Rhodium-catalyzed enantioselective vinylogous addition of enol ethers to vinyldiazoacetates

Article abstract of DOI:10.1021/ja3092399

A highly asymmetric vinylogous addition of acyclic silyl enol ethers to siloxyvinyldiazoacetate is described. The reaction features a diastereoselective 1,4-siloxy group migration event. Products are obtained in up to 97% ee. When more sterically crowded

Full text of DOI:10.1021/ja3092399

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Enantioselective Vinylogous Addition of Enol
Ethers to Vinyldiazoacetates
Austin G. Smith and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
Scheme 1. Comparison of Known Carbenoid (a) and
Vinylogous (b) Transformations with 1, and the Current
Studies (c)
ABSTRACT: A highly asymmetric vinylogous addition of
acyclic silyl enol ethers to siloxyvinyldiazoacetate is
described. The reaction features a diastereoselective 1,4-
siloxy group migration event. Products are obtained in up
to 97% ee. When more sterically crowded silyl enol ethers
are employed, an enantioselective formal [3+2] cyclo-
addition becomes the dominant reaction pathway. Control
experiments reveal the (Z)-olefin geometry to be critical
for high levels of enantiocontrol.
onor/acceptor carbenoids are valuable intermediates in
Denantioselective intermolecular C−C bond-forming
reactions.1 Vinyldiazoesters have emerged as a synthetically
useful class of carbenoid precursors when paired with chiral
dirhodium tetracarboxylate catalysts. In addition to C−H
insertion and cyclopropanation reactions, the vinyldiazoesters
can function in a diverse array of other carbenoid reactions,2
including the combined C−H functionalization/Cope rear-
rangement (CHCR) of vinyldiazoacetates and allylic C−H
bonds1b and the cyclopropanation/Cope rearrangement of
dienes.3
Vinylcarbenoids are further distinguished from aryl and alkyl
donor/acceptor carbenoids in that they possess electrophilic
character at both the carbenoid and vinylogous positions.
Selective vinylogous reactivity can be achieved through a
judicious choice of solvent,4 catalyst,4,5 ester substituent,6 and
degree of substitution at the vinyl terminus.2e,5,7 The effect of
this last variable can be quite pronounced. Recently we
demonstrated that cyclic silyl enol ethers of type 1 react with
methyl-substituted (Z)-siloxyvinyldiazoacetate 2 at the carbe-
noid position via a highly enantio- and diasteroselective
combined-CHCR in the presence of Rh2(S-PTAD)4 (Scheme
1a).8 In contrast, reaction of enol ether 1 with the terminally
unsubstituted siloxyvinyldiazoacetate 4 favors vinylogous
addition. The alkynoate products of type 5 are formed with
excellent diastereoselectivity but only low to moderate
enantioselectivity with chiral dirhodium catalysts. (Scheme
1b).9
Herein we describe a highly asymmetric vinylogous addition
of readily accessible, acyclic (Z)-silyl enol ethers (6) to
siloxyvinyldiazoacetate 4 (Scheme 1c). The reaction provides
disiloxyketal products of the opposite diastereomeric series with
respect to the cyclic system. The resultant disiloxyketals can be
readily deprotected with no erosion in enantiomeric excess,
thus providing an operationally simple protocol for the
enantioselective α-propargylation of ketones. We have further
found that subtle modification of the reaction conditions with
sterically demanding substrates promotes a formal [3+2]
cycloaddition to provide highly substituted cyclopentenes,
which give rise to enantioenriched cyclopentenone building
blocks.
The successful propargylation of cyclic enol ethers prompted
us to explore the use of acyclic substrates in this transformation.
Specifically, we postulated that the use of (Z)-enol ethers might
provide a solution to the low to moderate enantioinduction
observed in the cyclic series.10 We therefore initiated our
studies with the propiophenone-derived silyl enol ether (Z)-6a.
Our optimization studies are summarized in Table 1. A brief
screen of chiral dirhodium catalysts (Figure 1) revealed Rh2(S-
PTAD)4 to be optimal for this reaction; disiloxyketal 7a was
isolated in 65% yield and 77% ee (Table 1, entry 1).
