Reactivity and Enantioselectivity in the Reactions of Scalemic Stereogenic α-(N-Carbamoyl)alkylcuprates

Article abstract of DOI:10.1021/jo035845i

Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN·2LiCl react with vinyl iodides, vinyl triflates, β-iodo-α,β-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the α-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.

Full text of DOI:10.1021/jo035845i

Rea ctivity a n d En a n tioselectivity in th e Rea ction s of Sca lem ic
Ster eogen ic r-(N-Ca r ba m oyl)a lk ylcu p r a tes
R. Karl Dieter,* Gabriel Oba, Kishan R. Chandupatla, Chris M. Topping, Kai Lu, and
Rhett T. Watson
Howard L. Hunter Laboratory, Department of Chemistry, Clemson University,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received December 19, 2003
Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched)
N-Boc-2-lithiopyrrolidine and THF soluble CuCN‚2LiCl react with vinyl iodides, vinyl triflates,
â-iodo-R,â-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with
excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition
reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate
esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns
and the observed enantioselectivities appear to be more a function of cuprate-electrophile
reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios
are obtained with the R-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and
cuprate vinylation reactions proceed with retention of configuration.
In tr od u ction
tions have also been achieved in a variety of lithiated
benzylic systems.3,4 Configurational stability increases
with the covalent character of the C-M bond (i.e., in
configurational stability Zn9,10 > Mg11 > Li1-7) and
significant progress has also been made with organozinc
reagents,10 although attempts to prepare stereogenic zinc
reagents by direct reduction with active zinc results in
racemization.9
Modest configurational stability of stereogenic C-Cu
bonds was first demonstrated by Whitesides in norbornyl
systems12a and later extended to small and modest sized
monocyclic ring systems12b-h providing opportunities for
diastereoselective reactions upon quenching with elec-
trophiles. Diastereoselectivity was also observed with
stereogenic cuprate reagents containing a chiral auxiliary
near the reactive C-Cu bond.12h Early work by Fuchs13
and Linderman14a,b explored the reactions of scalemic
Stereogenic organometallic compounds1 containing a
C-M bond between an asymmetric carbon atom and the
metal counterion display a wide range of configurational
stabilities depending upon the metal ion, substrate
structure, and reaction conditions. They offer a poten-
tially powerful strategy for asymmetric synthesis despite
daunting challenges for stereocontrol in the formation of
the reagents and in their subsequent reactions with
electrophiles. Since the early work on scalemic (i.e.,
enantioeriched) R-alkoxyalkyllithium reagents2 impres-
sive progress has been achieved with scalemic lithiated
O-allyl and alkyl carbamates (i.e., lithiation adjacent to
oxygen),3 R-lithio N-alkyl carbamates (i.e., lithiation
adjacent to nitrogen),3-5 R-lithio formamidines,6 R-lithio-
amides,7 and R-lithio amines.1,3,4,8 Enantioselective reac-
(1) (a) For use of the term and a review see: Gawley, R. E Curr.
Org. Chem. 1997, 1, 71. (b) Basu, A.; Thayumanavan, S. Angew. Chem.,
Int. Ed. 2002, 41, 716.
(2) Still, W. C.; Sreekumar, C. J . Am. Chem. Soc. 1980, 102, 1201-
1202.
(9) (a) Guijarro, A.; Rieke, R. D. Angew. Chem., Int. Ed. 2000, 39,
1475-1479. (b) Guijarro, A.; Rosenberg, D. M.; Rieke, R. D. J . Am.
Chem. Soc. 1999, 121, 4155-4167.
(10) (a) Boudier, A.; Darcel, C.; Flachsmann, F.; Micouin, L.;
Oestreich, M.; Knochel, P. Chem. Eur. J . 2000, 6, 2748. (b) Knochel,
P. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Morlenbach, Germany, 2002; Chapter 2, pp 45-78.
(3) For a review see: Hoppe, D.; Hense, T Angew. Chem., Int. Ed.
Engl. 1997, 36, 2283-2316.
(4) For a review see: Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y.
S Acc. Chem. Res. 1996, 29, 552-560.
(11) (a) Hoffmann, R. W.; Ho¨lzer, B. J . Am. Chem. Soc. 2002, 124,
4204-4205. (b) Hoffmann, R. W.; Nell, P. G.; Leo, R.; Harms, K. Chem.
Eur. J . 2000, 6, 3559-3365.
(5) (a) Chong, J . M.; Park, S. B. J . Org. Chem. 1992, 57, 2220-
2222. (b) Pearson, W. H.; Lindbeck, A. C.; Kampf, J . W. J . Am. Chem.
Soc. 1993, 115, 2622-2636.
(12) (a) Whitesides, G. M.; Kendall, P. E. J . Org. Chem. 1972, 37,
3718-3725. (b) Yamamoto, H.; Kitatani, K.; Hiyama, T.; Nozaki, H.
J . Am. Chem. Soc. 1977, 99, 5816-5817. (c) Walborsky, H. M.;
Periasamy, M. P. J . Organomet. Chem. 1979, 179, 81-87. (d) Marino,
J . P.; Brown, L. J . Tetrahedron Lett. 1976, 3241-3244. Marino, J . P.;
Brown, L. J . Tetrahedron Lett. 1976, 3245-3252. (e) Piers, E.;
Nagakura, I.; Shaw, J . E. J . Org. Chem. 1978, 43, 3431-3432. (f) Piers,
E.; Ruediger, E. H. J . Chem. Soc., Chem. Commun. 1979, 166. (g)
Morgans, D. J ., J r.; Feigelson, G. B. J . Am. Chem. Soc. 1983, 105,
5477-5479. (h) Schollkopf, U.; Pettig, D.; Schulze, E.; Klinge, M.; Egert,
E.; Benecke, B.; Noltemeyer, M. Angew. Chem., Int. Ed. Engl. 1988,
27, 1194-1195.
(6) Meyers, A. I.; Elworthy, T. R. Tetrahedron 1994, 50, 6089-6096.
(7) Iula, D.; Gawley, R. E. J . Org. Chem. 2000, 65, 6169-6201.
(8) (a) Peterson, D. J . J . Organomet. Chem. 1970, 21, 63-64. (b)
Burchat, A. F.; Chong, J . M.; Park, S. B. Tetrahedron Lett. 1993, 34,
51-54. (c) Gawley, R. E.; Zhang, Q. Tetrahedron 1994, 50, 6077-6088.
(d) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R J . Am. Chem. Soc.
2000, 122, 3344-3350. (e) Coldham, I.; Dufour, S.; Haxell, T. F. N.;
Howard, S.; Vennall, G. P. Angew. Chem., Int. Ed. 2002 41, 3887. (f)
For R-lithio imines see: Pearson, W. H.; Postich, M. J . J . Org. Chem.
1992, 57, 6354-6357.
10.1021/jo035845i CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004
3076
J . Org. Chem. 2004, 69, 3076-3086

Scalemic Stereogenic R-(N-Carbamoyl)alkylcuprates
SCHEME 1
R-alkoxyalkylcuprates prepared from configurationally
stable R-alkoxyalkylithium reagents. These reagents
transferred the scalemic ligand with retention of config-
uration in various degrees of selectivity. Glucosyl and
4-(1,3-dioxanyl)copper reagents (i.e., RCu) gave excellent
retention of configuration in conjugate addition reactions
in the presence of BF3‚Et2O or TMEDA, respectively,
while the dialkylcuprate derived from the 4-(1,3-dioxa-
nylstannane) displayed poorer configurational stability
(Scheme 1). Stereocontrol was capricious in acyclic cu-
prate reagents14a (Scheme 1), although a recent investi-
gation with R-carbamoyloxy organocuprates14c proved
more reliable. The procedure has been extended to a
wider range of electrophiles with cuprates prepared from
conformationally biased 4-lithio-1,3-dioxanes and good
stereocontrol at the stereocenter â to the carbonyl was
achieved in these systems.14d Stereogenic R-alkoxyalkyl-
cuprates prepared via deprotonation of O-alkyl carbam-
ates appear to also afford reliable enantioselectivities,
although problems of reactivity were observed with both
the zinc and lithium alkylcyanocuprate reagents.15 Knoch-
el has achieved good diastereoselectivities in the reaction
of zinc alkylcuprates prepared via the transmetalation
sequence RBR′2 to RZnX to RCuCNZnX10 while scalemic
alkyl Grignard reagents11a require the intermediacy of
the zinc reagents for the preparation of stereogenic
cuprate reagents with stereochemical integrity.
