A practical method for enantioselective synthesis of all-carbon quaternary stereogenic centers through NHC-Cu-catalyzed conjugate additions of alkyl- and arylzinc reagents to β-substituted cyclic enones

Article abstract of DOI:10.1021/ja062061o

We present the first examples of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic β-substituted enones. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-b

Full text of DOI:10.1021/ja062061o

Published on Web 05/13/2006
A Practical Method for Enantioselective Synthesis of All-Carbon Quaternary
Stereogenic Centers through NHC-Cu-Catalyzed Conjugate Additions of Alkyl-
and Arylzinc Reagents to â-Substituted Cyclic Enones
Kang-sang Lee, M. Kevin Brown, Alexander W. Hird, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received April 5, 2006; E-mail: amir.hoveyda@bc.edu
Scheme 1
Catalytic asymmetric conjugate addition (ACA) of carbon-based
nucleophiles to unsaturated carbonyls provides a direct route for
synthesis of enantiomerically enriched organic molecules.1 Progress
has been achieved in connection with catalytic ACA of alkylmetals
to different classes of unsaturated carbonyl compounds. Such
advances include the development of amino acid-based chiral
phosphines in these laboratories for Cu-catalyzed ACA of alkylzinc
reagents to cyclic2 and acyclic enones,3 nitroalkenes,4 and N-
acyloxazolidinones.5 A related approach involves Cu- and Rh-
catalyzed hydride conjugate additions to â-substituted enones.1,6
The significant majority of the above investigations involve
catalytic enantioselective synthesis of tertiary C-C bonds. The more
challenging problem of catalytic ACAs that afford all-carbon
quaternary stereogenic centers,7 a task that cannot be addressed by
enantioselective hydride additions, has been the subject of only a
small cluster of disclosures. Alexakis reported in 2005 that chiral
phosphoramidite‚Cu complexes can be utilized to catalyze ACA
of Me3Al and Et3Al to â-alkyl-substituted cyclohexenones.8 Cata-
lytic ACA of the less reactive but more functional group-tolerant
dialkylzinc reagents have been limited to highly electrophilic
Table 1. Initial Screening Studiesa
(activated) substrates. We showed in 2005 that chiral amino acid-
based ligands may be employed for Cu-catalyzed ACA of acyclic
trisubstituted nitroalkenes9 and cyclic tetrasubstituted alkylidene
â-ketoesters.10 Carretero has used Rh-catalyzed ACA of alkenyl-
boronic acids to unsaturated pyridyl sulfones (chiraphos as lig-
and).11 Most recently, Fillion has outlined a method for Cu-cata-
lyzed ACA of dialkylzinc reagents to acyclic aryl-substituted
alkylidene â-ketoesters that are derived from Meldrum’s acid
(phosphoramidites again used as ligands).12 Our initial focus on
reactions of the more activated systems (nitroalkenes and unsatur-
ated â-ketoesters) stemmed from the fact that peptide‚Cu complexes
are ineffective in catalyzing ACAs of alkylzincs to simple
â-substituted enones (<50% conv and <20% ee). To address the
above reactivity and selectivity problems, we turned our attention
to chiral bidentate N-heterocyclic carbenes (Scheme 1), entities
developed in these laboratories for Ru-catalyzed enantioselec-
tive olefin metathesis13 and later applied to Cu-catalyzed allylic
alkylations.14
Herein we report the first examples of Cu-catalyzed ACAs of
alkyl- and arylzinc reagents to simple unactivated â-substituted
cyclic enones. Transformations are promoted with of 2.5-15 mol
% of a readily available chiral NHC-based Cu complex,15 and afford
products that bear all-carbon quaternary stereogenic centers in
67-98% yield and up to 97% ee. Catalytic reactions can be carried
out on a benchtop, with undistilled solvent and commercially
available (not purified) Cu salts and in reasonable scale. Tentative
mechanistic models, accounting for the observed levels and trends
in enantioselectivity, are provided.
