Alkylation of N′-[(S)-1′-phenylethyl]-N-(diphenylmethylene)glycinamide using a phase transfer catalyst (PTC) for practical asymmetric syntheses of α-amino acid derivatives

Article abstract of DOI:10.1055/s-2001-13389

The chiral auxiliary mediated stereoselective alkylation reaction of N′-[(S)-1′-phenylethyl]-N-(diphenylmethylene)glycinamide (1) using a phase transfer catalyst (PTC) is described. Alkylation of 1 using 18-crown-6 as a PTC for liquid-solid extraction of KOH in toluene gives best results. This methodology provides a practical protocol for the preparation of a variety of enantio-enriched unnatural α-amino acid derivatives up to 83:17 enantiomeric ratio.

Full text of DOI:10.1055/s-2001-13389

LETTER
613
Alkylation of N’-[(S)-1’-Phenylethyl]-N-(diphenylmethylene)glycinamide
using a Phase Transfer Catalyst (PTC) for Practical Asymmetric Syntheses of
-Amino Acid Derivatives
Hyun Ju Kim, Sang-kuk Lee, Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea
Fax: +822-3436-5382; E-mail: parkyong@kkucc.konkuk.ac.kr
Received 5 March 2001
Dedicated to Professor Peter Beak on the occasion of his 65th birthday
tions or solid bases (NaOH, KOH etc.) offer many advan-
Abstract: The chiral auxiliary mediated stereoselective alkylation
tages as a process technology in organic syntheses: high
reaction of N’- [ (S)-1’-phenylethyl]-N-(diphenylmethylene)glycina-
mide (1) using a phase transfer catalyst (PTC) is described. Alkyla-
tion of 1 using 18-crown-6 as a PTC for liquid-solid extraction of
yield, environmental aspects, safety, lower costs, and sim-
ple reaction procedures.1 For PTC-catalyzed asymmetric
KOH in toluene gives best results. This methodology provides a organic syntheses, an intensive progress has been made
practical protocol for the preparation of a variety of enantio-en-
recently, as there were only a limited number of success-
ful examples so far.2,3 Also, PTC-catalyzed asymmetric
riched unnatural -amino acid derivatives up to 83:17 enantiomeric
ratio.
syntheses using chiral auxiliary remain poorly studied,
Key words: phase transfer catalysis, asymmetric syntheses, alkyla-
tion, chiral auxiliaries, amino acids
even though asymmetric induction using chiral auxiliary
is still efficient and has some advantages.4
We have investigated the development of new chiral gly-
cine reagents for the asymmetric syntheses of -amino ac-
The alkylation reactions of enolates generated by phase
ids under PTC conditions amenable to easily scalable
transfer catalyst (PTC) and concentrated alkaline solu-
CH3
O
O
CH3
O
N
N
CPh2
CPh2
N
CPh2
Ph
N
MeO
S
S
H
1. H+
2. AcCl, MeOH
3. HN=CPh2
Ph
N
Ph
Base, PTC
Br
H
Ph
Ph
3
1
2
Table 1 Benzylation of N’- [ (S)-1’-phenylethyl]-N-(diphenylmethylene)glycinamide 1
(a) The yields are not optimized, and trace amount of imine moiety deprotected product was observed during purification by column chro-
matography. (b) The er’s of 3 are determined by CSP-HPLC (Chiralcel-OD) with hexane and 2-propanol as solvent.
Synlett 2001 No. 5, 613–616 ISSN 0936-5214 © Thieme Stuttgart · New York

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H. J. Kim et al.
