Efficient Catalytic Enantioselective Reaction of a Glycine Cation Equivalent with Malonate Anions via Palladium Catalysis

Article abstract of DOI:10.1021/jo961869w

The enantioselective alkylation of Schiff base acetates 1 with malonate types of stabilized carbon nucleophiles in the presence of a stable palladium source Pd(OAc)₂ and the chiral ligand (+)-BINAP was developed. The product 2, a protected β-carboxyaspartic acid (ASA), was obtained in up to 85percent enantiomeric excess by varying the ester protecting group on the substrate. The nature of the nucleophile has a significant effect on the enantioselectivity in this (2-aza-π-allyl)palladium system. While a rapid chemical conversion was achieved with Schiff base benzoates 5, the enantioselectivity was insensitive to the leaving group used. An optically active substrate (51percent ee) gave the same level of enantioselectivity as that obtained from the racemate. Temperature effects on the reaction were also studied; the best selectivity was obtained at 0°C. A laboratory-scale reaction of the reactive nucleophile KCH(COOCH₃)₂ with the tert-butyl ester substrate le gave, following a single recrystallization, product 2c with 95.5percent ee in an overall chemical yield of 62percent.

Full text of DOI:10.1021/jo961869w

3962
J . Org. Chem. 1997, 62, 3962-3975
Efficien t Ca ta lytic En a n tioselective Rea ction of a Glycin e Ca tion
Equ iva len t w ith Ma lon a te An ion s via P a lla d iu m Ca ta lysis
Martin J . O’Donnell,* Ning Chen, Changyou Zhou, and Angela Murray
Department of Chemistry, Indiana University-Purdue University at Indianapolis,
Indianapolis, Indiana 46202
Clifford P. Kubiak and Fan Yang
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907
George G. Stanley
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803
Received October 2, 1996 (Revised Manuscript Received March 21, 1997X)
The enantioselective alkylation of Schiff base acetates 1 with malonate types of stabilized carbon
nucleophiles in the presence of a stable palladium source Pd(OAc)2 and the chiral ligand (+)-BINAP
was developed. The product 2, a protected â-carboxyaspartic acid (ASA), was obtained in up to
85% enantiomeric excess by varying the ester protecting group on the substrate. The nature of
the nucleophile has a significant effect on the enantioselectivity in this (2-aza-π-allyl)palladium
system. While a rapid chemical conversion was achieved with Schiff base benzoates 5, the
enantioselectivity was insensitive to the leaving group used. An optically active substrate (51%
ee) gave the same level of enantioselectivity as that obtained from the racemate. Temperature
effects on the reaction were also studied; the best selectivity was obtained at 0 °C. A laboratory-
scale reaction of the reactive nucleophile KCH(COOCH3)2 with the tert-butyl ester substrate 1c
gave, following a single recrystallization, product 2c with 95.5% ee in an overall chemical yield of
62%.
In tr od u ction
ation as a mild, room-temperature reaction procedure.9
Catalytic, enantioselective PTC reactions with these
Schiff base substrates have been developed.10,11 To date,
enantioselectivities up to 85% ee have been obtained for
monoalkylation and 75% ee for dialkylation PTC chem-
istry. The principles developed in the PTC reactions of
activated anions and substrates have been extended to
the selective alkylation of peptide substrates.12 More
recently, the alkylation of resin-bound amino acid and
peptide substrates, termed “unnatural peptide synthesis
(UPS)”, which provides for the attachment of unnatural
side chains during normal solid-phase peptide synthesis
(SPPS), has been achieved.13
The palladium-catalyzed allylic substitution reaction
has been the subject of numerous recent studies.1 It is
a versatile process because of the range of substrates2
and nucleophiles3 used. Also, it is possible to obtain
excellent chemo-, regio-, and stereocontrol in this reac-
tion. Recently, with the development of a wide variety
of chiral ligands,4 attention has shifted to the modifica-
tion of the chiral catalyst to achieve high enantioselec-
tivity. The vast majority of allylic systems studied have
involved the all-carbon allylic substrates;5 the synthetic
utilization of heteroatom-substituted π-allyl systems is
much rarer.6-8
Our program for the synthesis of R-amino acids from
Schiff base-protected glycine and higher amino acid
derivatives has focused on use of the complementary
anionic and cationic equivalents for preparation of struc-
turally diversified amino acid products (Scheme 1).
Initial studies in the anionic series involved racemic bond
construction using phase-transfer catalytic (PTC) alkyl-
The complementary cationic equivalents of glycine,
readily available from the parent Schiff base esters, can
(2) For the scope of substrates and leaving groups used, see: (a)
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X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) For recent reviews on palladium-catalyzed allylic substitution
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S0022-3263(96)01869-5 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3963
be reacted with various nucleophilic reagents to prepare
racemic products.14 Thus, neutral heteroatom nucleo-
philes, carbanions, organoboranes, and neutral carbon
nucleophiles all react to replace the acetate with the
appropriate group regioselectively at the R-carbon.
Of particular interest is the 1990 report of the pal-
ladium-catalyzed coupling of malonate anions with Schiff
base acetates15-17 to form racemic â-carboxyaspartic acid
(ASA)18 derivatives. This reaction can be formally rep-
resented as involving reaction of a cationic (2-aza-π-allyl)-
palladium intermediate with nucleophiles (Scheme 2).
By utilizing the rich chemistry developed in the pal-
ladium-catalyzed allylic substitutions, particularly with
respect to the choice of chiral ligands and optimized
reaction conditions, we were interested in coupling our
substrate 119 with malonate-type stabilized carbon nu-
cleophiles in the presence of a palladium catalyst and
chiral phosphine ligands. Suitable deprotection of the
products 2 provides a convenient route to optically active
â-carboxyaspartic acid (ASA) derivatives 3 (Scheme 3).
The starting substrates in these reactions, Schiff base
acetates 1, are readily prepared15c,20 and undergo the
racemic variant of this reaction (Scheme 3, Ar ) Ph, R1
) CH3 or CH2Ph) with malonate types of stabilized
(“soft”) carbon nucleophiles (R2 ) H, R3 ) CH3 or CH2Ph)
in the presence of the achiral catalyst (Ph3P)4Pd.15a The
in situ generation of an active catalyst using a stable
palladium source (Pd(OAc)2) and various bidentate bis-
phosphine ligands was developed to bypass catalyst
preparation and isolation.15b The effect of tether length
between the two phosphines on the rate and yield of the
reaction is dramatic. Earlier studies demonstrated that
at least four methylene groups are needed to give both
rapid reaction and high conversion. A number of com-
mercially available chiral phosphine ligands, such as (-)-
O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-
butane (DIOP),21 (-)-(R)-N,N-dimethyl-1-[(S)-1′,2-
bis(diphenylphosphino)ferrocenyl]ethylamine (BPPF),22
(2S,4S)-1-(tert-butoxycarbonyl)-4-(diphenylphosphino)-2-
[(diphenylphosphino)methyl]pyrrolidine (BPPM),23 and
(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BI-
NAP)24 were surveyed in the model reaction (Ar ) Ph,
R1 ) CH3, R2 ) H, R3 ) CH3). Although DIOP and BPPF
resulted in good chemical conversion, the product was
racemic. In contrast, BPPM and BINAP gave low levels
of enantioselectivity (8% ee and 27% ee, respectively).15b
This study represented the first successful enantioselec-
tive synthesis of Schiff base glycine derivatives 2 via the
cationic glycine equivalents. The level of enantioselec-
tivity was increased to 37% with the BPPM ligand by
using the tert-butyl ester of the substrate (1c, Ar ) Ph,
R1 ) tBu).15c The optical purity of the product could be
increased further (to 77% ee) by a single recrystallization.
Additionally, this product (2c) could be subjected to PTC
alkylation to produce â-substituted ASA derivatives
without epimerization of the R-center.
In this paper, we report further detailed studies using
BINAP as the chiral ligand. A systematic study of the
various reaction parameters has allowed development of
a highly efficient catalytic enantioselective reaction
protocol.
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3964 J . Org. Chem., Vol. 62, No. 12, 1997
O’Donnell et al.
Resu lts a n d Discu ssion
ee). The enantioselectivity increased from 27% ee with
the methyl ester to 69% ee with the isopropyl ester.
Increasing the size of the ester group to tert-butyl led to
an 85% ee.27 However, the more sterically demanding
Su b st r a t e St r u ct u r a l Mod ifica t ion : Th e E st er .
Although the best enantioselectivity was obtained using
BINAP in the above model reactions (Schiff base methyl
ester acetate, sodium dimethyl malonate, Pd(OAc)2, and
(+)-BINAP), this ligand gave extremely slow chemical
conversion as well as low yield under the normal catalytic
conditions employed (5% Pd(OAc)2, 10% bidentate phos-
phines). Optimization of the reaction using a stronger
nucleophile (sodium dimethyl methylmalonate)25 illus-
trated that 10% catalyst (1:2 molar ratio of Pd/P) was
needed to ensure both rapid reaction and high conversion
of the starting material. These optimized conditions were
employed in the following studies.
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The effect of the nature of the ester protecting group
on the enantioselectivity of the reaction was explored by
introducing larger ester groups R (Table 1).20,26 It was
observed that the size of the ester group has a significant
impact on the enantioselectivity of the reaction (27-85%
(5) For recent mechanistic, structural, and computational studies
involving the all-carbon π-allylpalladium systems, see: (a) Pregosin,
P. S.; Ru¨egger, H.; Salzmann, R.; Albinati, A.; Lianza, F.; Kunz, R. W.
Organometallics 1994, 13, 83. (b) Pregosin, P. S.; Salzmann, R. Magn.
Reson. Chem. 1994, 32, 128. (c) Pregosin, P. S.; Ru¨egger, H. Magn.
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1523. (f) Breutel, C.; Pregosin, P. S.; Salzmann, R.; Togni, A. J . Am.
Chem. Soc. 1994, 116, 4067. (g) Pregosin, P. S.; Ru¨egger, H.; Salzmann,
R.; Albinati, A.; Lianza, F.; Kunz, R. W. Organometallics 1994, 13,
5040. (h) von Matt, P.; Lloyd-J ones, G. C.; Minidis, A. B. E.; Pfaltz,
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S. Helv. Chim. Acta 1995, 78, 265. (i) Martin, J . T.; Oslob, J . D.;
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metallics 1995, 14, 1688. (l) Amatore, C.; Carre´, E.; J utand, A.; M’Barki,
M. A. Organometallics 1995, 14, 1818. (m) Malet, R.; Moreno-Man˜as,
M.; Parella, T.; Pleixats, R. Organometallics 1995, 14, 2463. (n)
Castan˜o, A. M.; Aranyos, A.; Szabo´, K. J .; Ba¨ckvall, J .-E. Angew. Chem.,
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metallics 1995, 14, 5160. (q) Trost, B. M.; Bunt, R. C. J . Am. Chem.
Soc. 1996, 118, 235. (r) Yamaguchi, M.; Yabuki, M.; Yamagishi, T.;
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1996, 15, 3022. (ab) Burckhardt, U.; Gramlich, V.; Hofmann, P.;
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A.; Shullenberger, D. F.; Wu, S. Amino Acid and Peptide Synthesis
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1989, 111, 2353. (b) O’Donnell, M. J .; Wu, S. Tetrahedron: Asymmetry
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1994, 50, 4507.
(12) O’Donnell, M. J .; Burkholder, T. P.; Khau, V. V.; Roeske, R.
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(16) For the synthesis of â,γ-unsaturated amino acid derivatives by
alkyne carbometalation-palladium-catalyzed coupling, see: O’Donnell,
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(17) For the use of various benzophenone Schiff base derivatives as
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C.; Vo¨lkl, C.; Rogers, R. D. J . Organomet. Chem. 1993, 463, 135.

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3965
Sch em e 1. Sch iff Ba se-P r otected Der iva tives in Am in o Acid Syn th esis
group 1,1-diethylpropyl produced a slightly lower enan-
tioselectivity (78% ee).
