Catalytic, enantioselective alkylation of α-imino esters: The synthesis of nonnatural α-amino acid derivatives

Article abstract of DOI:10.1021/ja016838j

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of α-imino esters and N₁O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transiti

Full text of DOI:10.1021/ja016838j

Published on Web 12/04/2001
Catalytic, Enantioselective Alkylation of r-Imino Esters: The
Synthesis of Nonnatural r-Amino Acid Derivatives
Dana Ferraris, Brandon Young, Christopher Cox, Travis Dudding,
William J. Drury, III, Lev Ryzhkov,# Andrew E. Taggi, and Thomas Lectka*
Contribution from the Department of Chemistry, Johns Hopkins UniVersity,
3400 North Charles Street, Baltimore, Maryland 21218, and Department of Chemistry,
Towson UniVersity, 8000 York Road, Towson, Maryland 21252
Received August 14, 2001. Revised Manuscript Received October 22, 2001
Abstract: Methodology for the practical synthesis of nonnatural amino acids has been developed through
the catalytic, asymmetric alkylation of R-imino esters and N,O-acetals by enol silanes, ketene acetals,
alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The
alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity
(up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural
products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with R-imino esters
is presented to shed light on the mechanism of this reaction.
Introduction
ester, first used as precursors to amino acids in groundbreaking
work by Weinreb.5
One of the paramount goals of asymmetric catalysis has been
the synthesis of optically pure, nonnatural R-amino acids for
use in natural products, peptide, and pharmaceutical chemistry.1
While a spectrum of methods is available for this purpose,
potentially one of the most attractive approaches involves the
asymmetric alkylation of imines2 and N-acetals.3 One very
successful imine alkylation strategy that has recently emerged
is the catalytic, asymmetric Strecker reaction,4 in which a highly
oxidized nucleophile such as hydrogen cyanide or its synthetic
equivalent is added to imines asymmetrically to produce
R-cyanoamine products that can be hydrolyzed to the corre-
sponding optically enriched R-amino acids. An alternative
approach, which we employ, involves an imine containing a
highly oxidized carboalkoxy substituent, such as an R-imino
Our recent work has focused on the synthesis of enantio-
enriched R-amino acid derivatives through the catalytic asym-
metric alkylation of R-imino esters 1 with a variety of carbon-
based nucleophiles using late-transition metal bis(phosphine)
complexes as catalysts (eq 1, pathway A).6 A complementary
system reported by Sodeoka for R-imino ester alkylation using
a Pd(II)-based complex that operates through the catalytic
generation of enolates is contemporaneous with our work.2b Our
catalyst system has also been fruitfully used by others on closely
related reactions.7 Additionally, we have also developed a
practical, preparative scale synthesis of R-amino acid derivatives
using hydrolytically stable N,O-acetals 9 (eq 1, pathway B)
instead of imines with minimal loss in selectivity or yield.8 Our
first contribution concerned the alkylation of R-imino esters by
enol silanes (eq 1, pathway A, Nu ) 2).6 In a related
communication, we reported the first example of a catalytic,
enantioselective imino ene reaction (eq 1, pathway A, Nu )
11) to generate enantio-enriched allylic amino acids 4.9,10 Herein
# Towson University.
(1) Recent reviews of amino acid synthesis: (a) Bloch, R. Chem. ReV. 1998,
98, 1407. (b) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergammon: New York, 1989. (c) Duthaler, R. O. Tetrahedron 1994, 50,
1539. (d) Hegedus, L. Acc. Chem. Res. 1995, 28, 299. Synthesis of
nonnatural R-amino acids in natural products: (e) Boger, D. L.; Patane,
M. A.; Zhou, J. J. Am. Chem. Soc. 1994, 116, 8544. (f) Boger, D. L.;
Yohannes, D. J. Org. Chem. 1990, 55, 6000.
(5) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
(6) (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.
(2) For representative examples of Lewis acid-catalyzed enantioselective imine
alkylations, see: (a) Kobayashi, S.; Ishitiani, H. Chem. ReV. 1999, 99, 1069.
(b) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120,
2474. (c) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997, 119, 10049.
(d) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153. A proline-catalyzed asymmetric Mannich reaction has recently been
reported: (e) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(3) (a) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649. For reviews of
R-amidoalkylation reactions, see: (b) Zaugg, H. E. Synthesis 1984, 85. (c)
Zaugg, H. E. Synthesis 1984, 181.
(7) (a) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2000, 39, 4114. (b) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558. (c) Yao, S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem.-
Eur. J. 2000, 6, 2435. (d) Yao, S.; Fang, X.; Jørgensen, K. A. J. Chem.
Soc., Chem. Commun. 1998, 2547.
(8) Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org.
Chem. 1999, 64, 2168.
(9) Drury, W. J., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem.
Soc. 1998, 120, 11006.
(4) (a) Synopsis: Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (b) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(c) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2000, 122, 2657. (d) Sigman, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 1998, 120, 4901. (e) Kobayashi, S.; Ishitani, H.;
Ueno, M. J. Am. Chem. Soc. 1998, 120, 431. (f) Fujieda, H.; Kanai, M.;
Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060.
(10) (a) For a review of imino ene reactions, see: Borzilleri, R. B.; Weinreb, S.
M. Synthesis 1995, 347. (b) For a review of asymmetric ene reactions,
see: Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021. For two notable
examples of asymmetric ene reactions, see: (c) Evans, D. A.; Burgey, C.
S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem. Soc. 1998,
120, 5824. (d) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989,
111, 1940.
9
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J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 67

A R T I C L E S
Ferraris et al.
Table 1. Enantioselective Alkylation of 1b with Enolsilanes
Catalyzed by Chiral Phosphine Complexesa
we summarize the methodology involved in our R-amino acid
syntheses and report a new, alternative method to synthesize
allylic amino acids via asymmetric allylation of R-imino esters
(eq 1, pathway A, Nu ) 17).11 Furthermore, we present a kinetic
study of the ene reaction of R-imino esters.
entryb
nucleophile
catalyst
T (°C)
% yield
% ee
1
2c
3
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Me
2a: R ) Ph; R' ) Et
2b: R ) OPh; R' ) Me
2c: R ) 4-MeOPh; R' ) Me
2c: R ) MeOPh; R' ) Me
2d: R ) t-Bu; R' ) Me
2d: R ) t-Bu; R' ) Me
2e: R ) 3-NO2Ph; R' ) Me
2f: R ) 3,4-Cl2Ph; R' ) Me
3a
3a
3a
3b
3c
3d
3d
3d
3a
3d
3a
3d
3d
3d
-78
-78
-40
-78
-78
0
95
96
97
91
95
95
93
83
94
96
70
65
87
92
90
90
67
80
89
98
96
72
86
98
75
90
94
89
4d
5
6e
7
8
0
-78
-78
0
9
10
11
12
13
14
0
0
0
0
a Enantiomeric excesses were determined by a CHIRALCEL OD chiral
HPLC column unless otherwise noted. b Reactions were run with 0.4 mmol
imine 1b and 0.04 mmol catalyst (10 mol % metal salt, 10.5 mol % BINAP
or Tol-BINAP at the specified temperature for 24 h in THF). c One
equivalent of catalyst was used. d Reaction run in CH2Cl2. e 2 mol % catalyst
was used.
2) and also suggested that the uncatalyzed reaction plays a minor
role in affecting asymmetric induction under these con-
ditions. When we conducted this reaction at -40 °C, the
selectivity decreased to 67% ee (entry 3). The complex (R)-
BINAP•Pd(ClO4)2•(CH3CN)2 (3b) afforded somewhat lower ee
(80%, entry 4). A mechanistically distinct version of this catalyst
system was employed by Sodeoka and co-workers in their
studies.2b
Results and Discussion
Enantioselective Alkylation of Imino Esters. For our initial
investigations into asymmetric imino alkylations, we chose to
examine R-N-silylimino esters 1 with the view that the silyl
group would be easily removable in a subsequent deprotection
step. However, the reaction of 1a with enol silane 2a (R1 )
Ph; R2 ) H), catalyzed by a number of phosphine-based metal
complexes (3) at -78 °C, led exclusively to racemic products.
