Synthesis of methyl 3-amino-2-hydroxy-4-phenylbutanoates, important core intermediates for peptide mimics possessing biological activities

Article abstract of DOI:10.1016/S0040-4039(01)00120-4

Core intermediates for the synthesis of anti-cancer agents, inhibitors of aminopeptidases and HIV proteases, 3-amino-2-hydroxy-4-phenylbutanoates were synthesized by using H-C(CN)₂O-SiR₃ as a key reagent.

Full text of DOI:10.1016/S0040-4039(01)00120-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2145–2147
Synthesis of methyl 3-amino-2-hydroxy-4-phenylbutanoates,
important core intermediates for peptide mimics possessing
biological activities
Hisao Nemoto,* Rujian Ma, Xinming Li, Ichiro Suzuki and Masayuki Shibuya
Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-machi, Tokushima 770-8505, Japan
Received 21 November 2000; revised 21 December 2000; accepted 5 January 2001
Abstract—Core intermediates for the synthesis of anti-cancer agents, inhibitors of aminopeptidases and HIV proteases,
3-amino-2-hydroxy-4-phenylbutanoates were synthesized by using H-C(CN)2O-SiR3 as a key reagent. © 2001 Elsevier Science
Ltd. All rights reserved.
An unusual amino acid 1a, (2S,3R)-N,O-protected-3-
amino-2-hydroxy-4-phenylbutanoate as well as its 2R-
diastereomer 1b, is one of the important core
intermediates1 of several naturally occurring or artifi-
cially synthesized anti-cancer agents, inhibitors of
aminopeptidases and HIV proteases2 (Scheme 1). To
synthesize 1 or the related compounds, several methods
including the nucleophilic addition reaction to the N-
protected-2-amino-3-phenylpropionaldehydes 2 by a
masked formyl anion 33 have been reported. Although
the reaction is one of the most straightforward syn-
thetic routes, the methods generally consisted of several
steps including an unmasking procedure under vigorous
conditions.
protected-3-amino-2-hydroxy-4-phenylbutanates 9a–11a
as shown in Scheme 2 by using 2-(tert-butyldimethyl-
siloxy)malononitrile (H-MAC-TBS,4 4m) or 2-(triiso-
propylsiloxy)malononitrile (H-MAC-TIPS, 4n) in a
one-portion manipulation directly from 2Z or 2B.5
We first attempted the reaction of 2Z with H-MAC-
MOM (4l) in acetonitrile with various catalysts or
promoters in the presence of trapping reagents such as
acetic anhydride or diketene.6 However, no O-acylated
derivatives of the adducts 6 (R1=Cbz, R2=MOM)
were obtained, and more than 50% of the starting
material 2Z was recovered probably because of a
reversible reaction (Scheme 3). Therefore, we examined
4m instead of 4l since a silyl group could be migrated to
generate 7 or 8, which inhibits the reversible reaction.
We report the synthesis of the methyl (2S,3R)-N,O-
Scheme 1.
Keywords: amino acids and derivatives; amino aldehydes; acyl cyanides; acyl anion equivalents; biologically active compounds.
* Corresponding author. Tel.: +81 88 633 7284; fax: +81 88 633 9549; e-mail: nem@ph2.tokushima-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00120-4

2146
H. Nemoto et al. / Tetrahedron Letters 42 (2001) 2145–2147
We first carried out the one-pot but stepwise manipulation
as follows. Anticipating the generation of 7 or 8, a
mixture of DL-2Z and 4m in acetonitrile was stirred for
10 minutes, then pyridine and methanol were added.
However, the stepwise manipulation under various condi-
tions did not give the corresponding methyl esters DL-9.
Next, we examined the one-portion manipulation. In
methanol in the presence of pyridine, the desired methyl
esters 9 were obtained directly from 2Z in 36% yield
(entry 1 in Table 1). Encouraged by this result, further
various conditions were examined. When 4-(N,N-
dimethylamino)pyridine (DMAP) was used as base
Scheme 2.
Table 1. Reaction of (9)-2Z and 4m
Entry
Solvent
Base
Temp. (°C)
Period (h)
9
13
Yield
9a:9b
Yield
1
2
3
4
5
6
7
8
MeOH
MeOH
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Pyridine
DMAP
Pyridine
Imidazole
DMAP
PPY
rt
−25
rt
2
12
48
2
5
2
36
45
Trace
67
83
72:28
63:37
–
78:22
79:21
78:22
79:21
79:21
63
51
–
20
Trace
Trace
Trace
Trace
rt
0
rt
80
PPY
PPY
0
5
12
868
65
−25
A representative procedure (entry 7): A mixture of DL-2Z (23.4 mg, 0.083 mmol), 4m (32.4 mg, 0.165 mmol), PPY (12.2 mg, 0.083 mmol) and
methanol (10 ml, 0.247 mmol) in ether (2 ml) was stirred at 0°C for 5 h. The resulting mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (hexane/ethyl acetate=4:1) to afford 9a and 9b (total 32.4 mg, 0.071 mmol, 86% yield).
Scheme 3.

