Asymmetric lithiation-substitution sequences of substituted allylamines

Article abstract of DOI:10.1021/jo047752m

(-)-Sparteine-mediated asymmetric lithiation-substitution sequences of 2- and 3-substituted N-(Boc)-N-(p-methoxyphenyl) allylic amines with electrophiles have been investigated. Asymmetric lithiation-substitutions of N-(Boc)-N-(p-methoxyphenyl) allylic am

Full text of DOI:10.1021/jo047752m

Asymmetric Lithiation-Substitution Sequences of Substituted
Allylamines
Dwight D. Kim, Suk Joong Lee, and Peter Beak*
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
beak@scs.uiuc.edu
Received December 23, 2004
(-)-Sparteine-mediated asymmetric lithiation-substitution sequences of 2- and 3-substituted
N-(Boc)-N-(p-methoxyphenyl) allylic amines with electrophiles have been investigated. Asymmetric
lithiation-substitutions of N-(Boc)-N-(p-methoxyphenyl) allylic amines 11, 12, 13, 14, and 15 provide
highly enantioenriched enecarbamates in good yields. Further transformations to give aldehydes,
acids, ketones, and a Diels-Alder adduct are reported. The 1,4-addition products from reactions of
the lithiated allylic amines from 14 and 15 with conjugated activated alkenes gives enecarbamates
with two and three stereogenic centers in good yields with high diastereomeric and enantiomeric
ratios. Synthetic transformation of these products by acid hydrolysis and subsequent cyclization
provide stereoselective access to bicyclic compounds containing four and five stereogenic centers
with high diastereoselectivity and enantioselectivity. It is suggested that allyllithium complexes
generated by asymmetric deprotonation react with most electrophiles with inversion of configuration.
Introduction
amine 2, in the presence of (-)-sparteine (3) have been
developed in our laboratories (Scheme 1). Deprotonations
with n-BuLi carried out at -78 °C followed by reaction
with electrophiles give the highly enantioenriched prod-
ucts 5 and 7 in high yields with high enantiomeric ratios
(ers).9 The enecarbamate products from the N-Boc ally-
lamines are synthetically useful as they can be readily
converted to â-substituted carbonyl compounds, R-sub-
stituted aldehydes, and γ-substituted amine derivatives.
It has been shown that these reactions usually occur with
inversion of configuration at the lithiated intermediate.10
The lithiated intermediates 4 and 6 were characterized
by 6Li and 13C NMR of labeled n-BuLi and N-Boc
Carbon-carbon bond-forming reactions of lithiated
benzylic and allylic amine derivatives mediated by chiral
ligands are of current interest for asymmetric amine
synthesis and provide asymmetric homoenolate synthetic
equivalents. Sequences which begin with deprotonation
or tin-lithium exchange by alkyllithium bases at the
R-carbon of amine substrates provide examples of the
utility of this methodology.1-8
Asymmetric lithiation-substitution reactions of N-
aryl-N-Boc benzylamine 1 and of N-aryl-N-Boc cinnamyl-
(1) (a) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220. (b)
Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron Lett. 1993, 34,
51.
(2) (a) Pearson, W. H.; Lindbeck, A. C.; Kempf, J. W. J. Am. Chem.
Soc. 1993, 115, 2622. (b) Pearson, W. H.; Lindbeck, A. C. J. Am. Chem.
Soc. 1991, 113, 8546.
(3) (a) Gawley, R. E.; Zhang, Q. J. Org. Chem. 1995, 60, 5763. (b)
Gawley, R. E.; Zhang, Q. J. Am. Chem. Soc. 1993, 115, 7515. (c)
Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R. J. Am. Chem. Soc. 2000,
122, 3344. (d) Gawley, R. E. Curr. Org. Chem. 1997, 1, 71. (e) Gawley,
R. E.; Zhang, Q. Tetrahedron 1994, 50, 6077.
(4) (a) Elworthy, T. R.; Meyers, A. I. Tetrahedron 1994, 50, 6089.
(b) Meyers, A. I. Tetrahedron 1992, 48, 2589.
(5) Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315. (b)
Gross, K. M.; Beak, P. J. Org. Chem. 1997, 62, 7679.
(6) Coldham, I.; Copley, R. C. B.; Haxell, T. F. N.; Howard, S. Org.
Lett. 2001, 3, 3799.
(7) (a) Gaul, C.; Arvidsson, P. I.; Bauer, W.; Gawley, R. E.; Seebach,
D. Chem. Eur. J. 2001, 7, 4117. (b) Gaul, C.; Scharer, K.; Seebach, D.
J. Org. Chem. 2001, 66, 3059. (c) Gaul, C.; Seebach, D. Org. Lett. 2000,
2, 1501.
(8) (a) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64, 2996. (b)
Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123,
1004. (c) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2001, 3,
3737. (d) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak,
P. J. Am. Chem. Soc. 2002, 124, 11689.
(9) (a) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996,
118, 3757. (b) Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574. (c)
Kim, B. J.; Park, Y. S.; Beak, P. J. Org. Chem. 1999, 64, 1705.
(10) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552.
