen, and
Jean-Philippe Surivet
Siccanin (1), a mold metabolite isolated from the culture
broth of Helminthosposium siccans by Ishibashi in 1962,[1]
possesses an unusual cis,syn,cis-fused alicyclic ring system.
Siccanin exhibits potent antifungal activity, in particular
against several pathogenic fungi,[2] and its clinical effective-
ness against surface mycosis has also been established.[3]
As a result of its interesting biological activity, siccanin
has been the subject of a number of synthetic efforts.[4]
However, only two successful racemic syntheses of this
natural product have been reported to date.[4g–i] Herein we
[*] Prof. B. M. Trost, H. C. Shen, J.-P. Surivet
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0002
E-mail: bmtrost@stanford.edu
[**] We thank the National Science Foundation and the National
Institutes of Health, General Medical Sciences (GM-13598) for their
generous support of our programs. Mass spectra were provided by
the Mass Spectrometry Regional Center of the University of
California, San Francisco, supported by the NIH Division of
Research Resources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 3943 –3947
DOI: 10.1002/anie.200351868
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3943

Communications
prepare the same chiral chroman 6 by using
ligands of opposite chirality [Eq.(1) and
(2)].Use of the
Z allylic carbonate 7
afforded chiral chroman 6 with a substan-
tially higher ee value (97%) than did use of
its E counterpart 8 (84%).The resulting
chiral chroman 6 underwent a dihydroxyla-
tion followed by oxidative cleavage to afford
aldehyde 5 [Eq.(3)] (NMO = N-methylmor-
pholine N-oxide).
As shown in Equation (4), sulfone 4 can
be prepared from the readily available chiral
alcohol 9 in two steps (DIAD = diisopropyl
azodicarboxylate.)[7] The subsequent Julia
olefination[8] of chiral sulfone 4 with chiral
chroman aldehyde 5 proceeded in high yield
to give diene 10 [Eq.(5)].
Scheme 1. Retrosynthetic analysis of (À)-siccanin (1). L=ligand.
report the first enantioselective biomimetic total synthesis of
(À)-siccanin (1), which has a Pd-catalyzed asymmetric allylic
alkylation and an epoxyolefin radical cyclization as key steps
(Scheme 1).
Inspired by the biosynthetic pathway of 1,[5] we envisaged
that its B and E rings could be formed through an epoxyolefin
cyclization reaction of siccanochromene B (2), a proposed
biosynthetic precursor of 1.Siccanochromene B ( 2) can be
seen to be derived from 3, which itself could be prepared from
a coupling reaction of chiral sulfone 4 with chiral chroman 5.
Chroman 6, the precursor of 5, is in turn available through a
Pd-catalyzed asymmetric allylic alkylation reaction that has
been developed recently by our group [Eq.(1) and (2)]
(dba = dibenzylideneacetone).
Both the Z and the E allylic carbonates 7 and 8, readily
available through literature procedures,[6] can be used to
The epoxidation of diene 10 with mCPBA gave a
complex mixture of products.In contrast, the dihydrox-
ylation of 10 under the conditions of Sharpless and co-
workers[9] took place chemo- and diastereoselectively to
generate diol 11 (d.r. 10:1). The subsequent hydrogena-
tion smoothly afforded chroman diol 12 (Scheme 2).
DDQ oxidation[10] of diol 12 afforded chromene diol 13,
which was readily converted into epoxide 14, the methyl
ether of 2.
Our first approach to the biomimetic synthesis of 1
involved
a
proposed novel cationic cyclization
(Scheme 3).A Lewis acid should open epoxide 14 to
generate a tertiary cation 15, which could then be trapped
by the electron-rich olefin to form the B ring of siccanin,
as in 16.The resulting oxygen nucleophile could undergo
a 1,4-addition to the adjacent enone, facilitated by the
Lewis acid (LA), to construct the tetrahydrofuran ring
and form the siccanin methyl ether (17).This proposal
would allow 17 to be built up in one pot, with the cleavage
À
À
of one C O bond and the formation of one C C bond
À
and one C O bond.However, when 14 was treated with a
variety of Lewis acids, only decomposition or formation
of 1,2-hydride-shift product 18 were observed, and no
cyclization products were isolated [Eq.(6)].
