Stereoselective synthesis of anti-β-hydroxy-α-amino acids through dynamic kinetic resolution

Article abstract of DOI:10.1002/anie.200353072

Upping the anti: Asymmetric anti-selective hydrogenation of α-amino-β-keto esters through dynamic kinetic resolution has been achieved for the first time by using the Ru-binap catalyst. The reaction affords important anti-β-hydroxy-α-amino acids with 74-9

Full text of DOI:10.1002/anie.200353072

Communications
achieved stereoselective synthesis of all four stereoisomers of
3-hydroxyleucine.[3i] In this method, the syn isomer 2 of 3-
hydroxyleucine was directly prepared by the asymmetric
hydrogenation, but the anti isomer 4 needed to be constructed
from 2 by two additional steps, oxazoline formation with
internal Sn2 inversion and acid hydrolysis (Scheme 1). To our
Scheme 1. Synthesis of syn- and anti-b-hydroxy-a-amino acids through
dynamic kinetic resolution with the Ru–BINAP catalyst. Bz=benzoyl.
anti-Selective Hydrogenation
knowledge, direct preparation of the anti-b-hydroxy-a-amino
acids from the a-amino-b-keto esters by using an Ru–chiral-
phosphane catalyst has not been reported. Herein, we
describe the highly anti-selective hydrogenation of a-amino-
b-keto esters through dynamic kinetic resolution with the Ru–
BINAP catalyst. We envisioned hydrogenation through the
five-membered transition state 5 (Scheme 1) with the 2-amino
substituent of a-amino-b-keto ester 3 as a directing group;
this reaction would directly produce anti-b-hydroxy-a-amino
acid 4 in place of the syn product 2 that is produced through
the six-membered transition state 6.
Hydrogenation of methyl 2-amino-4-methyl-3-oxo-penta-
noate (3, where R = Me), the substrate producing 3-hydroxy-
leucine, was examined in detail, and the results are shown in
Table 1. Reactions were carried out with the Ru–(S)-BINAP
catalyst (4.2 mol%) at 508C under 100 atm of hydrogen. The
absolute and relative configurations of the hydrogenated
product were established, after transformation into benzoy-
lamide derivative 7, by comparison with authentic samples.[3i]
In the preliminary experiment with the TsOH salt in
methanol we were pleased to find that excellent anti
selectivity (97:3) was observed by 1H NMR analysis, although
the enantioselectivity needed to be improved (Table 1,
entry 1). With this encouraging result in hand, we extensively
surveyed the conditions for the anti-selective hydrogenation
with high enantioselectivity. First, the effect of counter anions
in ammonium salts was investigated. The hydrochloric acid
salt showed high anti diastereoselectivity with modest enan-
tioselectivity (Table 1, entry 3). Interestingly, the tetrafluor-
oboric acid salt inhibited the hydrogenation, and the starting
material was recovered (entry 2). Next, the effect of solvents
was screened. The use of a polar solvent such as water,
Stereoselective Synthesis of anti-b-Hydroxy-a-
amino Acids through Dynamic Kinetic Resolution
Kazuishi Makino, Takayuki Goto, Yasuhiro Hiroki, and
Yasumasa Hamada*
b-Hydroxy-a-amino acids are valuable constituents of a
variety of biologically active natural products and medicinally
important compounds, and many approaches for their enan-
tioselective synthesis have been reported.[1–4] In connection
with our ongoing research into the total synthesis of cyclo-
depsipeptides,[5] papuamides, and polyoxypeptins with bio-
logically interesting activities, we needed a new method for
the preparation of a large amount of (2R,3R)- and (2S,3S)-3-
hydroxyleucine bearing the skeleton of an anti-b-hydroxy-a-
amino acid, with control of both relative and absolute
configuration. It is reported that syn-b-hydroxy-a-amino
acid derivatives have been efficiently synthesized with high
diastereo- and enantioselectivities from chirally labile a-
amino-b-keto esters through dynamic kinetic resolution with
the Ru–BINAP catalyst (BINAP = 2,2’-bis(diphenylphos-
phanyl)-1,1’-binaphthyl), which was originally developed by
Noyori and co-workers.[3,4,6] Using this methodology, we have
[*] Dr. K. Makino, T. Goto, Y. Hiroki, Prof. Dr. Y. Hamada
Graduate School of Pharmaceutical Sciences
Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Fax : (+81)43-290-2988
E-mail: hamada@p.chiba-u.ac.jp
882
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200353072
Angew. Chem. Int. Ed. 2004, 43, 882 –882

Angewandte
Chemie
Table 2: The anti-selective asymmetric hydrogenation through dynamic kinetic resolution of other
a-amino-b-keto esters.[a]
ethylene glycol, or tert-butyl alcohol was
less or not effective for this hydrogenation.