H. Nemoto et al. / Tetrahedron Letters 42 (2001) 2145–2147
2147
6. The conditions we first examined were referred from our
previous publications. (a) Nemoto, H.; Kubota, Y.;
Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1994,
1665–1666. (b) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki,
I.; Shibuya, M. Tetrahedron 2000, 41, 1463–1468.
7. The reaction rates of both MAC anion and cyanide anion
to 2Z could be strongly affected by the polarity of
solvents. In fact, we observed that the aldehyde 2Z was
consumed within a short period in acetonitrile as well as
in methanol. In hexane or toluene as a representative
non-polar solvent, more than 10 hours were required to
finish the reaction. However, the ratio of the desired
compound 9a to the cyanohydrin 13 was independent
from the polarity of solvent. We chose ether since the
ratio in ether was higher than the ratios in other solvents.
8. According to the following publications, the major iso-
mer 9a is the product by non-chelation control. (a)
Herrantz, R.; Castro-Pichel, J.; Vinuesa, S.; Garcia-
Lopez, M. T. J. Org. Chem. 1990, 55, 2232–2234. (b)
Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W.
Tetrahedron Lett. 1988, 29, 3295–3598.
instead of pyridine, the yield was slightly increased
(entry 2). Since the cyanohydrin DL-13 was obtained in
briefly 50–60% yield as a major byproduct in entries 1
and 2, we considered that the formation of 13 could be
inhibited in less polar solvent than in methanol. There-
fore, we used ether7 as a solvent with 3 equivalents of
methanol with various bases. Using 4-pyrrolidinopy-
ridine (PPY) gave the best result (entry 6) of all the four
examinations (entries 3, 4, 5, and 6). Next, we carried
out the reactions with PPY at room temperature (rt),
0°C and −25°C (entries 6, 7 and 8, respectively). As
shown in entry 7, DL-9 was obtained at 0°C in satisfac-
tory yield. The distereomeric ratio of DL-9a and DL-9b
was 79:21.8,9 We also carried out the reaction of the
optically active compound
D
-2Z under the same condi-
tions as entry 7. No epimerization of the C3 position of
either 9a or 9b occurred in this experiment.10
The syntheses of 10 and 11 having alternative protect-
ing groups were also examined under similar conditions
to entry 7. Both were obtained in 80 and 85% yields,
respectively, with similar diastereoselectivity (10a:10b=
11a:11b=79:21). Stereochemistry of the compounds
9–11 was determined by well-known protection/
deprotection procedures to convert them to the known
compounds 12a and 12b.1,11
9. We also carried out the reaction based on entry 7 in the
presence of several Lewis acids such as zinc chloride,
magnesium bromide, triisobutylalminium and tin(II) tri-
flate. However, the diastereoselectivity of 9a was not
optimized. Furthermore, chemical yields were dramati-
cally decreased in some cases.
10. No epimerization was confirmed by HPLC analysis of the
