Enantioselective solution- and solid-phase synthesis of glutamic acid derivatives via Michael addition reactions

Article abstract of DOI:10.1016/S0957-4166(01)00116-1

The enantioselective conjugate addition of Schiif base ester derivatives to Michael acceptors either in solution (56-89% e.e.) or on solid-phase (34-82% e.e.) gave optically active unnatural α-amino acid derivatives. The reaction was conducted in the pres

Full text of DOI:10.1016/S0957-4166(01)00116-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 821–828
Enantioselective solution- and solid-phase synthesis of glutamic
acid derivatives via Michael addition reactions
a,
a
b
b
Martin J. O’Donnell, * Francisca Delgado, Esteban Dom ´ı nguez, Jes u´ s de Blas and
c
William L. Scott
a
Department of Chemistry, Indiana University Purdue University at Indianapolis, Indianapolis, IN 46202, USA
b
Centro de Investigaci o´ n Lilly, S.A. Avda de la Industria 30, 28108 Alcobendas, Madrid, Spain
c
Chemistry Research Technologies, Lilly Research Laboratories, Indianapolis, IN 46285, USA
Received 30 June 2000; accepted 19 February 2001
Abstract—The enantioselective conjugate addition of Schiff base ester derivatives to Michael acceptors either in solution (56–89%
e.e.) or on solid-phase (34–82% e.e.) gave optically active unnatural a-amino acid derivatives. The reaction was conducted in the
presence of chiral, non-racemic quaternary salts derived from the cinchona alkaloids using neutral, non-ionic phosphazene bases.
©
2001 Elsevier Science Ltd. All rights reserved.
followed by the introduction of more effective catalysts,
1
. Introduction
in which the free hydroxyl of the cinchona quat was
1
g,1h
replaced with an alkyl group.
In late 1997, indepen-
The benzophenone imines of glycine alkyl esters (e.g. 1)
have been used for the synthesis of a variety of a-amino
acid derivatives. Reacting 1 with electrophiles, using
asymmetric phase-transfer catalysts derived from the
cinchona alkaloids, is a particularly attractive route to
optically active a-amino acids because the chiral control
element is inexpensive and is used in only a catalytic
4 5
dent publications from the Corey and Lygo groups
introduced the 9-anthracenylmethyl group as a very
effective nitrogen substituent in these catalysts. For
example, the pseudoenantiomeric catalysts 3 and 4 gave
1
,2
6
high enantioselectivities in a variety of reactions. A
homogeneous, solution-phase enantioselective synthesis
of a-amino acids from Schiff base ester 1, which gave
optically active derivatives of a-amino acids in 83–97%
3
quantity. Early studies in our laboratory using the
N-alkyl cinchona quaternary ammonium salts were
1f
1j
e.e., has also been reported recently.
*
0
Corresponding author.
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00116-1

8
22
M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
We began utilising resin-bound Schiff base esters 2 for
the solid-phase synthesis of unnatural amino acids and
peptides, termed ‘unnatural peptide synthesis’ (UPS), in
2. Results and discussion
Initial experiments in solution (Table 1) were carried
out using methyl acrylate, a typical Michael acceptor.
The phosphazene base BEMP 5 or BTPP 6 was added
to a mixture of Schiff base 1, Michael acceptor
7
,8
1995. The methodology involves the introduction of
an unnatural amino acid side chain during normal
solid-phase peptide synthesis (SPPS). UPS chemistry
7
a,7c
has resulted in the preparation of mono-
dialkylamino acid and peptide derivatives
and
by alkyl-
(CH ꢀCH-Z, 5 equiv.), and a catalytic amount of the
2
7
b,7d
quaternary ammonium salt (3 or 4, 0.1 equiv.) in
methylene chloride at −40 or −78°C. For methyl acryl-
ate and the cinchonidine-derived catalyst 3, the best
results were obtained using BEMP at −78°C for 3 h,
which afforded (S)-7a in 93% yield and 89% e.e. (e.r.=
94.5:5.5). Using the stronger base BTPP, either at −40
or −78°C, resulted in slightly poorer induction. The
enantiomeric product (R)-7a was obtained by using the
pseudoenantiomeric cinchonine-derived catalyst 4,
albeit with poorer enantioselectivity, with (R)-7a
formed in 92% yield and 80% e.e. (e.r.=90:10). Michael
addition with BEMP as base and the reactive acceptors
acrylonitrile, methyl vinyl ketone or ethyl vinyl ketone
at −78°C over 3 h gave the corresponding Michael
adducts (S)-7b in 84% e.e., (S)-7c in 89% e.e. and
ations involving resin-bound anionic equivalents. In
addition, glutamic acid derivatives were prepared by
7
e
the corresponding Michael additions. The method was
extended to the enantioselective solid-phase synthesis of
a-amino acid derivatives, which were obtained in 51–
7
f
89% e.e.
7
The key to both the solid-phase UPS methodology and
the homogeneous, solution-phase enantioselective
1
j
synthesis was the use of the organic-soluble, non-ionic
9
Schwesinger bases BEMP 5 or BTPP 6. These bases
function in a manner similar to phase-transfer base
9b
systems since they do not react with alkyl halides and
thus can be added simultaneously with the electrophile
at the beginning of the reaction.
(
S)-7d in 87% e.e. using catalyst 3. In reactions with
catalyst 4, the enantiomeric (R)-products (R)-7b in 74%
e.e., (R)-7c in 56% e.e., and (R)-7d in 61% e.e. were
obtained.
With the less reactive phenyl vinyl sulfone the reaction
was completed over 7 h and gave 76% e.e. for (S)-7e
and 73% e.e. for (R)-7e. In all of the reactions exam-
ined, poorer enantioselectivities were observed using 4
as catalyst in comparison to reactions completed using
catalyst 3.
