Enantioselective synthesis of (R)- and (S)-α-alkylcysteines via phase-transfer catalytic alkylation

Article abstract of DOI:10.1021/jo061107t

We reported efficient enantioselective synthetic methodologies for (R)-α-alkylcysteines and (S)-α-alkylcysteines. The phase-transfer catalytic alkylation of 2-phenyl-2-thiazoline-4-carboxylic acid tert-butyl ester and 2-o-biphenyl-2-thiazoline-4-carboxyli

Full text of DOI:10.1021/jo061107t

a bislactim ether prepared from valine as a chiral auxiliary,5
(2) nucleophilic ring opening of a chiral aziridine or chiral
â-lactone with thiolates,6 (3) self-reproduction of chirality using
oxazolidinone or thiazolidinone derivatives,7 and (4) enzymatic
desymmetrization of monomethyl dimethylmalonate.8 However,
since most of the reported methods employed chiral starting
materials or chiral auxiliaries, their applications to industrial
processes for the mass production of chiral R-alkylcysteines
might not be straightforward. In this paper, we would like to
report new and efficient synthetic methods for (R)-R-alkylcys-
teines and (S)-R-alkylcysteines via phase-transfer catalytic
R-alkylation of thiazoline-4-carboxylates, which could be ap-
plied to industrial processes.
Enantioselective Synthesis of (R)- and
(S)-r-Alkylcysteines via Phase-Transfer Catalytic
Alkylation
Taek-Soo Kim,† Yeon-Ju Lee,† Byeong-Seon Jeong,‡
Hyeung-geun Park,*,† and Sang-sup Jew*,†
Research Institute of Pharmaceutical Science and College of
Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea,
and College of Pharmacy, Yeungnam UniVersity, Gyeongsan
712-749, Korea
hgpk@plaza.snu.ac.kr
Quite recently, we reported a new synthetic method for (()-
R-alkylserines by the selective R-alkylation of tert-butyl 2-phen-
yl-2-oxazoline-4-carboxylate in phase-transfer catalytic condi-
tions.9 As successive studies, the enantioselective versions using
chiral phase-transfer catalysts were also disclosed (Scheme 1).10
In addition, we reported a chiral auxiliary method via phase-
transfer catalytic alkylation of the oxazoline-4-carboxylate,
possessing camphorsultam as a chiral auxiliary (Scheme 1).11
These studies all showed that the phase-transfer catalytic
conditions are very efficient for the R-alkylation of the oxazo-
line-4-carboxylate system. Based on our previous results, we
attempted to apply the phase-transfer catalytic alkylation condi-
tions to 2-aryl-2-thiazoline-4-carboxylate esters (8) for the
enantioselective synthesis of chiral R-alkylcysteines (Scheme 2).
First, we prepared the thiazoline-4-carboxylate (8a, 8b). The
substrate 8a was easily prepared by the coupling of ethyl
benzimidate and cysteine methyl ester, followed by transesteri-
fication12 using AlMe3 in 80% yield from 11 (Scheme 3).
The substrate 8b was prepared from 2-biphenylcarboxylic acid
(13) in three steps. The coupling of 13 and 14, followed by
cyclization13 in the presence of triphenylphosphine oxide and
trifluoromethanesulfonic anhydride, gave the thiazoline methyl
ester 16, which was converted to the corresponding tert-butyl
ester 8b by transesterification using AlMe3 in 81% yield from
14 (Scheme 4).
ReceiVed May 31, 2006
We reported efficient enantioselective synthetic methodolo-
gies for (R)-R-alkylcysteines and (S)-R-alkylcysteines. The
phase-transfer catalytic alkylation of 2-phenyl-2-thiazoline-
4-carboxylic acid tert-butyl ester and 2-o-biphenyl-2-thia-
zoline-4-carboxylic acid tert-butyl ester, in the presence of
chiral catalysts (1 or 2), gave the corresponding alkylated
products, which could be hydrolyzed to provide (R)-R-
alkylcysteines (67->99% ee) and (S)-R-alkylcysteines (66-
88% ee), respectively.
As one of the R,R-dialkyl amino acids, R-alkylcysteines are
valuable building blocks for the biologically active peptidomi-
metics, since they can not only resist enzymatic degradation
but also form the stabilized, preferred conformations of the
peptide backbone.1 In addition, they are able to form a further
constrained cyclic peptide structure by disulfide bond formation.
Several natural products involving R-alkylcysteine moieties
exist, such as tantazoles,2 mirabazoles,3 and thiangazole,4 which
exhibit antitumor and anti-HIV-1 activities.
For the phase-transfer catalytic alkylation, we adapted our
previous reaction conditions.10 The phase-transfer catalytic
(5) (a) Groth, U.; Scho¨llkopf, U. Synthesis 1983, 37-38. (b) Singh, S.;
Rao, S. J.; Pennington, M. W. J. Org. Chem. 2004, 69, 4551.
(6) (a) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem. 1995, 60, 790-
791. (b) Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 1035-1037. (c)
Fukuyama, T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449-8450.
(7) (a) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5566-
5568. (b) Pattenden G.; Thom, S. M.; Jones, M. F. Tetrahedron 1993, 49,
2131-2138. (c) Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. Tetrahedron
1993, 49, 5359-5364.
A number of enantioselective synthetic methods for R-alky-
lcysteines have been reported so far. Their main synthetic
strategies can be classified as follows: (1) thiomethylation of
(8) Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403-5406.
(9) Park, H.-g.; Lee, J.; Kang, M. J.; Lee, Y.-J.; Jeong, B.-S.; Lee, J.-
H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Jew, S.-s. Tetrahedron 2004, 60,
4243.
(10) (a) Jew, S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee,
J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Ku, J.-M.; Park, H.-g. Angew.
Chem., Int. Ed. 2004, 43, 2382. (b) Lee, Y.-j.; Lee, J.; Kim, M.-j.; Kim,
T.-S.; Park, H.-g.; Jew, S.-s. Org. Lett. 2005, 7, 1557.
(11) Lee, J.; Lee, Y.-I.; Kang, M. J.; Lee, Y.-j.; Jeong, B.-S.; Lee, J. H.;
Kim, M.-j.; Choi, J.-y.; Ku, J.-M.; Park, H.-g.; Jew, S.-s. J. Org. Chem.
2005, 70, 4158.
* To whom correspondence should be addressed. Tel: 82-2-880-7871, Fax:
82-2-872-9129.
† Seoul National University.
‡ Yeungnam University.
(1) (a) Ma, J. S. Chim. OGGI 2003, 21, 65-68. (b) Goodman, M.; Ro,
S. In Burger’s Medicinal Chemistry and Drug DiscoVery, 5th ed.; Wolff,
M. E., Ed.; John Wiley & Sons: 1995; Vol. 1, Chapter 20, pp 803-861.
(2) Carmeli, S.; Paik, S.; Moore, R. E.; Patterson, G. M. L.; Yoshida,
W. Y. Tetrahedron Lett. 1993, 34, 6680-6684.
(3) (a) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35,
1379-1382. (b) Parsons, R. L.; Heathcock, C. H. Tetrahedron Lett. 1994,
35, 1383-1384.
(4) (a) Parsons, R. L.; Heathcock, C. H. J. Org. Chem. 1994, 59, 4733-
4734. (b) Boyce, R. L.; Mulqueen, G. C.; Pattenden, G. Tetrahedron Lett.
1994, 35, 5705-5708.
(12) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30,
6009.
(13) You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003,
42, 83.
10.1021/jo061107t CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006
8276
J. Org. Chem. 2006, 71, 8276-8278

