Highly enantioselectlve phase-transfer-catalytic alkylation of 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester for the asymmetric synthesis of α-alkyl serines

Article abstract of DOI:10.1002/anie.200353496

A facile synthesis of chiral α-alkyl serines 3 involves the asymmetric alkylation of substrates 1 with alkyl halides (RX) under phase-transfer catalysis (PTC), followed by acidic hydrolysis of the alkylation products 2. The phenyl oxazoline moiety enhance

Full text of DOI:10.1002/anie.200353496

Communications
Phase-Transfer Catalysis
Highly Enantioselective Phase-Transfer-Catalytic
Alkylation of 2-Phenyl-2-oxazoline-4-carboxylic
Acid tert-Butyl Ester for the Asymmetric
Synthesis of a-Alkyl Serines**
Sang-sup Jew,* Yeon-Ju Lee, Jihye Lee,
Myoung Joo Kang, Byeong-Seon Jeong, Jeong-Hee Lee,
Mi-Sook Yoo, Mi-Jeong Kim, Sea-hoon Choi, Jin-
Mo Ku, and Hyeung-geun Park*
Chiral a-alkyl serines have been extensively studied owing to
their important roles in synthetic and biological chemistry.[1]
Their quaternary chiral moieties are frequently found in
several biologically active natural products[2] and chiral a-
alkyl serines themselves are useful synthetic building blocks.[1]
Also, as the hydroxy group of (S)-serine has an important role
in stabilizing the a-helical secondary structure of enzymes by
hydrogen bonding with amide carbonyl groups, a-alkyl serine
moieties have been employed in the design of biologically
active peptidomimetics.[3] Historically, a number of enantio-
selective synthetic methods have been reported for chiral a-
alkyl serines,[4] but only a few are practical, and only one was
carried out under catalytic conditions.[4k]
Recently, several efficient chiral phase-transfer catalysts
were developed from Cinchona alkaloids (1,[5] 2,[6] 3,[7]) and
(S)-binaphthyl derivative (4[8]), and successfully applied to the
asymmetric synthesis of natural and non-natural a-amino
acids[5–8a] and a,a-dialkyl a-amino acids[8b,9]
protecting group for the both the amino and hydroxy groups
in the serine ester.
As shown in the synthetic strategy in Scheme 1, the
asymmetric phase-transfer alkylation of 7 with alkyl halides,
by the enantioselective alkylation of ben-
zophenone imine glycine tert-butyl ester
(5[10]) and aryl aldimine alanine tert-butyl
ester (6[9]), respectively. As part of our
program for the development of practical
and synthetic methods for a-alkyl serines,
Scheme 1. Asymmetric alkylation of 7 with alkyl halides under phase-transfer catalysis (PTC)
followed by acidic hydrolysis to provide chiral a-alkyl serines.
we examined the use of asymmetric phase-
transfer catalytic alkylation.[11]
First, we investigated the best substrate
for phase-transfer catalytic alkylation. It should have an
acidic proton for abstraction by mild bases, such as 5 and 6.
We chose the phenyl oxazoline derivative of serine tert-butyl
ester, 7. The oxazoline moiety not only enhances the acidity of
the a proton of the ester, but also acts as an excellent
followed by acidic hydrolysis provided chiral a-alkyl serines.