In this paper, we report our studies on an extension of
this work to the enantioselective synthesis of glutamic
acid derivatives both in solution- and solid-phase.
7e,10
Table 1. Catalytic enantioselective Michael additions of 1 in solution
Michael acceptor
Z
Q*X
Base
Temp. (°C)
Product
% Yield
% e.e.
Methyl acrylate
Methyl acrylate
Methyl acrylate
Methyl acrylate
Acrylonitrile
-CO Me
3
3
3
4
3
3
4
3
3
3
4
3
4
3
4
BEMP
BTPP
BTPP
BEMP
BEMP
BTPP
BEMP
BEMP
BTPP
−78
−78
−40
−78
−78
−40
−78
−78
−78
−40
−78
−78
−78
−78
−78
(S)-7a
(S)-7a
(S)-7a
(R)-7a
(S)-7b
(S)-7b
(R)-7b
(S)-7c
(S)-7c
(S)-7c
(R)-7c
(S)-7d
(R)-7d
(S)-7e
(R)-7e
93
92
87
92
83
83
81
82
80
81
80
87
85
91
90
89
86
87
80
84
67
74
89
66
65
56
87
61
76
73
2
-CO Me
2
-CO Me
2
-CO Me
2
-CN
-CN
-CN
-COMe
-COMe
-COMe
-COMe
-COEt
-COEt
Acrylonitrile
Acrylonitrile
Methyl vinyl ketone
Methyl vinyl ketone
Methyl vinyl ketone
Methyl vinyl ketone
Ethyl vinyl ketone
Ethyl vinyl ketone
Phenyl vinyl sulfone
Phenyl vinyl sulfone
BTPP
BEMP
BEMP
BEMP
BEMP
BEMP
-SO Ph
2
-SO Ph
2

M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
823
Table 2. Enantioselective Michael additions of resin-bound benzophenone imine of glycinate 2
Michael acceptor
Z
Q*X Base
Temp. (°C)
Product
% Yield (wt)
% Prod. (HPLC)
% e.e.a
Methyl acrylate
Methyl acrylate
Methyl acrylate
Acrylonitrile
Acrylonitrile
Acrylonitrile
Methyl vinyl ketone
Methyl vinyl ketone
Methyl vinyl ketone
Ethyl vinyl ketone
Ethyl vinyl ketone
Phenyl vinyl sulfone
Phenyl vinyl sulfone
Phenyl vinyl sulfone
-CO Me
3
3
4
3
3
4
3
3
4
3
4
3
3
4
BEMP
BTPP
−78
−40
−78
−78
−40
−78
−78
−40
−78
−78
−78
−78
−40
−78
(S)-10a
(S)-10a
(R)-10a
(S)-10b
(S)-10b
(R)-10b
(S)-10c
(S)-10c
(R)-10c
(S)-10d
(R)-10d
(S)-10e
(S)-10e
(R)-10e
96
96
94
94
98
93
87
88
86
89
90
97
99
98
97
97
98
90
91
92
80
77
79
81
80
96
95
94
74
74
33
82
75
59
74
56
34
76
34
81
70
49
2
-CO Me
2
-CO Me
BEMP
BEMP
BTPP
BEMP
BEMP
BTPP
BEMP
BEMP
BEMP
BEMP
BTPP
2
-CN
-CN
-CN
-COMe
-COMe
-COMe
-COEt
-COEt
-SO Ph
2
-SO Ph
2
-SO Ph
BEMP
2
a
%
e.e. determined by derivatisation of amino acid to 11; see text and Scheme 1.
Enantioselective Michael additions of the resin-bound
glycinate 2 were also studied (Table 2). Optimal results
were obtained when BEMP was used as the base in
dichloromethane at −78°C. As in our earlier enantio-
3. Conclusion
The enantioselective conjugate addition of Schiff base
ester derivatives to Michael acceptors, either in solution
or solid-phase, gave non-racemic unnatural a-amino
acid derivatives. The reaction was conducted in the
presence of chiral, non-racemic quaternary ammonium
salts derived from the cinchona alkaloids using neutral,
non-ionic phosphazene bases.
7f
selective alkylation studies on the resin-bound glyci-
nate 1, a full equivalent of the chiral quaternary ammo-
nium salt 3 or 4 was used. Following alkylation, imine
hydrolysis of the products 8 gave the resin-bound free
amino glycinates 9, which were analysed for yield and
the level of stereoinduction (Scheme 1). Acylation of
resin-bound 9 with quinaldic acid, followed by cleavage
1
1
from the resin, yielded products 10, which were sub-
jected to HPLC analysis to determine the purity of the
products. The level of induction was determined by
cleavage of the free amino glycinate 9 from the resin
and then conversion to the GITC-derived diastereomers
4. Experimental
4.1. General methods
7f,12
1
1 for HPLC analysis.
five Michael adducts were obtained in 74–82% e.e.
e.r.=87:13–91:9) using catalyst 3, while the corre-
The (S)-enantiomers of the
NMR analyses were performed on a GE 300 MHz; l is
in ppm relative to TMS as internal standard in either
CDCl , DMSO-d or CD CN. Infrared spectra were
(
3
6
3
sponding (R)-enantiomers were obtained with consider-
ably lower enantioselectivity with 33–59% e.e. (e.r.=
recorded on a Perkin–Elmer Model 1600 FTIR. High
resolution mass spectra (HRMS) were run in the FAB
mode on a ZAB-2SE instrument.
66:34–79:21).
Scheme 1. Analysis of reaction products from Michael additions on solid-phase.

8
24
M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
4
.2. General reaction procedure for the alkylation of
4.2.4.
