All-carbon quaternary stereogenic centers by enantioselective Cu-catalyzed conjugate additions promoted by a chiral N-heterocyclic carbene

Article abstract of DOI:10.1002/anie.200604511

(Chemical Equation Presented) Necessity is the mother of invention: When the available catalysts do not cut it, a new one has to be developed. A chiral N-heterocyclic carbene (NHC) is used in the first catalytic asymmetric conjugate addition of alkyl- and

Full text of DOI:10.1002/anie.200604511

Angewandte
Chemie
DOI: 10.1002/anie.200604511
Chiral Carbenes
All-Carbon Quaternary Stereogenic Centers by Enantioselective Cu-
Catalyzed Conjugate Additions Promoted by a Chiral N-Heterocyclic
Carbene**
M. Kevin Brown, Tricia L. May, Carl A. Baxter, and Amir H. Hoveyda*
The design of new chiral catalysts for enantioselective syn-
thesis of all-carbon quaternary stereogenic centers is a critical
and challenging objective in modern chemistry.[1] Such
catalysts must be enantio-differentiating but also especially
active because the desired reactions involve additions of
carbon nucleophiles to sterically congested electrophilic sites.
Herein,we disclose a readily available chiral N-heterocyclic
carbene (NHC) that can be used to promote the catalytic
asymmetric conjugate addition (ACA)[2] of organozinc
reagents to cyclic g-keto esters [Eq. (1)]; these transforma-
tions give rise to the enantioselective formation of all-carbon
quaternary stereogenic centers that bear a readily functiona-
lizable carboxylic ester substituent in up to 95% ee.[3–5] In
nearly all of the catalytic ACA reactions (one exception),the
new chiral NHC (Cu complex generated in situ) delivers
significantly higher efficiency and asymmetric induction than
the previously reported systems.
We began our investigation by examining the ability of Cu
complexes generated from the reaction of 1[5a] and 2[5c]
Scheme 1. Previously reported 1 and 2 and the new chiral NHC
complex 3.
(Scheme 1) with (CuOTf)2·C6H6 in promoting the ACA of
Me2Zn to five- and six-membered ring g-keto esters 4 and 5
(Table 1). With cyclopentenone 4a as the substrate and in the
presence of binaphthyl-based and (CuOTf)2·C6H6
(2.5 mol%),less than 10% conversion is detected after 24 h
(Table 1,entry 1). When biphenyl complex 2 is used,there is
only 15% conversion and 6 is formed in 30% ee (Table 1,
entry 2). With six-membered ring enone 5a,Cu-based com-
plexes derived from 1 and 2 (Table 1,entries 4–5) promote the
ACA of Me2Zn more efficiently (60% and > 98% conver-
sion) and with improved enantioselectivity (73% ee and
33% ee),but only in comparison to the reactions of cyclo-
pentenone 4a and not at synthetically useful levels.
1
[*] M. K. Brown, T. L. May, Dr. C. A. Baxter, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
Faced with the inferior activity and asymmetric induction
provided by the Cu complexes of 1 and 2,we set out to
identify a more effective chiral catalyst. This initiative led us
to discover that complex 3,[6] a sulfonate-containing chiral
NHC (Table 1,entry 3),promotes the addition of Me 2Zn to
4a with substantially higher efficiency (> 98% conversion,
17 h versus < 15% conversion with 1 and 2) and superior
enantioselectivity (84% ee versus ꢀ 30% ee with 1 and 2).
E-mail: amir.hoveyda@bc.edu
[**] We are grateful to the NIH(GM-47480) and the NSF (CHE-
0213009) for financial support. We thank Professor A. Alexakis
(University of Geneva) for generously sharing unpublished results
with us (reference [10]). M.K.B. and C.A.B. are recipients of an ACS
Graduate Fellowship in Organic Chemistry (sponsored by Schering-
Plough) and a Fulbright Distinguished Scholarship, respectively.
The X-ray facility at Boston College is supported by Schering-Plough;
Dr. R. J. Staples provided valuable assistance in obtaining X-ray
structures.