The methyl ester derivative was used as a substrate for the
synthesis of (Æ )-a-alkyl serines, but it requires a strong base
(such as LDA) and low temperatures (below À 508C)
otherwise b-eliminations are predominant.[4l] In the case of
nBuLi, only the corresponding n-butyl ketone was obtained
by substitution at À 1008C.[12] Recently, K2CO3
and
[13]
DBU[14] were used for the a epimerization of oxazoline
esters in a total synthesis, but these basic conditions gave
neither a-alkylation nor b-elimination products in the pres-
ence of alkyl halides.[15]
[*]Prof. S.-s. Jew, Y.-J. Lee, J. Lee, M. J. Kang, B.-S. Jeong, J.-H. Lee,
M.-S. Yoo, M.-J. Kim, S.-h. Choi, J.-M. Ku, Prof. H.-g. Park
Research Institute of Pharmaceutical Sciences and
College of Pharmacy
Seoul National University
San 56-1, Shinlim-Dong, Gwanak-Gu, Seoul 151-742 (Korea)
Fax: (+82)2-872-9129
Substrate 7 was easily prepared by the coupling of ethyl
benzimidate and serine tert-butyl ester in 98% yield.[16] For
the alkylation, we adapted the previously reported reaction
conditions for the synthesis of a,a-dialkyl a-amino acids.[9]
To choose the optimal catalyst, the enantioselective
phase-transfer-catalytic benzylation was performed in the
presence of the appropriate catalysts (1–4, 10 mol%) along
with 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester
E-mail: ssjew@plaza.snu.ac.kr
hgpk@plaza.snu.ac.kr
[**]This work was supported by a grant (R01-2002-000-0005-0) from the
Basic Research Program of the KOSEF (2003).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353496
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Angewandte
Chemie
(7), benzyl bromide (5.0 equiv), and solid KOH (5.0 equiv) in
toluene at 08C for 4–6 h. As shown in Table 1, the hydro-
cinchonidine-derived catalysts (1–3) all delivered (R)-8e with
moderate enantioselectivities (42–68% ee; Table 1, entries 1–
Table 1: Enantioselective phase-transfer benzylation of
by 1–4.
7
catalyzed
Entry
Catalyst
mol%
T [8C]
t [h]Yield [%]
ee [%][c, d]
1
2
3
4
5
6
7
8
1a
1b
2
10.0
10.0
10.0
10.0
10.0
10.0
0.25
0.5
1.0
2.0
2.5
5.0
0
0
0
0
0
0
0
0
0
5
4
4
6
4
4
6
6
5
5
5
4
3
6
48
85
93
90
84
88
99
60
74
85
92
98
99
57
88
67
42 (R)
68 (R)
68 (R)
50 (R)
56 (R)
>99 (S)
51 (S)
83 (S)
87 (S)
98 (S)
>99 (S)
>99 (S)
71 (S)
98 (S)
98 (S)
Figure 1. Relationship between the enantiomeric excess of (S)-8e and
the amount of catalyst 4b in the phase-transfer benzylation at 08C.
3a
3b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
benzylserine in 98% yield.[4m,17] Catalyst 4b was chosen for
further investigation of the enantioselective phase-transfer
alkylation with various alkyl halides under the optimized
reaction conditions. The very high ee values (> 93%) shown
in Table 2indicate that this reaction is a very efficient
9
10
11
12
13
14
15
0
0
0
Table 2: Catalytic enantioselective phase-transfer alkylation of 7 with
various alkyl halides in the presence of 4b (1 mol%).[a]
2.5
2.5
2.5
20
À20
À40
[a]The reaction was carried out with benzyl bromide (5.0 equiv) and
solid KOH (5.0 equiv) in the presence of 1–4 in toluene under the given
conditions. [b]Yields of isolated products. [c]The enantiopurity was
determined by HPLC analysis of the benzylated oxazoline 8e on a chiral
column (DAICEL Chiralcel OD-H) with hexanes/2-propanol (500:3.0) as
a solvent; in this case it was established by analysis of the racemate, of
which the enantioisomers were fully resolved. [d]The configurations are
given in parentheses. The absolute configurations were determined by
comparison of the optical rotation of a-benzylserine from the acidic
hydrolysis of 8e with the reported value.[4m,17]
[b]
RX
t [h]Yield [%]
ee [%][c, d]
20
3
48
87
93
97
3
6
85
86
96
97
5
5
98
99
>99
5), but fortunately the commercially available (S)-binaphthol-
derived catalyst 4b, recently disclosed by the Maruoka
group,[8b] provided (S)-8e with very high enantioselectivity
(> 99% ee; Table 1, entry 6). No b-eliminations or substitu-
tions were observed. We tentatively presumed that the
intermediate formed by the tight ionic binding between the
quaternary ammonium cation and the corresponding enolate
anion under the phase-transfer reaction conditions favors
a alkylation over b elimination. As we focused our attention
on optimizing this reaction for industrial processes, we
decreased the amount of catalyst. Lower amounts of 4b
preserved the high enantioselectivity, but less than 2.5 mol%
lowered the enantioselectivity (Table 1, entries 7–10;
Figure 1).
