A short enantioselective synthesis of (-)-bestatin via l-proline-catalyzed α-amination of an aldehyde

Article abstract of DOI:10.1016/j.tetlet.2008.09.054

A short and high yielding enantioselective synthesis of (-)-bestatin, a naturally occurring aminopeptidase inhibitor, is described via l-proline-catalyzed asymmetric α-amination of 3-phenylpropionaldehyde as the key reaction. The methodology also involves a Pd-catalyzed intramolecular cyclization of an allylic acetate giving a trans-oxazoline in a highly diastereoselective manner (dr > 14:1).

Full text of DOI:10.1016/j.tetlet.2008.09.054

Tetrahedron Letters 49 (2008) 6791–6793
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A short enantioselective synthesis of (ꢀ)-bestatin via
L-proline-catalyzed
a
-amination of an aldehyde
*
Shyla George, Gurunath S. Suryavanshi, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and high yielding enantioselective synthesis of (ꢀ)-bestatin, a naturally occurring aminopepti-
Received 4 August 2008
Revised 6 September 2008
Accepted 10 September 2008
Available online 13 September 2008
dase inhibitor, is described via L-proline-catalyzed asymmetric a-amination of 3-phenylpropionaldehyde
as the key reaction. The methodology also involves a Pd-catalyzed intramolecular cyclization of an allylic
acetate giving a trans-oxazoline in a highly diastereoselective manner (dr > 14:1).
Ó 2008 Elsevier Ltd. All rights reserved.
The aminopeptidases are a group of exopeptidases that specifi-
cally cleave polypeptide chains at the amino terminus. (ꢀ)-Bestatin
(1), a naturally occurring small peptide containing a non-proteino-
tion of benzamides via a p-allyl palladium complex is an elegant
method for the synthesis of highly functionalized compounds, par-
ticularly when chirality transfer is involved.18 We envisaged that
trans-oxazoline 8, obtainable via Pd-catalyzed cyclization of allylic
acetate 7, would be a suitable chiral building block for the synthe-
sis of (ꢀ)-bestatin (1).
genic
a-hydroxy-b-amino acid at the N-terminus of the peptide
chain, is an aminopeptidase inhibitor1 that exhibits immunostim-
ulatory activity as well as cytotoxic activity. It is used clinically
as an oral medication for the treatment of cancer,2 and shows
potential as an anti-inflammatory agent and for the treatment of
HIV.3 The stereochemistry of the hydroxyl as well as the amino
groups in (ꢀ)-bestatin (1) plays a vital role in the biological activity
of the molecule. Thus, controlling the stereochemistry at the C-2
and C-3 stereogenic centers for the introduction of the desired
(2S,3R) configuration of the N-terminal component becomes
important. A variety of stereoselective methods for the formation
Our synthesis of (ꢀ)-bestatin (1) started with the
a-amination
of 3-phenyl-propionaldehyde using List’s protocol.17a Accordingly,
3-phenylpropionaldehyde 2 was subjected to -amination with
dibenzyl azodicarboxylate in the presence of -proline (10 mol %)
