Asymmetric synthesis of the phytopathogen (+)-fomannosin

Article abstract of DOI:10.1002/anie.200702056

(Chemical Equation Presented) Three new construction features in one synthesis - for the fused cyclobutene ring, the cyclopentanone, and the functionalized six-membered lactone - characterize the procedure that leads to the natural (+)-enantiomer of the t

Full text of DOI:10.1002/anie.200702056

Angewandte
Chemie
DOI: 10.1002/anie.200702056
Phytopathogens
Asymmetric Synthesis of the Phytopathogen (+)-Fomannosin**
Leo A. Paquette,* Xiaowen Peng, and Jiong Yang
In 1967, the wood-rotting basidiomycete fungus Fomes
annosus (Fr.) Karst became recognized as the agent respon-
sible for generating a powerful phytopathogenic metabolite
called fomannosin (1; Scheme 1 shows the naturally occuring
+ form).[1] This sesquiterpene lactone causes the death of host
cells prior to hyphal invasion and is particularly toxic to Pinus
taeda seedlings.[1b] The substantial adverse economic impact
associated with infestations of this bacterial growth in pine
stands located in the southeastern United States has been
noted.[2,3] The quite unusual structural features of 1, in tandem
with the biological profile outlined above, have prompted
detailed studies of its biogenesis.[2,4] A synthesis of racemic
fomannosin has also been documented.[5] The lability of this
noncrystalline methylenecyclobutene toxin led to its struc-
tural definition by virtue of two X-ray crystallographic studies
involving 5,6-dihydro derivatives.[1b,6]
nosin family could be accessed. For this strategy to be
successful, viable tactics would be required for attaching the
dimethyl-substituted cyclopentanone to the four-membered
ring and for fusing the lactone ring across C-4 and C-7. We
reasoned further that the particular configuration at C-9
might well be subject on thermodynamic grounds to con-
trolled epimerization in either the R or S direction as a
function of overall substitution. Since we had earlier devel-
oped a preparatively attractive route from 3 to 2,[8] the
crafting of more advanced intermediate 9 was next pursued
(Scheme 2).
From the outset, we targeted a convergent, enantioselec-
tive approach featuring d-glucose (4) as starting material
(Scheme 1). Retrosynthetically, the plan entailed the trans-
Scheme 2. Synthesis of 9. Reagents and conditions: a) [Cp2ZrCl2],
nBuLi; THF, ꢀ788C!RT (60% plus 25% of the diastereomer);
b) TBSCl, imidazole, CH2Cl2, RT (90%); c) O3, Sudan III, CH2Cl2,
=
ꢀ788C, then PPh3 (91%); d) H2C CHCH2C(CH3)2CH2I, tBuLi, THF,
Scheme 1. Retrosynthetic analysis of (+)-fomannosin (1).
TBDPS=tert-butyldiphenylsilyl, PMB=p-methoxybenzyl, TBS=tert-
butyldimethylsilyl.
ꢀ788C, (96%); e) PDC, 4-Š MS, CH2Cl2, RT, 24 h (83%);
f) (CH3)3SiCH2Li, pentane/toluene (1:1), ꢀ788C; g) PTSA, C6H6, RT,
5 h (83% over two steps); h) Grubbs-2, C6H6, reflux, 4 h (91%);
i) TBAF, THF, RT, overnight (76%). PDC=pyridinium dichromate,
PTSA=p-toluenesulfonic acid, TBAF=tetrabutylammonium fluoride.
formation of 4 into enantiomerically pure 2 by application of
zirconocene-based deoxygenative ring contraction technol-
ogy.[7] The stepleading from 3 to 2 was intended to serve as a
branch point from which other stereoisomers of the foman-
The acquisition of 2 was followed by ozonolysis with
Sudan III serving as internal indicator.[9] The hindered, non-
enolizable aldehyde 5 so produced was reacted in turn with
the lithium reagent directly available by metalation of 5-iodo-
4,4-dimethyl-1-pentene to provide carbinol 6 in near-quanti-
tative yield. While 6 was uneventfully oxidized with PDC, the
projected olefination of 7 as a route to diene 8 proved
problematic, a likely consequence of prevailing steric con-
gestion. The blockade existing on the faces of the carbonyl
double bond inhibited customary operation of the Wittig,
Tebbe, and Nysted reagents. When Peterson olefination
conditions[10] were implemented instead, the targeted con-
[*] Prof. L. A. Paquette, Dr. X. Peng, Dr. J. Yang
Evans Chemical Laboratories
The Ohio State University
100 West 18th Avenue, Columbus, OH 43210-1185 (USA)
Fax: (+1)614-292-1685
E-mail: paquette.1@osu.edu
[**] This study was supported by The Ohio State University.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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version to 8 proceeded remarkably well. The latter diene was
tion of 12 (74%). Ultimately, we found that the hydroxy-
methylene groupcould be chemoselectively reduced with
NaBH4 at 08C in methanol containing KH2PO4.[15] The co-
formation of 13 and 14 proved not to be problematic as these
diastereomers can be independently transformed by a com-
parable route into 21. The pathway, exemplified for 13, began
with monoprotection as the TBS ether in advance of hydroxy-
directed osmylation[16] to generate 15. That the three hydroxy