1,1-Dimethylethyl
(2S)-[(diphenylmethylene)-
Schiff base 1 in solution
amino]-5-oxoheptanoate (S)-7d. (R=CH CH COCH -
2
2
2
1
CH ) 87% yield, e.e.=87%; H NMR (CDCl ): 1.00 (t,
3
3
All reactions were conducted under an argon atmo-
sphere in oven-dried glassware. The Michael acceptor
3H, J=7.4 Hz); 1.43 (s, 9H); 2.14 (q, 2H, J=7.4 Hz);
2.38–2.55 (m, 4H); 3.94 (t, 1H, J=5.9 Hz); 7.14–7.19
(m, 2H); 7.29–7.44 (m, 6H); 7.61–7.64 (m, 2H); HRMS
(
0.43 mmol, 5 equiv.) was added to a mixture of the
+
benzophenone imine of glycine tert-butyl ester 1 (25
mg, 0.085 mmol, 1.0 equiv.) and O-allyl-N-9-anthra-
cenylmethyl cinchonidinium bromide (0.1 equiv.) in
dry CH Cl (0.5 mL). The reaction mixture was then
cooled (−40 or −78°C) and the base BEMP 5 or BTPP
6
m/z calcd for C H NO 380.2225 for (M+H ), found
24
30
3
380.2205. HPLC: column, Chiracel OD; mobile phase,
hexane:iso-propanol (100:1 v/v); flow rate 1.0 mL/min;
retention times, (R) 9.78 and (S) 21.72 min.
4
a
2
2
9a
9
a
(5 equiv.) was added dropwise over a few seconds.
4.2.5.
1,1-Dimethylethyl
(2S)-[(diphenylmethylene)-
The reaction mixture was then stirred at −40 or −78°C
until the starting material 1 had been consumed (TLC).
The solvent was evaporated in vacuo and the residue
was purified by flash chromatography on silica gel to
give product (S)-7. Products (R)-7 were prepared using
the above procedure with the pseudoenantiomeric cata-
lyst, O-allyl-N-9-anthracenylmethyl cinchoninium bro-
amino]-4-(phenylsulfonyl)butanoate (S)-7e. (R=CH2-
1
CH SO Ph) 92% yield, e.e=76%; H NMR (CDCl ):
2
2
3
1.38 (s, 9H); 2.12–2.29 (m, 2H); 3.15–3.45 (m, 2H); 4.00
(dd, 1H, J=6.6 and 5.2 Hz); 7.11–7.14 (m, 2H); 7.29–
7.45 (m, 6H); 7.53–7.67 (m, 5H); 7.88–7.91 (m, 2H);
HRMS m/z calcd for C H NO S 464.1895 for (M+
27
30
4
+
H ), found 464.1907. HPLC: column, Chiracel OD;
mobile phase, hexane:iso-propanol (100:4 v/v); flow
rate 0.5 mL/min; retention times, (R) 27.50 and (S)
31.59 min.
7
f
mide. Chiral HPLC analyses of products 7 were
performed on a Varian 2010 system using the indicated
column and conditions.
4
.2.1. 1-(1,1-Dimethylethyl) 5-methyl N-(diphenylmethyl-
ene)- -glutamate (S)-7a. (R=CH CH CO CH ) 82%
yield, e.e.=89%; H NMR (CDCl ): 1.44 (s, 9H); 2.18–
4.3. Preparation of the benzophenone imine of Gly-
Wang-resin 2
L
2
2
2
3
1
3
2
1
7
2
1
1
.26 (m, 2H); 2.35–2.40 (m, 2H); 3.59 (s, 3H); 3.97 (t,
Fmoc-Gly-Wang resin (2.0 g, 0.92 mmol, 0.46 mmol/g,
H, J=6.3 Hz); 7.16–7.19 (m, 2H); 7.29–7.46 (m, 6H);
Novabiochem) was wetted with CH Cl (20 mL) and
2
2
13
.62–7.65 (m, 2H); C NMR (CDCl +DMSO-d ): 28.0,
drained. Piperidine (20% in 1-methyl-2-pyrrolidinone
(NMP), 20 mL) was added, briefly mixed and then
drained. Fresh piperidine (20% in NMP, 20 mL) was
added and the resulting slurry was mixed by rotation
for 30 min. The resin was filtered and washed with
3
6
8.6, 30.5, 51.5, 64.7, 81.2, 127.7, 127.9, 128.3, 128.5,
28.7, 130.2, 136.3, 139.3, 170.6, 173.4; IR (KBr): 1736,
624, 1150; HRMS m/z calcd for C H NO 382.2018
23
28
4
+
for (M+H ), found 382.2016. HPLC: column, Whelk-
1; mobile phase, hexane:iso-propanol (95:5 v/v); flow
rate 1.0 mL/min; retention times, (R) 10.09 and (S)
0
NMP and CH Cl2 (3×20 mL each). Benzophenone
2
imine (1.54 mL, 9.2 mmol, 10 equiv.) in NMP (20 mL)
was added to the resin followed by glacial acetic acid
12.08 min.
(
0.475 mL, 8.28 mmol, 9 equiv.) and the suspension was
mixed by rotation for 18 h at room temperature. The
resin was filtered and washed with NMP, THF,
THF:H O (3:1), THF and then CH Cl (3×20 mL) and
4
.2.2. 1,1-Dimethylethyl 4-cyano-(2S)-[(diphenylmethyl-
ene)amino]butanoate (S)-7b. (R=CH CH CN) 83%
2
2
2
2
2
1
yield, e.e.=84%; H NMR (CDCl ): 1.44 (s, 9H); 2.16–
then dried in vacuo (room temperature, overnight) to
3
2
.35 (m, 2H); 2.44–2.54 (m, 2H); 4.05 (dd, 1H, J=7.4
give 2.