Methanol, n-propanol, 2-propanol, and
dichloromethane were the solvents of
choice for the diastereoselectivity. In partic-
ular, when the reaction was carried out in
dichloromethane, the enantioselectivity of
the desired anti product was increased to
95% ee but the yield was poor (entry 6).
The decrease of the yield in dichlorome-
thane may be due to very lowsolubility of
the starting material. To improve the yield,
the influences of the ester group and the
solvent were next studied. Among the
various ester derivatives examined in
dichloromethane, the introduction of an
isopropyl or a benzyl ester group led to
the reaction being more effective in terms of
yield (Table 1, entries 8 and 9). Especially in
the case of a benzyl ester (Table 1, entry 9)
the yield was increased to 87% with excel-
lent diastereo- and enantioselectivity
(> 99% de, 96% ee). Although the reaction
time was not optimized, the hydrogenation
for 6 h under similar conditions was found
Entry
R1
R2
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12[e]
13[f]
iPr
Bn
Bn
Bn
Bn
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
CH2Cl2
nPrOH
nPrOH
CH2Cl2
CH2Cl2
nPrOH
CH2Cl2
CH2Cl2
nPrOH
CH2Cl2
nPrOH
MeOH
CH2Cl2
87
92
85
85
84
86
89
88
53
67
89
93
92
>99:1
83:17
96
81
95
97
96
97
76
74
58
60
79
4
cyclobutyl
cyclopentyl
cyclohexyl
cyclohexyl
cycloheptyl
Et
nPr
nPr
tBu
tBu
97.5:2.5
>99:1
97.5:2.5
97:3
89:11
94:6
91:1
71:29
96:4
Ph
cyclohexyl
>99:1
98:2
95
[a] Reaction conditions: Substrate (1 mmol), catalyst (3.8–4.6 mol%), and solvent (3 mL). [b] Yield over
two steps. [c] anti:syn diastereomeric ratio. Determined by 1H NMR analysis. [d] Value of the anti-3-
hydroxyamino acid esters. Determined by HPLC analysis. [e] Reaction was carried out at 1008C. The
product was analyzed after conversion into the corresponding acetamide. [f] The reaction was carried
out by using 0.4 mol% of the catalyst under 30 atm of hydrogen for 6 h.
to give almost the same result (Table 1, entry 11).
This method was then applied to various substrates to
clarify the generality of the hydrogenation, and the results are
shown in Table 2. The starting a-amino-b-keto ester hydro-
chlorides were easily prepared by the following three
methods: 1) acid hydrolysis of 4-alkoxycarbonyloxazoles
derived from carboxylic anhydrides and isocyanoacetic acid
tion,[7] and 3) acylation of the benzophenone ketimine
derived from a glycine ester in the presence of a strong base
followed by acid hydrolysis.[8] Under our reaction conditions,
the substrates with a secondary alkyl carbon, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl substituent at the a
position of the ketone carbonyl group afforded the anti
products with high diastereo- and enantioselectivities in
excellent yields (Table 2, entries 2–6).[9] Furthermore, it was
found that the hydrogenation of the cyclohexyl substrate was
completed in 6 h even with a substrate/catalyst ratio of 250
under 30 atm of hydrogen (Table 2, entry 13). In the case of
the n-alkyl substrate at the C4 position, the stereoselectivity
was decreased to moderate (Table 2, entries 7–9). The hydro-
genation of the a-amino-b-keto ester with the tert-butyl group
was maximized in n-propanol to give the product in 89%
yield and 79% ee with a diastereomeric ratio of 96:4 (Table 2,
entry 11). In an aromatic substrate the hydrogenation in
dichloromethane or n-propanol did not proceed under our
reaction conditions. After some experiments we found that
the hydrogenation of this substrate in MeOH at 1008C
afforded exclusively the anti product in 93% yield. However,
the enantioselectivity was poor. These results suggest that
hydrogenation with the Ru–BINAP catalyst is affected by the
structure at the C4 position of the a-amino-b-keto ester.