SCHEME 1
SCHEME 2
SCHEME 4
SCHEME 3
the alkylation of the oxazoline substrate 3, even in the presence
of a reduced amount of the catalyst 1 (1 mol %), instead of the
2.5 mol % of 1 used in the alkylation of the phenyloxazoline
substrate 3. In the case of the 2-biphenylthiazoline substrate
8b, the alkylations were performed using 10 mol % of the
catalyst 2 along with 8b, alkyl halide (5.0 equiv), and solid
CsOH (5.0 equiv) in dichloromethane at 0 °C for 40-120 min.
As shown in Table 2, high enantioselectivities were observed,
but they were slightly less than those of substrate 8a. Most of
the activated alkyl halides showed high chemical yields at 0
°C, but no alkylation product was observed with the aliphatic
halides. Relatively lower chemical yields, but comparable
enantioselectivities, were observed at -40 °C (data not shown).
The reaction rates were 10 times faster than those of the
alkylation of the oxazoline substrate 5, in agreement with the
alkylation of substrate 8b. The hydrolysis of 9a-e (>99% ee)
and 9b-d (84% ee) with 6 N HCl afforded (R)-(+)-benzylcys-
teine (98%) and (S)-(-)-benzylcysteine (97%), respectively.
In conclusion, we developed efficient enantioselective syn-
thetic methodologies for (R)-R-alkylcysteines and (S)-R-alky-
lcysteines by the phase-transfer catalytic alkylation of 2-phenyl-
alkylation of 8a was performed using 1 mol % of the catalyst
1 along with alkyl halides (5.0 equiv) and solid KOH (5.0 equiv)
in toluene at 0 °C for 30-45 min.
As shown in Table 1, very high enantioselectivities (84-
>99% ee) were observed, except with hexyl iodide (entry a,
67% ee). However, the chemical yields varied, depending on
the reactivity of the alkyl halides. All of the benzyl halides gave
high chemical yields (entry e-i; 90∼>99%), but the allylic
halides and propargylic halide gave modest chemical yields
(entry b-d; 67->68%). In the case of the aliphatic halide, an
even lower chemical yield was observed (entry a; 42%).
Notably, the reaction rates were 10 times faster than those of
J. Org. Chem, Vol. 71, No. 21, 2006 8277