More recently, good diastereoselectivity has been
achieved in conjugate addition reactions with stereogenic
R-aminoalkylcuprates16 under dynamic thermodynamic
control (Scheme 1),17 although poor diastereoselectivity
at the â-carbon atom was obtained with acyclic R,â-
enones. We have reported the first examples of high
enantioselective vinylation of R-(N-carbamoyl)alkylcu-
prates via asymmetric deprotonation (reproducibly 80-
87% ee, vide infra)18a or transmetalation18b and in this
(13) Hutchinson, D. K.; Fuchs, P. L. J . Am. Chem. Soc. 1987, 109,
4930-4939.
(14) (a) Linderman, R. J .; Griedel, B. D. J . Org. Chem. 1990, 55,
5428-5430. (b) Linderman, R. J .; Griedel, B. D. J . Org. Chem. 1991,
56, 5491-5493. (c) Tomooka, K.; Shimizu, H.; Nakai, T. J . Organomet.
Chem. 2001, 624, 364-366. (d) Rychnovsky, S. D.; Buckmelter, A. J .;
Dahanukar, V. H.; Skalitzky, D. J . J . Org. Chem. 1999, 64, 6849-
6860.
(15) Papillon, J . P. N.; Taylor, R. J . K. Org. Lett. 2002, 4, 119-122.
(16) Tomoyasu, T.; Tomooka, K.; Nakai, T. Tetrahedron Lett. 2000,
41, 345-349.
(17) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J . M.; Pippel,
D. J .; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715-727.
J . Org. Chem, Vol. 69, No. 9, 2004 3077

Dieter et al.
CHART 1
SCHEME 2
2LiCl (Scheme 2) gave either the lithium alkylcyanocu-
prate 13-CN (1.0 equiv CuCN) or the lithium dialkylcu-
prate 13-R (0.5 equiv CuCN) reagent. Although N-Boc
pyrrolidine was usually deprotonated in THF for prepa-
ration of the N-Boc-2-pyrrolidinyl cuprates in prior
studies,20-23 Beak had shown that this solvent was
unsuitable for asymmetric deprotonation and/or carban-
ion configurational stability19 and this was quickly
confirmed.
Cuprate reagents 13-CN and 13-R prepared via depro-
tonation of 12 in Et2O according to the Beak protocol19
followed by addition of a THF solution of CuCN‚2LiCl
underwent enantioselective substitution reactions with
vinyl iodides (Table 1). In all instances but one (entry 18
vs 19), 13-R and 13-CN gave comparable enantioselec-
tivities (entries 1 vs 2, 4 vs 6, 9 vs 11, and 15 vs 16).
Cuprate 13-CN gave no enantioselectivity with 3-iodocy-
clohexenone (entry 18). Selectivity diminished as cuprate
13-R was allowed to age at moderate (-60 to -40 °C)
temperatures decreasing from a 90:10 to a 73:27 er after
2 h. Preparation of 13-R with solid CuCN and briefly
warming the solution to 25 °C to ensure complete cuprate
formation resulted in little to no enantioselectivity (entry
3). Comparable enantiomeric ratios (88:15 to 88:12 vs 90:
10 to 93:7) were obtained with vinyl bromide 2a and 13-R
with significant er degradation with either a 2:1 or 4:1
THF:E2O solvent mixture (entries 4 and 5). 1-Bromo-1-
trimethylsilylethene required reaction at low tempera-
tures for long times to achieve excellent ers (entry 8 vs
7) which was not required for 2-iodo-1-alkenes 2c,d ,
1-idodocyclohexene 3a , or 3-iodo-R,â-enoates 4a ,b which
gave excellent enantioselectivities upon slow uncontrolled
warming of the reaction mixtures (entries 9-17). Scaling
the reaction of cuprate 13-R or 13-CN with 4a from 1 to
10 mmol gave very comparable ers, although there was
slight variation from experiment to experiment (entries
14-16). Reaction of 13-R with 6a gave enantioselectivi-
ties that were sensitive to time and temperature (entries
19 and 20). The use of CuCl‚2LiCl (i.e., 13-Cl) gave very
good but lower ers than 13-CN (entries 9 and 10).
A comparison of vinyl triflates and nonaflates with the
vinyl iodides was undertaken to examine the effect of
leaving group upon the enantioselectivity of the reaction
(Table 2). The vinyl triflates and nonaflates uniformly
gave higher chemical yields with the 13-CN/THF/
TMEDA cuprate/solvent/additive system than with the
full report detail the enantioselectivities achieved with
these scalemic stereogenic cuprate reagents (prepared via
asymmetric deprotonation) as a function of the reaction,
reagent composition, and reaction conditions. This survey
reveals for the first time that enantioselectivities appear
not to be an inherent function of the particular cuprate
reaction (e.g., substitution vs conjugate addition) sug-
gesting that scalemic stereogenic cuprate reagents may
provide a broadly general strategy for asymmetric syn-
thesis comparable to the emerging power of the lithium
reagents in synthetic utility.
Resu lts
N-Boc-pyrrolidinylcuprates provided an ideal system
for examination, since both the asymmetric deprotonation
reaction of N-Boc-pyrrolidine19 and various cuprate trans-
formations involving substitution (e.g., with vinyl tri-
flates,20a vinyl iodides,20b,c propargyl,21 and allylic22 sub-
strates) or conjugate addition23 had been studied in detail.
Anticipating reaction-dependent enantioselectivities, vi-
nyl halides 1, 2a -d , and 3a , â-iodo-R,â-enoates 4a ,b, and
enone 6a , â-trifluoromethylsulfonyloxy-R,â-enone 6b,
vinyl triflates 3b and 7a ,b, nonaflate 3c, propargyl
substrates 8a -d , allyl bromide 9, and R,â-unsaturated
carbonyl compounds 10 and 11a -c (Chart 1) were
examined.
Beak deprotonation19 of N-Boc-pyrrolidine (12) in
either THF or Et2O followed by treatment with CuCN‚
(18) (a) Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K J .
Am. Chem. Soc. 2001, 123, 5132-5133. (b) Dieter, R. K.; Watson, R.
T.; Goswami, R. Org. Lett. 2003, 6, 253-256.
(19) (a) Kerrick, S. T.; Beak, P. J . Am. Chem. Soc. 1991, 113, 9708-
9710. (b) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc.
1994, 116, 3231-3239.
(20) For vinylations see: (a) Dieter, R. K.; Dieter, J . W.; Alexander,
C. W.; Bhinderwala, N. S. J . Org. Chem. 1996, 61, 2930-2931. (b)
Dieter, R. K.; Sharma, R. R. Tetrahedron Lett. 1997, 38, 5937-5940.
(c) Dieter, R. K.; Topping, C. M.; Nice, L. E. J . Org. Chem. 2001, 66,
2302-2311.
(21) For propargyl substrates see: Dieter, R. K.; Nice, L. E.
Tetrahedron Lett. 1999, 40, 4293.
(22) Dieter, R. K.; Velu, S. E.; Nice, L. E. Synlett 1997, 1114-1116.
(23) (a) For conjugate additions to ketones and aldehydes see:
Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron 2000, 56,
2767-2778. (b) For conjugate additions to R,â-unsaturated carboxylic
acid derivatives see: Dieter, R. K.; Lu, K.; Velu, S. E. J . Org. Chem.
2000, 65, 8715-8724.
3078 J . Org. Chem., Vol. 69, No. 9, 2004

Scalemic Stereogenic R-(N-Carbamoyl)alkylcuprates
TABLE 1. Rea ction s of Sca lem ic r-(N-ca r ba m oyl)a lk ylcu p r a tes, P r ep a r ed fr om Sca lem ic r-Lith io N-Boc P yr r olid in e,
w ith a Va r iety of Electr op h iles
a
b
CuCN‚2LiCl was employed and reactions run on a 1.0 mmol (12) scale unless otherwise noted. Temperature and time at which
cuprate formation was achieved. c A ) THF/Et2O solvent ratio (1:1 (v/v) unless otherwise noted) arose by deprotonation of carbamate in
d
Et2O followed by addition of a THF solution of CuCN‚2LiCl. B ) Et2O. Temperature and time at which the cuprate/electrophile reaction
was allowed to proceed. e Transmetalation and cuprate reactions are assumed to proceed with retention of configuration13,14,18a from scalemic
N-Boc-R-lithiopyrrolidine.19 Confirmed for 14. f Based on products purified and isolated by flash column chromatography. g Enantioselectivity
(% er) was measured by chiral stationary phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on
h
i
j
k
l
silica gel]. Solid CuCN was used. 2.0-mmol scale. CuCl‚2LiCl was employed. 10-mmol scale. TMSCl (5.0 equiv) was employed.
