Highly enantioselective conjugate additions to α,β-unsaturated ketones catalyzed by a (salen)Al complex

Article abstract of DOI:10.1021/ja044999s

Chiral (salen)Al complex 1a catalyzes the highly enantioselective conjugate addition of carbon-and nitrogen-based nucleophiles to acyclic α,β-unsaturated ketones. This methodology is tolerant of substantial variation of the ketone structure, providing acc

Full text of DOI:10.1021/ja044999s

Published on Web 01/06/2005
Highly Enantioselective Conjugate Additions to
r,â-Unsaturated Ketones Catalyzed by a (Salen)Al Complex
Mark S. Taylor, David N. Zalatan, Andreas M. Lerchner, and Eric N. Jacobsen*
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received August 18, 2004; E-mail: jacobsen@chemistry.harvard.edu
Abstract: Chiral (salen)Al complex 1a catalyzes the highly enantioselective conjugate addition of carbon-
and nitrogen-based nucleophiles to acyclic R,â-unsaturated ketones. This methodology is tolerant of
substantial variation of the ketone structure, providing access to a wide range of useful chiral building
blocks in high yield and enantiomeric excess. Synthetic manipulations of the conjugate addition products
are demonstrated, including the straightforward preparation of â-amino ketones and highly enantioenriched
carbo- and heterocyclic compounds.
Introduction
have been achieved with a range of nucleophilic partners,
including malonates, nitro compounds, O-alkylhydroxylamines,
The conjugate addition of nucleophiles to electron-deficient
olefins represents one of the best-established and versatile bond-
construction strategies in organic chemistry. Such reactions often
result in generation of new stereocenters, and accordingly 1,4-
additions have a long and important history in asymmetric
catalysis. In 1975, Wynberg and co-workers reported the seminal
discovery of Cinchona-alkaloid-catalyzed enantioselective ad-
dition of cyclic ketoesters to methyl vinyl ketone,1 and research
in asymmetric catalysis of conjugate addition reactions has
received increasing attention ever since.2 Early work in this field
led to significant advances, although the reactions were mostly
narrow in substrate scope and restricted to a particular combina-
tion of nucleophile and electrophile type. More recently, several
catalyst systems have been identified that exhibit a significantly
higher degree of generality with respect to one, or both, of the
reaction components. For example, Hayashi and co-workers
have demonstrated that (binap)rhodium complexes promote the
enantioselective conjugate addition of organoboron and orga-
nometallic reagents to a range of structurally diverse electron-
deficient olefins, including cyclic and acyclic R,â-unsaturated
ketones, esters, amides, phosphonates, and nitro compounds.3
The research groups of Feringa and Hoveyda have developed
novel phosphorus-centered ligands for highly enantioselective
copper-catalyzed additions of diorganozinc reagents to several
important electrophile classes.4,5 The binol(metal) catalysts
studied by Shibasaki and co-workers promote a variety of
enantioselective conjugate additions to R,â-unsaturated ketones,
acid imidazolides, and N-acylpyrroles. High enantioselectivities
and hydroperoxides.6 Metal-bis(oxazoline) complexes have
been shown to activate substrates capable of two-point binding
in a number of diverse conjugate addition applications.7 The
use of chiral amines to activate enals and enones toward
nucleophilic attack through the intermediacy of iminium ions
has emerged recently as a highly general strategy and forms
the basis for the enantioselective conjugate addition of electron-
rich arenes, nitroalkanes, and â-dicarbonyl compounds.8
(5) (a) Degrado, S. J.; Mizutani, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755-756. (b) Mizutani, J.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779-781. (c) Luchaco-Cullis, C. A.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (d) Degrado, S. J.; Mizutani,
H.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362-13363. (e) Hird,
A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276-1279. (f)
Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-2832.
(6) For conjugate addition of â-dicarbonyl compounds to cyclic enones, see:
(a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571-
1572. (b) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J.
Am. Chem. Soc. 1995, 117, 6194-6198. (c) Arai, T.; Sasai, H.; Aoe, K.;
Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996,
35, 104-106. (d) Majima, K.; Takita, R.; Okada, A.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 15837-15845. For hydro-
peroxide epoxidation of enones and acid imidazolides, see: (e) Nemoto,
T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2725-2732 and references therein. (f) Nemoto, T.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9474-9475. For conjugate
addition of nitroalkanes to chalcones, see: (g) Funabashi, K.; Saida, Y.;
Kanai, M.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557-
7558. For conjugate addition of O-alkylhydroxylamines to enones, see: (h)
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
16178-16179. For conjugate additions to N-acylpyrroles, see: (i) Kinoshita,
T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 4680-4684. (j) Natsunaga, S.; Kinoshita, T.; Okada, S.;
Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559-7570.
