Enantioselective synthesis of (R)-α-alkylhomoserines and (R)-α-alkylhomocysteines via phase-transfer catalytic alkylation

Article abstract of DOI:10.1055/s-0028-1087808

Efficient enantioselective synthetic methods for (R)-α- alkylhomoserines and (R)-α-alkylhomocysteines have been developed. The phase-transfer catalytic alkylation of 2-phenyl-5,6-dihydro-4H-1,3-oxazine-4- carboxylic acid tert-butyl ester and 2-phenyl-5,6-

Full text of DOI:10.1055/s-0028-1087808

CLUSTER
671
Enantioselective Synthesis of (R)-a-Alkylhomoserines and
(R)-a-Alkylhomocysteines via Phase-Transfer Catalytic Alkylation
E
a
nantioselective
a
Synthesis
e
of
(
R
)-
a
-A
k
lkylhomoser
-
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Fax +82(2)8729129; E-mail: hgpk@snu.ac.kr
Institute for Drug Research and College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
b
Received 30 September 2008
Very recently, we reported highly enantioselective cata-
Abstract: Efficient enantioselective synthetic methods for (R)-a-
alkylhomoserines and (R)-a-alkylhomocysteines have been devel-
oped. The phase-transfer catalytic alkylation of 2-phenyl-5,6-di-
hydro-4H-1,3-oxazine-4-carboxylic acid tert-butyl ester and 2-
lytic synthetic methods of a-alkylserines 1 and a-alkyl-
cysteines
2 (Figure 1) by the alkylation of 2-
aryloxazoline-4-carboxylic acid tert-butyl ester (5,
phenyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylic acid tert-butyl X = O) for 1 and 2-arylthiazoline-4-carboxylic acid tert-
ester, in the presence of N-2¢,3¢,4¢-trifluorobenzylcinchonidinium
bromide, gave the corresponding alkylated products, which could
be hydrolyzed to provide (R)-a-alkylhomoserines (up to 97% ee)
and (R)-a-alkylhomocysteines (up to 91% ee), respectively.
butyl ester (5, X = S) for 2 under phase-transfer condi-
tions (Scheme 1).5
t
t
CO2 Bu
CO2 Bu
N
X
N
X
*
H+
Key words: phase-transfer catalytic alkylation, enantioselective
synthesis, (R)-a-alkylhomoserines, (R)-a-alkylhomocysteines
asymmetric
1 or 2
Ar
Ar
R
hydrolysis
PTC
alkylation
5
6
X = O or S
Together with optically active a,a-dialkyl amino acids,
chiral homoamino acids have been valuable building
blocks for the biologically active peptidomimetics, since
these non-natural synthetic amino acids cannot only resist
enzymatic degradation but also form higher binding affin-
ity due to their extra binding between an a-substituent and
receptor.1 In particular, hydroxy and thiol groups in a-
substitutents can affect the secondary structure of peptides
by hydrogen bonding or disulfide bond formation.2 There-
fore, a-alkylhomoserines and a-alkylhomocysteines can
be potentially valuable components in peptidomimetics,
and N-acylhomoserine lactones have been extensively
studied as quorum-sensing molecules in bacteria system.3
Scheme 1 Enantioselective synthesis of 1 and 2 by PTC alkylation
The previous studies revealed that the oxazoline and thia-
zoline moieties cannot only increase the acidity of a-pro-
ton for PTC alkylation but also act as efficient protecting
groups of a-amino and b-hydroxyl or b-thiol groups, re-
spectively. In addition, both the tert-butyl ester and the
nature of the 2-aryl group play important roles for high
enantioselectivity, and the phase-transfer catalytic condi-
tions are very efficient for the a-alkylation. Based on our
previous results, we attempted to prepare optically active
a-alkylhomoserines 3 and a-alkylhomocysteines 4 by
asymmetric PTC alkylation of 2-phenyl-5,6-dihydro-4H-
1,3-oxazine-4-carboxylic acid tert-butyl ester (7) and 2-
(X = O, n = 1)
(X = S, n = 1)
(X = O, n = 2)
(X = S, n = 2)
1, α-alkylserines
H2N
CO2H
R
*
2, α-alkylcysteines
3, α-alkylhomoserines
4, α-alkylhomocysteines
phenyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylic
tert-butyl ester (8), respectively (Scheme 2).