The nonselectivity in this reaction was attributed to a high
background rate and potential cis-trans isomerism about the
CdN bond that can interfere with metal binding. Although
discouraged, we reasoned that by changing the substituents on
the R-imino ester, background rates could be reduced. We then
decided to investigate tosyl imine 1b,12 aware that the substituent
modifications in asymmetric catalysis can provide the difference
between a successful or an unsuccessful reaction. A notable
uncatalyzed reaction rate in THF solution at -50 °C between
1b and 2a was initially a cause for some concern. Generally
speaking, reactions that have uncatalyzed rates at temperatures
of interest are poor candidates for asymmetric catalysis.
However, to our surprise, slow addition of 1.1 equiv of enol
silane 2a over the course of 2 h into a solution of the R-imino
ester 1b containing 10 mol % (R)-BINAP•AgSbF6 (3a)13 at -78
°C gave the protected amino acid 4a (eq 2, R ) Ph) in 95%
yield and 90% ee, implying that the catalyzed rate must be at
least one order of magnitude faster than the background reaction
under these conditions (eq 2, Table 1, entry 1). The use of 1
equiv of catalyst 3a led to identical selectivity (90% ee, entry
The straw-yellow complex (R)-BINAP•CuClO4•(CH3CN)2
(3c)14 performed as well as 3a (entry 5), whereas (R)-Tol-
BINAP•CuClO4•(CH3CN)2 (3d) provided the best results, giving
high yield (95%) and selectivity even when this reaction was
conducted at 0 °C in the presence of only 2 mol % catalyst
(98% ee, entry 6). This increase in selectivity when using (R)-
Tol-BINAP in preference to (R)-BINAP was also noted in the
recent findings of Carreira in a Cu(II)-phosphine catalyzed
asymmetric aldol reaction.15 Interestingly, a bulkier triethylsilyl
(TES) group on the enol silane does not adversely affect the
rate or the enantioselectivity of the reaction (entry 7). A
noteworthy feature of the reaction is that enol silanes react with
good selectivity, whereas silyl ketene acetals, classic substrates
(11) For recent examples of catalytic, asymmetric allylations, see: (a) Chen,
G.-M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int. Ed. 1999,
38, 825. (b) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem.
Soc. 1998, 120, 4242. (c) Yanagisawa, A.; Nakashima, H.; Ishiba, A.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723. (d) Fang, X.; Johannsen,
M.; Yao, S.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1999, 64, 4844.
(14) For the preparation of Cu(ClO4)•(MeCN)4 see: Kubas, G. J. In Inorganic
Synthesis; Shriver, D. F., Ed.; Plenum: New York, 1979; Vol. 19, p 90.
(15) (a) Pagenkopf, B. L.; Kru¨ger, J.; Stojanovic, A.; Carreira, E. M. Angew.
Chem., Int. Ed. 1998, 37, 3124. (b) Kruger, J.; Carreira, E. M. J. Am. Chem.
Soc. 1998, 120, 837.
(12) R-Imino ester 1b was first used by Weinreb: Tschaen, D. H.; Turos, E.;
Weinreb, S. M. J. Org. Chem. 1984, 49, 5058.
(13) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem.
Soc. 1996, 118, 4723.
9
68 J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002

Synthesis of Nonnatural R-Amino Acid Derivatives
A R T I C L E S
While our initial report was under review, Sodeoka et al.
described the use of binuclear Pd(II) catalysts for the enantio-
selective alkylation of N-aryl R-imino esters 1e with enol silanes
in enantiomeric excesses as high as 93%. Exhaustive physical
studies (NMR and MS) identified bimetallic complex structure
B (Figure 1), containing a metal-based enolate, as a likely
reactive intermediate.18 After noting our use of related anhydrous
dicationic Pd(II) catalyst 3b in reactions of 1b, they attempted
to apply their chiral enolate procedure of Pd(II)-aquo complexes
using N-tosyl imino ester 1b and were surprised to discover
that no asymmetric induction was observed in the reaction
products over a range of temperatures and changes in solvent.18
They ascertained that these Pd(II)-aquo complexes, with their
acidic protons, were nonselectively catalyzing the addition
reaction of 1b with enol silanes and that exclusion of water to
form a dicationic Pd(II) complex was necessary to attain
selectivity with imino ester 1b, per our results. In subsequent
experiments, Sodeoka et al. reported that N-aryl imino esters
1e proved to be poor substrates for activation with catalyst 3b,18
a result independently confirmed in our laboratories. Their NMR
investigation of this reaction showed peak broadening in the
signals attributed to N-aryl imino esters when combined with
catalyst 3b, an effect ascribed to strong coordination between
the imine and palladium center (but evidently not fulfilling the
requirements for asymmetric induction). Without question, the
substituent on the imine-N plays a critical role in controlling
both the selectivity and the reaction mechanism.
Carreira et al. have postulated that both Cu(I) and Cu(II)
enolates add enantioselectively (with ee’s up to 94%) to
aldehydes employing a complex derived from Tol-BINAP and
Cu(I) and Cu(II) fluorides formed in situ (Figure 1, structure
C).15 A subsequent detailed mechanistic study employing React
IR documented the involvement of Cu-based enolates in
Carreira’s system.15a For our part, several experiments were
performed to discern whether a Cu(I) enolate played a role as
an active nucleophile in our reaction. Treatment of a 1 mM
solution of enol silane 2a in CD2Cl2 with 1 equiv of catalyst
3d produced no discernible change in the 13C or 1H NMR spectra
of the enolate over the course of 1 week. Keeping in mind that
we had demonstrated a chelate-based interaction between imino
ester 1b and the catalyst 3c by IR spectroscopy (see below),6a
our results are consistent with catalysts 3 working as classical
Lewis acids. Nevertheless, this result does not rule out the
possibility of a small, but kinetically significant, quantity of
metal enolate in our reaction. To force the issue, a putative
copper enolate was formed by adding 1 equiv of KH to
acetophenone in THF, followed by metal metathesis with
(PPh3)2•CuClO4•(CH3CN)2 and precipitation of KClO4. This
brown mixture was then added to a solution of the imine 1b in
THF at low temperature and allowed to warm. After several
hours of stirring, no product formation occurred. Upon quench-
ing, only acetophenone and a polar, unidentified polymeric solid
were isolated. These results led us to conclude that a Cu(I)
enolate was probably not the active species in the alkylation of
imino ester 1b.
Figure 1. Reactive complexes for enantioselective reaction.
of aldol methodology, appear to possess high uncatalyzed rates
at the temperatures we screened, leading to lower selectivity
(entry 8).
We also determined that the use of slightly more reactive
enol silane 2c led to 86% ee at -78 °C with 10 mol % Ag(I)-
based catalyst 3a (eq 2, Table 1, entry 9) and 98% ee with Cu(I)-
based catalyst 3d (entry 10). Other enol silanes 2d-f (Table 1)
were also examined. For example, the enol silane 2d derived
from pinacolone gave much lower yield and reduced ee with
catalysts 3a and 3d (entries 11, 12). In general, aliphatic enol
silanes gave slightly lower ee’s. Competition experiments, in
the presence of 10 mol % catalyst 3d, showed that nucleophile
2c reacted the fastest, whereas nucleophiles 2e and 2f reacted
slower, correlating well with the relative nucleophilicity of the
enol silanes. The use of enol silanes 2e and 2f led to compounds
4e and 4f, precursors to γ-oxo-R-amino acids which are
currently of interest as inhibitors of kynurenine-3-hydroxylase
(entries 13 and 14).16These synthetic precursors are often
crystalline, and one recrystallization from ether/hexane afforded
enantiomerically pure materials (>99% ee). The tosyl group
can be removed from the products 4 by treatment with phenol
in a refluxing solution of HBr/AcOH, followed by addition of
water. For example, product 4a led to the corresponding amino
acid in 75% chemical yield with no detectable racemization (eq
3).17 Many acid-sensitive functional groups are not stable to
these strongly acidic conditions, and a practical synthesis of
γ-oxo-R-amino acids 5 using easily removable sulfonamido
groups is discussed below.
Structure of Catalyst 3c. Interesting reports on the inter-
mediacy of Pd(II)- and Cu(II)-based enolates in catalytic
asymmetric imine additions and aldol reactions appeared at the
time of our first submissions in this area and prompted us to
examine whether they might be involved in our system. As
postulated above, we believe that chiral Lewis acid complexes
3 chelate imino esters 1, activating them for enantioselective
addition (Figure 1, structure A).