Cyclopentene 9a was also isolated as a minor product in 12%
yield and 90% ee. The experiment with Rh2(S-DOSP)4
provided only cyclopentene 9a as a racemic mixture (entry
11
2), while the reaction with Rh2(S-BTPCP)4 produced a
roughly 1:1 mixture of 7a:9a in low yield and poor
enantioselectivity (entry 3). Rh2(S-PTTL)4 and Rh2(S-
Received: September 17, 2012
Published: October 25, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
a b
Communication
,
absolute and relative configuration of 10a was established by
single-crystal X-ray analysis and assigned to the remainder of
the products by analogy.13 Disiloxyketal 7a could also be
cleanly deprotected to the corresponding ketone 11a with no
detectable erosion in enantioenrichment in under five minutes
by treatment with tris(dimethylamino)sulfonium difluorotri-
methylsilicate (TASF) in DMF.14 This method thus provides a
two-step route to enantioenriched α-propargyl ketones.
Table 1. Optimization Results with 6a
% yield (% ee)
c
d
entry
catalyst
solvent
x
7a
9a
1
2
3
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-BTPCP)4
Rh2(S-PTTL)4
Rh2(S-NTTL)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexanes
pentane
2,2-DMB
2,2-DMB
2
2
2
2
2
2
2
2
1
65 (77)
12 (90)
40 (<5)
17 (−22)
<5 (na)
<5 (na)
15 (95)
14 (95)
7 (97)
Having established optimized conditions for the formation of
7a, we proceeded to explore the scope of enol ether substrates.
As described in Table 2, a variety of para- and meta-substituted
0
20 (−19)
39 (76)
18 (75)
65 (94)
76 (94)
84 (95)
85 (95)
e
4
f
5
a b c
, ,
Table 2. Substrate Scope
6
7
8
9
8 (97)
a
1
Products 7a and 9a were obtained in >20:1 dr as determined by H
NMR analysis of the crude reaction mixture. Yields refer to isolated
b
yield after silica gel chromatography. Products 7a and 9a were
obtained in >20:1 dr as determined by 1H NMR analysis of the crude
reaction mixture. Yields refer to isolated yield after silica gel
c
chromatography. ee determined by chiral HPLC analysis of the
d
corresponding propargylic alcohol. ee determined by chiral HPLC
e
f
analysis. 60% conversion. 40% conversion.
a
Products in >20:1 dr as determined by 1H NMR analysis of the crude
b
reaction mixture. Yield refers to isolated yield after silica gel
chromatography. Enantioenrichment determined by chiral HPLC
c
analysis of the corresponding propargyl ketone unless otherwise noted.
d
e
Determined by chiral HPLC analysis of the disiloxyketal. Experiment
performed at 70 °C in hexanes.
enol ethers provided the desired alkynoate products in high
yield with excellent levels of diastereo- and enantioselectivity
(70−84% yield, >20:1 dr, 95−97% ee, 7c−e, Table 2). The
reaction of the 2-naphthyl-derived enol ether 6f led to the
desired disiloxyketal 7f in moderate yield and enantioselectivity
(48%, 80% ee). The less nucleophilic (Z)-silyl enol ethers
derived from both hexane 3,4-dione (6g) and methyl 2-
oxobutanoate (6h) also provided the desired products at
elevated temperatures in refluxing hexanes. Disiloxyketal 7g was
isolated in 53% yield and 88% ee, while 7h was isolated in 62%
yield and 94% ee. In addition, the reaction of the 2-methoxy
enol ether 6i gave the desired product 7i in 74% yield and 97%
ee.
When the enol ether derived from butyrophenone (6j) was
employed under the standard reaction conditions, the desired
disiloxyketal was furnished in 95% ee; however, the ratio of
disiloxyketal to cyclopentene was significantly lower (5:1), and
the reaction proceeded with incomplete conversion (Table 3,
entry 1). Although performing this experiment at elevated
temperatures was effective at promoting complete consumption
of the starting enol ether, the product ratio was further eroded
(entry 2). This finding, coupled with the high level of
enantioenrichment (94% ee) and potential synthetic value of
9j, led us to explore the possibility of favoring the minor
cyclopentene byproduct in these reactions. Performing the
reaction at 70 °C in refluxing hexanes led to even higher yields
of 9j with only a slight drop in enantioselectivity (45% yield,
91% ee, entry 3). Furthermore, we observed that under these
reaction conditions, more sterically hindered silyl enol ethers
Figure 1. Structures of chiral dirhodium catalysts used in this study.
