Enantioselective Cu-catalyzed conjugate addition of diethylzinc to acyclic aliphatic enones

Article abstract of DOI:10.1021/ol048191o

(Chemical Equation Presented) A new P-chiral phosphine bis(sulfonamide) ligand has been developed that allows the Cu-catalyzed enantioselective conjugate addition of Et₂Zn to acyclic aliphatic enones. The reactions proceed with excellent levels

Full text of DOI:10.1021/ol048191o

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4117-4119
Enantioselective Cu-Catalyzed Conjugate
Addition of Diethylzinc to Acyclic
Aliphatic Enones
Andrew P. Duncan and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
leighton@chem.columbia.edu
Received September 7, 2004
ABSTRACT
A new P-chiral phosphine bis(sulfonamide) ligand has been developed that allows the Cu-catalyzed enantioselective conjugate addition of
Et2Zn to acyclic aliphatic enones. The reactions proceed with excellent levels of enantioselectivity (90−95% ee) with a range of enone substrates,
involve the use of only 1.2 equiv of Et2Zn, and give best results at ambient temperature.
The asymmetric copper-catalyzed addition of dialkylzinc
reagents to enones has matured into a powerful carbon-
carbon bond forming method,1 as a variety of highly
enantioselective (>90% ee) ligands/methods for cyclic
enones2 and for benzylideneacetones and chalcones2b,3 have
been reported. Aliphatic acyclic enones have proven to be a
far more challenging substrate class, however. Although
some substrate-specific successes have been recorded,4 to
date there has been only one report of a highly enantiose-
lective and general catalyst for this substrate class.5 We
recently reported a highly practical method for the addition
of dialkylzinc reagents to cyclic enones that employs a simple
phosphine sulfonamide ligand (Scheme 1).6 Subsequent
studies have shown that this ligand performs poorly with
acyclic enones. Given the appeal of the reaction described
in Scheme 1, we wondered whether this ligand could be
modified to address this limitation and report herein the
development of a ligand that is highly enantioselective and
general for a range of aliphatic acyclic enones.
Scheme 1
(1) For recent reviews, see: (a) Alexakis, A.; Benhaim, C. Eur. J. Org.
Chem. 2002, 3221-3236. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis
2001, 171-196. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.
(2) See ref 1 and (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J.
Am. Chem. Soc. 2001, 123, 755-756. (b) Alexakis, A.; Benhaim, C.; Rosset,
S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-5263. (c) Liang, L.;
Au-Yeung, T. T.-L.; Chan, A. S. C. Org. Lett. 2002, 4, 3799-3801. (d)
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 13362-13363.
(3) (a) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38,
3518-3521. (b) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699-3702. (c)
Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. Tetrahedron: Asymmetry
2003, 14, 3907-3915. (d) Morimoto, T.; Mochizuki, N.; Suzuki, M.
Tetrahedron Lett. 2004, 45, 5717-5722.
(4) (a) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 1375-1378. (b) Alexakis, A.; Polet, D.; Rosset,
S.; March, S. J. Org. Chem. 2004, 69, 5660-5667.
Our investigations began with the hypothesis that the
addition of a third donor element to the ligand scaffold might
lead to an improved catalyst. One straightforward way to
(5) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779-781.
(6) Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201-3203.
10.1021/ol048191o CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/08/2004

