Stereoselective synthesis of E,Z-configured 1,3-dienes by ring-closing metathesis. Application to the total synthesis of lactimidomycin

Article abstract of DOI:10.1021/ja2031085

Strategic positioning of a silyl group on the diene unit of a diene-ene substrate allows rigorous regio- and stereocontrol to be exerted during metathesis-based macrocyclization reactions. The versatility of this concise approach to E,Z-configured 1,3-die

Full text of DOI:10.1021/ja2031085

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pubs.acs.org/JACS
Stereoselective Synthesis of E,Z-Configured 1,3-Dienes
by Ring-Closing Metathesis. Application to the Total Synthesis
of Lactimidomycin
Daniel Gallenkamp and Alois F€urstner*
Max-Planck-Institut f€ur Kohlenforschung, D-45470 M€ulheim/Ruhr, Germany
S Supporting Information
b
significant stereodirecting effect, provided that the [2 þ 2]-
ABSTRACT: Strategic positioning of a silyl group on the
diene unit of a diene-ene substrate allows rigorous regio-
and stereocontrol to be exerted during metathesis-based
macrocyclization reactions. The versatility of this concise
approach to E,Z-configured 1,3-dienes of ring sizes of 12
or larger is demonstrated by an application to the total
synthesis of lactimidomycin, a potent translation and cell-
migration inhibitor.
cycloaddition step generates a trigonal bipyramidal metalla-
cyclic intermediate of the kind observed with small alkenes as
the substrates (Scheme 1).6,7 Under this premise, one can
anticipate that intermediate A is clearly favored over isomer B,
which suffers from severe nonbonding interactions between
the silyl residue and the alkyl chain R1 (which is tethered to R2
in the case of macrocyclizations); a concerted cycloreversion
of A leads to products of type C, which upon protodesilylation
afford the desired E,Z-dienes D.8 In view of the popularity of
O-silyl groups in target oriented synthesis, it is likely that the
necessary desilylation at carbon can be performed concomitant
with the standard O-deprotections and will hence not increase
the step count in many conceivable applications of this
methodology. Moreover, a C-silyl substituent opens many
additional possibilities for postmetathetic transformations other
than protodesilylation, most notably via oxidative cleavage
or cross coupling (see below). This outlook dictated the choice
of BnMe2Si,9 (2-thienyl)Me2Si,10a,b or PhMe2Si groups10c in our
studies, all of which turned out to entail the exact same
stereochemical consequences for the RCM reactions.
he formation of conjugated dienes or polyenes by ring-
T
closing metathesis (RCM) remains a formidable challenge,
as it requires rigorous control over the configuration of the newly
formed double bond to be accorded with strict regiocontrol.
Unfortunately, the currently available catalysts do not yet fully
meet either demand.1 Most notably, it remains difficult to
discriminate between the two olefinic sites of a given 1,3-diene
substrate. Activation of the internal double bond, however,
results in ring contraction, which may become the dominant or
even exclusive pathway. Although successful cases of metathetic
diene (polyene) syntheses are known, the data shown in Table 1
are representative and echo the difficulties previously encoun-
tered in the literature.2,3
Although the rationale outlined above is certainly oversimpli-
fied and does not account for any conformational effects imposed
on the stereodetermining step by the emerging macrocycle, we
were pleased to see that the outcome of a representative set of
model reactions matched our expectations very well (Scheme 2).
Using 6 as a sufficiently active catalyst,11 substrate 512 and
analogues reacted solely at the terminal olefins, leaving the
silylated alkene site untouched; the newly formed double
bonds were invariably E-configured according to NMR and
GC/MS. Once the macrocycle is closed, the double bond
geometry is effectively locked; even resubjection of the iso-
lated compound 7a to a fresh catalyst and stirring of the
mixture in refluxing toluene for 20 h under an atmosphere
of ethylene did not lead to the formation of any isomers, as
judged by GC and NMR (only small amounts of ring opening
with formation of substrate 5a were detected, ca. 8% after 20 h).
This control experiment confirms the effectiveness of the silyl
substituent as a protecting and directing group alike.
Independent of the chosen catalyst and the conditions, sub-
strate 1 was converted into mixtures consisting of three isomeric
diene products 2 and both isomers of the ring contracted
cycloalkene 3. With the first generation catalyst 4a, the diene
was major but the product ratio not very encouraging; un-
surprisingly, this mixture of five isomeric and/or homologous
products was inseparable by flash chromatography. When the
second generation Grubbs catalyst 4b was used, ring contraction
was already almost complete once the substrate was consumed
(4 h). Additional control experiments with other substrates
(Supporting Information) showed the exact same trends; in
no case investigated was a single 1,3-diene isomer formed
exclusively.