The above results demonstrate that the optimal sub-
strate in our system requires a relatively bulky ester
group.
while an electron-withdrawing group (-CF3) accelerated
the reaction substantially and also led to an excellent
chemical yield (91%, 0.5 h). The enantioselectivity
obtained in these two reactions decreased by about 10%
in each case (slightly higher with -CF3 compared to
-OCH3), likely due to a steric effect. These results imply
that the level of selectivity obtained is a combination of
both steric and electronic effects.
Because of the strong electron-withdrawing effect and
the minimal steric effect of fluorine, two fluorine-
substituted benzophenone Schiff base acetates 1h ,i were
synthesized next, using the recently published procedure
Su b st r a t e St r u ct u r a l Mod ifica t ion : Th e Im in e.
Following the success of the above reactions, modification
of the imine protecting group was investigated. The
initial consideration was introduction of a bulky group
on the phenyl rings to examine the steric effect on
selectivity at the imine. Therefore, the bis(3,5-dimethyl)-
benzophenone imine tert-butyl ester acetate 1e was
synthesized.28 Disappointingly, a lower enantioselectiv-
ity was obtained (58% ee), as well as a low chemical yield
(38%) and a slow reaction (35 h) (Table 2, entry 2).
The electronic effect of the substituents on the Schiff
base was studied next (Table 2, entries 3 and 4). Results
show that an electron-donating group (-OCH3) decreased
both the yield and the rate of the reaction (47%, 23 h),
(24) For lead references and reviews concerning the synthesis and
application of BINAP and its derivatives, see: (a) Miyashita, A.;
Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J .
Am. Chem. Soc. 1980, 102, 7932. (b) Miyashita, A.; Takaya, H.; Souchi,
T.; Noyori, R. Tetrahedron 1984, 40, 1245. (c) Takaya, H.; Mashima,
K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa,
S.; Noyori, R. J . Org. Chem. 1986, 51, 629. (d) Takaya, H.; Akutagawa,
S.; Noyori, R. Org. Synth. 1988, 67, 20. (e) Noyori, R.; Takaya, H. Acc.
Chem. Res. 1990, 23, 345. (f) Mashima, K.; Matsumura, Y.-I; Kusano,
K.-H; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa,
S.; Takaya, H. Chem. Commun. 1991, 609. (g) Noyori, R. Chemtech
1992, 360. (h) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P.
Synthesis 1992, 503. (i) Knierzinger, A.; Scho¨nholzer, P. Helv. Chim.
Acta 1992, 75, 1211. (j) Uozumi, Y. Tanahashi, A., Lee, S.-Y.; Hayashi,
T. J . Org. Chem. 1993, 58, 1945. (k) Noyori, R. Stereocontrolled Organic
Synthesis; Trost, B. M., Ed.; Blackwell Scientific Publications: Oxford,
1994; p 1. (l) Noyori, R. Tetrahedron 1994, 50, 4259. (m) Akutagawa,
S. Applied Catal. A: General 1995, 128, 171. (n) Schmid, R.; Broger,
E. A.; Cereghetti, M.; Crameri, Y.; Foricher, J .; Lalonde, M.; Mu¨ller,
R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996,
68, 131. (o) Kumobayashi, H. Recl. Trav. Chim. 1996, 115, 201. (p)
Noyori, R. Acta Chem. Scand. 1996, 50, 380.
(18) For the syntheses, properties, and applications of ASA and
derivatives, see: (a) Hauschka, P.; Henson, E. B.; Gallop, P. M. Anal.
Biochem. 1980, 108, 57. (b) Henson, E. B.; Gallop, P. M.; Hauschka,
P. V. Tetrahedron 1981, 37, 2561. (c) Christy, M. R.; Barkley, R. M.;
Koch, T. H. J . Am. Chem. Soc. 1981, 103, 3935. (d) Christy, M. R.;
Koch, T. H. J . Am. Chem. Soc. 1982, 104, 1771. (e) Richey, B.; Christy,
M. R.; Haltiwanger, R. C.; Koch, T. H.; Gill, S. J . Biochemistry 1982,
21, 4819. (f) Dixon, N. E.; Sargeson, A. M. J . Am. Chem. Soc. 1982,
104, 6716. (g) Rich, D. H.; Dhaon, M. K. Tetrahedron Lett. 1983, 24,
1671. (h) Haroon, Y. Anal. Biochem. 1984, 140, 343. (i) Koch, T. H.;
Christy, M. R.; Barkley, R. M.; Sluski, R.; Bohemier, D.; Van Buskirk,
J . J .; Kirsch, W. M. Methods Enzymol. 1984, 107, 563. (j) Van Buskirk,
J . J .; Kirsch, W. M.; Kleyer, D. L.; Barkley, R. M.; Koch, T. H. Proc.
Natl. Acad. Sci. U.S.A. 1984, 81, 722. (k) Scho¨llkopf, U.; Neubaubr,
H.-J .; Haupteif, M. Angew. Chem., Int. Ed. Engl. 1985, 24, 1066. (l)
Smalley, D. M.; Preusch, P. C. Anal. Biochem. 1988, 172, 241. (m)
Williams, R. M.; Sinclair, P. J .; Zhai, W. J . Am. Chem. Soc. 1988, 110,
482. (n) Annett, R. G.; Hassamal, V. M.; Fishpool, A. M.; Kosakarn,
P.; Cassamalli, A.; Allinson, E. T. Can. J . Chem. 1990, 68, 886. (o)
Nishimoto, S. K.; Zhao, J .; Dass, C. Anal. Biochem. 1994, 216, 159.
(19) The IUPAC name of 1 is alkyl (acetyloxy)[(diarylmethylene)-
amino]acetate.
(25) O’Donnell, M. J .; Chen, N.; Zhou, C. Unpublished results.
(26) O’Donnell, M. J .; Cook, G. K. L.; Rusterholz, D. B. Synthesis
1991, 989.
(27) The configuration of product 2c (R ) tBu) was determined by
the following procedure: 213 mg of sample (0.5 mmol, 85% ee) was
treated with ether (2 mL) and 1 N HCl (2 mL) at ambient temperature
for 3 h. The acid layer was separated and washed thoroughly with
ether to remove benzophenone. Then, 12 N aqueous HCl (2 mL) was
added (overall concentration ∼6 N). The reaction mixture was heated
at 85 °C for 20 h. Solvent was evaporated, and the product was dried
under vacuum (0.5 mmHg, 65 °C for 10 h). The resulting aspartic acid
hydrochloride (87 mg, 100%) was used directly in the optical rotation
determination: [R]25D +21.0° (c ) 1, 5 N HCl, S). An authentic sample
(20) O’Donnell, M. J .; Polt, R. L. J . Org. Chem. 1982, 47, 2663.
(21) Kagan, H. B.; Dang, T.-P. J . Am. Chem. Soc. 1972, 94, 6429.
(22) (a) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.;
Nagashima, N.; Hamada, Y.; Motsumoto, A.; Kawakami, S.; Konishi,
M.; Yamamoto, K.; Kumada, M. Bull. Chem. Soc. J pn. 1980, 53, 1138.
(b) Hayashi, T.; Konishi, M.; Fukushima, M.; Mise, T.; Kagotani, M.;
Tajika, M.; Kumada, M. J . Am. Chem. Soc. 1982, 104, 180.
of (S)-aspartic acid purchased from Aldrich gave [R]25 +24.6° (c ) 1,
D
5 N HCl).
(28) Pickard, P. L.; Tolbert, T. L. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 520.
(23) Achiwa, K. J . Am. Chem. Soc. 1976, 98, 8265.

3966 J . Org. Chem., Vol. 62, No. 12, 1997
O’Donnell et al.
Sch em e 2. Rea ction of a (2-Aza -π-a llyl)p a lla d iu m
A dramatic effect of the nature of the alkali metal
counterion on the reaction rate and yield was discovered
by substitution of Na by K or Li. With the counterion
potassium,33 the reaction was completed in 1 h and the
high enantioselectivity was maintained (Table 3, entry
5). Use of a catalytic amount of 18-crown-6 in conjunction
with KOtBu further increased both the rate and the yield
of the reaction (Table 3, entry 6). On the other hand, an
extremely slow reaction was observed with lithium (Table
3, entry 7), and the % ee also decreased. The use of BSA
with a catalytic amount of KOAc17k was found to also
decrease both the rate and the % ee of the reaction (Table
3, entry 8).
The above results showed that a rapid reaction can be
obtained by using a large alkali metal cation (K+) with
the appropriate complexing agent (18-crown-6).
Su bstr a te Str u ctu r a l Mod ifica tion : Th e Lea vin g
Gr ou p . The general palladium-catalyzed allylic substi-
tution reaction has been proposed to involve several key
steps: (1) initial complexation, (2) oxidative addition and
loss of anionic leaving group (i.e., acetate), (3) isomer-
ization, and (4) alkylation.4c
Com p lex w ith Nu cleop h iles
of Selva.29 The enantioselective coupling reaction with
sodium dimethyl malonate was then carried out (Table
2, entries 5 and 6). While the better electron-withdraw-
ing m-fluoro-substituted substrate gave a faster rate, the
enantioselectivity was slightly lower than that with the
p-fluoro-substituted derivative.
From the above results, it is concluded that the steric
effect of the substituents on the Schiff base moiety is the
main factor contributing to decreased enantioselectivity.
Electron-withdrawing groups increase the rate of the
reaction considerably and lead to better yields. However,
the enantioselectivity is not influenced greatly by elec-
tronic effects. The unsubstituted benzophenone imine
still gives the best level of enantioselectivity (85% ee),
while the p-trifluoromethyl-substituted benzophenone
imine results in the fastest reaction and highest chemical
yield (0.5 h, 91%).
Because of the cost and availability of precursors
(benzophenone, benzophenone imine, and Ph2CdNCH2-
CO2tBu are all commercially available), glycine cation
equivalents derived from the benzophenone imine of
glycine tert-butyl ester are used for the majority of the
following studies.
Ba ses, Cou n ter ion s, a n d Ad d itives. Substrate 1c
was coupled with malonate anion under standard condi-
tions with different bases or additives in order to study
the selectivity dependence on the nature of the nucleo-
phile and the effect of the counterion on the rate and
chemical yield of the reaction (Table 3).
The rate doubles when the reaction is run in an
ultrasonic bath (Table 3, entry 2). Similarly, use of a
catalytic amount of 15-crown-5 (10%)30 doubles the rate
of the reaction (entry 3). No improvement in enantio-
selectivity was observed with either of these modifica-
tions. Tetraalkylammonium malonate has been re-
ported31 to exist as a dimer in solution, which presumably
increases the size and reactivity (selectivity) of the
nucleophile in certain cases.32 However, it did not have
a substantial effect on either the reactivity or the
selectivity in the present system (entry 4). These find-
ings imply that the breakup of ion pairs and aggregation
does facilitate the nucleophilic attack, but it does not
affect the structure of the transition state during the
bond-forming step, which is essential to the enantio-
differentiation.
The 2-aza-π-allyl system is one of a class of π-allyls34,35
that can react through diastereomeric π-allyl intermedi-
ates, where the chirality of the π-allyl is caused by the
different groups on the termini of the allyl system. Since
one allyl terminus has identical groups (phenyls), π-σ-π
epimerization can occur. This is synthetically significant
because it provides the opportunity for using racemic
starting material (e.g., 1 or 5) to produce chiral, non-
racemic product 2.
To determine if the stereodiscriminating step occurs
in the first two steps and to probe if the π-σ-π epimer-
ization is important in our 2-azaallyl system,34 it is
necessary to study the effect of the leaving group on the
enantioselectivity. Attempts to make the Schiff base
tosylate, mesylate, and trifluoroacetate failed because it
was not possible to isolate and use these very reactive
species. However, success was achieved in the synthesis
of the Schiff base glycine tert-butyl ester benzoates 5.
Thus, our recently developed reduction of the R-keto
Schiff base ester 436 using Super-Hydride15c followed by
quenching with the aroyl halide gave three benzoates
with different substituents at the para position (Scheme
4).
