Enantioselectivity in the reactions of chiral α-(N-carbamoyl)alkylcuprates

Full text of DOI:10.1021/ja0156587

5132
J. Am. Chem. Soc. 2001, 123, 5132-5133
first examples of configurationally stable R-(N-carbamoyl)alkyl
cuprates not under dynamic thermodynamic control.5,12
Enantioselectivity in the Reactions of Chiral
r-(N-Carbamoyl)alkylcuprates
N-Boc pyrrolidinylcuprates provided an ideal system for
examination since both the asymmetric deprotonation reaction8,12
and various cuprate transformations11 had been studied in detail.
The known behavior of scalemic N-Boc 2-lithiopyrrolidine (1)13
provided a reference against which the configurational stability
of the reagents could be measured for the cuprate preparation
and reaction sequences. Anticipating that R-(N-carbamoyl)-
alkylcuprate configurational stability might be reaction and
electrophile dependent, vinylation reactions with (E) 1-iodo-2-
phenylethene (2), 2-iodo-4-tert-butyldimethylsilyloxy-1-butene
(3), (Z)-ethyl 3-iodo-2-propenoate (4), ethyl propiolate (5), (Z)-
ethyl 3-iodo-2-heptenoate (6), and 3-iodo-2-cyclohexenone (7)
were examined along with conjugate addition reactions on benzyl
2-propenoate (8) and propargyl substitution reactions on the
mesylate (9) of 3-phenyl-2-propyn-1-ol (eq 1). It was readily
R. Karl Dieter,* Chris M. Topping,
Kishan R. Chandupatla, and Kai Lu
Howard L. Hunter Laboratory, Department of Chemistry
Clemson UniVersity, Clemson, South Carolina 29634-0973
ReceiVed February 12, 2001
ReVised Manuscript ReceiVed April 10, 2001
Although significant progress has been made in asymmetric
organocopper reactions employing chiral anionic (e.g., RCuL*Li)
or neutral nontransferable heteroatom ligands [e.g., (RCuL)Li‚
L*],1 the use of chiral cuprates possessing a stereogenic center
at the carbon atom bound to copper in the transferable ligand
remains underdeveloped. Scalemic2 R-alkoxyalkylcuprates display
considerable varibility in enantioselectivity (0-96% ee) during
1,4-addition reactions3 and asymmetric variations have not been
examined in a wider range of copper-mediated transformations.
Methylation of a chiral N-protected R-aminoalkylcuprate reagent
(i.e., RCuCNLi) displayed no diastereoselectivity.4 Thermody-
namically controlled configurational stability has been demon-
strated for R-aminoalkylcuprate reagents derived from a chiral
lactam5 and the configurational stability of zinc cuprates derived
from organoboranes has been examined in substitution reactions.6
Pioneering work by Hoppe7 and Beak8 demonstrated the
viability of configurationally stable scalemic alkyl- and allyl-
lithium9 reagents derived from carbamate derivatives. R-Lithio
carbamate configurational stability is solvent, reaction temperature,
and electrophile dependent.10 Our successful development of R-(N-
carbamoyl)alkylcuprate chemistry prompted us to explore the
preparation and utilization of scalemic R-(N-carbamoyl)alkylcu-
prates.11 Expansion of scalemic R-lithio carbamate chemistry to
organocopper reagents requires carbanion configurational stability
during transmetalation to the copper reagent and during the
subsequent copper-mediated transformations. We report here the
confirmed by deuterium quenching that complete deprotonation
of N-Boc pyrrolidine could be achieved with sec-BuLi/(-)-
sparteine in Et2O at -78 °C over 1 h. Although THF was the
solvent of choice for the cuprate reactions, the configurational
lability of 1 in THF was problematic. Generation of 1 in THF
with sec-BuLi/(-)-sparteine followed by cuprate formation and
reaction with 2 gave racemic 10 as determined by chiral HPLC
analysis in good yield (Table, entry 1). Cuprate reagents prepared
via asymmetric deprotonation of N-Boc protected pyrrolidine [sec-
BuLi, (-)-sparteine, Et2O, -78 °C, 1 h]13 followed by trans-
metalation with either solid CuCN or a THF solution of CuCN‚
2LiCl permitted, respectively, use of Et2O and Et2O/THF solvent
systems. Quenching the dialkylcuprate reagent (i.e., R2CuLi‚
LiCN), prepared from CuCN‚2LiCl, with 2 at -78 °C afforded
the vinylation product (Table 1, entry 2) in good yield and with
excellent enantioselectivity (93:7% er). Excellent reproducibility
was obtained over several experiments ranging between 85 and
98% yield and 90:10 to 93:7 er. Increasing the temperature of
the reaction mixture during the cuprate formation stage or aging
the cuprate reagent resulted in slight deterioration of the enanti-
oselectivity (entries 3 and 4). Utilization of solid CuCN required
brief warming to 25 °C to ensure complete cuprate formation
and this protocol resulted in significant loss of enantioselectivity
(entry 5). Reaction of the dialkylcuprate with vinyl iodide 3 also
gave excellent yields and enantioselectivity (entries 6 and 7).