10.1021/jo047752m CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/10/2005
5376
J. Org. Chem. 2005, 70, 5376-5386

Lithiation-Substitution Sequences of Substituted Allylamines
SCHEME 1
6
chiral carbon. Li and 13C NMR studies indicated mon-
SCHEME 2
omeric species represented as 10 to be coordinated to the
R-carbon. A Sn-Li exchange study confirmed asymmetric
deprotonation to be the enantiodetermining event. The
formation of (Z,R)-9 and (E,S)-9 can be rationalized if
rotation about the C1-C2 axis is competitive with or
faster than reaction with the electrophile and the reaction
with methyl iodide proceeds with inversion of configu-
ration.
We now report lithiation-substitution reactions of
selectively substituted allylic amines. Lithiation-sub-
stitutions of 11-15 in the presence of (-)-sparteine
establish that the asymmetry of the sequence is main-
tained in the presence of an additional double bond, a
heteroaromatic ring, substitution on the central carbon
of the allyl group, and incorporation of the double bond
in a five- or six-membered ring. In addition to the
alkylation and addition reactions of the lithiated inter-
mediates, conjugate additions have been investigated.
amines.11 The NMR data support assignment of organo-
lithiums 4 and 6 as largely monomeric, with coordination
of the Boc carbonyl and 3 to the lithium. The diastere-
omeric ratios (drs) of 4 and 6 were found to be 91:9 and
96:4, respectively, consistent with high stereoselectivities
in reactions with electrophiles. The structure of 6 was
determined by X-ray crystallographic analysis. The ster-
eochemical course of these reactions were determined to
be asymmetric deprotonations to provide 4 and 6. Asym-
metric substitutions were ruled out by establishing that
racemic organolithium species on exposure to (-)-
sparteine followed by reactions with electrophiles did not
afford racemic products.9,11,12
Lithiation-substitution of the cyclohexyl-substituted
allylic amine derivative 8 with methyl iodide was inves-
tigated to evaluate the effects of alkyl vs aryl allylic
substitution on the allylic terminus.13 The cis product
(Z,R)-9 was obtained in 43% yield with a 91:9 er (Scheme
2). The trans isomer, (E,S)-9, was obtained in 27% with
a 93:7 er with the opposite absolute configuration at the
Results
(11) (a) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem.
Soc. 1997, 119, 11561. (b) Weisenburger, G. A.; Beak, P. J. Am. Chem.
Soc. 1996, 118, 12218. (c) Weisenburger, G. A.; Faibish, N. C.; Pippel,
D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522. (d) Pippel, D. J.;
Weisenburger, G. A.; Wilson, S. R.; Beak, P. Angew. Chem., Int. Ed.
1998, 37, 2522.
Asymmetric Lithiation-Substitution Sequence
of 11. The lithiation-substitution reaction sequence with
the N-Boc-N-(p-methoxyphenyl)pentadiene amine 11 was
carried out to determine the effect of an additional
conjugated double bond on product regioselectivity and
enantioselectivity. An interesting issue was whether ꢀ
substitution, presumably more remote than γ substitu-
tion, from the site of complexation of the lithium with
(12) Tin-lithium exchange occurs with retention of configuration:
Reich, H. J.; Borst, M. B.; Coplien, N. H.; Phillips, N. H. J. Am. Chem.
Soc. 1992, 114, 6577.
(13) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J.
Am. Chem. Soc. 2001, 123, 4919.
J. Org. Chem, Vol. 70, No. 14, 2005 5377

Lee et al.
SCHEME 3
TABLE 1. Asymmetric Lithiation-Substitutions of 11
substituted products 22, 23, 24, and 25. All isomers were
found to have good enantioenrichments of 89:11-93:7
(entries 2 and 3). With trimethylsilyl triflate as the
electrophile (entry 4), only the R-substituted product 26
was obtained in a good yield of 75% with a 96:4 er. The
absolute configurations are assigned by analogy to prod-
ucts obtained from 2 as (S). The isomers were separated
by preparatory HPLC, and the enantiomeric ratios were
determined by chiral stationary phase CSP-HPLC com-
parison to independently synthesized racemic samples.15,16
The olefin geometry of the products was determined by
the magnitude of the olefinic coupling constants, and
assignment to each proton was made unambiguously by
1H NMR spectroscopy using {1H, 1H} decoupling experi-
ments. Reaction with cyclohexanone as the electrophile
resulted in the formation of the γ-substituted product 27
with a 94:6 er, which could be improved to 99:1 after
recrystallization (entry 5).