The potential ease of interconversion between Cu(I) and
Cu(II) must also be taken into account.19 To our surprise, a
similar, although somewhat less effective, catalyst could also
be generated by mixing Cu(ClO4)2 with (R)- or (S)-BINAP in
(16) (a) Rover, S.; Cesura, A. M.; Huguenin, P.; Kettler, R.; Szente, A. J. Med.
Chem. 1997, 40, 4378. (b) Golubev, A. S.; Sewald, N.; Burger, K.
Tetrahedron 1996, 52, 14757. (c) Berre´e, F.; Chang, K.; Cobas, A.;
Rapoport, H. J. Org. Chem. 1996, 61, 715. (d) Botting, N. P. Chem. Soc.
ReV. 1995, 401. (e) Pellicciari, R.; Natalini, B.; Constantino, G. J. Med.
Chem. 1994, 37, 647.
(17) Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649.
(18) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
9
J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 69

A R T I C L E S
Ferraris et al.
Scheme 1. Proposed Catalytic Cycle for Enantioselective R-Imino
Ester Alkylation
Figure 2. Theoretical calculations of model imine 1c.
in THF or CH2Cl2, a fully competent catalyst solution was
formed. We also found that the catalyst could be stored in the
solid state under argon indefinitely for ease of use.
Mechanism of Catalytic Enol Silane Imino Alkylation. A
proposed catalytic cycle for our reaction is depicted below in
Scheme 1. The first step is the formation of an activated imine/
Cu(I) complex 6b (five-membered chelate) which rigidifies the
system, minimizing the degrees of freedom of the imine.
Evidence for chelate formation in the catalyzed reaction (eqs
1, 4) was obtained by FTIR spectroscopy. Upon the addition
of 1 equiv of catalyst 3c, the ester carbonyl band of 1b at 1735
cm-1 shifted by -38 cm-1 to 1697 cm-1, and the CdN
absorption shifted from 1630 to 1618 cm-1 (-12 cm-1). The
carbonyl band underwent the greater frequency shift, as would
be expected for chelate formation.24 Theoretical calculations of
model imine 1c and Cu(I) complex 6a fully optimized at the
B3LYP/6-31G* level25using Gaussian 98 indicated that in the
ground-state geometry of 1c the π-system of the imino group
lies perpendicular to that of the carbonyl group (Figure 2). The
activated complex 6a is calculated to be tetrahedral, consistent
with other complexes of Cu(I).26 A vibrational analysis of 6a
indicates a greater shift (-45 cm-1) for the carbonyl group than
for the imino group (-5 cm-1) relative to precursor 1c,
consistent with our experimental observations.27 Without this
chelate interaction, much of the selectivity is lost as illustrated
by the use of simple imines, which react sluggishly and produce
products with poor optical induction.28 The next steps include
stereochemistry-determining addition (re attack) and transilyl-
ation, which occurs from the carbonyl oxygen to the sulfon-
amido nitrogen yielding the silylated product N-TMS-4 and
regenerating the active catalyst 3c. The silylated product
N-TMS-4 can usually be seen by TLC and NMR, and desilyl-
ation only takes place after acidic workup, quenching with a
fluoride source, or column chromatography. Adding t-BuOH
(1 equiv) as a proton source in the reaction can intercept the
transilylation step, producing desilylated products directly and
a silyl ether as a byproduct with only a modest decrease in the
rate of reaction.
THF. This catalyst afforded product 4a in 85% ee under the
conditions of our screen (versus 89% ee with 3c). In addition,
major ligand-based byproducts of this reaction were identified
as the mono- and bis(phosphine) oxide of BINAP (BINAPO).20
To determine the source of oxygen in this phosphine oxidation,
Cu(ClO4)2 was added to (S)-BINAP in a THF solution to which
a slight excess of water enriched in H218O had been added.
Workup and MS analysis of the BINAPO byproduct showed a
corresponding isotopic incorporation of 18O into the phosphine
oxide moiety,21 implying that a small amount of adventitious
water is the oxygen source when BINAP is oxidized by
Cu(ClO4)2.22 We are aware that bisphosphine monoxides can
act as ligands in Lewis acid-catalyzed reactions,23 and for this
reason, we employed both Cu(I)• and Cu(II)•BINAPO com-
plexes in the alkylation of 1b. These catalysts led to racemic
products 4, implying that only Cu(I)•BINAP is the active
catalyst in our system, albeit present in small amounts when a
Cu(II) salt is employed as a starting material. Remarkably, the
other contaminants, and potentially competing catalysts, do not
interfere with selectivity to an appreciable extent.
Additionally, the UV spectra of catalysts 3c and 3d derived
from either Cu(I) or Cu(II) salts appeared virtually identical,
with features characteristic of Cu(I) (including the lack of d-d
absorption bands indicative of Cu(II)). Similarly, NMR spectra
showed none of the expected paramagnetic broadening associ-
ated with the use of Cu(II), even when Cu(ClO4)2 was the
starting copper salt. The structure of 3c was finally determined
by X-ray crystallography, as reported in our earlier communi-
cation.6b When single crystals of catalyst 3c were redissolved
Enantio- and Diastereoselective Imine Alkylation. We
recently noted that excellent anti diastereoselectivity (up to 25:
1) as well as enantioselectivity (up to 99% ee) can be obtained
(24) Structural evidence exists for the chelate binding of R-imino esters and
Zn(II): Van Vliet, R. P.; Van Koten, G.; Modder, J. F.; Van Beek, J. A.
M.; Klaver, W. J. J. Organomet. Chem. 1987, 319, 285. Chelate formation
is expected to enhance selectivity by restricting rotation about the bond
between nitrogen and the metal in the activated complex.
(19) Hathaway, B. J. In ComprehensiVe Coordination Chemistry; Wilkinson,
G., Fillard, R. D., McCleverty, J. A., Eds.; Pergamon: New York, 1987;
Vol. 5.
(20) The synthesis and characterization of BINAPO has been described: (a)
Tayaka, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629.
(21) Mass spectral analysis indicated an isotopic enrichment at the M + 2 and
M + 4 peaks of BINAPO.
(25) Hybrid density functional theory/Hartree-Fock (DFT/HF) theory is a
promising emerging method for the modeling of transition metal-based
complexes: (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B: Condens.
Matter 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (c)
Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
(22) Phosphine oxidation by Cu(SO4)2 is precedented: Berners-Price, S. J.;
Johnson, R. K.; Mirabelli, C. K.; Faucette, L. F.; McCabe, F. L.; Sadler,
P. J. Inorg. Chem. 1987, 26, 3383.
(26) Cotton, F. A.; Wilkinson, G. AdVanced Inorganic Chemistry; Wiley-
Interscience: New York, 1988; p 756.
(27) Calculated frequencies for 1c are 1565 cm-1 for the imino group and 1735
cm-1 for the carbonyl group; for 6b they are 1560 cm-1 for the imino
group and 1690 cm-1 for the carbonyl group.
(23) (a) Abu-Gnim, C.; Amer, I. J. Organomet. Chem. 1996, 516, 235. (b)
Wegman, R. W.; Abatjoglou, A. G.; Harrison, A. M. J. Chem. Soc., Chem.
Commun. 1987, 1891.
(28) Unpublished results from our laboratories.
9
70 J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002

Synthesis of Nonnatural R-Amino Acid Derivatives
A R T I C L E S
Table 2. Diastereoselective Alkylations of R-Imino Ester 1b
employed in the same reaction to afford the desired product in
a 1/4 anti/syn ratio with modest enantioselectivity (entry 6).
We were interested in whether an E-enol silane could reverse
the stereochemistry at the â-carbon leading to the syn product.