Scheme 2
Table 2. Scope of Reaction with Ligand 2d
entry
R1
Ph
Me
n-Pent
i-Pr
R2
Me
n-Hex
Me
yield (%)
eea
1
2
3
4
67
71
69
79
87
88
84
85
Me
a Enantiomeric excess determined by chiral GC (CDGTA).
accomplish this would be the introduction of a second
sulfonamide, affording (potentially) tridentate phosphine bis-
(sulfonamide) ([NPN]) ligands.7 The synthesis of several
phosphine bis(sulfonamides) followed the iterative one-pot
procedure shown in Scheme 2. A primary phosphine was
deprotonated using n-BuLi, and the resulting lithium phos-
phide was treated with 1 equiv of an aziridine8 to give the
lithiated phosphine sulfonamide intermediate (1a-e). This
sequence was then repeated to append the second sulfon-
amide arm. Phosphine bis(sulfonamides) 2a-e were prepared
in this fashion and isolated as moderately air-sensitive
colorless oils or white solids.
performed significantly less well (entry 5), establishing the
superior performance of the triflamide group.
On the basis of these initial studies, ligand 2d was selected
for further study. Of particular interest was whether 2d would
provide consistent levels of enantioselectivity for conjugate
additions to a range of acyclic aliphatic enones (Table 2).
Further optimization revealed that the catalyst loading and
the amount of Et
2Zn could be significantly reduced. As
shown, under these optimized conditions ligand 2d consis-
tently provided enantioselectivities in the 84-88% ee range
for several aliphatic enones (entries 1-4).
With these new ligands 2a-e in hand, an initial screen of
their performance in the Cu(OTf)2-catalyzed conjugate
addition of Et2Zn to benzylidene acetone was performed
(Table 1). All reactions were carried out in Et2O at ambient
Although phosphine bis(sulfonamides) are potentially
tridentate ligands, it is unlikely that the species responsible
for catalysis would have all three donors of the [NPN] ligand
and the requisite alkyl residue bound to a single Cu center;
such a coordinatively and electronically saturated complex
would not be expected to be reactive. More likely is that
one of the sulfonamides is not associated with the Cu during
catalysis but rather performs a distinct function. We therefore
considered ligands bearing two different sulfonamide groups,
with the expectation that each of the sulfonamides could be
tuned to optimize its specific reaction role.
Treatment of lithium cyclohexylphosphide with the aziri-
dine derived from (S)-tert-leucinol and Tf2O gave phosphine
sulfonamide 3 as a mixture (1.3:1) of diastereomers in 88%
yield (Scheme 3). The second sulfonamide arm of the ligand
was installed under neutral conditions by reaction of 3 with
the aziridine derived from (S)-tert-leucinol and 3,5-bis-
(trifluoromethyl)bezenesulfonyl chloride (ArFSO2Cl) in CF3-
CH2OH at 70 °C. After treatment with BH3‚Me2S, the
diastereomeric phosphine-borane complexes 4a and 4b (dr
) 1.5:1.0) were separated and isolated as air-stable solids
(79% total yield).9 Deprotection of 4a and 4b with 1,4-
diazabicyclo[2.2.2]octane (DABCO) afforded P-chiral [NPN′]
ligands 5a and 5b in 84% and 76% yield, respectively.10
The performance of ligands 5a and 5b was then compared
in the Cu(OTf)2-catalyzed addition of Et2Zn to benzylidene
acetone (Scheme 4). In terms of enantioselectivity, ligand
Table 1. Performance of Ligands 2a-e
entry
ligand
R1
R2
R3
eea
1
2
3
4
5
2a
2b
2c
2d
2e
Ph
Ph
Cy
Cy
Cy
i-Pr
t-Bu
i-Pr
t-Bu
t-Bu
Tf
Tf
Tf
Tf
Ts
48
12
79
84
67
a Enantiomeric excess determined by chiral GC (CDGTA).
temperature as these proved to be optimal conditions.
Reactions with phenylphosphine-derived ligands 2a and 2b
were sluggish and afforded the conjugate addition product
in poor to modest enantioselectivities (entries 1 and 2). In
contrast, the more basic cyclohexylphosphine-derived ligand
2c yielded a substantial improvement in enantioselectivity
(entry 3). A further substitution of tert-butyl for iso-propyl
on the ligand backbone (2d) resulted in an increase in
selectivity to 84% ee (entry 4). Finally, bis(tosylamide) 2e
(7) This is a new ligand class. For related [NPN] ligands, see: (a) Jiang,
Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38, 6565-6568.
(b) Schrock, R. R.; Seidel, S. W.; Schrodi, Y.; Davis, W. M. Organome-
tallics 1999, 18, 428-437. (c) Fryzuk, M. D.; Johnson, S. A.; Rettig, S. J.
J. Am. Chem. Soc. 1998, 120, 11024-11025.
(8) Cernerud, M.; Skrinning, A.; Be´rge`re, I.; Moberg, C. Tetrahedron:
Asymmetry 1997, 8, 3437-3441.
(9) An X-ray crystallographic study of the minor diastereomer allowed
the assignment of relative configuration for 4a and 4b. See Supporting
Information.
(10) During the course of this work, Nelson reported the synthesis of an
amino bis(sulfonamide) ligand bearing identical differential substitution on
the two sulfonamide arms: Nelson, S. G.; Zhu, C.; Shen, X. J. Am. Chem.
Soc. 2004, 126, 14-15.
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Org. Lett., Vol. 6, No. 22, 2004

Scheme 3
Table 3. Scope of Reaction with Ligand 5a
entry
R1
R2
Me
n-Hex
Me
Me
Me
yield (%)
eea
1
2
3
4
5
Ph
Me
83
76
81
76
73
94
95
90
91
90
n-Pent
i-Pr
BnOCH2
a Enantiomeric excess determined by chiral GC (CDGTA).
excellent enantioselectivities were obtained with a range of
aliphatic acyclic enones (90-95% ee, entries 1-5).
The performance of ligand 5a with dimethylzinc was also
probed (Scheme 5). Although these reactions were less
Scheme 5
5a proved superior to ligand 5b, and both provided improve-
ment over ligand 2d. A significant difference in the efficiency
of the catalysis with ligands 5a and 5b was noted as well.
Prior to settling on 5a as the ligand of choice, it seemed
prudent to examine the performance of the pseudosymmetric
bis(ArF) sulfonamide ligand 6. As shown, although 6
provided excellent enantioselectivity, the efficiency of
catalysis was inferior and similar to that of ligand 5b. Taken
together, these results provide compelling evidence for
different roles for the two sulfonamide groups in the catalytic
cycle (an example of bifunctional catalysis), one likely
associated with the copper center during catalysis and the
other likely performing a distinct function that can be
independently optimized.
efficient and required somewhat higher catalyst loadings,
excellent enantioselectivities were nevertheless observed.
We have reported the development of a new P-chiral
[NPN′] phosphine bis(sulfonamide) ligand that provides
excellent levels of enantioselectivity in the Cu-catalyzed
conjugate addition of Et2Zn to acyclic aliphatic enones. The
reactions are practical, requiring only 1.2 equiv of Et2Zn and
proceeding in less than 1.5 h in Et2O at ambient temperature.
In addition, we have provided evidence that the two
sulfonamides play distinct roles in the reaction. Further
development of this new ligand class may be anticipated,
and such studies are in progress.
Ligand 5a was evaluated with several different aliphatic
acyclic enones (Table 3). Optimized conditions involved the
use of only 1.2 equiv of Et2Zn, 1.5 mol % of Cu(OTf)2, and
2.25 mol % of ligand 5a. Under these conditions, consistently
Acknowledgment. We thank Dr. Kevin Janak (Parkin
research group) for the X-ray structure of 4b. The NIH
(NIGMS) is gratefully acknowledged for a postdoctoral
fellowship to A.P.D. We are grateful to Amgen for generous
research support.
Scheme 4
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048191O
Org. Lett., Vol. 6, No. 22, 2004
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