(7) For the Mukaiyama Michael reaction, see: (a) Johnson, J. S.; Evans, D.
A. Acc. Chem. Res. 2000, 33, 325-335 and references therein. For
conjugate addition of electron-rich aryl groups, see: (b) Jensen, K. B.;
Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 160-163. (c) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030-
9031. (d) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu,
J. J. Am. Chem. Soc. 2003, 125, 10780-10781. For conjugate addition of
carbamates, see: (e) Palumo, C.; Oiarbide, M.; Halder, R.; Kelso, M.;
Go´mez-Bengoa, E.; Garc´ıa, J. M. J. Am. Chem. Soc. 2004, 126, 9188-
9189. (f) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem.
Soc. 1998, 120, 6615-6616. (g) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2,
3393-3396. (h) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C.
P. J. Am. Chem. Soc. 2003, 125, 11796-11797.
(1) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 4057-4060. (b) Hermann,
K.; Wynberg, H. J. Org. Chem. 1979, 44, 2238-2244.
(2) For a review, see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-
8061.
(3) For a review, see: Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169-
196.
(4) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353 and references
therein. (b) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2003, 125, 3700-3701.
9
10.1021/ja044999s CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 1313-1317
1313

A R T I C L E S
Taylor et al.
Scheme 1. Asymmetric Conjugate Additions to R,â-Unsaturated
Imides Catalyzed by 1
actively pursued problem in asymmetric catalysis since the
inception of the field, and a variety of structurally diverse
catalysts have been developed to fulfill this purpose.11 Despite
these efforts, significant challenges remain, particularly with
respect to electrophile scope. Whereas additions to cyclic enone
substrates arguably constitute a solved problem for asymmetric
catalysis due to the elegant heterobimetallic catalysts developed
by Shibasaki,6a-d highly enantioselective conjugate addition to
acyclic enones remains an area of active investigation. In
particular, catalyst systems that exhibit generality with respect
to the ketone structure are rare. In this regard, the organocatalytic
addition of cyclic 1,3-dicarbonyl compounds reported recently
by Jørgensen constitutes the state-of-the-art system.8c
(a) Conjugate Addition of Nitriles. The addition of methyl
cyanoacetate to 4-phenyl-3-buten-2-one was chosen as a model
system for our investigation. A systematic optimization of the
reaction parameters revealed that the optimal conditions for
conjugate additions to enone substrates are virtually identical
to those previously reported for imide substrates; oxo-bridged
dimer 1a is the most active catalyst,12 and cyclohexane provides
the highest enantioselectivity of the solvents examined.13
However, the behavior of enones differed from that of imides
in two significant respects. First, addition of tert-butyl alcohol
was not necessary to accomplish complete conversion of ketone
substrates, although this additive was crucial to obtaining high
yield in the reactions of imides. Second, the catalyst loadings
needed for efficient reaction of ketone substrates were ap-
proximately 5-fold lower than those required for imides. Thus,
using 1.0 mol % catalyst and unpurified commercial reagents,
without the use of inert atmosphere techniques, the conjugate
addition product 2a was obtained in excellent yield (91%) and
enantiomeric excess (93%) after 16 h at 23 °C. Adduct 2a results
from the addition of methyl cyanoacetate to the re face of the
enone, consistent with results obtained previously with imide
electrophiles.
Our own efforts in the area of conjugate addition chemistry
have revealed that (salen)aluminum complexes catalyze the
efficient enantioselective 1,4-addition of a variety of weakly
acidic species, including hydrazoic acid, cyanide, thiols, nitrogen
heterocycles, and oximes, to R,â-unsaturated imides (Scheme
1).9 Secondary imides, and particularly N-benzoyl imides,
proved to be uniquely effective electrophiles among carboxylic
acid derivatives, suggesting that the special features of this
functional group (e.g., the N-H bond and/or the potential for
two-point binding to a metal center) might be tied intrinsically
to reactivity and high enantioselectivity with the (salen)-
aluminum catalysts. We report here that imides are in fact not
unique substrates for this conjugate addition chemistry, with
the discovery that simple R,â-unsaturated ketones undergo
highly enantioselective and exceptionally efficient conjugate
addition of carbon and nitrogen nucleophiles catalyzed by
complex 1a. This observation indicates that simple one-point
binding of an electrophile is sufficient for high enantioselectivity
in reactions catalyzed by (salen)aluminum complexes.10 In
addition to expanding the generality of these catalysts signifi-
cantly in conjugate addition chemistry, this result is an advance
of practical importance: a wide range of acyclic enones undergo
highly selective conjugate addition, providing access to useful
bifunctional building blocks for organic synthesis.
