Cu-catalyzed enantioselective conjugate addition of alkylzincs to cyclic nitroalkenes: Catalytic asymmetric synthesis of cyclic α-substituted ketones

Article abstract of DOI:10.1021/ja020605q

An efficient and highly enantioselective (≥92% ee) catalytic method for conjugate addition of alkylzinc reagents to cyclic nitroalkenes is reported. Reactions are promoted in the presence of 0.5-5 mol % (CuOTf)₂·C₆H₆ and 1

Full text of DOI:10.1021/ja020605q

Published on Web 06/19/2002
Cu-Catalyzed Enantioselective Conjugate Addition of Alkylzincs to Cyclic
Nitroalkenes: Catalytic Asymmetric Synthesis of Cyclic r-Substituted
Ketones
Courtney A. Luchaco-Cullis and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received April 26, 2002
Table 1. Asymmetric Conjugate Addition of Alkylzincs to 1a
We have reported that amino acid-based chiral ligands, in the
presence of Cu(I) salts and alkylzinc reagents, promote efficient
and highly enantioselective conjugate additions1 and allylic sub-
stitutions.2 The conjugate addition protocols are of particular note
because of their effectiveness with cyclopentenyl and aliphatic
acyclic substrates, systems that had previously proved problematic.3
A related class of transformations, for which an effective method
has not been reported, is the catalytic enantioselective additions of
alkylmetals to nitroolefins. Such catalytic processes are valuable,
since (depending on the workup conditions) nitronates may be
converted to synthetically versatile compounds (e.g., nonracemic
R-substituted ketones). Others have examined catalytic asymmetric
conjugate additions involving nitroalkenes. One reported variant
is the catalytic process of Hayashi,4 where arylboronic acids are
used with high reactivity and selectivity; the related alkyl addition
products, however, cannot be obtained by the Rh-catalyzed
procedure. Various other disclosures involve catalytic additions of
alkylzincs to R,â-unsaturated nitroalkenes;5 these reactions mostly
involve acyclic substrates, are largely limited to additions of Et2Zn,
and afford products in low selectivities. Herein, we report an
efficient method for catalytic asymmetric addition of alkylzincs to
small-, medium-, and large-ring nitroolefins, promoted by readily
available amino acid-based chiral phosphines.6 Selectivities are
typically >90% ee, and the derived ketones can be readily obtained.
With commercially available Et2Zn and 1, screening studies
indicated that reactions with phosphine 3 and (CuOTf)2‚C6H6
in toluene at 0 °C are optimal. We established that, as depicted
in eq 1, treatment of 1 with Et2Zn, 1 mol % 3 and 0.5 mol %
(CuOTf)2‚C6H6 delivers 2a in 96% ee and 92% yield (>98% conv,
12 h, 0 °C; 85% syn).7
a Conditions: toluene, 0 °C, 12 h, N2 atm (24 h for entry 3). b Determined
by analysis of the 400 MHz 1H NMR spectrum of unpurified reaction
mixtures. c Isolated yields after chromatography. d Determined by GLC and
analysis of 400 MHz 1H NMR spectra. e Determined by chiral GLC analysis
(Chiraldex GTA column).
(3) Use of excess chiral ligand (vs Cu(I) salt) does not lead to
enhancement in rate or ee. (4) The less reactive Me2Zn (entry 1)
and carbonyl-containing alkylzinc 5 (entry 3) require higher catalyst
loadings and longer reaction times than the more reactive (4-
methylpentyl)2Zn 4 in entry 2 (10 mol % vs 1 mol % 3 for >98%
conv in 12 h).
In all the reactions involving 1, the syn product is formed as the
major diastereomer (eq 1 and Table 1).8 However, as the data
depicted in Scheme 1 illustrate, treatment of syn chiral nitroalkanes
2a-d with 1 equiv of DBU (22 °C, 12 h) leads to the efficient
formation of the corresponding trans isomers without a lowering
of enantiomeric excess. The present protocol thus allows access to
both syn- and anti-nitrocyclohexane diastereomers in high yield
and enantiopurity.
Scheme 1. Synthesis of Anti Products upon Treatment with DBUa
Additional results are summarized in Table 1. As these data
indicate, the Cu-catalyzed processes are not limited to reactions
with Et2Zn: 2b-d are synthesized efficiently and with high
enantioselectivity (>98% conv, g93% ee). Several points regarding
catalytic asymmetric reactions of 1 are noteworthy: (1) Catalytic
reactions proceed to >98% conv but are less selective in alternative
solvents (e.g., CH2Cl2, THF, Et2O). (2) Enantioselectivities remain
unchanged or decrease when the reaction temperature is below 0 °C.
a Conditions: 1 equiv DBU, Et2O, 22 °C, 12 h; yields are of isolated
materials after chromatography.
The Cu-catalyzed asymmetric conjugate addition can be per-
formed with the smaller five-membered ring nitroalkenes with high
enantioselectivity. As the example in eq 2 illustrates, addition to 6
proceeds to afford 7 in 93% ee and 61% yield (>98% conv). In