Two synthetic transformations of 20 were demon-
strated. The hydrolytic conversion of 20 to an enantioen-
riched δ-substituted R,â-unsaturated aldehyde was ac-
complished with hydrochloric acid. The hydrolysis pro-
ceeded smoothly to give 28 in moderate yield, demon-
strating that lithiated 11 can be a homoenolate synthetic
equivalent.11
Conversion of 20, which has E,Z geometry, to 29, which
has E,E geometry, was carried out to provide a diene
suitable for the concerted [4 + 2] cycloaddition (Scheme
4). Isomerization of 20 to 29 proceeded in good yield with
dry, catalytic trifluoroacetic acid. Access to this isomer
also confirmed that 29 was not detected from the lithia-
tion-substitution sequence of 11. Reaction of 29 with
maleic anhydride and N-methylmaleimide in toluene
resulted in the formation of the highly diastereomerically
enriched products presumed to arise by favored endo
addition to give 30 and 31 in moderate and good yields
as 95:5 mixtures of diastereomers.17
yield
entry
1
electrophile
CH3OTf
E
product (%)
er
-CH3
-CH2C6H5
CH2dCHCH2Br -CH2CHdCH2
20
21
22
23
24
25
26
60
10
57
25
29
44
75
88:12
78:22
93:7
2
3
4
5
C6H5CH2Br
91:9
90:10
89:11
96:4
(CH3)3SiOTf
(CH2)5CO
-Si(CH3)3
-COH(CH2)5
27
79
94:6
(99:1)a
a After recrystallization.
the ligand and carbonyl oxygen, would give a high
enantiomeric ratio.
The synthesis of 11 was initiated by esterification of
the unsaturated acid 16 under acidic conditions to afford
the methyl ester 17 in high yield.14 Reduction with
DIBAL-H to the alcohol 18 was followed by conversion
to bromide 19 with PBr3. Coupling of 19 with the sodium
salt of N-Boc-p-anisidine yielded the desired N-protected
amine 11 (Scheme 3).
Treatment of 11 with 1.1 equiv of n-BuLi and 1.1 equiv
of 3 in toluene at -78 °C for 1 h, followed by the addition
of electrophiles, provides the products 20-27 shown in
Table 1. Reaction with methyl triflate as the electrophile
provided products 20 and 21 (entry 1). A solvent study
was performed to determine optimal conditions with
respect to yield, regioselectivity, and enantioselectivity.
With toluene as the solvent, a 60% yield of 20 was
obtained, although a minor amount of isomer 21 was also
formed in 10% yield. The er of 20 was determined to be
88:12. Etheral solvents were surveyed and found to
provide the products with lower regioisomeric and enan-
tiomeric ratios.
Asymmetric Lithiation-Substitution Sequences
of 12. To test the methodology in a system bearing a
(15) Racemic samples were synthesized using TMEDA as the ligand.
(16) Compound enantiomeric ratios (er’s) were determined by
comparison of chiral stationary phase CSP-HPLC data to indepen-
dently synthesized racemic compounds. Diastereomeric ratios (dr’s),
when applicable, were determined by 1H NMR integrations. Diaster-
eomers were separated by column chromatography or preparatory
HPLC.
(17) (a) Overman, L. E.; Freerks, R. L.; Petty, C. B.; Clizbe, L. A.;
Ono, R. K.; Taylor, G. F.; Jessup, P. J. J. Am. Chem. Soc. 1981, 103,
2816. (b) Wu, T.-C.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2293. (c)
Zezza, C. A.; Smith, M. B. J. Org. Chem. 1988, 53, 1161. (d)
Wasserman, H. H.; Blum, C. A. Tetrahedron Lett. 1994, 35, 9787. (e)
Grant-Young, K.; Smith, M. B.; Ovaska, T.; Wang, C.-J. Synth.
Commun. 1998, 28, 4233.
Two halide electrophiles, benzyl bromide and allyl
bromide, gave isomeric mixtures of C-5- and C-3-
(14) Drew, J.; Letellier, M.; Morand, P.; Szabo, A. G. J. Org. Chem.
1987, 52, 4047.
5378 J. Org. Chem., Vol. 70, No. 14, 2005

Lithiation-Substitution Sequences of Substituted Allylamines
SCHEME 4
TABLE 2. Asymmetric Lithiation-Substitutions of 12a
tion of 38 and 40. Compound 33 was easily converted to
the corresponding aldehyde 38 by treatment with HCl.
The ketone 40 was prepared by R-lithiation of 32 with
t-BuLi and TMEDA in THF followed by addition of
methyl triflate to give 39. Subsequent hydrolysis under
acidic conditions provided ketone 40.19
entry
electrophile
CH3OTf
E
product yield (%) er
1
2
3
4
-CH3
-CH2C6H5
32
33
34
35
80
70
65
68
97:3
98:2
97:3
98:2
C6H5CH2Br
CH2dCHCH2Br -CH2CHdCH2
(CH2)5CO -COH(CH2)5
a Three reaction sequences were carried out to test further the
durability of the furan ring.
sensitive heterocyclic ring, the effect of a furan ring on
the terminus of the allylic system was investigated with
the lithiation-substitution of 12.18 The scope of the
asymmetric reaction of 12 is summarized in Table 2, with
products 32-35 obtained in yields of 65-80%, with ers
of 97:3-98:2.16 The absolute configurations are assigned
by analogy to the reactions of 2.11 These results are
similar to those found with 2.
Three reactions were carried out to test the durability
of the furan ring to further conversions. Deprotection of
the amine and reduction of the olefin of 32 demonstrated
access to enantioenriched γ-substituted amines. Hydro-
genation of 32 at atmospheric pressure to give 36
proceeded smoothly. Reduction at pressures higher than
50 psi or longer reaction times did result in furan ring
reduction. Subsequent Boc deprotection with TFA pro-
vided 37.