Nonetheless, the results of the above asymmetric reaction
with the Ru–BINAP catalyst are noteworthy not only because
this represents the first example of anti-selective hydrogena-
tion of a-amino-b-keto esters with high diastereo- and
enantioselectivity through dynamic kinetic resolution but
also because the amino group in the substrate is shown to
serve as a stronger directing substituent than the ester
function. Although the mechanism of the asymmetric induc-
tion with a high level of anti selectivity is not clear at present,
esters,[3i] 2) base-mediated N C acyl migration of N-tert-
À
butoxycarbonyl-N-acylglycine esters and then acid deprotec-
Table 1: The anti-selective asymmetric hydrogenation through dynamic
kinetic resolution.[a]
Entry
R
HX
Solvent
Yield [%][b]
d.r.[c]
97:3
ee [%][d]
1
2[e]
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Et
iPr
Bn
Bn
Bn
TsOH
HBF4
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
MeOH
MeOH
MeOH
nPrOH
iPrOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
iPrOH
CH2Cl2
72
–
22
–
–
71
69
81
38
73
96
87
94
82
99:1
99:1
99:1
99:1
96:4
98:2
>99:1
98:2
>99:1
56
69
81
95
93
92
96
76
98
10
11[f]
[a] Reaction conditions: Substrate (1 mmol), catalyst (3.8–4.6 mol%),
and solvent (3.0 mL). Abbreviations: TsOH=toluene-4-sulfonic acid,
Bn=benzyl. [b] Yield over two steps. [c] anti:syn diastereomeric ratio.
Determined by 1H NMR analysis. [d] Value of the anti-3-hydroxyamino
acid ester. Determined by HPLC analysis. [e] No reaction. [f] Reaction
time for hydrogenation: 6 h.
Angew. Chem. Int. Ed. 2004, 43, 882 –882
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
883

Communications
Manaviazar, V. M. Delisser, Tetrahedron 1994, 50, 9181 – 9188;
e) L. Williams, Z. Zhang, F. Shao, P. J. Carroll, M. M. Joulli›,
Tetrahedron 1996, 52, 11673 – 11694; f) J. S. Panek, C. E. Masse, J.
Org. Chem. 1998, 63, 2382 – 2384; g) M. Amador, X. Ariza, J.
Garcia, S. Sevilla, Org. Lett. 2002, 4, 4511 – 4515; h) N. Yoshikawa,
M. Shibasaki, Tetrahedron 2002, 58, 8289 – 8298.
we speculate that the reaction proceeds via a sterically
constrained five-membered transition state.
In conclusion, we have succeeded in developing a new
method for the preparation of anti-b-hydroxy-a-amino acids
from a-amino-b-keto esters by using the Ru–BINAP catalyst
in a dynamic kinetic resolution; this method provides the first
example of the anti-selective hydrogenation and four-step
access to the important (2R,3R)- and (2S,3S)-b-hydroxy-a-
amino acids from readily available acid anhydrides or acid
chlorides. Further studies to elucidate the reaction mecha-
nism and extend the scope of the method's synthetic utility
are in progress in our laboratory.
[2] For recent reports on the stereoselective synthesis of erythro-b-
hydroxy-a-amino acids, see: a) B. G. Jackson, S. W. Pedersen,
J. W. Fisher, J. W. Misner, J. P. Gardner, M. A. Staszak, C. Doecke,
J. Rizzo, J. Aikins, E. Farkas, K. L. Trinkle, J. Vicenzi, M.
Reinhard, E. P. Kreoeff, C. A. Higginbotham, R. J. Gazak, T. Y.
Zhang, Tetrahedron, 2000, 56, 5667 – 5677; b) A. Avenoza, C.
Cativiela, F. Corzana, J. M. Peregrina, M. M. Zurbano, Tetrahe-
dron: Asymmetry 2000, 11, 2195 – 2204; c) D. A. Evans, J. M.
Janey, N. Magomedov, J. S. Tedrow, Angew. Chem. 2001, 113,
1936 – 1940; Angew. Chem. Int. Ed. 2001, 40, 1884 – 1888; d) J. B.
