Asymmetric PTC Alkylation of Glycine Imines: Variation of the Imine Ester Moiety

Article abstract of DOI:10.1055/s-2003-43368

Studies into the enantioselective phase-transfer alkylation of a series of glycine imine esters are presented. Using a quaternary ammonium salt catalyst derived from α-methylnaphthylamine, high enantioselectivities were obtained in reactions involving imi

Full text of DOI:10.1055/s-2003-43368

326
LETTER
Asymmetric PTC Alkylation of Glycine Imines: Variation of the Imine
Ester Moiety
A
symmetric PT
C
a
A
lkylation
r
of
G
lyc
r
ine Imin
y
es Lygo,* Bryan Allbutt
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: B.Lygo@Nottingham.ac.uk
Received 9 September 2003
the strong acid or base normally employed in the hydro-
Abstract: Studies into the enantioselective phase-transfer alkyla-
tion of a series of glycine imine esters are presented. Using a qua-
ternary ammonium salt catalyst derived from a-methyl-
naphthylamine, high enantioselectivities were obtained in reactions
involving imines containing tert-butyl, benzhydryl, and benzyl es-
ters. In contrast, a quaternary ammonium salt catalyst derived from
dihydrocinchonidine gave highest enantioselectivities with tert-bu-
tyl and ethyl esters. Application of the benzhydryl ester alkylation
in the preparation of a differentially protected aspartic acid deriva-
tive is also presented.
lytic cleavage of esters 2a.7
Pioneering studies by the O’Donnell group included in-
vestigations into the C-benzylation of these four imine es-
ters using N-(4-trifluoromethylbenzyl)cinchoninium
bromide as the phase-transfer catalyst.8 This work estab-
lished tert-butyl ester 1a as the optimal substrate for reac-
tions of this type, the product 2a (R¢ = Bn) being
generated in 56% ee with this particular catalyst. Interest-
ingly the benzyl and benzhydryl esters gave the lowest
levels of enantioselectivity (28% ee and 14% ee respec-
tively) in this study. Similar trends have also been report-
ed for reactions involving C2-symmetric binaphthyl
derived phase-transfer catalysts.4a
Key words: amino acids, asymmetric alkylation, phase-transfer ca-
talysis, quaternary ammonium salts
In recent years the asymmetric phase-transfer catalyzed
alkylation of glycine imines (Scheme 1) has emerged as a
highly effective method for the enantioselective synthesis
of a-amino acids.1–4 This chemistry has now been devel-
oped to the point that it is regularly being exploited in tar-
get synthesis.5 Throughout the development of this
methodology most work has focused on the identification
of highly effective phase-transfer catalysts and the optimi-
zation of reaction conditions. In contrast, relatively little
variation in the nature of the glycine imine ester function
has been reported, with the vast majority of studies in-
volving only tert-butyl ester 1a.3 With this in mind, we
have recently examined the enantioselective alkylation of
alternative glycine imine esters and in this paper report
preliminary results arising from this work.
Our own work in this area2 has concentrated on the use of
phase-transfer catalysts such as O-benzyl-N-(9-anthra-
cenylmethyl)dihydrocinchonidinium bromide (3). Cata-
lysts of this type give very high levels of enantio-
selectivity in the alkylation of glycine imine 1a,1 but their
similarity to the catalysts employed in the O’Donnell
study suggested that they may not work so well with the
alternative esters. Partly because of this, we have recently
being developing strategies for the rapid generation and
screening of asymmetric phase-transfer catalyst libraries2b
and this work has established that salt 4 is also capable of
delivering very high levels of enantioselectivity in the
alkylation of imine 1a.2a
CF3
chiral PTC
Ph2C=N
CO2t-Bu
Ph2C=N
R'
CO2t-Bu
OMe
base, R'-Br
2a
1a
Et
H
t-Bu
N
CF3
CF3
Br-
Scheme 1
N+
H
OBn
+
N
We have examined the asymmetric alkylation of four dif-
ferent glycine imine esters 1 (a: R = t-Bu; b: R = CHPh2;
c: R = CH2Ph; d: R = Et). These particular imines were
selected because they are straightforward to prepare6 and
because they incorporate synthetically versatile ester
functions. In particular, the benzhydryl and benzyl esters
were of interest to us because of they are readily cleaved
via hydrogenolyzis, thus offering a useful alternative to
Br-
3
H
t-Bu
4
OMe
CF3
Figure 1
Although quaternary ammonium salts 3 and 4 give similar
levels of enantioselectivity in the alkylation of imine 1a,
there is little similarity between the two structures and
so it seemed likely that they would perform differently
with the imine esters chosen for study. Thus, we initially
SYNLETT 2004, No. 2, pp 0326–0328
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43368; Art ID: D22703ST.pdf
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
2.