entry
catalyst
mol (%)
time (h)
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
(S,S)-1
(S,S)-2
(S,S)-4; CuCl2‚2H2O
(S,S)-4; Cu(OTf)2
(S,S)-4; CuOAc
(S,S)-4; CuTC
2.5
2.5
2.5; 5
2.5; 5
2.5; 5
2.5; 5
48
48
48
48
6
6
6
48
32
53
56
45
98
93
94
85
72
59
48
78
89
91
93
96
(S,S)-4; (CuOTf)2‚C6H6 2.5; 2.5
(S,S)-3; (CuOTf)2‚C6H6 2.5; 2.5
a Reactions performed under N2 atm. b Determined by 1H NMR analysis.
c Determined by chiral GLC analysis (see the SI for details).
as the representative process (Table 1). These studies indicated that,
although inefficient (32% conv, 48 h, -30 °C), Cu(II) complex 1
promotes the ACA with appreciable enantioselectivity (72% ee;
entry 1, Table 1). The “second-generation” NHC‚Cu complex 2
proved to be more effective (53% conv, 48 h), delivering 6 in 59%
ee. Next, we investigated NHC‚Ag(I) complex 4, which is precursor
to 2,14 and the ability of the derived in situ generated NHC‚Cu
complexes to promote ACA. As illustrated in entries 3-7 (Table
1), in all cases, including air-stable CuOAc and CuTC salts (entries
5-6), reactions proceed readily (93-98% conv in 6 h), and the
desired product is isolated with high asymmetric induction. The
highest enantioselectivity is obtained with (CuOTf)2‚C6H6, used in
conjunction with 4, affording 6 efficiently (94% conv in 6 h; 92%
Preliminary investigations focused on chiral NHC complexes
1-4 (Scheme 1); conversion of cyclohexenone 5 to ketone 6 served
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C O M M U N I C A T I O N S
Table 2. Cu-Catalyzed ACA of Dialkylzinc Reagents to
â-Substituted Cyclic Enonesa
Table 3. Cu-Catalyzed ACA of Diarylzinc Reagents to
â-Substituted Cyclic Enonesa
a-d See Table 2; 48 h. e At -15 °C. f At -15 °C, in toluene, 72 h. g Time
) 72 h.
performed with 10 mol % 4. (3) Catalytic ACAs of cycloheptenones
(entries 6-8, Table 2) deliver cyclic enones 11-13 in 76-85% ee
and 67-83% isolated yield. However, these transformations are
slower than their six-membered ring analogues. (4) Reactions of
eight-membered rings are slower and less selective than â-sub-
stituted cyclohexenones and cycloheptenones; the example pro-
vided in entry 9 (Table 2) is illustrative. The relatively unreactive
Me2Zn cannot be used (<5% conv, 48 h), and there is <5%
conversion with cyclopentenones (after 48 h).
The Cu-catalyzed protocol can be used to promote ACA of
diarylzinc reagents; desired cyclic ketones are obtained in 88-95%
isolated yield and 89-97% ee (Table 3). Transformations with
Ph2Zn proceed less readily than those involving dialkylzinc reagents,
but with higher enantioselectivity (e.g., compare entries 1-3 of
Table 3 with entries 1-3 of Table 2). Cu-catalyzed ACA can be
extended to an electron-rich diarylzinc reagent (entry 4 of Table
3), albeit with lower enantioselectivity (90% ee vs 97% ee in entry
1). Attempts to effect addition with the corresponding (p-CF3C6H4)2-
Zn16 gave rise to <5% conversion (e.g., with enone 5). As the
example in entry 5 of Table 3 indicates (18 formed in 96% ee),
ACA of Ph2Zn to â-substituted cycloheptenones proceeds with
enantioselectivity levels similar to those observed with cyclohex-
enones. To the best of our knowledge, catalytic ACA transforma-
tions of an arylmetal to afford an all-carbon quaternary stereogenic
center have not been reported previously.17
Cu-catalyzed ACA of dialkylzinc reagents (Table 2) proceed in
the opposite sense compared to reactions with diarylzinc reagents
(e.g., compare entry 5 of Table 2 and entry 2 of Table 3). Pre-
liminary mechanistic models that account for the observed enan-
tioselectivity, as well as the aforementioned reversal in the sense
of asymmetric induction, are presented in Scheme 2.18 Alkyl-cuprate
NHC complexes may undergo ACA through I; unfavorable steric
interaction involving the enone substituent (Me) and the NHC’s
biphenol moiety is therefore avoided. In contrast, with aryl-cuprate
complexes, the steric interaction between the enone’s â-substituent
and the aryl-Cu unit might be the dominant factor, giving rise to
preference for complex II.