13-R/THF/Et2O/(-)-sparteine system (entries 1 vs 2, 3
vs 6, 7 vs 8, and 9 vs 10). For Nonaflate 3c, where a direct
comparison of the two cuprates was made, the chemical
yields are a function of both the solvent and the cuprate
reagent since 13-R gives higher chemical yields than 13-
CN in either solvent and both reagents give higher
chemical yields in THF alone (entries 3-6). The R-sub-
stituent in the vinyl substrate has a small effect upon
the chemical yields. Since an R-phenyl substitutent with
a smaller A-value24 than a tert-butyl substituent gives a
lower chemical yield (entries 9 and 10 vs 7 and 8)
electronic factors appear to be more important than steric
factors. The vinyl iodide analogue of 7b failed to undergo
substitution reactions with pyrrolidinyl cuprates. Chemi-
cal yields for the cyclohexenyl derivatives 3a -c decreased
along the series Tf > I > Nf for both cuprate-solvent-
additive systems [13-CN/THF/TMEDA: 80, not avail-
able, 53; entries 1 and 3 Table 2; 13-R/THF/Et2O/(-)-
sparteine: 65, 58, 50 entries 2 and 6 Table 2, entry 13,
Table 1]. Despite the chemical yield variation as a
function of leaving group and substrate structure, vinyl
iodide 3a and triflates 3b and 7a ,b gave excellent ers
(i.e., 89.5:10.5 to 95.5:4.5, entry 13 Table 1, entries 2, 8,
and 10 Table 2) upon reaction with 13-R in THF/Et2O.
For 13-R and 3a -c the er was comparable along the
series OTf ≈ ONf ≈ I, while 13-CN gave a low er with
3c (Table 2, entry 4) in contrast to vinyl iodides 1, 2c,
and 4a and vinyl bromide 2a , all of which gave modest
to excellent ers (Table 1, entries 2, 9, 16, and 6).
The reaction of N-Boc-2-pyrrolidinylcuprates with pro-
pargyl substrates generally gave modest chemical yields
and variable ers (Table 3). The alkylcyanocuprate reagent
13-CN gave significantly better chemical yields than the
dialkylcuprate reagent 13-R (entries 2 vs 3, 4 vs 5, and
6 vs 7) in the THF/Et2O mixed solvent system and the
high chemical yields were uniformly obtained with 13-
CN in THF alone (70-86%). Unfortunately, no to poor
enantioselectivities were obtained with 13-CN and 8b,c
(entries 2 and 4) while 13-CN and 8d gave modest ers
comparable to 13-R and 8d (entries 6 and 7). Excellent
ers could be achieved with 13-R and 8c (entry 5) while
modest ers were achieved with propargyl bromide (8a ,
(24) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994; pp 696-
697. (b) Hirsh, J . A. Top. Stereochem. 1967, 1, 199. (c) Eliel, E. L.;
Manoharan, M. J . Org. Chem. 1981, 46, 1959-1962.
J . Org. Chem, Vol. 69, No. 9, 2004 3079

Dieter et al.
TABLE 2. Rea ction s of Ra cem ic a n d Sca lem ic 2-P yr r olid in ylcu p r a tes w ith En ol Tr ifla tes or Non a fla tes
a
Conditions for the deprotonation of the N-Boc carbamate: A ) s -BuLi, TMEDA, THF, -78 °C, 1 h. B ) s-BuLi, (-)-sparteine, Et2O,
b
-78 °C, 1 h. Cuprate prepared from RLi and CuCN‚2LiCl at -78 °C, 1 h. Electrophile added at -78 °C and warmed to room temperature
overnight. c Based on products purified and isolated by chromatography. Enantioselectivity (% er) was measured by chiral stationary
d
phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]. e Transmetalation and cuprate
reactions are assumed to proceed with retention of configuration13,14,18a from scalemic N-Boc-R-lithiopyrrolidine.19
TABLE 3. Rea ction s of Sca lem ic r-(N-Ca r ba m oyl)a lk ylcu p r a tes, P r ep a r ed fr om Sca lem ic r-Lith io N-Boc P yr r olid in e,
w ith P r op a r gyl a n d Allylic Su bstr a tes
a
b
CuCN‚2LiCl was employed unless otherwise noted. Temperature and time at which cuprate formation was achieved. 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. c Temperature
d
and time at which the cuprate/electrophile reaction was allowed to proceed. Transmetalation and cuprate reactions are assumed to
proceed with retention of configuration13,14,18a from scalemic N-Boc-R-lithiopyrrolidine.19 e Based on products purified and isolated by
flash column chromatography. f Enantioselectivity (% er) was measured by chiral stationary phase HPLC on a CHIRALCEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel].
entry 1) or mesylate (8b, entry 3) and with the phenyl-
substituted propargyl mesylate 8d (entry 7). Allyl bro-
mide gave excellent chemical yields and enantioselectiv-
ity with 13-R (entry 8).
6). Reexamination of the reaction with methyl acrylate
11c revealed that poor ers could be achieved with the
use of the HMPA/TMSCl additive (entry 7).25
In an effort to explore whether reversible cuprate/
enoate d-π* complexation played any role in the dimin-
ished ers observed for the conjugate addition reactions,
several control experiments were performed. Cuprate
13-R was treated with 5,6-dihydro-2H-pyran-2-one and
TMSCl at -78 °C for 30 min followed by addition of vinyl
iodide 4a . In two experiments, a pale yellow color
appeared upon addition of the lactone to 13-R and
product 19a obtained via coupling of 4a with 13-R gave
good chemical yields (86-89%) and enantioselectivities
(92.5:7.5% er).
Conjugate addition reactions were examined using the
very reactive ethyl propiolate (10) and methyl vinyl
ketone (11a ) as well as the less reactive acrylate esters
11b,c (Table 4). The reaction of 13-CN with 10 gave a
mixture of E:Z diastereomers each of which was obtained
with the same modest er (entry 1). The very reactive 11a
gave comparable chemical yields with either 13-CN or
13-R and very excellent ers (entries 2-4). The use of
nBu3P in place of LiCl with 13-CN gave the same results
(entries 2 and 3). Initial studes with acrylate ester 11b
gave excellent chemical yields in the presence of TMSCl
and in all cases gave no enantioselectivity (entries 5 and
(25) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I.
Tetrahedron 1989, 45, 349-362.
3080 J . Org. Chem., Vol. 69, No. 9, 2004

Scalemic Stereogenic R-(N-Carbamoyl)alkylcuprates
TABLE 4. Rea ction s of Sca lem ic r-(N-ca r ba m oyl)a lk ylcu p r a tes, P r ep a r ed fr om Sca lem ic r-Lith io N-Boc P yr r olid in e
w ith r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s
a
b
CuCN‚2LiCl was employed unless otherwise noted. Temperature and time at which cuprate formation was achieved. 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. c Temperature
and time at which the cuprate/electrophile reaction was allowed to proceed. TMSCl (5.0 equiv) was employed as an additive.
Transmetalation and cuprate reactions are assumed to proceed with retention of configuration13,14,18a from scalemic N-Boc-R-
d
lithiopyrrolidine.19 e Based on products purified and isolated by chromatography. f Enantioselectivity (% er) was measured by chiral
g
stationary phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]. E:Z ) 59:41; 72:28 er
for each diastereomer. nBu3P (2.0 equiv) was added to solubilize CuCN. HMPA/TMSCl (2.0 equiv) was added along with the methyl
h
i
acrylate.
Several experiments were performed with acyclic ben-
zylic stereogenic cuprate reagents and in all cases low
to modest yields and enantioselectivities were obtained.
