Highly practical and enantioselective Cu-catalyzed conjugate addition of alkylzinc reagents to cyclic enones at ambient temperature

Article abstract of DOI:10.1021/ol034983r

(Matrix presented) A new ligand for Cu-catalyzed enantioselective additions of dialkylzincs to cyclic enones has been developed. In addition to providing good to excellent enantioselectivities with a range of cyclic enones and dialkylzincs, the ligand has several notworthy features: it can be readily prepared in just two steps, is an air-stable crystalline solid, and provides optimal performance at ambient temperature.

Full text of DOI:10.1021/ol034983r

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3201-3203
Highly Practical and Enantioselective
Cu-Catalyzed Conjugate Addition of
Alkylzinc Reagents to Cyclic Enones at
Ambient Temperature
Isaac J. Krauss and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
leighton@chem.columbia.edu
Received June 2, 2003
ABSTRACT
A new ligand for Cu-catalyzed enantioselective additions of dialkylzincs to cyclic enones has been developed. In addition to providing good
to excellent enantioselectivities with a range of cyclic enones and dialkylzincs, the ligand has several notworthy features: it can be readily
prepared in just two steps, is an air-stable crystalline solid, and provides optimal performance at ambient temperature.
The development of catalysts for the copper-catalyzed
asymmetric addtion of diorganozincs to enones has recently
received increased attention. Following the seminal discovery
of Alexakis,1 several groups have reported effective ligand
systems for various structural classes of enones.2 Most
notably, Hoveyda and co-workers have introduced a new
family of ligands that allow the highly enantioselective
reactions of a wide variety of both cyclic and acyclic enones
and cyclic nitroalkenes.3 We have initiated our own inves-
tigation into this important carbon-carbon bond-forming
reaction and report herein a new ligand that achieves good
to excellent enantioselectivities with a range of cyclic enones.
Notably, the ligand is an easily prepared air-stable crystalline
solid that provides optimal results at ambient temperature.
Our investigations began with the preparation of a set of
phosphine sulfonamide ligands derived in two steps from
amino alcohols (Scheme 1).4 Thus, treatment of either valinol
or tert-leucinol with p-toluenesulfonyl chloride (TsCl),
methane-sulfonyl chloride (MsCl), or trifluoromethane-
sulfonic anhydride (Tf2O) produced sulfonyl aziridines 1a-
e. Treatment of aziridines 1 with LiPPh2 produced ligands
(1) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993,
4, 2427-2430.
(3) (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756. (b) Mizutani, H.; 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.
(4) This class of ligand is known and has been investigated in several
asymmetric catalytic reactions. See: (a) Okada, T.; Morimoto, T.; Achiwa,
K. Chem. Lett. 1990, 999-1002. (b) Sakuraba, S.; Awano, K.; Achiwa, K.
Synlett 1994, 291-292. (c) Sakuraba, S.; Okada, T.; Morimoto, T.; Achiwa,
K. Chem. Pharm. Bull. 1995, 43, 927-934. (d) Hiroi, K.; Hidaka, A.;
Sezaki, R.; Imamura, Y. Chem. Pharm. Bull. 1997, 45, 769-777. (e)
Gustafsson, M.; Bergqvist, K.-E.; Frejd, T. J. Chem. Soc., Perkin Trans. 1
2001, 1452-1457.
(2) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Hu, X.;
Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 3518-3521. (c)
Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002,
124, 5262-5263. (d) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699-
3702. (e) Liang, L.; Au-Yeung, T. T.-L.; Chan, A. S. C. Org. Lett. 2002,
4, 3799-3801. (f) Zhou, H.; Wang, W.-H.; Fu, Y.; Xie, J.-H.; Shi, W.-J.;
Wang, L.-X.; Zhou, Q.-L. J. Org. Chem. 2003, 68, 1582-1584. For recent
reviews, see: (g) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-
196. (h) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236.
(i) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002;
pp 224-258.
10.1021/ol034983r CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/07/2003