MacMillan, T. F. Molinski, Org. Lett. 2002, 4, 1883 – 1886; e) T.
Ooi, M. Taniguchi, M. Kameda, K. Maruoka, Angew. Chem. 2002,
114, 4724 – 4726; Angew. Chem. Int. Ed. 2002, 41, 4542 – 4544.
[3] For the synthesis of b-hydroxy-a-amino acids by dynamic kinetic
resolution, see: a) R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm,
M. Kitamura, H. Takaya, S. Akutagawa, N. Sayo, T. Saito, T.
Taketomi, H. Kumobayashi, J. Am. Chem. Soc. 1989, 111, 9134 –
9135; b) J.-P. GenÞt, S. Mallart, S. JugØ, French Patent 8911159,
1989; c) K. Mashima, Y. Matsumura, K. Kusano, H. Kumobaya-
shi, N. Sayo, Y. Hori, T. Ishizaki, S. Akutagawa, H. Takaya, J.
Chem. Soc. Chem. Commun. 1991, 609; d) J.-P. GenÞt, C. Pinel, S.
Mallart, S. Juge, S. Thorimbert, J. A. Laffitte, Tetrahedron:
Asymmetry 1991, 2, 555 – 567; e) M. Kitamura, M. Tokunaga, R.
Noyori, J. Am. Chem. Soc. 1993, 115, 144 – 152; f) K. Mashima, K.
Kusano, N. Sato, Y. Matsumura, K. Nozaki, H. Kumobayashi, N.
Sayo, Y. Hori, T. Ishizaki, S. Akutagawa, H. Takaya, J. Org. Chem.
1994, 59, 3064 – 3076; g) J.-P. GenÞt, M. C. C. de Andrade, V.
Ratovelomanana-Vidal, Tetrahedron Lett. 1995, 36, 2063 – 2066;
h) E. Coulon, M. C. C. de Andrade, V. Ratovelomanana-Vidal, J.-
P. GenÞt, Tetrahedron Lett. 1998, 39, 6467 – 6470; i) K. Makino, N.
Okamoto, O. Hara, Y. Hamada, Tetrahedron: Asymmetry 2001,
12, 1757 – 1762.
[4] For dynamic kinetic resolution under transfer hydrogenation, see:
B. Mohar, A. Valleix, J.-R. Desmurs, M. Felemez, A. Wagner, C.
Mioskowski, Chem. Commun. 2001, 2572 – 2573.
[5] a) N. Okamoto, O. Hara, K. Makino, Y. Hamada, Tetrahedron:
Asymmetry 2001, 12, 1353 – 1358; b) ref. [3i]; c) K. Makino, Y.
Hennmi, Y. Hamada, Synlett 2002, 613 – 615; d) K. Makino, A.
Kondoh, Y. Hamada, Tetrahedron Lett. 2002, 43, 4695 – 4698;
e) N. Okamoto, O. Hara, K. Makino, Y. Hamada, J. Org. Chem.
2002, 67, 9210 – 9215; f) K. Makino, T. Suzuki, S. Awane, O. Hara,
Y. Hamada, Tetrahedron Lett. 2002, 43, 9391 – 9395.
[6] For reviews on dynamic kinetic resolution, see: a) R. Noyori, M.
Tokunaga, M. Kitamura, Bull. Chem. Soc. Jpn. 1995, 68, 36 – 56;
b) R. S. Ward, Tetrahedron: Asymmetry 1995, 6, 1475 – 1490; c) T.
Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric
Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, 2000, pp. 1 – 110;
d) H. Pellissier, Tetrahedron 2003, 59, 8291 – 8327.
Experimental Section
Typical procedure: DMF (400 mL) was added to a mixture of
[{RuCl2(C6H6)}2] (9.8 mg, 19.6 mmol) and (S)-BINAP (26.4 mg,
42.4 mmol) in a Schlenk tube under an argon atmosphere. After
being degassed, the mixture was stirred for 10 min at 1008C. The
resulting mixture was cooled and concentrated in vacuo at 508C for
2.5 h to give the reddish-brown catalyst. A degassed solution of a-
amino-b-ketoester 8 (R1 = iPr, R2 = Bn, 271.5 mg, 1.0 mmol) in
CH2Cl2 (1 ” 2.5 mL, 1 ” 0.5 mL) was added dropwise to the catalyst
through a canula under an argon atmosphere. The mixture was stirred
at 508C under hydrogen (100 atm) for 6 h. The solvent was removed
in vacuo to afford a-amino-b-hydroxy ester 9 which was used in the
next step without further purification.