and 4.4 Hz); 7.18–7.21 (m, 2H); 7.32–7.49 (m, 6H); 7.65
13
(
d, 2H, J=6.6 Hz); C NMR (CDCl +DMSO-d ):
4.4. Michael addition of the benzophenone imine of
Gly-Wang-resin to give 8
3
6
1
1
1
3
3.9, 28.7, 29.5, 63.7, 81.8, 119.4, 127.6, 128.0, 128.5,
28.7, 130.6, 136.0, 139.0, 169.8, 172.0; IR (KBr): 2250,
730, 1619, 1147; HRMS m/z calcd for C H N O
2
Method A. The benzophenone imine of Wang resin 2
(50 mmol, 111 mg, substitution=0.45 mmol/g) was
weighed into a 3–4 mL capacity test tube. Dry CH Cl
(2 mL) was added, followed by the catalyst (30 mg, 50
mmol, 1 equiv.) and the Michael acceptor (0.25 mmol, 5
equiv.). The reaction mixture was cooled to −78°C,
22
25
2
+
49.1916 for (M+H ), found 349.1929. HPLC: column,
Chiracel OD, mobile phase, hexane:iso-propanol (95:5
v/v); flow rate 1.0 mL/min; retention times, (R) 15.26
and (S) 20.07 min.
2
2
9a
BEMP 5 (73 mL, 0.25 mmol, 5 equiv.) was added, and
the reaction mixture was maintained at −78°C for 7 h
with gentle stirring (slow magnetic stirring and manual
agitation) under argon. The resin was then collected by
filtration and washed with dichloromethane (6×1.5
mL).
4
.2.3. 1,1-Dimethylethyl N-(diphenylmethylene)-5-oxo-
nor- -leucinate (S)-7c. (R=CH CH COCH ) 93%
yield, e.e.=89%; H NMR (CDCl ): 1.43 (s, 9H); 2.07–
L
2
2
3
1
3
2
.18 (m, 5H); 2.52 (app. q, 2H, J=7.4 Hz); 3.95 (t, 1H,
J=6.3 Hz); 7.16–7.17 (m, 2H); 7.30–7.44 (m, 6H); 7.64
(
d, 2H, J=7.4 Hz); HRMS m/z calcd for C H NO
3
2
3
28
+
3
66.2069 for (M+H ), found 366.2057. HPLC: column,
Method B. The benzophenone imine of Wang resin 2
(50 mmol, 111 mg, substitution=0.45 mmol/g) was
weighed into a 3–4 mL capacity test tube. Dry
dichloromethane (2 mL) was added, followed by the
Chiracel OD; mobile phase, hexane:iso-propanol (100:1
v/v); flow rate 1.0 mL/min; retention times, (R) 11.92
and (S) 15.28 min.

M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
825
catalyst (30 mg, 50 mmol, 1 equiv.) and the Michael
very hydrophobic amino acids, 90% aqueous CH CN
3
acceptor (0.50 mmol, 10 equiv.). The reaction mixture
containing 0.4% (w/v) of Et N was used). A 250 mL
3
9
a
was cooled to −40°C, BTPP 6 (153 mL, 0.50 mmol, 10
equiv.) was added, and the reaction mixture was main-
tained at −40°C for 7 h with gentle stirring (slow
magnetic stirring and manual agitation) under argon.
The resin was then collected by filtration and washed
with dichloromethane (6×1.5 mL).
aliquot of this amino acid solution was mixed with 50
mL of a solution of 0.2% (w/v) 2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl isothiocyanate (GITC) in CH CN
3
and the resulting mixture was allowed to stand at room
12b
temperature for 90 min.
For the amino acids with
aromatic side chains, a 0.25% (w/v) solution of
ethanolamine in CH CN (0.100 mL) was added to
3
12c
4.5. Hydrolysis of the imine
scavenge excess GITC.
After 10 min, 10–15 mL of
TFA were added and a 5 mL aliquot was injected
directly onto the HPLC column. A Varian 9010/9050
Series HPLC was used to analyse the GITC amino acid
derivatives 11. A Zorbax SB-C18 column (4.6×75 mm,
3.5 micron particle size) was eluted with CH CN/H O
The resin-bound imine 8 (50 mmol) was washed with
THF and then THF:H O (3:1) (3×1.5–2 mL each). 1N
2
HCl:THF (1:2) (1.5–2 mL) was added to the resin and
the suspension was mixed by rotation for 4 h at room
temperature. The reaction mixture was filtered and
washed with THF (3×1.5–2 mL) and then neutralised
with 10% N,N-di-iso-propylethylamine (DIEA)/NMP
3
2
gradients containing 0.1% TFA at 1 mL/min. The
products were detected at u=250 nm (gradient A=0–
25% CH CN 25 min; gradient B=0–50% CH CN 25
3
3
(
3×1.5–2 mL each). This was followed by washing with
min; gradient C=15–25% CH CN 9 min, 25–50%
3
NMP, CH Cl and then NMP (3×1.5–2 mL each) to
give product 9.
CH CN 25 min).
2
2
3
4
.9. Products 10 and GITC derivatives 11 from resin-
4
resin
.6. Acylation of monosubstituted amino acids of Wang
bound amino acids 9
4
.9.1. 5-Methyl hydrogen N-(2-quinolinylcarbonyl)-L-
To the resin-bound amino acid 9 (50 mmol) was added
NMP (1.50 mL) followed by a solution of quinaldic
acid (1 M, 250 mL, 5 equiv.), 1 M solution of 1-hydroxy-
glutamate (S)-10a and GITC derivative 11a. (R=
CH CH CO CH ) 96% mass recovery, 97% purity
(HPLC), e.e.=74%; H NMR (CDCl ): 2.13–2.22 (m,
2
2
2
3
1
3
benzotriazole hydrate (HOBt·H O) (250 mL, 5 equiv.)