Scheme 1
Table 2. Enantioselective Cu-Catalyzed Conjugate Addition of
Dialkylzincs to Cyclic Enones at Ambient Temperature
entry
n
R
R′
methoda
t (h)
yield (%)b
eec
1
2
3
4d
5d
6
7
8d
0
0
1
1
1
1
2
2
H
Me
H
H
H
Me
H
H
i-Pr
Et
Et
n-Bu
i-Pr
Et
A
B
B
A
A
B
B
A
0.25
24
2
4
0.5
24
3
1
64
58
83
52
89
90
67
76
86
84
97
94
96
97
97
88
2a-e in good overall yield for the straightforward two-step
sequence. In the case of 2e (R1 ) t-Bu, R2 ) Tf) no
chromatography is required and the ligand may simply be
recrystallized from hexanes to give 2e in 56% overall yield.
With a set of ligands in hand, their performance in the
reaction of Et2Zn with cyclohexenone was evaluated (Table
1). Employing Cu(OTf)2 (2 mol %) as the catalyst precursor,
Et
i-Pr
a Method A: R′2Zn added after enone. Method B: R′2Zn added before
enone. b Isolated yield. c Enantiomeric excess determined by chiral GLC
(CDGTA). d Reaction run with 1 mol % Cu(OTf)2.
Table 1. Optimization of Ligand and Reaction Conditions
these studies, it was noted that small but significant (and
reproducible) differences in the enantioselectivities were
recorded based on order of addition of the reagents (methods
A and B). 2-Cyclopenten-1-one substrates reacted to give
good enantioselectivities and moderate yields of the alkylated
products (entries 1 and 2). 2-Cyclohexen-1-ones consistently
engaged in highly enantioselective reactions with a range of
dialkylzinc reagents (entries 3-5), albeit not with dimeth-
ylzinc, the use of which led to poor reaction performance.
As with the cyclopentenone substrates, γ,γ-dialkyl substitu-
tion is well-tolerated (entry 6). Finally, 2-cyclohepten-1-one
may be alkylated with high levels of enantioselectivity
(entries 7 and 8). Thus, ligand 2e shows encouraging
generality with respect to a range of cyclic enone structures,
and it is noteworthy that ligand 2e consistently provides the
highest enantioselectivities recorded to date with i-Pr2Zn
(entries 1, 5, and 8).
entry
ligand
R1
R2
temp (°C)
eea
1
2
3
4
5
6
7
8b
2a
2c
2c
2c
2b
2d
2e
2e
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Ts
Tf
Tf
Tf
Ms
Ts
Tf
Tf
-20
-20
-78
23
23
23
50
80
52
88
31
82
95
97
23
23
a Enantiomeric excess determined by chiral GLC (CDGTA). b Reaction
run with 3.0 equiv of Et2Zn.
ligand 2a (5 mol %) provided the conjugate addition product
in 50% ee (entry 1). The substitution of triflamide for tosyl
amide (ligand 2c) led to a more selective reaction (80% ee;
entry 2). We were then surprised to discover an unusual
relationship between temperature and enantioselectivity:
whereas at -78 °C, ligand 2c provided only 52% ee, 88%
ee was recorded at ambient temperature (entries 3 and 4).5
At higher temperatures still (e.g., 38 °C), the ee is lower
(85%); thus, the enantioselectivity is at its maximum at
ambient temperature. Methane sulfonamide 2b was then
evaluated and provided poor results (entry 5). We then turned
to the tert-leucinol-derived ligands 2d and 2e. Consistent with
the above results, triflamide 2e proved to be superior to tosyl
amide 2d and at ambient temperature provided the product
in 95% ee (entries 6 and 7). Additional optimization revealed
that the ee could be raised to 97% by employing 3.0 equiv
of Et2Zn (entry 8).
Scheme 2
We have optimized the reaction of 2-cyclohexen-1-one on
a larger scale (10 g, 104 mmol) and were delighted to find
that the reaction performed well with only 1.2 equiv of Et2-
Zn and that the Cu(OTf)2 loading could be dropped to 0.10
mol % and the ligand 2e loading to 0.25 mol %. Under these
conditions, the reaction was complete in <1.5 h, and the
product was isolated in 86% yield and 97% ee. Apart from
the use of a slight excess of Et2Zn, it is difficult to imagine
a more ideal process in terms of experimental ease, ef-
ficiency, and practicality.
With ligand 2e identified as the most effective, a survey
of the reaction scope was then undertaken (Table 2). During
An interesting promise of asymmetric catalysis is the
possibility of overriding an inherent bias in a chiral substrate,
(5) Hoveyda has documented a similar effect in the reactions of acyclic
enones. See ref 3b.
3202
Org. Lett., Vol. 5, No. 18, 2003

