11006
J. Am. Chem. Soc. 1998, 120, 11006-11007
upon the electrocyclic transition state.9 Reaction of 1 equiv each
of 1 and 2a catalyzed by 5 mol % (R)-Tol-BINAP-CuClO4•
(CH3CN)2 (3) in THF at room temperature is clean and enantio-
selective (87% ee) but slow and low yielding (35%, Table 1, entry
1). Performing the reaction in CH2Cl2 moderately improved the
enantioselectivity but did not greatly increase the yield, whereas
refluxing the reaction mixture improved yield but eroded enan-
tioselectivity (entries 2-4). We were intrigued by the proposal
that aromatic solvents can increase the rates of certain formally
electrocyclic reactions;10 however, Lewis acid complex 3 is not
soluble in nonpolar aromatic solvents such as toluene or benzene.
Encouraged by a recent report detailing the similar polarity
characteristics of CH2Cl2 and benzotrifluoride (BTF),11 we tested
this aromatic solvent in our reaction. Catalyst 3 is soluble in BTF,
and this led to a marked increase in selectivity (99% ee) although
the yield after 18 h remained low (entry 5). Screening several
other polar aromatic solvents demonstrated similarly high selec-
tivity but modest yields (entries 6-8). We discovered that if we
simply doubled the concentration of alkene, the reaction reached
completion after 18 h while excellent ee (99%, entry 9)12 was
maintained. Several other transition-metal (R)-BINAP complexes
were screened for catalytic activity and enantioselectivity, as
shown in Table 2. However, our original system proved superior
to these alternatives in each case. Additionally, although our
standard screening protocol employed 5 mol % catalyst, we found
that a multigram scale reaction between 1 and 2a could be
conducted with 2 mol % catalyst, affording product in 90% yield
and 99% ee.
With optimal conditions for R-methylstyrene (2a) in hand,13
several other alkenes were investigated, all affording good to
excellent yield and enantioselectivity (Table 3).14 For example,
tetralene 2b provided 4b in 94% yield and 99% ee, and an
aliphatic ene, methylenecyclohexane 2c, similarly led to product
in 85% yield and 95% ee. Heteroatom-containing ene substrates
are also compatible with our reaction conditions, demonstrating
that the catalyst is tolerant of various functional groups and Lewis
basic sites on the alkene. For example, vinyl sulfide 2d (entry 4)
is an excellent substrate, affording product in 85% yield and 98%
ee. The transformation on an amino-containing ene allows the
construction of tryptophan derivative 4e (entry 5, 90% yield and
85% ee). This is interesting because there currently exists no
general synthetic method for the construction of tryptophan
analogues in optically active form through catalytic methodol-
ogy.15 Finally, an oxygen-containing ene provided fufurylalanine
4f in 85% yield and 89% ee (entry 6). It is noteworthy that most
of the products (4a,b,d,f) can be obtained in optically pure form
A Novel Synthesis of r-Amino Acid Derivatives
through Catalytic, Enantioselective Ene Reactions of
r-Imino Esters
William J. Drury, III, Dana Ferraris, Christopher Cox,
Brandon Young, and Thomas Lectka*
Department of Chemistry, Johns Hopkins UniVersity
3400 N. Charles St., Baltimore, Maryland 21218
ReceiVed June 29, 1998
The Lewis acid-catalyzed ene reaction of carbonyl compounds
with alkenes represents a powerful method for selective C-C
bond formation,1 and two notable catalytic, enantioselective
variants are known.2 However, the corresponding catalytic,
enantioselective ene reaction between alkenes and imines has not
been reported even though the allylic amines that would be
generated are useful synthetic intermediates.3 The diastereo-
selective version of the imino ene reaction is nevertheless well-
precedented4 and has been elegantly applied in the total synthesis
of members of the methanomorphanthridine class of natural
products5 as well as (-)-perhydrohistrionicotoxin.6 Lewis acid
catalysis of the imino ene reaction is also well-known although,
in many cases, stoichiometric quantities of promoter are
employed.4a-e From our standpoint, the use of catalytic amounts
of a chiral Lewis acid catalyst in combination with R-imino
esters4e-g,5 as enophiles would unveil a novel route to a variety
of enantiopure nonnatural R-amino acids. In previous work, we
demonstrated catalytic, enantioselective alkylation of chelating
R-imino ester 1 with enolsilane nucleophiles through the use of
the versatile Lewis acid catalysts (R)- or (S)-Tol-BINAP-
CuClO4‚(CH3CN)2 (3).7 In this paper, we report an operationally
convenient and efficient, catalytic, enantioselective imino ene
reaction of R-imino ester 1 with alkenes 2a-f catalyzed by Lewis
acid complex 3 and show this reaction to be a useful new pathway
to R-amino acid derivatives 4a-f (eq 1).
