Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones

Article abstract of DOI:10.1002/anie.200802910

(Chemical Equation Presented) Solution to pesky problems: Effective methods for catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents with unactivated β-substituted cyclopentenones are now available (see scheme). Transformations, pr

Full text of DOI:10.1002/anie.200802910

Communications
DOI: 10.1002/anie.200802910
Asymmetric Conjugate Additions
Enantioselective Synthesis of All-Carbon Quaternary Stereogenic
Centers by Catalytic Asymmetric Conjugate Additions of Alkyl and
Aryl Aluminum Reagents to Five-, Six-, and Seven-Membered-Ring
b-Substituted Cyclic Enones**
Tricia L. May, M. Kevin Brown, and Amir H. Hoveyda*
Dedicated to Professor Elias J. Corey
Catalytic asymmetric conjugate addition (ACA) reactions of
carbon-based nucleophiles to b,b-disubstituted enones pres-
ent an efficient approach to enantioselective synthesis of all-
carbon quaternary stereogenic centers[1] that reside adjacent
to synthetically versatile enolates [Eq. (1)]. In spite of recent
(5 mol%), are efficient (up to 97% yield) and highly selective
(up to > 99: < 1 e.r., greater than 98% ee). In the case of
transformations involving additions of aryl units, the requisite
aluminum-based reagents are prepared in situ from commer-
cially available dimethylaluminum chloride and the corre-
sponding aryl lithium compounds.
We began our investigations by examining the ability of
NHC complexes 1–4 (Scheme 1), previously developed in our
laboratories,[9] to promote ACA of trialkyl aluminum
reagents to cyclic enones. As the main objective of these
studies is reactions of b-substituted cyclopentenones, we
selected 6a to serve as the representative substrate (Table 1).
Our focus on aluminum-based reagents[10] is partly due to the
higher reactivity as well as the significantly lower cost of this
class of alkylating agents (vs. dialkyl zinc reagents).
advances involving catalytic ACA reactions of alkyl metal
(mostly dialkyl zinc) reagents,[2–5] a number of critical short-
comings remain unaddressed. One noteworthy challenge
concerns transformations of b-substituted cyclopentenones,
processes that are often less efficient[6,7] (vs. reactions of
larger rings) but can deliver products that may be used in
enantioselective syntheses of a variety of biologically active
natural products.[8] Previously reported approaches, involving
zinc-based reagents, are only effective with five-membered-
ring substrates when the enone bears an additional activating
substituent.[4] Additions of trialkyl aluminum reagents to b-
substituted cyclopentenones catalyzed by chiral copper phos-
phoramidites have been shown to proceed in three cases. In
only a single instance, however, is high selectivity observed
(ACA with Et3Al; 96.5:3.5 e.r., 93% ee).[5a] Herein, we
disclose an efficient set of protocols for catalytic ACA
reactions of alkyl and aryl aluminum reagents with a range
of unactivated b-substituted cyclic enones, including cyclo-
pentenones. Reactions, promoted in the presence of a chiral
bidentate N-heterocyclic carbene (NHC) copper complex
Through an initial screening study (Table 1), we estab-
lished that the first two generations of aryloxide-containing
NHC copper complexes derived from 1 and 2[9a–b] do not
[*] T. L. May, M. K. Brown, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: amir.hoveyda@bc.edu
[**] The NIH (GM-47480) and the NSF (CHE-0715138) provided
financial support. T.L.M. is grateful for LaMattina and Novartis
graduate fellowships; M.K.B. was the recipient of a Bristol-Myers
Squibb graduate fellowship. Mass spectrometry facilities at Boston
College are supported by the NSF (CHE-0619576).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802910.
Scheme 1. Air-stable chiral NHC silver(I) complexes that serve as
precursors to the corresponding copper-based catalysts.
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Chemie
Table 1: Initial screening of various NHC silver(I) complexes.[a]
be used effectively. The reactions in entries 8 and 9 of Table 2
are particularly noteworthy: the derived ACA products
represent b,b-disubstituted cyclopentanones that would be
obtained from ACA with alkynyl (not yet reported) and aryl
metal reagents (see below) to b-alkyl-substituted cyclic
enones, respectively.
