Enantioselective synthesis of quaternary carbon stereogenic centers through copper-catalyzed conjugate additions of aryl- and alkylaluminum reagents to acyclic trisubstituted enones

Article abstract of DOI:10.1002/anie.201304035

Acyclic quaternary carbons by conjugate addition: The first examples of catalytic enantioselective conjugate additions of aryl and alkyl units that generate acyclic all-carbon quaternary stereogenic centers have been developed (see scheme). The requisite

Full text of DOI:10.1002/anie.201304035

Angewandte
Chemie
Communications
Enantioselective Catalysis
J. A. Dabrowski, M. T. Villaume,
A. H. Hoveyda*
&&&& — &&&&
Enantioselective Synthesis of Quaternary
Carbon Stereogenic Centers through
Copper-Catalyzed Conjugate Additions of
Aryl- and Alkylaluminum Reagents to
Acyclic Trisubstituted Enones
Acyclic quaternary carbons by conjugate
addition: The first examples of catalytic
enantioselective conjugate additions of
aryl and alkyl units that generate acyclic
all-carbon quaternary stereogenic centers
have been developed (see scheme). The
requisite organoaluminum reagents can
either be prepared in situ from easily
available organolithiums or purchased at
low cost.
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DOI: 10.1002/anie.201304035
Enantioselective Catalysis
Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers
through Copper-Catalyzed Conjugate Additions of Aryl- and
Alkylaluminum Reagents to Acyclic Trisubstituted Enones**
Jennifer A. Dabrowski, Matthew T. Villaume, and Amir H. Hoveyda*
Development of methods for efficient catalytic enantioselec-
tive conjugate addition (ECA) of readily accessible carbon-
based nucleophiles to a,b-unsaturated carbonyls is a major
objective of research in chemical synthesis.[1] Progress has
been made in designing effective chiral complexes that
promote a variety of catalytic ECA reactions. One especially
challenging area corresponds to transformations that furnish
all-carbon quaternary stereogenic centers;[2] recent years
have witnessed a number of important advances in this
regard,[3–6] including applications to synthesis of complex
natural products.[7] Nonetheless, several important limitations
remain. One shortcoming is that the majority of processes
relate to reactions with cyclic systems.[4–7] The paucity of ECA
processes that involve acyclic trisubstituted substrates might
be because their transformations, unlike those of cyclic
enones, are not facilitated by ring strain; catalysts shown to
be effective in differentiating the enantiotopic faces of a Z
cyclic olefin might not provide optimal enantioselectivity with
commonly used linear E alkenes. The limited number of cases
involving acyclic substrates[3] correspond to incorporation of
alkyl groups or highly activated Meldrum acid derivatives.[3b–d]
There is one report of enantioselective Rh-catalyzed ECA of
acyclic enoates with sodium tetraarylborates (one aryl unit
transferred);[8] in a recent disclosure, three related examples
of Pd-catalyzed ECAwith PhB(OH)2 are shown to proceed in
up to 80:20 enantiomeric ratio (e.r.).[6c] Another study relates
to Cu-catalyzed ECA of methyl units to acyclic a,b-unsatu-
rated aryl- or heteroaryl-substituted ketones; in all but one
case (with Et3Al), Me3Al was used.[9]
The value of catalytic ECA processes that allow for
incorporation of aryl and different alkyl groups is demon-
strated in Scheme 1. A carbonyl group with a b-stereogenic
center substituted with a phenyl and a thienyl group has been
utilized in enantioselective preparation of a serotonin recep-
tor inhibitor;[10] another example is the agent against meta-
Scheme 1. Catalytic ECA of acyclic enones to afford all-carbon quater-
nary stereogenic centers can be applied to the total synthesis of
biologically active molecule and/or facilitate the elucidation of their
absolute stereochemical identity.
bolic disorder.[11] Access to
a related enantiomerically
enriched carboxylic acid, but one that carries two alkyl and
an aryl unit at its quaternary carbon stereogenic site, was
required to ascertain the absolute stereochemistry of acetyl-
choline esterase inhibitor physostigmine.[12]
Herein, we report the first Cu-catalyzed method for
efficient ECA of aryl and commonly occurring alkyl groups to
a range of trisubstituted acyclic enones. Arylaluminum
reagents are easily prepared in situ from aryllithium species
and commercially available dialkylaluminum halides; tri-
alkylaluminum reagents are inexpensive. A robust chiral
bidentate N-heterocyclic carbene (NHC) of silver and
commercially available Cu(OTf)2 are combined to form the
chiral catalyst (0.5–3.0 mol%; 0.5–24 h); products are formed
in 33–95% yield and 90:10 to > 99:1 e.r. It should be noted
[*] J. A. Dabrowski, M. T. Villaume, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center, Boston
College, Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[**] Financial support was provided by the NIH (GM-47480); J.A.D. is
grateful for a LaMattina Graduate Fellowship. We thank E. M. Vieira
for helpful suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304035.