Asymmetric Lithiation-Substitution Sequences
of 13. The sequence was investigated with 13 to deter-
mine if substitution on the central atom of the allyl
system would affect the reaction. Treatment of 13 with
1.1 equiv of n-BuLi and 1.1 equiv of 3 at -78 °C for 1 h
and subsequent additions of electrophiles provided the
products 41-46 in good yields with high ers (Table 3).16
In most cases, only the (Z)-enecarbamate product was
obtained. The (Z) geometry of 41-44 and 46 was con-
firmed by 1H NOE NMR experiments (+4.13% to +9.68%)
which indicated through-space couplings between the
â-methyl group and the olefinic proton.
The γ-substituted products with halide and triflate
carbon electrophiles were obtained in good yields with
er’s ranging from 90:10 to 93:7 (entries 1-3). With a silyl
electrophile, the product was formed from reaction in 87%
yield with a 93:7 er, as shown in entry 4. This is in
contrast with the lithiation-substitution of 2 with tri-
methylsilyl triflate which gave both the (Z)-enecarbamate
product and the R-substituted product in nearly equal
Conversion of the enecarbamates to â-substituted
aldehydes and ketones was demonstrated by the forma-
(18) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak,
P. J. Am. Chem. Soc. 2002, 124, 11689.
(19) Poirier, J.-M.; Dujardin, G. Heterocycles 1987, 25, 399.
J. Org. Chem, Vol. 70, No. 14, 2005 5379

Lee et al.
TABLE 3. Asymmetric Lithiation-Substitutions of 13
yield
(%)
entry
electrophile
CH3OTf
E
product
er
1
2
3
4
5
6
-CH3
41
42
43
44
45
46
78
86
85
87
91:9
93:7
C6H5CH2Br
CH2dCHCH2Br
(CH3)3SiOTf
C6H5CHO
-CH2C6H5
-CH2CHdCH2
-Si(CH3)3
90:10
93:7
99:1, 84:16
93:7
-CH(OH)C6H5
-COH(CH2)5
90 (60:40 dr)
77
(CH2)5CO
SCHEME 5
SCHEME 6
yields.11 With benzaldehyde as the electrophile (entry 5),
low diastereoselectivity was observed even when trans-
metalating agents such as Et2AlCl were employed.20 One
diastereomer was highly enantioenriched, while the other
diastereomer had only moderate enantioenrichment.
Cyclohexanone reacted with lithiated 13 to afford 46 with
a 93:7 er with the absolute configuration is assigned by
analogy to retentive addition found for the reaction of 2
with cyclohexanone.11
Determination of Absolute Configurations and
Further Transformations. The absolute configuration
of 6 has been established, and the same configuration is
assigned by analogy to the lithiated intermediate in the
lithiation-substitution sequence beginning with 13. De-
termination of the absolute configuration of the products
then allows assignments of the substitutions as retentive
or invertive. The absolute configuration of 42 was deter-
mined by conversion to 49, a crystalline compound
suitable for X-ray crystallography. Acid hydrolysis of 42
provided aldehyde 47 as a 60:40 mixture of diastereomers
in 80% yield. Oxidation of the diastereomeric mixture to
the acid 48 was accomplished in 95% yield and followed
by coupling to (S)-(-)-R-methylbenzylamine, a compound
of known configuration. The two diastereomers of product
49 were separated by chromatography, and crystal
growth of a single diastereomer of 49 was carried out by
slow evaporation in a CDCl3 solution in 32% yield
(Scheme 5).11,21
X-ray crystallographic analysis of 49 demonstrates the
newly formed chiral center to be (S). This absolute
configuration of 49 is taken to indicate that reactions
between the lithiated intermediate from 13 and halide
electrophiles occur with inversion of configuration.
The absolute configuration of diastereomeric products
45a and 45b, arising from reaction of the lithiated
intermediate from 13 with benzaldehyde, was also de-
termined. Since X-ray quality crystals of derivatives were
not available, an alternative method was used. Deoxy-
genation of 45a and 45b each began with conversion to
the oxalates 50a and 50b in good yields (Scheme 6).
Deoxygenation then gave (S)-42. All samples of 42, from
lithiation-substitution using benzyl bromide and from
the two diastereomers of 45, had the same retention
(20) Whisler, M. C.; Vaillancourt, L.; Beak, P. Org. Lett. 2000, 2,
2655.
(21) Kim, D. D. Unpublished results.
5380 J. Org. Chem., Vol. 70, No. 14, 2005

Lithiation-Substitution Sequences of Substituted Allylamines
TABLE 4. Asymmetric Lithiation-Substitutions of 14
a Isolated yields (%) for mixture of diastereomers. b Absolute configurations for entries 1, 3, 4, 6, and 9 were assigned by X-ray
crystallography and that for entries 2, 5, 7, and 8 were assigned by analogy. c Diastereomeric ratios were determined by 1H NMR integration.
Drs for entries 2 and 3 were determined after separation of diastereomers by preparative HPLC, respectively. d Enantiomeric ratios were
determined by CSP-HPLC analysis by comparison with authentic materials.15 e Isolated yield for mixture (E/Z ) 69:31). f Enantiomeric
ratio was determined to be minimum >95:5 by 1H NMR analysis.