It is interesting to note that substrates 5a and 5b gave
the same enantioselectivity as that obtained from the
corresponding acetate (Table 2, entry 1: 10 h, 74%, 85%
ee). The rate of the reaction generally increased with
the benzoate compared to the acetate due to the better
leaving group ability of the former. This modification
provides the possibility of “tuning” the reactivity of these
glycine electrophiles. Substrate 5c was very unstable
and could not be isolated in pure form. It decomposed
(33) For the use of KCH(COOCH3)2 as a nucleophile in palladium-
catalyzed reaction, see: RajanBabu, T. V. J . Org. Chem. 1985, 50, 3642
and references cited therein.
(29) Selva, M.; Tundo, P.; Marques, C. A. Synth. Commun. 1995,
25, 369.
(30) Brown, J . M.; Hulmes, D. I.; Guiry, P. J . Tetrahedron 1994,
50, 4493.
(31) For the structure of tetrabutylammonium salts in solution,
see: (a) Reetz, M. T.; Hutte, S.; Goddard, R. J . Am. Chem. Soc. 1993,
115, 9339. (b) Reetz, M. T.; Hu¨tte, S.; Goddard, R.; Minet, U. Chem.
Commun. 1995, 275.
(32) For the effect of the nature of the ion-pair on rate and
enantioselectivity of the reaction, see: (a) Ellington, J . C., J r.; Arnett,
E. M. J . Am. Chem. Soc. 1988, 110, 7778. (b) Trost, B, M.; Bunt, R. C.
Tetrahedron Lett. 1993, 34, 7513. (c) Trost, B. M.; Bunt R. C. J . Am.
Chem. Soc. 1994, 116, 4089 and cited references.
(34) (a) Bosnich, B.; Mackenzie, P. B. Pure Appl. Chem. 1982, 54,
189. (b) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J . Am. Chem.
Soc. 1985, 107, 2033. (c) Mackenzie, P. B.; Whelan, J .; Bosnich, B. J .
Am. Chem. Soc. 1985, 107, 2046. (d) Farrar, D. H.; Payne, N. C. J .
Am. Chem. Soc. 1985, 107, 2054.
(35) For examples of all-carbon allyl systems involving π-σ-π
epimerization of palladium complexes, see: (a) Reference 34. (b)
Reference 4a. (c) Reference 30. (d) Dawson, G. J .; Williams, J . M. J .;
Coote, S. J . Tetrahedron Lett. 1995, 36, 461. (e) Dawson, G. J .;
Williams, J . M. J .; Coote, S. J . Tetrahedron: Asymmetry 1995, 6, 2535.
(f) Bower, J . F.; Williams, J . M. J . Synlett 1996, 685. (g) Reference 1k.
(36) O’Donnell, M. J .; Arasappan, A.; Hornback, W. J .; Huffman, J .
C. Tetrahedron Lett. 1990, 31, 157.

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3967
Sch em e 3. P r ep a r a tion of ASA Der iva tives by P d Ca ta lysis
Ta ble 1. Effects of Ester P r otectin g Gr ou p
Ta ble 3. Effects of Differ en t Ba ses, Cou n ter ion s, a n d
Ad d itives
entry
substrate (R)
product (% yielda)
% eeb
base and
additives used
time
(h)
%
%
1
2
3
4
1a (-Me)
1b (-iPr)
1c (-tBu)
1d (-CEt3)
2a (78)
2b (59)
2c (74)
2d (71)
27
69
85
78
entry
M
yieldi eej
1
2
3
4
5
6
7
8
Na
Na
Na
NaHa
10
4.5
5
9
1
0.6
70
47
74
82
84
72
90
92
32
60
85b
85
85
84
83
77
64
72
NaHa,c
NaH + 15-crown-5a,d
a
b
Yields obtained after flash chromatography. % ee was de-
termined by chiral HPLC using a Chiralcel OD column.
(C8H17)4N NaH + (C8H17)4NBre
K
K
Li
K
KOtBuf
KOtBu + 18-crown-6f,g
BuLif
Ta ble 2. Effects of Im in e P r otectin g Gr ou p s
KOAc + BSAh
a
1.8 equiv of base was added to 3.0 equiv of dimethylmalonate.
This reaction also reported in Table 1. c The reaction was run in
b
d
an ultrasonic bath at a constant temperature of 28 °C. 10% of
15-crown-5 was added to the reaction. e Stoichiometric amounts
of NaH and (C8H17)4NBr added to 3.0 equiv of dimethyl malonate.
f 2.0 equiv of base was added to 3.0 equiv of dimethyl malonate.
10% 18-crown-6 was added to the reaction. 10% KOAc added
to stoichiometric amount of BSA + 3.0 equiv of dimethyl malonate.
Yields obtained after flash chromatoghaphy. % ee was deter-
entry
substrate (Ar)
time (h) product (% yielda) % eeb
g
h
1
2
3
4
5
6
1c (Ph)
10
35
23
0.5
6
2c (74)
2e (38)
2f (47)
2g (91)
2h (79)
2i (86)
85c
58
73
77
82
77
1e (3,5-diMePh)
1f (4-MeOPh)
1g (4-CF3-Ph)
1h (4-FPh)
1i (3-FPh)
i
j
mined by chiral HPLC using a Chiralcel OD column.
1.5
with methyl or tert-butyl ester Schiff base acetates 1a
and 1c to study dependence of the enantioselectivity on
the nucleophile (Table 4).
a
b
Yields were obtained after flash chromatography. % ee was
determined by chiral HPLC using Chiralcel OD column. c This
reaction was also reported in Table 1.
Surprisingly, the structure of the nucleophile has a
considerable effect on the enantioselectivity in this 2-aza-
π-allyl system, in contrast to the findings of Bosnich with
the related all-carbon system (Ph2CdCHCH(OAc)Ph). In
the latter case, optical yields were insensitive to the
nature of the nucleophiles used.34b In the case of methyl
ester Schiff base acetate 1a , the enantioselectivity in-
creased (27% to 40% and 62%) with increasing size of
the ester in the nucleophiles (Table 4, entries 1-3).
However, with the corresponding tert-butyl ester 1c, the
% ee decreased considerably (85% ee to 50% ee) with the
more sterically demanding nucleophile (Table 4, entries
7 and 8). These results demonstrate that the nucleophile
participates in the enantiodifferentiating step and a high
level of selectivity can be achieved by a judicious choice
of the nucleophile and the substrate.
to benzophenone readily during the catalytic reaction,
and only ∼10% product was observed by TLC.
The optically active Schiff base acetate (1c, 51% ee,
absolute configuration unknown) was prepared by reduc-
tion of 4 with NB-Enantride followed by quenching with
acetic anhydride. Reaction of this optically enriched
electrophile under conditions identical to those used for
the racemic acetate 1c (Table 2, entry 1) resulted in a
result (11 h, 71% yield, 85% ee) identical to that obtained
from racemic acetate (10 h, 74% yield, 85% ee). This
important finding implies that the chirality of the
substrate is completely lost at some point in the catalytic
cycle before the formation of final product. The most
likely racemization mechanism is π-σ-π epimerization
at the R-carbon of the azaallyl.34 Another possibility is
a metal-exchange reaction that occurs via the coordina-
tion of a Pd(0)-BINAP “nucleophile” to the exo-face of
[pro-R-Pd(BINAP)(η3-azaallyl)]+. This produces the op-
posite chirality pro-S-Pd(II)-BINAP-azaallyl complex,
displacing the previously bound metal as Pd(0)-BINAP.37
Temperature control experiments (Table 4, entries 3-6
and 9-12) showed that the optical yields were sensitive
to temperature employed38 and that the highest % ee was
obtained at 0 °C.25 It has been suggested by Sharpless38c
that such temperature-dependent enantioselectivities
(38) For the effect of temperature on selectivity in transition-metal-
catalyzed reactions, see: (a) Muchow, G.; Vannoorenberghe, Y.; Buono,
G. Tetrahedron Lett. 1987, 28, 6163. (b) Buschmann, H.; Scharf, H.-
D.; Hoffmann, N.; Esser, P. Angew. Chem., Int. Ed. Engl. 1991, 30,
477. (c) Go¨bel, T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1993,
32, 1329. (d) Marko´, I. E., Chesney, A.; Hollinshead, D. M. Tetrahe-
dron: Asymmetry 1994, 5, 569. (e) Brunne, J .; Hoffmann, N.; Scharf,
H.-D. Tetradehron 1994, 50, 6819 and references cited therein.
Ster ic F a ctor s in th e Nu cleop h ile a n d Tem p er a -
tu r e Effects. The study was continued by employing
various malonate types of nucleophiles in combination
(37) Granberg, K. L.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1992, 114,
6858.

3968 J . Org. Chem., Vol. 62, No. 12, 1997
Sch em e 4. P r ep a r a tion a n d Utiliza tion of Sch iff Ba se Ben zoa tes
O’Donnell et al.
Ta ble 4. Effects of Nu cleop h iles a n d Tem p er a tu r e
entry
substrate (R1)
nucleophile NaCR2(COOR3)2
T (°C)
time (h)
product (% yielda)
% ee
1
2
3
4
5
6
7
8
9
1a (Me)
1a (Me)
1a (Me)
1a (Me)
1a (Me)
1a (Me)
1c (tBu)
1c (tBu)
1c (tBu)
1c (tBu)
1c (tBu)
1c (tBu)
NaCH(COOMe)2
NaCH(COOtBu)2
NaCMe(COOMe)2
NaCMe(COOMe)2
NaCMe(COOMe)2
NaCMe(COOMe)2
NaCH(COOMe)2
NaCH(COOtBu)2
NaCMe(COOMe)2
NaCMe(COOMe)2
NaCMe(COOMe)2
NaCMe(COOMe)2
25
25
25
4
2
1
2.5
2.5
3
10
5
3
7
10
11
2a (78)
2j (52)
27b,c
40b
62d
68d
59d
50d
85b,c
50b
80b
86b
85b
84b
2k (55)
2k (56)
2k (66)
2k (69)
2c (74)
2l (83)
2m (69)
2m (77)
2m (72)
2m (20)
0
-10
-40
25
25
25
0
-10
-40
10
11
12
All yields were obtained after flash chromatography. % ee was determined by chiral HPLC using a chiral OD column. c This reaction
a
b
d
was also reported in Table 1. % ee was determined by NMR using Eu(hfc)3 as shift reagent.
imply that the reaction pathway may contain at least two
enantioselective steps and that each step contributes
differentially at different temperatures.
highly reactive 14 e, Pd(0) intermediate Pd(dppe).40 In
a control experiment, we photolyzed (dppe)Pd(C2O4) in
the presence of allyl acetate and observed by 31P{1H}
NMR a singlet at 52.2 ppm that corresponds to [Pd(η3-
C3H5)(dppe)]+.40 Some side reactions that give rise to
weaker 31P{1H} signals at 57.6 and 61.3 ppm were also
observed. These side products also result from irradia-
tion of (dppe)Pd(C2O4) without substrate. Irradiation of
(dppe)Pd(C2O4) in the presence of substrate 1c re-
sulted only in 31P{1H} signals of these side products.
However, isolated residues from these photolyses produce
a plasma desorption mass spectrum (PDMS) signal at
m/ e 798, consistent with an azaallylpalladium dppe
cation.
At t em p t s a t Isola t ion of η3-(Aza a llyl)p a lla d iu m
In ter m ed ia tes. In order to rationalize the results
obtained from the catalytic reactions, efforts were made
to isolate intermediates that would account for the high
levels of selectivity. In particular, we focused on rational
approaches to the synthesis and characterization of stable
η3-(azaallyl)palladium complexes. First, actual catalyst
solutions were examined by 31P NMR spectroscopy. A
solution containing stoichiometric amounts of Pd(OAc)2,
(R)-(+)-BINAP, and substrate 1c in CH3CN revealed no
signals of AB or AX quartets expected of a diastereomeric
substrate-catalyst η3-complex. Only signals correspond-
ing to the known complexes Pd(OAc)2-(+)-BINAP and
Pd[(+)-BINAP]2 were observed.39 Upon addition of ma-
lonate nucleophile, these signals diminished and gave a
complex spectrum that defies interpretation. We con-
clude that any η3-(azaallyl) intermediates must be present
at very low concentration and that equilibrium favors
starting materials.