In many cases, simple E-enol silanes are difficult to synthesize
isomerically pure without laborious purification. One way to
approach the problem of diastereoselective enolization is to
enforce E-geometry by using a cyclic framework. Contrary to
our presumptions, the cyclic enol silane 2h affords a 20/1 anti/
syn ratio of product 4h in >99% ee with catalyst 3d (Table 2,
entry 7). Enol silane 2i, derived from the corresponding known
ketone,32 can be viewed as a masked equivalent of an E-enol
silane. This silyl tetralone 2i afforded the product 4i with anti
stereochemistry in 99% ee at -78 °C (15/1 anti/syn, entry 8).33
We found that higher reaction temperatures drastically eroded
the enantio- and diastereoselectivity of 4i due to an appreciable
nonselective background rate between 1b and 2i. The enol silane
2j derived from cyclohexanone affords product 4j in 71% yield
(88% ee, 11:1 anti/syn, entry 10) with catalyst 3d. Once again,
both the enantioselectivity and diastereoselectivity diminished
slightly with the use of catalyst 3c (78% ee, 7/1 anti/syn, entry
9). Ketene acetal 2k, derived from coumarinone, yielded the
protected amino acid 4k in 91% ee and 71% yield with excellent
anti diastereoselectivity (entry 11). Compound 2k is the only
ketene acetal that we found to work well in the reaction. Its
“flat” geometry and the presence of an aromatic ring seem to
favor enhanced selectivity, as well as the reduced background
rate due to R-substitution.
c
entrya
nucleophile
catalyst
yield
ee %
anti/syn
1
2
3
4
5
2g: R ) Me
3c
3d
3e
3c
3c
3b
3d
3d
3c
3d
3c
80
86
86
77
78
81
82
75
75
71
71
92
98
10/1
25/1
1.3/1
14/1
16/1
1/4
20/1
15/1
7/1
2g: R ) Me
2g: R ) Me
2g: R ) Et
95
95
38
>99
99
78
88
91
2g: R ) Me(Ph)2
6
7
2g: R ) Me
2h
2i
2j
2j
2k
8b
9b
10b
11b
11/1
17/1
a Reactions were carried out at 0 °C to room temperature. b Reaction
carried out at -78 °C. c Enantiomeric excesses were determined by a
CHIRALCEL OD chiral HPLC column.
when substituted enol silanes are employed in the alkylation
reaction (eq 4) regardless of the geometry of the enol silane.6,29
We also observed that the nature of the phosphine ligands we
employed (PPh3, BINAP, Tol-BINAP) is directly responsible
for the diastereoselectivity of the products.
Initial screening focused on the reaction of Z-enol silane 2g30
with R-imino ester 1b. As part of our standard procedure, slow
addition of a CH2Cl2 solution of 1.1 equiv of 2g over 1 h to a
mixture of catalyst (1-10 mol % 3c) and imine (1b) at 0 °C
afforded product 4g with good yield (80%) and excellent ee
(92%) and diastereoselection (anti/syn ) 10/1; Table 2, entry
1). Once again, the yield, enantioselectivity, and diastereo-
selectivity all increased noticeably with the use of (S)-Tol-
BINAP•CuClO4•(CH3CN)2 (3d) (entry 2), while the diastereo-
selectivity all but vanished with the use of achiral catalyst
CuClO4•(PPh3)2•(CH3CN)2 (3e)31 (anti/syn ) 1.3/1; entry 3).
As noted in the previous section, the size of the silane substituent
did not appreciably affect the enantioselectivity; however, the
diastereoselectivity noticeably improved. For example, increas-
ing the size of the silane group (e.g., triethylsilyl TES-2g and
diphenylmethylsilyl DPMS-2g) led to anti/syn ratios of 14:1
and 16:1, respectively, with catalyst 3c (entries 4, 5). An
interesting reversal of diastereoselectivity was noted when the
putative square planar complex (R)-BINAP•Pd(ClO4)2 (3b) was
The absolute and relative stereochemistry of 4g were deter-
mined by a diastereoselective reduction/cyclization sequence to
yield the lactone 7, followed by removal of the tosyl group.
BOC-protection of the amino group then led to the known
compound 8 (eq 5).34 This methodology thus provides a
convenient way to synthesize asymmetrically trisubstituted
lactones that are building blocks for many natural products.35
Similarly, syn-4c is a potential precursor to the nonnatural amino
acid segment of the nikkomycin family of antibiotics (eq 6).36
The absolute and relative stereochemistry of 4h was determined
from the crystal structure of (1′R,2S)-4h.37 Stereoregularity was
then inferred for the cyclic products 4i, 4j, and 4k.
(32) Barcza, S.; Hoffman, C. W. Tetrahedron 1975, 31, 2363.
(33) Desilylation of 4i can be performed in a number of ways, see: (a) Hayes,
M. A. In ComprehensiVe Organic Functional Group Transformations;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: New York,
1995; Vol. 1, p 447. (b) Mukai, C.; Miyakawa, M.; Mihira, A.; Hanaoka,
M. J. Org. Chem. 1992, 57, 2034. (c) Mukai, C.; Cho, W.-J.; Kim, I. J.;
Hanaoka, M. Tetrahedron 1991, 47, 3007.
(34) (a) Gair, S.; Jackson, R. F. W.; Brown, P. A. Tetrahedron Lett. 1997, 38,
3059. (b) Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B.
J. Org. Chem. 1993, 58, 5972.
(29) Mukaiyama and co-workers also note predominant anti addition to aldehydes
regardless of double bond geometry in the presence of a Lewis acid
catalyst: (a) Mukayama, T.; Kobayashi, S.; Tamura, M.; Sagawa, Y. Chem.
Lett. 1987, 491. (b) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem.
Lett. 1985, 447.
(30) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J.
E.; Lampe, J. J. Org. Chem. 1980, 45, 1066.
(31) Ruthkosky, M.; Kelly, C. A.; Zaros, M. C.; Meyer, G. J. J. Am. Chem.
Soc. 1997, 119, 12004.
(35) (a) Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J. J. Chem.
Soc., Perkin Trans. 1 1994, 1719. (b) Raffauf, R. F.; Zennie, T. M.; Onan,
K. D.; LeQuesne, P. W. J. Org. Chem. 1984, 49, 2714.
9
J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 71

A R T I C L E S
Ferraris et al.
Table 3. Asymmetric Alkylations of 1d and Acetals Using Catalyst
In fact, the selectivity increased as a solution of 9d and
catalyst 3d (5 mol %) was mixed at 0 °C with 2 equiv of enol
silane 2a for 5 h, leading to compound 4a in 93% yield and
95% ee (Table 3, entry 5). Although substrate 9d is a highly
crystalline and stable starting material, removal of the tosyl
group in a subsequent step requires long reaction times and
highly acidic conditions.We envisaged that other more easily
removable sulfonamido protecting groups could be substituted
for the tosyl group to provide complementary deprotection pro-
cedures.41 As noted in a previous communication,6a the sulfonyl
groups are interchangeable, but variations in selectivity and yield
occur (Table 3, entries 6, 7). For example, when mesyl N,O-
acetal 9g reacts with enol silane 2a in the presence of catalyst
3d, compound 10g is produced with only 87% ee (entry 8).
3da
entry
acetal
nucleophile
% yield
% ee
product
1
2
3
4b
5
6
7c
8
1d
2a
2a
2a
2a
2a
2e
2a
2a
84
86
89
96
93
86
78
89
62
60
56
50
95
87
98
85
10a
10a
10b
10c
4a
10d
10e
10f
9a (X ) Bz; LG ) Br)
9b (X ) p-An; R ) Br)
9c (X ) Ac; R ) OH)
9d (X ) Ts; R ) OH)
9e (X ) Ns; R ) Br)
9f (X ) SES; R ) OH)
9g (X ) Ms; R ) OH)
a Abbreviations: Bz, benzoyl; p-An, 4-methoxybenzoyl; Ac, acetyl; Ts,
p-toluenesulfonyl; Ms, methanesulfonyl; Ns, p-nitrobenzenesulfonyl; SES,
trimethylsilyl-ethanesulfonyl. Enantiomeric excesses were determined by
a CHIRALCEL OD chiral HPLC column. b Reaction carried out in refluxing
CH2Cl2. c Enantiomeric excesses were determined by 1H NMR in the
presence of (+)-Pr(hfc)3 chiral shift reagent.