Asymmetric lithiation of 14 by reaction of n-BuLi/3 at
-78 °C followed by addition of alkyl halide, aromatic
aldehyde, and activated olefins with electron-withdraw-
ing substituents as electrophiles provided the enantioen-
riched products 52-60 in good yields as shown in Table
4.
The reaction of (-)-sparteine lithiated 14 with p-
bromobenzyl bromide afforded a mixture of isomers,
(E,R)-52 and (Z,S)-52, in 80% yield (E/Z ) 69:31). The
stereochemistry (E,R)-52 with a 99:1 er was determined
by X-ray crystallography. The diastereomeric ratio of
82:18 observed in reaction of 14 with p-bromobenzalde-
hyde showed remarkable selectivity with respect to
aromatic aldehydes as compared to the poor selectivity
observed with the trans-cinnamyl allylic amine 2.20
times for the major enantiomer on CSP-HPLC, indicating
all three compounds have the same absolute configura-
tion at the benzylic center. Accordingly, these products
are considered to be formed by invertive reactions with
the lithiated intermediate from 13.
Asymmetric Lithiation-Substitution Sequences
of Cyclic Allylamines 14 and 15. Extension of the
methodology to systems with endocyclic double bonds in
six- and five-membered rings was investigated with 14
and 15. Each reactant was synthesized according to
previously described procedures by the established reac-
tions of reductive amination and Boc reaction or ester
reduction, bromination, and amine coupling.22-24
High Diastereoselective and Enantioselective
Lithiation-Substitution Sequence of 14. The asym-
metric lithiation-substitution sequence of 14 using the
standard reaction protocol with 1.1 equiv of base and
ligand resulted in poor yields and incomplete deuterium
incorporation. However, the use of 2.2 equiv of n-BuLi
and 3, over a 3-4 h period, resulted in a 70% yield of 51
with complete deuterium incorporation.25
The absolute configurations of (Z,S,R)-54 and (Z,R,R)-
54 were directly confirmed by X-ray crystallography. Acid
hydrolysis of (Z,S,R)-54 to aldehyde (S,R,R)-54a followed
by intramolecular cyclization afforded 3-(p-bromophenyl)-
octahydroisobenzofuran-1-ol 61 in 73% yield and with a
diastereomeric ratio of 74:26 (Scheme 7).
(22) For a synthesis of the prochiral amine substrate, see the
Supporting Information.
(23) Concellon, J. M.; Llavona, L.; Bernad, P. L., Jr. Tetrahedron
1995, 51, 5573.
(24) Kozyrkov, Y. Y.; Kulinkovich, O. G. Synlett 2002, 3, 443.
(25) The requirement of 2 equiv of base is made by analogy to the
N-Boc piperidine analogue. See: Bailey, W. F.; Beak, P.; Kerrick, S.
T.; Ma, S.; Wiberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889.
J. Org. Chem, Vol. 70, No. 14, 2005 5381

Lee et al.
SCHEME 7
SCHEME 8
SCHEME 9
configurations of the other compounds reported herein
are based on analogy to these assignments.
High Diastereoselective and Enantioselective
Lithiation-Substitution Sequence of 15. Asymmetric
lithiation of 15 with n-BuLi/3 at -78 °C followed by
addition to p-bromobenzaldehyde afforded a mixture of
diastereomers, (Z,S,R)-68 and (Z,R,R)-68, in 93% yield
and with diastereomeric ratio 87:13 (Table 5). The
absolute configuration of crystalline (Z,S,R)-68 was
determined by X-ray crystallography.
Lithiation-substitution sequences of 15 with activated
trans-olefins provided the corresponding enecarbamates
(Z)-69-73 with the two or three newly generated ste-
reogenic centers in good yields and with diastereo- and
enantioselectivities shown in Table 5.
The absolute configuration of enantioenriched (Z,S,R)-
69 was assigned by suitable X-ray crystallography of
crystalline (R,R,R)-76, obtained after condensation of
thiosemicarbazide with the aldehyde (R,R,R)-75 formed
by acid hydrolysis of (Z,S,R)-69 with TFA (Scheme 10).
The reaction of (-)-sparteine lithiated 15 with (S)-(+)-
N-benzylidene-p-toluenesulfinamide provided (Z,S,R,S)-
74 in excellent yield but with lower diastereo- and
enantioselectivity than observed for the reaction from (-)-
sparteine lithiated 14.
Asymmetric Deprotonations. The diastereomeric
enantiodetermining step in the two-step sequences of
these reactions could be either the lithiation or the
substitution. If the asymmetric deprotonation step is
enantiodetermining, the enantioenrichment of the prod-
ucts is determined in the formation of a configurationally
stable anion which undergoes substitution with high
The stereochemistry of the four stereogenic centers in
crystalline major diastereomer 61 was established by
X-ray crystallography. Reaction of (-)-sparteine lithiated
14 with benzaldehyde also gave enantioenriched (Z,S,R)-
53 and (Z,R,R)-53 with 99:1 and 87:13 er’s and with 82:
18 dr.
Lithiation-substitution sequences from 14 with trans-
olefins activated with nitro, ester, sulfonyl, and nitrile
groups provided the enecarbamates (Z)-55-59 with the
two or three newly generated stereogenic centers in good
yields and with high diastereo- and enantioselectivities.