acid
n
XH
Figure 1
t
t
Ph
N
CO2 Bu
Ph
N
CO2 Bu
H+
hydrolysis
asymmetric
3 or 4
R
PTC
alkylation
X
X
So far, a number of enantioselective synthetic methods
have been developed for chiral a-alkylhomoserines, but
most of them employed chiral auxiliaries, and a direct
synthetic method for chiral a-alkylhomocysteines has not
been reported yet.4 In this letter, we report new catalytic
enantioselective synthetic methods of (R)-a-alkylho-
moserines and (R)-a-alkylhomocysteines via phase-trans-
fer catalytic (PTC) alkylation, which could be applied to
industrial processes.
9 X = O
10 X = S
7 X = O
8 X = S
Scheme 2 Strategy for the synthesis of 3 and 4
The oxazine substrate 7 was prepared from commercially
available tert-butyl a-allylglycinate (11) in four steps with
84% overall yield (Scheme 3). Ozonolysis of terminal
alkene in the N-benzoyl derivatives of 11 in the presence
of triphenylphosphine followed by reduction of the result-
ing aldehyde with sodium borohydride afforded the alco-
hol 12. Cyclization of 12 with DAST6 gave the oxazine
substrate 7. The thiazine substrate 8 was prepared from 12
in four steps with 77% overall yield (Scheme 3). After
SYNLETT 2009, No. 4, pp 0671–0674
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087808; Art ID: Y01008ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

672
T.-S. Kim et al.
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TBS protection of the hydroxy group of 12, thionation of
the amide carbonyl was carried out with Lawesson’s
reagent to provide the thioamide. Deprotection of the TBS
group gave 13, and finally DAST-mediated cyclization af-
forded the thiazine substrate 8.
Table 1 Optimization of Reaction Conditions
PTC (10 mol%)
BnBr (5 equiv)
t
t
CO2 Bu
*
Ph
N
CO2 Bu
Ph
N
base (5 equiv)
toluene, 0 °C
O
O
Ph
7
9d
1. PhCOCl, NaHCO3
H2O–THF (1:1)
r.t., 2 h, 94%
Entry
PTC
Base
Time
(h)
Yield
(%)a
ee
t
(%)b
H
N
t
H2N
CO2 Bu
Ph
CO2 Bu
1
14
15
16
17
16
16
16
16
16
solid KOH
solid KOH
solid KOH
solid KOH
solid KOH
solid KOH
solid NaOH
solid CsOH
50% aq KOH
2
83
65
70
46
37
36
20
55
48
93
67
97
93
85
95
39
86
91
2. O3, EtOAc, –78 °C, 1.5 h;
Ph3P, 0 °C, 20 min, 99%
O
2
8
OH
3. NaBH4, MeOH
0 °C, 10 min, 94%
11
12
3
1
DAST
4c
5d
6e
7
15
CH2Cl2
–78 °C
3 h
2.5
1. TBSCl, imidazole
CH2Cl2, r.t., 15 min, 99%
H
N
7 (96%)
8 (96%)
t
12
22
1
Ph
CO2 Bu
12
DAST
CH2Cl2
–78 °C, 1 h
2. Lawesson's reagent
C6H6, reflux, 30 min, 82%
S
8
3. n-Bu4NF, CH2Cl2
r.t., 30 min, 99%
OH
13
9
90
Scheme 3 Preparation of PTC substrates 7 and 8
a Isolated yield.
b The enantiopurity was determined by HPLC analysis of the corre-
sponding methyl ester prepared from 9d via the hydrolysis of tert-
butyl ester in trifluoroacetic acid followed by methyl esterification
with diazomethane, using a chiral column (Chiralcel AD-H) with
hexanes–2-PrOH (95:5) as eluent (1.0 mL/min).