Mixed results were obtained with vinyl iodides 4, 6, and 7
containing electron-withdrawing groups. Reaction of the dialkyl
pyrrolidinylcuprate, R2CuLi‚LiCN, with 4 or 6 gave 12a,b,
respectively, in good yields and excellent enantioselectivity
(entries 8-9, and 11) while reaction with 7 gave excellent yields
but modest enantioselectivity (entries 13 and 14). Reaction of 7
with the alkyl(cyano)cuprate, RCuCNLi, gave excellent yields
but no enantioselectivity (entry 12). In contrast to the vinylation
reactions, conjugate addition of either pyrrolidinylcuprate with
benzyl acrylate (8) gave no enantioselectivity (entries 15-17),
while the RCuCNLi reagent gave modest selectivity with 5 (entry
10). With the propargyl mesylate (9), the cyanocuprate reagent
gave modest chemical yields and poor to modest enantioselectivity
(entries 18 and 19) while the dialkylcuprate gave poor chemical
(1) For reviews see: (a) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992,
92, 771. For reviews on catalysis involving chiral heteroatom cuprates prepared
from anionic ligands see: (b) Krause, N. Angew. Chem. Int. Ed. Engl. 1997,
36, 187. (c) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1998, 37,
283. For reviews on copper catalysis involving neutral chiral heteroatom
ligands see: (d) Alexakis, A. Chimia 2000, 54, 55. (e) Feringa, B. Acc. Chem.
Res. 2000, 33, 346.
(2) The descriptive term scalemic (uneven or lopsided) has been suggested
by James Brewster and employed by Clayton H. Heathcock as an alternative
to “enantioenriched” or “enantiomerically enriched”: Heathcock, C. H. Chem.
Eng. News , 1991, Feb. 4, 3.
(3) (a) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4930.
(b) Linderman, R. J.; Griedel, B. D. J. Org. Chem. 1990, 55, 5428. (c)
Linderman, R. J.; Griedel, B. D. J. Org. Chem. 1991, 56, 5491.
(4) Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem. 1989, 54,
175.
(5) Tomoyasu, T.; Tomooka, K.; Nakai, T. Tetrahedron Lett. 2000, 41,
345.
(6) (a) Lhermitte, F.; Knochel P. Angew. Chem., Int. Ed. 1998, 37, 2459.
(b) Boudier, A.; Hupe, E.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2294.
(7) For a review see: Hoppe, D.; Hense, T. Angew. Chem. Int. Ed. Engl.
1997, 36, 2283.
(8) For a review see: Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
(9) (a) Wu, S. D.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715. (b)
Prasad, K. R. K.; Hoppe, P. Synlett 2000, 1067.
(10) Gross, K. M. B.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
(11) For conjugate addition reactions of R-(N-carbamoyl)alkylcuprates
see: (a) Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron 2000, 56,
2767. (b) Dieter, R. K.; Lu, K.; Velu, S. E. J. Org. Chem. 2000, 65, 8715. (c)
Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283. For acylation reactions see:
(d) Dieter, R. K.; Sharma, R. R.; Ryan, W. Tetrahedron Lett. 1997, 38, 783.
For vinylation reactions see: (e) Dieter, R. K.; Alexander, C. W.; Bhinderwala,
N. S. J. Org. Chem. 1996, 61, 2930. (f) Dieter, R. K.; Sharma, R. R.
Tetrahedron Lett. 1997, 38, 5937. For reaction with propargyl substrates see:
(g) Dieter, R. K.; Nice, L. E. Tetrahedron Lett. 1999, 40, 4293.
(12) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D.
J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715.
(13) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708. (b)
Beak, P.; Kerrick, S. T.; Wu, S. D.; Chu, J. X. J. Am. Chem. Soc. 1994, 116,
3231.
