Formation of vinyl-, vinylhalide-or acyl-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed enantioselective conjugate additions of Si-containing vinylaluminums to β-substituted cyclic enones

Article abstract of DOI:10.1021/ja110054q

A catalytic method for enantioselective conjugate addition (ECA) of Si-containing vinylaluminum reagents to β-substituted cyclopentenones and cyclohexenones is described. Reactions are promoted by 1.0-5.0 mol % of a bidentate NHC-Cu complex, which is prep

Full text of DOI:10.1021/ja110054q

COMMUNICATION
pubs.acs.org/JACS
Formation of Vinyl-, Vinylhalide- or Acyl-Substituted Quaternary
Carbon Stereogenic Centers through NHC-Cu-Catalyzed
Enantioselective Conjugate Additions of Si-Containing
Vinylaluminums to β-Substituted Cyclic Enones
Tricia L. May, Jennifer A. Dabrowski, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S Supporting Information
b
Scheme 1. Versatility of Catalytic Conjuagte Additions with
Si-Substituted Vinylaluminum Reagents
ABSTRACT: A catalytic method for enantioselective con-
jugate addition (ECA) of Si-containing vinylaluminum
reagents to β-substituted cyclopentenones and cyclohexe-
nones is described. Reactions are promoted by 1.0-5.0 mol
% of a bidentate NHC-Cu complex, which is prepared
from air-stable CuCl2•2H2O and used in situ, and typically
proceed to completion within 15-20 min. The requisite
vinylmetals are generated efficiently by a site-selective
hydroalumination of an alkyne with dibal-H. The desired
products, containing a quaternary carbon stereogenic cen-
ter, are obtained in 48-95% yield after purification and in
89:11 to >98:2 enantiomer ratio (er). The vinylsilane
moiety within the products can be functionalized to afford
acyl, vinyliodide, or desilylated alkenes in 67% to >98% yield
and with >90% retention of the alkene's stereochemical
identity. The utility of the catalytic process is illustrated
in the context of a concise enantioselective synthesis of
riccardiphenol B.
instances where the vinylmetal is a small molecule, the impracti-
cality of isolation or purification of volatile alkynes or vinylhalides
can be avoided. Third, and perhaps most importantly, as illustrated
in Scheme 1, efficient synthesis of a variety of enantiomerically
enriched products that cannot be directly prepared or, at least,
easily synthesized by a catalytic process would become feasible due
to the presence of the vinylsilane.
Herein, we report a method for enantioselective conjugate
addition of 1-Si-substituted vinylaluminum reagents to five- and
six-membered β-substituted cyclic enones. Reactions are cata-
lyzed by a chiral bidentate NHC-Cu complex derived from
air-stable and commercially available CuCl2•2H2O and afford
the desired products in up to 95% yield and >98:2 enantiomeric
ratio (er). The resulting enantiomerically enriched vinylsi-
lanes can be protodesilylated, converted to the correspond-
ing vinyl halides, or oxidized to β-acyl-substituted enones
in >66% yield. The utility of the NHC-Cu-catalyzed reaction
is illustrated through a concise total synthesis8 of natural
product riccardiphenol B.9
From the outset, we appreciated that efficiency of the afore-
mentioned processes would hinge on identification of a chiral
catalyst that accomplishes the demanding task of forming the
highly congested C-C bond. We were aware that the attendant
steric congestion, as well as stabilization of electron density at the
Si-bearing carbon might result in diminution of vinylaluminum
nucleophilicity to decelerate the vinyl addition process, allowing
alternative pathways to become competitive. In the context of
Cu-catalyzed allylic substitutions, we had observed that Si-
substituted vinylaluminums, although effective in reactions that