desilylated derivatives (+)-12a and (+)-12b (Daicel OD
chiral column 4.6 mm F×250 mm length, hexane/etha-
nol=15:1, flow rate=0.7 ml/min. (+)-12a: rt=24.7 min,
(−)-12a: rt=30.6 min, (+)-12b: rt=34.3 min, (−)-12b:
rt=31.9 min).
11. To determine the relative stereochemistry of all the com-
pounds, we carried out the following reactions.
9a or 9b“12a or 12b (Bu4NF in THF at 0°C for 30 min,
88% yield)
In conclusion, we have synthesized methyl N-protected-
3-amino-2-siloxy-4-phenylbutanoates including opti-
cally active ones in a one-portion manipulation in high
yields with good diastereoselectivity. Further synthetic
studies for biologically active compounds are now in
progress.
References
9a or 9b“10a or 10b (Pd(OH)2/H2, Boc2O, in MeOH at
rt for 2 h, 91% yield)
11a or 11b“12a or 12b (Bu4NF in THF at 0°C for 30
min, 91% yield)
1. May, B. C. H.; Abell, A. D. Synth. Commun. 1999, 29,
2515–2525.
2. For example: (a) Sakurai, M.; Higashida, S.; Sugano, M.;
Komai, T.; Yagi, R.; Ozawa, Y.; Handa, H.; Nishigaki,
T, Yabe, Y. Bioorg. Med. Chem. 1994, 2, 807–825. (b)
Nagai, M.; Kojima, F.; Nagasawa, H.; Hamada, M.;
Aoyagi, T.; Takeuchi, M. J. Antibiot. 1997, 50, 82–84.
3. Recent examples of masked acyl anions: (a) Satoh, T.;
Onda, K.-I.; Yamakawa, K. Tetrahedron Lett. 1990, 31,
3567–3570. (b) Mizuno, M.; Shioiri, T. Tetrahedron Lett.
1998, 39, 9209–9210. (c) Katritzky, A. R.; Yang, Z.; Lam,
J. N. Synthesis 1990, 666–669. (d) Dondoni, A.; Perrone,
D.; Semola, T. Synthesis 1995, 181–185. (e) Aggarwal, V.
K.; Thomas, A.; Schade, S. Tetrahedron 1997, 53, 16213–
16228.
9a: colorless oil; FT-IR (CHCl3): 3437, 2953, 1753, 1717,
1
1504, 1146, 840 cm−1; H NMR (300 MHz): l 7.40–7.10
(m, 10H), 5.17 (brd, J=8.5 Hz, NH), 5.01 (d, J=12.3
Hz, 1H), 4.97 (d, J=12.3 Hz, 1H), 4.41–4.29 (m, 1H),
4.23 (d, J=1.4 Hz, 1H), 3.64 (s, 3H), 2.87 (d, J=7.5 Hz,
2H), 0.96 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H). 13C NMR (75
MHz): l 172.2, 155.7, 137.5, 136.5, 129.2, 128.5, 128.5,
128.1, 128.0, 126.6, 72.1, 66.6, 55.5, 52.0, 38.1, 25.8,
18.4, −4.7, −5.3; EI-HRMS calcd for C25H35NO5Si (M+):
457.2285. Found 457.2302.
9b: colorless oil; FT-IR (CHCl3): 3443, 2954, 1753, 1719,
1507, 1254, 1150, 838 cm−1 1H NMR (300 MHz): l
;
7.39–7.10 (m, 10H), 5.03 (s, 2H), 4.86 (brd, J=7.6 Hz,
NH), 4.45 (d, J=3.1 Hz, 1H), 4.50–4.25 (m, 1H), 3.64 (s,
3H), 2.87–2.62 (m, 2H), 0.93 (s, 9H), 0.08 (s, 3H), 0.01 (s,
3H). 13C NMR (75 MHz): l 171.7, 155.6, 137.3, 136.4,
129.4, 128.5, 128.4, 128.1, 128.0, 126.7, 73.3, 66.7, 55.0,
51.8, 35.5, 25.7, 18.3, −5.0, −5.5; EI-HRMS calcd for
C25H35NO5Si (M+): 457.2285. Found 457.2249.
4. ‘-MAC-’ is the abbreviation of ‘-C(CN)2O-’. Nemoto, H.;
Ibaragi, T.; Bando, M.; Kido, M.; Shibuya, M. Tetra-
hedron Lett. 1999, 40, 1319–1322.
5. The aldehydes DL-2Z,
D-2Z, and DL-2B were prepared
according to the available procedure. Fehrentz, J.-A.;
Castro, B. Synthesis 1983, 676–678.
.