1H); 2.30–2.42 (m, 1H); 2.46–2.51 (m, 2H); 3.59 (s, 3H);
4.72 (td, 1H, J=8.8 and 5.1 Hz); 7.73 (t, 1H, J=7.4
Hz); 7.88 (t, 1H, J=7.4 Hz); 8.04 (d, 1H, J=8.1 Hz);
8.19 (t, 2H, J=8.8 Hz); 8.53 (d, 1H, J=8.1 Hz); 8.73
2
and 1,3-diisopropylcarbodiimide (DIC) (39 mL, 5 equiv.).
The suspension was mixed by rotation for 18 h at room
temperature. The reaction was filtered and washed with
NMP, THF, and then CH Cl (3×1.5–2 mL).
1
3
(d, 1H, J=8.1 Hz); C NMR (CDCl +DMSO-d ):
2
2
3
6
2
7.5, 30.1, 51.4, 118.2, 127.2, 127.5, 128.8, 129.4, 129.6,
136.9, 145.9, 148.7, 163.8, 172.9, 174.1; IR (KBr): 1726,
650; HRMS m/z calcd for C H N O 317.1137 for
(M+H ), found 317.1129. HPLC of GITC derivative
11a: gradient B; retention times, (S) 16.70 and (R)
17.26 min.
4
.7. Cleavage of the acylated product from the resin
1
16
17
2
5
+
To the resin-bound product (50 mmol), 95% tri-
fluoroacetic acid (TFA)/H O (1.5–2 mL) was added
and the reaction was mixed by rocking for 2 h at room
2
temperature. The reaction mixture was filtered into a
tared vial and the resin was washed with TFA/H O
4.9.2.
4-Cyano-(2S)-[(2-quinolinylcarbonyl)amino]but-
2
(
3×1.5–2 mL) and then CH Cl (3×1.5–2 mL). The
anoic acid (S)-10b and GITC derivative 11b. (R=
2
2
solvents were evaporated under a stream of argon and
the residue was dried in a vacuum oven at room
temperature for several hours to give product 10. The
purity of compound 10 was determined by HPLC on a
Varian 9010/9050 system using a Nova-Pak C18
column (150×3.9 mm) with mobile phases consisting of
CH CH CN) 94% mass recovery, 90% purity (HPLC),
2
2
1
e.e.=82%; H NMR (CDCl ): 2.16–2.31 (m, 1H); 2.33–
3
2.50 (m, 1H); 2.56 (t, 2H, J=7.4 Hz); 4.75 (td, 1H,
J=8.8 and 5.2 Hz); 7.71 (t, 1H, J=7.4 Hz); 7.87 (t, 1H,
J=7.4 Hz); 8.03 (d, 1H, J=8.1 Hz); 8.16 (d, 1H, J=8.1
Hz); 8.21 (d, 1H, J=8.1 Hz); 8.49 (d, 1H, J=8.8 Hz);
8.79 (d, 1H, J=5.2 Hz); C NMR (CDCl +DMSO-d ):
12.9, 27.2, 50.2, 117.5, 126.7, 127.0, 127.1, 128.6, 129.2,
129.3, 136.5, 145.3, 148.1, 163.4, 173.2; IR (KBr): 2255,
13
0
.1% (v/v) TFA/H O (A) and 0.08% (v/v) TFA/CH CN
2
3
3 6
(
1
B) with a gradient of 0–80% B in 20 min at a flow of
mL/min with detection at 220 nm.
1
731, 1671; HRMS m/z calcd for C H N O 284.1035
15 14 3 3
+
4
.8. GITC derivatisation and HPLC analysis procedure
for (M+H ), found 284.1031. HPLC of GITC deriva-
tive 11b: gradient C; retention times, (S) 10.78 and (R)
for products 11a–e
1
1.92 min.
The crude amino acids (racemic or optically active
reaction products) were obtained by cleavage with 95%
4.9.3. 5-Oxo-N-(2-quinolinylcarbonyl)-
L
-norleucine (S)-
TFA/H O from the resin-bound amino acid 9 as in the
10c and GITC derivative 11c. (R=CH CH COCH )
2
2
2
3
1
previous procedure. The crude amino acids were deriva-
tised for HPLC analysis with GITC by the slightly
87% mass recovery, 80% purity (HPLC), e.e.=74%; H
NMR (CDCl ): 2.21 (app. sept., 1H, J=7.4 Hz); 2.18
3
1
2a
modified method of Nimura et al. A 1 mg sample of
the amino acid was dissolved in 50% (v/v) aqueous
CH CN (1 mL) containing 0.4% (w/v) Et N (for the
(s, 3H); 2.41 (app. sept., 1H, J=7.4 Hz); 2.63–2.86 (m,
2H); 4.82 (app. q, 1H, J=8.1 Hz); 7.64 (t, 1H, J=7.4
Hz); 7.79 (t, 1H, J=7.4 Hz); 7.88 (d, 1H, J=8.1 Hz);
3
3

8
26
M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
8
.17 (d, 1H, J=8.1 Hz); 8.25 (d, 1H, J=8.8 Hz); 8.33
Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111,
2353–2355; (g) O’Donnell, M. J.; Wu, S.; Huffman, J. C.
Tetrahedron 1994, 50, 4507–4518; (h) O’Donnell, M. J.;
Wu, S.; Esikova, I.; Mi, A. US Patent, 1996, 5,554,753;
(i) O’Donnell, M. J.; Chen, N.; Zhou, C.; Murray, A.;
Kubiak, C. P.; Yang, F.; Stanley, G. G. J. Org. Chem.
1997, 62, 3962–3975; (j) O’Donnell, M. J.; Delgado, F.;
Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998,
39, 8775–8778.
. For other recent applications of the benzophenone imine
of amino acid derivatives in solution, see: (a) Lee, W.