a See Table 1 for conditions; 6 h for entry 1, 24-48 h otherwise. b By
1H NMR analysis. c Isolated yields. d Determined by chiral GLC analysis
(see the SI for details). e Reaction performed at -15 °C.
yield) and in 93% ee. Use of NHC-Ag(I) complex 3 and (CuOTf)2‚
C6H6 also leads to improvement in reactivity and selectivity (entry
8 vs with NHC-Cu(II) complex 1 in entry 1); the combination in
entry 7, however, delivers a more facile ACA. The data summarized
in Table 1 indicate that, when Cu(I) salts are used to generate the
chiral complex (entries 5-6), higher catalyst efficiency is achieved
(vs Cu(II) salts; >98% conv for entries 5-6 vs 45-55% conv for
entries 3-4). This difference in reactivity may arise from the slow
rate of Cu(II) f Cu(I) reduction under the reaction conditions, or
could be due to low solubility of Cu(II) salts in Et2O.
The combination of NHC‚Ag(I) complex 4 and (CuOTf)2‚C6H6
can be utilized to promote catalytic ACAs of commercially available
(not purified) dialkylzinc reagents to â-alkyl- and â-aryl-substituted
cyclic enones in 54-95% ee (Table 2).
Several points regarding the data in Table 2 are noteworthy: (1)
Transformations typically proceed to >80% conv after 6-48 h
(-30 °C); comparison between percent conversion and isolated
yield demonstrates that there is minimal formation of byproducts
(e.g., 1,2-addition). (2) Rates of reactions and levels of enantio-
selectivity are sensitive to steric factors. There is <5% conversion
when (i-Pr)2Zn is used. Catalytic ACA of Me-substituted enone
(6) in entry 1 (Table 2) requires 2.5 mol % 4 (94% conv), affording
the desired product in 93% ee; 5 mol % catalyst is needed for
n-alkenyl-substituted enone in entry 3 to proceed to 93% conversion,
delivering 8 in 84% ee. Consistent with this trend, enantioslective
synthesis of â-phenyl-substituted 10 (90% ee, 85% conv) must be
The optically enriched Zn-enolate intermediates can be converted
to versatile enolsilane or enoltriflate derivatives for further func-
tionalization.19 Representative cases are depicted in Scheme 3.
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C O M M U N I C A T I O N S
Scheme 2. Proposed Mechanistic Models
In summary, we have developed the first Cu-catalyzed ACA of
alkyl- and arylzinc reagents to unactivated â-substituted cyclic
enones; the catalytic protocol is operationally straightforward and
delivers cyclic ketones that bear all-carbon quaternary stereogenic
centers in excellent yields and 54-97% ee. This is the first
application of this class of chiral bidentate NHC ligands to catalytic
ACA reactions.
Acknowledgment. Financial support was provided by the NIH
(GM-47480) and the NSF (CHE-0213009). M.K.B. is a recipient
of an ACS Graduate Fellowship in Organic Chemistry (2005-6,
sponsored by Schering-Plough).
Supporting Information Available: Experimental procedures and
spectral, analytical data for all reaction products. This material is
available free of charge via the Internet at http://www.pubs.acs.org
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yield when the mixture from Cu-catalyzed ACA of Ph2Zn to 5 is
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The present class of transformations can be performed under
operationally simple conditions. As illustrated in eq 1, reactions
can be carried out with undistilled solVent and set up on benchtop
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commercially available (CuOTf)2‚toluene; nonetheless, use of
freshly prepared (CuOTf)2‚C6H6 leads to higher conversion.
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maximum activity), as the examples in entries 5-6 of Table 1
indicate, more user-friendly Cu salts are effective. When the
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and air stable CuOAc, 6 is isolated in 86% yield and 90% ee. Cu-
catalyzed additions can be performed on reasonable scale; the
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8-12 h), delivers 6 in 87% ee and in quantitative yield.
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