2
0
0
4

LETTER
Asymmetric PTC Alkylation of Glycine Imines
327
tested the two catalysts in trial experiments involving the ies. With the benzhydryl and benzyl esters 1b and 1c, use
alkylation of imine esters 1a–d with benzyl bromide. Sev- of catalyst 4 resulted in significantly higher enantioselec-
eral additional alkylation reactions were then performed tivity in the test alkylation (entries 5–6, 9, 10), whereas
on each imine ester substrate, using the catalyst that gave the ethyl ester 1d gave higher selectivity with catalyst 3
the highest enantioselectivity in these initial experiments. (entries 13, 14).
Follow up experiments involving alkylation of imine 1b
Table 1 Asymmetric PTC Alkylation of Glycine Imine Esters
with allyl and 2-bromoallyl bromide suggest that this sub-
strate, in conjunction with catalyst 4, should give high
enantiomeric excesses with a range of electrophiles. In
contrast, benzyl and ethyl esters 1c and 1d gave variable
results, but again high enantioselectivities could be ob-
tained (80–90% ee and 73–87% ee respectively).
Using Catalysts 3 and 49
catalyst 3 or 4
Ph2C=N
R'
CO2R
Ph2C=N
CO2R
15 M aq KOH,
PhMe, 0 °C
R'-Br
H
1
2
En
try
R
R¢-Br
Prod- Catalyst Yield Ee
uct
Overall these results suggest that all four glycine imine es-
ters 1a–c could have application in the enantioselective
synthesis of a-amino acid derivatives, and that benzhydryl
ester 1b is an excellent alternative to the tert-butyl ester
1a. To further probe this we examined the utility of ester
1b in the synthesis of a differentially protected L-aspartic
acid derivative 5 (Scheme 2). In order to achieve this,
alkylation of imine 1b with tert-butyl bromoacetate is re-
quired. In our experience, glycine imine alkylations in-
volving this particular electrophile generally result in
significantly lower levels of enantioselectivity than those
obtained with other types of alkyl halide,2 consequently
this represents a useful test of the limitations of this meth-
odology.
(mol%)a (%) (%)b,c
1
2
3
4
t-Bu
PhCH2Br
2a
3 (10) 90
93 (S)
97 (R)
94 (R)
93 (R)
PhCH2Br
2a
4 (1)
4 (1)
89
71
77
CH2=CHCH2Br
CH2=CBrCH2Br
2a'
2a'' 4 (1)
5
6
Ph2CH PhCH2Br
PhCH2Br
2b
2b
2b¢
3 (10) 96
63 (S)
92 (R)
98 (R)
94 (R)
79 (S)
86 (R)
90 (R)
80 (R)
4 (1)
4 (1)
95
78
68
7
CH2=CHCH2Br
CH2=CBrCH2Br
PhCH2 PhCH2Br
8
2b¢¢ 4 (1)
ent-4 (1 mol%)
Ph2C=N CO2CHPh2
9
2c
3 (10) 68
1b
15 M aq KOH,
PhMe, 0 °C, 1 h
BrCH2CO2t-Bu
2b'''
H
10
11
12
PhCH2Br
2c
4 (1)
4 (1)
4 (1)
86
51
91
t-BuO2C
CH2=CHCH2Br
CH2=CBrCH2Br
2c¢
2c¢¢
cat. 3 (10 mol%)
cat. ent-4 (1 mol%)
57% (23% e.e.)
100% (86% e.e.)
H2N
CO2CHPh2
15% aq citric acid
THF/H2O
5
H
13 Et
14
PhCH2Br
2d
2d
2d¢
4 (1)
88
55 (R)
87 (S)
81 (S)
73 (S)
t-BuO2C
85% overall
PhCH2Br
3 (10) 63
3 (10) 86
Scheme 2
15
CH2=CHCH2Br
CH2=CBrCH2Br
16
2d¢¢ 3 (10) 83
Since the use of catalyst 4 appears to result in selectivity
for the (R)-imines 2b, access to the L-amino acid deriva-
tive 5 required use of its enantiomer (ent-4). Thus, alkyla-
tion of 1b was investigated using this latter catalyst. Using
our standard conditions,9 the desired product 2b¢¢¢ was iso-
lated in excellent yield and high enantiomeric excess
(86% ee). The enantioselectivity of this alkylation could
be further improved to 90% ee by employing CsOH·H2O
as the base and running the alkylation at –78 °C10 for 4
hours. In contrast, use of catalyst 3 gave low levels of se-
lectivity (23% ee at 0 °C) illustrating the difficulties asso-
ciated with obtaining high enantioselectivity in this
particular alkylation. Hydrolysis of the imine function in
2b¢¢¢ then provided the desired aspartic acid derivative 5 in
good overall yield (Scheme 2).
a Catalyst 4 exhibits higher activity than 3 and so can be used at lower
loadings. Similar levels of enantioselectivity were obtained if 5 mol%
of 4 was used.
b All ee’s were determined by HPLC comparison with racemic
samples.
c Stereochemical assignments (in parentheses) of products 2a were
established by comparison with authentic samples. Stereochemical
assignments for products 2b–d are assumed, based on those found for
2a.