The reaction displays impressive generality with respect to
the enone â-substituent, with substrates bearing aryl, heteroaryl,
and alkyl groups undergoing highly enantioselective conjugate
addition (Table 1). Furthermore, although methyl ketones
generally provide the best results, n-butyl, phenyl, and isopropyl
ketones are all useful substrates (products 2e-2g, respectively).
As seen previously in conjugate additions to imides, methyl
cyanoacetate is not a uniquely effective nucleophile. Other
electron-deficient nitriles, such as malononitrile and benzene-
sulfonylacetonitrile, may also be used successfully (products
2h and 2i, respectively). In reactions of methyl phenylcyano-
acetate, two stereocenters, including an all-carbon-substituted
quaternary center, are generated with high diastereo- and
enantioselectivity (Scheme 2). The relative configuration of 2j
was established unambiguously by X-ray crystallography.
Results and Discussion
I. Enantioselective Conjugate Additions of Carbon-
Centered Nucleophiles. The enantioselective addition of sta-
bilized carbon-centered nucleophiles to enones has been an
(8) For conjugate addition of â-dicarbonyl compounds, see: (a) Yamaguchi,
M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1173-
1175. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 661-665. (c) Halland, N.; Hansen, T.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 4955-4957. For conjugate addition of
nitroalkanes, see: (d) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975-
2978. (e) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002,
67, 8331-8338. For conjugate addition of electron-rich aryl groups, see:
(f) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370-
4371. (g) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172-1173. (h) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 7894-7895. For the Mukaiyama Michael reaction, see:
(i) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 1192-1194.
(9) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
5960. (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442-4443. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 11204-11205. (d) Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 14724-14725. (e) Chen, Q.; Delmonte, A. G.; Gandelman,
M. A.; Jacobsen, E. N. Unpublished results.
(11) For a review, see: Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 3, Chapter 31.2.
(12) (Salen)aluminum complexes 1a-c (10 mol % Al loading) were tested as
catalysts for the addition of methyl cyanoacetate to 4-phenyl-3-buten-2-
one (0.2 M cyclohexane, 23 °C, 6.5 h). 1a: 93% conversion, 94% ee. 1b:
61% conversion, 94% ee. 1c: <2% conversion.
(10) (a) Salen-Red-Al-catalyzed Michael additions to cyclic ketones have been
described: Jha, S. C.; Joshi, N. N. Tetrahedron: Asymmetry 2001, 12,
2463-2466. (b) Catalyst 1c has been employed in enantioselective
conjugate additions of indoles to 1-aryl-3-buten-2-ones: Bandini, M.;
Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetrahedron
Lett. 2003, 44, 5843-5846.
(13) Various solvents were tested for the addition of methyl cyanoacetate to
4-phenyl-3-buten-2-one (5 mol % 1a, 0.2 M solvent, 23 °C, 14 h). In
general, highest yields and enantioselectivities were observed in solvents
having low dielectric constants. Diethyl ether: 96% conversion, 90% ee.
Toluene: 97% conversion, 89% ee. Tetrahydrofuran: 87% conversion, 88%
ee. Dichloromethane: 60% conversion, 62% ee.