furnish tertiary C-C bonds, give rise to inefficient and non-
selective processes when quaternary carbon stereogenic centers
are to be generated.10 Such concerns were validated in the
atalytic enantioselective conjugate additions of easily acces-
C
sible C-based nucleophiles to unsaturated carbonyls facil-
itates the synthesis of a range of enantiomerically enriched
biologically active molecules and are therefore of significant
value.1 Nevertheless, in spite of recent advances,2 notable short-
comings persist in this area, particularly in the context of reactions
furnishing quaternary carbon stereogenic centers.3 One deficiency
relates to the paucity of protocols for catalytic conjugate additions
of vinyl units.4 A report regarding Cu-phosphine-catalyzed
enantioselective conjugate addition (ECA) reactions of vinylalu-
minums with β-substituted cyclic enones has appeared; however,
substrate and reagent scope is narrow and the preparation of the
requisite vinylmetals via vinylhalides can be limiting (details
below).5 We set out to examine whether Cu complexes of
N-heterocyclic carbenes (NHCs) can effect ECA of vinylmetals
togenerate quaternary carbonstereogenic centers.6 Inthis context,
use of Si-substituted vinylmetals would be attractive for several
reasons. First, efficient and stereoselective hydroaluminations
of silylacetylenes with inexpensive diisobutyaluminum hydride
(dibal-H) afford the requisite vinylaluminums (Scheme 1).6 Thus,
the need for stereoselective synthesis of vinylhalides, only a few of
which can be purchased and whose preparation often requires
strongly acidic conditions,7 would not be necessary. Second, in
Received: November 9, 2010
Published: December 20, 2010
r
2010 American Chemical Society
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|

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COMMUNICATION
Table 1. Initial Examination of Various Chiral NHC Complexesa
Table 2. Cu-NHC-Catalyzed Enantioselective Conjugate
Additions of Si-Substituted Vinylaluminums to β-Substituted
Cyclic Enonesa
temp (°C); vinyl:
vinyl
prod
substrate
(R; n)
reagent
(R1)
time
i-Bu
entry
(min)
addnb yield (%)c erd
1
2
3
4
5
6
7
8
9
Me; 1
7a n-Pr
7b n-Hex
7c (CH2)4Ot-Bu
7d Ph
7e p-MeOC6H4
22; 15
22; 15
0; 15
22; 15
22; 20
22; 15
0; 20
0; 20
0; 20
0; 20
0; 20
95:5
91:9
95:5
90:10
92:8
76
91
80
75
67
95
64
85
85
50
66
63
93:7
94:6
92.5:7.5
95:5
94:6
95.5:4.5
96:4
97:3
96:4
98.5:1.5
98.5:1.5
96:4
Me; 1
Me; 1
Me; 1
Me; 1
(CH2)2Ph;1 7f n-Hex
95:5
Me; 2
Me; 2
Me; 2
10a n-Hex
10b n-Pr
10c (CH2)4Ot-Bu
10d Ph
10e p-MeOC6H4
71:29
85:15
96:4
67:33
78:22
80:20
10 Me; 2
11 Me; 2
12 4-hexenyl; 2 10f n-Pr
0; 20
a Reactions performed under N2 atm. b Determined by analysis of
400 MHz 1H NMR spectra of unpurified mixtures and refers to
consumption of the substrate. c Yields of isolated and purified vinyl
addition products. d Determined by GLC or HPLC analysis; see the
Supporting Information for details.
sulfonate-based NHC-Cu complexes. The precise reason for
such reactivity and selectivity difference is unclear but might
be partly due to higher electrophilicity of unsaturated carbo-
nyls (vs allylic phosphates).
a Reactions performed under N2 atm. b Determined by analysis of 400
MHz 1H NMR spectra of unpurified mixtures and refers to consumption
of the substrate. c Determined by GLC analysis; see the Supporting
Information for details. nd = not determined.
β-Alkyl-substituted cyclopentenones and a range of alkyl- as
well as aryl-substituted 1-trimethylsilyl-vinylaluminums (entries
1-6, Table 2) undergo ECA efficiently (>98% conv in 20 min)
and with high enantioselectivity (92.5:7.5-95.5:4.5 er). Reac-
tions with β-substituted cyclohexenones proceed to afford the
desired products in up to 98.5:1.5 er (entries 7-12, Table 2).