The absolute configuration of (Z,S,R)-57 was directly
determined by X-ray crystallography and that of (Z,S,R)-
55 was confirmed by synthesis of crystalline 62 by acid
hydrolysis (Scheme 8).
The reaction of (-)-sparteine lithiated 14 with (S)-(+)-
N-benzylidene-p-toluenesulfinamide provided the enecar-
bamate (Z,S,R,S)-60 in 90% yield and with 99:1 dr and
>95:5 er. The absolute configuration of (Z,S,R,S)-60 was
established by conversion to the crystalline N-p-bro-
mobenzyl enecarbamate (Z,S,R,S)-63 and X-ray crystal-
lography. Hydrolysis of (Z,S,R,S)-60 in the presence of 6
N HCl provided the chiral amine (Z,S,R)-64 in 83% yield
without C-N bond cleavage of enamine moiety (Scheme
9).
(26) The absolute configuration of R-(E,S)-65 was established by
X-ray crystallography. Subsequent transmetalation of R-(E,S)-65 with
n-BuLi and (-)-sparteine did not give any tin-lithium exchanged
product and R-(E,S)-65 was recovered in 85(%) yield after column
chromatography.
The reaction of (-)-sparteine lithiated 14 with Ph3SnCl
provided a mixture of R-stannylated (E,S)-65 and γ-stan-
nylated (E,S)-65 in 40% and 47% yields.26 The absolute
5382 J. Org. Chem., Vol. 70, No. 14, 2005

Lithiation-Substitution Sequences of Substituted Allylamines
TABLE 5. Asymmetric Lithiation-Substitutions of 15
a Isolated yields (%) for mixture of diastereomer. b Absolute configurations for entries 1 and 2 were assigned by X-ray crystallography
and those for entries 1, 2, and 5-9 were assigned by analogy. c Diastereomeric ratios were determined by 1H NMR integration. Dr for
entry 1 was determined after separation of diastereomers by preparative HPLC. d Enantiomeric ratios were determined by CSP-HPLC
analysis by comparison with racemic materials.15 e Enantiomeric ratio was determined to be minimum >86:14 by 1H NMR analysis.
SCHEME 10
stereoselectivity. If an asymmetric substitution is the key
step, either a dynamic kinetic resolution or dynamic
thermodynamic resolution could be operative.10,11,27
The configurational stability of the organolithium
intermediate was examined and found to support an
asymmetric deprotonation pathway. The enantioenriched
tin compound (S)-77 was prepared in 63% yield with a
97:3 er from 12. Addition of a premixed, precooled
solution of n-BuLi and 3, followed by benzyl bromide,
produced compound (R)-33 in 60% yield with an 80:20
er (Scheme 12).
These results suggest solvent and structure can affect
the course of this reaction. When the lithiation-substitu-
tion sequence is carried out in toluene, the product is (S)-
33 in 70% yield with a 98:2 er (Table 2).28 The reduction
The enantiocontrolling step with 12 was evaluated by
tin-lithium exchange experiments. The racemic tin
compound 77 was obtained in 60% yield by lithiation of
12 with n-BuLi/TMEDA and reaction with tributyltin
chloride. Transmetalation of 77 with n-BuLi, followed by
addition of (-)-sparteine and benzyl bromide, afforded
racemic 33. This lack of enantioenrichment is taken as
evidence that a post-deprotonative enantioinduction is
not operative and that an asymmetric deprotonation
must be the enantiodetermining step for the sequences
from 12 with n-BuLi/3 (Scheme 11).
(28) The net inversion in configuration of these products is consistent
with the previously reported inversion-retention pathway in the tin-
lithium exchange process. It is noted the sequence with (S)-77 shows
greater loss of enantioenrichment than with (S)-33 suggesting a role
for the furanyl oxygen in the epimerization process.
(27) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel,
D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715.
J. Org. Chem, Vol. 70, No. 14, 2005 5383

Lee et al.
SCHEME 11
SCHEME 12
SCHEME 13
SCHEME 14
in er from 97:3 for (S)-77 to 80:20 for (R)-33 in the
presence of MTBE could occur during or after the
transmetalation process or in the reaction with the
electrophile. It should be noted that the lithiated species
from tin-lithium exchange of 77 and deprotonation of
12 which are epimeric at the lithiated carbon, are
diasteromeric as both epimers are complexed with (-)-
sparteine.
Similar studies suggest that an asymmetric deproto-
nation is also stereochemically determining for the
sequence with 13. The racemic tin product 78 was
synthesized, and subsequent tin-lithium exchange fol-
lowed by sequential addition of (-)-sparteine and methyl
triflate provided racemic 41 (Scheme 13). The formation
of a racemic product indicates the process is not an
asymmetric substitution. An enantiodetermining depro-
tonation step is considered to be the enantiocontrolling
step.
To assess the configurational stability of this lithiated
intermediate, the tin-lithium exchange was carried out
from the organotin (S)-78. The chiral tin compound was
synthesized from 13 in 88% yield, with a 92:8 er.
