Synthesis of unnatural amino acids via suzuki cross-coupling of enantiopure vinyloxazolidine derivatives

Article abstract of DOI:10.1021/ol005645i

(R and S)-α-Amino alcohols and α-amino acids, including 4-methoxyhomophenylalanine, with a variety of unnatural side chains have been synthesized via palladium-catalyzed cross-coupling Suzuki reactions. The key building blocks 1 and 2, synthesized from the common achiral precursor 2-butene-1,4-diol, were made enantiopure utilizing a Pseudomonas cepacia lipase-catalyzed kinetic resolution. The optimal conditions for the Suzuki cross-coupling and the subsequent oxidations of the resultant α-amino alcohols are described.

Full text of DOI:10.1021/ol005645i

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1089-1092
Synthesis of Unnatural Amino Acids via
Suzuki Cross-Coupling of Enantiopure
Vinyloxazolidine Derivatives
Mark Sabat and Carl R. Johnson*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
crj@chem.wayne.edu
Received February 10, 2000
ABSTRACT
(R and S )-r-Amino alcohols and r-amino acids, including 4-methoxyhomophenylalanine, with a variety of unnatural side chains have been
synthesized via palladium-catalyzed cross-coupling Suzuki reactions. The key building blocks 1 and 2, synthesized from the common achiral
precursor 2-butene-1,4-diol, were made enantiopure utilizing a Pseudomonas cepacia lipase-catalyzed kinetic resolution. The optimal conditions
for the Suzuki cross-coupling and the subsequent oxidations of the resultant r-amino alcohols are described.
Nonproteinogenic R-amino acids have been widely used as
synthetic building blocks and display interesting biological
properties.1 Analogues of homophenylalanines,2 such as
4-methoxyhomophenylalanine (40),2e,3 have received par-
ticular attention as constituents of potential pharmaceuticals.
A methodology to the synthesis of R-amino acids and
R-amino alcohols, of both R and S epimers and containing
a variety of unnatural side chains was desired. Recently
Taylor and co-workers published the synthesis of unnatural
R-amino acids utilizing palladium-catalyzed Suzuki cross-
coupling.4 Similar work has been the focus of this laboratory;
however, the protocol disclosed in this Letter offers signifi-
cant advantages in terms of coupling efficiency and diver-
sity: specifically, the synthesis and use of (R)- and (S)-1
and -2, the development of cross-coupling methodology
compatible with aryl triflates and nitrogen heterocycles, and
facile oxidation protocols.
Compounds 15 and 26 have previously been prepared and
exploited as versatile intermediates. The Suzuki cross-
coupling reaction of these compounds would constitute an
efficient synthesis of unnatural R-amino acids through direct
introduction of functional groups to the amino acid moiety.
Our synthesis of (R)- and (S)-1 and (R)- and (S)-2 is
illustrated in Scheme 1. Commercial grade cis-butene-1,4-
diol (3) was converted to bis-imidate 4.7 Treatment of this
material with PdCl2(CH3CN)2 afforded the unexpected ox-
azoline 5 presumably via a π-allyl mechanism.8 Hydrolysis
(1) (a) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825. (b)
Duthaler, R. O. Tetrahedron 1994, 50, 1539. (c) Williams, R. M. Synthesis
of Optically ActiVe R-Amino Acids; Baldwin, J. E., Ed.; Pergamon Press:
Oxford, 1989. (d) Barrett, G. C. Chemistry and Biochemistry of the Amino
Acids; Chapman and Hall: London, 1985.
(2) (a) Ehrlich, P. P.; Jeffrey, W. R.; Michaelides, R. M. J. Org. Chem.
1997, 62, 2782. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (c) Baxter, A. D.; Murray, P. J.; Taylor, R. J. H. Tetrahedron
Lett. 1992, 33, 2331. (d) Jackson, R. F. W.; Wishart, N.; Wood, A.; James,
K.; Wythes, M. J. J. Org. Chem. 1992, 57, 3397. (e) Melillo, D. G.; Larsen,
R. D.; Mathre, D. J.; Shukis, W. F.; Wood, A. W.; Colleluori, J. R. J. Org.
Chem. 1987, 52, 5143 (f) Nordlander, J. E.; Payne, M. J.; Njoroge, F. G.;
Visahwanath, V. M.; Gi, R. H.; Laikos, G. D.; Balk, M. A. J. Org. Chem.
1985, 50, 3619. (g) Urbach, H.; Henning, R. Tetrahedron Lett. 1984, 25,
1143. (h) Weller, H. N.; Gordon, E. M. J. Org. Chem. 1982, 47, 4160.
(3) (a) Yamada M.; Nagashima N.; Hasegawa J.; Takahashi S. Tetra-
hedron Lett. 1998, 39, 9019. (b) Cecchi, R.; Crochi, T.; Bogegrain, R.;
Boveri, S.; Baroni, M.; Boccardi, G.; Guimbard, J. P.; Guzzi, U. Eur. J.
Med. Chem. 1994, 29, 259. (c) Williams, R. M.; Sinclair, P. J.; Zhai, D.;
Chen, D. J. Am. Chem. Soc. 1988, 110, 1547. (d) Yato, M.; Homma, K.;
Ishida, A. Heterocycles 1995, 41, 17. (e) Kosui, N.; Waki, M.; Kato, T.;
Izumiya, N. Bull. Chem. Soc. Jpn. 1982, 55, 918. (f) Evans, W. C.; Walker,
N. J. Chem. Soc. 1947, 1571. (g) Sahoo, S. P.; Caldwell, C. G.; Chapman,
K. T.; Durette, P. L.; Esser, C. K.; Kopka, I. E.; Polo, S. A.; Sperow, K.
M.; Niedzwiecki, L. M.; Izquierdo-Martin, M.; Chang, B. C.; Harrison, R.
K.; Stein, R. L.; MacCoss, M.; Hagmann, W. K. Bioorg. Med. Chem. Lett.
1995, 5, 2441.
(4) Campbell A. D.; Raynham T. M.; Taylor R. J. K. Tetrahedron Lett.
1999, 40, 5263.
10.1021/ol005645i CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/18/2000