Furthermore,catalytic ACA of Me Zn to cyclohexenone 5a
2
proceeds efficiently with the Cu complex generated in situ
from 3,which affords 7 in 75% ee. Thus,in one case (compare
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Initial screening of various NHC–AgI complexes.[a]
Table 2: Initial screening of various NHC–AgI complexes.[a]
Entry
n
NHC–AgI
t [h]; Conversion [%][b]
ee [%][c]
Entry
n
NHC–AgI
t [h]; Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
1
1
1
2
2
2
(S)-1
24; <10
24; 15
17; >98
16; 60
18; >98
15; >98
n.d.
30
84
73
33
75
1
2
3
4
5
6
1
1
1
2
2
2
(S)-1
15; <2
42; 26
42; >98
21; 43
21; >98
18; >98
n.d.
25
81
46
93
(S,S)-2
(S,S)-3
(S)-1
(S,S)-2
(S,S)-3
(S,S)-2
(S,S)-3
(S)-1
(S,S)-2
(S,S)-3
À17
[a] Reaction performed under N2. [b] Conversions determined by analysis
of the 400 MHz HNMR spectra. [c] Enantioselectivities determined by
[a]–[c] See Table 1.
1
chiral GLC analysis; see the Supporting Information for details. n.d.=
not determined.
3. In contrast to the monomeric CuI complexes derived from 1
and 2,[8] in which the bidentate ligand gives rise to an eight-
membered chelate,the sulfonate-bearing system contains a
more geometrically constrained seven-membered ring. The
chelating heteroatom in complexes derived from 3 is less
basic. The latter difference is underlined by the chemical shift
values for the benzylic protons (proximal to biphenyl and aryl
Table 1,entries 4 and 6),the new NHC delivers the appreci-
able enantioselectivity offered by 1 (75% ee versus 73% ee)
together with higher reaction efficiency (> 98% conversion
versus 60% conversion). In another case (compare Table 1,
entries 5 and 6), 3 provides the high activity of 2 (> 98%
conversion) but also a significantly higher product enantio-
purity (75% ee versus 33% ee).[7]
Similar studies were performed with commercially avail-
able Ph2Zn. As illustrated in Table 2,entries 1 and 2,with 4b
as the substrate,reactions involving 1 and 2 are inefficient
(< 2% and 26% conversion in 15 h and 42 h,respectively). In
sulfonate) of complexes
2
(d = 5.36 ppm) and 3 (d =
À
6.55 ppm),as well as variations in the C Ag coupling constant
values (JCÀAg = 267.1 and 231.5 Hz for complex 2 versus JCÀ
Ag = 186.8 and 182.5 Hz for complex 3).[13] The unique
attribute of the sulfonate unit is further highlighted by the
finding that the related NHC–AgI complex that bears a
carboxylate group (versus a sulfonate),similar to 1 and 2,is
ineffective in promoting the present class of ACA reactions
(< 30% ee).[9]
the presence of 3,however,ACA of Ph Zn to cyclopentenone
2
4b is promoted with significantly higher efficiency (> 98%
conversion,81% ee in 42 h versus < 30% conversion and
< 30% ee with 1 and 2). The catalytic ACA of Ph2Zn to
cyclohexenone 5b (Table 2,entries 4–6) is the only instance in
which 3 is not superior to 1 or 2.
The differences in the reactivity and selectivity levels
mentioned above are substantial,and they likely arise from
significant steric and electronic differences between NHCs 1–
With the availability of complex 3,a variety of cyclic
ketones bearing carboxylic ester substituted all-carbon qua-
ternary stereogenic centers can be synthesized efficiently and
in high enantiomeric purity (Table 3). The improved selectiv-
ities in Table 3 (versus those in Table 1) are due to subsequent
studies that led us to establish that the addition of dialkylzinc
Table 3: Catalytic ACA of organozinc reagents to g-keto esters promoted with NHC complex 3.[a]
Entry
Substrate (R1)
R2Zn
Solvent; t [h]
Chiral NHC complex
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
4b (Me)
4a (tBu)
4b (Me)
4b (Me)
4a (tBu)
4b (Me)
4a (tBu)
5b (Me)
5a (tBu)
5b (Me)
5b (Me)
Me2Zn
Me2Zn
Et2Zn
[(Me)2CH(CH2)2]2Zn
(iPr)2Zn
Ph2Zn
Ph2Zn
Me2Zn
tBuOMe; 15
tBuOMe; 42
tBuOMe; 1
tBuOMe; 18
tBuOMe; 15
Et2O; 42
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-2
61
68
83
53
80
72
98
89
86
57
82
91
90
88
87
95
81
82
89
84
73
93
Et2O; 42
tBuOMe; 15
tBuOMe; 15
tBuOMe; 15
Et2O; 21
9
Me2Zn
(iPr)2Zn
Ph2Zn
10[e]
11
[a] Reactions performed under a N2 atmosphere; all conversion >98%. [b] Yield of isolated product after purification. [c] Enantioselectivities
determined by chiral GLC analysis (see the Supporting Information for details). [d] In this reaction, 5 mol% catalyst and 6 equiv Me2Zn was used.
