Toward more "ideal" polyketide natural product synthesis: A step-economical synthesis of zincophorin methyl ester

Article abstract of DOI:10.1021/ja201467z

A highly efficient and step-economical synthesis of zincophorin methyl ester has been achieved. The unprecedented step economy of this zincophorin synthesis is principally due to an application of the tandem silylformylation-crotylsilylation/Tamao oxidati

Full text of DOI:10.1021/ja201467z

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Toward More “Ideal” Polyketide Natural Product Synthesis:
A Step-Economical Synthesis of Zincophorin Methyl Ester
Tyler J. Harrison, Stephen Ho, and James L. Leighton*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S Supporting Information
b
ABSTRACT: A highly efficient and step-economical synthesis
of zincophorin methyl ester has been achieved. The unprece-
dented step economy of this zincophorin synthesis is principally
due to an application of the tandem silylformylationÀcrotylsi-
lylation/Tamao oxidationÀdiastereoselective tautomerization
reaction, which achieves in a single step what would typically
Figure 1. Zincophorin and zincophorin methyl ester.
require a significant multistep sequence.
Scheme 1. Four-Step Synthesis of 7 from 3
olyketide natural products continue to influence small-mole-
P
cule drug development efforts. Both natural products (e.g., dis-
codermolide1) and designed analogues thereof (e.g., fludelone2)
have progressed into clinical trials, and it seems reasonable to
anticipate that it might only be a matter of time before approved
drugs begin to emerge from such medicinal chemistry programs.
It is equally reasonable to anticipate that most such compounds
will have to be synthesized (as will most analogues, of course), as
was certainly the case for both discodermolide3 and fludelone.
For this reason, despite decades of beautiful, powerful, and
profoundly influential chemistry devoted to the synthesis of such
structures, there remains a great need for creative new ap-
proaches that achieve significantly greater levels of “ideality”.4
Progress in this regard would be expected to have an impact on
every aspect of polyketide natural product-based synthesis and
drug development efforts.
Zincophorin (1) and its methyl ester (2)5 have been popular
targets for synthetic chemists ever since the groundbreaking synth-
esis by Danishefsky in 1987 (Figure 1).6,7 Two additional total
syntheses have been reported since then, one by Meyer and Cossy8
and the other by Miyashita9 (in addition to numerous reports of
fragment syntheses10), and interestingly, all three syntheses (of 2)
required ∼47/∼52 total steps11 with longest linear sequences of 36,
28, and 37 steps, respectively. As part of a broad program devoted to
the development of highly efficient and step-economical syntheses
of polyketide structures of this type,12 we decided to undertake a
new synthesis of zincophorin methyl ester. Our primary motivation
was to set for ourselves the goal of completing the synthesis in about
half the number of total steps as the three previous syntheses
because we felt that achieving this would require a fresh approach
and true methodological innovation (i.e., greater ideality). We
report here the results of these efforts, which culminated in a
synthesis of 2 having 27/31 total steps.
and set the stage for an application of the tandem silylformyla-
tionÀcrotylsilylation/Tamao oxidationÀdiastereoselective tau-
tomerization reaction.12k Applied to 6, this complex series of
chemical events produced 7 in 67% yield with g15:1 overall
diastereoselectivity. The transformation of 6 into 7 (which we have
carried out on a multigram scale) is remarkable not only for the
direct installation of a ketone, three stereocenters, and an alkene but
also for the simplicity of the starting materials (a crotyl-SiH
fragment, a propynyl fragment, CO, and H2O2). Overall, com-
pound 7, which contains five of the 10 stereocenters of the
C(1)ÀC(16) fragment, was accessed in just four steps from 3, and
this sequence is further noteworthy for what was not employed:
protecting groups, nonstrategic redox reactions, and chiral
auxiliaries, controllers, and/or reagents. Using Baran’s algorithm,
The synthesis commenced with an asymmetric epoxidation of
alkene 313 using Shi’s catalyst14 to provide 4 in 87% yield and
90% ee (Scheme 1). Epoxide opening using Pagenkopf’s