* To whom correspondence should be addressed. E-mail: amir.hoveyda@bc.edu.
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C O M M U N I C A T I O N S
contrast to reactions of 1, however, anti-7 is formed as the
predominant isomer.9
certainsbut not allscases the more easily accessible ligand 14 can
be sufficient. As an example, addition of Me2Zn to 1 is promoted
by 14 (identical conditions to those in Table 1) to afford 2b in
96% ee and 75% isolated yield (82% syn). However, in contrast to
ligand 3, the corresponding addition to 12 proceeds only to e25%
conversion when 14 is employed (after 24 h; 82% ee). Studies aimed
at delineation of factors that determine the identity of the optimal
catalysts in this class of asymmetric transformations are in progress.
The catalytic asymmetric process can be effected on medium-
ring electrophiles. A representative example, involving the seven-
membered nitroalkene 8, is depicted in Scheme 2. The reaction
proceeds as smoothly as the cases involving substrates 1 and 6.
However, unlike the smaller-ring systems, the same workup
procedure (aqueous NH4Cl) leads to the exclusive formation of the
ketone product in 93% ee and 42% isolated yield (>98% conv;
low yield partly due to volatility). As the reactions in Scheme 2
further illustrate (1f10 and 11), a similar Nef reaction can be
carried out in situ with six-membered ring conjugate addition
products, without significant loss of optical purity, but only when
workup is changed to the addition of a 20% aqueous solution of
H2SO4.10
Development of additional catalytic asymmetric C-C bond
forming reactions promoted by amino acid-based ligands and their
application to enantioselective synthesis is also underway.
Acknowledgment. This research was supported by the NIH
(GM-47480)andSchering-Plough(GraduateFellowshiptoC.A.L.-C.).
Supporting Information Available: Experimental procedures and
spectral and analytical data for all substrates and reaction products
(PDF). This material is available free of charge via the Internet at
http://www.acs.pubs.org.
Scheme 2. Catalytic Enantioselective Synthesis of Cyclic Ketones
References
(1) (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.
(2) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2001, 40, 1456-1460.
(3) For a recent review on asymmetric conjugate additions, see: Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(4) (a) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716-10717. (b) Hayashi, T. Synlett 2001, 879-887.
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J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 1375-1378. (e)
Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262-5263. For related stoichiometric processes, see: (f)
Schafer, H.; Seebach, D. Tetrahedron 1995, 51, 2305-2324. For Mg-
catalyzed asymmetric additions of 1,3-dicarbonyls to acyclic nitroalkenes,
see: (g) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.;
Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215-10216.
(6) For representative enantioselective reactions (in addition to refs 1 and 2),
promoted by amino acid-based chiral metal complexes, see: (a) Nitta,
H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem. Soc. 1992, 114,
7969-7975. (b) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J.
P. A.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996,
35, 1668-1671. (c) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.;
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1009-1012.
a Isolated yield (volatile product). b GLC yield (volatile products; decane
used as standard).
Macrocyclic nitroalkenes readily undergo Cu-catalyzed asym-
metric conjugate addition in the presence of phosphine 3. As
shown in eq 3, treatment of 12-membered ring 12 (>20:1 E:Z)
with 10 mol % of the chiral Cu complex and 3 equiv of Me2Zn,
followed by treatment with 10% H2SO4 for 1 h leads to the
formation of ketone 13 in 96% ee and 86% yield.
(7) Absolute stereochemistry of products is based on optical rotations obtained
from ketones 9, 10, 11, and 13 in comparison with the reported values
(see the Supporting Information for details).
(8) The corresponding anti isomers are obtained with similar levels of
enantioselectivity. For a plausible rationale for the predominant formation
of the syn isomer, see ref 4 and references therein.
(9) A similar trend was observed in the study by Hayashi and co-workers
(see ref 4).
A final note regarding the identity of the chiral ligand should be
mentioned. Although our studies clearly indicate that bis(amino
acid) ligand 3 is the optimal choice for all the above substrates, in
(10) Control experiments indicate that the reduction in product enantiopurity
is due to adventitious isomerization upon in situ Nef reaction.
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