The total synthesis of (+)-migrastatin

Article abstract of DOI:10.1021/ja0349103

The first total synthesis of (+)-migrastatin, a macrolide natural product with interesting antimetastatic properties, has been accomplished. Our concise and flexible approach utilizes a Lewis acid-catalyzed diene aldehyde condensation to install the three

Full text of DOI:10.1021/ja0349103

Published on Web 04/25/2003
The Total Synthesis of (+)-Migrastatin
Christoph Gaul, Jon T. Njardarson, and Samuel J. Danishefsky*
†
†
,†,‡
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10021, and Department of Chemistry, Columbia UniVersity, HaVemayer Hall,
3
000 Broadway, New York, New York 10027
Received February 27, 2003; E-mail: s-danishefsky@ski.mskcc.org
Apropos of our ongoing program to exploit natural products as
Scheme 1. Structure of Migrastatin (1) and Synthetic Strategy
leads for new anticancer agents, we initiated experiments directed
to the total synthesis of migrastatin (1) (Scheme 1). This novel
macrolide, recently isolated from two different strains of Strepto-
myces, inhibits human tumor cell migration.1 Because in vivo cell-
ular motility and fusion are key elements of the complex phenom-
enology of metastasis, small molecules which might modulate the
relocation of cells with metastatic potential are of great interest,
particularly if the effect could be realized in a clinical setting.3
Minimally, such agents could be useful as in vitro probes aimed at
the deconvolution of the transduction sequence which culminates
in metastasis.
,2
Scheme 2. Preparation of the C7-C13 Core Fragmenta
Given our long-term commitment to the thorough evaluation of
the migrastatins, substantial amounts of material could well be
necessary. Accordingly, high priority was assigned to a total
synthesis that would be characterized by conciseness, workable
yields, and high margins of selectivity.
In an earlier paper, we formulated a general vision toward a
synthesis of migrastatin and demonstrated that the approach could
be used to reach a stripped-down core system.4 An important
component of the plan involved the use of the chelation controlled
Lewis acid-catalyzed diene aldehyde cyclocondensation (LAC-
5
DAC) to build the stereocenters at future carbons 8, 9, and 10 as
well as the otherwise potentially difficult C11-C12 (Z)-olefin. As
described below, in a major advance directed to conciseness and
convergence, we took recourse to the rather interesting â,γ-
unsaturated aldehyde 5 (Scheme 2), prepared and used here for
the first time. We note parenthetically that 5, derived from L-tartrate,
serves as a valuable bridging intermediate from the well-established
chiral pool to optically defined migrastatin (vide infra).
A second element of our scheme contemplated resort to the ring-
closing olefin metathesis (RCM) to fashion the migrastatin mac-
rolactone ring from an appropriate ester precursor. The seco system
would presumably be assembled by an acylation reaction, joining
a dienoic acid to the secondary C13 alcohol. Unexpectedly, this
seemingly straightforward projected union brought with it significant
complications in the total synthesis relative to the core model
system, wherein a corresponding acylation was conducted at a
primary alcohol. Of course, the total synthesis goal also brought
with it the need to accommodate new stereogenic centers at C13
and C14 and a keto function at C15, leading, ultimately, to a
γ-substituted glutarimide moiety. A comprehensive solution to this
multifaceted problem is provided below.
a
Reagents and conditions: (a) DIBALH, then ZnCl2, H2CdCHMgBr,
PhMe, -78 °C to room temperature, 75% (ds > 90%); (b) (i) NaH, MeI,
DMF, room temperature, (ii) 3 N HCl, THF, reflux, 80%; (c) Pb(OAc)4,
Na2CO3, CH2Cl2, room temperature; (d) (i) TiCl4, CH2Cl2, -78 °C, (ii)
TFA, CH2Cl2, room temperature, 75% from 4; (e) (i) NaBH4, CeCl3‚7H2O,
MeOH, 0 °C, (ii) CSA, H2O, THF, reflux; (f) LiBH4, H2O, THF, room
temperature, 44% from 7; (g) (i) Ac O, DMAP, pyridine, CH Cl , room
temperature, (ii) TBSOTf, 2,6-lutidine, CH2Cl2, room temperature, (iii)
K2CO3, H2O, MeOH, room temperature, 90%; (h) Dess-Martin periodinane,
CH2Cl2, room temperature.
2
2
2
glycol cleavage to yield R-methoxy-â-vinyl aldehyde 5. This
sensitive aldehyde was used directly for the LACDAC sequence:
Reaction of 5 with the synergistically activated diene 6 under the
influence of TiCl furnished the R-chelation controlled dihydro-
pyrone product 7 as a single diastereoisomer. The cycloconden-