Although previous studies either did not report or noted
a solvent dependence26 on the regioselective deprotona-
tion of N-Boc-N-methylbenzylamine 29a , deprotonation
[s-BuLi (1.2 equiv), THF, TMEDA, -78 °C, 2 h] followed
by quenching with MeI gave alkylation at the benzylic
position, the methyl position, and at both sites [50.3%,
37%, and 12.7%, respectively]. Consequently, we chose
to examine the N-ethyl analogue 29b to minimize this
complication (eq 1). N-Boc-N-ethylbenzylamine 29b was
Et2O with the s-BuLi/(-)-sparteine complex [-78 °C, 5
h] followed by quenching with MeI at -78 °C gave the
alkylation product (i.e., 34) in 68% yield and with an
enantioselectivity of 83:17 (66% ee), which compares
favorably with the 62% ee reported26a for the asymmetric
deprotonation and methylation of 29a . Utilization of this
longer deprotonation time did not increase the enantio-
selectivity of the cuprate-mediated conjugate addition
reaction (31:69 er vs 28.3:71.7 to 35.7:66.3). Both proce-
dures gave low selectivities in THF (14-19% ee) and the
same selectivity was obtained with CuCN‚2LiCl. The
major enantiomer was the opposite of that obtained in
Et2O consistent with the results reported for quenching
the benzyllithium reagent generated from 29a .26a In
contrast to the N-methyl analogue 29a 26a no precipitate
was observed in THF during the deprotonation of 29b
with concentrations of 29b ranging between 1 and 0.33
M. Alkylation of 30b with MeI in THF afforded the
R-phenylethylamine in good chemical yield with low
enantioselectivity (9-12% ee). Again, no precipitation
was observed at -78 °C after 3 h. Generation of 30b in
toluene with n-BuLi/(-)-sparteine [-78 °C, 4 h] followed
by cuprate formation and treatment with methyl vinyl
ketone gave 31b with a diminished selectivity (er: 63.3:
36.7). (S)-d1-29a fails to undergo metalation with s-BuLi/
(-)-sparteine26a and assignments of absolute stereochem-
istry for 30b are predicated on the assignments and
assumptions reported for 29a , although these appear not
to have been rigorously established.26a-c The assignments
for 31b also require the assumption that Li to Cu
transmetalation and the subsequent organocopper reac-
tion both proceed with retention of configuration as
previously observed12a,13,14 and demonstrated for 14,18
15a , 22, and 26 (vide infra).
deprotonated in Et2O or THF and allowed to stir at -78
°C for 2-3 h to allow the dominant R-lithiocarbamate/
(-)-sparteine complex to form.26a CuCN solubilized with
n-Bu3P was employed in these experiments. No enantio-
selectivity was observed in Et2O when the cuprate
solution was allowed to warm to room temperature
slowly. Modest selectivities (36-40% ee) were obtained
when the solution was rapidly warmed to room temper-
ature irrespective of the temperature at which the
electrophile was added if the temperature was at or below
-60 °C. In control experiments, deprotonation of 29b in
Asymmetric deprotonation of 29b and reaction of the
alkylcyanocuprate (i.e., RCuCNLi) derived from 30 with
(E)-1-iodo-1-hexene (32) gave good chemical yields of
the vinylation product 33 [i.e., (E)-PhCH(EtNBoc)-
CHdCHnBu] but no enantioselectivity, while utilization
of the dialkylcuprate (i.e., R2CuLi) gave no vinylation
product. Scalemic (R) R-phenylethylbenzylamine 34
(26) (a) Schlosser, M.; Limat, D. J . Am. Chem. Soc. 1995, 117,
12342-12343. (b) Voyer, N.; Roby, J . Tetrahedron Lett. 1995, 36, 6627-
6630. (c) Barberis, C.; Voyer, N.; Roby, J .; Che´nard, S.; Tremblay, M.;
Labrie, P. Tetrahedron 2001, 57, 2965-2972. (d) Park, Y. S.; Boys, M.
L.; Beak, P. J . Am. Chem. Soc. 1996, 118, 3757-3758. (e) Park, Y. S.;
Beak, P. Bull. Korean Chem. Soc. 1998, 19, 1253-1256. (f) Dieter, R.
K.; Yu, H. Org. Lett. 2000, 2, 2283-2286.
J . Org. Chem, Vol. 69, No. 9, 2004 3081

Dieter et al.
showed similar enantioselectivities in THF/TMEDA,
THF/(-)-sparteine, and Et2O/TMEDA (eq 2) but reduced
specific rotation [R]24D +28.1 (c 1.35, CHCl3), the opposite
rotation to that reported in the literature ([R]23 -63.1
D
(c 1.02, CHCl3))28c for the (S)-enantiomer. This is again
consistent with both cuprate formation and vinylation
proceeding with retention of configuration.
Discu ssion
Organocopper reagents are generally prepared by
transmetalation reactions and the stereochemical integ-
rity of this event, as well as that of the subsequent
reaction with an electrophile, increases the difficulties
of developing synthetically useful stereogenic organocu-
prate methodologies. Stereogenic cuprate reagents may
lose stereochemical integrity during either transforma-
tion or as an epimerization process competitive with the
cuprate-electrophile reaction. Previous studies offer no
consistent explanation for the loss of stereochemical
integrity in stereogenic organocopper reagents. The 2-en-
donorbornylcuprate study showed that cuprate configu-
rational integrity decreased along the series RCutBuLi
(99:1) > RCuMeLi (94:6) > R2CuMgBr (i.e., Grignard +
5 mol % of ICuPBu3, 81:19) > RCuPBu3 (47:53) [R )
2-endonorbornyl, 99:1) in the conjugate addition reactions
with mesityl oxide. The greater loss of stereochemical
integrity with cuprates derived from 65:35 endo:exo
equilibrium mixtures of 2-norbornylmagnesium bromides
suggests formation of byproducts that increase epimer-
ization of the cuprate reagents.12a
Racemization in R-alkoxyalkylcuprates occurs at higher
temperatures in both cyclic and acyclic systems and is
reported to be highly dependent upon trace impurities
[e.g., oxygen, Cu(II), or tin impurities] in the reaction
mixture.13,14a,b Oxygen-induced dimer formation from an
enantiopure R-alkoxyalkylcuprate with retention of con-
figuration (40% yield, >90% retention) suggests that
racemization does not occur during the transmetalation
step. Racemization increases with increasing amounts of
dimer and both events may be induced by trace amounts
of oxygen.14 Both the norbornyl and the stereogenic
R-alkoxyalkylcuprate studies confirm that the conjugate
addition is not proceeding by a radical pathway and
racemization has been postulated to occur prior to the
enone oxidative addition-reductive elimination sequence
even though the fast 1,4-addition process racemizes the
stereogenic ligand significantly faster than the dimer-
ization pathway.14a In the cyclic systems, enantiopure
R-alkoxyalkylcopper reagents prepared from CuBr‚
SMe213 or CuI‚TMSI [e.g., >98% de vs 40% de with ethyl
propiolate]14a give retention of configuration to a greater
extent in conjugate addition reactions than R2CuLi‚LiCN
reagents (Scheme 1). More recently, it has been suggested
that racemization is faster or more facile in the first
transmetalation step forming RCuMgX then in the
second transmetalation step forming R2CuMgX during
the preparation of magnesium cuprates from stereogenic
Grignard reagents.11a
selectivity in Et2O/(-)-sparteine consistent with the
solvent-dependent enantioselection reported for 30a .26a
Initial deprotonation of 34 must lead to the (R)-benzyl-
lithium reagent and, assuming retention (relative to the
stereogenic C-Li bond) of configuration during cuprate
formation and subsequent reaction, assignment of the
S-configuration to the major enantiomer of 35 can be
made. Related studies on scalemic R-phenylethylamines
have employed n-BuLi/(-)-sparteine for deprotonation.27
Nevertheless, benzylic cuprates derived from 34 show
modest enantioselectivity for the sequence of events
involving deprotonation, cuprate formation, and the
vinylation reaction (eq 2). Further efforts to optimize
these results were not undertaken.