9
1314 J. AM. CHEM. SOC. VOL. 127, NO. 4, 2005

(Salen)Al-Catalyzed Conjugate Additions to Enones
A R T I C L E S
Table 1. Asymmetric Conjugate Additions of Nitriles to
R,â-Unsaturated Ketones Catalyzed by 1a
Table 2. Enantioselective Conjugate Additions of Nitroalkanes
Catalyzed by 1a
product
R
R
′
EWG
1a (mol %)
yield (%)a
ee (%)b
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
2-thienyl
n-Pr
CH2CH2OBn CH3
Ph
Ph
Ph
CH3
CH3
CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
1.0
1.0
1.0
1.0
1.0
5.0
5.0
0.25
1.0
91
93
86
90
91
91
85
76
91e
93c
90
product
R
R
′
R
′′
1a (mol %)
yield (%)a
ee (%)b
89d
83
3a
3b
3c
3d
3e
3f
Ph
CH3
CH3
CH3
CH3
n-Bu
i-Pr
H
7.5
7.5
5
7.5
7.5
7.5
10
90
80
70
85
95
93
93
92
92
4-MeOC6H4
4-MeC6H4
4-BrC6H4
Ph
H
H
H
H
H
n-Bu CO2CH3
Ph
i-Pr
CH3
CH3
82
87
CO2CH3
CO2CH3
CN
75
72
n-Pr
n-Pr
94d
96f
Ph
Ph
76
88
3g
3h
CH3
CH3
CH3
CH3
90c,d
75c
92/91e
93/92e
SO2Ph
4-BrC6H4
7.5
a Isolated yield after purification. b Determined by HPLC using com-
mercially available chiral columns, unless otherwise noted. The % ee reflects
the 3R/3S or 3S/3R ratio. Products 2a-2g and 2i are isolated as mixtures
of diastereomers (1.0-3.0:1 diastereomeric ratio). c Absolute configuration
determined by correlation to known compound (see Supporting Information
for details). d Enantiomeric excess determined by GC after derivatization
(see Supporting Information for details). e With 1.2 equiv of 3-hepten-2-
one. f Absolute configuration determined by X-ray crystallography.
a Isolated yield after chromatography. b Determined by HPLC or GC
using commercially available chiral columns. c Product obtained as a 1.1:1
mixture of diastereomers. d (S,S)-1a was used. e The ee of each diastereomer
(major/minor).
Scheme 3. Krapcho Decarboxylation of Enantioenriched
Cyanoacetate
Scheme 2. Enantio- and Diastereoselective Conjugate Addition of
Methyl Phenylcyanoacetate
Scheme 4. Preparation of Enantioenriched 2,4-cis-Disubstituted
Piperidine
(b) Conjugate Addition of Nitroalkanes. The versatility of
the nitro group in organic synthesis renders the conjugate
addition of nitroalkanes to R,â-unsaturated carbonyl compounds
an attractive method for accessing a number of interesting
classes of bifunctional compounds. To date, success in the
development of enantioselective variants of this transformation
has been limited; current catalyst systems capable of this trans-
formation are limited by narrow scope or modest enantioselec-
tivity.14 Nitromethane and nitroethane were found to undergo
highly enantioselective conjugate addition to a variety of â-aryl-
substituted enones in the presence of 5-7.5 mol % 1a (Table
2).15 In contrast to the addition of nitrile nucleophiles (see
above), which requires no Brønsted base additive, the use of
triethylamine (30 mol %) was necessary to promote the addition
of nitroalkanes. In addition, the presence of tert-butyl alcohol
(1.2-2.7 equiv) was required in order to achieve efficient
catalysis. The results with nitroalkanes represent the sole
examples identified thus far where enones are effective sub-
strates in (salen)Al-catalyzed conjugate additions while conju-
gated imides are not. This is most likely due to the incompat-
ibility of the mildly acidic N-H group of the imide with the
basic reaction conditions required for nitroalkane additions.
(c) Synthetic Manipulations of the Conjugate Addition
Products. The enantioenriched γ-cyanoketone products obtained
with this new methodology are useful materials for further
synthetic manipulation. Krapcho decarboxylation16 of adduct
2a occurred smoothly to provide 4, the product of formal
acetonitrile conjugate addition, in good yield (85% yield over
two steps from 4-phenyl-3-buten-2-one), and without compro-
mise of enantiopurity (Scheme 3).
The versatility of the nitrile functional group permits the use
of 4 as a precursor to several cyclic compounds of interest. Thus,
Raney nickel-catalyzed hydrogenation results in formation of
the cis-2,4-disubstituted piperidine 5 as a single diastereomer,
the relative stereochemistry of which was established by X-ray
crystallography (Scheme 4). Such products have previously been
prepared in enantioenriched form by alkylation of chiral bicyclic
lactams;17 this new approach provides a versatile method to
access this class of compounds by asymmetric catalysis.