Synthesis of γ-Oxo-r-Amino Acids from Acetals. With the
optimization of enantio- and diastereoselective imino alkylation
in hand, we decided to address practical issues of our methodol-
ogy, namely product deprotection and the hydrolytic stability
of the starting material. We reported the synthesis of γ-oxo-R-
amino acids from easy-to-synthesize N,O-acetals 9 using 5 mol
% catalyst 3d.8 Initially, we screened amides 9a-c, which are
easily prepared from glycine ethyl ester in two steps.38,39 If the
catalyst could promote the elimination of the leaving group,
the corresponding R-imino esters 1 would then serve as the
activated intermediate, and enantioselective alkylation would
afford acylated amino acid derivatives 10 (eq 7).
Once again, a variety of protecting groups including 2-tri-
methylsilylethylenesulfonyl (SES), benzoyl (Bz), and nosyl (Ns)
were demonstrated to be effective under the reaction conditions
producing products 10 in moderate to excellent enantioselec-
tivity. In the deprotection step, compounds 10a-e can be
converted to amino acids 5 in yields ranging from 60 to 87%
with no detectable racemization (eq 8). In fact, we used this
methodology for the multigram synthesis of (L)-3-nitrobenzoyl-
alanine (5e) in 48% overall yield from acetal 9e (Table 3, entry
6) using only 1 mol % 3d. This compound is currently one of
the best inhibitors of kynurenine-3-hydroxylase and kynureni-
nase. Our methodology affords this amino acid in higher
enantioselectivities and yield than any of the previously reported
syntheses.42
With the issues of practicality and flexibility addressed, we
turned our attention to a curious mechanistic aspect of the N,O-
acetal reaction, which differs from imino ester alkylation
reactions by the necessity of generating the imine in situ. One
manifestation of this difference is the requirement for 2 equiv
of enol silane 2a for the acetal alkylation to go to completion.
To our surprise, the use of 1 equiv of enol silane 2a with N,O-
acetal 9d did not lead to product 4a with 5 mol % 3d; however,
when 2 equiv were used, product 4a was formed in good yield.
Although silyl ketene acetals can be quenched through silyl
transfer reactions with alcohols, enol silanes are also known to
act as silylating reagents.43 This anomaly prompted us to
examine the enol silane reaction through 1H NMR experiments.
For example, when acetal 9d was dissolved in CD2Cl2 along
with 1 equiv of enol silane 2a, an immediate change in the 1H
NMR spectrum occurred. The enol silane resonances disap-
peared, and those characteristic of acetophenone and silylacetal
In entries 2-4 (9a-c, Table 3) which we investigated, the
X-substituent on the N,O-acetal was either an acyl or an aryl
group. The reaction between amides 9a-c and enol silane 2a
did not proceed to any appreciable extent in the absence of
catalyst 3d. However, as shown in Table 3, the maximum
enantiomeric excess was only 60% using 5 mol % catalyst 3d
(Table 3, entry 2). We realized that, not surprisingly, sulfon-
amido N,O-acetals proved to be the most useful acetal sub-
strates.40
(36) (a) Barrett, A. G. M.; Dhanak, D.; Lebold, S.; Russell, M. A. J. Org. Chem.
1991, 56, 1894. (b) Helms, G. L.; Moore, R. E.; Niemczura, W. P.;
Patterson, G. M. L.; Tomer, K. B.; Gross, M. L. J. Org. Chem. 1988, 53,
1298.
(37) A sample of compound 4h was donated to the National Cancer Institute as
a potential antiproliferative agent as part of their study to identify new
classes of anticancer drugs.
(38) (a) Mu¨nster, P.; Steglich, W. Synthesis 1987, 223. (b) Kober, R.; Steglich,
W. Liebigs Ann. Chem. 1983, 599.
(41) (a) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53, 15787. (b)
Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J. Am. Chem. Soc. 1990,
112, 3475. (c) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron
Lett. 1986, 42, 2099.
(42) (a) Kosikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983, 48, 366. (b)
Salituro, F.; Tomlinson, R. C.; Baron, B. M.; Palfreyman, M. G.; McDonald,
I. A. J. Med. Chem. 1994, 37, 334.
(39) For glycine derived N-acetals used for the chiral auxiliary-based asymmetric
synthesis of R-amino acids see: Williams, R. M.; Sinclair, P. J.; Zhai, D.;
Chen, D. J. Am. Chem. Soc. 1988, 110, 1547.
(40) Matuszczak, B. Monatsh. Chem. 1996, 127, 1291.
9
72 J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002

Synthesis of Nonnatural R-Amino Acid Derivatives
A R T I C L E S
Table 4. Ene Reactions of 11a-e with 1b Catalyzed by 3d
TMSO-9d developed. A second equivalent of enol silane 2a
was then added to the mixture, and the reaction was monitored;
no product formation was noted even after extended periods of
time. After addition of the catalyst 3d, however, resonances due
to product began to appear. Interestingly, peaks due to the
intermediate imine 1b were not observed, nor were those for
the N-trimethylsilylated product N-TMS-4 (Scheme 1). In the
reaction of N,O-acetal 9d with enol silane 2a, no silylated
product is observed by 1H NMR or TLC. This finding leads us
to suggest that adventitious water, silanol, or an LnCu•ROH
species is protonating the product immediately after alkylation.44
Not surprisingly, only 1 equiv of enol silane 2 is needed to
alkylate N,O-acetal 9a, 9b, and 9e, reactions in which O-
silylation cannot take place.
We have used this mechanistic information to optimize the
reaction further in the form of a one-pot procedure. By using 1
equiv of TMSCl, acetal 9d (which is formed in situ from ethyl
glyoxylate and TsNH2) can be silylated in the pot to form the
putative silylacetal TMSO-9d, thus obviating the need to
sacrifice an additional equivalent of enol silane in the reaction
of 9 and 2. TMSCl is added to the reaction after the acetal has
been added to the catalyst solution, and the reaction is stirred
for 15 min (eq 9). The solution is then cooled to 0 °C and
submitted to the standard reaction with enol silanes 2.
Catalytic, Enantioselective Imino Ene Reaction. In an
initial report,9 we demonstrated the first effective example of a
catalytic, enantioselective imino ene reaction (eq 10) to form
R-amino acid derivatives.45 Through this effort, optimal condi-
tions for the reaction in terms of solvent, temperature, and
reaction times were achieved. Benzotrifluoride (BTF) was found
to be the ideal solvent for all reactions; it combines solubilizing
power with an aromatic nature that seems to be beneficial to
selectivity. The olefins we investigated were subjected to the
standard reaction conditions (BTF solvent, room temperature,
5 mol % catalyst, and a 2:1 olefin:imino ester stoichiometry),
affording products in excellent yield and enantioselectivity
(Table 4, and eq 10).46
a Reactions were conducted under standard conditions in BTF or CH2Cl2
at room temperature unless otherwise noted. b Isolated yield after chroma-
tography. c Enantiomeric excesses before crystallization were determined
by CHIRALCEL OD chiral HPLC column. d Enantiomeric excesses were
determined by 1H NMR in the presence of (+)-Pr(hfc)3 chiral shift reagent.
e Reaction performed on 5 mmol scale.
was conducted on a gram scale with 1 mol % 3d, both the
selectivity and yield were maintained. Aliphatic olefins worked
well under the reaction conditions as methylenecyclohexane 11b
led to product 12b in 85% yield and 95% ee (entry 2).
Heteroatom-containing ene substrates are also compatible with
our reaction conditions, demonstrating that the catalyst is tolerant
of various functional groups and moderately Lewis basic sites
on the alkene. For example, tryptophan derivatives can be
synthesized by the alkylation of 1b with 11c forming 12c in
90% yield and 85% ee (entry 3). This reaction is important
because no general synthetic method for the construction of
tryptophan analogues in optically active form through catalytic
methodology exists.47 Rich et al. have used this process to
synthesize a substituted tryptophan intermediate in high yield
(44) For acid-catalyzed siloxane formation, see: Grubb, W. T. J. Am. Chem.
Soc. 1954, 76, 3408.
(45) Subsequent to our report, Jørgensen published an imino ene reaction using
catalyst 3d: Yao, S.; Fang, X.; Jørgensen, K. A. J. Chem. Soc., Chem.
Commun. 1998, 2547.
(46) Conversion of 12a into compound 5a established the sense of induction as
(S). Stereoregularity was inferred for products 12b-j.
Our test olefinic substrate R-methylstyrene 11a was subjected
to the reaction conditions (BTF, room temperature, 12 h) to
afford the protected amino acid 12a in 95% yield and 99% ee
using 5 mol % catalyst (Table 4, entry 1). When the reaction
(43) (a) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. Chem. Pharm.