The prevalence of macrocyclic dienes in nature makes a more
reliable approach highly desirable. We were particularly keen on
gaining access to E,Z-dienes, which are a recurrent motif in
bioactive natural products as witnessed by the few selected examples
shown in Chart 1. To this end, a multitasking C-silylation
strategy was envisaged, based on the notion that a suitably
located silyl substituent should protect the internal double
bond against attack by Grubbs-type complexes and hence
effectively cut off the undesirable ring contraction.4,5 At the
same time, a bulky R3Si group was expected to exert a
As can be seen from the examples compiled in Scheme 2, this
pattern was independent of the ring size as well as of the tether
length between the reacting sites and the polar substituents. The
isolated yields were good to excellent, except for the highly
strained 12-membered lactone 10 which was formed somewhat
Received: April 5, 2011
Published: May 23, 2011
r
2011 American Chemical Society
9232
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Table 1. Ring Contraction Interfering with an Attempted
RCM-based 1,3-Diene Synthesisa
Scheme 2. Silyl-Directed Synthesis of Macrocyclic E,Z-Con-
figured 1,3-Dienesa
No.
Cat.
T (°C)
t (h)
2 (dr)b
3 (dr)
1
2
3
4
4a
4a
4b
4b
20
110c
20
24
22
4
86% (3:1:1)
91% (2.7:1:1)
<5%
14% (5:1)
9% (5:1)
95% (7:1)
88% (6:1)
110c
4
12% (1:3:4)
a All reactions were performed in toluene (c = 2 mM) with 10 mol %
catalyst loading. b The underlined number shows the ratio of the desired
E,Z-isomer in the crude mixture as determined by GC; the assignment
was made by comparison with the authentic material prepared as
described below. c In the presence of Cy3PdO (10 mol %).
a Reagents and conditions: (a) 6 (10 mol %, slowly added), Cy3PdO
Chart 1. Selected Macrolides Containing E,Z-Diene Motifs
(10 mol %), toluene, 60 °C; (b) TBAF, THF, 85%; (c) (i) TBAF 3H2O,
3
THF; (ii) PhꢀI, Pd2(dba)3 CHCl3 (5 mol %), THF, 78% (from 7b).
3
Products 10ꢀ23 were obtained analogously by RCM and protodesilyla-
tion; Si = SiMe2Bn.
closure at a tolerable level (e5%).15 As expected, the proto-
desilylation of the primary products with the aid of TBAF
occurred smoothly, as did a prototype HiyamaꢀDenmark type
cross-coupling reaction16 with iodobenzene as the model sub-
strate (Scheme 2).
Next, we sought to scrutinize the methodology by an
application to the total synthesis of lactimidomycin.17 As the
formation of the 12-membered lactone 10 had been the least
efficient among all model compounds investigated, the equally
12-membered core of this natural product represented a
particularly stringent test. At the same time, lactimidomycin
is a highly valuable material: this compound not only exhibits
appreciable antiproliferative properties in vivo against various
tumors including the highly invasive MDA MB 231 human
breast adenocarcinoma17,18 but also constitutes an important
lead structure in the quest for small molecule inhibitors
of cell migration, which may ultimately serve to combat
metastasis.19 In this regard, lactimidomycin seems to rival or
even surpass the well investigated migrastatin family in po-
tency, although its mode of action may be different at the
molecular level.20
Scheme 1. A Silyl Substituent as a Protecting and Stereodi-
recting Group; L = Cy3P or N-Heterocyclic Carbene
Aldol 24 served as the point of departure, which was elabo-
rated into the known aldehyde 29 according to a route previously
described in the literature (Scheme 3).21 A subsequent Evans
boron aldol reaction22 followed by removal of the auxiliary gave
Weinreb amide 30, which was reduced with Dibal-H, and the
resulting aldehyde converted to enyne 32 with the aid of the
OhiraꢀBestmann reagent 3623 followed by a Sonogashira coup-
ling with vinyl bromide.24
less efficiently (53%). It is of note, however, that this and the
other entries were not fully optimized; as will be shown below, a
proper choice of catalyst allows significantly better yields to be
obtained even for more congested 12-membered rings. However,
it was mandatory to run the reactions in the presence of catalytic
amounts of Cy3PdO13 or tetrafluoro-p-quinone14 as additives to
keep the amount of double bond isomerization prior to ring
We were pleased to note that the hydrosilylation of this
compound catalyzed by the platinum carbene complex 3725
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Journal of the American Chemical Society
COMMUNICATION
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) see Table 2; (b) DDQ, CH2Cl2, pH 7
buffer, 0 °C, 87%; (c) TBAF, THF, 60 °C, 85%; (d) see ref 30.
a Reagents and conditions: (a) LDA, MeI, THF/HMPA, ꢀ78 °Cf0 °C,
92%; (b) LiAlH4, Et2O, 0 °C; (c) (MeO)2C6H3CHO, pTsOH cat.,
benzene, 80 °C, 65% (over both steps); (d) Dibal-H, CH2Cl2,
ꢀ50 °Cf0 °C, 98%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °Cf
0 °C, 99%; (f) Ph3PdC(Me)COOEt, CH2Cl2, 93%; (g) Dibal-H,
Table 2. Catalyst Optimization for the RCM of Substrate 34a
No.