93
6
3
93
99
98
90
91
94
>99
>99
>99
97
10
8
12
The optimal reaction temperature was 08C. Higher
temperatures (208C) decreased the enantioselectivity
(Table 1, entry 12), and lower temperatures (À 20, À 408C)
conserved the enantioselectivity albeit with longer reaction
times and lower chemical yields than those at 08C (Table 1,
entries 13 and 14). The hydrolysis of 8e (> 99% ee) with HCl
(6n) followed by purification through an ion-exchange resin
led to the facile generation of optically pure (S)-(+)-a-
[a]The reaction was carried out with RX (5.0 equiv) and solid KOH
(5.0 equiv) in the presence of 4b (2.5 mol%) in toluene at 08C. [b]Yields
of isolated products. [c]The enantiopurity was determined by HPLC
analysis of the alkylated oxazoline 8 on a chiral column (DAICEL Chiralcel
OD-H) with hexanes/2-propanol as a solvent; in this case it was
established by analysis of the racemate, of which the enantioisomers
were fully resolved. [d]The absolute configurations of all the products
were tentatively assigned to be S based on the absolute configuration of
8e (Table 1, entry 10).
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Communications
enantioselective method for the preparation of a-alkyl
serines.
Keywords: alkylation · asymmetric catalysis · oxazolines ·
phase-transfer catalysis · synthetic methods
.
Based on these results as well as on the reported X-ray
crystal structure of 4b,[8c] a plausible transition state in the
catalytic alkylation is proposed in Figure 2. The conformation
[1] a) E. M. Wilson, E. E. Snell, J. Biol. Chem. 1962, 237, 3180;
b) E. H. Flynn, J. W. Hinman, E. L. Caron, D. O. Jr. , Woolf, J.
Am. Chem. Soc. 1953, 75, 5867; c) S. Hanessian, T. H. Haskell,
Tetrahedron Lett. 1964, 5, 2451; d) T. Wirth, Angew. Chem. 1997,
109, 235; Angew. Chem. Int. Ed. Engl. 1997, 36, 225; e) C.
Cativiela, M. D. T. Diaz-de-Villegas, Tetrahedron: Asymmetry
1998, 9, 3517; f) C. Cativiela, M. D. T. Diaz-de-Villegas, Tetrahe-
dron: Asymmetry 2000, 11, 645.
[2] a) T. Fujita, K. Inoue, S. Yamamoto, T. Ikumoto, S. Sasaki, R.
Toyama, M. Yoneta, K. Chiba, Y. Hosino, T. Okumoto, J.
Antibiot. 1994, 47, 216; b) S. Omura, T. Fujimoto, K. Otoguro, K.
Matsuzaki, R. Moriguchi, H. Tanaka, Y. Sasaki, J. Antibiot. 1991,
44, 113; c) S. Omura, K. Matsuzaki, T. Fujimoto, K. Kosuge, T.
Furuya, S. Fujita, A. Nakagawa, J. Antibiot. 1991, 44, 117; d) T.
Yamashita, M. lijima, H. Nakamura, K. Isshiki, H. Naganawa, S.
Hattori, M. Hamada, M. Ishizuka, T. Takeuchi, J. Antibiot. 1991,
44, 557; e) M. Kawatsu, T. Yamashita, M. Ishizuka, T. Takeuchi,
J. Antibiot. 1995, 48, 222.
Figure 2. The plausible transition-state structure of a chiral spiro am-
monium E enolate derived from 4b and 7.
[3] a) G. C. Barrett in Amino Acids, Peptides and Proteins, Vol. 13,
Chemical Society, London, 1980, p. 1; b) S. Hunt, Chemistry and
Biochemistry of the Amino Acids (Ed: G. C. Barrett), Chapman
and Hall, London, 1985, p. 55; c) J. S. Richardson, Biophys. J.
1992, 63, 1186; d) H. Mickos, K. Sundberg, B. Luning, Acta
Chem. Scand. 1992, 46, 989; e) J. Gante, Angew. Chem. 1994, 106,
1780; Angew. Chem. Int. Ed. Engl. 1994, 33, 1699; f) M.