For the phase-transfer catalytic alkylation of 7 and 8, we
adapted our previous reaction conditions.5 To find the op-
timal chiral quaternary ammonium salt as a phase-transfer
catalyst, enantioselective phase-transfer catalytic benzy-
lation was performed in the presence of the representative
catalysts7 14–17 (Figure 2) along with the oxazine sub-
strate 7, benzyl bromide (5.0 equiv), and solid KOH (5.0
equiv) in toluene at 0 °C.
c 1 mol% of PTC 17 was used.
d Dichloromethane was used as a solvent.
e The reaction was carried out at –20 °C.
HCD
HCD
HCD
HCD
As shown in Table 1, the cinchona catalyst having 2,3,4-
trifluorobenzyl moiety 16 delivered the benzylated prod-
uct 9d with the highest enantioselectivity (entry 3, 70%,
97% ee) among the employed catalysts (entries 1–4). (S)-
Binaphthol-derived catalyst 17 showed comparable enan-
tioselectivity (entry 4, 46%, 93% ee) but quite longer
reaction time with lower chemical yield. It was notable
that these results were quite different from the benzylation
of the oxazoline substrate 5.5a In the case of tert-butyl phe-
nyl-2-oxazoline-4-carboxylate (5), the best enantioselec-
tivity was achieved with the catalyst 17 but all other
cinchona catalysts 14–16 gave far lower enantioselectivi-
ties. We presumed that catalyst 16 could form more favor-
able ionic complex intermediate with the E-enolate of the
six-membered oxazine substrate than that of the five-
membered oxazoline substrate. The lower temperature
gave comparable enantioselectivity but showed quite de-
crease of chemical yield (entry 6, 36%, 95% ee). Both
lower enantioselectivity and chemical yield were ob-
served in dichloromethane as solvent (entry 5, 37%, 85%
ee). Base screening was also performed (entries 3, 7–9),
and solid KOH provided the best enantioselectivity. Gen-
erally, the higher basicity gave the higher enantioselectiv-
ity with lower reaction time.
F
F
14
15
F
F
F
16
F
F
HCD =
Br–
N
Br–
N
O
N
F
F
17
Figure 2
alkyl halides under optimized reaction conditions (entry 3
in Table 1). As shown in Table 2, both the enantioselec-
tivity and the chemical yield were dependent on the reac-
tivity of the alkyl halides. Very high enantioselectivities
were obtained with active alkyl halides (Table 2, entries
2–7, 90–97% ee), but relatively lower enantioselectivity
with longer reaction time was observed with methyl
The catalyst 16 was chosen for further investigation of the
enantioselective phase-transfer alkylation with various
Synlett 2009, No. 4, 671–674 © Thieme Stuttgart · New York

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Enantioselective Synthesis of (R)-a-Alkylhomoserines
673
Table 2 Enantioselective PTC Alkylation of the Oxazine Substrate 7
Table 3 Enantioselective PTC Alkylation of the Thiazine Substrate 8
16 (10 mol%)
t
t
16 (10 mol%)
t
t
Ph
N
CO2 Bu
Ph
N
CO2 Bu
Ph
N
CO2 Bu
Ph
N
CO2 Bu
RX (5 equiv)
RX (5 equiv)
R
R
KOH (5 equiv)
toluene, 0 °C
KOH (5 equiv)
toluene, 0 °C
O
O
S
S
9
7
8
10
Entry RX
Time
Yield ee
Config.c
Entry RX
Time Yield ee
(min) (%)a (%)b
Config.c
(min) (%)a
(%)b
1
2
MeI
480
20
56
70
78
R
R
1
2
MeI
120
40
56
67
85
88
R
R
95
Br
Br
Br
Br
3
4
20
60
76
70
90
97
R
R
3
4
40
20
71
70
88
91
R
R
Br
Br
Br
Br
Br
Br
5
6
7
30
20
25
73
80
82
97
97
96
R
R
R
5
6
7
20
10
20
72
77
74
87
89
89
R
R
R
F
F
Br
Br
a Isolated yield.
a Isolated yield.
b The enantiopurity was determined by chiral HPLC analysis of the
corresponding methyl esters prepared from 9.