Bull. 1992, 40, 12. (b) Onaka, M.; Ohno, R.; Izumi, Y. Tetrahedron Lett.
1989, 30, 747.
9
J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 73

A R T I C L E S
Ferraris et al.
and ee toward the total synthesis of complestatin.48 The oxygen-
containing ene49 11d provided the protected fufurylalanine 12d
in 92% yield and 90% ee (entry 4). Other substrates with
aromatic rings, such as 11e, work well (entry 5). Additonally,
the more nucleophilic enol sulfide 11f is a superior substrate
(entry 6). It is noteworthy that most of the products (12a-g)
can be obtained in analytically pure form without chromatog-
raphy by straightforward crystallization of the organic concen-
trate (EtOAc/hexanes) after aqueous workup.
Figure 3. Proposed closed transition state model for the diastereoselective
imino ene reaction.
Development of a Syn-Selective Ene Reaction. One of our
goals was to devise a syn-selective, â-alkyl-R-amino acid
synthesis as a prelude to the total synthesis of the nikkomycin
class of antifungals. For example, on the basis of kinetic isotope
effect studies, we believe that the reaction proceeds through a
classical, closed six-membered transition state for relatively
nonpolar olefins such as R-methylstyrene. Proposed transition
state models are illustrated in Figure 3. Weinreb et al. have
postulated that endo transition states for imino ene reactions
are energetically more favorable than are the exo due to the
complementary charge attraction of the nitrogen lone pair and
the positive charge that develops on the central carbon in the
ene during the course of a concerted, but nevertheless asyn-
chronous, transition state.50a However, in our system, the steric
interaction between the large tetrahedral metal ligand complex
and the ene nucleophile means that the reaction is less likely to
go through an endo transition state (Figure 3). For this reason,
the more plausible transition states for the catalyzed imino ene
reaction are exo. Consequently, syn diastereoselectivity should
result from the exo-E transition state and an appropriately
substituted E-olefin (Figure 3).
class of natural products,51 as well as (-)-perhydrohistrionico-
toxin.52 We first subjected substrate 11g (entry 7, Table 4) to
standard conditions at room temperature in BTF solvent over
the course of 3 days. The major product of this reaction is indeed
12g (77% yield and 94% ee for the syn isomer; crude anti/syn
1/6), albeit formed sluggishly in moderate diastereoselectivity.
Upon ozonolysis syn-12g would be a precursor to the amino
acid segment of nikkomycin B.
Recently Gagne´ et al. reported that the addition of excess
p-trifluoromethylphenol to glyoxylate ene reactions provides a
notable rate enhancement.53 Gagne´ postulated that the acidic
phenol promotes counterion dissociation through hydrogen
bonding. Following this lead, we tried p-trifluoromethylphenol
in the ene reaction of trisubstituted alkene 11g with imino ester
1b and found that the rate of reaction increases by a sub-
stantial amount (eq 11). This allowed us to conduct the reaction
at 0 °C in BTF over the course of 10 h, although unfortunately
the diastereoselectivity is eroded somewhat (anti/syn 1/3),
although the ee (94%) is maintained. We believe, though, that
this rate acceleration will prove to be general for a variety of
substrates.
The diastereoselective version of the prototype imino ene
reaction is well precedented50 and has been elegantly applied
in the total synthesis of members of the methanomorphanthridine
(47) To date the syntheses of optically active tryptophan derivatives have
centered on transfer of chirality: (a) Tabushi, I.; Kuroda, Y.; Yamada, M.;
Higashimura, H. J. Am. Chem. Soc. 1985, 107, 5545. Enzymatic resolu-
tion: (b) Gebler, J.; Woodside, A. B.; Poulter, C. D. J. Am. Chem. Soc.
1992, 114, 7354. (c) Gerig, J. T.; Klinkenborg, J. C. J. Am. Chem. Soc.
1980, 102, 4267. Preparatory chiral HPLC separations: (d) Sakagami, Y.;
Manabe, K.; Aitani, T.; Thiruvikraman, S. V.; Marumo, S. Tetrahedron
Lett. 1993, 34, 1057.
(48) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443.
(49) Miles, W. H.; Berreth, C. L.; Smiley, P. M. Tetrahedron Lett. 1993, 34,
5221.
(50) (a) Weinreb, S. M.; Smith, D. T.; Jin, J. Synthesis 1998, 61, 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, 5058. (g) Tschaen, D. M.; Weinreb, S. M.
Tetrahedron Lett. 1982, 23, 3015.
(51) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5774.
(52) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907.
(53) Koh, J. H.; Larsen, A. O.; Gagne´, M. R. Org. Lett. 2001, 3, 1233.
(54) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry, 2nd ed.;
VCH: Weinheim, 1988; pp 164-165.
Kinetics of the Catalyzed Imino Ene Reaction. One
advantage to slow reactions is that they can be very amenable
to kinetic studies. Along those lines, we sought to study the
9
74 J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002

Synthesis of Nonnatural R-Amino Acid Derivatives
A R T I C L E S
Figure 4. Pseudo first-order behavior of catalytic imino ene reaction.
Figure 5. Effect of catalyst loading on rate of imino ene reaction.
mechanism of the imino ene reaction (which proceeds smoothly
at 0 °C over the course of hours) in greater detail. Prototype
ene reactions have been proposed to proceed through a
concerted, nonpolar transition state.54 During the course of our
studies, we noted a general insensitivity to solvent polarity in
the rate of reaction of 1b with 11a, consistent with a concerted
reaction pathway. However, the possibility of a stepwise reaction
does exist, particularly when an aryl group is available to
stabilize a transient carbocation. To shed light on this mecha-
nistic question, we investigated the reaction through kinetic
isotope effect (KIE) studies. A 1:1 mixture of alkenes 11a and
11a-d3 was subjected to our standard reaction conditions in both
BTF and THF solvents in the presence of 1b and 5 mol % 3d
(eq 12). Analysis of the reaction mixture at 5% conversion
indicated a KIE kH/kD3 of 4.4 in THF and BTF.55 The observed
KIE is a superposition of normal primary and R-secondary
KIE’s, and as a consequence, the primary KIE should account
for ∼80% of the observed value.56 The result is nevertheless
consistent with a large degree of rate-determining transfer of
H(D) in the transition state, in line with a concerted mechanism
(structure 13). If the reaction were to proceed stepwise through
the cationic intermediate 14, an observed â-secondary KIE in
the neighborhood of 1.9 (or lower) would be expected. Whether
the reaction would be concerted for more polar alkenes is
questionable.
These KIE studies established that the alkene plays a role in
the rate-determining step of the imino ene reaction. We also
found that by doubling the concentration of alkene, the rate of
reaction was doubled. Similarly, a 4-fold increase in alkene
concentration brought about a 4-fold rate increase. These results
prompted us to examine, in more detail, the kinetic order of
the catalyst and other reagents in the rate equation. The rate of
the imino ene reaction between 1b and 11a is documented to
be moderate at room-temperature, making it optimal to study
for kinetic experiments.10 Solutions of R-methylstyrene 11a
(psuedo first-order, 5 M) and imine 1b (0.2 M) were subjected
to 2.5 mol % 3d at 0 °C in CH2Cl2. Aliquots of the reaction
mixture were assayed over a 5 h period to determine the rate of
product formation with respect to an internal standard of
biphenyl. This rate correlated well with the rate of consumption
of imine 1b. Under these conditions, the reaction followed first-
order kinetics as indicated by a log plot (Figure 4).
us to propose a rate equation for the reaction (eq 13). The
observed rate constant k′ was determined to be 6.8 × 10-3 min-1
as derived from eq 13. Factoring out the concentrations of
R-methylstyrene 11a and catalyst 3e, the rate constant k was
found to be 3.4 × 10-2 min-1 M-2
-d[1b] d[12a]
.
rate )
)
) k′[1b] ) k[11a][3d][1b] (13)
dt
dt
In each of the log plots, one can discern a very slight
downward curvature that may be indicative of product inhibition.