Entry
NHC–AgI
Conversion [%][b]
e.r.[c]
ee [%][c]
Copper-catalyzed ACA of trialkyl aluminum reagents can
be extended to larger size cyclic enones (Table 3). Thus, under
the conditions described for the transformations in Table 2
(2.5 mol% NHC–AgI complex), b-substituted cyclohexe-
nones 8a–8c (entries 1–3, Table 3) as well as seven-mem-
bered-ring enone 9a (entries 4–5, Table 3) are transformed to
the corresponding b,b-disubstituted cyclohexanones or cyclo-
heptanones efficiently (85–91% yield after purification) and
with high enantioselectivity (91.5:8.5–95:5 e.r., 83–90% ee). It
is noteworthy that, compared to the previously reported
transformations involving bidentate NHC complex 2 and
dialkyl zinc reagents (up to 15 mol% 2 required), the present
method offers a more efficient approach to enantioselective
synthesis of b,b-disubstituted cyclohexanones and cyclohep-
tanones.[3g] Three additional points in connection with the
data in Tables 2 and 3 merit mention: 1) Although 5 is optimal
1
2
3
4
5
1
2
3
4
5
<2
<2
56
72
88
–
–
–
–
43
67
89
71.5:28.5
83.5:16.5
94.5:5.5
[a] Reactions were performed under N2 atmosphere. [b] Conversions
were determined by analysis of 400 MHz 1H NMR spectra of product
mixtures prior to purification. [c] Enantiomeric ratios and excesses were
determined by chiral gas–liquid chromatography (GLC) analysis; see the
Supporting Information for details.
promote the reaction of Me3Al with 6a at À788C (entries 1
and 2, Table 1).[11] In contrast, under identical conditions, the
copper complex derived from NHC sulfonate 3[4b] generates
56% conversion, affording 7a in 43% ee (71.5:28.5 e.r.,
entry 3, Table 1). Deletion of one of
the phenyl groups of the chiral
Table 2: Catalytic ACA reactions of trialkyl aluminum reagents to cyclopentenones promoted by NHC
NHC compound (complex 4,
entry 4, Table 1), a previously uti-
lized ligand alteration[9g] that we
surmised would enhance the effec-
tive size of a less geometrically
constrained mesityl substituent,
copper complexes.[a]
Entry Substrate [R]
(alkyl)3Al NHC–AgI T [8C] t [h] Yield [%][b] e.r.[c]
ee [%][c]
improves
enantioselectivity
(83.5:16.5 e.r., 67% ee). To explore
whether reaction efficiency and
enantiopurity of products can be
further enhanced, we prepared
NHC–AgI complex 5, which carries
the more sterically demanding
diethylphenyl substituent (entry 5,
Table 1). Copper-catalyzed ACA in
the presence of 2.5 mol% 5 pro-
ceeds to 88% conversion to furnish
7a in 89% ee (94.5:5.5 e.r.; entry 5,
Table 1).
1
2
3
4
5
6
7
8
6a [CH2CH2Ph]
6a [CH2CH2Ph]
6a [CH2CH2Ph]
6b [nBu]
6b [nBu]
6c [Me]
Me3Al
Et3Al
iBu3Al
Me3Al
Et3Al
5
5
5
5
4
4
4
5
5
3
À78
À78
À30
À78
À78
À78
À30
À78
À78
À78
24
4
21
15
6
71
97
74
80
86
97
83
71[d]
87
76
94.5:5.5 89
96:4 92
93.5:6.5 87
94:6
93:7
88
86
Et3Al
iBu3Al
4
98.5:1.5 97
94.5:5.5 89
95.5:4.5 91
6c [Me]
15
24
15
6
6d [CꢀC-nhep] Me3Al
9
10
6e [Ph]
Et3Al
Et3Al
98.2
96
6 f [CO2Me]
94.5:5.5 89
[a] Reactions were performed under N2 atmosphere; greater than 98% conversion in all cases. [b] Yields
of isolated, purified products. [c] Determined by chiral GLC analysis; see the Supporting Information for
details. [d] 5 mol% NHC and 10 mol% Cu salt was used to ensure complete conversion.