allowing access to diastereomers that might otherwise be
difficult to obtain. This, of course, is exactly the opposite of
what is required for an effective kinetic resolution,6 but it
may be argued that this is more useful than kinetic resolution
in cases where the racemic starting material is not extra-
ordinarily inexpensive. The addition of Me2CuLi to enone
3 has been reported to give the trans product exclusively,7
and we have confirmed this result (Scheme 3). In contrast,
Figure 1. Enantioselectivity vs ligand/Cu at -20 and 23 °C.
Scheme 3
ligand:Cu ratios less than 1, high enantioselectivity was
maintained, while at ratios greater than 2, a large decrease
in enantioselectivity was recorded.
On the basis of these data, it is reasonable to propose that
at low ligand:Cu ratios, the same catalyst species is operative
at both temperatures. The observation of similar negative
nonlinear effects (2:1 ligand/Cu) at both temperatures sup-
ports this hypothesis.9 More interestingly, it is clear that at
high ligand:Cu ratios, a distinct and less highly enantio-
selective catalyst species is accessed at -20 °C, but not at
ambient temperature.
A simple new ligand for the enantioselective copper-
catalyzed conjugate addition of dialkylzinc reagents to cyclic
enones has been developed. This ligand is unique in
consistently providing maximum enantioselectivity at room
temperature. Combined with its ease of preparation, a high
level of practicality has been established. Our current focus
is on further development of this ligand class and investiga-
tion of its utility with nucleophiles other than organozincs.
subjection of 3 to the reaction with Et2Zn catalyzed by Cu-
(OTf)2/2e led to the smooth production of the cis product in
69% yield and 97:3 dr.8
One of the more intriguing and practical aspects of this
chemistry is the observation of maximum enantioselectivity
at ambient temperature. We have examined this phenomenon
in more detail and have found that it is highly dependent on
the ligand:Cu ratio (Figure 1). For the reaction of 2-cyclo-
hexen-1-one with Et2Zn (employing ligand 2e), a series of
experiments was carried out varying the ligand:Cu ratio both
at ambient temperature and at -20 °C. Whereas at ambient
temperature, the ee of the reaction asymptotically approached
a maximum value at higher ligand:Cu ratios, at -20 °C,
radically different results were observed. Thus, even at
Acknowledgment. We are grateful to Merck Research
Laboratories for financial support. J.L.L. is a recipient of a
Pfizer Award for Creativity in Organic Chemistry.
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(6) A kinetic resolution of chiral 2-cyclohexenones based on this type
of reaction has been reported. See: Naasz, R.; Arnold, L. A.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 927-930.
(7) Satoh, T.; Kaneko, Y.; Okuda, T.; Uwaya, S.; Yamakawa, K. Chem.
Pharm. Bull. 1984, 32, 3452-3460.
(8) Feringa has reported examples of catalyst control with chiral enones.
No measure of the “intrinsic” diastereofacial bias of these enones was
reported. See: Imbos, R.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2001,
57, 2485-2489.
OL034983R
(9) For a comprehensive review on nonlinear effects, see: Girard, C.;
Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922-2952.
Org. Lett., Vol. 5, No. 18, 2003
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