Horikawa, T. Nakajima, Y. Ohfune, Synlett 1998, 609.
of the E enolate of tert-butyl oxazoline ester 7 packs well into
the molecular pocket of 4b, and the Si face of the enolate is
shielded by the binaphthyl and the 3’,4’,5’-trifluorophenyl
moieties. Consequently, alkyl halides can only approach the
Re face of the enolate, affording the R isomer 8 in accordance
with the results.
In conclusion, we report the first use of an asymmetric
phase-transfer-catalytic alkylation for the synthesis of chiral
a-alkyl serines. The easy preparation of the substrate, the high
enantioselectivity, and the very mild phase-transfer reaction
conditions make this a promising method for industrial
application.
[4] a) D. Seebach, J. D. Aebi, Tetrahedron Lett. 1984, 25, 2545; b) V.
Alezra, M. Bonin, A. Chiaroni, L. Micouin, C. Riche, H. P.
Husson, Tetrahedron Lett. 2000, 41, 1737; c) R. M. Williams,
M. N. Im, J. Cao, J. Am. Chem. Soc. 1991, 113, 6976; d) S. H.
Moon, Y. Ohfune, J. Am. Chem. Soc. 1994, 116, 7405; e) S. Sano,
M. Takebayashi, T. Miwa, T. Ishii, Y. Nagao, Tetrahedron:
Asymmetry 1998, 9, 3611; f) D. Obrecht, M. Altorfer, C.
Lehmann, P. Schonholzer, K. Muller, J. Org. Chem. 1996, 61,
4080; g) S. Hatakeyama, H. Matsumoto, H. Fukuyama, Y.
Mukugi, H. Irie, J. Org. Chem. 1997, 62, 2275; h) M. Carda, J.
Murga, S. Rodriguez, F. Gonzalez, E. Castillo, J. A. Marco,
Tetrahedron: Asymmetry 1998, 9, 1703; i) F. A. Davis, Y. Zhang,
A. Rao, Z. Zhang, Tetrahedron 2001, 57, 6345; j) S. Sano, K.
Hayashi, T. Miwa, T. Ishii, M. Fujii, H. Mima, Y. Nagao,
Tetrahedron Lett. 1998, 39, 5571; k) Y. Ito, M. Sawamura, E.
Shirakawa, K. Hayashizaki, T. Hayashi, Tetrahedron Lett. 1988,
29, 235; l) P. J. Reider, R. S. Eichen, E. Conn, P. Davis, V. J.
Granda, A. J. Zambito, E. J. J. Grabowski, J. Org. Chem. 1987,
52, 3326; m) M. Horikawa, T. Nakajima, Y. Ohfune, Synlett 1997,
253; n) Y. N. Belokon, V. L. Tararov, T. F. Savel'eva, Izv. Akad.
Nauk Ser. Khim. 1991, 1175.
[5] a) U.-H. Dolling, P. Davis, E. J. J. Grabowski, J. Am. Chem. Soc.
1984, 106, 446; b) S.-s. Jew, M.-S. Yoo, B.-S. Jeong, H.-g. Park,
Org. Lett. 2002, 4, 4245.
[6] a) B. Lygo, P. G. Wainwright, Tetrahedron Lett. 1997, 38, 8595;
b) E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119,
12414.
[7] a) S.-s. Jew, B.-S. Jeong, M.-S. Yoo, H. Huh, H.-g. Park, Chem.
Commun. 2001, 1244; b) H.-g. Park, B.-S. Jeong, M.-S. Yoo, M.-k.
Park, H. Huh, S.-s. Jew, Tetrahedron Lett. 2001, 42, 4645; c) H.-g.
Park, B.-S. Jeong, M.-S. Yoo, J.-H. Lee, M.-K. Park, Y.-J. Lee, M.-
J. Kim, S.-s. Jew, Angew. Chem. 2002, 114, 3162; Angew. Chem.
Int. Ed. 2002, 41, 3036; d) H.-g. Park, B.-S. Jeong, M.-S. Yoo, J.-
H. Lee, B.-s. Park, M. G. Kim, S.-s. Jew, Tetrahedron Lett. 2003,
44, 3497.