[e] Reaction was carried out with 5 equiv styrene.
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reagents affords higher ee values when tBuOMe is used as the
solvent (versus Et2O). For example,as shown in Table 3,
entry 8,catalytic ACA of Me 2Zn to 5b leads to the formation
of the desired product in 89% ee (versus 75% ee in Et2O).
Several additional points are noteworthy: 1) In all cases,with
the addition of Ph2Zn to cyclohexenone 5b (Table 3,entry 11)
being the only exception,NHC-sulfonate 3 delivers the
highest enantioselectivity. 2) Methyl ester (4b and 5b) and
the more sterically hindered tert-butyl ester (4a and 5a)
substrates can be used. Typically,catalytic ACA of cyclo-
pentenones 4a–b (Table 3,entries 1–7) proceed to furnish
products in higher enantiomeric purity than those of cyclo-
hexenones 5a–b (Table 3,entries 8–11). 3) The effect of
added styrene as a radical scavenger in the reactions of
organozinc reagents was investigated.[10] In one case (Table 3,
entry 10),the selectivity improves to 73% ee from 60% ee; in
other instances,minimal ( < 5%) alteration of the enantiose-
lectivity is observed.
are simple to perform: as depicted in Equation (4),reactions
can be set up on a benchtop and performed with commercially
available (CuOTf)2·toluene (Aldrich,not purified),in undis-
tilled solvent,and with commercial grade organozinc
reagents.
Chiral NHCs,relative newcomers on the scene,have had a
notable influence on enantioselective synthesis.[13] A new
chiral NHC impacts asymmetric catalysis involving a variety
of metals[13] and can facilitate the utility of such carbenes as
catalysts.[14] With its distinct steric and electronic attributes,
complex 3 enhances the possibility to achieve higher reac-
tivities and selectivities in catalytic asymmetric processes.
Realization of such goals,study of the mechanistic details of
the present class of ACA reactions,and applications to target-
oriented synthesis are the subjects of ongoing investigations.
The special versatility of the enantiomerically enriched
product obtained by the Cu-catalyzed protocol is partly
because,in contrast to b,b’-dialkyl ketones,[3b,c,g,h] the carbox-
ylic ester unit provides a convenient handle for many
structural manipulations. As the enantioselective synthesis
of alcohol 10 illustrates [Eq. (2)],the carboxylic ester can be
reduced while the ketone group is masked as a Zn enolate;
Received: November 3,2006
Published online: January 3,2007
Keywords: asymmetric catalysis · asymmetric synthesis ·
.
carbenes · conjugate addition · quaternary centers
[1] J. Christophers,A. Baro (Eds.), Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis,Wiley-VCH,
Weinheim, 2006.
[2] a) N. Krause,A. Hoffmann-Röder, Synthesis 2001,171 – 196;
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Weinheim, 2002,pp. 224 – 258.