We initiated our study with the reaction between 1 and
R-methylstyrene 2a.8 This ene substrate was chosen on the basis
of the known stabilization that an aromatic substituent at C-2 has
(1) (a) Snider, B. B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 527. (b) Snider, B. B. In
ComprehensiVe Organic Synthesis; Trost; B. M., Ed.; Pergamon Press: Oxford,
1991; Vol 5, p 1.
(2) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. W. J. Am. Chem. Soc. 1998, 120, 5824. (b) Mikami, K.; Terada, M.; Nakai,
T. J. Am. Chem. Soc. 1989, 111, 1940.
(3) For a review of imino ene reactions, see: (a) Weinreb, S. M. Top. Curr.
Chem. 1997, 190, 131. (b) Borzilleri, R. B.; Weinreb, S. M. Synthesis 1995,
347.
(8) The rate of reaction between 1 and 2a at ambient temperature and
pressure is slow. No product is noted after 5 days regardless of solvent used.
(9) Thomas, B. E.; Houk, K. N. J. Am. Chem. Soc. 1993, 115, 790.
(10) Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779.
(11) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(12) It is well-known that the ene reaction has a negative entropy of
activation (Franzus, B. J. Org. Chem. 1963, 28, 2954) and is believed to have
a negative volume of activation (Matsumoto, K.; Sera, A. Synthesis 1985,
999). We expected high-pressure conditions to produce a rate enhancement.
As expected, impression of 12 kbar upon the reaction in BTF gave a
quantitative yield of 4a even without a catalyst present. However, under these
high pressure conditions the reaction proceeds by a nonselective pathway,
leading only to racemic 4a.
(13) A general procedure for the conduction of imino ene reactions consists
of the following: All manipulations prior to workup were performed under
N2, either in a drybox or by syringe techniques. To 0.5 mmol of R-imino
ester 1 stirring in 1 mL of BTF was added 0.025 mmol of catalyst 3 (formed
by stirring 0.025 mmol Cu(MeCN)4ClO4 and 0.026 mmol (R)-Tol-BINAP in
1 mL of BTF for 1 h) followed by addition of 1 mmol of ene substrate 2. The
reaction was then stirred until TLC indicated complete conversion of the
starting material. The mixture was quenched by the addition of H2O and ex-
tracted with CH2Cl2. Combination of the organic extracts, drying with Na2SO4,
concentration by rotary evaporation, and finally purification by flash column
chromatography with EtOAc/hexanes as eluent provided analytically pure 4.
(14) See Supporting Information for proof of absolute stereochemistry.
(4) (a) Weinreb, S. M.; Smith, D. T.; Jin, J. Synthesis 1998, 509. (b) Laschat,
S.; Fro¨hlich, R.; Wibbeling, B. J. Org. Chem. 1996, 61, 9. (c) Laschat, S.;
Grehl, M. Chem. Ber. 1994, 127, 2023. (d) Laschat, S.; Grehl, M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 458. (e) Mikami, K.; Kaneko, M.; Yajima, T.
Tetrahedron Lett. 1993, 34, 4841. (f) Tschaen, D. M.; Turos, E.; Weinreb, S.
M. J. Org. Chem. 1984, 49, 9, 5058. (g) Tschaen, D. M.; Weinreb, S. M.
Tetrahedron Lett. 1982, 23, 3015.
(5) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5774.
(6) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907.
(7) (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
1998, 120, 4548. (b) Ferraris, D.; Young, B.; Cox, C.; Drury, W. J., III.;
Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090. (c) Carreira et al.
have employed a Tol-BINAP-CuF2 complex as an effective catalyst for the
asymmetric aldol reaction, see: Kruger, J.; Carreira, E. M. J. Am. Chem. Soc.
1998, 120, 837.
10.1021/ja982257r CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/09/1998