In the presence of 2.5 mol%
NHC–AgI complexes 3–5 and
5 mol% Cu(OTf)2, an assortment Table 3: Catalytic ACA reactions of trialkyl aluminum reagents with cyclohexenones and cyclohepte-
nones promoted by NHC copper complexes.[a]
of b-substituted cyclopentenones
undergo efficient ACA with three
commercially available trialkyl alu-
minum reagents (Table 2). These
catalytic transformations deliver
the desired products in 86–97% ee
(93:7–98.5:1.5 e.r.) and up to 97%
yield after purification. Five-mem-
bered-ring enones that bear an alkyl
(entries 1–7, Table 2), an alkynyl
(entry 8, Table 2), an aryl (entry 9,
Entry Substrate [R]
(alkyl)3Al NHC–AgI T [8C] t [h]
Yield [%][b] e.r.[c]
ee [%][c]
1[d]
2
8a [Me]
8b [5-hexenyl] Me3Al
iBu3Al
4
5
3
5
5
22
À78
À78
À78
22
0.25 89
95:5
95:5
90
90
12
6
12
85
91
90
3
4
8c [CO2Me]
9a [nBu]
Et3Al
Me3Al
Et3Al
91.5:8.5 83
92.5:7.5 85
94.5:5.5 89
5
9a [nBu]
0.25 87
Table 2), or
a carboxylic ester
(entry 10, Table 2) substituent can [a–c] See Table 2. [d] 5 mol% CuCl2·2H2O was used.
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Communications
for most processes, in certain cases, the related NHC–AgI
the sp2-hybridized carbon-based substituents of aluminum-
based reagents is significantly more facile than of those that
are sp3-hybridized.[9g] Accordingly, as illustrated in Table 4,
treatment of phenyllithium with one equivalent of commer-
cially available Me2AlCl in pentane (À78 to 228C, 12 h)
affords a solution of Me2PhAl containing LiCl, which can be
used directly—without filtration or purification—in copper-
catalyzed ACA reactions of b-substituted cyclic enones (e.g.,
cyclopentenone 6c and cyclohexenone 8a).
Due to the substantially different nature of the aluminum-
based reagent derived from phenyllithium (vs. trialkyl alumi-
num compounds),[3g] we decided to probe the ability of copper
complexes derived from 1–5 in promoting the addition of the
in situ generated reagent to 6c and 8a. As the results
summarized in Table 4 indicate, reactions performed at 228C
in the presence of 2.5 mol% NHC–AgI complex 2 (entries 2
and 7, Table 4) furnish the highest degrees of asymmetric
induction. When the catalytic ACA is carried out at À508C
(48 h; see entry 1, Table 5), 12c is obtained in 66% yield and
72% ee (86:14 e.r.).
complexes 3 and 4 deliver higher selectivity; such differences
are, however, not significant (not more than 10% ee). 2) In
some instances, ACA reactions proceed faster and deliver
slightly higher enantioselectivity when performed at rela-
tively elevated temperatures; the processes in entries 1 and 5
of Table 3 are notable in this regard. For example, ACA of b-
substituted cycloheptenone 9a (entry 5, Table 3) proceeds to
greater than 98% conversion at 228C within fifteen minutes
to afford the desired product in 89% ee (94.5:5.5 e.r.),
whereas at À788C, 12 h is required and the desired product is
obtained in 85% ee (92.5:7.5 e.r.). 3) In the reaction shown in
entry 1 of Table 3, involving iBu3Al and performed at 228C,
significant amounts of the [1,2]-hydride addition product (10–
15%) is isolated when Cu(OTf)2 is used. When CuCl2·2H2O is
used instead, the aforementioned byproduct is not observed
(less than 2% by 1H NMR spectroscopic analysis), while 10a
is generated with the same selectivity as obtained with
Cu(OTf)2. It should be noted that for reactions carried out at
À788C, use of CuCl2·2H2O (along with a chiral NHC) leads to
less than 10% conversion.