NTTL)4 provided 7a with enantioenrichment comparable to
that obtained with Rh2(S-PTAD)4; however, these reactions
were hampered by poor yields and lower overall conversions
(entries 4 and 5). The use of nonpolar solvents provided a
significant increase in the enantioselectivity of 7a, albeit with
only moderate product ratios (entries 6 and 7). Performing the
reaction with 2,2-dimethylbutane (2,2-DMB) as the solvent
gave the desired product in slightly higher yield with a
substantially improved ratio of 7a:9a (12:1, entry 8).12 We
found the reaction to be equally effective at 1 mol % catalyst
loading; under these optimized conditions, alkynoate 7a was
isolated in 85% yield and 95% ee with only 8% yield of
cyclopentene 9a (entry 9).
To demonstrate product utility, 7a was treated with
diisobutylaluminum hydride (DIBAL-H) in CH2Cl2 to provide
the propargylic alcohol 10a in 84% yield and 95% ee with no
observable reduction of the disiloxyketal (Scheme 2). The
Scheme 2. Product Derivatizations
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Journal of the American Chemical Society
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Communication
,
in 66% overall yield and 91% ee. As a highlight of this method,
sterically and electronically demanding silyl enol ethers 6m−o,
which reacted poorly under the standard conditions at room
temperature, provided the desired cyclopentenones 8m−o in
good yield (51−70%) and high enantioselectivity (90−94% ee).
In order to obtain information about the absolute stereo-
chemical configuration at C3 in cyclopentenones 8 we
synthesized cyclopentenone 8p as described in Scheme 3
Table 3. Formal [3+2] Optimization
% yield (% ee)
c
d
entry
solvent
temp
R1
7
9
e
1
2,2-DMB
2,2-DMB
hexanes
hexanes
rt
Et (6j)
Et (6j)
Et (6j)
Ph (6k)
49 (95)
61 (92)
47 (90)
0
10 (96)
30 (94)
45 (91)
2
3
4
50 °C
70 °C
70 °C
Scheme 3. Synthesis of 12p
86 (91)
a
1
Products 7 and 9 were obtained in >20:1 dr as determined by H
b
NMR analysis of the crude reaction mixture. Yield refers to isolated
yield after silica gel chromatography. ee determined by chiral HPLC
analysis of the corresponding propargyl ketone. ee determined by
chiral HPLC analysis. 75% conversion.
c
d
e
such as 6k provided only the cyclopentene product; 9k was
obtained in 86% yield and 91% ee (entry 4).15
The formal [3+2] cycloadducts (9) could be directly
converted into highly enantioenriched cyclopentenone building
blocks under Lewis acidic conditions with no erosion in
enantiomeric excess. Upon treatment of enantioenriched
cyclopentene 9k (91% ee) with BF3·OEt2 at 0 °C, cyclo-
pentenone 8k was obtained in 81% yield and 91% ee (eq 1).
(59% yield, 78% ee). Subsequent reduction of 8p to the
corresponding diol with DIBAL-H yielded cyclopentene 12p as
a 2.5:1 mixture of diastereomers. From this mixture we were
able to obtain a crystal of 12p suitable for X-ray diffraction
analysis. The absolute stereochemistry at C4 of 12p (C3 of 8p)
was determined to be of (S)-configuration and assigned to the
remainder of the cyclopentenones by analogy.16
In an effort to probe the mechanism of the unusual 1,4-siloxy
group transfer observed in Table 2, we performed the following
control experiment. A 2.3:1 mixture of (E)/(Z)-6a was
subjected to the standard reaction conditions described in
Table 2 (eq 2). Disiloxyketal 7a was isolated in 70% yield as a
We subsequently found that these enantioenriched cyclo-
pentenones could be synthesized via a one-pot operation with
minimal reduction in the overall yield (Table 4). Thus, the
a b
,
Table 4. One-Pot Synthesis of Cyclopentenones 8
2.3:1 mixture of isomers favoring the opposite diastereomer
from that observed with (Z)-6a. The major diastereomer was
obtained in 43% ee, while the minor diastereomer was
determined to be in 95% ee.
The observation that (E)-6a, a substrate that is able to
undergo bond rotation after nucleophilic addition, provided the
opposite diastereomer from that observed with (Z)-6a strongly
suggests a 1,4-siloxy group transfer that occurs faster than σ
bond rotation. These data indicate that the high diastereose-
lectivity observed in Table 2 is thus a function of enol ether
geometry. In addition, the asymmetric results obtained from
the experiment described in eq 2 also reveal a requirement for
the (Z)-enol ether geometry in order to achieve high
enantioselectivity, which is consistent with the low to moderate
levels of enantioinduction observed in the cyclic series.9
A tentative mechanism that rationalizes the observed
enantioselectivity and product divergency is described in
Scheme 4. Ample precedent exists for Rh2(S-PTAD)4, in
combination with 4, to direct substrate approach from the re-
face of the carbenoid in enantioselective cyclopropanation and
C−H insertion reactions.1b,3,8 Based on these results, we
propose the silyl enol ether approaches the chiral rhodium
carbenoid from the front face as drawn (13). The (Z)-geometry
of the enol ether most likely dictates attack via an “end-on”
a
Yield refers to isolated yield after silica gel chromatography.