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Table 1: NHC-Cu-catalyzed ECA with various aryl(dimethyl)aluminum reagents.[a]
that, although efficient catalytic enantioselective
allylic substitutions (EAS) with the same types of
organoaluminum reagents have been reported,[13]
ECA processes present a distinct challenge for
several reasons. In both cases, nucleophilic addition
of an organocopper intermediate is likely followed
by reductive elimination; the first key step, however,
Entry Ar1
Ar
Product Conv. [%][b]
Yield [%][c]
;
Ar vs. Me e.r.[d]
addn[b]
À
is reversible only in ECA, requiring C C bond
1
2
3
4
5
6
7
8
2-thienyl; 2c
o-FC6H4; 2d
p-F3CC6H4; 2e
p-MeOC6H4; 2 f Ph
Ph; 2b
Ph; 2b
3-thienyl; 2a
3-thienyl; 2a
Ph
Ph
Ph
3b
3c
3d
3e
3 f
73; 57
88; 33
89; 76
>98; 82
>98; 82
>98; 77
>98; 83
>98; 89
>98:2
55:45
92:8
>98:2
92:8
>98:2
>98:2
>98:2
92:8
>99:1
94:6
98:2
98:2
>99:1
96:4
>99:1
formation to be sufficiently rapid. Moreover, the
relative position of the alkene and the phosphate or
carbonyl unit in EAS and ECA processes, respec-
tively, are different; such factors are significant in
reactions that likely involve association of the Lewis
basic groups with the catalytic complex.[14]
pF3CC6H4
pMeOC6H4 3g
pF3CC6H4
pMeOC6H4 3i
3h
We began by exploring the possibility of access-
ing the thienyl-containing ketone, used in the syn-
thesis of a serotonin receptor inhibitor (Scheme 1),
by an efficient enantioselective ECA. We thus
established that treatment of enone 2a with three
equivalents of Ph(Me)2Al, generated in situ from
reaction of PhLi and Me2AlCl, and 3.0 mol% of an
[a] Reactions were performed under N2 atmosphere. [b] Determined through
1
analysis of 400 MHz H NMR spectra of unpurified mixtures. [c] Yield of isolated
and purified products. [d] Determined by HPLC analysis (Æ2%); see the Supporting
Information for details.
which emerged as the superior choice, has not been previously
employed.[13]
A range of trisubstituted enones and in situ generated
aryl(dialkyl)aluminum reagents can be used (Table 1). Reac-
tion involving 2-thienyl-substituted 2c (vs. 3-substituted 2a,
Scheme 2) with Ph(Me)2Al leads to 73% conversion in 12 h
(entry 1), and 3b is isolated in 57% yield with complete
transfer of the phenyl unit in 92:8 e.r. Formation of the
sterically demanding stereogenic center that contains two aryl
groups is relatively sluggish when one bears an ortho unit; the
example in entry 2 is illustrative (17% conv. with the derived
ortho chloroaryl substrate). Synthesis of ortho-fluoroaryl 3c
thus proceeds in 33% yield and is accompanied by the
product derived from Me transfer (Ph:Me 55:45); however,
the ECA remains exceptionally enantioselective (> 99:1 e.r.).
Cu-catalyzed ECA with enones that contain electron-defi-
cient or electron-rich aryl units proceed efficiently and with
high enantioselectivity: 3d and 3e are obtained in 76% and
82% yield, with 92% and > 98% group selectivity and in 94:6
and 98:2 e.r., respectively (entries 3 and 4). Similarly high
efficiency and enantioselectivity is observed with aryl-
(dimethyl)aluminum reagents that carry electron-withdraw-
ing or -donating groups (entries 5–8). The example in
Scheme 2. Preparation of aryl(dimethyl)aluminum reagents and their
in situ use in NHC-Cu-catalyzed ECA reactions with trisubstituted
enones to generate all-carbon quaternary stereogenic centers.
Equation (1), regarding formation of 3j in 67% yield,
> 98% transfer of Ph group and 96:4 e.r., demonstrates that
catalytic ECA can be performed with high selectivity with
enones that contain only alkyl substituents.