LETTER
CH3
O
O
CH3
O
E+
N
CPh2
N
N
CPh2
CPh2
Ph
N
S
MeO
h
N
S
H
1. H+
2. AcCl, MeOH
3. HN=CPh2
KOH
18-Crown-6
toluene
H
E
E
1
4 E = CH2Ph-m-Cl
5 E = CH2Ph-m-OMe
6 E = CH2Ph-m-CH3
7 E = CH2Ph-m-I
8 E = CH2CH3
10 E = CH2Ph-m-Cl
11 E = CH2Ph-m-OMe
12 E = CH2Ph-m-CH3
13 E = CH2Ph-m-I
14 E = CH2CH3
9 E = CH2CO2t-Bu
15 E = CH2CO2CH3
Table 2 Alkylations of N’-[(S)-1’-phenylethyl]-N-(diphenylmethylene)glycinamide 1
(a) 10 equiv of KBr is used. (b) The yields are not optimized, and trace amount of imine moiety deprotected product was obser-
ved during purification by column chromatography. (c) The er’s of products are determined by CSP-HPLC (Chiralcel-OD) with
hexane and 2-propanol as solvent. (d) Low yield (The yield is not determined). (e) The absolute configuration of major enantio-
mer is assigned by comparison of CSP-HPLC retention time with authentic material prepared from commercially available (S)-
aspartic acid.
processes. Here we wish to report preliminary results on er of 3 (entry 3). The reaction at -40 °C proceeded very
the chiral auxiliary mediated stereoselective alkylation re- slowly. Lowering the temperature results in the decreases
action of N’-[(S)-1’-phenylethyl]-N-(diphenylmethyl- of both rate and yield in the reactions with TBAB. When
ene)glycinamide (1)5 using PTC. (S)-1-Phenylethylamine the reaction is carried out in CH2Cl2 under the same solid-
is chosen as a chiral inducer of the diastereoselective alky- liquid PTC conditions, 2 is obtained with similar yield and
lation because it is inexpensive and available in high diastereoselectivity at room temperature (entry 4). In an
quantity in both enantiomeric forms. Initial studies on effort to improve the stereoselectivity of the reaction, a
alkylation of 1 are carried out with benzyl bromide (1.5 variety of PTC is employed in CH2Cl2 at room tempera-
equiv), tertrabutylammonium bromide (TBAB, 30 mol%) ture (entries 5-9). Most of the employed PTC’s, such as
and powered KOH (4 equiv) in toluene at room tempera- BC (benzethonium chloride), TEAB (tetraethylammoni-
ture. The reaction is completed after 30 min and provides um bromide), TBPB (tertrabutylphosphonium bromide)
the benzylated product 2 in 63% yield. The stereochemi- and poly-DADMAC (poly-diallyldimethylammonium
cal outcome of this alkylation process is determined after chloride) give the product with similar yields and er’s.
direct acidic hydrolysis of the crude reaction mixture to The lowest er is observed for the alkylation of 1 when
-
remove chiral auxiliary and imine moiety.6 The diastereo- [Fe(phen)3]22+PF6
[Tris(1,10-phenanthroline)iron(II)
meric mixture of 2 is transformed into methyl N-(diphe- hexafluorophosphate] is used as a PTC (entry 9).8
nylmethylene)glycinate (3) in 82% yield by the acidic
cleavage followed by both NH2 and CO2H protections.
When 18-crown-6 is used with KOH in CH2Cl2, the reac-
tion gives 2 in 66% yield with 68:32 er of 3 (entry 10). In
toluene, the reaction at room temperature for 10 min with
18-crown-6 gives increased stereoselectivity (74:26 er,
The enantiomeric ratio (er) of 3 is 68:32 with the S-enan-
tiomer as major enantiomer as shown in Table 1 (entry 1).7
The same reaction at 0 °C for 2 h gives the product 2 in entry 11). At -40 °C in toluene for 2 h, the reaction gives
52% yield with 68:32 er of 3 (entry 2) and the reaction at the benzylated product 2 in 63% yield with the 80:20 er of
-20 °C for 4 h gives the product 2 in 37% yield with 63:37 3 (entry 15). The choice of the cation of the base em-
Synlett 2001, No. 5, 613–616 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Practical Stereoselective Alkylation of Glycinamide
615
Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
(g) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron:
Asymmetry 2000, 11, 3277.
ployed has been proved to be of importance. With CsOH
at -40 °C for 12 h, the reaction gives the product 2 in 28%
yield with 55:45 er of 3 (entry 16), while with NaOH at
-40 °C the reaction proceeds very slowly. The low stereo-
selectivity and slow rate that are observed for the reaction
with CsOH or NaOH are probably explained by ineffi-
cient chelation of Cs+ or Na+ by 18-crown-6 and different
conformation of the generated enolate.9 At -78 °C in tolu-
ene for 6 h, the er of 3 dropped to 66:34 (entry 17).