Although there is 4-33% i-Bu addition in transformations
shown in Table 2, <2% adventitious 1,2-reduction (cf. 9,
Table 1) is detected and pure β-vinyl cycloalkanones are isolated
in 50-95% yield. Two additional points regarding the reactions in
Table 2 are noteworthy: (1) Cyclopentenones, a particularly
challenging substrate class for ECA reactions,18 generally react more
efficiently than cyclohexenones (90:10-95:5 vs 67:33-96:4 vinyl:
i-Bu addition). (2) Cu-catalyzed ECA can be performed with lower
catalyst loading than used in the studies summarized in Table 2. As
an example, with 0.5 mol % 3b and 1.0 mol % CuCl2•2H2O, the
processes in entries 1 and 8 of Table 2 proceed to >98% conv in 1.5
h(22°C) to afford products with the same level of enantioselectivity
and in 68% and 85% yield, respectively.
Catalytic additions to cycloheptenones are inefficient (20-40%
conv to the vinyl addition product). A relatively large β substituent
leads to diminished reaction rates, as demonstrated by the
transformation of enone 11 (Scheme 2), affording 12 in 48%
yield after purification and 89:11 er. Efficient and highly enantio-
selective synthesis of 13 (Scheme 2), bearing a gem-dimethyl
group at its C20 position, demonstrates that improved selectivity
can be achieved with sterically demanding enones (>98:2 er vs
93:7 er in entry 1, Table 2). As the preparation of 14 and 15
illustrates, vinylaluminum reagents bearing a more hindered silyl
unit (t-BuMe2Si vs SiMe3) can be used to access β-vinyl carbonyls
present studies by the observation that with the NHC-Cu
derived from dimeric Ag complex 1 (easily accessed from the
imidazolinium salt and Ag2O)11 and CuCl2•2H2O, ECA with
β-methylcyclopentenone and vinylsilane 6 delivers 20% of the
desired 7a (10:90 er)12 along with 15% of allylic alcohol 9 (entry
1, Table 1). Reaction facility (>98% vs 35% conv) and the
preference for transfer of the vinyl unit (85% vs 20%) improve
significantly with the sulfonate-bridged complex derived from 213
to afford the β-vinyl ketone in 80:20 er (entry 2, Table 1). Similar
activity is furnished by the Cu-complex accessed through 3a
(entry 3), but stereoselectivity is increased to 90:10 er. Further
improvement in efficiency (<2% unidentified products) and
selectivity (95% 7a in 93:7 er; 5% 814) are attained with 3b,
which contains a larger NAr group (entry 4, Table 1). Somewhat
surprisingly, NHC-Cu complex derived from 3c, where the size
of the NAr is increased further, proves to be substantially less
effective (entry 5). As the data in entries 6-7 of Table 1 indicate,
ECA with monodentate NHC-Cu complexes, are inefficient,
although in one case reasonably selective (17:83 er in entry 6).15
The relative ineffectiveness of complexes derived from 4 and 5 is
in contrast to ECA processes that generate C-B16 or C-Si17
bonds, where monodentate NHC-Cu catalysts emerge as
optimal. The above findings thus illustrate that, contrary to
allylic substitutions with trisubstituted alkenes,10 ECA to
cyclic enones with Si-substituted vinylaluminums proceed
readily and with high enantioselectivity in the presence of
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Journal of the American Chemical Society
COMMUNICATION
Scheme 2. More Variations in Vinylaluminum Reagent and
Substratea
Scheme 4. Application to Enantioselective Synthesis of Ric-
cardiphenol B
a Reactions performed under conditions used in Table 1-2, with the
noted specifications; conv. (>98% in all cases), yields and selectivity
values determined as in Tables 1-2. Percent vinyl addition is relative to
the i-Bu byproduct and not an absolute value.
Conditions: (a) 1. 2.5 equiv n-BuLi, thf, 0-22 °C, 1.5 h; 10 equiv of
23, -78-22 °C, 12 h. 2. 10 equiv of MeLi, thf, 0-22 °C, 3 h; 70%
overall (two steps). (b) 1. 10 equiv of SOCl2, pyr, 0-22 °C; 61%. 2.
10 equiv of (n-Bu)4NF, 110 °C, 6 h; 62%.