The absolute configuration of 14 was established by
chemical correlation with (S)-proline, using an estab-
lished procedure.28a Oxidation of 14 [NaIO4, ReCl3‚H2O,
CCl4, CH3CN, 25 °C] to N-(tert-butoxycarbonyl)proline
followed by amide formation [dicyclohexylcarbodimide,
3,4-dimethylaniline, hydroxybenzotriazole] gave material
with an enantiomeric purity of 89.5:10.5 as determined
by chiral stationary phase HPLC on a CHIRALCEL OD
column, which compares favorably with the 91.4:8.6 er
determined for the starting material 14. The major
isomer eluted first at 11.50 min with the minor isomer
eluting at 16.08 min while the amide prepared from
commercially available (S) proline eluted at 15.74 min.18a
Formation of the (R)-amide establishes that cuprate
formation and the cuprate vinylation reaction18a both
proceed with retention of configuration from (S)-N-Boc-
2-lithiopyrrolidine.19,28a The (S)-ethyl carbamate analogue
of 15a ([R]24 +13.3 (c 1.43, THF) for er 88:12) has a
D
reported28a specific rotation of [R]22 -23.2 (c 1, EtOH)
D
for an er 83:17, resulting in assignment of the (R)-
configuration to 15a consistent with retention of config-
uration in cuprate formation and reaction with vinyl
bromide. Similarly, 26 ([R]24 +38.0 (c 3.69, THF) for er
D
89:11) can by assigned the (R)-configuration by compari-
son with the reported28b specific rotation for the known
(S)-enantiomer ([R]25 -32.4 (c 1.56, CHCl3). Ozonolyis
D
of 22 gave the corresponding ketone in 95% yield with a
Although no kinetic measurements were undertaken,
the present survey of enantioenriched lithium 2-pyrro-
lidinylcuprates suggests that relative rates between
racemization and cuprate-electrophile reaction in this
series may be the principal factor governing stereoselec-
tivities and stereochemical integrity. While the ers listed
in Tables 1-4 range from nonexistent to excellent, poor
(27) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J . Am. Chem. Soc.
1997, 119, 11561-11570.
(28) (a) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J . J .
Org. Chem. 1999, 64, 1160-1165. (b) Park, S. O.; Kang, H. J .; Ko, S.;
Park, S.; Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621-2624.
(c) Ookawa, A.; Soai, K. J . Chem. Soc., Perkin Trans. 1 1987, 1465-
1471.
3082 J . Org. Chem., Vol. 69, No. 9, 2004

Scalemic Stereogenic R-(N-Carbamoyl)alkylcuprates
ers could often be improved by optimization of reaction
parameters including cuprate reagent, substrate struc-
ture, solvent, temperature, and time elements, as well
as the use of additives.
reactive electrophiles 13-CN gives reduced ers (vinyl
bromide 2a ) while high ers are still obtained with 13-R.
This view is bolstered with the observation that 13-R
reacts with sterically hindered 1-iodovinyl silane 2b to
give modest enantioselectivity when the solution slowly
warms to room temperature and excellent ers when the
reaction mixture is stirred at -60 °C for 10 h. This result
suggests that when the reaction of the cuprate with an
electrophile is slow racemization becomes a competitive
process. As noted above, it appears that both cuprate
reagents begin to racemize slowly around -60 to -40 °C.
Thus a more reactive 13-R may undergo complete reac-
tion at lower temperatures while a less reactive 13-CN
may require higher temperatures where racemization
now becomes competitive.30 It has recently been reported11a
that greater racemization occurs in the initial transmeta-
lation to form RCuCNMgX than in the second transfor-
mation to form R2CuMgX for enantioenriched magnesium
cuprate reagents and this does not seem to be the case
with the lithium R-(N-carbamoyl)alkylcuprates.
The importance of relative reactivity is also seen in the
combination of cuprate reagent and leaving group. For
13-R and 3a -c the enantioselectivity is nearly identical
within experimental error along the series OTf ≈ ONf ≈
I (Tables 1 and 2) while nonaflate 3c gives low chemical
yields and low enantioselectivity with the less reactive
cuprate 13-CN. It should be noted that while triflate 7b
gave good ers the corresponding vinyl iodide failed to
afford significant amounts of 22. When a particular vinyl
iodide gives low chemical yields or enantioselectivities,
better results can generally be achieved by carrying the
reaction out at lower temperatures for longer periods of
time. This optimization protocol suggests that in difficult
reactions vinyl iodide decomposition pathways are sup-
pressed at lower temperature and similar decomposition
pathways are unavailable to the vinyl triflates. The
chemically unstable vinyl triflate 6b gave racemic 20.
Electronic factors are also important in determining
resultant chemical yields as the more sterically hindered
7a (A value > 4.5)24a,b gives a higher yield of 21 than 7b
(A value ) 2.9)24a,c does of 22. Although we do not have
rate data to quantify this perspective, it appears that the
relative reactivities of both the cuprate and substrate
play important roles in determining both chemical yields
and enantioselectivities.
This exploratory survey demonstrates that stereogenic
R-(N-carbamoyl)alkylcuprates can be prepared efficiently
from N-Boc-2-lithiopyrrolidine when soluble forms of Cu-
(I) salts are employed and that configurational integrity
is maintained in the copper-mediated reactions with
certain electrophiles. Use of soluble Cu(I) salts promotes
rapid cuprate formation at -78 °C where racemization
of the precursor organolithium reagent is slowed. When
pyrrolidinylcuprates 13-CN and 13-R were allowed to age
at -60 (105 min, 89:11 er) and -40 °C (120 min, 73:27
er), respectively, before addition of trans-â-iodostyrene
(1), good enantioselectivities were still obtained. These
results indicate that 13-CN and 13-R racemize slowly
at temperatures below -40 °C. The reactions of cuprates
13-CN and 13-R with electrophiles to give 14, 15a , 22,
and 26 were shown to proceed with retention of config-
uration about the stereogenic carbon center consistent
with previous observations.12-14,16 When these results are
taken as a whole, the principal pattern that emerges is
one of relative reactivities involving both the cuprate
reagents and electrophiles governing stereochemical
outcome. Thus, the enantioselectivity of the reactions
appears to be less a function of the reaction type (e.g.,
vinyl vs propargyl substitution vs conjugate addition)
than of the reactivity of the electrophile and/or cuprate
employed. The vinylation reactions listed in Table 1
generally proceed with comparable or higher ers when
lithium dialkylcuprate 13-R is used and either a 2:1 or
4:1 THF:Et2O solvent mixture (achieved upon addition
of CuCN‚2LiCl/THF) gives significantly lower ers (entries
4 and 5). Although rate acceleration of organocuprate
substitution reactions occurs in polar solvents29 (e.g.,
THF), there is also an increase in the rate of racemiza-
tion1b of the stereogenic organometallic reagents. Increas-
ing amounts of THF may accelerate the substitution
reaction while also enhancing the rate of racemization
of the stereogenic cuprate reagent and/or the organo-
lithium reagent during cuprate formation. The organo-
lithium reagent appears to racemize more rapidly
as evidenced by the lower er observed in a 2:1 or 4:1
THF:Et2O mixture obtained during mixing of the orga-
nolithium reagent with the THF solution of CuCN‚2LiCl
(entry 5) and the slow racemization of the cuprate
reagents (i.e., both 13-R and 13-CN) as the solution is
allowed to stand at -60 to -40 °C for 1.75-2 h. Rapid
racemization also occurs when solid CuCN is employed
and the reaction mixture is warmed to 25 °C for brief
periods of time (Table 1, entry 3). The slow formation of
the cuprate reagent with solid CuCN again points toward
rapid racemization of the organolithium reagent as
solvent polarity and temperature are increased.
The relative cuprate/substrate reactivity profiles are
also important in the proparyl substitution reactions
(Table 3). Propargyl bromide 8a and propargyl mesylates
8b,c react with the less reactive cuprate 13-CN to give
higher chemical yields but no enantioselectivity while the
more reactive cuprate 13-R gives modest to excellent ers
but low chemical yields. The chemical yield profile
remains the same for propargyl mesylate 8d but both
cuprates now give comparable ers. Excellent chemical
yield and enantioselectivity is observed with the very
reactive allyl bromide.
The importance of relative reactivity also emerges from
a comparison of the Gilman reagent 13-R (R2CuLi) and
the cyanocuprate 13-CN (RCuCNLi) since the latter is
significantly less reactive in vinylation and conjugate
addition reactions.20c With reactive electrophiles (e.g., 1,
2c, 4a ) both reagents give comparable ers while with less
Initial conjugate addition studies with acrylic esters
gave no eantioselectivity, suggesting a dependence upon
(30) A referee has pointed out that “increase selectivity [of 13-R at
lower reaction temperatures can occur] by increased kinetic dif-
ferentiation between two diastereomeric reaction pathways [leading]
to different enantiomers”. This effect would also account for 13-R giving
higher ers than the less reactive 13-CN. The formation of diastereo-
meric cuprate-substrate complexes would provide such a pathway,
although their involvement in vinylation reactions is unclear.
(29) House, H. O.; Wilkins, J . M. J . Org. Chem. 1978, 43, 2443-
2454.