[3] For previous studies regarding Cu-catalyzed ACA to afford all-
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4585; b) A. W. Hird,A. H. Hoveyda, J. Am. Chem. Soc. 2005,
127,14988 – 14989; c) M. dꢀAugustin,L. Palais,A. Alexakis,
Angew. Chem. 2005, 117,1400 – 1402; Angew. Chem. Int. Ed.
thus,the need for protection/deprotection of the more
reactive ketone carbonyl is obviated.[11] On the basis of initial
studies,enantioselective synthesis of 10 and its protected
variants through catalytic ACA of dialkyl- and diarylzinc
reagents to the corresponding b-substituted cyclic enones
with 1–3 are either inefficient and/or proceed with low
selectivity. For example,Cu-catalyzed ACA of Me 2Zn (to
afford benzyl-protected 10) and Ph2Zn to b-benzyloxymethyl
cyclohexenone in the presence of 2.5 mol% 1–3 proceeds to
less than 30% conversion. The above findings underline the
unique ability of the present protocol to allow access to
enantiomerically enriched b,b’-disubstituted ketones. As
2005, 44,1376 – 1378; d) P. Mauleon,J. C. Carretero,
Commun. 2005,4961 – 4963; e) E. Fillion,A. Wilsily,
Chem.
J. Am.
shown in Equation (3),Ph Zn,prepared in situ from the less
2
expensive commercial grade PhLi,[12] can be employed
Chem. Soc. 2006, 128,2774 – 2775; f) R. Shintani,W.-L. Duan,T.
Hayashi, J. Am. Chem. Soc. 2006, 128,5628 – 5629; g) K. Lee,
M. K. Brown,A. W. Hird,A. H. Hoveyda, J. Am. Chem. Soc.
2006, 128,7182 – 7184; h) D. Martin,S. Kehrli,M. dꢀAugustin,H.
Clavier,M. Mauduit,A. Alexakis, J. Am. Chem. Soc. 2006, 128,
8416 – 8417.
directly (see Table 3,entry 11). Cu-catalyzed ACA processes
[4] For Cu-catalyzed asymmetric allylic alkylations that afford all-
carbon quaternary stereogenic centers,see: a) M. A. Kacprzyn-
ski,A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126,10676 – 10681;
b) A. O. Larsen,W. Leu,C. Nieto-Oberhuber,J. E. Campbell,
A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126,11130 – 11131;
c) J. J. Van Veldhuizen,J. E. Campbell,R. E. Giudici,A. H.
Hoveyda, J. Am. Chem. Soc. 2005, 127,6877 – 6882; for NHC-
catalyzed asymmetric allylic alkylations with alkyl Grignard
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Communications
reagents,see: d) Y. Lee,A. H. Hoveyda, J. Am. Chem. Soc. 2006,
128,15604 – 15605.
[10] K. Li,A. Alexakis, Angew. Chem. 2006, 118,7762 – 7765; Angew.
Chem. Int. Ed. 2006, 45,7600 – 7603.
[5] For examples of Cu-catalyzed enantioselective reactions that
deliver all-carbon quaternary stereogenic centers and involve
catalysts bearing a chiral NHC, see references [3g,h] and [4b,c].
[6] Ag complex 3 is obtained in 98% yield (> 98% de) by treatment
of the imidazolium salt with Ag2O (THF/C6H6; 808C). The chiral
imidazolium salt is prepared in four steps from commercially
available starting materials. See the Supporting Information for
all details.
[7] For details regarding the proof of the stereochemical identities
of catalytic ACA products,see the Supporting Information.
[8] On the basis of steric considerations,it is likely that it is the
derived monomeric chiral NHC complexes that serve as active
catalysts; also see reference [3g].
[11] For functionalization of enolates derived from catalytic ACA
reactions,see: O. Knopff,A. Alexakis, Org. Lett. 2002, 4,3835 –
3837.
[12] a) D. Peꢁa,F. Lꢂpez,S. R. Harutyunyan,A. J. Minnaard,B. L.
Feringa, Chem. Commun. 2004,1836 – 1837; b) J. G. Kim,P. J.
Walsh, Angew. Chem. 2006, 118,4281 – 4284; Angew. Chem. Int.
Ed. 2006, 45,4175 – 4178.
[13] For a review regarding synthesis,catalytic activity,and structural
characteristics of NHC complexes,see: J. C. Garrison,W. J.
Youngs, Chem. Rev. 2005, 105,3978 – 4008.
[14] For an enantioselective NHC-catalyzed protocol that affords all-
carbon quaternary stereogenic centers,see: M. S. Kerr,T. Rovis,
J. Am. Chem. Soc. 2004, 126,8876 – 8877.
[9] We are grateful to K.-s. Lee for carrying out these experiments.
Details will be disclosed in a separate account.
1100
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