groups in 15 had been installed in an all-cis relationshipwas
strongly supported by NOESY experiments performed on its
Swern oxidation product 16.
With this stereochemical assignment secure, the objec-
tives that remained consisted of serial removal of the
unneeded OH group in the cyclopentane ring, proper
introduction of the two sites of unsaturation resident in the
target, and ultimate desilylation. The first of these goals was
met by treating 16 with samarium diiodide in the presence of
tert-butyl alcohol as the proton source[17] (Scheme 4). This
process afforded in 64% yield an inseparable mixture of the
tricyclic keto lactone diastereomers 17. Although 17 proved
resistant to many conditions for PMB deprotection, the
desired unmasking of the cyclobutanol OH groupcould be
accomplished with trifluoroacetic acid in anhydrous
CH2Cl2.[18] Pure samples of 18 (50%) were separated from
its C-9 diastereomer (8%) by chromatography. The chemical-
shift values and coupling patterns of the C-8 lactonic
methylene protons in these isomers are distinctively different
(in CDCl3). Although these characteristics are evident in
many 5,6-dihydrofomannosins,[19] we did not consider the
cyclized under mandatory high-dilution conditions through
the action of the Grubbs-2 ruthenium catalyst.[11] Generation
of the cyclopentene ring in this manner set the stage for
effective desilylation to give diol 9.
Introduction of the lactone sector was next addressed.
Highlights of the sequence ultimately developed include the
regioselective monoesterification of 9 with ethylsulfanylcar-
bonyl acetic acid[12] as promoted by EDCI[13] (Scheme 3).
Ethylsulfanylcarbonyl acetic acid was selected because it held
the prospect, once incorporated into 9, of allowing for
chemoselective reduction in the presence of the labile lactone
functionality. Direct oxidation of the esterification product
with IBX afforded 10 and 11. Chemical homogeneity was
reinstalled through their combined treatment with 10% Pd/C
in the presence of triethylsilane.[14] Not only did these
conditions lead to aldol ring closure (in the case of 10) but
to subsequent reductive desulfurization as well with forma-
Scheme 3. Synthesis of lactone 16. Reagents and conditions:
a) HOOCCH2COSEt, EDCI, CH2Cl2, ꢀ408C!RT; b) IBX, DMSO, RT,
3 h (44% over two steps); c) Pd/C, Et3SiH, CH2Cl2, then silica gel
(74%); d) NaBH4, MeOH, KH2PO4, HOAc, 08C; e) TBSOTf, 2,6-
lutidine, CH2Cl2, ꢀ788C (89%); f) OsO4, THF/py (4:1), 08C, then H2S
(76%); g) ClCOCOCl, DMSO, CH2Cl2, Et3N, ꢀ788C!RT (78%).
EDCI=1-dimethoxyaminopropyl-3-ethylcarbodiimide hydrochloride,
IBX=o-iodoxybenzoic acid.
Scheme 4. Completion of the (+)-fomannosin (1) synthesis. Reagents
and conditions: a) SmI2, tert-butyl alcohol/THF (1:4), 15 min (64%);
b) CF3CO2H, CH2Cl2, RT, 8 min; c) SOCl2, Et3N, CH2Cl2, RT; d) DBU,
CH2Cl2, 08C, 20 min; e) DBU, CH2Cl2 (see text); f) (CF3SO2)2O,
CH2Cl2, 08C; g) DBU, C6H6, RT (35% over two steps); h) TBAF, THF,
08C (86%).
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Angewandte
Chemie
existing correlation to be sufficiently developed to form a
reliable basis for configurational assignment to C-9. In the
present examples, the presence of a C-5 hydroxy group, and
particularly its capacity for intramolecular hydrogen bonding,
could have an unforeseen effect.
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reactions by thin layer chromatography revealed that the
respective conversions to 19 and 20 were occurring rapidly (<
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nent mixtures in a 1:1 ratio. By the proper adjustment of
reaction parameters, funneling of all material through 19 was
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(1H NMR analysis). Desilylation was achieved uneventfully
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graphed, the resulting dextrorotatory carbinol exhibited
spectroscopic properties that matched those reported for
formannosin.[2,4] The configurations of 18–21 could now be
assigned unequivocally.
An enantioselective synthesis of 1 has been achieved in a
convergent manner that features novel modes of construction
of the fused cyclobutene ring, the pendant cyclopentanone,
and the functionalized six-membered lactone. The flexibility
provided by the modes of assembly of the structural
components should also allow the synthesis of analogues
and antipodes. From such compounds might well arise a fuller
definition of the structural requirements for phytopathoge-
nicity.
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Received: May 9, 2007
Published online: September 6, 2007
Keywords: cyclobutanes · phytopathogenicity ·
.
ring-closing metathesis · samarium diiodide reduction ·
zirconocene
Angew. Chem. Int. Ed. 2007, 46, 7817 –7819
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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