Enantioselective synthesis of boron-substituted quaternary carbons by NHC-Cu-catalyzed boronate conjugate additions to unsaturated carboxylic esters, ketones, or thioesters

Article abstract of DOI:10.1021/ja104777u

A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic α,ss-unsaturated carboxylic esters, ketones, and thioesters is disclosed. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C₁-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired ss-boryl carbonyls in up to >98:2 enantiomer ratio (er). Processes involving unsaturated thioesters proceed with higher enantioselectivity (vs carboxylic esters or ketones), and the resulting products can be functionalized by Ag-mediated or Pd-catalyzed reactions that furnish the derived carboxylic ester or various ketones. Routine oxidation affords ss-hydroxy ketones or carboxylic esters, ketone aldol products that cannot be otherwise prepared efficiently by an alternative catalytic enantioselective protocol.

Full text of DOI:10.1021/ja104777u

Published on Web 07/19/2010
Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by
NHC-Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic
Esters, Ketones, or Thioesters
Jeannette M. O’Brien, Kang-sang Lee, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received June 3, 2010; E-mail: amir.hoveyda@bc.edu
electrophiles such as nitroalkenes3 and Meldrum acid derivatives4 or
Abstract: A Cu-catalyzed method for enantioselective boronate
conjugate additions to trisubstituted alkenes of acyclic R,ꢀ-unsatur-
ated carboxylic esters, ketones, and thioesters is disclosed. All
transformations are promoted by 5 mol % of a chiral monodentate
NHC-Cu complex, derived from a readily available C1-symmetric
imidazolinium salt, and in the presence of commercially available
bis(pinacolato)diboron. Reactions are efficient (typically, 60% to
>98% yield after purification) and deliver the desired ꢀ-boryl
pyridylsulfones (with vinylboronic acids).5 Of particular significance
are related processes that furnish B-substituted quaternary carbons
(Scheme 1);6 subsequent oxidation would deliver the product of a
ketone aldol process in high enantiomeric purity.7 We have introduced
enantioselective processes involving aryl alkenes8 and terminal
alkynes,9 where Cu-based NHC complexes serve as catalysts to
generate tertiary B-substituted carbon centers. More recently, we have
set out to examine the ability of such NHC-Cu complexes, developed
carbonyls in up to >98:2 enantiomer ratio (er). Processes involving
unsaturated thioesters proceed with higher enantioselectivity (vs
carboxylic esters or ketones), and the resulting products can be
in these laboratories, to promote enantioselective formation of B-
substituted quaternary carbon stereogenic centers.10
functionalized by Ag-mediated or Pd-catalyzed reactions that furnish
Table 1. Initial Evaluation of Various Chiral NHC Complexesa
the derived carboxylic ester or various ketones. Routine oxidation
affords ꢀ-hydroxy ketones or carboxylic esters, ketone aldol products
that cannot be otherwise prepared efficiently by an alternative
catalytic enantioselective protocol.
Herein, we report the first cases of catalytic enantioselective
conjugate boronate additions1 to trisubstituted alkenes of acyclic R,ꢀ-
unsaturated carboxylic esters, ketones, and alkylthioesters, resulting
in the formation of B-substituted quaternary carbon stereogenic centers
(Scheme 1). Transformations proceed with commercially available
bis(pinacolato)diboron (1) and are promoted by a readily accessible
(three steps; ∼40% overall yield) chiral C1-symmetric Cu-based
N-heterocyclic carbene (NHC) complex; the desired ꢀ-boryl carbonyls
are formed in up to 99:1 enantiomeric ratio (er). Oxidation affords
ꢀ-hydroxy ketones or carboxylic esters (ketone aldol products; Scheme
1). Reactions of unsaturated thioesters are generally more enantiose-
lective (vs carboxylic esters or ketones); such processes may be
followed by Ag-mediated or Pd-catalyzed cross-coupling reactions
involving the S-based moiety, allowing conversion to carboxylic esters
and unsaturated ketones, respectively.
Scheme 1. B-Substituted Quaternary Centers by Cu-Catalyzed
Conjugate Additionsa
a Reactions performed under N2 atmosphere. b Values determined by
analysis of 400 MHz 1H NMR spectra of unpurified mixtures. c Values
determined by HPLC analysis; see the Supporting Information for
details. B(pin) ) pinacolatoboron.
a B(pin) ) pinacolatoboron.