J . Org. Chem, Vol. 69, No. 9, 2004 3083

Dieter et al.
reaction type and pathway. Control experiments involv-
ing formation of nonproductive olefin-cuprate π-com-
plexes with nonreactive R,â-unsaturated lactones fol-
lowed by addition of reactive electrophiles showed no
diminution in the ers. This is consistent with stereo-
chemical integrity during reversible olefin-cuprate com-
plexation events. Subsequent work with methyl vinyl
ketone revealed that excellent enantioselectivities could
be achieved in conjugate addition reactions with 13-R
and with 13-CN. Modest selectivities were achieved with
ethyl propiolate and with methyl acrylate when the rate-
accelerating additive HMPA/TMSCl was employed. These
observations again suggest that ers are largely governed
by relative reactivities. Reactive substrates and cuprates
give excellent ers even when the more reactive cuprate
gives lower chemical yields.
enantioselectivities observed with TMEDA and (-)-
sparteine. Significantly, the ers observed for the orga-
nocopper reactions in this study largely mirror those
reported for the organolithium reactions, suggesting that
preservation of stereochemical integrity during Li-Cu
transmetalation and cuprate reaction is a general phe-
nomenon and not inherently a function of the cuprate
reaction.
Su m m a r y
In summary, we have shown that excellent enantio-
selectivities can be achieved in the substitution (e.g.,
vinylation, allylation, and propagylation) and conjugate
addition reactions of stereogenic R-(N-carbamoyl)alkyl-
cuprates. The cuprate enantioselectivities largely mirror
the organolithium selectivities and deviations from the
lithium reagents appear to be a function of the relative
reactivity of the cuprate/electrophile pair and not of the
intrinsic reaction type or mechanistic pathway. This
observation holds considerable promise for future devel-
opment and synthetic applications since reactivity pat-
terns can be modulated by judicious choice of cuprate
reagent, substrate structure, solvent combinations, tem-
perature, time combinations, and additives.
The benzylic substrates pose challenging problems for
both the organolithium26a-e and organocopper31 reagents.
The configurational stability of benzylic lithium reagents
is dependent upon a combination of the N-substitution
pattern as well as solvent, additives, and tempera-
ture.1b,3,4,26,27 In some instances, the benzylic carbanions
in these systems approach planarity26a,c and the chirality
arises via facial selectivity in the complexation of the
benzylic lithium reagent with the chiral diamine (e.g.,
sparteine). Benzylic lithium/(-)-sparteine contact species
(CS) derived from 29a exhibit dynamic properties and
opposite enantioselection was observed in hexane or Et2O
(retention) and THF (inversion).26a In THF, little enan-
tioselectivity was observed until a benzyllithium/sparteine
complex precipitated from solution26a and a 68:32 er (36%
ee, conditions not specified) has been reported26d,e in the
reaction with methyl iodide. Treatment of racemic 30a
with (-)-sparteine followed by CO2 affords the racemic
acid in Et2O26c and the scalemic acid in THF (82% ee).26a
These results (for 29a /30a ) have been interpreted in
terms of a dynamic kinetic resolution mechanism,26a an
enantioselective deprotonation-substitution mechanism,
or a competition of the two pathways.26c The evidence on
whole suggests an enantioselective deprotonation-
substitution in Et2O and a dynamic resolution in THF.
Reactions of the organocuprates derived from 29b with
methyl vinyl ketone displayed enantioselectivities in Et2O
[28.3:71.7 to 35.7-66.3 vs (24.5:75.5 to 16.5-83.5)26a and
(21:79)26c for lithium reagent 30a with various electro-
philes] and in THF [53.3:46.7 vs 68:32 for methylation
of 30a ,26d,e and 57:43 for carboxylation of 30a 26c] compa-
rable to the lithium reagent derived from 29a . Although
significantly lower ers were observed for the cuprate
reagent derived from 30b in THF than those reported
by Schlosser for the lithium reagent 30a , the lithium
reagent 30b never formed a precipitate with sparteine
as did 30a , which was required for high enantioselectiv-
ity. Similar ers were observed for the tertiary alkylcu-
prate derived from 34 in both THF and ether with
TMEDA but low ees were obtained with Et2O/(-)-
sparteine. This is consistent with the solvent-dependent
stereoselection observed for 30a and for the cuprates
derived from 30b. The use of (R)-34/s-BuLi-(-)-sparteine
is expected to correspond to a matched pair in the
asymmetric deprotonation26a accounting for the similar
Exp er im en ta l Section
Gen er a l P r oced u r e. N-Boc pyrrolidine (0.17 g. 1.0 mmol),
(-)-sparteine (0.28 g, 1.2 mmol), and diethyl ether (4.0 mL)
were added to a flame-dried round-bottom flask equipped with
a septum and stirring bar and placed under an argon atmo-
sphere. The flask was cooled to -78 °C, s-BuLi (0.75 mL, 1.6
M, 1.2 mmol) was added dropwise under argon, and the
reaction mixture was stirred at this temperature for 1 h. In a
second flask under argon, a mixture of CuCN (0.045 g, 0.5
mmol) and LiCl (0.043 g, 1.0 mmol) in 3.0 mL of THF was
stirred at room temperature for 10 min to afford a solution of
CuCN‚2LiCl. This solution was added via syringe to the
R-lithio-N-Boc-pyrrolidine solution and the mixture was stirred
for an additional hour (shorter times may be used). The
electrophile was added to the reaction mixture at -78 °C and
allowed to warm to room temperature overnight at an unsu-
pervised rate. The reaction mixture was quenched with
saturated aqueous NH4Cl (4.0 mL) and diluted with diethyl
ether (3.0 mL), and the aqueous phase was extracted with Et2O
(3 × 5.0 mL). The combined organic extracts were dried over
MgSO4 and concentrated in vacuo, and the residue was
purified by column flash chromatography (silica gel, ethyl
acetate/petroleum ether, 94/6 (v/v)).
1-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-et h en ylp yr r oli-
d in e (15a ). [R]24 +13.3 (c 1.43, THF) for sample with er 88:
D
12 by chiral HPLC; [R]24 +9.1 (c 1.43, THF) for sample with
D
er 72.9:27.1 by chiral HPLC; IR (neat) 1698, 1651, 1365, 1253
cm-1; NMR δ 1.36 (s, 9H), 1.55-2.10 (m, 4H), 3.12-3.37 (m,
2H), 4.10-4.30 (m, 1H), 4.85-5.10 (m, 2H), 5.62-5.80 (m, 1H);
13C NMR δ 23.1 (br s), 28.3, 31.2 (br, s), 46.2, 58.7, 78.9, 113.7,
149.0, 154.4; mass spectrum m/z (rel intensity) EI 197 (0.5,
M+), 141 (33), 124 (12), 96 (27).
N -[(1,1-Dim e t h yle t h oxy)ca r b on yl]-2-(1-t r im e t h ylsi-
lyleth en yl)p yr r olid in e (15b). IR (neat) 3051, 2965, 2871,
1700, 1478, 1453, 1384, 1239, 1162, 1111, 1085, 931 cm-1; 1H
NMR δ 0.03 (s, 9H), 1.28-1.35 (m, 9H), 1.37-1.49 (m, 1H),
1.63-1.73 (m, 2H), 1.78-1.95 (m, 1H), 3.28-3.35 (m, 2H),
4.34-4.43 (m, 1H), 5.22 (br s, 1H), 5.36 (br s, 1H); 13C NMR δ
-1.0, 21.7 (22.7), 28.3, 31.3 (32.0), 46.4 (46.7), 60.6 (61.2), 78.7,
121.1 (121.8), 152.4 (151.4), 154.3 (rotamer); mass spectrum,
m/z (rel intensity) EI 269 (2, M+), 213 (14), 198 (100), 114 (88),
70 (80), 57 (84).
(31) (a) Linderman, R. J .; Godfrey, A.; Horne, K. Tetrahedron 1989,
45, 495-506. (b) Van Heerden, P. S.; Bezuidenhoudt, B. C. B.;
Steenkamp, J . A.; Ferreira, D. Tetrahedron Lett. 1992, 33, 2383-2386.
3084 J . Org. Chem., Vol. 69, No. 9, 2004

Scalemic Stereogenic R-(N-Carbamoyl)alkylcuprates
N-[(1,1-Dim eth yleth oxy)car bon yl]-2-[2-(1-h exen yl)]pyr -
EI 273 (0.5, M+), 217 (23), 114 (100). Anal. Calcd for C17H23
NO2: C, 74.72; H, 8.42. Found: C, 74.71; H, 8.61.