procedure15 gave 5 in 43% yield.16 NaH-catalyzed silane alco-
holysis with di-cis-crotylsilane12d then provided 6 in 97% yield
Received: February 16, 2011
Published: April 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja201467z J. Am. Chem. Soc. 2011, 133, 7308–7311
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Scheme 2. Synthesis of the C(11), C(7), and C(6)
Stereocenters
Scheme 3. Completion of the C(1)ÀC(16) Fragment
this adds up to a four-step sequence that delivers five stereo-
centers with 100% ideality.4
A series of straightforward steps (selective protection to give 8,
syn-selective β-hydroxyketone reduction17 to give 9, diol protec-
tion to give 10, and alkene oxidative cleavage) converted ketone 7
into aldehyde 11 and set up a crotylation reaction to establish the
C(6) and C(7) stereocenters (Scheme 2). The desired product,
12, is the expected result of Felkin addition of a type-I trans-
crotylmetal reagent to aldehyde 11, and this is a fully matched
case18 that should not require external asymmetric induction for
very high levels of diastereoselectivity.19 A survey of various type-I
trans-crotylmetal reagents revealed that the potassium trans-crotyl-
trifluoroborate reagent introduced by Batey20 possessed superior
characteristics from the perspective of both efficiency and practi-
cality/ease of use. In the present case, its use led to the isolation of
12 in 85% yield (from 10) with g20:1 diastereoselectivity.
The final stereochemical challenges in the synthesis of the
C(1)ÀC(16) fragment were the C(2) and C(3) stereocenters
that would accompany tetrahydropyran ring synthesis. It was
clear that the most direct way to accomplish those goals in a
single step would be the addition of a propionate enolate to an
oxocarbenium ion at C(3). To set up such a reaction, 12 was
subjected to hydroformylation to give hemiacetal 13, which was
acetylated to give 14 in 94% overall yield (Scheme 3). While the
well-established preference for axial attack on the oxocarbenium
ion generated from 14 would give the desired outcome at C(3),
control of the C(2) center was much more speculative. Extensive
experimentation with various achiral propionate enolate species
failed to reveal an adequate solution, and we therefore turned to
the use of chiral enolates that would allow for control of the
enolate face selectivity. Romea and Urpí21 have developed a
protocol for the highly stereoselective addition of the titanium
enolate derived from 15 to oxocarbenium ions derived from acetals,
glycals, and pseudoglycals, and this appeared to be a highly relevant
precedent. Indeed, the titanium enolate derived from 15 was
treated with 14 and SnCl4 to produce 16 in 91% yield as a single
diastereomer. Methanolysis proceeded exceptionally smoothly
to give 17, and this was followed by a three-step conversion of the
benzyl ether into N-phenyltetrazolylsulfone 20.
Scheme 4. Synthesis of the C(17)ÀC(25) Fragment
cis-crotylsilane 2122 (Scheme 4).23 This reaction proceeded
smoothly at ambient temperature to provide 22 in 97% yield
(based on the use of 21 as the limiting reagent) and 93% ee.
Highly trans-selective (>20:1) cross-metathesis with excess
methacrolein and the second-generation HoveydaÀGrubbs
catalyst24 was followed without purification by alcohol tosylation
using the Tanabe protocol25 to provide 23 in 79% yield. A second
application of the Sc(OTf)3-catalyzed crotylation reaction with
trans-crotylsilane 24 then gave 25 in 81% yield with excellent
(19:1) diastereoselectivity. Protection of the alcohol as its p-
methoxybenzyl (PMB) ether was followed in the same pot by
tosylate reduction with LiBEt3H to give 26 in 86% yield. Finally,
one-pot oxidative cleavage produced aldehyde 27 in 87% yield.
The synthesis of the C(17)ÀC(25) fragment commenced
with a Sc(OTf)3-catalyzed crotylation of propionaldehyde using
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COMMUNICATION
Scheme 5. Completion of the Synthesis
National Science Foundation (CRIF-0840451) for funding the
acquisition of a 400 MHz NMR spectrometer.
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’ AUTHOR INFORMATION
Corresponding Author
leighton@chem.columbia.edu
’ ACKNOWLEDGMENT
This work was supported by a grant form the National
Institute of General Medical Sciences (GM58133). T.H. was
supported by an NSERC Postdoctoral Fellowship. We thank the
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