We began by probing the ability of Cu complexes derived from
In spite of advances made regarding catalytic enantioselective
conjugate addition reactions,2 protocols that involve acyclic R,ꢀ-
unsaturated carbonyls (vs cyclic enones) and deliver quaternary carbon
stereogenic centers remain scarce. The limited number of existing
methods involves additions of alkylmetals to strongly activated acyclic
imidazolinium salts 2-6 to serve as chiral catalysts; unsaturated ester
7 served as the initial substrate. As the data in Table 1 indicate, use of
bidentate 211 leads to an efficient process but affords 8 with low
enantioselectivity (68.5:31.5 er). Conjugate additions with 3a-b12 are
significantly more selective (up to 88:12 er), but relatively low catalytic
9
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10.1021/ja104777u  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Cu-NHC-Catalyzed Enantioselective Boronate
Table 2. NHC-Cu-Catalyzed Enantioselective Boronate Conjugate
Additions to Aryl-Substituted R,ꢀ-Unsaturated Estersa
Conjugate Additions to Alkyl-Substituted R,ꢀ-Unsaturated Estersa
entry
aryl
R
time (h)
conv (%)b
yield (%)c
erd
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
24
24
24
36
18
12
24
36
18e
>98
>98
38
>98
>98
>98
>98
73
80
92
31
>98
96
93
93
69
90
96.5:3.5
95.5:4.5
53:47
96.5:3.5
97:3
98:2
99:1
95:5
94.5:5.5
o-BrC6H4
o-MeC6H4
2-naphthyl
m-BrC6H4
p-BrC6H4
p-CF3C6H4
p-OMeC6H4
Ph
a All reactions performed under identical conditions used to obtain R-10.
Transformation carried out at -50 °C.
b
>98
Scheme 3. Cu-NHC-Catalyzed Enantioselective Boronate
Conjugate Additions to R,ꢀ-Unsaturated Ketones
a See footnote a in Table 1. b See footnote b in Table 1. c Yields of
purified products. d Determined by HPLC analysis. See the Supporting
Information for details. e Performed at -15 °C.
activity is furnished by the derived NHC-cuprates. A number of
structurally distinct monodentate Cu-carbenes were also investigated
(entries 4-8, Table 1) and found to offer improved efficiency (95%
to >98% conv), with the C1-symmetric Cu complex of 5c delivering
the highest er (88:12). Although the reaction with the C2-symmetric
Cu complex 4 generates higher selectivity than the C1-symmetric 5a,
it was through modification of the symmetric N-aryl moiety of the
latter system that improvement in enantioselectivity was achieved (cf.
entry 5 vs 7). The above observations underline a notable advantage
of the monodentate C1-symmetric complexes, which can be more easily
modified compared to the more symmetric variants.13
complex of 5c (Scheme 2). ꢀ-Boryl ester R-10 is isolated in 80%
yield and 95.5:4.5 er; similar efficiency and selectivity are observed
in the formation of S-10 from Z-9 (vs R-10 from E-9). This is in
contrast to aryl-substituted substrates. For example, when Z-7 is
used, conjugate addition must be performed at -30 °C for
appreciable conversion levels (vs -78 °C for E-7 in entry 1, Table
2),15 affording R-8 in 61% yield (72% conv) and 89.5:10.5 er along
with ∼20% of the conjugate reduction product. The lower reactivity
of Z-7 vs Z-9 may be because the larger phenyl unit raises the
energy of the substrate conformer where the carbonyl properly
overlaps with the alkene [A(1,3)-type interaction]. Such consider-
ations are congruent with the significance of the strong σ-donating
ability of NHC-Cu complexes and π Lewis acidity of the
unsaturated carbonyl, as suggested by theoretical investigations.16
Formation of ꢀ-boronate ester 11 (Scheme 2), containing a
ꢀ-branched alkyl group, is efficient but substantially less selective
(73.5:26.5 er) than generation of 10, or the cyclohexyl-bearing 12,
which is generated in 94:6 er and quantitative yield.
Unsaturated ketones can be used in the NHC-Cu-catalyzed
processes as well, but reactions prove to be somewhat less
enantioselective than the aforementioned carboxylic esters (Scheme
3). Thus, ꢀ-boryl ketones 14-15 are obtained in 73-89% yield
and in 82.5:17.5-92:8 er. The transformation with the sterically
demanding phenylketone 13b, which must be performed at -30
°C for appreciable conversion, proceeds with lower selectivity than
that of the corresponding methyl ketone 13a.