b The enantiopurity was determined by chiral HPLC analysis of the
corresponding methyl esters prepared from 9.
c For determination of the absolute configuration, see text.
c For determination of the absolute configuration, see text.
iodide (entry 1, 78% ee). The absolute configuration of 9a
was assigned as R by the comparison of the specific opti-
cal rotation value of the a-methylhomoserine {3a, [a]D
+10.3 (c 1.0, H2O)} prepared by acidic hydrolysis of 9a
with the literature value {(S)-(–)-3a,8 [a]D27 –15.3 (c 0.9,
H2O)}. The absolute configurations of the other products
9b–g were tentatively assigned as R from the absolute
configuration of 9a.
and (R)-(+)-a-benzylhomocysteine (97% yield), respec-
tively.
25
In summary, we have developed efficient enantioselective
synthetic methods for (R)-a-alkylhomoserines and (R)-a-
alkylhomocysteines by the phase-transfer catalytic alkyla-
tion of 2-phenyl-5,6-dihydro-4H-1,3-oxazine-4-carbox-
ylic acid tert-butyl ester (7) and 2-phenyl-5,6-dihydro-
4H-1,3-thiazine-4-carboxylic acid tert-butyl ester (8), re-
spectively.10 The easy preparation of the substrates, the
high level of stereoinduction, and the very mild reaction
conditions could make these new methods quite efficient
and practical for industrial processes.
Phase-transfer catalytic alkylation of the thiazine sub-
strate 8 was performed under the same reaction conditions
as of the oxazine substrate 7. As shown in Table 3, high
optical purities (85–91% ee) were also observed, but
slightly less than those of the oxazine product 9. The reac-
tion rates were relatively faster than those of the oxazine
substrate 7, in agreement with the alkylation of the five-
membered substrate 5.5 The absolute configuration of 10d
was assigned as R by the comparison of the specific opti-
Acknowledgment
This work was supported by a grant (10541) from the Seoul R&BD
Program.
25
cal rotation value of the a-benzylmethionine {[a]D
+11.5 (c 0.5, H2O)} prepared by acidic hydrolysis of 10d
followed by S-methylation with the literature value {(R)-
References and Notes
(+)-a-benzylmethionine,9 [a]D +15.0 (c 0.63, H2O)}.
20
(1) (a) Ma, J. S. Chim. Oggi 2003, 21, 65. (b) Goodman, M.;
Ro, S. In Burger’s Medicinal Chemistry and Drug
Discovery, 5th ed., Vol. 1; Wolff, M. E., Ed.; John Wiley and
Sons: Chichester, 1995, Chap. 20, 803–861.
(2) (a) Barrett, G. C. Amino Acids, Peptides and Proteins, Vol.
13; The Chemical Society: London, 1980, 1. (b) Hunt, S. In
Chemistry and Biochemistry of the Amino Acids; Barrett,
G. C., Ed.; Chapman and Hall: London, 1985, 55.
The absolute configurations of the other products 10a–c
and 10e–g were also tentatively assigned as R from the ab-
solute configurations of 10d.
Hydrolysis of 9d (97% ee) and 10d (91% ee) with 6 N
HCl afforded (R)-(+)-a-benzylhomoserine (98% yield)
(c) Richardson, J. S. Biophys. J. 1992, 63, 1186.
Synlett 2009, No. 4, 671–674 © Thieme Stuttgart · New York

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T.-S. Kim et al.
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(3) (a) Chhabra, S. R.; Harty, C.; Hooi, D. S. W.; Daykin, M.;
Williams, P.; Telford, G.; Pritchard, D. I.; Bycroft, B. W.
J. Med. Chem. 2003, 46, 97. (b) Geske, G. D.; O’Neill, J. C.;
Blackwell, H. E. ACS Chem. Biol. 2007, 2, 315.
(7) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414. (b) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee,
J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew.
Chem. Int. Ed. 2002, 41, 3036. (c) Jew, S.-s.; Yoo, M.-S.;
Jeong, B.-S.; Park, H.-g. Org. Lett. 2002, 4, 4245. (d) Ooi,
T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
5139.