Alternatively, cyanoketone 4 can be converted to 5-phenyl-
3-cyclohexen-1-one by reduction of the nitrile to the corre-
sponding aldehyde and intramolecular aldol condensation. Such
chiral cyclohexenones serve as useful building blocks for the
(14) High (>90%) enantioselectivities for this transformation have been limited
to chalcone derivatives and cyclic substrates. See refs 6g and 8d and: Bako´,
P.; Bojor, Z.; To¨ke, L. J. J. Chem. Soc., Perkin Trans. 1 1999, 3651-
3655. Jørgensen and co-workers (ref 8e) have reported conjugate additions
of nitroalkanes to R,â-unsaturated methyl ketones, providing the products
in 50-99% yield and 49-86% ee.
(15) Enones bearing â-alkyl substituents were found to undergo moderately
enantioselective conjugate additions, but poor yields were obtained due to
slow reaction rates. For example, addition of nitromethane to 3-hexen-2-
one proceeded in 75% ee and 31% yield after 72 h using 7.5 mol % 1a.
(16) Krapcho, A. P. Synthesis 1982, 805-822 and 893-913.
(17) Dwyer, M. P.; Lamar, J. E.; Meyers, A. I. Tetrahedron Lett. 1999, 40,
8965-8968.
9
J. AM. CHEM. SOC. VOL. 127, NO. 4, 2005 1315

A R T I C L E S
Taylor et al.
Scheme 5. Preparation of 5-Phenyl-3-cyclohexen-1-one by Aldol
Condensation
Table 3. Asymmetric Conjugate Addition of Hydrazoic Acid to
R,â-Unsaturated Ketones Catalyzed by 1a
product
R
R
′
1a (mol %)
yield (%)a
ee (%)b
7a
7b
7c
7d
7e
7f
n-Pr
i-Pr
CH2CH2OBn
CH3
CH3
CH3
CH3
n-Bu
Ph
2.5
2.5
2.5
5.0
5.0
5.0
5.0
88c
81
96
72d
88
90
97
94
94
85
84
89e
77
61e
C(CH3)2CH2CH2CN
n-Pr
n-Pr
n-Pr
synthesis of highly substituted cyclohexanes through transfor-
mations governed by cyclic stereocontrol.18,19 The preparation
of cyclohexenone 6 was commenced by protection of ketone 4
as the dimethyl ketal. Diisobutylaluminum hydride reduction
was followed by workup with aqueous tartaric acid, accomplish-
ing hydrolysis of the resulting imine and the labile ketal. Aldol
condensation was achieved using catalytic camphorsulfonic acid
in refluxing toluene, yielding the desired product without
deterioration of enantiopurity and in good yield over the four-
step sequence.
7g
i-Pr
a Isolated yield after purification. b Determined by HPLC using com-
mercially available columns or by GC (γ-TA column), unless otherwise
noted. c Absolute configuration determined by correlation (see Supporting
Information for details). d Reaction carried out at -30 °C. e Determined
by HPLC after derivatization (see Supporting Information for details).
We found that the use of sodium azide, an inexpensive and
easily handled hydrazoic acid precursor, in combination with
concentrated aqueous hydrochloric acid, provided the best
results. In the presence of 2.5-5.0 mol % 1a in methylcyclo-
hexane at -40 °C, â-azido ketone products were obtained in
high enantioselectivity and yield. Substantial variation of the
ketone structure was tolerated within the context of enones
bearing alkyl â-substituents.23 As observed previously in the
conjugate addition of azide to imide derivatives,9a enones
bearing aryl â-substituents exhibited poor reactivity.24
(b) Synthetic Manipulations of â-Azido Ketones. The
enantioenriched azides 7 are readily converted to suitably
protected â-amino ketones. For example, hydrogenation of 7a
and in situ protection as the tert-butyl carbamate yielded 8 in
94% ee and 79% yield over two steps from 3-hepten-2-one.25
The reactivity of the azide functional group in [3 + 2] dipolar
cycloaddition chemistry could also be exploited for the synthesis
of nitrogen-containing heterocycles.26 Azido ketone 7a under-
went thermal cycloaddition with activated alkynes, or highly
regioselective copper-catalyzed cycloaddition with terminal
alkynes,27 to provide triazoles 9a and 9b without detectable
racemization. Product 7d, which bears a tethered nitrile group,
underwent cyclization to form bicyclic tetrazole 10 under
thermal conditions.