The results of this study are shown in Table 1. With the
glycine imine tert-butyl ester 1a, both catalysts gave sim-
ilar levels of enantioselectivity in the reaction with benzyl
bromide (entries 1, 2). This result is entirely expected
based on previous studies involving these catalysts,2 and
served as a benchmark for the subsequent alkylation stud-
Synlett 2004, No. 2, 326–328 © Thieme Stuttgart · New York

328
B. Lygo, B Allbutt
LETTER
(5) See for example ref.4a and: (a) Kim, S.; Lee, J.; Lee, T.;
In conclusion, we have studied the asymmetric phase-
transfer alkylation of a series of glycine imine esters and
found that the benzhydryl esters can serve as a useful al-
ternative to the more commonly employed tert-butyl es-
ters. Exploitation of this in target synthesis is currently
under investigation and will be reported in due course.
Park, H. G.; Kim, D. Org. Lett. 2003, 5, 2703.
(b) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331.
(c) Lygo, B.; Andrews, B. I. Tetrahedron Lett. 2003, 44,
4499. (d) Boisnard, S.; Carbonnelle, A.-C.; Zhu, J. Org. Lett.
2001, 3, 2061. (e) Lygo, B. Tetrahedron Lett. 1999, 40,
1389.
(6) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
(7) For examples that illustrate of the utility of this see:
(a) Mitchell, S. A.; Pratt, M. R.; Hruby, V. J.; Polt, R. J. Org.
Chem. 2001, 66, 2327. (b) Tilley, J. W.; Sarabu, R.;
Wagner, R.; Mulkerins, K. J. Org. Chem. 1990, 55, 906.
(c) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki,
C.; Meienhofer, J. J. Org. Chem. 1978, 43, 4194.
Acknowledgment
We thank the EPSRC for funding and AstraZeneca for a studentship
(to B.A.). We also thank Mr. S. R. James, Dr. D. Levin and Dr. B.
McKeever for helpful discussions, and acknowledge use of the
EPSRC’s Chemical Database Service at Daresbury.
(8) O’Donnell, M. J.; Sennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353.
(9) Representative Procedure: A solution of salt ent-4 (1.2
mg, 1 mol%) and imine 1b (50 mg, 0.12 mmol) in toluene
(4 mL) was cooled to 0 °C, degassed, and placed under an
argon atmosphere. tert-Butyl bromoacetate (22 mL, 0.14
mmol) was added followed by degassed 15 M aq KOH
(1mL). The resulting mixture stirred at 1500 rpm for 45 min,
then diluted with H2O (5 mL) and extracted with EtOAc
(3 × 4 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Residual
tert-butyl bromoacetate was removed under vacuum (1 mm
Hg, r.t.) to afford imine 2b¢¢¢ as a colourless oil (64 mg,
100%, 86% ee). 1H NMR (400 MHz, CDCl3): d = 7.62–7.60
(2 H, m, ArH), 7.41–7.23 (16 H, m, ArH), 7.16–7.13 (2 H,
m, ArH), 6.89 (1 H, s, OCHPh2), 4.58 (1 H, dd, J = 7.5, 5.5
Hz, H-2), 2.99 (1 H, dd, J = 15.5, 5.5 Hz, H-3a), 2.85 (1 H,
dd, J = 15.5, 7.5 Hz, H-3b), 1.35 (9H, s, t-Bu). 13C NMR
(100 MHz, CDCl3): d = 171.8 (C), 170.0 (C), 139.9 (C),
139.9 (C), 139.6 (C), 136.0 (C), 130.5 (CH), 129.0 (CH),
128.8 (CH), 128.5 (CH), 128.0 (CH), 128.0 (CH), 127.9
(CH), 127.4 (CH), 127.1 (CH), 80.8 (C), 77.5 (CH), 62.3
(CH), 39.5 (CH2), 28.1 (CH3). HPLC: Chiralpak AD column
(150 × 2.1 mm), hexane/i-propanol (97.5/2.5), 0.2 mL/min,
Rt = 13.9 min (R)-isomer, 18.8 min (S)-isomer.