In the control reaction of (dppb)Pd(C2O4) with allyl
acetate, an intense 31P{1H} signal at 21.1 ppm is observed
that corresponds to [Pd(η3-C3H5)(dppb)]+. Some side
reactions that give rise to weaker 31P{1H} signals at 30.7
and 30.8 ppm were also observed. As in the dppe case,
these side products also result from irradiation of (dppb)-
Pd(C2O4) without substrate. Irradiation of (dppb)Pd-
(C2O4) in the presence of substrate 1c resulted only in
31P{1H} signals of these side products. Crude residues
from these photolyses produce a PDMS signal at m/ e
826, which is consistent with an (aza-allyl)palladium-
dppb complex. We conclude that under the photolysis
conditions Pd(diphosphine) reactive intermediates do not
Second, precedented procedures for the synthesis of
palladium η3-allyl complexes from organopalladium pre-
cursors and allyl acetate were attempted using tert-
butyl(acetyloxy)[(diphenylmethylene)amino] acetate (1c).
Trogler has reported that UV photolysis of (dppe)Pd-
(C2O4) leads to decarboxylation and the formation of the
(40) Paonessa, R. S.; Prignano, A. L.; Trogler, W. C. Organometallics
1985, 4, 647.
(39) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3969
Sch em e 5. P r op osed Mod el for th e P a lla d iu m Ca ta lysis
react with substrate 1c at rates that are competitive with
side reactions known to occur in the absence of any
substrate.
We conclude that η3-(azaallyl)palladium complexes are
likely intermediates in the oxidative addition reaction of
substrate 1c to palladium(0)-phosphine complexes. These
η3-(azaallyl)palladium-phosphine complexes appear to
be quite unstable and have consistently eluded our best
attempts at isolation. The often mutually exclusive
relationship between stable intermediates and active
catalyst systems has complicated many detailed mecha-
nistic studies in the field of homogeneous catalysis.44,45
Mech a n istic Mod el. A number of different aspects
of selectivity need to be considered in this reaction. In
terms of chemoselectivity, the reaction occurs at the Pd-
coordinated cationic π-allyl system rather than the
isolated ester group. The regioselectivity also strongly
favors reaction of the malonate at the R-carbon rather
than the γ-carbon or the enolate oxygen of the ester.
Similar high levels of chemo- and regioselectivity have
been observed with the related anionic glycine equiva-
lents [(Ph2CdNCHCO2tBu)-].9 The lack of reaction at
the γ-carbon likely results from the considerable steric
effect of the two phenyl groups at this position.
Several important conclusions can be drawn from the
experiments reported in this paper concerning the stereo-
chemical outcome of the reaction: (1) the ester protecting
group on the substrate affects the % ee significantly (a
relatively large group is preferred); (2) steric bulk on the
diphenylketimino group decreases the % ee; (3) various
leaving groups do not affect the enantioselectivity; (4) the
optically active Schiff base acetate (51% ee) gives the
same % ee as that obtained with the racemic acetate; and
(5) the nature of the nucleophile has a considerable effect
on the enantioselectivity.
The complex (η3-allyl)(η5-cyclopentadienyl)palladium(II)
is a convenient precursor to Pd(0) organometallic com-
plexes. The reaction of (η3-allyl)(η5-cyclopentadienyl)-
palladium(II) with allyl acetate at room temperature in
the presence of dppe or dppb led to the clean conversion
to [Pd(η3-C3H5)(dppe)][OAc]40 and [Pd(η3-C3H5)(dppb)]-
[OAc],41 respectively. Reaction of (η3-allyl)(η5-cyclopen-
tadienyl)palladium(II) with substrate 1c in the presence
-
of dppe and one of the noncoordinating anions PF6 or
BPh4- led to the prompt appearance of an AX quartet in
the 31P{1H} spectrum. However, this intermediate was
too unstable to be isolated as a solid. In a similar vein,
Pd(PCy3)2 is a two-coordinate 14-electron palladium(0)
complex. A consequence of the bulky tricylcohexylphos-
phine ligands is that reactivity of the PdL2 species is
lower than that of Pd(dppe) or Pd(dppb). Pd(PCy3)2 is
an isolable complex that is sufficiently stable to be stored
in a drybox for months. In the control reaction of Pd-
(PCy3)2 with allyl acetate only the monophosphine com-
plex, [Pd(η3-C3H5)(OAc)(PCy3)], is obtained due to the
steric demands of the PCy3 ligand.42 Normally, [Pd(η3-
C3H5)Cl]2 reacts with dppe or other phosphines to give
bis-phosphine complexes, [Pd(η3-C3H5)L2]+.34c The reac-
tion of [Pd(η3-C3H5)Cl]2 with PCy3 leads to the initial
formation of [Pd(η3-C3H5)Cl(PCy3)].42 AgPF6 in the pres-
ence of excess PCy3 is required to convert [Pd(η3-C3H5)-
Cl(PCy3)] to [Pd(η3-C3H5)(PCy3)2][PF6].43 The attempted
oxidative addition reaction of 1c to Pd(PCy3)2 in the
presence of NH4PF6 or other noncoordinating anions such
as BPh4- gave clean AX multiplet 31P{1H} spectra. This
asymmetric complex could not be isolated as a solid.
A working mechanistic model is presented in Scheme
5 for the palladium-catalyzed reaction of malonate anion
with the Schiff base acetate 1c. Initially, Pd(OAc)2 is
complexed with BINAP to give a Pd(OAc)2-BINAP
(41) Kumobayashi, H.; Mitsuhashi, S.; Akutagawa, S.; Ohtsuka, S.
Chem. Lett. 1986, 157.
(42) Yamamoto, T.; Saito, O; Yamamoto, A. J . Am. Chem. Soc. 1981,
103, 5600.
(43) Carturan, G.; Biasiolo, M.; Daniele, S.; Mazzocchin, G. A.; Ugo,
P. Inorg. Chim. Acta 1986, 119, 19.
(44) Halpern, J . Science 1982, 217, 401.
(45) Alcock, N. W.; Brown, J . M.; Derome, A. E.; Lucy, A. R. Chem.
Commun. 1985, 575.

3970 J . Org. Chem., Vol. 62, No. 12, 1997
O’Donnell et al.
complex. This is then reduced to generate the active
catalyst, Pd(0)-BINAP.39,46 With the introduction of
substrate 1c, a cationic palladium-BINAP-η3-azaallyl
substrate complex is formed by nucleophilic displacement
of acetate by Pd(0). The η3-azaallyl species, once formed,
is present in low concentration. Finally, nucleophilic
attack by malonate anion on the cationic allylic complex
produces, by reductive elimination, the product and
regenerates the active catalyst.
The net prediction from this electronic analysis is that
the rate of the nucleophilic attack step is likely to be
considerably faster than that seen in the Bosnich system.
The experimental results appear to support this proposi-
tion. Under proper conditions, we observe the conversion
of 10 equiv of 1c in as little as 1 h (entry 5, Table 3;
average rate 10 turnovers/h), while in the Bosnich system
at least 5 h was needed to convert 200 equiv of substrate
(average rate 40 turnovers/h). We know from our 31P
NMR studies that the amount of [Pd(BINAP)(η3-azaal-
lyl)]+ complex present in solution is less than 2%, while
in the Bosnich system the [Pd((S,S)-chiraphos)(η3-allyl)]+
concentration is nearly 100%. Taking into account the
amount of Pd(II) complex present in each system during
the nucleophilic step (100% vs <2%), the rate constant
for this step in our system could be at least 12 times
faster (a factor of 0.25 for the rate-determining step, and
another factor of 50 for concentration) than that seen
with the Bosnich [Pd((S,S)-chiraphos)(η3-allyl)]+ catalyst.
It was demonstrated that the Bosnich catalyst had
time to allow sufficient π-σ-π epimerization to produce
Curtin-Hammett conditions, under which the enantio-
selectivity only depends on the difference in free energy
of the two diastereomeric transition states during nu-
cleophillic attack. There is every indication that the
π-σ-π epimerization rate in this system is consider-
ably faster than the rate-determining step, indicating
that we are also working under Curtin-Hammett condi-
tions.
This mechanism is similar to that proposed by Bosnich
and co-workers for their [Pd((S,S)-chiraphos)(η3-allyl)]+
catalyst system.34 The kinetic situation, however, ap-
pears to be quite different. Bosnich found that Pd(0)-
(S,S)-chiraphos reacts in high yield with a variety of
substituted allyl acetates to produce stable [Pd((S,S)-
chiraphos)(η3-allyl)]+ complexes that were carefully stud-
ied. The oxidative addition of racemic-1,1,3-trisubstitut-
ed allyl acetates to Pd(0)-(S,S)-chiraphos produces two
diastereomeric [Pd((S,S)-chiraphos)(η3-((R)-, or (S)-allyl)]+
complexes in ratios that track the final enantioselectivity
of the catalyzed nucleophilic substitution by malonate
anion. Thus, the primary enantioselectivity of the Bos-
nich system arose from the thermodynamic stability of
the two diastereomeric [Pd((S,S)-chiraphos)(η3-((R)-, or
(S)-allyl)]+ complexes, coupled with the nucleophilic
attack of the malonate nucleophile on these diastereo-
mers. The rate-determining step in the Bosnich system
is the attack of the nucleophile on the diastereomeric
[Pd((S,S)-chiraphos)(η3-((R)-, or (S)-allyl)]+ complex.
The current Pd(BINAP)/1c system is quite different.
Here, the rate-determining step is the initial oxidative
addition of substrate 1c to the Pd(0)-BINAP catalyst.
The fact that we do not see any appreciable amounts of
the [Pd(BINAP)(η3-azaallyl)]+ complex in solution implies
that it is not very stable and that nucleophilic attack to
give either product or starting substrate is at least as
fast or, most likely, faster (vide infra) than the oxidative
addition of substrate to the Pd(0)-BINAP species. Oth-
erwise, we would have observed the buildup of diaster-
eomeric [Pd(BINAP)(η3-azaallyl)]+ complexes as seen
with [Pd((S,S)-chiraphos)(η3-allyl)]+.
The instability of the [Pd(BINAP)(η3-azaallyl)]+ com-
plex is probably mainly electronic in origin and involves
the difference between allyl and azaallyl ligands. The
anionic azaallyl ligand with an electron-withdrawing
central nitrogen atom and ester group will not be as good
a donor ligand to the cationic electron-deficient Pd(II)-
BINAP complex after oxidative addition of the starting
azaalkene acetate substrate to the Pd(0)-BINAP. The
poorer Pd-azaallyl bonding changes the thermodynamics
to make the [Pd(BINAP)(η3-azaallyl)]+ complex unstable
enough to favor the starting Pd(0) complex.
One final experiment demonstrates how much faster
the current catalyst system is relative to the Bosnich
[Pd((S,S)-chiraphos)(η3-allyl)]+ system. We examined the
possibility that the observed product enantioselectivity
could be lowered by side reactions with the excess base
present. Reaction product 2c was purified to 96.8% ee
and used as starting material for this experiment. The
reaction of (S)-2c (1.0 equiv, 96.8% ee) with Pd(OAc)2 (0.1
equiv), (R)-(+)-BINAP (0.1 equiv), NaH (1.8 equiv), and
dimethylmalonate (3.0 equiv) in acetonitrile at room
temperature produced product [(S)-2c] of 85.4% ee as
quickly as the reaction could be mixed and analyzed. The
enantioselectivity of the product in the reaction mixture
then stayed constant over the course of the reaction
(85.2% ee at 28 h). This experiment reveals a number
of interesting features about the catalytic reaction: (1)
the product can very readily back-react with the catalyst
to reenter the catalytic cycle; (2) the excess base does not
participate in any deprotonation/racemization reactions
with the free product; and (3) the π-σ-π epimerization
to produce Curtin-Hammett conditions is very fast.
Finally, the conversion of 96.8% ee product 2c within a
few minutes to 85.4% ee product indicates that the rate
of catalysis is also very fast (but not faster than the rate
of epimerization), in agreement with the previous discus-
sion.