Chromatographia 1999, 49, 61–64; (b) El Khalabi, R.; El
Hallaoui, A.; Ouazzani, F.; Elachqar, A.; El Hajji, S.;
Atmani, A.; Roumestant, M. L.; Viallefont, P.; Martinez,
J. Phosphorus, Sulfur, Silicon 1999, 149, 85–94; (c) Khleb-
nikov, A. F.; Novikov, M. S.; Nikiforova, T. Y.;
Kostikov, R. R. Russian J. Org. Chem. 1999, 35, 91–99;
(
d, 1H, J=8.8 Hz); 8.90 (d, 1H, J=7.4 Hz); HRMS
+
m/z calcd for C H N O 301.1188 for (M+H ), found
3
1
6
17
2
4
01.1188. HPLC of GITC derivative 11c: gradient A;
retention times, (S) 17.46 and (R) 18.03 min.
4
.9.4. 5-Oxo-(2S)-[(2-quinolinylcarbonyl)amino]heptan-
oic acid (S)-10d and GITC derivative 11d. (R=
CH CH COCH CH ) 89% mass recovery, 81% purity
2
2
2
3
1
2
(
HPLC), e.e.=76%; H NMR (CDCl ): 1.03 (t, 3H,
3
J=7.4 Hz); 2.15–2.27 (m, 1H); 2.36–2.48 (m, 3H);
2
7
1
.55–2.79 (m, 2H); 4.80 (td, 1H, J=8.1 and 7.4 Hz);
.62 (t, 1H, J=7.4 Hz); 7.77 (t, 1H, J=7.4 Hz); 7.86 (d,
H, J=8.1 Hz); 8.16 (d, 1H, J=8.1 Hz); 8.24 (d, 1H,
J=8.8 Hz); 8.30 (d, 1H, J=8.8 Hz); 8.84 (d, 1H, J=7.4
Hz); HRMS m/z calcd for C H N O 315.1345 for
17
19
2
4
+
(
1
1
M+H ), found 315.1370. HPLC of GITC derivative
(
d) Lemaire, C.; Guillouet, S.; Plenevaux, A.; Brihaye, C.;
Aerts, J.; Luxen, A. J. Labelled Cpd. Radiopharm. 1999,
2, Suppl. 1, S113–S115; (e) Calmes, M.; Daunis, J.
1d: gradient B; retention times, (S) 15.72 and (R)
6.28 min.
4
Amino Acids 1999, 16, 215–250; (f) Yamaguchi, M.;
Ohba, K.; Tomonaga, H.; Yamagishi, T. J. Mol. Catal. A
1999, 140, 255–258; (g) D o¨ lling, K.; Merzweiler, K.;
Wagner, C.; Weichmann, H. Z. Naturforsch. 1999, 54b,
293–299; (h) B o¨ hm, A.; Polborn, K.; Beck, W. Z. Natur-
forsch. 1999, 54b, 300–304; (i) Bouifraden, S.; Drouot, C.;
El Hadrami, M.; Guenoun, F.; Lecointe, L.; Mai, N.;
Paris, M.; Pothion, C.; Sadoune, M.; Sauvagnat, B.;
Amblard, M.; Aubagnac, J. L.; Calmes, M.; Chevallet,
P.; Daunis, J.; Enjalbal, C.; Fehrentz, J. A.; Lamaty, F.;
Lavergne, J. P.; Lazaro, R.; Rolland, V.; Roumestant, M.
L.; Viallefont, P.; Vidal, Y.; Martinez, J. Amino Acids
4
.9.5. 4-(Phenylsulfonyl)-(2S)-[(2-quinolinylcarbonyl)am-
ino]butanoic acid (S)-10e and GITC derivative 11e. (R=
CH CH SO Ph) 97% mass recovery, 96% purity
2
2
2
1
(
HPLC), e.e.=81%; H NMR (CDCl ): 2.16–2.28 (m,
3
1
H); 2.31–2.43 (m, 1H); 2.33 (app. td, 2H, J=10.3 and
.9 Hz); 4.75 (td, 1H, J=8.8 and 5.2 Hz); 7.59 (t, 2H,
5
J=7.4 Hz); 7.71 (q, 2H, J=7.4 Hz); 7.85–7.90 (m, 3H);
.03 (d, 1H, J=8.1 Hz); 8.15 (d, 1H, J=5.0 Hz); 8.18
d, 1H, J=5.0 Hz); 8.50 (d, 1H, J=8.1 Hz); 8.75 (d,
8
(
1
3
1
5
1
H, J=8.1 Hz); C NMR (CDCl +DMSO-d ): 25.6,
3 6
0.3, 52.2, 118.0, 127.1, 127.3, 127.5, 128.7, 129.1,
29.6, 133.2, 138.0, 136.9, 145.7, 148.1, 163.7, 171.7; IR
1999, 16, 345–379; (j) Ma, D.; Cheng, K. Tetrahedron:
Asymmetry 1999, 10, 713–719; (k) Rutjes, F. P. J. T.;
Tjen, K. C. M. F.; Wolf, L. B.; Karstens, W. F. J.;
Schoemaker, H. E.; Hiemstra, H. Org. Lett. 1999, 1,
(
KBr): 1654, 1301; HRMS m/z calcd for C H N O S
2
0
19
2
5
+
3
99.1014 for (M+H ), found 399.1016. HPLC of GITC
derivative 11e: gradient B; retention times, (S) 19.50
and (R) 20.00 min.
717–720; (l) Rutjes, F. P. J. T.; Veerman, J. J. N.;
Meester, W. J. N.; Hiemstra, H.; Schoemaker, H. E. Eur.
J. Org. Chem. 1999, 1127–1135; (m) Ederer, T.; S u¨ nkel,
K.; Beck, W. Z. Anorg. Allg. Chem. 1999, 625, 1202–
1206; (n) Lygo, B.; Crosby, J.; Peterson, J. A. Tetra-
hedron Lett. 1999, 40, 1385–1388; (o) Lygo, B.
