α-Lithiation of N-(tert-butoxycarbonyl)-N-(p-methoxyphenyl)allylamines mediated by (-)-sparteine: Enantioselective syntheses of either enantiomer of 3-substituted enecarbamates

Full text of DOI:10.1021/ja962793o

12218
J. Am. Chem. Soc. 1996, 118, 12218-12219
Communications to the Editor
Scheme 1
r-Lithiation of N-(tert-Butoxycarbonyl)-N-(p-
methoxyphenyl)allylamines Mediated by
(-)-Sparteine: Enantioselective Syntheses of Either
Enantiomer of 3-Substituted Enecarbamates
Gerald A. Weisenburger and Peter Beak*
Department of Chemistry
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
ReceiVed August 12, 1996
The chiral ligand approach to asymmetric synthesis with
organolithium intermediates has emerged as an important
synthetic transformation.1-9 Lithiation-substitution sequences
of pyrrolidine, benzylamine, and allylcarbamate derivatives
afford high levels of enantioenrichment in the presence of (-)-
sparteine.1-3,5 The R-lithioamine synthetic equivalents which
have been provided are shown as 1 and 2. We now report
extension of the methodology to enantioselective elaboration
of allylic amines to furnish either enantiomer of a γ-allyl
lithioamine synthetic equivalent represented as 3. Facile
conversions of the enecarbamate to amine and carbonyl func-
tionalities complete a new approach to enantioenriched com-
pounds which have a 1,3 relationship between the functional
group and the asymmetric center.10,11
Table 1. Yields and Enantiomeric Ratios of the Products from
Reactions of N-Boc-N-(p-methoxyphenyl)cinnamylamine (5) with
n-BuLi/4 in Toluene Followed by Reaction with an Electrophile
electrophile
CH3OTf
product
yield (%)
er (% ee)a
(S)-7
(S)-7
74
73
72
70
77
34
46
96.0:4.0 (92)
97.5:2.5 (95)
97.0:3.0 (94)
98.0:2.0 (96)
99.0:1.0 (98)
97.0:3.0 (94)
98.0:2.0 (96)
CH3I
H2CdCHCH2Br
PhCH2Br
(S)-8
(S)-9
(CH2)5CdO
Me3SiOTf
(R)-10
(S)-11a
(S)-11b
Treatment of N-Boc-N-(p-methoxyphenyl)cinnamylamine (5)
(Boc ) tert-butoxycarbonyl) with 1.1 equiv of n-butyllithium/4
at -78 °C in toluene for 1 h followed by addition of an
electrophile affords products 7-11 with enantiomeric ratios (er
) enantiomeric ratio) greater than 96:4 in good yields as shown
in Table 1 (Scheme 1). Deprotonation R to nitrogen provides
the allylic carbanion 6 which reacts with electrophiles either at
the γ or R position. Carbon-carbon bond forming electrophiles
react at the γ position to afford the enecarbamates 7-10.12 The
trans isomers of 7-10 are obtained in 2-3% yield and can be
separated by preparative HPLC. The absolute configurations
of (S)-9, the product of reaction with benzyl bromide, and (R)-
10, the product of reaction with cyclohexanone, were assigned
a Enantiomeric ratios were determined by CSP-HPLC.
by independent chemical syntheses and comparison of chiral
stationary phase(CSP)-HPLC retention times. The sense of
electrophilic substitution of the carbonyl electrophile is opposite
to that for the alkyl halide electrophiles for these reactions.3,13-15
The absolute configurations of 7 and 8 are provisionally assigned
on the basis of their correspondence to 9 as the more retained
isomer on the CSP-HPLC column.16 Use of trimethylsilyl
triflate as the electrophile provides a mixture of the R isomer
(S)-11b and the γ isomer (S)-11a in 46 and 34% yields,
respectively. The absolute configuration of (S)-11a was as-
signed by independent chemical synthesis and comparison by
CSP-HPLC. The absolute configuration of (S)-11b is assigned
by analogy to (S)-11a and is provisional.
(1) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
We investigated a transmetalation-substitution sequence as
an approach to obtain either enantiomer of the products.3,14,15
Use of trimethyltin chloride as the electrophile provides a
mixture of the R isomer (R)-12b and the γ isomer (R)-12a in
24 and 49% yields with a 95:5 enantiomeric ratio.17-19 The
enantioenriched lithium intermediate 6 is prepared by tin-
lithium exchange of enantioenriched (R)-12a (95:5 er) in the
presence of (-)-sparteine. Addition of allyl bromide affords
(2) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715.
(3) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118,
3757.
(4) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.; Kolczewski,
S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479.
(5) Zschage, O.; Hoppe, D. Tetrahedron 1992, 48, 5657.
(6) Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis 1996, 141.
(7) Klein, S.; Marek, I.; Poisson, J. F.; Normant, J. F. J. Am. Chem.
Soc. 1995, 117, 8853.
(8) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075.
(9) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N. J.;
Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685.
(10) Hoppe has reported an asymmetric homoenolate synthetic equivalent
with 2-alkenyl esters of carbamic acid with sec-BuLi/(-)-sparteine which
provides this relationship.5,6
(11) Normant has reported asymmetric carbolithiation of cinnamate
derivatives in the presence of (-)-sparteine which provides this relationship.7
(12) The olefin geometry is assigned as cis by the magnitude of the
coupling constant between the two olefinic protons (J ) 9.5 Hz). The cis
enecarbamates isomerize to the trans isomers without racemization in
CDCl3.