Next, we turned our attention towards developing a
procedure for catalytic ACA of aryl-based aluminum
reagents. Since only one triaryl aluminum compound[12] is
commercially available (Ph3Al), and use of such reagents
would not be particularly atom-economical, an alternative
procedure that provides access to a wider range of aryl metal
reagents is required. To address this problem, as shown in
Table 4, we envisioned that reaction of a readily accessible
aryl lithium reagent with a commercially available and
inexpensive dialkyl aluminum halide, such as Me2AlCl,
could lead to the formation of the corresponding dialkyl
aryl aluminum species.[13] It is well-established that transfer of
As the additional data summarized in Table 5 illustrate,
catalytic ACA with aryl aluminum reagents, generated in situ,
Table 5: Copper-catalyzed ACA of aryl aluminum reagents to b-substi-
tuted cyclic enones.[a]
Entry Substrate Ar
T
t
Yield
e.r.[c]
ee
[8C] [h] [%][b]
[%][c]
1
2
3
4
5
6
7
8
9
6c
6c
6c
6c
8a
8a
8a
8a
8a
C6H5
oMeC6H4
À50 48 66
À15 48 85
86:14
99:1
85.5:14.5 71
97.5:2.5 95
95:5
98:2
92:8
93:7
88:12
72
98
pOMeC6H4 À50 48 67
oOMeC6H4 À15 48 55
Table 4: Synthesis and in situ use of aryl aluminum reagents in copper-
catalyzed ACA.[a]
C6H5
À30 36 71
90
96
84
86
83
oMeC6H4
+4 42 49
pOMeC6H4 À50 36 61
pCF3C6H4 À30 36 52
oOMeC6H4 +4 48 60
[a–c] See Table 2. [c] Determined by chiral GLC or HPLC analysis (see the
Supporting Information for additional details).
can be performed on five- as well as six-membered b-
substituted cyclic enones, affording the desired products in up
to 98% ee (entry 2, Table 5). Examination of the findings
depicted in Table 5 indicates that aryl lithium species bearing
electron-donating (e.g., entries 3, 4, 7 and 9, Table 5) and
electron-withdrawing (entry 8, Table 5) substituents can be
used effectively.[14] Enantioselectivities appear to be highest,
however, when the aryl unit is sterically more encumbered
(i.e., carries an ortho group: entries 2, 4, and 6, Table 5). Two
additional points are noteworthy: 1) All aryl lithium reagents
(except for commercially available PhLi) were easily obtained
by treatment of commercially available aryl bromides with
nBuLi.[15] 2) Not only can the aryl aluminum reagents be used
Entry NHC–AgI Substrate Conversion [%][b] e.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
1
2
3
4
5
6c
6c
6c
6c
6c
8a
8a
8a
8a
8a
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
68.5:31.5
73.5:26.5
50:50
34:66
46.5:53.5
64:36
89:11
38:62
26:74
42.5:57.5 À15
37
47
<2
À32
À7
28
78
À24
À48
[a–c] See Table 1. Three equivalents of the aluminum-based reagent were
used.
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directly (without removal of LiCl),[16] the solution generated
from reaction of aryl lithium compounds with Me2AlCl can be
stored under N2 for more than two months and used in
catalytic ACA reactions without any noticeable diminution in
efficiency or enantioselectivity.
8416 – 8417; i) Y. Matsumoto, K-i. Yamada, K. Tomioka, J. Org.
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2008, 10, 2801 – 2804.
[4] a) Ref. [3b]; b) M. K. Brown, T. L. May, C. A. Baxter, A. H.
Hoveyda, Angew. Chem. 2007, 119, 1115 – 1118; Angew. Chem.
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The catalytic ACA reactions of b-substituted cyclopente-
nones outlined herein put forth an additional example of the
ability of bidentate NHC metal complexes in promoting
processes that are not effectively initiated by alternative
catalytic systems.[4b,9d,f] We demonstrate that this recently
developed class of chiral carbenes, prepared in five or six
steps,[17] can be structurally modified for achieving optimal
results (e.g., 3–5).[18] Although the transformations involving
cyclohexenones and cycloheptenones (i.e., Table 3), in some
cases, are slightly less selective than those performed in the
presence of other catalysts,[3c,5b] the present approach is more
general, since it offers an effective solution to the important
problem of ACA of five-membered-ring substrates. The
protocols presented are attractive from the practical point
of view, as they require the use of inexpensive and/or readily
available trialkyl aluminum reagents, aryl halides, or dialkyl
aluminum chlorides. In the case of ACA reactions of aryl
aluminum reagents, the requisite aryl metal reagent is
conveniently prepared and used in situ. The above attributes
render the catalytic enantioselective methods presented
herein of significant potential utility in enantioselective
chemical synthesis.[19] Development of additional catalytic
asymmetric protocols involving aluminum-based reagents
and application of the present processes to the total synthesis
of complex molecule natural products are among the
objectives being pursued in our laboratories.
[5] a) M. Vuagnoux-dꢀAugustin, S. Kehrli, A. Alexakis, Synlett 2007,
2057 – 2060; b) M. Vuagnoux-dꢀAugustin, A. Alexakis, Chem.
Eur. J. 2007, 13, 9647 – 9662.