To access a wider range of ꢀ-boryl carbonyls of high enantiomeric
purity, as well as address the diminished selectivity with which certain
aforementioned conjugate additions proceed, we turned to the reactions
of other substrate classes. First, the suitability of a Weinreb amide
was examined; the R,ꢀ-unsaturated amide corresponding to 7, however,
proved inert under the conditions described in Table 1 or Scheme 2
(<2% conv, 22 °C). Accordingly, we turned to unsaturated thioesters,17
leading us to establish that, as depicted in Scheme 4, NHC-Cu-
catalyzed boronate addition to thioester 16 furnishes the derived ꢀ-boryl
thioester 17 in 87% yield and 99:1 er. Although the reaction of 16 is
more sluggish than that of the corresponding carboxylic ester 7 and
must be performed at -50 °C (vs -78 °C), the desired product is
obtained with higher enantiomeric purity (99:1 er vs 96.5:3.5 er). A
similar trend in enantioselectivity is observed in reactions of alkyl-
With a reasonably effective NHC-Cu complex identified, further
optimization of conditions was performed (-78 °C and acidic
MeOH to ensure quench at low temperature14), allowing us to
establish that various aryl-substituted unsaturated esters undergo
highly enantioselective Cu-catalyzed boronate conjugate additions
(Table 2). Transformations with substrates bearing an o-bromo- or
a 2-naphthyl substituent (entries 2 and 4, Table 2) proceed to afford
the desired boronate in 92% and quantitative yield and 95.5:4.5
and 96.5:3.5 er, respectively. In contrast, however, the presence of
an o-Me unit results in substantial diminution in reactivity and
enantioselectivity (entry 3). Reactions with substrates bearing a m-
or p-bromo aryl group (entries 5-6, Table 2) or a trifluoromethyl
unit (entry 7) furnish the desired products in 93-96% yield and
97:3 to >98:2 er. Conjugate addition of the unsaturated ester bearing
an electron rich p-methoxyphenyl group affords the desired ꢀ-boryl
ester in 69% yield and 95:5 er but is relatively sluggish, likely due
to diminished substrate electrophilicity. A substrate that contains
an Et-substituted alkene (entry 9, Table 2) undergoes an efficient
and equally selective process at -15 °C (vs -78 °C in entry 1,
Table 2). With the corresponding unsaturated ester containing a
more sizable i-Pr unit, however, only the hydride conjugate addition
product is isolated (51% conv, 33% yield at 22 °C, 24 h). The
larger alkyl group may thus disfavor boronate addition at the more
hindered carbon, causing Cu-B addition to occur with the same
site selectivity as that in reactions of disubstituted aryl alkenes
(benzylic C-Cu).8 Alternatively, with a less reactive substrate, the
catalytically active NHC-Cu-B(pin) might react with MeOH to
generate MeOB(pin) and a sterically less demanding NHC-Cu-H,
which promotes conjugate hydride addition. The proposed inter-
mediacy of a chiral NHC-Cu complex is consistent with the finding
that the saturated ester product is formed in 78:22 er.
Alkyl-substituted unsaturated esters also undergo enantioselective
boronate conjugate additions in the presence of the NHC-Cu
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C O M M U N I C A T I O N S
Scheme 4. Cu-NHC-Catalyzed Enantioselective Boronate
Conjugate Additions to R,ꢀ-Unsaturated Thioestersa
Figure 1. Proposed models for NHC-Cu-catalyzed boronate conjugate
additions.
a Reactions performed under identical conditions used to obtain 17; >98%
Intermediacy of neutral B-Cu complex I (Figure 1, vs cuprates
from bidentate ligands) provides a rationale for the levels and trends
in selectivity. Alkene coordination likely occurs such that the Cu-B
bond is aligned with the substrate π*, while the carbonyl moiety
resides proximal to the NHC’s monosubstituted N-Ar (vs II). The
model accounts for the enhanced selectivity as the size of the
substituents of the symmetric N-Ar unit is increased (entries 5-7,
Table 1), as well as the inferior enantioselectivity with NHC-Cu
complex derived from meta-substituted 6. However, it is difficult
to explain the origin of lower enantioselectivity delivered by the
C2-symmetric complex derived from 4 (vs 5c); such variations may
be the result of subtle conformational changes of the four contiguous
aryl units of the NHC, caused by the presence of the 2,4,6-(i-Pr)3-
phenyl moiety. The lower er values of a ꢀ-branched substrate (e.g.,
11 vs 10 or 12) may be due to steric repulsion with methyl groups
of the pinacol. The reasons for inactivity of a Weinreb amide or
improved selectivities with thioesters, on the other hand, require
more detailed mechanistic investigations.
conv in all cases.
Scheme 5. Conversion of R-Boryl Thioesters to Esters and
Ketonesa
a See the Supporting Information for details. TC ) thiophene-2-
carboxylate.
substituted thioesters that deliver 18-20 (Scheme 4; compare to 10-12
in Scheme 2).
Acknowledgment. Financial support was provided by the NIH
(GM-57212) and the NSF (CHE-0715138). J.M.O. is a LaMattina
graduate fellow. We thank Dr. S. J. Meek for helpful suggestions.
Mass spectrometry facilities at Boston College are supported by
the NSF (DBI-0619576).
With a highly enantioselective method for synthesis of ꢀ-boryl
thioesters available, we turned to exploring selected modes of
product functionalization. Carboxylic esters (e.g., R-10) and aryl
or R,ꢀ-unsaturated ketones (e.g., 15) can be obtained via the
corresponding alkylthioesters in 62-85% yield through Ag-
mediated18 and Pd-catalyzed19 procedures, respectively (Scheme
5). The above two-step protocol thus furnishes products that are of
significantly higher enantiomeric purity than is available by
transformations of unsaturated esters or ketones.
Supporting Information Available: Experimental procedures and
spectral, analytical data for all products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Oxidation of the C-B bond delivers tertiary alcohols in high
yield (e.g., 21 in >98% yield, eq 1). The corresponding reactions
for efficient C-B to C-N conversion are yet to be disclosed; the
present study underlines the significance of such future develop-
ments, furnishing routes to enantiomerically enriched Mannich-
type products with N-substituted quaternary carbons.
References
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C O M M U N I C A T I O N S
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