II. Enantioselective Conjugate Addition of Hydrazoic
Acid. The asymmetric catalytic conjugate addition of hydrazoic
acid to enones represents a straightforward approach to the
enantioselective synthesis of â-amino ketones. A variety of
catalytic methods, including the asymmetric conjugate addition
of nitrogen-centered nucleophiles,20 have been developed for
the enantioselective synthesis of â-amino acid derivatives. In
contrast, Shibasaki’s recent report of enantioselective 1,4-
addition of O-alkyl hydroxylamines to aryl-substituted enones
stands as the only example of the highly efficient preparation
of â-amino ketones by asymmetric catalytic conjugate addition.6h
Alternatively, â-amino ketones have been accessed by enantio-
selective additions of ketones or enol ether derivatives to
imines.21 The Mannich approach has proven successful for the
addition of acetone or hydroxy ketones to aryl- or carbonyl-
substituted imines, but the enantioselectivities are generally
moderate for imines bearing simple unbranched aliphatic
substituents. Accordingly, with an interest in establishing a
useful complement to the Mannich reaction, our attention was
focused particularly on conjugate additions of azide to â-alkyl-
substituted enones.
(a) Reaction Optimization and Scope. To avoid the pre-
generation and storage of quantities of hydrazoic acid, we sought
to devise a practical method for generating the reagent in situ.22
Conclusions and Outlook
We have demonstrated a substantial expansion of the substrate
scope of (salen)aluminum-catalyzed asymmetric conjugate ad-
dition reactions to include acyclic R,â-unsaturated ketones. Both
carbon- and nitrogen-centered nucleophiles were shown to
participate in conjugate additions with high enantioselectivity
for a range of enone structures. The products of this new
methodology are useful synthetic intermediates; moreover, the
(18) (a) Carvone, a naturally occurring 5-substituted 3-cyclohexen-1-one, has
been used as a starting material for the synthesis of complex natural
products. For examples, see: Srikrishna, A.; Satyanarayana, G. Org. Lett.
2004, 6, 3143-3144 and references therein. (b) For a recent example of
the application of synthetic 3-cyclohexen-1-ones in natural product
synthesis, see: Miyashita, M.; Sasaki, M.; Hattoria, I.; Sakai, M.; Tanino,
K. Science 2004, 305, 495-499.
(19) Several diastereoselective approaches to this class of compounds have been
developed: (a) Schwarz, J. B.; Devine, P. N.; Meyers, A. I. Tetrahedron
1997, 53, 8795-8806. (b) Schwarz, J. B.; Meyers, A. I. J. Org. Chem.
1998, 63, 1732-1735. (c) Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron
Lett. 1997, 38, 8299-8302. (d) Sarakinos, G.; Corey, E. J. Org. Lett. 1999,
1, 811-814. (e) Hareau, G. P.-J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am.
Chem. Soc. 1999, 121, 3640-3650. (f) Naasz, R.; Arnold, L. A.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 927-930 (catalytic
kinetic resolution approach).
(23) The conjugate addition of hydrazoic acid to cyclic enones catalyzed by 1a
proceeds with low enantioselectivity. 3-Azidocyclohexanone and 3-azi-
docycloheptanone are obtained in 8 and 14% ee, respectively (5 mol %
1a, methylcyclohexane, -40 °C).
(24) The conjugate addition of hydrazoic acid to 4-phenyl-3-buten-2-one
proceeds to 14% conversion in 79% ee after 14 h (5 mol % 1a,
methylcyclohexane, -45 °C).
(20) See refs 7e-h, 9a, and: Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc.
2002, 124, 2134-2136.
(25) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989,
30, 837-838.
(21) For an example of the synthesis of â-amino ketones by asymmetric Mannich
reaction, see: List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.
(22) For the in situ generation of hydrazoic acid from azidotrimethylsilane and
carboxylic acids, see: Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org.
Lett. 1999, 1, 1107-1109.
(26) For a prior demonstration of this approach to enantioenriched triazoles,
see ref 20.
(27) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596-2599.
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1316 J. AM. CHEM. SOC. VOL. 127, NO. 4, 2005

(Salen)Al-Catalyzed Conjugate Additions to Enones
A R T I C L E S
Scheme 6. Synthetic Manipulations of Enantioenriched â-Azido
with dichloromethane (total volume of 125 mL). The filtrate was
concentrated in vacuo, yielding the aluminum complex 1a as a pale
yellow solid in 85% yield (1.61 g, 1.40 mmol).