On the other hand, the electron-withdrawing groups
on 1c should enhance the kinetics of the nucleophillic
attack of the Pd(0)-BINAP complex at the R-carbon site.
Similarly, when the [Pd(BINAP)(η3-azaallyl)]+ complex
is formed there will be an increased shift of electron
density away from the γ- and especially the R-carbon allyl
donor atoms by the electron-withdrawing ester group,
nitrogen atom, and cationic Pd2+ center. This should
significantly enhance the electrophilicity and reactivity
of the R-allyl carbon atom with respect to nucleophillic
attack by malonate (or acetate) anions.
Selective Dep r otection a n d Sca le-Up Rea ction To
P r ep a r e En a n tiom er ica lly En r ich ed P r od u ct. The
ultimate goal of asymmetric synthesis is to obtain opti-
cally pure products in high chemical yield and short
reaction times. General methods to increase the enantio-
selectivity are necessary even though the reaction has
already produced high levels of optical yields. Since the
products of our coupling reaction are often crystalline, it
was found that the % ee of products can often be
increased by recrystallization. Scheme 6 illustrates the
sequence used in the laboratory-scale preparation of
(46) Amatore, C.; J utand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009.

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3971
Sch em e 6. La bor a tor y-Sca le Rea ction To P r od u ce En a n tiom er ica lly En r ich ed P r od u cts
phine)palladium(0)49 were prepared according to published
procedures.
highly optically enriched product (S)-2c (95.5% ee) and
selective deprotection to produce optically active ASA
HPLC analyses of product samples were performed using a
Chiralcel OD column (5 µm, 4.6 × 250 mm) and, unless
otherwise noted, 100:1 hexane/iPrOH (v/v) as mobile phase at
a flow rate of 1.0 mL/min and UV detection at 254 nm.
Gen er a l P r oced u r e for th e P r ep a r a tion of Sta r tin g
Ma ter ia l. For the individual alkyl (acetyloxy)[(substituted
diphenylmethylene)amino]acetate 1, the corresponding alkyl
N-(substituted diphenylmethylene)glycinate was first pre-
pared20 and then oxidized according to the published pro-
cedure:15c
derivative 6 and 7. Schiff base tert-butyl acetate 1c (3.55
g, 10 mmol) was coupled with potassium dimethyl
malonate using Pd(OAc)2-(+)-BINAP to generate prod-
uct (S)-2c (79% ee, 90% yield). A single recrystallization
gave enriched (S)-2c (95.5% ee, 62% yield). The crystals
were selectively hydrolyzed to 1,1-dimethyl 2-amino-2-
carboxy-(S)-1,1-ethanedicarboxylate hydrochloride (6)
(93.4% ee, 48% overall yield) or to the 2-tert-butyl 1,1-
dimethyl 2-amino-(S)-1,1,2-ethanetricarboxylate hydro-
choride (7) (93.4% ee, 54% overall yield).
Isop r op yl (a cet yloxy)[(d ip h en ylm et h ylen e)a m in o]-
a ceta te (1b): yield 37%; white crystals; mp 92.5-93.5 °C; IR
(KBr) 1738, 1629, 1241, 1103, 699 cm-1; H NMR (CDCl3) δ
1
Con clu sion s
1.24 (dd, 6H, J ) 3.0, 3.0 Hz), 2.17 (s, 3H), 5.05 (dq, 1H, J )
6.0 Hz), 6.13 (s, 1H), 7.30-7.69 (m, 10H); 13C NMR (CDCl3) δ
21.0, 21.6, 69.9, 84.4, 127.9, 128.1, 128.4, 129.2, 129.3, 131.3,
135.5, 138.6, 166.3, 169.9, 174.3. Anal. Calcd for C20H21NO4:
C, 70.78; H, 6.24; N, 4.13. Found: C, 70.99; H, 6.26; N, 4.19.
In summary, a systematic study of substrate, nucleo-
phile, additives, and reaction conditions has led to a
simple, highly stereoselective synthesis of â-carboxy-
aspartic acid derivatives using palladium catalysis. The
optical purity of the products can be increased by recrys-
tallization. Studies on the identification of the reaction
intermediate and use of other potential nucleophiles are
currently underway.
1,1-Diet h ylp r op yl (a cet yloxy)[(d ip h en ylm et h ylen e)-
a m in o]a ceta te (1d ): yield 35%; colorless oil; IR (neat) 1745,
1625, 1237, 1134, 702 cm-1; 1H NMR (CDCl3) δ 0.78 (t, 9H, J
) 7.5 Hz), 1.82 (dq, 6H, J ) 6.0 Hz), 2.16 (s, 3H), 6.09 (s, 1H),
7.29-7.69 (m, 10H); 13C NMR (CDCl3) δ 7.4, 20.9, 26.7, 84.5,
91.0, 127.8, 128.0, 128.2, 128.4, 129.1, 129.3, 131.1, 135.5,
138.7, 165.4, 169.7, 173.9; HRMS m/ z (M+) calcd 396.2175,
found 396.2171.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions using palladium catalysis
were performed under argon or nitrogen using standard
Schlenk line and drybox techniques. CH3CN and CH2Cl2 were
distilled from CaH2. Benzene was degassed and dried over
molecular sieves. THF and ether were distilled from sodium
benzophenone ketyl. All chemicals were commercially avail-
able and reagent grade unless otherwise specified. The ligands
(R)-BINAP((R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphth-
yl), tricyclohexylphosphine, dppe (1,2-bis(diphenylphosphino)-
ethane), and dppb (1,2-bis(diphenylphosphino)butane) were
purchased from Strem Chemical, Inc. Allyl acetate and allyl
chloride were purchased from Aldrich Chemical Co. The
diphosphinepalladium(II) oxalate complexes,47 (η3-allyl)(η5-
cyclopentadienyl)palladium(II),48 and bis(tricyclohexylphos-
ter t-Bu tyl N-[bis(3,5-d im eth ylp h en yl)m eth ylen e]gly-
cin a t e: yield 85%; colorless oil; IR (neat) 1742, 1626, 1200
cm-1 1H NMR (CDCl3) δ 1.47 (s, 9H), 2.28 (s, 6H), 2.34 (s,
;
6H), 4.12 (s, 2H), 6.78 (s, 2H), 7.04 (d, 2H, J ) 6.9 Hz), 7.29
(s, 2H); 13C NMR (CDCl3) δ 21.1, 21.2, 28.0, 56.1, 80.7, 125.0,
126.4, 130.1, 131.9, 136.3, 137.3, 137.9, 139.4, 169.9, 172.4;
HRMS m/ z (M+) calcd 352.2277, found 352.2259.
ter t-Bu tyl (a cetyloxy)[[bis(3,5-d im eth ylp h en yl)m eth -
ylen e]a m in o]a ceta te (1e): yield 38%; colorless oil; IR (neat)
1739, 1626, 1240, 1156 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H),
2.17 (s, 3H), 2.29 (s, 6H), 2.35 (s, 6H), 6.02 (s, 1H), 6.87 (s,
2H), 7.07 (s, 2H), 7.28 (s, 2H); 13C NMR (CDCl3) δ 21.0, 21.1,
21.3, 27.9, 82.6, 84.8, 125.4, 127.0, 130.6, 132.9, 135.7, 137.5,
137.8, 138.9, 165.9, 169.9, 174.7; HRMS m/ z (M+) calcd
410.2331, found 410.2335.
(47) Anderson, G. K.; Lumetta, G. J .; Siria, J . W. J . Organomet.
Chem. 1992, 434, 253.
(48) Tatsuno, Y.; Yoshida, T.; Seiotsuka. Inorg. Synth. 1979, 19, 220.
(49) Yoshida, T.; Otsuka, S. Inorg. Synth. 1990, 28, 113.

3972 J . Org. Chem., Vol. 62, No. 12, 1997
O’Donnell et al.
ter t-Bu tyl (a cetyloxy)[[bis(4-m eth oxyp h en yl)m eth yl-
en e]a m in o]a ceta te (1f): yield 39%; colorless oil; IR (neat)
131.1, 133.2, 135.7, 138.9, 165.4, 165.8, 174.0; HRMS m/ z (M+)
calcd 416.1862, found 416.1870.
1
1739, 1616, 1250, 1155, 1033 cm-1; H NMR (CDCl3) δ 1.45
ter t-Bu t yl [(4-m et h oxyb en zoyl)oxy][(d ip h en ylm et h -
ylen e)a m in o]a ceta te (5b): yield 2.54 g, 57%; colorless oil;
(s, 9H), 2.16 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 6.05 (s, 1H),
6.84 (d, 2H, J ) 8.7 Hz), 6.97 (d, 2H, J ) 8.7 Hz), 7.24 (d, 2H,
J ) 8.7 Hz), 7.63 (d, 2H, J ) 8.7 Hz); 13C NMR (CDCl3) δ 21.1,
27.9, 55.3, 82.7, 84.9, 113.3, 113.7, 127.8, 129.6, 131.2, 131.9,
160.0, 162.1, 166.1, 170.0, 173.5; HRMS m/ z (M+) calcd
414.1917, found 414.1905.
1
IR (neat) 1720, 1624, 1264, 1102, 699 cm-1; H NMR (CDCl3)
δ 1.47 (s, 9H), 3.86 (s, 3H), 6.26 (s, 1H), 6.92 (d, 2H, J ) 8.7
Hz), 7.34-7.71 (m, 10H), 8.09 (d, 2H, J ) 8.7 Hz); 13C NMR
(CDCl3) δ 27.9, 55.4, 82.8, 84.7, 113.5, 122.0, 128.0 (2C), 128.4,
129.2, 129.4, 131.1, 132.1, 135.7, 138.9, 163.6, 165.1, 166.0,
173.9; HRMS m/ z (M+) calcd 446.1967, found 446.1959.
ter t-Bu tyl [[4-(tr iflu or om eth yl)ben zoyl]oxy][(d ip h en -
ylm eth ylen e)a m in o]a ceta te (5c): light-yellow oil as crude
product, decomposed on column; IR (neat) 1731, 1625, 1325,
1271, 1101, 697 cm-1; 1H NMR (CDCl3) δ 1.48 (s, 9H), 6.31 (s,
1H), 7.32-7.71 (m, 12H), 8.25 (d, 2H, J ) 8.1 Hz); 13C NMR
(CDCl3) δ 27.9, 83.2, 85.3, 125.3-138.8 (m), 164.2, 165.5, 174.4;
HRMS m/ z (M+) calcd 484.1736, found 484.1741.
ter t-Bu tyl (a cetyloxy)[[bis[4-(tr iflu or om eth yl)p h en yl]-
m eth ylen e]a m in o]a ceta te (1g): yield 59%; colorless oil; IR
1
(neat) 1749, 1631, 1326, 1231, 1130 cm-1; H NMR (CDCl3) δ
1.46 (s, 9H), 2.17 (s, 3H), 5.98 (s, 1H), 7.49 (d, 2H, J ) 8.4
Hz), 7.62 (d, 2H, J ) 8.4 Hz), 7.74-7.79 (m, 4H); 13C NMR
(CDCl3) δ 20.9, 27.8, 83.6, 84.2, 125.2, 125.3, 125.5, 125.6,
125.7, 128.5 (2C), 129.4 (2C), 131.5, 132.0, 132.9, 133.3, 138.5,
141.1, 165.0, 169.8, 170.8; HRMS m/ z (M+) calcd 490.1453,
found 490.1438.