Benzoyl chloride (130 mL, 1.12 mmol) and triethylamine (440 mL,
0.316 mmol) were added dropwise to a solution of the crude 9 in THF
(2.0 mL) at 08C. After stirring for 1 h at 238C, the reaction mixture
was quenched with water and diluted with ethyl acetate/n-hexane
(5:1). The mixture was washed with aqueous 1n HCl, water, saturated
aqueous NaHCO3, and brine, dried with Na2SO4, and filtered. The
filtrate was then concentrated in vacuo. The residue was purified by
silica gel column chromatography (ethyl acetate/n-hexane (1:2)) to
give 10 (278.1 mg, 0.815 mmol, 82% yield (2 steps), > 99% de,
98% ee): HPLC analysis with a Chiralcel OD-H chiral column
(eluent = n-hexane/iPrOH (90:10, 0.5 mLminÀ1)): retention time for
(2R,3R)-10 = 21.6 min, for (2S,3S)-10 = 30.3 min; [a]2D4 = + 33.9 (c =
1.00, CHCl3); m.p. 95.5–968C; IR (KBr): n˜ = 3414, 2961, 2935, 2858,
1
1749, 1647, 1519, 1192, 1064 cmÀ1; H NMR (400 MHz, CDCl3): d =
0.95 (d, J = 6.6 Hz, 3H; (CH3)2CH), 1.13 (d, J = 6.6 Hz, 3H;
(CH3)2CH), 1.71 (m, 1H; (CH3)2CH), 2.92 (d, J = 8.4 Hz, 1H;
CHOH), 3.63 (dt, J = 3.1, 8.4 Hz, 1H; CHOH), 4.99 (dd, J = 3.3,
7.3 Hz, 1H; CHNH), 5.23 (d, J = 12 Hz, 1H; CH2Ph), 5.29 (d, J =
12 Hz, 1H; CH2Ph), 7.14 (d, J = 7.3 Hz, 1H; CHNH), 7.34–7.39 (m,
5H; ArH), 7.43–7.47 (m, 2H; ArH), 7.52–7.56 (m, 1H; ArH), 7.81–
7.83 ppm (m, 2H; ArH); 13C NMR (100 MHz, CDCl3): d = 18.9, 19.0,
31.5, 56.2, 67.6, 78.9, 127.2, 128.4, 128.6, 128.7, 132.0, 133.4, 134.9,
167.5, 170.8 ppm; HRMS (FAB, NBA): calcd for C20H24NO4:
342.1705 [M+ + 1]; found: 342.1682; elemental analysis: calcd for
C20H23NO4: C 70.36, H 6.79, N 4.10; found: C 70.26, H 6.82, N 4.06.
[7] O. Hara, M. Ito, Y. Hamada, Tetrahedron Lett. 1998, 39, 5537 –
5540.
[8] J. Singh, T. D. Gordon, W. G. Earley, B. A. Morgan, Tetrahedron
Lett. 1993, 34, 211 – 214.
[9] To optimize the cyclopentyl substrate, the catalyst derived from
[(cod)Ru(methallyl)2] (cod = cycloocta-1,5-diene) and (S)-
BINAP was examined and was found to be less effective (34%
yield, 93:7 d.r., 92% ee) than the one from [{RuCl2(C6H6)}2] and
(S)-BINAP.
Received: October 13, 2003 [Z53072]
Keywords: amino acids · asymmetric synthesis · hydrogenation ·
.
kinetic resolution · ruthenium
[1] For representative reports on the synthesis of (2S, 3S)- and (2R,
3R)-3-hydroxyleucine, see: a) C. G. Caldwell, S. S. Bondy, Syn-
thesis 1990, 34 – 36; b) E. J. Corey, D.-H. Lee, S. Choi, Tetrahedron
Lett. 1992, 33, 6735 – 6738; c) S. Kanemasa, T. Mori, A. Tatsu-
kawa, Tetrahedron Lett. 1993, 34, 8293 – 8296; d) K. J. Hale, S.
884
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angew. Chem. Int. Ed. 2004, 43, 882 –884