dimethoxypropoane (DMP) afforded S-(1), [R]20 -17.0 (c
D
1.4, CHCl3) [lit.5i [R]20 -17.1 (c 1.2, CHCl3)]. Similar
Scheme 1a
D
treatment of 10 with DMP resulted in (R)-1, [R]20 +17.2
D
(c 1.2, CHCl3). The kinetic resolution of the N-Cbz protected
7 proved more difficult and required termination at 40%
conversion to obtain 11, or at 60% conversion to obtain 9
with high enantioenrichment. Compound 11 displayed [R]20
D
-32.3 (c 1.0, CHCl3) [lit.12g [R]25 -32.1 (c 3.1, CHCl3)].
D
Treatment of 9 with KCN resulted in the epimer of 11 with
[R]20D +31.2 (c 1.0, CHCl3). The analogous (S)-2 and (R)-2
were obtained by similar treatment with DMP.
With the key building blocks 1 and 2 in hand, we
embarked on the investigation of conditions for hydrobora-
tion of 1 and coupling with p-bromoanisole (Table 1) en
Table 1. Hydroboration Using 9-BBN and Suzuki
Cross-Coupling Studies of Compound 1 with 1213
hydroboration
conditions
yield of
entry
Pd cat. coupling conditions 12a (%)
a (a) CCl3CN, KH, 90-93%; (b) PdCl2(CH3CN)2, THF, 85%;
(c) i. 6 N HCl; ii. Boc2O (6), Cbz2O (7), 55%-65% (two steps); (d)
PS-30 lipase, isopropenyl acetate, 38-46% (94%-99% ee); (e)
KCN, 93% MeOH; (f) DMP, acetone, BF3‚Et2O, quantitative.
1
2
3
4
5
6
7
8
9
THF, rt
THF, rt
THF, 67 °C
THF, rt
THF, 67 °C
toluene, 80 °C
toluene, 67 °C
toluene, 80 °C
toluene, 80 °C
toluene, 80 °C
a
a
a
a
b
b
b
b
b
b
Cs2CO3, rt
39
25
29
66
72
94
78
80
75
56
K2CO3, DMF, rt
K3PO4, DMF, rt
3.2 N NaOH, 55 °C
3.2 N NaOH, 80 °C
3.2 N NaOH, 99 °C
CsF, 88 °C
3 N NaOH, 80 °C
K3PO4, DMF, 100 °C
K2CO3, DMF, 100°C
of the somewhat volatile 5 proceeded best under acidic
conditions. Subsequent protection of the resultant amine salt
with either Boc2O or Cbz2O10 under biphasic conditions
afforded compounds 611 or 7, respectively.12 Kinetic resolu-
tions of these compounds were achieved with Pseudomonas
cepecia (Amano PS-30) lipase in CH2Cl2/isopropenyl acetate.
For the N-Boc protected 6, the kinetic resolution was stopped
10
a 5 mol % of PdCl2(dppf)2. b 3 mol % of Pd(PPh3)4.
at 50% completion to afford 10 in 46% chemical yield with
route to 4-methoxyhomophenylalanine (40). Hydroboration
of 1 in THF at rt proved to be exceedingly slow, and
considerable starting material was present even after 24 h.
However, when the reaction was run in toluene at 80 °C,
the starting material disappeared completely within 15-30
min (entry 6).
With this satisfactory result, a wide variety of cross-
coupling conditions were explored (Table 1). Our experi-
ments indicate that a biphasic toluene/3.2 N NaOH system
25
[R]20 -28.5 (c 1.0, CHCl3) [lit.5i [R]
-30.5 (c 1.2,
D
D
CHCl3)]. Treatment of 8 with KCN followed by 2,2-
(5) (a) Beaulieu, P. L.; Duceppe, J.; Johnson, C. J. Org. Chem. 1991,
56, 4196. (b) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org.
Chem. 1991, 56, 4167. (c) Boyd, E. C.; Paton, R. M. Tetrahedron Lett.
1993, 34, 3169. (d) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis,
N. Synthesis 1994, 31. (e) Wei, Z.; Knaus, E. E. Synthesis 1994, 1463. (f)
Kawate, T.; Fukuta, N.; Nishida, A.; Nakagawa, M. Chem. Pharm. Bull.
1997, 45, 2116. (g) Moriwake, T.; Hamano, S.; Saito, S.; Torii, S. Chem.
Lett. 1987, 2085. (h) Kumar, J. S. R.; Datta, A. Tetrahedron Lett. 1997,
38, 6779. (i) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis
1998, 1707.
(11) (a) Horikawa, M.; Hashimoto, K.; Shirahama, H. Tetrahedron Lett.
1993, 34, 331. (b) Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195.
(c) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1984, 25, 1071. (d) Crisp,
G. T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465. (e) Naito, T.; Ikai,
M.; Shirakawa, M.; Fujimoto, K.; Ninomiya, I.; Kiguchi, T. J. Chem. Soc.,
Perkin Trans. 1 1994, 7, 773. (f) Ohfune, Y.; Kurokawa, N. Tetrahedron
Lett. 1984, 25, 1587. (g) Matsunaga, H.; Ishizuka, T.; Kunieda, T.
Tetrahedron 1997, 53, 1275. (h) Kiguchi, T.; Ikai, M.; Shirakawa, M.;
Fujimoto, K.; Ninomiya, I.; Naito, T. J. Chem. Soc., Perkin Trans. 1 1998,
5, 893. (i) Naito, T.; Shirakawa, M.; Ikai, M.; Ninomiya, I.; Kiguchi, T.
Recl. TraV. Chim. Pays-Bas 1996, 115, 13. (j) See also refs 5a, 5b, 5c, 5d,
5g, and 5i.
(6) Reginato, G.; Mordini, A.; Capperucci, A.; Degl’Innocenti, A.;
Manganiello, S. Tetrahedron 1998, 54, 10217.
(7) (a) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49,
2037. (b) Cardillo, G.; Orena, M.; Sandri, S. J. Org. Chem. 1986, 51, 713.
(8) In our hands Overman rearrangement of the bisimidate 4 under
reported conditions7a resulted in incomplete conversion of starting material.
Under more forceful thermal rearrangement conditions, significant losses
were incurred due to charring and the formation of 5‚HCl
(12) (a) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29,
99. (b) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621. (c)
Yoo, S.; Lee, S.; Jeong, N.; Cho, I. Tetrahedron Lett. 1993, 34, 3435. (d)
Yoo, S.; Lee, S. J. Org. Chem. 1994, 59, 6968. (e) Wade, P. A.; Singh, S.
M.; Pillay, M. K. Tetrahedron 1984, 40, 601. (f) Crisp, G. T.; Glink, P. T.
Tetrahedron 1992, 48, 3541. (g) Trost, B. M.; Bunt, R. C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 99. (h) See also ref 11d. (i) Huwe, C. M.; Blechert,
S. Tetrahedron Lett. 1994, 35, 9533; 9537. (j) Huwe, C. M.; Velder, J.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376. (k) Huwe, C.
M.; Blechert, S. Synthesis 1997, 61. (l) See also refs 11c and 11f.
which sublimed at 180 °C. The structure of this material was verified by
treatment of 5 with a dry ether solution of HCl which yielded a crystalline
product with identical spectroscopic properties. Overman rearrangement
(heating, K2CO3 to neutralize acidic species)9 likewise resulted in only partial
conversion of starting material 4.
(9) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998,
63, 188.
(10) Sennyey, G.; Barcelo, G.; Senet, J. Tetrahedron Lett. 1986, 27, 5375.
1090
Org. Lett., Vol. 2, No. 8, 2000