Gen er a l P r oced u r e for th e Asym m etr ic Cou p lin g
Rea ction Usin g P d Ca ta lysis: 2-ter t-Bu tyl 1,1-Dim eth yl
2-[(Dip h en ylm et h ylen e)a m in o]-(S)-1,1,2-et h a n et r ica r -
boxyla te (2c). Palladium acetate (45 mg, 0.2 mmol) and (+)-
BINAP (125 mg, 0.2 mmol) were added to a three-necked
round-bottom flask (flask A, 50 mL) equipped with a gas
bubbler, magnetic stirring bar, and rubber septum. NaH (60%,
144 mg, 3.6 mmol) was added to a similar flask (flask B, 25
mL). Flasks A and B were both connected to a vacuum line,
allowed to deoxygenate under reduced pressure, and then
flushed with argon using a manifold. This operation was
repeated three times. Acetonitrile (5 mL) was added to flask
A in one portion, and the mixture was stirred for 5 min at
ambient temperature. Then, tert-butyl (acetyloxy)[(diphenyl-
methylene)amino]acetate (1c) (706 mg, 2 mmol) in acetonitrile
(5 mL) was introduced by syringe to the flask A, and the
reaction mixture was stirred for an additional 5 min. At the
same time, dimethyl malonate (792 mg, 6 mmol) in acetonitrile
(5 mL) was added to flask B. After bubbling (H2) had ceased,
the light-gray solution in flask B was transferred dropwise by
syringe to flask A. The entire mixture was then stirred at
ambient temperature for 10 h until TLC (EtOAc:hexane ) 1:4)
showed complete disappearance of starting material. The
reaction mixture was quenched with H2O (50 mL, added in
one portion), and then EtOAc (70 mL) was added. The organic
phase was separated, dried over MgSO4, filtered, and concen-
trated in vacuo to give a red oil as the crude product. This
product was purified by flash chromatography (hexane:EtOAc
) 8:1) to yield 2-tert-butyl 1,1-dimethyl 2-[(diphenylmethyl-
ene)amino]-1,1,2-ethanetricarboxylate (2c) (629 mg, 74%) as
a colorless oil, which solidified on standing. The purified
product (oil) was analyzed by chiral HPLC (column: Chiralcel
OD; hexane:iPrOH ) 100:1): 85% ee [10.15 min (R), 20.52 min
(S)]. Recrystallization from CH2Cl2/hexane gave white crys-
tals: mp 98-98.5 °C; IR (KBr) 1752, 1623, 1262, 1148, 701
ter t-Bu tyl (a cetyloxy)[[bis(4-flu or op h en yl)m eth ylen e]-
a m in o]]a ceta te (1h ): yield 58%; colorless oil; IR (neat) 1755,
1629, 1235, 1153, 1051 cm-1; 1H NMR (CDCl3) δ 1.46 (s, 9H),
2.17 (s, 3H), 5.99 (s, 1H), 7.03 (t, 2H, J ) 8.7 Hz), 7.18 (t, 2H,
J ) 8.7 Hz), 7.29-7.34 (m, 2H), 7.63-7.68 (m, 2H); 13C NMR
(CDCl3) δ 21.0, 27.8, 83.2, 84.4, 115.1, 115.4, 115.6, 115.8, 130.0
(2C), 131.1, 131.4, 131.5, 134.8 (2C), 161.4, 163.1, 164.7, 165.6,
166.5, 169.9, 171.7; HRMS m/ z (M+) calcd 390.1517, found
390.1525.
ter t-Bu tyl (a cetyloxy)[[bis(3-flu or op h en yl)m eth ylen e]-
a m in o]a ceta te (1i): yield 57%; colorless oil; IR (neat) 1755,
1629, 1235, 1159, 1055 cm-1; 1H NMR (CDCl3) δ 1.46 (s, 9H),
2.17 (s, 3H), 6.00 (s, 1H), 7.08-7.50 (m, 8H); 13C NMR (CDCl3)
δ 21.0, 27.9, 83.4, 84.3, 115.2, 115.5 (2C), 115.8, 116.4, 116.7,
118.3, 118.6, 123.5, 125.2, 129.6, 129.7, 130.4, 130.5, 136.9,
137.0, 140.3, 140.4, 160.8, 161.0, 164.1, 164.3, 165.2, 169.9,
170.9; HRMS m/ z (M+) calcd 390.1517, found 390.1525.
P r ep a r a tion of Op tica lly Active Sch iff Ba se Aceta te:
ter t-Bu tyl (Acetyloxy)[(diph en ylm eth ylen e)am in o]acetate
(1c). A solution of NB-Enantride (0.5 M, 24 mL, 12 mmol)
was added dropwise to a solution of freshly prepared 436 (3.09
g, 10 mmol) in THF (20 mL) over 10 min at -78 °C. The
mixture was stirred at -78 °C for 30 min. Acetic anhydride
(1.53 g, 15 mmol) was added, and the mixture was stirred for
30 min at -78 °C and then at ambient temperature for 5 h.
The solvent was evaporated, and the residue was dissolved in
methylene chloride (50 mL). The organic phase was washed
with saturated NaHCO3 (2 × 30 mL), dried over Na2SO4,
filtered, and evaporated. The crude product was purified by
flash chromatography (hexane:EtOAc ) 12:1) to give 2c (918
mg, 26%) as a colorless oil. The purified product, an oil, was
analyzed by chiral HPLC (column: Chiral BakerBond; hexane:
iPrOH ) 600:1): 51% ee [34.6 min, 35.6 min]. Recrystalliza-
tion from ether/hexane gave white crystals: mp 105-106 °C;
IR (KBr) 1740, 1625, 1232, 1153, 1059 cm-1; 1H-NMR (CDCl3)
δ 1.45 (s, 9H), 2.20 (s, 3H), 6.10 (s, 1H), 7.30-7.70 (m, 10 H);
13C-NMR (CDCl3) δ 21.0, 27.8, 82.8, 84.6, 127.9, 128.0, 128.3,
129.1, 129.3, 131.2, 135.6, 138.8, 165.7, 169.8, 173.9. Anal.
Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C,
71.41; H, 6.48; N, 3.99.
cm-1 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.69 (s, 3H), 3.70 (s,
;
3H), 4.32 (d, 1H, J ) 8.4 Hz), 4.67 (d, 1H, J ) 8.4 Hz), 7.28-
7.59 (m, 10H); 13C NMR (CDCl3) δ 27.8, 52.5, 55.1, 65.2, 82.1,
127.9, 128.1, 128.2, 128.8, 129.0, 130.4, 135.7, 139.5, 167.6,
167.7, 168.3, 172.6. Anal. Calcd for C24H27NO6: C, 67.75; H,
6.40; N, 3.29. Found: C, 67.95; H, 6.45; N, 3.24.
2-Isop r op yl 1,1-Dim et h yl 2-[(Dip h en ylm et h ylen e)-
a m in o]-(S)-1,1,2-eth a n etr ica r boxyla te (2b). Following the
general procedure for the asymmetric coupling reaction using
palladium catalysis gave 2b: 481 mg, 59% yield. The purified
product (oil) was analyzed by chiral HPLC (column: Chiralcel
OD; hexane:iPrOH ) 100:1): 69% ee [13.04 min (R), 18.85 min
(S)]. Recrystallization from CH2Cl2/hexane gave white crys-
tals: mp 83.5-84.2 °C; IR (KBr) 1755, 1625, 1288, 1149, 700
cm-1; 1H NMR (CDCl3) δ 1.23 (t, 6H, J ) 6.6 Hz), 3.69 (s, 3H),
3.70 (s, 3H), 4.37 (d, 1H, J ) 8.4 Hz), 4.75 (d, 1H, J ) 8.4 Hz),
5.02 (dq, 1H, J ) 6.3 Hz), 7.28-7.59 (m, 10H); 13C NMR
(CDCl3) δ 21.6, 52.5, 55.0, 64.6, 69.3, 128.0, 128.2, 128.3, 128.8,
129.0, 130.5, 135.7, 139.5, 167.6, 167.7, 168.8, 173.0. Anal.
Calcd for C23H25NO6: C, 67.14; H, 6.12; N, 3.40. Found: C,
66.95; H, 6.07; N, 3.38.
Gen er a l P r oced u r e for th e P r ep a r a tion of Sch iff Ba se
Ben zoa tes: ter t-Bu tyl (Ben zoyloxy)[(d ip h en ylm eth yl-
en e)a m in o]a ceta te (5a ). A solution of Super Hydride (1.0
M, 12 mL, 12 mmol) was added dropwise to a solution of
freshly prepared 436 (3.09 g, 10 mmol) in THF (20 mL) over
10 min at -78 °C. The mixture was stirred at -78 °C for 30
min. Benzoyl chloride (2.11 g, 15 mmol) was added dropwise,
and the mixture was stirred for 30 min at -78 °C and then at
ambient temperature for 2 h. The solvent was evaporated,
and the residue was dissolved in methylene chloride (50 mL).
The organic phase was washed with saturated NaHCO3 (2 ×
30 mL), dried over Na2SO4, filtered, and evaporated. The
crude product was purified by flash chromatography (hexane:
EtOAc ) 10:1) to give 5a (1.953 g, 47%) as a colorless oil: IR
1
(neat) 1727, 1622, 1269, 1108, 703 cm-1; H NMR (CDCl3) δ
1.47 (s, 9H), 6.30 (s, 1H), 7.33-7.49 (m, 10H), 7.71 (d, 2H, J )
7.2 Hz), 8.14 (d, 2H, J ) 7.2 Hz); 13C NMR (CDCl3) δ 27.9,
82.8, 84.9, 128.0 (2C), 128.3, 128.4, 129.1, 129.3, 129.6, 130.0,
2-(1′,1′-Dieth ylp r op yl)-1,1-d im eth yl 2-[(d ip h en ylm eth -
ylen e)a m in o]-(S)-1,1,2-eth a n etr ica r boxyla te (2d ). Fol-
lowing the general procedure for the asymmetric coupling

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3973
reaction using palladium catalysis gave 2d : 661 mg, 71% yield.
The purified product (oil) was analyzed by chiral HPLC
(column: Chiralcel OD; hexane:iPrOH ) 100:1): 78% ee [7.55
min (R), 10.21 min (S)]. Recrystallization from CH2Cl2/hexane
gave white crystals: mp 78.0-79.0 °C; IR (KBr) 1751, 1617,
NO6: C, 62.47; H, 5.46; N, 3.04; F, 8.23. Found: C, 62.61; H,
5.48; N, 3.06; F, 8.40.
2-ter t-Bu tyl 1,1-Dim eth yl 2-[[Bis(3-flu or op h en yl)m eth -
ylen e]a m in o]-(S)-1,1,2-eth a n etr ica r boxyla te (2i). Follow-
ing the general procedure for the asymmetric coupling reaction
using palladium catalysis gave 2i: 790 mg (colorless oil), 86%
yield. The purified product was analyzed by chiral HPLC
(column: Chiralcel OD; hexane:iPrOH ) 100:1): 77% ee [ 9.60
min (R), 12.77 min (S)]: IR (neat) 1739, 1627, 1271, 1253, 1153
1
1277, 1154, 705 cm-1; H NMR (CDCl3) δ 0.77 (t, 9H, J ) 7.5
Hz), 1.81 (dq, 6H, J ) 7.2 Hz), 3.67 (s, 3H), 3.69 (s, 3H), 4.36
(d, 1H, J ) 8.7 Hz), 4.75 (d, 1H, J ) 8.4 Hz), 7.27-7.56 (m,
10H); 13C NMR (CDCl3) δ 7.4, 26.6, 52.5, 54.9, 65.2, 90.5, 127.9,
128.1, 128.3, 128.8, 129.0, 130.4, 135.6, 139.5, 167.7, 168.0,
172.4. Anal. Calcd for C27H33NO6: C, 69.36; H, 7.11; N, 3.00.
Found: C, 69.41; H, 7.05; N, 3.01.
cm-1 1H NMR (CDCl3) δ 1.45 (s, 9H), 3.71 (s, 3H), 3.73 (s,
;
3H), 4.32 (d, 1H, J ) 8.1 Hz), 4.61 (d, 1H, J ) 8.1 Hz), 7.05-
7.50 (m, 8H); 13C NMR (CDCl3) δ 27.8, 52.5 (2C), 54.8, 65.2,
82.5, 115.1, 115.3, 115.4, 115.6, 116.0, 116.3, 117.5, 117.8,
123.9, 124.8, 129.5, 129.6, 130.1, 130.2, 137.1, 137.2, 141.0,
141.1, 160.8, 160.9, 164.1, 164.2, 167.5, 167.6, 167.8, 169.8;
HRMS m/ z (M+) calcd 462.1728, found 462.1728.