Transmetalation at -78 °C with a premixed, precooled
solution of n-BuLi/3, followed by reaction with benzyl-
bromide provided (R)-42 with a 91:9 er, demonstrating
configurational stability of the organolithium/3 complex
at -78 °C.28 To eliminate the possibility of a kinetic
resolution, the er of recovered (S)-78 was examined and
found to be 92:8. Since the product from this tin-lithium
exchange sequence has the expected opposite absolute
configuration found from the reaction sequence of Table
3, these results also demonstrate an approach to obtain-
ing both enantiomers with the single chiral ligand
(Scheme 14).12
The reaction pathway for the cyclic substrate 15 was
also evaluated. Synthesis of racemic 79 was accomplished
in 68% yield from 15 and tributyltin chloride. Trans-
metalation with n-BuLi, addition of 3, and reaction with
methyl triflate provided 66 in 45% yield as a racemic
compound (Scheme 15). This is taken as strong evidence
that an asymmetric deprotonation is the enantiodeter-
mining step in this sequence.
The configurational stability of the lithiated intermedi-
ate was examined as heretofore. Enantioenriched (S)-79
was prepared with a 79:21 er. Addition of the chiral
lithium reagent, followed by methyl triflate, produced (R)-
66 as an 80:20 mixture of enantiomers, demonstrating
configurational stability of the lithiated intermediate
(Scheme 16). Again a route to the opposite absolute
configuration from that observed for the direct reaction
is provided by this sequence.
Effects of Substitution on the Allyl System. The
present work probes the effect of substitution at the 2-
and 3-positions of the allyl group of the N-Boc allylamines
on the enantioenrichment of products from (-)-sparteine-
mediated lithiation-substitution sequences.22
Previously, the sequence with N-Boc cinnamylamines
with substitutions of methyl groups at the 1- and 3-posi-
5384 J. Org. Chem., Vol. 70, No. 14, 2005

Lithiation-Substitution Sequences of Substituted Allylamines
SCHEME 15
SCHEME 16
tions was found to lead to eroded enantioenrichments
relative to the unsubstituted system as shown for 80 and
81.21,29
to lithium is considered to direct the electrophile to the
3-position with retention.
The enecarbamate products formed by (-)-sparteine
lithiation-substitution of the N-Boc amines 12 and 13,
summarized in Tables 2 and 3, provide (Z)-enecarbamate
products with good to high ers. By analogy to 2, the base/
(-)-sparteine complex is considered again to selectively
remove the pro-R proton to give configurationally stable
organolithium intermediates in both cases.
Incorporation of the electrophile with inversion or
retention of configuration is highly electrophile depend-
ent. It has been demonstrated both by X-ray crystal-
lographic analysis of 49 and by analogy to products
derived from 2, that halide electrophiles react with
inversion of configuration.11 It has also been demon-
strated that cyclohexanone reacts with retention of
configuration.11 In the case of benzaldehyde, reaction
occurs with inversion of configuration, although the
electrophile has a coordinating carbonyl group. Presum-
ably benzaldehyde is more reactive than cyclohexanone
and does not require precoordination to lithium prior to
substitution to assist the reaction.
For reactions from 14 and 15 formation of an η1-
complex, analogous to 10, seems likely to be generated
by asymmetric deprotonation of pro-R proton as shown
for 83. To rationalize the absolute configurations deter-
mined by X-ray crystallographic analysis, a rotamer 84
of the initial species is considered to react with p-
bromobenzylbromide with inversion of configuration to
give enantioenriched (E,R)-52 (er ) 99:1). For p-bro-
mobenzaldehyde, reaction occurs with inversion of con-
figuration to provide high enantioenriched (Z,S,R)-54 (er
) 99:1) as major diastereomer (dr ) 82:18). For the
reaction of 83 with activated olefins with electron-
withdrawing groups, the absolute configuration at the
newly formed chiral carbon is consistent with inversion.
In the present work, substitution of a methyl group at
the 2-position of the cinnamyl system for 13 provides
products with high enantiomeric ratios. Replacement
of the phenyl group of the cinnamyl system with the
vinyl phenyl of 11 or the 1-furanyl group of 12 also
provides products from the lithiation-substitution se-
quence with high enantiomeric ratios. In the case of 12,
a possible competitive deprotonation of the furan ring
does not interfere with the reaction. The products of
the reactions of 14 and 15 show that this approach
for asymmetric syntheses can be extended to cyclic
systems.
The enantioenrichments of the ꢀ-substituted products
from the lithiation-substitution of 11 shows that exten-
sion of the position of substitution by two carbon atoms
does not reduce stereoselectivity. The enantiomeric ratios
for the isomeric pairs 20/21, 22/23, and 24/25 shows
the C-3- and C-5-substituted products to have com-
parable ers (Table 1). If the structure of lithiated 11
is assumed to resemble its cinnamyl analogue 6 as
an η3-complex, coordination of lithium to the Boc car-
bonyl suggests favorable location of lithium over C-1
to C-3. Bond formation on alkylation can be rational-
ized to take place with inversion at the sterically
most accessible carbon on the bottom face of the de-
localized carbon anion as shown for 82 based on analogy
to the reaction pathway of 2. For the reaction of 82
with cyclohexanone, coordination of the carbonyl oxygen
(29) Weisenburger, G. A. Ph.D. Thesis, University of Illinois at
Urbana-Champaign, 1998.