As noted previously, the imine 1b could be an effective bidentate
ligand for the catalyst 3d. The product 12a, however, could
also serve as a modest inhibitor of the catalyst 3d at higher
concentrations through a similar chelate structure. To determine
the effect of product inhibition on the imino ene reaction, three
experiments were performed simultaneously.57 In all three
reactions, concentrations of R-methylstyrene 11a (0.2 M) and
imine 1b (0.2 M) were kept constant. In the second reaction, a
0.1 M solution of product (S)-12a was added to the imine/styrene
mixture. Likewise, a 0.1 M solution of product (R)-12a was
added to the third reaction. All three reactions were initiated at
0 °C by addition of catalyst 3d. The reaction rates were
measured over a 2 h period by GC analysis of the reaction
mixture, using a constant amount of biphenyl as an internal
standard. For the second and third reaction, an approximate 50%
reduction in rate was observed, presumably due to the nonpro-
ductive, nonenantioselective binding of the catalyst to the
product.
To determine the effect of catalyst loading on this reaction,
the concentrations of imine 1b and R-methylstyrene 11a in
CH2Cl2 were kept constant (0.2 M), and depletion of imine 1b
was measured over a 5 h period varying only the concentration
of catalyst 3d. Once again, at low conversion, the reactions
followed pseudo first-order kinetics. A rate enhancement was
observed as the concentration of catalyst increased, as shown
in Figure 5. Doubling the concentration of the catalyst from
2.5 to 5 mol % doubled the rate of reaction at 0 °C, and
subsequent doubling of the catalyst concentration to 10 mol %
led to a further 2-fold increase in rate, indicating that the reaction
is first-order in catalyst. Consequently, the kinetic data allow
(55) The kH/kD was determined by mass spectral analysis of the products resulting
from the competition reaction carried out on a 1: 1 mixture of 11a and
11a-d3. This observed primary kinetic isotope effect is in line with previous
observations on prototype ene systems, see: (a) Achmatowicz, O., Jr.;
Szymoniak, J. J. Org. Chem. 1980, 45, 4. (b) Kwart, H.; Brechbiel, M. W.
J. Org. Chem. 1982, 47, 3355. (c) Dai, S.-H.; Dolbier, W. R., Jr. J. Am.
Chem. Soc. 1972, 94, 3953.
Catalytic, Enantioselective Allylations of r-Imino Esters.
Complementary to our work with enol silane and alkene
(56) Carpenter, B. K. Determination of Organic Reaction Mechanisms; Wiley:
New York, 1984; pp 83-111.
(57) (a) Laidler, K. J. Chemical Kinetics; Harper and Row: New York, 1987.
(b) Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083.
9
J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 75

A R T I C L E S
Ferraris et al.
Table 5. Allylation Reactions of 1b with 17a-h Catalyzed by 3d
nucleophiles, we have also developed a catalytic, enantio- and
diastereoselective procedure for the addition of allylsilanes
17a-h to R-imino ester 1b catalyzed by complex 3d, demon-
strating the utility of this reaction as an alternative means to
homoallylic R-amino acid derivatives 12 (eq 14).58 Jørgensen
et al. have also reported an allylation method using catalyst 3d
affording products in moderate to good ee’s.11d Generally
speaking, allylsilanes are intermediate in nucleophilicity between
simple alkenes and enol silanes. They are often postulated to
react through open, or Mukaiyama-type, transition states such
as enol silanes. Consequently, anti-diastereoselectivity could
analogously be expected in their catalyzed reactions with
R-imino ester 1b.
Using our previous work as a model, we subjected R-imino
ester 1b to allyltrimethylsilane 17a (R2, R3 ) H, R1 ) H)
catalyzed by 5 mol % (R)-Tol-BINAP•CuClO4•(CH3CN)2 (3d)
in CH2Cl2 at -78 °C. The reaction proceeded smoothly,
affording the expected allylated product 12h in good yield (87%)
with modest enantioselectivity (64%, Table 5, entry 1). In an
effort to improve the selectivity, we screened a number of
solvents including THF and BTF, obtaining product 12h in 56%
ee and 57% ee, respectively, and in comparable yield. A minimal
solvent effect on selectivity seems to operate in this process,
affording us little room for optimization. This led us to explore
how the nature of the silane affected the reaction. The slightly
more reactive triethylallylsilane 17b gave 12h in 88% yield and
72% ee, whereas the bulkier tri-n-butylsilane of 17c (R1, R2,
R3 ) H, R ) n-Bu) afforded 12h in 89% yield and 51% ee in
CH2Cl2. Clearly, a delicate balance exists between the size of
the silane substituents and the selectivity of the reaction.
The “Aromatic” Effect. In an attempt to improve selectivity
in the allylation reaction, we found that aromatic substituents
on the allyl group could dramatically improve the enantio-
selectivity of the reaction (Table 5). For example, phenyl-
substituted allylsilane 17d provided 12a in 91% yield and 94%
ee using catalyst 3d (entry 4). As a general trend in several
classes of reactions, we have found that placement of aromatic
substituents on the reacting nucleophiles increases the enantio-
selectivity significantly. As to whether this indicates the presence
of possible beneficial π-stacking interactions with the catalyst,
we can only speculate. To emphasize the practicality of these
allylations, silane 17d also alkylated hydrolytically stable acetal
9e in 90% ee and 85% yield under these conditions (entry 5).
Allylsilane 17e led to product 12i in 85% yield and 75% ee
(entry 6). Compound 12i is a precursor to styrylalanine, a
nonnatural amino acid with great importance in the pharma-
ceutical industry.59 Interestingly, the presence of an aryl group
on the allylsilane improves the enantioselectivity in an analogous
a Reactions run at -78 °C in CH2Cl2. b Enantiomeric excess was
determined by CHIRALCEL OD chiral HPLC column. c dr represents the
(anti/syn) ratio. d Reaction run with acetal 9e rather than imine 1b.
manner to the enol silane as illustrated by the naphthyl allylsilane
17f that afforded product 12j in 93% ee (entry 7). Next, we
explored the diastereoselectivity of the imino allylations. Using
17g as a control, we determined the effect of alkene geometry
on the diastereoselectivity of product formation. The Z-
allylsilane 17g was readily available from Ni-catalyzed cross
coupling of (trimethylsilylmethyl)magnesium chloride with the
corresponding enolsilane 2g.60 Allylation of 1b by 17g under
the standard reaction conditions afforded 12k in excellent
enantio- and anti-diastereoselectivity, presumably through an
open transition state (entry 8).61 Next, the tetralone derivative
17h was prepared to establish how the alternate E-allylsilane
geometry would effect the outcome of the reaction. Product 12l
was isolated in 88% yield, possessing excellent de (10:1 anti:
syn) and ee (anti 12l ) 87%, entry 9).
Summary
We have developed a broadly based methodology for the
practical synthesis of nonnatural R-amino acids by catalytic
enantioselective alkylation of R-imino esters and acetals with
enol silanes, allylsilanes, and olefins. The most effective
catalysts for these alkylations are derived from chiral Cu(I)-
phosphine complexes. Using these catalysts, imino alkylations
lead to direct precursors of natural products and pharmaceuticals
with high enantioselectivities (up to 99% ee) and anti-dia-
(58) (a) Chen, G.-M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825. (b) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J.
Am. Chem. Soc. 1998, 120, 4242. (c) Nakamura, K.; Nakamura, H.;
Yamamoto, Y. J. Org. Chem. 1998, 64, 2614. (d) Yanagisawa, A.;
Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
4723.
(59) Burk, M. J.; Bedingfield, K. M.; Kiesman, W. F. Tetrahedron Lett. 1999,
40, 3093.
(60) Hayashi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980, 21, 3915.
(61) The absolute stereochemistry of the products 12i was determined by a simple
oxidative cleavage of the alkene as reported in Viski, P.; Szevere´nyi, Z.;
Sima´ndi, L. J. Org. Chem. 1986, 51, 3213.