(3) Recently, a new C2-symmetric chiral quatenary ammonium
salt derived from (S)-binaphthol has been successfully used:
(a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519. (b) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
(4) The studies of which we aware which use a chiral auxiliary to
provide significant diastereoselective PTC-catalyzed
alkylation are the alkylations of Oppolzer’s camphorsultam, 2-
[N-(N’-benzylprolyl)amino]benzophenone and 1,5-dimethyl-
4-phenylimidazolidin-2-one derivatives: Oppolzer, W.;
Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 6009.
Miyabe, H; Fujii, K.; Naito, T. Organic Lett. 1999, 1, 569.
Belokon, Y. N.; Tararov, V. I.; Maleev, V. I., Saleleva, T. F.;
Ryzhov, M. G. Tetrahedron: Asymmetry 1998, 9, 4249.
Guillena, G.; Najera, C. J. Org. Chem. 2000, 65, 7310.
(5) Preparation of 1 was performed by acylation of (S)-1-
phenylethylamine with chloroacetyl chloride, ammonolysis
with NH4OH in DMF and subsequent condensation with
benzophenone imine in 72% overall yield. Compound 1 is
stable at room temperature for several days, however,
sensitive to acidic conditions.
(6) Because two diastereomers of 2 are not clearly distinguishable
by 1H NMR (400 MHz), diastereomeric ratio (dr) of 2 is not
determined by 1H NMR.
(7) The presence of N-H bond is crucial for high yield and
selectivity. Under the same conditions, N’-Methyl-N’-[(S)-1'-
phenylethyl]-N-(diphenylmethylene)glycinamide gives the
benzylated product in 18% yield with 52:48 dr.
(8) Recently, Ru(II) complex and Ni(II) complex were used as a
PTC: Tzalis, D.; Knochel, P. Tetrahedron Lett. 1999, 40,
3685. Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmar,
V. S.; Kumar, R.; Kagan, H. B. Chinchilla, R.; Mar, P.; Niera,
C. Tetrahedron: Asymmetry 1998, 9, 851.
(9) Gobbi, A.; Landini, D.; Maia, A.; Petricci, S. J. Org. Chem.
1998, 63, 5356. Recent examples for using macrocyclic
polyethers as chiral PTCs: Bako, P.; Vizvardi, K.; Bajor, Z.;
Toke, L. Chem. Commun. 1998, 1193. Toke, L.; Fenichel, L.;
Albert, M. Tetrahedron Lett. 1995, 36, 5951.
(10) General procedure for the asymmetric alkylation of N’-
[(S)-1’-phenylethyl]-N-(diphenylmethylene)glycinamide
(1): To a solution of 1 in toluene (ca. 0.1 M) at -40 °C were
added 18-crown-6 (30 mol%), electrophile (2.0 equiv) and
powdered KOH (4 equiv). The resulting reaction mixture was
stirred at -40 °C for 2 h, and then 10 mL of ether was poured
into the mixture. The solid was removed from the mixture by
filtration and the filtrate was evaporated to give crude
alkylated product mixture. The crude material was purified by
column chromatography to give N’-[(S)-1’-phenylethyl]-N-
(diphenylmethylene)phenyl alaninamide (2). From 600 mg of
1, 476 mg (63% isolated yield) of a mixture of two
The reaction condition which gives best results in the
asymmetric syntheses of phenylalanine derivative (Table
1, entry 15) is used for reactions with various different
electrophiles.10 As shown in Table 2, four different meta-
substituted benzyl bromides are employed as electro-
philes for the syntheses of the unnatural meta-substituted
phenylalanine derivatives 10, 11, 12 and 13. The meta-
substituents seem to have no significant influence on the
obtained yields and er’s compared to benzyl bromide (en-
tries 1-4), m-iodobenzyl bromide providing 13 in 65%
yield with 83:17 er. The reaction with ethyl iodide gives
the alkylated product 8 with decreased yield and stereose-
lectivity (entry 5). Use of -bromo t-butylacetate as an
alkylating agent gives aspartic acid derivatives 15 with an
er of 80:20 with the S-enantiomer as the major enantiomer
(entry 6). The addition of KBr (10 equiv) to the reaction
mixture has no significant influence on yields and er’s as
shown in Table 2 (entries 1 and 6).