J. Org. Chem, Vol. 70, No. 14, 2005 5385

Lee et al.
of (S)-N-(tert-Butoxycarbonyl)-N-(4-methoxyphenyl)-5-
phenyl-(Z,E)-1,3-hexadien-1-amine (20) and (R)-N-(tert-
Butoxycarbonyl)-N-(4-methoxyphenyl)-3-methyl-5-phenyl-
(Z,E)-1,4-pentadien-1-amine (21). A solution of 11 (173 mg,
0.474 mmol) and (-)-sparteine (0.12 mL, 0.521 mmol) in
toluene (10 mL) was cooled to -78 °C. n-BuLi (0.326 mL, 0.
521 mmol) was added, and the solution was stirred for 1h.
Methyl triflate (0.107 mL, 0.948 mmol) was added and stirred
for 1 h. The reaction was quenched with methanol at -78 °C,
and after warming to ambient temperature, standard workup,
chromatography (1:10 ethyl acetate/hexane), and preparative
HPLC (3.5% ethyl acetate/hexane) afforded 20 and 21 (107 mg,
60%; 18 mg, 10%, respectively). 20: 1H NMR (acetone-d6, 400
MHz) δ 1.05 (d, J ) 7.1, 3H), 1.40 (s, 9H), 3.20 (quint, J ) 6.8,
1H), 3.81 (s, 3H), 5.30 (m, 2H), 5.58 (m, 1H), 6.55 (d, J ) 8.3,
1H), 6.90-7.05 (m, 4H), 7.11-7.28 (m, 5H); 13C NMR (acetone-
d6, 100 MHz) δ 20.9, 28.2, 42.8, 55.7, 81.4, 114.9, 123.8, 126.8,
127.0, 127.9, 129.1, 129.5, 135.6, 138.4, 146.4, 153.7, 159.0;
HRMS (M+) calcd for C24H29NO3 379.2147, found 379.2148.
The enantiomeric ratio of 20 was determined to be 88:12 by
CSP-HPLC Chiralpak AD (1.0% i-PrOH/hexane, 1.0 mL/min).
The major enantiomer had a retention time of 12.8 min, and
the minor enantiomer had a retention time of 10.4 min. 21:
1H NMR (acetone-d6, 400 MHz) δ 0.85 (d, J ) 6.8, 3H), 1.40
(s, 9H), 2.73 (m, 1H), 3.79 (s, 3H), 4.75 (t, J ) 9.8, 1H), 5.90
(m, 2H), 6.58 (d, J ) 9.3, 1H), 6.91 (m, 2H), 7.10-7.30 (m,
7H); 13C NMR (acetone-d6, 100 MHz) δ 19.9, 27.3, 33.6, 54.7,
80.0, 113.5, 113.7, 125.7, 126.6, 126.7, 127.6, 128.2, 133.2,
135.1, 137.6, 153.0, 157.8; HRMS (M+) calcd for C24H29NO3
379.2147, found 379.2147. The enantiomeric ratio of 21 was
determined to be 78:22 by CSP-HPLC Chiralpak AD (1.0%
i-PrOH/hexane, 1.0 mL/min). The major enantiomer had a
retention time of 8.6 min, and the minor enantiomer had a
retention time of 7.7 min.
Summary
A broad survey of asymmetric lithiation-substitution
reactions has been carried out with 2 and 3 substituted
N-Boc allylamines. Product enantioenrichments are gen-
erally high, and the enantiodetermining step is consid-
ered to be an asymmetric deprotonation. Determination
of absolute configurations, along with previously known
organolithium structural information, suggest reactions
with inversion of configuration are the most favored
pathway for reaction of these organolithium nucleophile
with most electrophiles. Synthetic applications including
enecarbamate manipulation, Diels-Alder sequences, and
cyclizations following hydrolysis are illustrated by the
present studies.
Experimental Procedures
General Information. All reactions involving air-sensitive
compounds were carried out under a nitrogen atmosphere in
oven or flame-dried glassware which was cooled under nitro-
gen. All commercial reagents were used without further
purification, unless otherwise noted. Solvents were distilled
immediately prior to use; diethyl ether and THF were distilled
from Na/benzophenone ketyl under nitrogen, and toluene and
methylene chloride were distilled over CaH2 under nitrogen.
(-)-Sparteine was distilled over CaH2. The base n-BuLi was
titrated according to the method of Suffert.30
Acknowledgment. We are grateful to the National
Institutes of Health (GM-18874) for support of this
work.
Supporting Information Available: Experimental pro-
cedures, characterization data, and X-ray crystallographic
structures (CIF) for 49, 52, 54, 57, 61, 62, 63, 65, 68, and 76.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Representative Lithiation of N-(tert-Butoxycarbonyl)-
N-(4-methoxyphenyl)-5-phenyl-(E,E)-2,4-pentadien-1-
amine (11) and Electrophilic Substitution: Preparation
(30) Suffert, J. J. Org. Chem. 1989, 54, 510.
JO047752M
5386 J. Org. Chem., Vol. 70, No. 14, 2005