Experimental Section
For the synthesis of 7, see Supporting Information.
General procedure (alkylation of 7): Benzyl bromide (0.12mL,
1.00 mmol) was added to a solution of 7 (50.0 mg, 0.200 mmol), 4b
(9.55 mg, 0.005 mmol), and KOH (56.1 mg, 1.00 mmol) in toluene
(0.80 mL) at 08C. The reaction mixture was stirred for 5 h. Upon
completion of the reaction, the mixture was diluted with ethyl acetate
(20 mL), washed with water (2 ” 5 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexanes/EtOAc 20:1) to afford 8e
(65 mg, 98% yield) as a pale yellow oil. The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexane/2-propanol (500:3.0), flow rate = 1.0 mLminÀ1, 2 83C, l =
254 nm, retention times: S (major) 9.5 min, R (minor) 16.1 min,
> 99% ee). The absolute configuration was determined by compar-
ison of the optical rotation of a-benzyl serine from the acid hydrolysis
of 8e with the reported value.[4m,17]
General procedure (hydrolysis of 8): HCl (6n; 1.5 mL) was added
to a solution of 8e (500 mg, 1.48 mmol) in ethanol (1.5 mL), and the
reaction mixture was heated at reflux for 24 h. After the solvent was
removed in vacuo, the residue was purified by column chromatog-
raphy (15% aqueous NH4OH) through an ion-exchange resin
(Dowex 50WX8–100[17]) to give (S)-(+)-a-benzyl serine as a white
solid (365 mg, 98%). [a]2D0 = + 16.4 (c = 0.89, H2O) [lit.[4m] [a]D20 = +
16.4 (c = 0.81, H2O)]. Physical and spectral properties were consistent
with the literature values.[4m, 17]
[8] a) T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 1999, 121,
6519; b) T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am.
Received: December 10, 2003 [Z53496]
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Chemie
Chem. Soc. 2000, 122, 5228; c) T. Ooi, M. Kameda, K. Maruoka,
J. Am. Chem. Soc. 2003, 125, 5139.
[9] a) M. O'Donnell, S. Wu, Tetrahedron: Asymmetry 1992, 3, 591;
b) B. Lygo, J. Crosby, J. A. Perterson, Tetrahedron Lett. 1999, 40,
8671; c) S.-s. Jew, B.-S. Jeong, J.-H. Lee, M.-S. Yoo, Y.-J. Lee, B.-s.
Park, M. G. Kim, H.-g. Park, J. Org. Chem. 2003, 68, 4514.
[10] a) M. O'Donnell, J. M. Boniece, S. E. Earp, Tetrahedron Lett.
1978, 19, 2641; b) M. O'Donnell, R. L. Polt, J. Org. Chem. 1982,
47, 2663.
[11] For recent reports on asymmetric phase-transfer catalytic
reactions, see: a) T. Shioiri, S. Arai, in Stimulating Concepts in
Chemistry (Eds.: F. Vogtle, J. F. Stoddart, M. Shibasaki), Wiley-
VCH, Weinheim, 2000, pp. 123 – 143; b) M. J. O'Donnell in
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-VCH,
New York, 2000, chap. 10; c) M. J. O'Donnell, Aldrichimica Acta
2001, 34, 3; d) K. Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013.
[12] S. J. Blarer, Tetrahedron Lett. 1985, 26, 4055.
[13] H. Tanaka, A. M. Sawayama, T. J. Wandless, J. Am. Chem. Soc.
2003, 125, 6864.
[14] D. A. Evans, J. M. Janey, N. Magomedov, J. S. Tedrow, Angew.
Chem. 2001, 113, 1936; Angew. Chem. Int. Ed. 2001, 40, 1884.
[15] H.-g. Park, J. Lee, M. J. Kang, Y.-J. Lee, B.-S. Jeong, J.-H. Lee,
M.-S. Yoo, M.-J. Kim, S.-H. Choi, S.-s. Jew, unpublished results.
[16] H. Huang, D. R. Dalton, J. Org. Chem. 1997, 62, 372.
[17] F. A. Davis, Y. Zhang, A. Rao, Z. Zhang, Tetrahedron 2001, 57,
6345.
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