NHC–Cu catalyst derived from Ag complex 1 and Cu-
[15]
(OTf)2 leads to the formation of (R)-3a in 85% yield and
99:1 e.r. (Scheme 2). Reaction is complete in 12 h at À308C
without generating any detectable amount of byproducts
derived from Me transfer.[13] As further depicted in Scheme 2,
we evaluated the possibility of performing an enantioselective
ECA with the corresponding thienyl-aluminum reagent and
phenyl-substituted a,b-unsaturated ketone 2b. Under the
latter conditions, the transformation proceeds to complete
conversion in 12 h, affording (S)-3a in 80% yield and > 99:1
e.r.; however, there is 15% of the achiral product derived
from Me transfer.[16] The NHC–Cu complex derived from 1,
Access to the corresponding enantiomerically enriched
carboxylic acid derivatives increases the value of the protocol
(cf. Scheme 1); nonetheless, our attempts to identify condi-
tions for efficient ECA with related derivatives (e.g., Weinreb
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amides, N-acyloxazolidinones, carboxylic esters, thioesters)
proved unsuccessful (< 10% conv.). To address the above
problem, we identified a two-step procedure that can be
completed in less than 2 h, without the need for purification of
the silyl enol ether intermediate, to obtain the derived
carboxylic acid; the example leading to 4 in 95% yield is
representative [Eq. (2)].
We subsequently turned our attention to catalytic ECA
with Et3Al (Table 2), of which a single example exists
involving the transformation of a phenyl ketone.[9] We
therefore established that aryl- and heteroaryl-substituted
enones of different steric and electronic attributes can be used
Table 2: NHC-Cu-catalyzed ECA of aryl-substituted enones with Et3Al.[a]
Scheme 3. Representative cases of efficient and enantioselective NHC-
Cu-catalyzed ECA reactions with Et3Al and non-aryl-substituted enones
as well as with Me3Al and (iBu)3Al reagents.
Entry Ar; Substrate
Product t [h] Conv. [%][b]
;
e.r.[d]
differentiable carbonyl groups, illustrates that addition to the
site b to the ketone unit, versus to the carboxylic ester, is
exclusive in spite of formation of a more hindered quaternary
carbon stereogenic center. Representative reactions with
Me3Al are shown in Scheme 3 as well;[9] (R)-5a and (R)-5d
are obtained in 77% and 95% yield and > 99:1 and 97:3 e.r.,
respectively. Enantioselective synthesis of isobutyl-substi-
tuted ketone 7, generated in 82% yield and 98:2 e.r., shows
that the NHC-Cu-catalyzed protocol can be extended to ECA
with (iBu)3Al, another commercially available organoalumi-
num species the ECA of which has not been reported with
trisubstituted acyclic enones.
In addition to the efficient two-step protocol depicted in
Equation (2), ECA products without a relatively sensitive
heterocyclic substituent prone to adventitious oxidation (such
as 3a)[17] can be converted directly to the desired carboxylic
acids in a single step with commercial bleach.[18] The trans-
formation in Equation (3), resulting in the formation of
enantiomerically enriched 8 in 61% yield (98:2 e.r.) is
illustrative (cf. Scheme 1).
Yield [%][c]
1
2
3
4
5
6
7
Ph; 2b
2-thienyl; 2c
pF3CC6H4; 2e
5a
5b
5c
0.5
1.0
1.0
1.0
2.5
12
>98; 93
>98; 86
>98; 89
>98; 92
97; 94
98:2
98.5:1.5
99:1
99:1
97.5:2.5
pMeOC6H4; 2 f 5d
2-naphthyl; 2h
oBrC6H4; 2i
mFC6H4; 2j
5e
5 f
5g
98; 87
>99:1
96.5:3.5
3.0
>98; 90
[a] Reactions were performed under N2 atmosphere. [b] Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures.
[c] Yield of isolated and purified products. [d] Determined by GC analysis
(entries 1 and 2) or HPLC analysis (Æ2%); see the Supporting
Information for details.
in transformations that require 0.5 mol% of the NHC–Cu
complex to proceed to ꢀ 97% conversion, affording the
desired products in 96.5:3.5 to > 99:1 e.r. It is noteworthy that,
in contrast to ECA with the sterically more demanding
aryl(dimethyl)aluminum reagents, additions to substrates that
possess relatively large substituents, such as a 2-naphthyl or
an ortho-bromo unit (entries 5 and 6 of Table 2), proceed to
ꢀ 97% conversion with equally high enantioselectivities as
the less hindered acyclic enones.
The products shown in Scheme 3 underscore several vital
characteristics of the approach. Processes involving Et3Al
that lead to the formation of 6a and 6b demonstrate that
dialkyl-substituted enones can be used; the lower e.r. in the
case of 6a (90:10 vs. 98.5:1.5 for 6b) is likely due to
a diminished degree of differentiation between a Me and
a benzyl group (vs. a cyclohexyl). Enantioselective synthesis
of 6c, a product that contains two functionalizable and
Development of additional catalytic ECA protocols and
applications to complex molecule synthesis are in progress.
Received: May 10, 2013
Published online: && &&, &&&&
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5628; with Cu-based catalysts and arylaluminum reagents,
Keywords: copper · enantioselective conjugate additions ·
N-heterocyclic carbenes · organoaluminums ·
quaternary carbons
.
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[15] For data in connection to chiral ligand and Cu salt screening, see
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[16] Determination of the precise origin for the difference in aryl vs.
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reagents are reversible under the reaction conditions.
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´
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