9
76 J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002

Synthesis of Nonnatural R-Amino Acid Derivatives
A R T I C L E S
Representative Alkylation Procedure of Acetals 9. The catalyst
3d was made by dissolving (R)-Tol-BINAP (15 mg, 0.022 mmol) and
CuClO4•(CH3CN)2 (7 mg, 0.021 mmol) in CH2Cl2 (1 mL). To the tosyl
acetal 1b (100 mg, 0.37 mmol) in CH2Cl2 (2 mL) was added the solution
of catalyst 3d. This reaction mixture was cooled to 0 °C, and the enol
silane 2a (142 mg, 0.74 mmol) was added to the reaction mixture over
a period of 30 min. The reaction was stirred at room temperature or
heated to reflux until completion as shown by TLC (30% EtOAc/
hexanes). The reaction was partitioned with water (3 mL) and CH2Cl2
(3 mL). The organic layer was dried with MgSO4, and the solvent was
removed in vacuo. The crude residue (200 mg) was subject to column
chromatography on silica gel to yield 128 mg of the final product (93%
yield, 95% ee).
stereoselectivities (up to 25:1/anti:syn). The kinetic data for the
imino ene reaction, including isotope effects and rate studies,
provide detailed evidence for the presence of a concerted, closed
transition state and classical Lewis acidic activation of the imino
ester substrate.
Experimental Section
General Alkylation Procedure using Ag(I) and Cu(I) Complexes.
The metal BINAP complexes were formed by dissolving (R)-BINAP
(25 mg, 0.04 mmol) or (R)-Tol-BINAP (with Cu(I) or Ag(I)) perchlorate
or hexafluoroantimonate (0.035 mmol) in THF (1-2 mL) and were
stirred at room temperature under nitrogen for 30 min. The R-imino
ester 1b (100 mg, 0.40 mmol) was then added to the metal complex
solution. The mixture was then cooled to -78 °C using a MeOH
cryogenic bath (FTS Systems). A solution of the enol silane 2a (83
mg, 0.43 mmol) in THF (0.5 mL) was added to the reaction mixture
dropwise over 2 h. The reaction was stirred overnight at -78 °C to
ensure complete reaction and was then quenched dropwise with MeOH
(5 mL). Upon warming the quenched reaction to room temperature, it
was diluted with water (10 mL) and extracted with CH2Cl2 (2 × 10
mL). The combined organic layers were washed with saturated NaHCO3
(5 mL) and brine (5 mL). The organic layer was dried over Na2SO4,
filtered, and the solvent was removed under reduced pressure. The crude
residue (175 mg) was subject to column chromatography (20% EtOAc/
hexanes) on a small silica gel plug yielding 138 mg of 4a (95% yield).
Recrystallization from ether/hexane afforded the product in >99% ee.
General Alkylation Procedure for Pd(II) Complexes. The metal
ligand complex was made by mixing (R)-BINAP•PdCl2 (Aldrich, 31
mg, 0.04 mmol) and AgClO4 (15 mg, 0.076 mmol) in acetonitrile. The
fluffy white precipitate (AgCl) was filtered off, and the resulting
acetonitrile solution was concentrated in vacuo leaving the (R)-
BINAP•Pd(ClO4)2 as a yellow crystalline solid. The solid was dissolved
in CH2Cl2 and used in an analogous manner to the aforementioned
procedure.
Representative Ene Alkylation Procedure. The Cu(I) phosphine
complexes were formed by dissolving (R)-Tol-BINAP (20.4 mg, 0.030
mmol) with CuClO4•(CH3CN)4 (8.2 mg, 0.025 mmol) in benzotrifluo-
ride (1 mL) or CH2Cl2 and by stirring at room temperature for 30 min
to give a pale yellow solution. The R-imino ester 1b (128 mg, 0.50
mmol) was added to the metal complex solution. The mixture was
placed under nitrogen at room temperature, and a solution of the olefin
11a (R ) Me, R′ ) Ph) (118 mg, 1.00 mmol) in BTF (0.5 mL) was
added to the reaction mixture. The reaction was allowed to stir for 18
h at room temperature to ensure completion. The reaction was quenched
with water (5 mL) and extracted with CH2Cl2 (2 × 5 mL). The
combined organic layers were dried over MgSO4, and the solvent was
removed under reduced pressure. The crude residue was subjected to
column chomatography (5-20% EtOAc/hexanes) on a small silica gel
plug (2.5 × 3 cm) yielding 176.5 mg of 12a (95% yield).
Representative Allylation Procedure. The Cu(I) phosphine com-
plexes were formed by dissolving (R)-Tol-BINAP (15 mg, 0.022 mmol)
with CuClO4•(CH3CN)4 (7 mg, 0.021 mmol) in CH2Cl2 (1 mL) with
stirring at room temperature for 30 min to give a pale yellow solution.
The R-imino ester 1b (128 mg, 0.50 mmol) was added to the metal
complex solution. The mixture was removed from the glovebox and
placed under nitrogen and cooled to -78 °C. A solution of the
allylsilane 17d (95 mg, 0.5 mmol) in CH2Cl2 (0.5 mL) was added to
the reaction mixture dropwise over 1 h. The reaction was stirred for
12 h and allowed to gradually warm to room temperature. The reaction
was quenched with water (5 mL) and extracted with CH2Cl2 (2 × 5
mL). The combined organic layers were dried over MgSO4, and the
solvent was removed under reduced pressure. The crude residue was
subjected to column chromatography (5-20% EtOAc/hexanes) on a
small silica gel plug (2.5 × 3 cm) yielding 170 mg of 12a (94% ee,
91% yield).
Representative Alkylation of 1b with Cu(ClO4)2 and (S)-BINAP.
A solution of (S)-BINAP (25 mg, 0.04 mmol) and Cu(ClO4)2 (10 mg,
0.04 mmol) in THF (1 mL) was stirred for 30 min in a drybox. The
greenish color of the solution eventually faded, and the mixture turned
pale yellow. This catalyst was added to a solution of imino ester 1b
(100 mg, 0.40 mmol) in THF (1 mL). The mixture was cooled to 0 °C,
and a solution of 2a (R′ ) H) (84 mg, 0.44 mmol) in 0.5 mL of THF
was added to the catalyst/imine solution over a 1 h period. After 12 h
of stirring, the mixture was quenched with MeOH and washed with
H2O/CH2Cl2 (10 mL). The organic layer was partitioned, and the
aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined
organics were dried, concentrated, and purified by flash chromatography
to yield 85% of the product amino ester in 85% ee.
Acknowledgment. The authors thank Professors Kenneth
Karlin for a supply of the Cu(ClO4)•(MeCN)4 complex and John
Toscano for use of his FTIR spectrometer. For financial support
T.L. thanks the NSF Career Program, Eli Lilly, DuPont, the
Dreyfus Foundation, and the Sloan Foundation. C.C. and A.T.
thank the Organic Division of the American Chemical Society
for Graduate Fellowships sponsored by Organic Reactions, Inc.
(1997-1998 and 2001-2002, respectively). The authors thank
Dr. Victor G. Young, Jr., director of the X-ray Crystallographic
Laboratory at the University of Minnesota, for obtaining the
crystal structures of 4h and 3c.
Representative Diastereoselective Alkylation Procedure. The
Cu(I) phosphine complexes were formed by dissolving (R) or (S)-
BINAP (13 mg, 0.02 mmol) or (R) or (S)-Tol-BINAP with CuClO4•
(CH3CN)4 (6.2 mg, 0.019 mmol) in THF or CH2Cl2 (1 mL) and by
stirring at room temperature for 30 min. Then 100 mg (0.40 mmol) of
1b was added to the metal complex solution. The mixture was placed
under nitrogen at 0 °C, and a solution of the enol silane 2g (90 mg,
0.44 mmol) in CH2Cl2 (0.5 mL) was added to the reaction mixture
dropwise over 1 h. The reaction was gradually warmed to room
temerature overnight to ensure complete reaction and was then quenched
dropwise with MeOH (2 mL). Upon warming the quenched reaction
to room temperature, it was diluted with water (5 mL) and extracted
with CH2Cl2 (2 × 5 mL). The combined organic layers were washed
with brine (5 mL) and aqueous 10% KF (5 mL). The organic layer
was dried over Na2SO4, and the solvent was removed under reduced
pressure. The crude residue (200 mg) was subject to column chroma-
tography (20% EtOAc/hexanes) on a small silica gel plug yielding 135
mg of 4g (86% yield).
Supporting Information Available: Experimental details and
characterization data for 1a, 4a-j, 5e, 7, 9d-g, 10c, 10e, 12a-
e, 12h-l, 17d, 17e. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA016838J
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J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 77