Ketonesa
General Procedure for the Conjugate Addition of Nitriles to
Enones: (S)-2-Cyano-5-oxo-3-phenylhexanoic Acid Methyl Ester
(2a). Methyl cyanoacetate (529 µL, 6.0 mmol, 1.2 equiv) was added
to a solution of 4-phenyl-3-buten-2-one (731 mg, 5.0 mmol) and (R,R)-
1a (57.7 mg, 0.05 mmol, 1.0 mol %) in cyclohexane (25.0 mL). The
solution was stirred at 23 °C for 16 h, and then the solvent was removed
in vacuo and the residue purified by chromatography on silica (20%
ethyl acetate in hexanes). Residual methyl cyanoacetate after chroma-
tography was removed by gentle heating in vacuo. The product was
obtained as a colorless oil in 91% yield (1.23 g) and 93% ee, as
determined by chiral HPLC [(S,S)-Whelk-01, 14% ethanol/hexanes, 1.4
mL/min, 220 nm, tr(min) ) 9.6 min, tr(maj) ) 11.2 min]. R25D ) -29°
(c ) 1.45, CHCl3).
a Reaction conditions: (a) toluene, 110 °C; (b) CuSO4 (1 mol %), sodium
ascorbate (10 mol %), ethanol/water, 23 °C.
CAUTION! Hydrazoic acid is a highly toxic and potentially
explosive compound and should be handled with great care in a well-
ventilated fume hood.
knowledge that simple one-point binding of carbonyl compounds
to 1a is sufficient for high enantioselectivity in catalytic
processes may serve as a useful starting point for the develop-
ment of new methodology. Current investigations are underway
to gain mechanistic insight into the catalyst system28 and to
continue to delineate its scope.
General Procedure for the Conjugate Addition of Hydrazoic Acid
to Enones: (R)-4-Azidoheptan-2-one (5a): Hydrochloric acid (164 µL,
37% aqueous, 2.0 mmol, 2.0 equiv) was added dropwise to a suspension
of sodium azide (130 mg, 2.0 mmol, 2.0 equiv) in methylcyclohexane
(5.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min,
and then warmed to 23 °C and stirred for 1.5 h. The resulting orange
heterogeneous mixture was cooled to -78 °C, and 3-hepten-2-one (132
µL, 1.0 mmol) and then catalyst (S,S)-1a (28.8 mg, 0.025 mmol, 2.5
mol %) were added sequentially. The mixture was warmed to -40 °C
and stirred for 24 h. After the mixture was warmed to 23 °C, ether (15
mL) was added. The solution was washed twice with 1 M aqueous
sodium hydroxide (10 mL each), then passed through a short silica
plug, eluting with 1:1 hexanes/ether. The solution was concentrated
carefully in vacuo, yielding the product as a colorless oil, in 88% yield
(136 mg) and 94% ee, as determined by chiral GC [γ-TA, 100 °C
isothermal, tr(min) ) 9.7 min, tr(maj) ) 13.0 min]. R25D ) -28° (c )
1.31, CHCl3).
Experimental Section
Complete experimental procedures for all substrates are provided
as Supporting Information.
Catalyst 1a. In a flame-dried round-bottomed flask equipped with
a stir bar and reflux condenser, (S,S)-N,N′-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediamine (1.79 g, 3.28 mmol) was suspended
in acetonitrile (10 mL) and toluene (3.3 mL). Trimethylaluminum (1.64
mL, 2.0 M solution in toluene, 3.28 mmol, 1.00 equiv) was added
dropwise by syringe at 23 °C. The mixture was stirred at 23 °C for 30
min, and then heated to reflux and stirred for 5 h. After the mixture
was cooled to 23 °C, water (59 µL, 3.28 mmol, 1.00 equiv) was added
by syringe. The resulting mixture was heated to reflux and stirred for
15 h. After it was cooled to 23 °C, acetonitrile (25 mL) was added and
the mixture filtered through Celite and washed with acetonitrile (total
volume of 200 mL). The filtrate was discarded and the Celite washed
Acknowledgment. This work was supported by the NIH
(GM-43214). We thank the Swiss National Science Foundation
for fellowship support to A.M.L.
Supporting Information Available: Complete experimental
procedures and characterization data (PDF and CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) The heterogeneity of the reaction mixtures in the enone conjugate addition
reactions has limited our ability to carry out accurate kinetic analyses of
these processes. However, studies on closely related additions to R,â-
unsaturated imides catalyzed by 1a point to a cooperative mechanism
wherein the catalyst activates both nucleophile and electrophile. See ref
9e and: Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
9928-9929.
JA044999S
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