a
L
to produce an aminoaldehyde, which upon in situ reduction with
NaBH4 afforded the protected aminoalcohol 319 in 92% yield and
95% ee.20 Aminoalcohol 3 was then subjected to hydrogenolysis
[over Raney nickel,21 H2 (60 psi), 25 °C] to give the free amine,
which was protected (BzCl, Et3N, THF, 25 °C) as its benzamide 4
in 70% yield over two steps. Oxidation of alcohol 4 with Dess–Mar-
tin periodinane gave the corresponding aldehyde 5, which on reac-
tion with vinylmagnesium bromide in THF at 0 °C afforded allylic
alcohol 6 as a 1.1:1 mixture of syn/anti isomers (determined by
1H NMR analysis) in 85% yield. Acetylation of 6 (Ac2O, Py, DMAP,
CH2Cl2, 25 °C) gave the secondary allylic acetate 7 in 98% yield.
The Pd-catalyzed intramolecular cyclization22 of allylic acetate 7
using Pd(PPh3)4 and K2CO3 in CH3CN proceeded readily to give
the desired trans-oxazoline 823 as an inseparable mixture of diaste-
reomers (dr > 14:1, as determined by 1H and 13C NMR spectral
analysis) in 79% yield. Oxidative degradation of the vinylic group
in 8 was carried out as indicated in the following sequence of reac-
tions: (i) the olefin function in 8 was initially dihydroxylated
of b-amino-
a
-hydroxy acids have been reported, including amin-
ohydroxylation,4 reduction of
a
-keto acid derivatives,5 nucleo-
philic addition to chiral aminoaldehydes,6 olefins,7 imines,8 ring
opening procedures on chiral epoxides,9 halocyclocarbamation of
allylamines,10 and transformation of chiral sugars11 and b-amino
acids.12 Due to its promising biological activity and intriguing
structure, more than 25 syntheses of bestatin (1) have been repor-
ted,6a,13 many of which utilized unnatural
D
-phenylalanine as a chi-
ral starting material.5,6b–e,10,13c,14 As part of our program15 directed
toward expanding the synthetic utility of -proline-catalyzed
asymmetric -amination, we report a short, efficient method for
L
a
the enantioselective synthesis of (ꢀ)-bestatin (1) starting from
3-phenylpropionaldehyde (Scheme 1).
Proline, an abundant, inexpensive amino acid available in both
enantiomeric forms, has emerged as a practical and versatile
(OsO4, NMO); (ii) the diol so formed was subsequently cleaved
24
organocatalyst.16 Asymmetric
a
-amination of aldehydes using
proline as the catalyst represents17 a burgeoning field of synthetic
efforts toward synthesizing chiral building blocks, such as -amino
on treatment with NaIO4,
which gave the corresponding
aldehyde; (iii) the crude aldehyde, being labile, was immediately
oxidized (NaClO2, NaH2PO4),25 without purification, to the corre-
sponding carboxylic acid 9. Acid 9 was readily condensed with
a
acids and alcohols. Also, the Pd-catalyzed intramolecular cycliza-
the benzyl ester of L
-leucine (DCC, HOBT in THF)26 to provide the
amide 10 in 70% yield over the four steps. Finally, catalytic
hydrogenolysis [20% Pd(OH)2/C, H2 (75 psi), MeOH/AcOH (9:1),
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.054