Scheme 3. Utility of the Enantiomerically Enriched Vinylsilanes
91% yield as a 91:9 Z:E mixture. Similar conversion to 18
proceeds in quantitative yield and without detectable loss of
alkene stereochemistry (>98% Z). Protodesilylation with tri-
fluoroacetic acid is highly effective as well: synthesis of 19-20 in
76% and >98% yield, respectively, are representative.23
The utility of the method is demonstrated through enantioselective
synthesis of riccardiphenol B (Scheme 4).24 NHC-Cu-catalyzed
reaction of commercially available β-methylcyclohexenone
with complex 3b and vinylaluminum 21, conveniently and selec-
tively prepared by hydroalumination of the corresponding enyne,
followed by treatment with Ac2O furnishes enol acetate 22 in
67% overall yield and 98.5:1.5 er. Generation of the correspond-
ing Li-enolate by subjection of 22 to n-BuLi and addition of
excess o-quinone methide 23, prepared and used in situ,25 leads
to the formation of the derived R-benzyl adduct (>98:2 dr).26
Subsequent ketone alkylation with MeLi affords tertiary carbinol
24 in 70% overall yield. Formation of the tetrasubstituted olefin
with SOCl2 and protodesilylation delivers the target molecule.
Development of additional catalytic enantioselective C-C
bond-forming processes that are promoted by NHC-based chiral
catalysts and involve vinylic organometallic reagents as nucleo-
philes are in progress.
Conditions: (a) 1. 1.5 equiv of m-chloroperbenzoic acid, CH2Cl2, 0 °C,
3 h; 96%. 2. HCO2H, 100 °C, 1 h; 70%. (b) 2.6 equiv of N-iodosuccinimide,
MeCN, 0-22 °C, 12 h. (c) F3CCO2H, CHCl3, 22 °C, 6 h.
’ ASSOCIATED CONTENT
efficiently and in high er. Protodesilylation of 14 or 15 (see below
for procedure) will generate β-vinyl products that cannot be
as easily accessed through the use of the volatile vinyl halide
(metal-halogen exchange/reaction with aluminum-halide)
or hydroalumination of acetylene.
The transformations depicted in Scheme 3 highlight the utility
of the Si-containing ECA products. Through a two-step proce-
dure that includes site-selective epoxidation of the vinylsilane
followed by a rearrangement induced by a mild acid,19 enone
16;the product of a hitherto unknown enantioselective acyl
anion conjugate addition20;is obtained in 67% yield. Subjection
of 7b to N-iodosuccinimide21 delivers enantiomerically enriched
vinyl iodide 17, which can be used in catalytic cross-coupling,22 in
S
Supporting Information. Experimental procedures and
b
spectral, analytical data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
’ ACKNOWLEDGMENT
Financial support was provided by the NIH (GM-47480).
T.L.M. is grateful for a Raymond L. Rodin graduate fellowship.
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Journal of the American Chemical Society
COMMUNICATION
We thank Dr. Simon J. Meek for valuable discussions. Mass
spectrometry facilities at Boston College are supported by the
NSF (DBI-0619576).
(15) The opposite sense of absolute stereochemistry observed with
sulfonate-containing Cu complexes derived from 2 and 3a-c (entries
2-5, Table 1), vs those obtained through phenoxy-based 1 (entry 1) or
monodentate 4 (entry 6), might be due to their unique stereochemical
characteristics. Structural studies indicate that, unlike the bridging
aryloxide in 1 or monodentate carbenes such as those obtained via 4
and 5, the sulfonate in such chiral Cu complexes is oriented syn to the
neighboring Ph group of the NHC backbone. See: Lee, Y.; Li, B.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 11625.
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stereochemistry. Investigations regarding identification of cata-
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and enantioselectivity are in progress and will be reported in due
course.
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alkylation product. In contrast, when benzyl bromide is used, the desired
product is obtained in 74% yield (>20:1 dr). The above findings suggest
that subtle structural alterations of the electrophile can inhibit reaction of
the sterically congested enolate. The stereochemical identity of the
alkylation product (>98% dr) is projected on the basis of steric factors
and has not been rigorously determined.
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