3944
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3943 –3947

Angewandte
Chemie
epoxide 14 to form a tertiary radical 19.Inter-
mediate 19 then cyclizes in a 6-exo-trig fashion to
form benzylic radical 23, which reacts further with a
second equivalent of the TiIII species to form a C
À
TiIV bond.Subsequent hydrolysis leads to the
formation of tetracyclic product 21 with the desired
stereochemistry.Alternatively, 19 may undergo
cyclization to benzylic radical 25, which is diaster-
eomeric with respect to 23.It appears that the
proximity of the TiIV-bonded oxygen atom to the
benzylic carbon radical in 25 leads to a further
cyclization.Radical recombination as illustrated
liberates TiIII and produces 22.
Scheme 2. Synthesis of epoxide 14. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none; DMAP=4-(dimethylamino)pyridine; Ts=toluenesulfonyl.
Scheme 4. Proposed biomimetic radical cyclization. Cp=cyclopenta-
dienyl.
The final key step in the synthesis of siccanin involves a
free-radical remote functionalization of 21 under conditions
reported by Suarez and co-workers[12] to provide pentacyclic
compound 28, presumably via iodide 26 and oxonium ion
27(Scheme 6).PM3 calculations showed that the energy of
natural siccanin methyl ether (28) is 16.5 kcalmolÀ1 lower
than that of 11-epi-siccanin methyl
Scheme 3. Proposed biomimetic cationic cyclization.
ether (29).The energy of the tran-
sition states that lead to 28 or 29
should reflect the strain energy of
the product.Therefore, the product
with significantly lower energy is
formed preferentially.Further-
more, the preferred conformation
To overcome this problem, we proposed a radical
cyclization of epoxide 14 in the presence of Cp2TiIIICl.[11]
The resulting tertiary radical 19 should undergo a 6-exo-trig
cyclization to form benzylic radical 20 (Scheme 4).After
considerable experimentation, we were pleased to observe
that the TiIII-mediated cyclization of 14 afforded the desired
tetracyclic compound 21, and the 5-epi-
of intermediate 27 acts as a constraint on the hydroxy
nucleophile to attack 27 from the face that leads to the cis-
fused ring system of the desired pentacyclic compound 28
(Scheme 6).
Finally, the pentacyclic compounds 28 and 22 were
demethylated to afford (À)-siccanin (1) and (À)-5-epi-sicca-
siccanin methyl ether (22) as a side
product, in a 3:1 ratio and 81% com-
bined yield [Eq.(7)].
A mechanistic rationale for the
formation of 21 and 22 is proposed in
III
Scheme 5.The Ti
species, generated
in situ by the reduction of titanocene
dichloride with manganese, opens
Angew. Chem. Int. Ed. 2003, 42, 3943 –3947
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3945

Communications
nin (30), respectively [Eq.(8) and (9)] (DMF =
N,N-dimethylformamide).
In summary, we have carried out the first
enantioselective total synthesis of (À)-siccanin
(1), inspired by the biosynthetic route and based
on our development of the Pd-catalyzed asym-
metric allylic alkylation and a novel radical
epoxide cyclization.Our synthesis consists of 13
linear steps from allyl carbonate 7 or 8. These
results may have implications for the under-
standing of the biosynthetic pathway—that is,
whether the corresponding biocyclization is
cationic or radical in nature.
Received: May 12, 2003 [Z51868]
Scheme 5. Proposed mechanism for the radical cyclization.
Keywords: asymmetric synthesis · biomimetic
.
synthesis · cyclization · natural products ·
radical reactions
[1] K.J.Ishibashi, J. Antibiot. Ser. A 1962, 15, 161.
[2] a) K.Ishibashi, K.Hirai, M.Arai, S.Sugasawa,
A.Endo, A.Yasumura, H.Matsuda, T.Mura-
matsu, Annu. Rep. Sankyo Res. Lab. 1970, 22, 1;
b) M.G.Belloti, L.Riviera, Chemioterapia 1985,
4, 431.