Catalyst (mol %)
T (°C)
Yield (%)
38:39b
63:37c
79:21d
nd
CH2Cl2, ꢀ78 °C; (h) SO3 pyridine, DMSO, Et3N, CH2Cl2, 82%
1
2
3
4
5
6 (20)
6 (20)
80
120
80
56
3
(over both steps); (i) 35, Bu2BOTf, Et3N, CH2Cl2, ꢀ78 °CfRT, 95%;
54
(j) MeNH(OMe) HCl, Me3Al, THF, ꢀ20 °CfRT, 90%; (k) TESOTf,
3
41 (2 ꢁ 20)
42 (20)
43 (10)
35
2,6-lutidine, CH2Cl2, 0 °C, 90%; (l) Dibal-H, THF, ꢀ78 °C; (m) 36,
K2CO3, MeOH, 0 °CfRT, 76% (over both steps); (n) H2CdCHBr,
CuI, (PPh3)2PdCl2 (5 mol %), iPr2NH, THF, 88%; (o) 37 (1 mol %),
BnMe2SiH (3 equiv), 93% (dr = 96:4); (p) PPTS cat., EtOH, 89%;
60
dimer
76ꢀ78
120
95:5d,e
a All reactions were performed in toluene; c = 1ꢀ2 mM. b Determined by
1H NMR. c In the presence of Cy3PdO (20 mol %). d The catalyst was
added over 2 h via syringe pump. e In the presence of tetrafluoro-p-
quinone (2 ꢁ mol % of catalyst loading); nd = not determined.
(q) 6-heptenoic acid, EDC HCl, DMAP, CH2Cl2, 0 °CfRT, 97%.
3
proceeded with a remarkable level of regiocontrol to give the
desired product 33. The reaction was best performed neat, using
an excess of the silane; under these conditions, the required
isomer was consistently obtained in excellent yield with g95:5
selectivity. Although the hydrosilylation of alkynes in general has
been intensely studied,26 applications to such conjugated enynes
are essentially missing; the case presented herein, however,
encourages a more comprehensive study.
Cleavage of the TES-ether in 33 followed by esterification of
the resulting alcohol with 6-heptenoic acid set the stage for the
metathetic closure of the elaborate macrocycle. Under the
standard conditions of the model series using complex 611 as
the catalyst, the desired product 38 was obtained in moderate
yield, contaminated with significant amounts of the 11-membered
homologue 39, which could not be removed by flash chroma-
tography (Scheme 4). The reluctance of 34 to form the highly
strained product gives alkene isomerization a chance to
compete with productive RCM and explains the partial loss
of one methylene unit from the tether.15 Replacement of
catalyst 6 by the somewhat slimmer complex 41,27 designed
for metathesis reactions of sterically hindered substrates, gave
rather poor results, whereas the molybdenum alkylidene 4228
furnished only dimeric products (Table 2). Gratifyingly
though, the use of the more encumbered ruthenium carbene
43 recently reported by the Dorta group largely suppressed
the competing isomerization.29 This catalyst gave the desired
product 38 in appreciable yields, and only very small amounts
of the 11-membered congener 39 were detected.
The further elaboration of 38 was straightforward, comprising
the deprotection of the dimethoxybenzyl (DMP) group with
buffered DDQ followed by removal of the stereodirecting silyl
substituent with TBAF (Scheme 4). The resulting product 40
intercepts our previous total synthesis of lactimidomycin and can
be elaborated into this target in five high yielding operations.30
In summary, we have shown that the strategic positioning of a
silyl group allows E,Z-configured macrocyclic 1,3-dienes to be
formed in good to excellent yields with unprecedented levels
of regio- and stereocontrol. The R3Siꢀ moiety functions as a
protecting group for the internal alkene and, at the same time,
plays an active role as the key stereodirecting substituent. A
successful application to the total synthesis of the cell migration
inhibitor lactimidomycin underscores the relevance of this
methodology, which also deserves a conceptual remark. One of
the greatest triumphs of ruthenium-based metathesis catalysts in
general stems from the fact that they allow alkenes to be
selectively activated in the presence of almost any polar sub-
stituent. This exquisite profile largely obviated the need for
protecting group chemistry and hence strongly improved the
“economy of steps” of contemporary synthesis.31 Yet, the
current study seems to imply that an ever increasing catalyst
activity may actually render “protecting groups for alkenes”
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Journal of the American Chemical Society
COMMUNICATION
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental section, addi-
b
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NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
fuerstner@kofo.mpg.de
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