-
r olid in e (16). [R]24 +28.8 (c 3.19, THF) for sample with er
D
97.8:2.2 by chiral HPLC; IR 2965, 2934, 2879, 1701, 1389,
Carbamate 22 (137 mg, 0.5 mmol) was dissolved in meth-
ylene chloride (10 mL), cooled to -78 °C, and then treated with
ozone for 5 min. When a slight blue color was observed, Me2S
(122 mg, 2.0 mmol) was added and stirring continued for 30
min while warming to room temperature. Then aqueous
NaHCO3 (5 mL) was added and the layers were separated.
The organic layer was dried (MgSO4) and concentrated in
vacuo to give a clear yellow oil that was purified by column
chromatography (Rf 0.40, petroleum ether/EtOAc, 80:20 (v/v))
to give the known ketone (2-benzoylpyrrolidine-1-carboxylic
1
1366, 1178, 1124, 878, 770 cm-1; H NMR δ 0.91 (t, J ) 7.5
Hz, 3 H), 1.17-1.64 (m, 13 H), 1.64-1.92 (m, 3 H), 1.92-2.39
(m, 3 H), 3.44 (br s, 2 H), 4.19 (4.28) (br s, 1 H), 4.71 (s, 1 H),
4.75 (s, 1H) (rotamer); 13C NMR δ 13.9, 22.6, 23.0, 28.4, 30.2,
31.3, 32.7, 46.5, 61.3, 78.9, 107.2, 150.2, 154.6; mass spectrum
m/z (rel intensity) EI 253 (0.5, M+), 197 (13), 180 (13), 154 (18),
144 (100), 83 (1). Anal. Calcd for C15H27NO2: C, 71.15; H,
10.67. Found: C, 70.87; H, 10.69.
N-[(1,1-Dim eth yleth oxy)ca r bon yl]-2-[1-(1-m eth ylid in e-
3-ter t-bu tyld im eth ylsilyloxy)p r op yl]p yr r olid in e (17). IR
(neat) 3068, 2948, 2880, 1709, 1649, 1470, 1384, 1247, 1162,
acid, tert-butyl ester)28c as a clear colorless oil (95%): [R]23
D
+28.1 (c 1.35, CHCl3); IR (neat) 2985 (m), 1703 (vs), 1411 (vs),
1170 (s), cm-1; 1H NMR (CDCl3) δ 1.23 (1.43) (2 s, 9H), 1.75-
2.05 (m, 3H), 2.25-2.40 (m, 1H), 3.35-3.75 (m, 2H), 5.14 (5.30)
(dd, J ) 3.7 Hz, J ) 5.0 Hz, 1H), 7.35-7.60 (m, 3H), 7.85-
8.00 (m, 2H) (rotamers); 13C NMR (CDCl3) δ 23.1 (24.1), 28.2
(28.4), (29.8) 30.8, 46.6, (46.8), (61.1) 61.3, (79.6) 79.7, 128.1,
128.7 133.2, 133.2, 135.3, 153.8, (198.4) 198.9 (rotamers); mass
spectrum, m/z (rel intensity) 275 (0.5, M+), 202 (10), 170 (48),
158 (12), 130 (6), 114 (91), 70 (100), 57 (82).
1
1102, 837, 760; H NMR δ 0.01 (s, 6H), 0.84 (s, 9H), 1.35 (s,
9H), 1.70-1.81 (m, 3H), 1.83-1.94 (m, 1H), 2.13-2.35 (m, 2H),
3.37-3.39 (m, 2H), 3.69-3.83 (m, 2H), 4.11-4.31 (m, 1H), 4.73
(s, 2H); 13C NMR δ 1.4, 18.2, 22.4 (22.7), 25.9, 28.4, 31.3 (31.0),
36.6 (36.3), 46.5 (46.3), 61.4, 62.5, 78.9, 108.9, 140.8 (140.7),
154.5 (rotamer); mass spectrum, m/z (rel intensity) EI 355 (0.4,
M+), 282 (12), 255 (12), 242 (64), 212 (39), 198 (51), 182 (21),
122 (35), 110 (97), 75 (44), 57 (100). Anal. Calcd for C19H37
NO3Si: C, 64.22; H, 10.42. Found: C, 64.39; H, 10.50.
-
N-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-[1-(1,2-p r op a d i-
en yl)]p yr r olid in e (23). IR (neat) 3068, 2974, 2880, 1948,
1-[(1,1-Dim eth yleth oxy)ca r bon yl]-2-[1-cycloh exen yl]-
1
1690, 1463, 1181, 1295, 1181, 1102, 844; H NMR δ 1.41 (s,
1
p yr r olid in e (18). IR (neat) 1695, 1629, 1454, 1395 cm-1; H
9H), 1.75-1.85 (m, 4H), 3.32 (br s, 2H), 4.28 (br s, 1H), 4.74-
4.77 (m, 2H), 5.17 (br s, 1H); 13C NMR δ 22.5 (23.6), 28.5, 32.3
(31.2), 45.8, 57.5, 77.2, 79.0, 93.0 (92.5), 154.5, 207.0 (rotamer);
mass spectrum, m/z (rel intensity) 170 (4), 153 (40), 136 (13),
114 (70), 70 (79), 57 (100). Anal. Calcd for C12H19NO2: C, 68.90;
H, 9.10; N, 6.70. Found: C, 69.01; H, 9.15; N, 6.72.
NMR δ 1.21-2.00 (m, 21H), 3.21-3.50 (m, 2H), 3.84-4.24 (m,
1H), 3.32 (s, 1H); 13C NMR δ 22.6, 23.1, 24.7, 28.3, 31.2, 46.6,
61.3, 62.5, 78.6, 120.0, 137.5, 155.0; mass spectrum, EI, m/z
251(0.5, M+), 195 (44), 178 (9), 114 (100). Anal. Calcd for
C15H25NO2: C, 71.73; H, 9.95. Found: C, 71.75; H, 10.08.
N-[(1,1-Dim eth yleth oxy)ca r bon yl]-2-(3-oxo-1-cycloh ex-
N-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-[1-[1-(3-p h en yl-
p r op yl)-1,2-p r op a d ien yl]]p yr r olid in e (24). IR (neat) 3017,
2969, 2921, 2872, 1963, 1689, 1439, 1391, 1359, 1254, 1166,
1109, 844; 1H NMR δ 1.41 (s, 9H), 1.74-1.92 (m, 8H), 2.63 (t,
J ) 7.4 Hz, 2H), 3.29-3.35 (m, 2H), 4.12-4.21 (m, 1H), 4.71-
4.76 (m, 2H), 7.14-7.26 (m, 5H); 13C NMR δ 22.6 (23.2), 28.4,
28.6 (3C), 29.2, 30.2 (31.2), 35.4, 45.9, 58.9 (58.7), 78.2, 78.7,
106.2 (105.8), 125.5, 128.1, 128.3, 142.1, 154.2, 204.4 (rotamer);
mass spectrum, m/z (rel intensity) 271 (28), 254 (5), 167 (37),
114 (100), 91 (32), 70 (91), 57 (94), 41 (45), 29 (16).
1
en yl)p yr r olid in e (20). H NMR δ 1.27-1.34 (m, 9H), 1.64-
1.78 (m, 3H), 1.85-2.30 (m, 7H), 3.31-3.43 (m, 2H), 4.15-
4.28 (m, 1H), 5.76 (s, 1H); 13C NMR δ 22.6 (23.2), 26.1 (26.6),
28.2, 30.4, 31.8, 37.5, 46.7, 61.8 (61.3), 79.5, 123.6 (123.1),
154.5, 166.7 (166.1), 199.3 (rotamer); mass spectrum, m/z (rel
intensity) EI 266 (1, M+ + 1), 209 (50), 192 (23), 164 (18), 137
(44), 114 (46), 70 (51), 57 (100).