References
(1) For recent reviews covering phase-transfer alkylation of
glycine imines see: (a) Maruoka, K.; Ooi, T. Chem. Rev.
2003, 103, 3013. (b) O’Donnell, M. J. Aldrichimica Acta
2001, 34, 3.
(2) (a) Lygo, B.; Allbutt, B.; James, S. R. Tetrahedron Lett.
2003, 44, 5629. (b) Lygo, B.; Andrews, B. I.; Crosby, J.;
Peterson, J. A. Tetrahedron Lett. 2002, 43, 8015. (c) Lygo,
B.; Humphreys, L. D. Tetrahedron Lett. 2002, 43, 6677.
(d) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron 2001,
57, 6447. (e) Lygo, B.; Crosby, J.; Lowdon, T. R.; Peterson,
J. A.; Wainwright, P. G. Tetrahedron 2001, 57, 2403.
(f) Lygo, B.; Crosby, J.; Lowdon, T. R.; Wainwright, P. G.
Tetrahedron 2001, 57, 2391. (g) Lygo, B.; Crosby, J.;
Peterson, J. A. Tetrahedron Lett. 1999, 40, 1385. (h) Lygo,
B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(3) For examples of asymmetric PTC alkylation of glycine
imines other than tert-butyl ester 1a see ref. 1 and: (a) Ooi,
T.; Tayama, E.; Maruoka, K. Angew. Chem. Int. Ed. 2003,
42, 579; amides. (b) Mazon, P.; Chinchilla, R.; Najera, C.;
Guillena, G.; Kreiter, R.; Gebbink, ; R, J. M. K.; van Koten,
G. Tetrahedron: Asymmetry 2002, 13, 2181; iso-propyl
ester. (c) Vyskocil, S.; Meca, L.; Tislerova, I.; Cisarova, I.;
Polasek, M.; Harutyunyan, S. R.; Belokon, Y. N.; Stead, R.
M. J.; Farrugia, L.; Lockhart, S. C.; Mitchell, W. L.;
Kocovsky, P. Chem.–Eur. J. 2002, 8, 4633; Ni salt of PBP
imine.
(4) For leading references to asymmetric PTC alkylations of
glycine imine1a not covered in ref.1 and ref.2, see: (a) Ooi,
T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
5139. (b) Mase, N.; Ohno, T.; Hoshikawa, N.; Ohishi, K.;
Morimoto, H.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2003,
44, 4073. (c) Park, H. G.; Jeong, B. S.; Yoo, M. S.; Lee, J.
H.; Park, B. S.; Kim, M. J.; Jew, S. S. Tetrahedron Lett.
2003, 44, 3497. (d) Thierry, B.; Plaquevent, J. C.; Cahard,
D. Tetrahedron: Asymmetry 2003, 14, 1671. (e) Danelli, T.;
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Tocco, G. Tetrahedron: Asymmetry 2003, 14, 461.
(f) Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 1515.
(g) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.;
Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry
2001, 12, 1567. (h) O’Donnell, M. J.; Delgado, F.;
Dominguez, E.; de Blas, J.; Scott, W. L. Tetrahedron:
Asymmetry 2001, 12, 821.
Imine 2b¢¢¢ (38 mg) was then dissolved in THF (1 mL) and
treated with 15% aq citric acid (1 mL). The resulting solution
was stirred at r.t. for 3 h, then washed with Et2O (3 × 2 mL).
The aqueous layer was basified (sat. aq K2CO3) and
extracted with CHCl3 (3 × 5 mL). The combined organic
extracts were dried (MgSO4) and concentrated under
reduced pressure to afford amine 5 as a colourless oil (22
mg, 85%). 1H NMR (400 MHz, CDCl3): d = 7.36–7.27 (10
H, m, ArH), 6.92 (1 H, s, OCHPh2), 3.84 (1 H, dd, J = 6.5,
4.5 Hz, H-2), 2.80 (1 H, dd, J = 16.5, 4.5 Hz, H-3a), 2.72
(1 H, dd, J = 16.5, 6.5 Hz, H-3b), 1.88 (2 H, s, broad, NH2),
1.38 (9 H, s, t-Bu). 13C NMR (100 MHz, CDCl3): d = 173.5
(C), 170.3 (C), 139.8 (C), 128.6 (CH), 128.6 (CH), 128.2
(CH), 128.1 (CH), 127.2 (CH), 127.2 (CH), 81.5 (C), 77.8
(CH), 51.6 (CH), 39.8 (CH2), 28.1 (CH3)
(10) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
Synlett 2004, No. 2, 326–328 © Thieme Stuttgart · New York