10.1021/ja0156587 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/04/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5133
Table 1. Reactions of Scalemic R-(N-carbamoyl)alkylcuprates, Prepared from Scalemic R-Lithio N-Boc Pyrrolidine (1), with a Variety of
Electrophiles
a CuCN‚2LiCl was employed unless otherwise noted. b Temperature and time at which cuprate formation was achieved. c THF/Et2O solvent
ratio (1:1, v/v) arose by deprotonation of carbamate in Et2O followed by addition of a THF solution of CuCN‚2LiCl. d Temperature and time at
which the cuprate/electrophile reaction was allowed to proceed. e Cuprate reactions assumed to proceed with retention of configuration3 from scalemic
1.13 f Based on products purified and isolated by chromatography. g Enantioselectivity (er) was measured by chiral stationary phase HPLC on a
CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]. h Solid CuCN was used. i TMSCl (5 equiv) was employed.
j E:Z ) 59:41, 72:28 er for each diastereomer.
yields and a modest er (entry 20). Oxidative cleavage of 10
followed by amide formation14 gave the R amide confirming
retention of configuration in the cuprate formation and reaction
steps.13
Reaction of either cuprate reagent with 8 where only the 1,4-
addition pathway is available gives no enantioselectivity sug-
gesting that configurational lability of the chiral R-(N-carbamoyl)-
alkylcuprate occurs along the reaction coordinate leading to
conjugate addition. The loss of enantioselectivity in these 1,4-
addition reactions may arise from an equilibrium between a
cuprate-enone d,π* complex and starting cuprate and enone,
consistent with the er increasing with increasing substrate
reactivity (e.g., 5 vs 8). The modest er values observed with the
propargyl substrate clearly indicate a temperature dependence.
These results establish that configurational stability can be
achieved in the generation and reaction of chiral R-(N-carbamoyl)-
alkylcuprates containing a stereogenic center at the carbon bound
to copper, although the enantioselectivity is a function of the
particular reaction, substrate, temperature, solvent, and cuprate
reagent. The high enantioselectivities observed in the vinylation
reactions with 2-4 and 6 suggest that these reactions proceed
with configurational stability in the cuprate reagent. The slight
loss of er when the cuprate reagent is formed or aged at higher
temperatures (e.g., -60 to -40 °C) could reflect slow racem-
ization of either the organolithium reagent or the cuprate reagent.
The presumably slow formation of the cuprate reagent in Et2O
with insoluble CuCN requires elevated temperatures for complete
cuprate formation and this procedure shows almost complete loss
of enantioselectivity consistent with rapid racemization of the
organolithium reagent at elevated temperatures.
Reaction of RCuCNLi with 7 gave good yields of 13 but no
enantioselectivity while reaction with R2CuLi‚LiCN gave a low
er that could be increased by longer reaction at lower temperature.
This suggests that 7, in contrast to 4, may react by competing
reaction pathways involving conjugate addition-elimination and
direct substitution with the latter pathway giving rise to the
observed enantioselectivity. The absence of enantioselectivity with
RCuCNLi may reflect the lower reactivity of the reagent requiring
higher temperatures to effect the reaction where competing
racemization becomes a problem. Alternatively, the RCuCNLi
reagent may effect the transformation via the conjugate addition-
elimination pathway only.
In summary, chiral R-(N-carbamoyl)alkylcuprates with a ste-
reogenic center bound to copper can display excellent configu-
rational stability during cuprate formation and reaction depending
upon solvent, temperature, particular cuprate reaction, and cuprate
reagent. Although the absence of enantioselectivity in the
conjugate addition reactions with enoates appears to be intimately
involved with the reaction pathway, the observed er values in
the substitution reactions appear to revolve around temperature
and substrate reactivity effects. Use of chiral R-(N-carbamoyl)-
alkylcuprates is a synthetically viable strategy for direct substitu-
tion reactions with vinyl iodides.
Acknowledgment. This work was generously supported by the
National Institutes of Health (GM-60300-01) and the Petroleum Research
Fund (ACS-PRF 33626-ACI). Support of the NSF Chemical Instrumenta-
tion Program for purchase of a JEOL 500 MHz NMR instrument is
gratefully acknowledged (CHE-9700278).
Supporting Information Available: Synthesis of 10 and
12a and absolute configuration for 10 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J. Org. Chem.
1999, 64, 1160.
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