Table 2. Suzuki Coupling of (R and S)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine
a PPTS in MeOH. b Chromatographically separable 1:1 mixture.
at elevated temperature and with Pd(PPh3)4 as catalyst
resulted in maximum yields. Under these reaction conditions
a variety of aryl halides and triflates including nitrogen
heterocyles13c underwent Suzuki cross-coupling with good
to excellent yields (Table 2).
With a variety of protected chiral amino alcohol derivatives
in hand, ways to convert these to amino acids were sought.
Compounds 12a and 17a were chosen as representative
examples (Scheme 2). The isopropylidene moiety was first
removed using PPTS. Subsequent oxidation with various
agents including PDC,14a Jones,14b O2/Pt,14c TPAP,14d and
CrO3/H5IO614e gave either no reaction or a complex mixture
of products. TEMPO14h proved to be a capricious oxidant
which afforded no reaction in acetone14i but delivered the
aldehyde smoothly in toluene/H2O;14g subsequent oxidation
by NaClO2 resulted in a modest yield of amino acid. A two-
step procedure consisting of Sharpless RuCl3 oxidation14i to
the aldehyde stage followed with NaClO2 treatment to obtain
the amino acid 34 gave the best result.14f However, even these
conditions resulted in modest yields and were not general.
As a more robust system was deemed necessary, the N-Cbz-
protected analogues (Table 3) were examined. Compounds
(14) (a) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997, 53,
1275. (b) Dondoni, A.; Marra, A.; Massi, A. Chem. Commun. 1998, 1741.
(c) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem. Soc. 1984, 106,
1095. (d) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639. (e) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323. (f) Lubell,
W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990, 55, 3511. (g)
Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33,
5029. (h) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
1996, 1153. (i) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207.
(13) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Miyaura,
N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314. (c) Watanabe, T.; Miyaura, N.; Suzuki, A.
Synlett 1992, 207. (d) Ishikura, M.; Kamada, M.; Terashima, M. Synthesis
1984, 936. (e) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org.
Chem. 1994, 59, 6095.
Org. Lett., Vol. 2, No. 8, 2000
1091