Tetrahedron Lett. 1999, 40, 1389–1392; (p) Selva, M.;
Bombem, A.; Tundo, P. Synth. Commun. 1999, 29, 1561–
1569; (q) Perosa, A.; Selva, M.; Tundo, P. J. Chem. Soc.,
Perkin Trans. 2 1999, 2485–2492; (r) de Meijere, A.;
Ernst, K.; Zuck, B.; Brandl, M.; Kozhushkov, S. I.;
Tamm, M.; Yufit, D. S.; Howard, J. A. K.; Labahn, T.
Eur. J. Org. Chem. 1999, 3105–3115; (s) Tzalis, D.;
Knochel, P. Tetrahedron Lett. 1999, 40, 3685–3688; (t)
Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetra-
hedron Lett. 1999, 40, 3843–3846; (u) Dorizon, P.; Su, G.;
Ludvig, G.; Nikitina, L.; Paugam, R.; Ollivier, J.; Sala u¨ n,
J. J. Org. Chem. 1999, 64, 4712–4724; (v) Park, K.-H.;
Kurth, M. J. Tetrahedron Lett. 1999, 40, 5841–5844; (w)
Polt, R.; Sames, D.; Chruma, J. J. Org. Chem. 1999, 64,
6147–6158; (x) Dehmlow, E. V.; Wagner, S.; M u¨ ller, A.
Tetrahedron 1999, 55, 6335–6346; (y) Ooi, T.; Kameda,
M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519–
6520; (z) Ezquerra, J.; Pedregal, C.; Merino, I.; Fl o´ rez, J.;
Barluenga, J.; Garc ´ı a-Granda, S.; Llorca, M.-A. J. Org.
Chem. 1999, 64, 6554–6565; (aa) Barlaam, B.; Koza, P.;
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Ibarra, C.; Cs a´ k y¨ , A. G.; Mart ´ı n, M. E.; Quiroga, M. L.
Acknowledgements
We gratefully acknowledge the National Institutes of
Health (GM28193) and the Lilly Research Laboratories
for support of this research. We thank Nicholas A.
Honigschmidt for his assistance.
References
1
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(
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0, 1413–1415; (an) Ooi, T.; Tayama, E.; Doda, K.;
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2959–2962.
7
. References from the authors’ laboratories for the solid-
phase synthesis of amino acid and peptide derivatives
using the benzophenone imine of glycine esters: (a)
O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem.
Soc. 1996, 118, 6070–6071; (b) Scott, W. L.; Zhou, C.;
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(
M. J. Am. Chem. Soc. 2000, 122, 1675–1683; (ap) Berge,
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814; (aq) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Cao,
3695–3698; (c) O’Donnell, M. J.; Lugar, C. W.; Pottorf,
B.-X.; Sun, J. Chem. Commun. 2000, 1933–1934; (ar)
Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003–3006;
R. S.; Zhou, C.; Scott, W. L.; Cwi, C. L. Tetrahedron
Lett. 1997, 38, 7163–7166; (d) Griffith, D. L.; O’Donnell,
M. J.; Pottorf, R. S.; Scott, W. L.; Porco, Jr., J. A.
Tetrahedron Lett. 1997, 38, 8821–8824; (e) Dom ´ı nguez,
E.; O’Donnell, M. J.; Scott, W. L. Tetrahedron Lett.
(as) Alvarez-Ibarra, C.; Cs a´ k y¨ , A. G.; G o´ mez de las
Oliva, C. J. Org. Chem. 2000, 65, 3544–3547; (at) Langer,
P.; Wuckelt, J.; D o¨ ring, M.; G o¨ rls, H. J. Org. Chem.
2
000, 65, 3603–3611; (au) Razavi, H.; Polt, R. J. Org.
1998, 39, 2167–2170; (f) O’Donnell, M. J.; Delgado, F.;
Chem. 2000, 65, 5693–5706; (av) Rainier, J. D.; Kennedy,
A. R. J. Org. Chem. 2000, 65, 6213–6216; (aw) Guillena,
G.; N a´ jera, C. J. Org. Chem. 2000, 65, 7310–7322; (ax)
Ooi, T.; Kameda, M.; Tannai, H.; Maruoka, K. Tetra-
hedron Lett. 2000, 41, 8339–8342; (ay) Gmouh, S.; Jamal-
Eddine, J.; Valnot, J. Y. Tetrahedron 2000, 56,
Pottorf, R. S. Tetrahedron 1999, 55, 6347–6362; (g)
O’Donnell, M. J.; Delgado, F.; Drew, M. D.; Pottorf, R.
S.; Zhou, C.; Scott, W. L. Tetrahedron Lett. 1999, 40,
5831–5834; (h) O’Donnell, M. J.; Drew, M. D.; Pottorf,
R. S.; Scott, W. L. J. Comb. Chem. 2000, 2, 172–181.
. For various other solid-phase syntheses involving the
benzophenone imine of amino acid derivatives, see: (a)
Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J.
Tetrahedron Lett. 1998, 39, 821–824; (b) Lee, S.-H.;
Chung, S.-H.; Lee, Y.-S. Tetrahedron Lett. 1998, 39,
8
8
361–8366; (az) Hermann, C.; Pais, G. C. G.; Geyer, A.;
K u¨ hnert, S. M.; Maier, M. E. Tetrahedron 2000, 56,
461–8471.
8
3
. For recent reviews of PTC, see: (a) O’Donnell, M. J.;
Esikova, I. A.; Mi, A.; Shullenberger, D. F.; Wu, S. In
Phase-Transfer Catalysis: Mechanisms and Synthesis
9469–9472; (c) Bhandari, A.; Jones, D. G.; Schullek, J.
R.; Vo, K.; Schunk, C. A.; Tamanaha, L. L.; Chen, D.;
Yuan, Z.; Needels, M. C.; Gallop, M. A. Bioorg. Med.