(8) Terashima, S.; Achiwa, K.; Yamada, S.-i. Chem. Pharm.
Bull. 1965, 13, 1399.
(9) Procopiou, P. A.; Ahmed, M.; Jeulin, S.; Perciaccante, R.
Org. Biomol. Chem. 2003, 1, 2853.
(c) Kaufmann, G. F.; Sartorio, R.; Lee, S.-h.; Mee, J. M.;
Altobell, L. J. III; Kujawa, D. P.; Jeffries, E.; Clapham, B.;
Meijler, M. M.; Janda, K. D. J. Am. Chem. Soc. 2006, 128,
2802. (d) Geske, G. D.; O’Neill, J. C.; Miller, D. M.;
Mattmann, M. E.; Blackwell, H. E. J. Am. Chem. Soc. 2007,
129, 13613.
(4) (a) Schollkopf, U.; Lonsky, R. Synthesis 1983, 675.
(b) Seebach, D.; Aebi, J. D.; Naef, R.; Weber, T. Helv. Chim.
Acta 1985, 68, 144. (c) Smith, A. B. III; Pastemak, A.;
Yokoyama, A.; Hirschmann, R. Tetrahedron Lett. 1994, 35,
8977. (d) Ayoub, M.; Chassaing, G.; Loffet, A.; Lavielle, S.
Tetrahedron Lett. 1995, 36, 4069. (e) Berkowitz, D. B.;
McFadden, J. M.; Sloss, M. K. J. Org. Chem. 2000, 65,
2907.
(5) (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) 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. (c) LeeY, j.; Lee, J.; Kim,
M.-j.; Kim, T.-S.; Park, H.-g.; Jew, S.-s. Org. Lett. 2005, 7,
1557. (d) LeeY, j.; Lee, J.; Kim, M.-j.; Jeong, B.-S.; Lee,
J.-H.; Kim, T.-S.; Ku, J.-M.; Park, H.-g.; Jew, S.-s. Org. Lett.
2005, 7, 3207. (e) Lee, J.; Lee, Y.-I.; Kang, M. J.; LeeY, 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.
(f) Kim, T.-S.; LeeY, j.; Jeong, B.-S.; Park, H.-g.; Jew, S.-s.
J. Org. Chem. 2006, 71, 8276.
(10) Representative Procedure for the Enantioselective
Alkylation (Benzylation) of tert-Butyl 2-Phenyl-5,6-
dihydro-4H-1,3-oxazine-4-carboxylate (7)
To a solution of tert-butyl 2-phenyl-5,6-dihydro-4H-1,3-
oxazine-4-carboxylate (7, 50 mg, 0.2 mmol) in toluene (1.0
mL) were successively added the chiral PTC 16 (11 mg, 0.02
mmol), solid KOH (54.1 mg, 1.0 mmol), and benzyl bromide
(0.1 mL, 1.0 mmol) at 0 °C. The reaction mixture was stirred
for 1 h at 0 °C. After completion of the reaction, the reaction
mixture was diluted with EtOAc (20 mL), and the EtOAc
solution was washed with brine (2 × 5 mL). The organic
solution was then dried over anhyd MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2; hexanes–EtOAc, 50:1) to afford the
benzylated product 9d (47 mg, 70% yield) as a pale yellow
oil. Because the two enantiomers of 9d were not fully
separated by chiral HPLC, the enantioselectivity was
determined by the chiral HPLC analysis of the
corresponding methyl ester which was prepared from the
hydrolysis of 9d followed by methylation using the excess of
diazomethane. The enantioselectivity was determined as
97% ee [Chiralcel AD-H column, hexanes–2-PrOH (95:5),
flow rate = 1.0 mL/min, 23 °C, 254 nm, tR (R, major) = 5.2
min; tR (S, minor) = 6.8 min, 97% ee]. Absolute configu-
ration was tentatively determined as R based on the absolute
configuration of 9a.
(6) Mahler, S. G.; Serra, G. L.; Antonow, D.; Manta, E.
Tetrahedron Lett. 2001, 42, 8143.
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