DOI: 10.1002/anie.201006438
Natural Product Synthesis
Total Synthesis of Pederin and Analogues**
Fanghui Wu, Michael E. Green, and Paul E. Floreancig*
The search for the causitive agent for Paederis dermatitis, an
inflammatory condition that results from contact with beetles
of the Paederis family, resulted in the isolation of pederin
(1).[1] Pederin subsequently inspired a substantial wave of
investigation that led to the determination of its correct
structure,[2] the observation of its potent cytotoxicity,[3] the
postulation of protein synthesis inhibition as its likely mode of
biological activity,[4] the identification of the 60S subunit of
the ribosome as its potential biological target,[5] and the
establishment of bacterial symbionts as its true biogenetic
source.[6] Pederinꢀs interesting biological activity and chal-
lenging structural features have spawned significant synthetic
efforts, resulting in several total, formal, and analogue
syntheses.[7] A noteworthy advance in pederin accessibility
was recently disclosed by Rawal and Jewett,[7e] who reported
that pederin could be prepared through a 12-step (longest
linear sequence) route. In accord with our interest in the
pederin family of molecules,[8] we report our total synthesis of
1. In addition to the brief linear sequence, this approach
highlights the utility of a late-stage multicomponent con-
struction of the N-acyl aminal structure that allows for the
efficient construction of analogues with structural variation in
each of three distinct subunits.
Scheme 1. Retrosynthetic analysis of pederin. P=protecting group.
We envisioned pederin to arise (Scheme 1) from the union
of a pederic acid derivative (2), a tetrahydropyranyl nitrile
(3), and MeOH through our recently reported[9] multicompo-
nent amide synthesis. This late-stage construction of the N-
acyl aminal unit is well-suited for analogue synthesis through
variations on the pederic acid unit, the nitrile, and the alcohol.
The nitrile can be prepared from lactol 4, which can be
accessed from keto alcohol 5, a known compound[8c] that can
be prepared in multigram quantities and with high enantio-
meric purity in three steps from isobutyraldehyde.
Silylation of 5 proceeded through standard conditions to
yield ether 6 (Scheme 2). We postulated that the remaining
carbons of the right-hand fragment could be introduced
through an aldol reaction between an enolate of 6 and
methoxyacetaldehyde. High levels of 1,5-anti-diastereocon-
trol have been reported for aldol reactions between aldehydes
Scheme 2. Synthesis of the nitrile component. Reagents and condi-
tions: a) TESCl, imidazole, CH2Cl2, 100%; b) (+)-DIP-Cl, Et3N,
MeOCH2CHO, Et2O, À788C, 88%, d.r.=15:1; c) NaBH4, Et2BOMe,
MeOH, THF, À408C, 95%; d) (+)-DIP-Cl, Et3N, Et2O, À788C, then
LiBH4, À408C, 80%; e) O3, CH2Cl2, À788C, then Ph3P, 95%;
f) TMSCN, BiBr3, CH3CN, 08C, then BF3·OEt2, À408C, 63%; g) MeOTf,
2,6-tBu2Py, CH2Cl2, 86%. DIP-Cl=B-chlorodiisopinocamphenylborane,
TMSCN=trimethylsilyl cyanide, MeOTf=methyl trifluoromethanesul-
fonate, 2,6-tBu2Py=2,6-di-tert-butylpyridine, TES=triethylsilyl.
and dialkylboron enolates of b-alkoxy ketones, but b-silyloxy
enolates show poor levels of control.[10] Thus we employed
Patersonꢀs pinene-derived boron enolate aldol strategy[11] to
effect the conversion of 6 to 7 in 88% yield as a 15:1 mixture
of diastereomers upon oxidative cleavage of the borinate
intermediate. This degree of stereocontrol was gratifying in
consideration of the modest levels of selectivity that are
normally observed for aldol reactions with (Ipc)2B enolates of
methyl ketones (Ipc = isopinocampheyl). Stereoselective
reduction of 7 with Et2BOMe and NaBH4 yielded 8 effi-
ciently. While the yields and stereocontrol for the aldol and
reduction reactions were satisfactory, diol 8 could be accessed
[*] Dr. F. Wu, Dr. M. E. Green,[+] Prof. Dr. P. E. Floreancig
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
E-mail: florean@pitt.edu
[+] Current address: Pfizer Global Research and Development
Groton, CT 06340 (USA)
[**] We thank the National Science Foundation for generous support of
this work through grant CHE-0848299, and the NIH for the 700 mhz
NMR at the University of Pittsburgh (S10RR023404).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 1131 –1134
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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