We conclude that N’-[(S)-1’-phenylethyl]-N-(diphenylm-
ethylene)glycinamide (1) is a practical chiral glycine re-
agent for the asymmetric syntheses of unnatural -amino
acid derivatives by alkylation-hydrolysis reactions under
very simple and mild PTC conditions. The commercial
availability of both enantiomers of the chiral auxiliary and
the relative ease in obtaining highly enantio-enriched
products suggest that this approach should be further de-
veloped. Application of this methodology to the asymmet-
ric syntheses of , -disubstituted amino acids is under
investigation.
Acknowledgement
This work was supported by Korea Research Foundation Grant
(KRF-99-003-D00126).
References and Notes
(1) (a) Dehmlow, E. V.; Dehmlow, S. S. In Phase Transfer
Catalysis; VCH: Weinheim 1993. (b) Starks, C. M.; Liotta, C.
L.; Halpern M. In Phase Transfer Catalysis-Fundamentals,
Application and Industrial Perspectives; Chapman and Hall:
New York 1994. (c) Halpern M. Phase Transfer Catalysis:
Mechanism and Syntheses ACS Symposium Series 659 1997.
(2) Most of successful examples use ammonium salts derived
from cinchona alkaloids as a chiral PTC: (a) Corey, E. J.; Noe,
M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (b) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599. (c) Arai,
S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39, 7563. (d)
Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron Lett. 1998,
39, 2997. (e) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am.
Chem. Soc. 1998, 120, 13000. (f) Horikawa, M.; Busch-
diastereomers of 2 was obtained as a colorless oil. 1H NMR
(CDCl3, 400 MHz): = 7.57-6.43 (m, 19H), 5.19 (m, 1H),
4.17 (dd, J = 3.4 and 8.7 Hz, 1H), 3.62 (s, 3H), 3.20-2.95 (m,
2H) 1.50 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
= 172.1, 170.4, 143.9, 143.7, 138.2, 135.9, 130.9, 129.1,
129.0, 128.8, 128.6, 128.5, 127.8, 127.6, 126.7, 126.3, 115.1,
68.1, 48.6, 42.0, 22.6. An aqueous solution of HCl (5 M,
4 mL) was added to 2 and the resulting solution was heated at
reflux for 24 h. The acidic solution was extracted with 20 mL
portions of CH2Cl2 and the aqueous layer was concentrated
in vacuo. The crude deprotected amino acid was treated
with acetyl chloride (1 mL) and CH3OH (3 mL) at room
temperature and concentrated in vacuo to give the methyl ester
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616
H. J. Kim et al.
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material prepared from commercially available (S)-
Phenylalanine. (Chiralcel OD column; 10% 2-propanol in
hexane; 0.5 mL/min; The S-enantiomer (major) had a
retention time of 18 min, and the R-enantiomer (minor) had a
retention time of 9 min).
amino acid hydrochloride. The resulting material was treated
with benzophenone imine (1.0 equiv) in CH2Cl2 for 12 h
followed by regular extractive workup and column
chromatography to give 3 as a colorless oil in 82% yield. 1H
NMR (CDCl3, 400 MHz): = 7.58-6.59 (m, 15H), 4.26 (dd,
J = 4.4 and 8.6 Hz, 1H), 3.73 (s, 3H), 3.30-3.15 (m, 2H). The
enantiomeric ratio of 3 was determined to be 80:20 in favor of
the S-enantiomer by chiral HPLC using racemic material as a
standard. The absolute configuration was assigned by
comparison of CSP-HPLC retention time with authentic
Article Identifier:
1437-2096,E;2001,0,05,0613,0616,ftx,en;Y06101ST.pdf
Synlett 2001, No. 5, 613–616 ISSN 0936-5214 © Thieme Stuttgart · New York