sation had thus enabled proper presentation of the three contiguous
stereocenters of the macrolide (carbons 8, 9, and 10) and set the
stage for establishing the trisubstituted (Z)-alkene C11-C12. Luche
reduction of enone 7 afforded the corresponding allylic alcohol,
which smoothly underwent aqueous Ferrier rearrangement to give
lactol 8. Reductive opening of 8, protection of the secondary
hydroxyl group, and oxidation of the primary alcohol yielded the
C7-C13 core fragment 11.
Construction of the C13-C14 bond called for an anti-selective
aldol-type union. We found that a recently disclosed protocol was
5
8
4
9
10
11
Our synthesis commenced with commercially available dimethyl
2,3-O-isopropylidene-l-tartrate 2 (Scheme 2). Reduction of 2,
followed by a highly diastereoselective divinylzinc addition to the
in situ generated dialdehyde, produced the desired vinyl carbinol
6
3
. Methylation of the two hydroxyl groups and removal of the
12
particularly well suited for this task. Propionyl oxazolidinone 12
added smoothly to the angelic-like aldehyde 11, in the presence of
7
acetonide protecting group led to diol 4, which was subjected to
†
2
MgCl and TMSCl, thereby delivering exclusively the aldol product
13 in good yield (Scheme 3). Protection of the resulting secondary
Sloan-Kettering Institute for Cancer Research.
Columbia University.
‡
6042
9
J. AM. CHEM. SOC. 2003, 125, 6042-6043
10.1021/ja0349103 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Scheme 3. Incorporation of the Glutarimide Side Chaina
to RCM precursor 20. In the event, when this seco compound was
subjected to ring-closing metathesis under the conditions shown,
1
8
only the desired (E,E,Z)-trienyl 14-membered macrolactone was
obtained. This result is in accord with our expectations that the
ruthenium carbene would be initially formed at the less congested
of the two terminal olefins and would then cyclize onto the most
accessible of the three remaining double bonds. Finally, cleavage
of the silyl ether yielded (+)-migrastatin (1), whose physical
properties are identical to those reported for natural migrastatin.
In summary, a total synthesis of (+)-migrastatin has been
accomplished for the first time. In retrospect, success was achieved
by interfacing the dihydropyrone matrix chemistry, developed in
5
our laboratories in the 1980s, with the RCM methodology of
18
Grubbs and the powerful auxiliary-dominated stereochemical
control of Evans.12 The flexible approach provided above will allow
us to enter the biological phase of the program. Toward this end,
efforts to establish an SAR profile for the migrastatins and to
identify the targets of its action are currently underway.
a
Reagents and conditions: (a) (i) MgCl2, Et3N, TMSCl, EtOAc, room
19
temperature, (ii) TFA, MeOH, room temperature, 67% from 10; (b) (i)
TESCl, imidazole, CH2Cl2, room temperature, (ii) LiBH4, MeOH, THF,
room temperature, 83%; (c) (i) Dess-Martin periodinane, CH2Cl2, room
temperature, (ii) methyl dimethylphosphonate, BuLi, THF, -78 °C to room
temperature, (iii) Dess-Martin periodinane, CH2Cl2, room temperature; (d)
LiCl, DBU, MeCN, room temperature, 57% from 14.
Acknowledgment. Support for this research was provided by
the National Institutes of Health (AI 16943). Postdoctoral fellowship
support is gratefully acknowledged by C.G. (Deutscher Akademi-
scher Austauschdienst, DAAD) and J.T.N. (General Motors Cancer
Research Program). We thank Drs. Erik Henke and Robert Benezra
Scheme 4. Completion of the Total Synthesisa
(Sloan-Kettering Institute for Cancer Research) for performing the
wound healing assay.
Supporting Information Available: Physical data for key inter-
mediates 4, 7, 10, 14, 18, and (+)-migrastatin (1) (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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Reagents and conditions: (a) (i) [(Ph3P)CuH]6, PhMe, room temper-
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(
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). Surprisingly, the acylation of 18 with dienoic acid 19 turned
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(
16
4
out to be challenging. Various coupling conditions employed led
to either extensive decomposition of starting material or products
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(
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(19) Fully synthetic migrastatin was tested in a wound healing assay, and the
1
results confirmed the findings of Imoto et al. for natural migrastatin.
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