2-ter t-Bu tyl 1,1-Dim eth yl 2-[[Bis(3,5-d im eth ylp h en yl)-
m eth ylen e]am in o]-(S)-1,1,2-eth an etr icar boxylate (2e). Fol-
lowing the general procedure for the asymmetric coupling
reaction using palladium catalysis gave 2e: 312 mg, 38% yield.
The purified product (oil) was analyzed by chiral HPLC
(column: Chiralcel OD; hexane:iPrOH ) 100:1): 58% ee [ 7.24
min (R), 10.36 min (S)]. Recrystallization from CH2Cl2/hexane
gave white crystals: mp 109-109.5 °C; IR (KBr) 1738, 1621,
1258, 1152 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.27 (s, 6H),
2.35 (s, 6H), 3.68 (s, 3H), 3.71 (s, 3H), 4.29 (d, 1H, J ) 8.7
Hz), 4.65 (d, 1H, J ) 8.7 Hz), 6.86 (s, 2H), 7.04 (d, 2H, J )
10.8 Hz), 7.17 (s, 2H); 13C NMR (CDCl3) δ 21.2, 21.4, 27.9, 52.4
(2C), 55.2, 65.2, 81.9, 125.8, 126.8, 130.3, 132.1, 136.0, 137.3,
137.5, 139.9, 167.6, 167.8, 168.6, 173.4. Anal. Calcd for
1,1-Di-ter t-b u t yl 2-Met h yl 2-[(Dip h en ylm et h ylen e)-
a m in o]-(S)-1,1,2-eth a n etr ica r boxyla te (2j). Following the
general procedure for the asymmetric coupling reaction using
palladium catalysis gave 2j: 486 mg, 52%. The purified
product (oil) was analyzed by chiral HPLC (column: Chiralcel
OD; hexane:iPrOH ) 100:1): 40% ee [8.49 min (R), 10.12 min
(S)]. Recrystallization from CH2Cl2/hexane gave white crys-
tals: mp 103.5-104.5 °C; IR (KBr) 1740, 1625, 1278, 1136,
700 cm-1; 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.42 (s, 9H), 3.71 (s,
3H), 4.13 (d, 1H, J ) 9 Hz), 4.73 (d, 1H, J ) 9 Hz), 7.28-7.61
(m, 10H); 13C NMR (CDCl3) δ 27.9, 52.3, 57.3, 64.6, 81.6, 81.8,
127.9, 128.2, 128.4, 128.8, 129.1, 130.4, 135.6, 139.6, 166.6,
170.3, 172.5. Anal. Calcd for C27H33NO6: C, 69.36; H, 7.11;
N, 3.00. Found: C, 69.49; H, 6.96; N, 3.03.
C
28H35NO6: C, 69.83; H, 7.33; N, 2.91. Found: C, 69.66; H,
7.54; N, 2.88.
2-ter t-Bu tyl 1,1-Dim eth yl 2-[[Bis(4-m eth oxyp h en yl)-
m eth ylen e]am in o]-(S)-1,1,2-eth an etr icar boxylate (2f). Fol-
lowing the general procedure for the asymmetric coupling
reaction using palladium catalysis gave 2f: 453 mg, 47% yield
(colorless oil). The purified product was analyzed by chiral
HPLC (column: Chiralcel OD; hexane:iPrOH ) 97:3): 73%
ee [12.09 min (R), 22.49 min (S)]: IR (neat) 1739, 1619, 1251,
1153, 1031 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 9H), 3.67 (s, 3H),
3.70 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 4.29 (d, 1H, J ) 8.7
Hz), 4.68 (d, 1H, J ) 8.7 Hz), 6.81 (d, 2H, J ) 8.7 Hz), 6.97 (d,
2H, J ) 8.7 Hz), 7.24 (d, 2H, J ) 8.7 Hz), 7.52 (d, 2H, J ) 8.7
Hz); 13C NMR (CDCl3) δ 27.8, 52.5 (2C), 55.1, 55.2 (2C), 65.1,
81.8, 113.2, 113.4, 128.2, 129.8, 130.6, 132.9, 159.8, 161.5,
167.6, 167.7, 167.9, 168.6; HRMS m/ z (M+) calcd 486.2128,
found 486.2123.
Tr im et h yl 1-[(Dip h en ylm et h ylen e)a m in o]-(S)-1,2,2-
p r op a n etr ica r boxyla te (2k ). Following the general proce-
dure for the asymmetric coupling reaction using palladium
catalysis gave 2k : 437 mg, 55% yield. The purified product
(oil) was analyzed by NMR using Eu(hfc)3 as chiral shift
reagent: 62% ee. Recrystallization from CH2Cl2/hexane gave
white crystals: mp 125-125.5 °C; IR (KBr) 1752, 1629, 1258,
1
1105, 709 cm-1; H NMR (CDCl3) δ 1.60 (s, 3H), 3.67 (s, 3H),
3.71 (s, 3H), 3.78 (s, 3H), 4.73 (s, 1H), 7.18-7.60 (m, 10H); 13
C
NMR (CDCl3) δ 18.5, 52.4, 52.7, 52.8, 58.3, 68.7, 127.6, 128.0,
128.5, 128.9, 129.0, 130.7, 135.9, 139.3, 170.1, 170.4, 170.9,
172.7. Anal. Calcd for C22H23NO6: C, 66.49; H, 5.83; N, 3.52.
Found: C, 66.52; H, 5.88; N, 3.54.
Tr is-ter t-bu tyl 2-[(Diph en ylm eth ylen e)am in o]-(S)-1,1,2-
eth a n etr ica r boxyla te (2l). Following the general procedure
for the asymmetric coupling reaction using palladium catalysis
gave 2l: 845 mg, 83% yield. The purified product (oil) was
analyzed by chiral HPLC (column: Chiralcel OD; hexane:
iPrOH ) 97:3): 50% ee [9.16 min (R), 10.45 min (S)].
Recrystallization from CH2Cl2/hexane gave white crystals: mp
2-ter t-Bu tyl 1,1-Dim eth yl 2-[[Bis[4-(tr iflu or om eth yl)-
p h e n yl]m e t h yle n e ]a m in o]-(S )-1,1,2-e t h a n e t r ica r b ox-
yla te (2g). Following the general procedure for the asym-
metric coupling reaction using palladium catalysis gave 2g:
1021 mg, 91% yield. The purified product (oil) was analyzed
by chiral HPLC (column: Chiralcel OD; hexane:iPrOH ) 100:
1): 77% ee [6.97 min (R), 9.36 min (S)]. Recrystallization from
CH2Cl2/hexane gave white crystals: mp 101-101.5 °C; IR
95-95.5 °C; IR (KBr) 1730, 1619, 1257, 1151, 699 cm-1
NMR (CDCl3) δ 1.39 (s, 9H), 1.41 (s, 9H), 1.44 (s, 9H), 4.16 (d,
1H, J ) 9 Hz), 4.61 (d, 1H, J ) 9 Hz), 7.27-7.61 (m, 10H); 13
;
1H
1
(KBr) 1742, 1626, 1317, 1265, 1140 cm-1; H NMR (CDCl3) δ
C
1.44 (s, 9H), 3.72 (s, 3H), 3.73 (s, 3H), 4.35 (d, 1H, J ) 8.4
Hz), 4.58 (d, 1H, J ) 8.4 Hz), 7.48 (d, 2H, J ) 8.7 Hz), 7.58 (d,
2H, J ) 8.4 Hz), 7.66 (d, 2H, J ) 8.4 Hz), 7.77 (d, 2H, J ) 8.7
Hz); 13C NMR (CDCl3) δ 27.8, 52.6 (2C), 54.8, 65.4, 82.8, 125.1,
125.2, 125.4, 125.5, 125.6, 128.8 (2C), 129.1 (2C), 131.2, 131.6,
132.3, 132.7, 138.7, 141.9, 167.5 (2C), 167.6, 169.9. Anal.
Calcd for C26H25F6NO6: C, 55.62; H, 4.49; N, 2.49; F, 20.30.
Found: C, 55.75; H, 4.56; N, 2.48; F, 20.34.
NMR(CDCl3) δ 27.9, 57.1, 65.5, 81.4, 81.6, 81.7, 127.8, 128.0,
128.5, 128.7, 129.1, 130.2, 135.7, 139.9, 166.8, 166.9, 168.7,
172.0. Anal. Calcd for C30H39NO6: C, 70.70; H, 7.71; N, 2.73.
Found: C, 70.82; H, 7.64; N, 2.74.
1-ter t-Bu t yl 2,2-Dim et h yl 1-[(Dip h en ylm et h ylen e)-
a m in o]-(S)-1,2,2-p r op a n etr ica r boxyla te (2m ). Following
the general procedure for the asymmetric coupling reaction
using palladium catalysis gave 2m : 586 mg, 69% yield. The
purified product (oil) was analyzed by chiral HPLC (column:
Chiralcel OD; hexane:iPrOH ) 100:1): 80% ee [14.17 min (S),
18.26 min (R)]. Recrystallization from CH2Cl2/hexane gave
white crystals: mp 98.5-99.5 °C; IR (KBr) 1740, 1627, 1242,
2-ter t-Bu tyl 1,1-Dim eth yl 2-[[Bis(4-flu or op h en yl)m eth -
ylen e]a m in o]-(S)-1,1,2-eth a n etr ica r boxyla te (2h ). Fol-
lowing the general procedure for the asymmetric coupling
reaction using palladium catalysis gave 2h : 724 mg, 79% yield.
The purified product (oil) was analyzed by chiral HPLC
(column: Chiralcel OD; hexane:iPrOH ) 100:1): 82% ee [10.04
min (R), 19.71 min (S)]. Recrystallization from CH2Cl2/hexane
gave white crystals: mp 134-135 °C; IR (KBr) 1736, 1624,
1
1151, 711 cm-1; H NMR (CDCl3) δ 1.41 (s, 9H), 1.62 (s, 3H),
3.65 (s, 3H), 3.76 (s, 3H), 4.58 (s, 1H), 7.21-7.60 (m, 10H); 13
C
NMR (CDCl3) δ 18.4, 27.8, 52.5, 58.3, 69.0, 81.9, 127.7, 127.9,
128.4, 128.7, 128.9, 130.4, 136.2, 139.4, 168.2, 170.4, 170.9,
171.9. Anal. Calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19.
Found: C, 68.22; H, 6.55; N, 3.19.
1
1242, 1222, 1152 cm-1; H NMR (CDCl3) δ 1.44 (s, 9H), 3.69
(s, 3H), 3.72 (s, 3H), 4.30 (d, 1H, J ) 8.1 Hz), 4.60 (d, 1H, J )
8.1 Hz), 6.99 (t, 2H, J ) 8.7 Hz), 7.16 (t, 2H, J ) 8.7 Hz), 7.29-
7.33 (m, 2H), 7.53-7.58 (m, 2H); 13C NMR (CDCl3) δ 27.8, 52.5
(2C), 54.9, 65.1, 82.4, 114.9, 115.2, 115.3, 115.6, 130.2, 130.3,
131.0, 131.1, 131.3, 131.4, 135.6 (2C), 161.3, 162.7, 164.5,
166.0, 167.7 (2C), 168.1, 170.5. Anal. Calcd for C24H25F2-
P h otoch em ica l Rea ction s of ter t-Bu tyl (Acetyloxy)-
[(d ip h en ylm et h ylen e)a m in o]a cet a t e w it h
(Dip h os-
ph in e)palladiu m (II) Oxalate (Diph osph in e ) dppb, dppe).
To (diphosphine)Pd(C2O4) (0.01 mmol) in a quartz tube was
added 3 mL of CH3CN to form a suspension. tert-Butyl

3974 J . Org. Chem., Vol. 62, No. 12, 1997
O’Donnell et al.
(acetyloxy)[(diphenylmethylene)amino]acetate (35.3 mg, 0.1
mmol) in 1 mL of CH3CN was then added dropwise into the
tube. The mixture was irradiated (λ ) 254 nm) at 5 °C with
an Oriel 1000W Xe arc lamp for 30 min to give a yellow
solution along with a trace of colloidal palladium. The solids
were filtered from the solution, and the solvent was removed
under vacuum, leaving a yellow solid. Similar reactions were
done using only the phosphine complexes and no acetate.