6792
S. George et al. / Tetrahedron Letters 49 (2008) 6791–6793
OH
H
N
NH2
O
CO2H
(-)-Bestatin (1)
CHO
NHBz
OH
N
CHO
c
a
d
R1
R2
5
2
3, R1 = Cbz; R2 = NHCbz
4, R1 = H; R2 = Bz
b
O
OR
X
i
g
f
(-)-Bestatin (1)
O
N
O
NHBz
N
Ph
Ph
6, R = H
8
e
7, R = Ac
9, X = O H
10, X = HN
h
CO2Bn
Scheme 1. Reagents and conditions: (a) dibenzyl azodicarboxylate, L-proline (10 mol %), CH3CN, 0–25 °C, 3 h then NaBH4, EtOH, 0 °C, 30 min, 92%, 95% ee; (b) (i) H2 (60 psi),
Raney nickel, MeOH, AcOH, 25 °C, 20 h; (ii) benzoyl chloride, Et3N, THF, 0–25 °C, 30 min, 70% (over two steps); (c) Dess–Martin periodinane, CH2Cl2, 25 °C, 2 h; (d)
CH2@CHMgBr, THF, 0–25 °C, 1 h, 85% (over two steps); (e) Ac2O, Py, DMAP, CH2Cl2, 25 °C, 12 h, 98%; (f) Pd(PPh3)4 (5 mol %), K2CO3, CH3CN, reflux, 24 h, 79%, dr > 14:1; (g) (i)
OsO4, 50% aq NMO, acetone/H2O (9:1), 25 °C, 12 h; (ii) NaIO4, CH2Cl2, 25 °C, 10 min; (iii) NaClO2, NaH2PO4, t-BuOH, H2O, 25 °C, 2 h; (h)
HOBT, THF, 0–25 °C, 16 h, 70% (over 4 steps); (i) 20% Pd(OH)2/C, H2 (75 psi), MeOH/AcOH (9:1), 25 °C, 36 h, 72%.
L-leucine benzyl esterꢂTsOH, DCC,
25 °C, 36 h]22b of 10 furnished (-)-bestatin (1) in 72% yield {½a 2D5
ꢁ
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ꢀ13.5 (c 0.5, 1 N HCl); lit.26
½
a 2D5
ꢁ
ꢀ14.3 (c 0.5, 1 N HCl)}. The spec-
troscopic data of 1 were in full agreement with those reported in
the literature.26
In conclusion, we have described a short synthetic route to (ꢀ)-
bestatin 1 with an overall yield of 22%, which includes a successful
application of L-proline-catalyzed asymmetric a-amination of an
aldehyde to give the corresponding aminoalcohol in 95% ee. The
protocol also demonstrates the synthetic utility of the Pd-catalyzed
intramolecular cyclization of benzamide 7 to give trans-oxazoline 8
in a highly diastereoselective fashion.
Acknowledgments
S.G. thanks CSIR, New Delhi for the award of research fellow-
ship. The authors are thankful to Dr. B.D. Kulkarni, Head, CEPD,
for his support and encouragement, and to Mrs. S.S. Kunte for
recording chiral HPLC analysis.
References and notes
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S. George et al. / Tetrahedron Letters 49 (2008) 6791–6793
6793
14. (a) Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. J. Antibiot. 1976, 29, 600–601;
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Elemental Anal.: C25H26N2O5 (434.48) requires C, 69.11; H, 6.03; N, 6.45.
Found: C, 69.43; H, 5.82; N, 6.26.
20. The enantiomeric purity of 3 was determined as 95% by chiral HPLC analysis of
the corresponding oxazolidinone obtained from the protected aminoalcohol 3
by following the literature procedure.17a HPLC conditions: Kromasil 5-
AmyCoat column (250 ꢃ 4.6 mm), petroleum ether: i-PrOH (90:10), 0.5 mL/
min, 254 nm.
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16. For
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23. Spectral data for 8: ½a D25
ꢁ
ꢀ35.5 (c 1.2, CHCl3); IR (CHCl3)
m
max: 3353, 2945, 2831,
;
2596, 2044, 1701, 1650, 1450, 1417, 1114, 1029 cmꢀ1
1H NMR (200 MHz,
CDCl3): d 2.85 (dd, J = 8.6, 13.7 Hz, 1H), 3.31 (dd, J = 5.3, 13.8 Hz, 1H), 4.26–4.36
(m, 1H), 4.81 (t, J = 6.6 Hz, 1H), 5.08–5.16 (m, 2H), 5.75 (ddd, J = 6.6, 10.2,
17.0 Hz, 1H), 7.27–7.35 (m, 5H), 7.41–7.54 (m, 3H), 8.01–8.05 (m, 2H); 13C
NMR (50 MHz, CDCl3): d 41.46, 73.75, 84.54, 116.39, 126.51, 128.25, 128.29,
128.43, 129.44, 131.29, 136.21, 137.38, 162.92; Elemental Anal.: C18H17NO
(263.33) requires C, 82.10; H, 6.51; N, 5.32. Found: C, 82.43; H, 6.32;
N, 5.11.
19. Spectral data for 3: mp 110–116 °C; ½a D25
ꢁ
+11.43 (c 1.8, CHCl3); IR (CHCl3) mmax
:
3446, 1716, 1496, 1456, 1409, 1261, 1217, 1134, 729 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 2.67–2.75 (m, 2H), 3.29 (br s, 1H), 3.55–3.74 (m, 2H), 4.62–4.79 (m,
1H), 5.09–5.08 (m, 4H), 6.72 (br s, 1H), 7.13–7.44 (m, 15H); 13C NMR (50 MHz,
CDCl3): d 34.38, 61.50, 67.47, 67.79, 68.17, 126.44, 127.42, 127.64, 127.97,
128.14, 128.29, 128.35, 128.48, 128.59, 135.00, 135.50, 137.17, 156.60;
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