TABLE 1. Enantioselective Phase-Transfer Catalytic Alkylation
TABLE 2. Enantioselective Phase-Transfer Catalytic Alkylation
a Isolated yields. b The enantiopurity was determined by HPLC analysis
of the corresponding methyl esters (9a′) prepared from 9a using a chiral
column (Chiralcel AD or OD) with hexanes/2-propanol as eluents. c The
absolute configuration was assigned by the comparison of the specific optical
rotation value of the R-benzylcysteine prepared by the acidic hydrolysis of
9a-e with the literature value.7b
a Isolated yields. b The enantiopurity was determined by HPLC analysis
of 9b using a chiral column (Chiralcel AD) with hexanes/2-propanol as
eluents. c The absolute configuration was assigned by the comparison of
the specific optical rotation value of the R-benzylcysteine prepared by the
acidic hydrolysis of 9b-d with the literature value.7b
chromatography (silica gel, hexanes/EtOAc ) 50:1) to afford 9a-e
(63.7 mg, 90% yield) as a pale yellow oil. Because the two
enantiomers of 9a-e were not fully separated by chiral HPLC, the
enantioselectivity was determined by the chiral HPLC analysis of
the corresponding methyl ester, prepared from the hydrolysis of
9a-e followed by methylation using the excess of diazomethane.
The enantioselectivity was determined as >99% ee [chiral HPLC
analysis (Chiralcel AD-H, hexanes:2-propanol ) 99:1), flow rate
) 1.0 mL/min, 23 °C, ) 254 nm, retention time, S (minor) 12.3
min, R (major) 15.5 min, >99% ee]. Absolute configuration was
determined by the comparison of the optical rotation of R-benzyl-
cysteine prepared from the acidic hydrolysis of 9a-e with the
reported value.7b
2-thiazoline-4-carboxylic acid tert-butyl ester (8a) and 2-o-
biphenyl-2-thiazoline-4-carboxylic acid tert-butyl ester (8b),
respectively. The easy preparation of the substrate, the high
enantioselectivity, and the very mild reaction conditions could
make this method quite practical for industrial processes
involving chiral R-alkylcysteines.
Experimental Section
General Procedure for the Enantioselective Alkylation of
2-Phenyl-2-thiazoline-4-carboxylic Acid tert-Butyl Ester (8a) or
2-Biphenyl-2-yl-4,5-dihydrothiazole-4-carboxylic Acid tert-Butyl
Ester (8b) under Phase-Transfer Conditions (Benzylation). To
a toluene (1.0 mL) solution of 2-phenyl-2-thiazoline-4-carboxylic
acid tert-butyl ester (8a, 50.0 mg, 0.2 mmol) were added the chiral
catalyst 1 (1.8 mg, 0.002 mmol), KOH (56.1 mg, 1.0 mmol), and
benzyl bromide (0.1 mL, 1.0 mmol) at 0 °C, and the reaction
mixture was stirred for 40 min. After completion of the reaction,
the reaction mixture was diluted with ethyl acetate (20 mL), washed
with brine (2 × 5 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
Acknowledgment. This work was supported by a grant
(10541) from the Seoul R&BD Program.
Supporting Information Available: Representative experi-
mental procedures as well as spectroscopic characterizations of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO061107T
8278 J. Org. Chem., Vol. 71, No. 21, 2006