1-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-[1-(1,1-d im et h yl-
eth yl)eth en yl]p yr r olid in e (21). [R]24 +39.9 (c 2.68, THF)
D
for sample with er 89.5:10.5 by HPLC; IR (neat) 1697, 1652,
1476, 1392, cm-1; NMR δ 1.08 (s, 9H), 1.37 (s, 9H), 1.55-2.60
(m, 4H), 3.21-3.54 (m, 2H), 4.29-4.47 (s, 1H), 4.64-4.82 (s,
1H); 13C NMR δ 21.9, 28.6, 30.4, 30.6, 33.1, 35.0, 46.9, 57.8,
78.7, 105.6, 158.7; mass spectrum, m/z (rel intensity) EI 253
(0.5, M+), 197 (14), 114 (100). Anal. Calcd for C15H27NO2: C,
71.14; H, 10.67. Found: C, 70.72; H, 10.88.
N-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-[1-(1-p h en yl-1,2-
p r op a d ien yl)]p yr r olid in e (25). IR (neat) 3051, 2972, 2884,
1944, 1689, 1442, 1386, 1243, 1171, 1115, 1075, 868, 797; H
NMR δ 1.38-1.44 (m, 9H), 1.77-2.09 (m, 4H), 3.30-3.48 (m,
2H), 4.75-4.91 (m, 1H), 5.03-5.16 (m, 2H), 7.09-7.41 (m, 5H);
13C NMR 22.5 (23.5), 28.4, (30.9) 32.0, 45.9 (46.2), 57.3 (57.0),
80.1, 78.9, 109.4 (108.3), 126.8, 126.4, 128.4, 135.2 (134.7),
154.3, 207.0 (rotamer); mass spectrum, m/z (rel intensity) 281
(2), 229 (77), 212 (13), 184 (28), 114 (100), 89 (16), 70 (78), 57
(89).
1
1-[(1,1-Dim eth yleth oxy)ca r bon yl]-2-[1-p h en yleth en yl]-
p yr r olid in e (22). N-Boc pyrrolidine (12, 171 mg, 1.0 mmol)
was dissolved in freshly distilled Et2O (3.0 mL) along with (-)-
sparteine (234 mg, 1.0 mmol). The reaction mixture was cooled
to -78 °C under an argon atmosphere and s-BuLi (1.0 mL,
1.0 mmol) was added dropwise by syringe. The resultant
solution was stirred at -78 °C for 1 h. Then a solution
containing CuCN (90 mg, 1.0 mmol) and LiCl (90 mg, 2.0
mmol) in THF (3.0 mL) was added dropwise by syringe. The
mixture was allowed to stir at -78 °C for 30 min before the
addition of enol triflate 7b (252 mg, 1.0 mmol). The reaction
mixture was allowed to warm quickly to -50 °C and then
slowly to room temperature overnight. The reaction mixture
was diluted with Et2O (20 mL) and quenched with HCl (5%
aqueous, 15 mL). Upon separation of the layers, the organic
layer was dried (MgSO4) and concentrated in vacuo to give an
oil that was purified by column chromatography (Rf 0.25,
petroleum ether/Et2O, 85:15, v/v) affording 22 as a clear
N-[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-(2-p r op en -1-yl)-
p yr r olid in e (26). [R]24 +38.0 (c 3.69, THF) for sample with
D
er 89.0:11.0 by HPLC [lit.28b [R]25 -32.4 (c 1.56, CHCl3)]; IR
D
1
(neat) 1696, 1645, 1365, 1252 cm-1; H NMR δ 1.41 (s, 9H),
1.54-1.84 (m, 4H), 2.00-2.20 (m, 1H), 2.32-2.54 (m, 1H),
3.14-3.40 (m, 2H), 3.61-3.80 (m, 1H), 4.91-5.12 (m, 2H),
5.58-5.72 (m, 1H); 13C NMR δ 23.1, 28.5, 30.0, 28.1, 45.6, 53.7,
78.8, 116.9, 135.2, 145.0; mass spectrum, m/z (rel intensity)
EI 170 (6.4), 114 (54), 70 (100).
5-P h en yl-5-[[(1,1-dim eth yleth oxy)car bon yl]eth ylam in o]-
p en ta n -2-on e (31). 1H NMR δ 0.80-0.95 (m, 3H), 1.56 (s, 9H),
2.22 (s, 3H), 2.23-2.40 (m, 2H), 2.52-2.70 (m, 2H), 2.92-3.10
(m, 2H), 5.20-5.45 (m, 1H), 7.25-7.42 (m, 5H); 13C NMR δ
15.0, 24.5, 28.5, 30.1, 38.1, 40.4, 56.3, 78.9, 127.3, 127.7, 128.3,
140.5, 156.3, 208.1; mass spectrum, m/z (rel intensity) EI 305
(0.5, M+), 249 (22), 204 (7), 178 (42); high-resolution mass
spectrum m/z 305.1997 (M+) (calcd for C18H27NO3 305.1991).
1-[(1,1-Dim eth yleth oxy)ca r bon yl]eth yl[(E)-1-p h en yl-2-
h ep ten yl]a m in e (33). IR (neat) 2961, 2930, 2868, 1683, 1443,
colorless oil (56%, 91% ee): IR (neat) 1697, 1623, 1558, 1446,
1
1394 cm-1
;
H NMR δ 1.50 (1.56) (s, 9H), 1.66-2.16 (m, 4H),
3.42-3.71 (m, 2H), 4.82 (d, J ) 8.0 Hz, 1H), 4.92 (d, J ) 8.0
Hz, 1H), 5.05 (s, 1H), 5.27 (5.30) (s, 1H), 7.30-7.41 (m, 5H);
13C NMR δ 22.2, 28.4, 31.5, 46.5, 60.6, 79.2, 110.8, 126.7, 127.4,
128.3, 140.1, 150.0, 154.4; mass spectrum, m/z (rel intensity)
1
1412, 1381, 1272, 1164, 963, 877 cm-1; H NMR δ 0.97-1.13
(m, 6H), 1.34-1.66 (m, 14H), 2.17-2.24 (m, 2H), 3.09-3.30
J . Org. Chem, Vol. 69, No. 9, 2004 3085

Dieter et al.
(m, 2H), 5.68-5.85 (m, 2H), 7.27-7.50 (m, 5H); 13C NMR δ
13.8, 14.8, 22.1, 28.4, 31.2, 32.0, 39.7, 61.3, 79.2, 126.8, 127.3,
128.1, 134.5, 144.2, 155.4; mass spectrum, m/z (rel intensity)
EI 317 (0.5, M+), 261 (78), 216 (16), 204 (87), 173 (42), 160
(25), 133 (42), 117 (95), 104 (29), 91 (62), 57 (100).
01) and the National Science Foundation (CHE-0132539).
Support of the NSF Chemical Instrumentation Program
for the purchase of a J EOL 500 MHz NMR instrument
is gratefully acknowledged (CHE-9700278).
Eth yl (Z)-4-P h en yl-4-[[(1,1-d im eth yleth oxy)ca r bon yl]-
eth yla m in o]-2-p en ten oa te (35). 1H NMR δ 1.20-1.42 (m,
15H), 1.94 (s, 3H), 3.46-3.64 (m, 2H), 4.15 (q, J ) 6.0 Hz, 2H),
5.79 (d, J ) 12.0 Hz, 1H), 6.37 (d, J ) 12.1 Hz, 1H), 7.32-
7.42 (m, 5H); 13C NMR δ 14.0, 15.5, 26.9, 28.1, 40.4, 60.2, 64.29,
79.62, 117.30, 125.4, 126.7, 127.9, 146.5, 150.6, 155.0, 166.8;
mass spectrum, m/z (rel intensity) EI 291 (20), 245 (19); high-
Su p p or tin g In for m a tion Ava ila ble: Expanded Tables 1,
3, 4, and 5 (for eq 1), materials (references for the preparation
of 1, 2c,d , 3a -c, 4a -b, 6a ,b, 7a ,b, and 8b-d and for data
reductions of 14, 15a , 19a , b, 26, 27, 28a , and 28c), general
experimental information, 13C NMR spectra for compounds
15a , 15b, 16, 17, 18, 19a , 20, 21, 22, 23, 24, 25, 26, 31, 33,
and 35, and chiral HPLC traces for 14, 15a ,b, 16, 18, 19a ,
20, 21, 22, 23, 25, 26, 28a , 31, and 35. This material is
available free of charge via the Internet at http://pubs.acs.org.
resolution mass spectrum, m/z 347.2095 (M+) (calcd for C20H29
-
NO4 347.2097).
Ack n ow led gm en t. This work was generously sup-
ported by the National Institutes of Health (GM-60300-
J O035845I
3086 J . Org. Chem., Vol. 69, No. 9, 2004