Chem. Lett. 1998, 8, 2303–2308; (d) Zhengpu, Z.; Yong-
mer, W.; Zhen, W.; Hodge, P. React. Funct. Polym. 1999,
(ACS Symposium Series 659); Halpern, M. E., Ed.
Amino acid and peptide synthesis using phase-transfer
catalysis. American Chemical Society: Washington, D.C.,
1
997; Chapter 10; (b) Shioiri, T. In Handbook of Phase
4
1, 37–43; (e) Sauvagnat, B.; Kulig, K.; Lamaty, F.;
Lazaro, R.; Martinez, J. J. Comb. Chem. 2000, 2, 134–
42; (f) Chinchilla, R.; Mazon, P.; N a´ jera, C. Tetra-
Transfer Catalysis; Sasson, Y.; Neumann, R., Eds. Chiral
phase transfer catalysis. Blackie Academic & Profes-
sional: London, 1997; Chapter 14; (c) For two short
reviews on asymmetric PTC reactions, see: O’Donnell, M.
J. Phases 1998, Issue 4, 5–8 and Phases 1999, Issue 5, 5–8
1
hedron: Asymmetry 2000, 11, 3277–3281.
. (a) Abbreviations: BEMP=2-tert-butylimino-2-diethy-
lamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine;
9
(
Phases is a PTC newsletter published by SACHEM, Inc.,
BTPP=t-butylimino-tri(pyrrolidino)phosphorane;
(b)
8
21 E. Woodward, Austin, TX 78704); (d) Recent
Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.;
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Tetrahedron Symposium-in-Print Number 72, Tetra-
hedron 1999, 55, Issue 20; (e) Martyres, D. Synlett 1999,
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10. For selected examples of the use of Michael reactions in
solution with benzophenone imines of amino acid deriva-
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Taguchi, T. Tetrahedron 1996, 52, 271–278; (b) Bensadat,
A.; F e´ lix, C.; Laurent, A.; Laurent, E.; Faure, R.;
1
3
508; (f) Nelson, A. Angew. Chem., Int. Ed. Engl. 1999,
8, 1583–1585; (g) O’Donnell, M. J. In Catalytic Asym-
metric Synthesis, 2nd Edition; Ojima, I., Ed. Asymmetric

8
28
M. J. O’Donnell et al. / Tetrahedron: Asymmetry 12 (2001) 821–828
Thomas, T. Bull. Soc. Chim. Fr. 1996, 133, 509–514; (c) in pure CD CN or CDCl , an equilibrium mixture
3
3
1
Herrad o´ n, B.; Fenude, E.; Bao, R.; Valverde, S. J. Org.
Chem. 1996, 61, 1143–1147; (d) L o´ pez, A.; Moreno-
Ma n˜ as, M.; Pleixats, R.; Roglans, A.; Ezquerra, J.;
Pedregal, C. Tetrahedron 1996, 52, 8365–8386; (e)
Caturla, F.; N a´ jera, C. Tetrahedron 1996, 52, 15243–
approximately 1:1 of 10/12 was found by H NMR of the
crude product. Cyclised products 12 gave a clean triplet
(no NH coupling) for the a-proton in CDCl [12c, 4.75 (t,
3
1H, J=8.8 Hz); 12d, 4.79 (t, 1H, J=8.8 Hz)]. It was not
possible to isolate pure 12, but an HRMS analysis of the
1
1
5256; (f) Javidan, A.; Schafer, K.; Pyne, S. G. Synlett
997, 100–102; (g) Pyne, S. G.; Safaei, G. J.; Schafer, K.;
crude mixtures of 10 and 12 (−H O) indicated the pres-
ence of both compounds. HRMS [M −H]; 10c: calcd for
2
+
Javidan, A.; Skelton, B. W.; White, A. H. Aust. J. Chem.
C H N O 301.1188, observed 301.1188: 12c: calcd for
16
17
2
4
1
998, 51, 137–158; (h) Sung, S. Y.; Sin, K. S. Arch.
C H N O 283.1083, observed 283.1043. 10d: calcd for
16 15 2 3
Pharm. Res. 1998, 21, 187–192; (i) L o´ pez, A.; Pleixats, R.
Tetrahedron: Asymmetry 1998, 9, 1967–1977; (j) Guillena,
G.; N a´ jera, C. Tetrahedron: Asymmetry 1998, 9, 3935–
C H N O 315.1345, observed 315.1370. 12d: calcd for
17 19 2 4
C H N O 297.1239, observed 297.1253.
17
17
2
3
3
938; (k) Guillena, G.; Manche n˜ o, B.; N a´ jera, C.;
Ezquerra, J.; Pedregal, C. Tetrahedron 1998, 54, 9447–
456; (l) Reference 2j; (m) Reference 2s; (n) Reference 2z;
o) Reference 2ab; (p) Reference 2al; (q) Vivanco, S.;
9
(
Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.;
Cossio, F. P. J. Am. Chem. Soc. 2000, 122, 6078–6092; (r)
Reference 2aw; (s) Reference 4b.
11. For the Michael addition of 2 with methyl or ethyl vinyl
ketone, an equilibrium between the open ketoamide 10
and the cyclic form 12, generated by intramolecular
addition of the amide NH to the ketone carbonyl, was
observed. This equilibrium depends on the solvent. In
H O/CH CN, the solvent used for HPLC and LC/MS
12. (a) Nimura, N.; Ogura, H.; Kinoshita, T. J. Chromatogr.
1980, 202, 375–379; (b) P e´ ter, A.; T o¨ r o¨ k, G.; T o´ th, G.;
Van Den Nest, W.; Laus, G.; Tourw e´ , D. J. Chromatogr.
A 1998, 797, 165–176; (c) Tian, Z.; Hrinyo-Pavlina, T.;
Roeske, R. W.; Rao, P. N. J. Chromatogr. 1991, 541,
297–302.
2
3
analyses, only the open form 10 was observed. However,
.