Enantioenrichment determined by chiral HPLC analysis.
b
rhodium-catalyzed formal [3+2] cycloaddition was conducted
in hexanes at 70 °C; subsequent evaporation of hexanes,
addition of CHCl3 and treatment with BF3·OEt2 at 0 °C
provided cyclopentenones 8j−o with only one purification step
required. The less hindered substrates 6j and 6l provided the
desired products in modest yield and high enantioselectivity
(8j,l, 29−41% yield, 91−92% ee, Table 4), while the one-pot
reaction with silyl enol ether 6k led to aryl cyclopentenone 8k
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Scheme 4. Proposed Mechanism for the Formation of 7 and
9
REFERENCES
■
(1) For leading reviews, see: (a) Davies, H. M. L.; Beckwith, R. E. J.
Chem. Rev. 2003, 103, 2861−2904. (b) Davies, H. M. L.; Lian, Y. Acc.
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(2) For selected examples, see: (a) Doyle, M. P.; Hu, W.; Timmons,
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mode, in which the bulky OTMS and R1 groups are pointed
away from the phthalimido blocking groups.17 Vinylogous
addition is followed by rapid OTBS group migration/β-
elimination from a fleeting intermediate 14 in which the
oxocarbenium ion is properly aligned with a participating lone
pair on the OTBS group. We postulate that a negative steric
interaction between a bulky R1 group and the catalyst “wall”
disfavors a trajectory that promotes siloxy group migration and,
instead, favors a still highly facial selective “side-on” approach
(15). Reaction through this approach would provide
intermediate 16, which is aligned to undergo a diastereose-
lective ring closure to access 9. The similar but not quite
identical levels of enantioinduction for the formation of the two
classes of products (Tables 1 and 3) is consistent with two
mechanisms that are differentiated by a subtle alteration in the
trajectory of approach of the substrate to the rhodium
carbenoid. Further studies are being conducted in our
laboratory in an attempt to gain a better understanding of
the mechanistic nuances that control this striking product
divergence.
We have demonstrated a highly enantio- and diastereose-
lective vinylogous addition/1,4-siloxy group migration of silyl
enol ethers and siloxyvinyldiazoacetate catalyzed by Rh2(S-
PTAD)4. The isolated disiloxyketal products are easily
deprotected to the subsequent carbonyl to provide access to
highly enantioenriched α-propargyl ketones. Reactions with
sterically demanding substrates allow for the one-pot synthesis
of enantioenriched cyclopentenone building blocks. Extending
this unusual transformation to other nucleophiles, as well as
exploring the migratory aptitude of other leaving groups on the
diazo precursor, comprises our future interests.
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[3+3] cycloaddition of nitrones with 4. See ref 2e.
(11) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.;
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(12) 2,2-DMB has previously been demonstrated to be an optimal
solvent for enantioselective C−H functionalization, especially of
unreactive substrates. For example, see ref 1a and references cited
therein.
(13) The crystal structures of 10a and 12p have been deposited at
the Cambridge Crystallographic Data Centre, and the deposition
numbers CCDC 899871 and 899870 were allocated, respectively. For
X-ray crystallographic data of 10a, see the Supporting Information.
(14) The use of TBAF resulted in lower yields for the deprotection of
7a.
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silyl enol ethers, see: (a) Singleton, D. A.; Church, K. M.; Lucero, M. J.
Tetrahedron Lett. 1990, 39, 5551−5554. (b) Fang, J.; Ren, J.; Wang, Z.
Tetrahedron Lett. 2008, 47, 6659−6662. (c) Komatsu, M.; Suehiro, I.;
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12075−12079.
(16) For X-ray crystallographic data of a single isomer of 12p, see the
Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
(17) (a) Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.;
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AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Institutes of Health
(GM-099142-01). We thank Dr. John Bacsa and Kelly Kluge
(Emory University) for the X-ray crystallographic analysis.
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