[3] a) D.Crippa, C.G.Albanese, G.P.Sala,
G. Ital.
Dermatol. Venereol. 1985, 120, LVII and refer-
ences therein; b) M.Arai, K.Ishibashi, H.
Okazaki, Antimicrob. Agents Chemother. 1969,
247; c) S.Sugawara, Antimicrob. Agents Chemo-
ther. 1969, 253.
[4] a) S.Nozoe, K.Hirai, Tetrahedron 1971, 27, 6073;
b) S.Oida, Y.Ohashi, A.Yoshida, E.Ohki,
Chem. Pharm. Bull. 1972, 20, 2634; c) A.Yosh-
ida, S.Oida, Y.Ohashi, C.Tamura, E.Ohki,
Chem. Pharm. Bull. 1972, 20, 2642; d) S.Oida, Y.
Ohashi, E.Ohki, Chem. Pharm. Bull. 1973, 21,
528; e) H.Liu, B.Ramani,
Tetrahedron Lett.
1988, 29, 6721; f) M.Kato, Y.Matsuma, K.
Heima, A.Yoshikoshi, Bull. Chem. Soc. Jpn.
Scheme 6. The synthesis of pentacyclic compound 28.
1988, 61, 1991; g) M.Kato, K.Heima, Y.Mat-
suma, A.Yoshikoshi, J. Am. Chem. Soc. 1981,
103, 2434; h) M.Kato, Y.Matsuma, K.Heima, N.Fukamiya, C.
Kabuto, A.Yoshikoshi, Tetrahedron 1987, 43, 711; i) B.M.Trost,
F.J.Fleitz, W.J.Watkins,
[5] a) S.Nozoe, K.T.Suzuki,
J. Am. Chem. Soc. 1996, 118, 5146.
Tetrahedron 1971, 27, 6063; b) K.T.
Suzuki, S.Nozoe, Bioorg. Chem. 1974, 3, 72; c) K.T.Suzuki, S.
Nozoe, J. Chem. Soc. Chem. Commun. 1971, 527; d) D.J.
Goldsmith, C.F. Philips, J. Am. Chem. Soc. 1969, 91, 5862;
e) D.J.Goldsmith, B.C.Clark,
Tetrahedron Lett. 1967, 8, 1215.
[6] B.M.Trost, N.Asakawa, Synthesis 1999, 1491.
3946
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3943 –3947

Angewandte
Chemie
[7] H.Tanimoto, T.Oritani, Tetrahedron 1997, 53, 3527.
[8] a) M.Julia, JM. .Paris,
Tetrahedron Lett. 1973, 4833; b) P.
Kocienski, Phosphorus Sulfur Relat. Elem. 1985, 24, 97.
[9] H.C.Kolb, M.S.VanNieuwenhze, K.B.Sharpless,
1994, 94, 2483.
Chem. Rev.
[10] a) A.N.Starrat, A.Stoesl, Can. J. Chem. 1977, 55, 2360; b) V.K.
Ahluwalia, R.S. Jolly, Synthesis 1982, 74; c) D.R. Buckle, in
Encyclopedia of Reagents for Organic Synthesis, Vol. 3 (Ed.:
L.A.Paquette), Wiley, New York, 1995, p.1699.
[11] a) T.V.RajanBabu, W.A.Nugent, M.S.Beattie,
J. Am. Chem.
Soc. 1990, 112, 6408; b) A.Gansauer, M.Pierobon, H.Bluhm,
Synthesis 2001, 2500; c) T.V.RajanBabu, W.A.Nugent, J. Am.
Chem. Soc. 1994, 116, 986; d) S.C.Roy, K.K.Rana, C.Guin,
Org. Chem. 2002, 67, 3242.
J.
[12] J.T.Concepcion, C.G.Francisco, R.Hernandez, J.A.Salaza, E.
Suarez, Tetrahedron Lett. 1984, 25, 1953.
Angew. Chem. Int. Ed. 2003, 42, 3943 –3947
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3947