(13) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc.
1994, 116, 9755.
(14) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 1575.
(15) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097.
(16) Pirkle, W. H.; Pochapsky, T. C.; Mahler, G. S.; Corey, D. E.; Reno,
D. S.; Alessi, D. M. J. Org. Chem. 1986, 51, 4991.
(17) The assignment of absolute configuration to the organostannane 12
is based on the assumption of invertive stannylation.14,15,25
(18) Zschage, O.; Schwark, J.-R.; Kra¨mer, T.; Hoppe, D. Tetrahedron
1992, 48, 8377.
(19) Rapid addition of Me3SnCl (1 M solution in hexanes) is necessary
in order to obtain consistent enantiomeric ratios.
S0002-7863(96)02793-X CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 48, 1996 12219
(R)-8 in 60% yield with an 87:13 er. The same product, (R)-8,
is obtained in 77% yield with a 90:10 er when (R)-12b (95:5
er) is submitted to the same reaction sequence.20
hydrogens is selectively removed to give a configurationally
stable organolithium anion, and an asymmetric substitution, in
which the enantiomeric ratio is established in a post-deproto-
nation step.25 Generation of the racemic lithiated intermediate
6 by reaction of 5 with n-BuLi followed by addition of (-)-
sparteine and allyl bromide affords 8 in 76% yield with a 61:
39 er. Generation of 6 by tin-lithium exchange of racemic
12a or racemic 12b with n-BuLi followed by addition of (-)-
sparteine and allyl bromide affords racemic 8 in 41 and 70%
yields, respectively.26 These results suggest that the enantio-
determining step in the sequence is an asymmetric deprotonation.
The high enantioselectivity and regioselectivity observed in
this reaction is not limited to cinnamate derivatives. Treatment
of N-Boc-N-(p-methoxyphenyl)-3-cyclohexyl-(E)-2-propene-1-
amine (13) with n-BuLi/4 at -78 °C in toluene for 1.5 h
followed by addition of methyl iodide affords a mixture of the
cis and trans γ isomers (R)-14a and (S)-14b in 43 and 27%
yields with 92:8 and 96:4 er, respectively.21 The absolute
configuration of (R)-14a is assigned by analogy to the sequence
with 5. The absolute configuration of (S)-14b was assigned
by isomerization to (S)-14a.18
The lithiated intermediate 6 must be configurationally stable
if asymmetric deprotonation is the enantiodetermining step.
Configurational stability is consistent with transmetalation of
the enantioenriched tin derivatives (R)-12a and (R)-12b to afford
enantioenriched (R)-8 and the observation that lithiation-
substitution of 5 provides enantioenriched (S)-8 (Vide supra).
If 6 were not configurationally stable, the same enantiomer of
the product (S)-8 should be produced regardless of the starting
material (5, (R)-12a, or (R)-12b) used to generate 6. In contrast,
when enantioenriched 6 is prepared by tin-lithium exchange
of enantioenriched (R)-12b with n-BuLi or n-BuLi/TMEDA
followed by addition of allylbromide, racemic 8 is obtained in
52 and 41% yields, respectively. These results show that while
the enantioenriched organolithium intermediate 6 maintains its
configuration in the presence of (-)-sparteine it does not
maintain its configuration by itself or in the presence of
TMEDA.27
This methodology can provide either enantiomer of a ho-
moenolate synthetic equivalent and a γ-lithioamine synthetic
equivalent.22 Hydrolysis of (S)-9 with HCl affords the enan-
tioenriched aldehyde (R)-15 in 81% yield with 93:7 er.23
Synthetic applications, determination of the structures of
intermediates, and investigation of the mechanism of the reaction
are matters of future interest.
Reduction of (R)-10 followed by oxidative cleavage of the
p-methoxyphenyl group with ceric ammonium nitrate (CAN)24
provides the highly enantioenriched protected primary amine
(R)-16 in 55% yield with 97:3 er.
The two limiting pathways for asymmetric replacement of a
prochiral hydrogen in a lithiation-substitution sequence are an
asymmetric deprotonation, in which one of the prochiral
Acknowledgment. We are grateful to the National Institute of
Health and the National Science Foundation for support of this work.
Supporting Information Available: Experimental procedures and
spectroscopic data for compounds 5, (S)-7, (S)-8, (S)-9, (R)-10, (S)-
11a, (S)-11b, (R)-12a, (R)-12b, 13, (R)-14a, (S)-14b, (R)-15, (R)-16,
transmetalation procedures for (R)-12a and (R)-12b, and absolute
configuration determinations of (S)-9, (R)-10, and (S)-11a (16 pages).
See any current masthead page for ordering and Internet access
instructions.
(20) The product (R)-8, derived from 12, contains ca. 20% of the E
isomer.
(21) The R isomer is obtained in 6% yield.
JA962793O
(22) Ahlbrecht, H.; Enders, D.; Santowski, L.; Zimmermann, G. Chem.
Ber. 1989, 122, 1995.
(25) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 0000.
(23) The erosion of er is attributed to the trans isomer (R)-9 present in
(S)-9. The isomers can be separated by preparative HPLC but were not in
this case to demonstrate that high enantioenrichment is possible without
this added step.
(26) Furthur work is under way to determine the origin of the 61:39 er
observed when 5 is metalated followed by addition of (-)-sparteine and
allyl bromide.
(24) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.
(27) The influence of (-)-sparteine on the configurational stability of
an anion has been previously observed.3