31P{1H} (CD3CN) for the dppe reactions was δ 57.2, 61.0, 66.8
(with or without substrate) and for the dppb reactions δ 30.3,
30.8 (with or without substrate).
mg, 1 mmol) and (+)-BINAP (635 mg, 1 mmol) were added to
a three-necked round-bottom flask (flask A, 100 mL) equipped
with a gas bubbler, magnetic stirring bar, and rubber septum.
Dimethyl malonate (3.964 g, 30 mmol) was added to a similar
flask (flask B, 50 mL). Flasks A and B were both connected
to a vacuum line, allowed to deoxygenate under reduced
pressure, and then flushed with argon using a manifold. This
operation was repeated three times. Acetonitrile (25 mL) was
added to flask A in one portion, and the mixture was stirred
for 10 min at ambient temperature. Then, tert-butyl (acetyl-
oxy)[(diphenylmethylene)amino]acetate (1c) (3.53 g, 10 mmol)
in acetonitrile (25 mL) was introduced by syringe to the flask
A, and the reaction mixture was stirred for an additional 10
min. At the same time, KOtBu (20 mL, 1.0 M solution in THF)
was added to flask B. After bubbling (H2) had ceased, flask B
with the white milky solution was connected to an oil pump
to remove all the THF. Acetonitrile (25 mL) was then added
to flask B. The resulting white milky solution was transferred
to flask A by syringe. The entire mixture was then stirred at
ambient temperature for 1 h until TLC (EtOAc:hexane ) 1:4)
showed complete disappearance of starting material. The
reaction mixture was quenched with H2O (100 mL, added in
one portion), and then EtOAc (150 mL) was added. The
organic phase was separated, dried over MgSO4, filtered, and
concentrated in vacuo to give a red oil as the crude product.
This product was purified by flash chromatography (hexane:
EtOAc ) 8:1) to yield 2-tert-butyl 1,1-dimethyl 2-[(diphenyl-
methylene)amino]-1,1,2-ethanetricarboxylate (2c) (3.83 g, 90%)
as a colorless oil, which solidified on standing. The purified
product (oil) was analyzed by chiral HPLC (column: Chiralcel
OD; hexane:iPrOH ) 100:1): 79% ee [10.15 min (R), 20.52 min
(S)]. All of the purified product was transferred to a 500 mL
round-bottom flask, and mixed solvent (hexane:iPrOH)100:
1, 450 mL) was added. The mixture was stirred until a
homogenous solution was obtained. The flask was then kept
in a freezer at -10 °C for 24 h. After recrystallization was
complete, the white needle-like crystals were separated from
the filtrate, washed with a small amount of hexane (20 mL),
and dried on a vacuum line. A yield of 62% (2.65 g) was
obtained with an optical purity of 95.5% ee (S). The filtrate
was evaporated to dryness and found to be 60.2% ee (S, 1.15
g). An analytical sample (20 mg) of 99.8% ee (S) was obtained
by recrystallization of the optically enriched product (79% ee,
S) in a mixed solvent of hexane/iPrOH (100:1) at ambient
Reaction of (η3-Allyl)(η5-cyclopen tadien yl)palladiu m (II)
w ith d p p e a n d Allyl Aceta te. A benzene solution of dppe
(39.8 mg, 0.1 mmol) and allyl acetate (20 mg, 0.2 mmol)
mixture was added to a benzene solution of (η3-allyl)(η5-
cyclopentadienyl)palladium(II) (21.0 mg, 0.1 mmol). After
addition, the solution was stirred at ambient temperature for
10 h and dried under vacuum. 31P{1H} (CD3CN) δ 52.2 (s).
Similar reaction using dppb instead of dppe gave 31P{1H}
(CD3CN) δ 20.9 (s). Reaction using tert-butyl (acetyloxy)-
[(diphenylmethylene)amino]acetate instead of allyl acetate
together with 2 equiv of NaBPh4 in CH3CN resulted in an AX
quartet: 31P{1H} (CD3CN) NMR δ 38.90, 47.79 (J AX ) 7.3 Hz).
Rea ction of ter t-Bu tyl (Acetyloxy)[(d ip h en ylm eth yl-
en e)a m in o]a ceta te w ith Bis(tr icycloh exylp h osp h in e)-
p a lla d iu m (0). tert-Butyl (acetyloxy)[(diphenylmethylene)-
amino]acetate (53.0 mg, 0.15 mmol) and NH4PF6 (33 mg, 0.2
mmol) in 3 mL of CH3CN was added dropwise to a benzene
solution of Pd(PCy3)2 (66.6 mg, 0.10 mmol). The orange
solution was stirred overnight at room temperature. Solvents
were removed under vacuum, leaving an orange solid: 31P{1H}
-
(CD3CN) AX quartet, δ 34.17, 42.50 (J AX ) 21.8 Hz), and PF6
septet, δ -143.7.
P r od u ct Ra cem iza tion Stu d y. Palladium acetate (8 mg,
0.036 mmol), (R)-(+)-BINAP (23 mg, 0.036 mmol), and 2-tert-
butyl 1,1-dimethyl 2-[(diphenylmethylene)amino]-(S)-1,1,2-
ethanetricarboxylate (2c) (153 mg, 0.36 mmol, 96.8% ee) were
added to a three-necked round-bottom flask (flask A, 50 mL)
equipped with a gas bubbler, magnetic stirring bar and rubber
septum. NaH (60%, 26 mg, 0.648 mmol) was added to a
similar flask (flask B, 25 mL). Flasks A and B were both
connected to a vacuum line, allowed to deoxygenate under
reduced pressure, and then flushed with argon using a
manifold. This operation was repeated three times. Aceto-
nitrile (1 mL) was added to flask A in one portion, and the
mixture was stirred for 5 min at ambient temperature. At
the same time, dimethyl malonate (143 mg, 1.08 mmol) in
acetonitrile (1.25 mL) was added to flask B. After bubbling
(H2) had ceased, the light-gray solution in flask B was
transferred dropwise by syringe to flask A. A sample (0.1 mL)
was taken from the reaction mixture at the indicated time
intervals, filtered through cotton, and diluted with 5 mL of
mixed solvent (hexane and isopropyl alcohol), and then the
solution was injected onto the chiral HPLC column. HPLC
results: 0 min (immediately following above mixing), 85.5%
ee; 20 min, 85.4% ee; 40 min, 85.5% ee; 1 h, 85.6% ee; 1.5 h,
85.8% ee; 3 h, 86.0% ee; 5 h, 86.0% ee.
After 5 h, half of the reaction mixture from above was
transferred to a second flask. To the first flask, an amount of
catalyst and ligand equivalent to that initially used was
added: palladium acetate (8 mg, 0.036 mmol) and (R)-(+)-
BINAP (23 mg, 0.036 mmol). To the second flask, an amount
of base (substrate anion) equivalent to that initially used was
added: base made from NaH (60%, 26 mg, 0.648 mmol) and
dimethyl malonate (143 mg, 1.08 mmol) in acetonitrile (1.25
mL). Samples (0.1 mL) were taken from the two reaction
mixtures at the indicated time intervals, filtered through
cotton, and diluted with 5 mL of mixed solvent (hexane and
isopropyl alcohol), and then the solutions were injected onto
the chiral HPLC column. HPLC results: (a) with extra
catalyst: 6 h, 86.3% ee; 28 h, 85.2% ee; with extra base: 6 h,
85.8% ee; 28 h, 87.2% ee.
temperature. The optical rotation was determined to be [R]25
D
-238.5° (c ) 1.3, MeOH).
1,1-Dim eth yl 2-Am in o-2-ca r boxy-(S)-1,1-eth a n ed ica r -
boxyla te Hyd r och lor id e (6). To a 50 mL round-bottom flask
was added 2-tert-butyl 1,1-dimethyl 2-[(diphenylmethylene)-
amino]-1,1,2-ethanetricarboxylate (2c) (2.65 g, 6.24 mmol,
95.5% ee, S), 5 N HCl (10 mL), and CHCl3 (10 mL). The
reaction mixture was stirred at ambient temperature for 4 h
until TLC showed complete disappearance of starting material.
The CHCl3 layer was then removed, the aqueous layer was
washed with CHCl3 (3 × 20 mL) and separated, and the
solvent was evaporated to give 1,1-dimethyl 2-amino-(S)-1,1,2-
ethanetricarboxylate hydrochloride (1.16 g, 77%, overall 48%
from acetate) as a white solid: IR (KBr) 3350-2340 (br), 1751,
1
1736, 1509, 1241 cm-1; H NMR (CD3COOD) δ 3.82 (s, 3H),
3.84 (s, 3H), 4.54 (bs, 1H), 4.89 (bs, 1H); 13C NMR (CD3COOD)
δ 52.9, 54.3 (2C), 167.8, 167.9, 169.8; MS (FAB, m/ z) 206, 192,
160. The optical purity was determined by hydrolyzing a small
sample (118 mg, 0.4 mmol) in 6 N HCl at 85 °C for 20 h. The
solvent was evaporated to yield (S)-aspartic acid (66 mg, 97%),
which was analyzed by chiral HPLC (column: CrownPack;
perchloric acid solution, pH 1.5, 0 °C): 93.4% ee [6.42 min (R),
8.53 min (S)] and compared with a commercial sample of (S)-
aspartic acid (Aldrich).
2-ter t-Bu tyl 1,1-Dim eth yl 2-Am in o-(S)-1,1,2-eth a n etr i-
ca r boxyla te Hyd r och or id e (7). To a 50 mL round-bottom
flask was added 2-tert-butyl 1,1-dimethyl 2-[(diphenylmeth-
ylene)amino]-1,1,2-ethanetricarboxylate (2c) (2.65 g, 6.24 mmol,
95.5% ee, S), NH2OH.HCl (402 mg, 6.24 mmol), and absolute
ethanol (30 mL). The reaction mixture was refluxed for 2 h
until TLC showed complete disappearance of starting material.
Ethanol was then evaporated, and the crude product (white
La bor a tor y-Sca le P r ep a r a tion of 2-ter t-Bu tyl 1,1-Di-
m eth yl 2-[(Dip h en ylm eth ylen e)a m in o]-(S)-1,1,2-eth a n e-
tr ica r boxyla te (2c) a n d th e Selective Dep r otection to
Op tica lly Active ASA Der iva tives. Palladium acetate (229

Enantioselective Reaction of a Glycine Cation Equivalent
J . Org. Chem., Vol. 62, No. 12, 1997 3975
solid) was washed with ether (3 × 20 mL), filtered, and dried
to give 2-tert-butyl 1,1-dimethyl 2-amino-(S)-1,1,2-ethanetri-
carboxylate hydrochoride (1.59 g, 86%, overall 54% from
acetate). Recrystallization from EtOH/Et2O gave white crys-
tals: mp 128-128.5 °C; IR (KBr) 3300-2350 (br), 1759, 1741,
1509, 1220 cm-1; 1H NMR (CD3OD) δ 1.50 (s, 9H), 3.81 (s, 3H),
3.83 (s, 3H), 4.29 (d, 1H, J ) 3.9 Hz), 4.57 (d, 1H, J ) 3.9 Hz);
13C NMR (CD3OD) δ 28.0, 52.9, 53.9 (2C), 86.3, 166.7, 167.6,
167.8; MS (FAB, m/ z) 262, 206, 192, 160. The optical purity
was determined by hydrolyzing a small sample (150 mg, 0.5
mmol) in 6 N HCl at 85 °C for 20 h. The solvent was
evaporated to yield (S)-aspartic acid (84 mg, 98%), which was
analyzed by chiral HPLC (column: CrownPack; perchloric acid
solution, pH 1.5, 0 °C): 93.4% ee [6.49 min (R), 8.82 min (S)]
and compared with a commercial sample of (S)-aspartic acid
(Aldrich).
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM 28193) for support
of this research. F.Y. and C.P.K. acknowledge support
from the Purdue Cancer Center.
J O961869W