[6] Catalytic ACA reactions to cyclopentenones are more challeng-
ing than other classes of cyclic enones. For example, see: a) I. H.
Escher, A. Pfaltz, Tetrahedron 2000, 56, 2879 – 2888; b) S. J.
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Org. Lett. 2002, 4, 3799 – 3801.
[7] For catalytic ACA reactions with cyclic enones where reactions
of cyclopentenones are either not discussed or reported to be
highly inefficient, see: a) Ref. [3c]; b) Ref. [3g]; c) Ref. [3h];
d) Ref. [3i].
[8] For representative examples of natural products bearing a b,b-
disubstituted cyclopentanone or related derivatives, see: a) G. L.
Chetty, S. Dev, Tetrahedron Lett. 1964, 5, 73 – 77; b) M. Segawa,
N. Enoki, M. Ikura, K. Hikichi, R. Ishida, H. Shirahama, T.
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A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 11130 – 11131;
b) J. J. Van Veldhuizen, J. E. Campbell, R. E. Giudici, A. H.
Hoveyda, J. Am. Chem. Soc. 2005, 127, 6877 – 6882; c) Y. Lee,
A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604 – 15605;
d) D. G. Gillingham, A. H. Hoveyda, Angew. Chem. 2007, 119,
3934 – 3938; Angew. Chem. Int. Ed. 2007, 46, 3860 – 3864;
e) Ref [3g]; f) M. A. Kacprzynski, T. L. May, S. A. Kazane,
A. H. Hoveyda, Angew. Chem. 2007, 119, 4638 – 4642; Angew.
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Received: June 18, 2008
Revised: July 1, 2008
Published online: August 7, 2008
[10] For a recent review on 1,2- and 1,4-additions with aluminum-
based reagents, see: P. von Zezschwitz, Synthesis 2008, 1809 –
1831.
[11] Screening of various Cu salts indicates that Cu(OTf)2 and
(CuOTf)2·C6H6 are generally most effective for this class of ACA
reactions. We selected Cu(OTf)2 as it is commercially available
and reaction outcomes promoted by this copper source tend to
be completely reproducible. Further details will be provided in
the full account of this work.
[12] For catalytic asymmetric reactions involving (aryl)3Al reagents,
see: a) K.-H. Wu, H.-M. Gau, J. Am. Chem. Soc. 2006, 128,
14808 – 14809; b) C.-A. Chen, K.-H. Wu, H.-M. Gau, Angew.
Chem. 2007, 119, 5469 – 5472; Angew. Chem. Int. Ed. 2007, 46,
5373 – 5376.
Keywords: asymmetric synthesis · homogeneous catalysis ·
N-heterocyclic carbenes · organoaluminum reagents ·
quaternary carbon centers
.
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[14] The somewhat moderate yields for the reactions in Table 5,
which are in spite of conversions greater than 98%, are partly
due to difficulties associated with removal of biphenyl formed in
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the course of the transformation. Modified procedures that
address this complication are under development.
experience, the required sequences do not require any signifi-
cant experimental expertise. It should be noted that NHC
complex 3 has already been used in a key step at an early stage of
a complex-molecule total synthesis: K. M. Peese, D. Y. Gin,
Chem. Eur. J. 2007, 14, 1645 – 1665.
[15] See the Supporting Information for additional details.
[16] Control experiments involving filtered solutions of aryl alumi-
num reagents or those where excess LiCl is added to the mixture
indicate that the presence of LiCl does not have any favorable or
deleterious effects on the catalytic ACA reactions when chiral
complex derived from 2 is used.
[18] For a general discussion regarding the significance of the ease of
structural modification of chiral catalysts to achieving optimal
results, see: A. H. Hoveyda, A. W. Hird, M. A. Kacprzynski,
Chem. Commun. 2004, 1779 – 1785.
[19] Studies involving vinylaluminum reagents (derived from reac-
tion of diisobutylaluminum hydride (dibal-H) with terminal
alkynes; cf. Ref. [9g]) indicate that this class of reactions requires
the development of more effective NHC-based catalyst systems.
[17] NHC–AgI complexes 4 and 5 are not yet commercially available
but can be prepared on a multigram scale in six steps from
commercially available tert-butoxycarbonylphenylglycinol (ca.
20% overall yield of isolated product). See the Supporting
Information for experimental and spectral details. In our
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Angew. Chem. Int. Ed. 2008, 47, 7358 –7362