Scheme 2a
Table 3. Suzuki Coupling of (R and S)-
3-(Benzyloxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine
a (a) i. PPTS, MeOH, 24 h; ii. RuCl3, H5IO6, CCl4/CH3CN; (b)
i. TEMPO, NaOCl; ii. NaClO2; (c) 1 M Jones reagent; (d) i. Dess-
Martin/THF; ii. NaClO2, NaH2PO4; (e) H2, Pd/C.
17b, 20b, and 30a were oxidized efficiently with 1 N Jones
reagent.14b These conditions, however, afforded low yields
in the cases of analogues protected with N-Boc or analogues
containing activated aromatic rings such as 29a and 12a/b.
Only analogues with alkyl-substituted aromatic groups were
stable to the 1 N Jones reagent.
a HCl in MeOH, 24 h.
lidines were obtained via lipase-catalyzed kinetic resolutions.
Key in this convergent approach was Pd-mediated Suzuki
cross-coupling.
Dess-Martin oxidation of compound 29a to the aldehyde
stage followed by NaClO2 treatment afforded the optically
pure amino acid 38 in excellent yield. Compound 12b after
identical oxidation was fully deblocked to afford 4-methoxy-
homophenylalanine (40) in excellent yield: [R]20D -43.4 (c
Acknowledgment. Support of this work by the National
Science Foundation is gratefully acknowledged (CHE-
9801679). We thank Dr. Mary Jane Heeg for the X-ray
structure determinations and Dr. Lew Hryhorczuk for as-
sistance with mass spectrometry analyses.
0.1, 5 M HCl) [lit.3a for (S)-40 [R]25 +42.2 (c 0.1, 5 M
D
HCl)].
In summary, a concise method for the preparation of
diverse R-amino alcohols and R-amino acids in both enan-
tiomeric series from readily available achiral starting materi-
als has been developed. Included in the analogues is
4-methoxyhomophenylalanine, a compound of current inter-
est. The precursor vinyl amino alcohols and vinyl oxazo-
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL005645I
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Org. Lett., Vol. 2, No. 8, 2000