A total synthesis of (-)-bestatin using Shibasaki's asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tetlet.2005.08.153

A total synthesis of the potent aminopeptidase inhibitor (-)-bestatin has been achieved using Shibasaki's asymmetric Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex in 26% overall yield.

Full text of DOI:10.1016/j.tetlet.2005.08.153

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7581–7582
A total synthesis of (À)-bestatin using ShibasakiÕs
asymmetric Henry reaction
Naminita Gogoi, Joshodeep Boruwa and Nabin C. Barua*
Natural Products Chemistry Division, Regional Research Laboratory (CSIR), Jorhat 785 006, Assam, India
Received 25 April 2005; revised 19 August 2005; accepted 26 August 2005
Available online 13 September 2005
Abstract—A total synthesis of the potent aminopeptidase inhibitor (À)-bestatin has been achieved using ShibasakiÕs asymmetric
Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex in 26% overall yield.
ꢀ 2005 Published by Elsevier Ltd.
The a-hydroxy b-amino acid (AHBA) moiety is a com-
mon structural fragment in numerous natural products.1
The presence of this moiety and the stereochemistry of
the hydroxy as well as the amino group play a vital role
in the biological activity of the molecules containing it.
Moreover, a number of their amide derivatives, isolated
from bacterial cultures display significant activity
against aminopeptidases.2 One such molecule (À)-besta-
tin 1 (Fig. 1), a dipeptide, was isolated from Strepto-
myces olivoreticulithe by Umezawa et al. in 1976.3
an adjuvant in cancer chemotherapy5 and in hyperten-
sion.6 Structure-modification studies on bestatin and
similar molecules like phebestin 27 and probestin 38 indi-
cated that the presence of syn-amino alcohol fragments
and the 2S-configuration of the a-hydroxy group
are important factors for tight interaction with the
enzyme.9
The biological activity of bestatin has attracted consid-
erable interest in its total synthesis.10 However, most
of the reported syntheses still have difficulties in control-
ling the stereochemistry at the C-2 and C-3 stereogenic
centres for the introduction of the desired (2S,3R)-con-
figuration of the N-terminal component.
This potent aminopeptidase inhibitor also exhibits
immunomodulatory activity4 and is used clinically as
In continuation of our interest on the synthesis of phar-
macologically important natural products using ali-
phatic nitro compounds,11 we report here a potentially
significant route to (À)-bestatin that is not only consid-
erably shorter and higher in yield, but also experimen-
tally much simpler involving ShibasakiÕs asymmetric
Henry reaction as the key step.
O
NH2
O
NH2
O
N
H
Ph
OH
Ph
OH
N
H
N
H
OH
O
Ph
OH
O
Phebestin 2
Bestatin 1
NH2
O
Treatment of ethyl glyoxalate with 2-phenyl-1-nitro-
ethane as per the procedure described by Shibasaki
et al.12 at À50 ꢁC in the presence of the La-(R)-BINOL
catalyst13 (10 mol %) in THF provided (2S,3R)-4 in 81%
yield and 93% ee14 as the sole product (Scheme 1). The
assigned C-2, C-3 relative stereochemistry rested on the
observed coupling constant (J2,3 = 3.6 Hz). Our attempt
to reduce selectively the nitro group in the presence of
the ester using NaBH4 (2.5 equiv) and Pd–C in THF15
was unsuccessful and resulted in reduction of the ester
to an alcohol with survival of the nitro group. We then
N
OH
N
Ph
N
H
O
O
OH
O
Probestin 3
Figure 1.
Keywords: AHBA; Aminopeptidase; Asymmetric Henry reaction;
La-BINOL complex.
Corresponding author. Tel.: +91 376 2370121; fax: +91 376
2370011; e-mail: ncbarua12@rediffmail.com
*
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.153

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N. Gogoi et al. / Tetrahedron Letters 46 (2005) 7581–7582
1. Acetylation (94%)
NO2
O
2. 10% Pd-C,
Ethyl glyoxalate
Ph
H2, MeOH, NaBH4 (60%)
Ph
OEt
NO2
La-(R)-BINOL, THF, -50 ºC
OH
(81%)
ee 93%
(2S,3R)-4
1. N-ethylmorpholine,
isobutyl chloroformate,
L-leucine benzyl ester,
THF, -10 ºC
BocNH
NH2
O
O
1. (Boc)2O, aq. NaHCO3
EtOAc (92%)
Ph
Ph
OH
OH
OAc
OAc
2. H2, 10% Pd-C, MeOH
(77% two steps)
(2S,3R)-5 ee 93%
ee 93%
(2S,3R)-6
BocNH
O
1 K2CO3, MeOH
(73%)
Ph
OH
1
N
H
2. TFA
OAc
O
ee 95%
(2S,3R)-7
Scheme 1.
3. (a) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1976, 29, 97; (b) Nishino, N.;
Powers, J. C. Biochemistry 1979, 18, 4340.
4. Nakamura, H.; Suda, H.; Takita, T.; Aoyagi, T.; Ume-
zawa, H.; Iitaka, Y. J. Antibiot. 1976, 29, 102.
5. Ino, K.; Goto, S.; Nomura, S.; Isobe, K.-I.; Nawa, A.;
Okamoto, T.; Tomoda, Y. Anticancer Res. 1995, 15, 2081.
6. Dzoljicacute, E.; Varagicacute, V. M. Fundam. Clin.
Pharmacol. 1987, 1, 307.
7. Nagai, M.; Kojima, F.; Naganawa, H.; Hamada, M.;
Aoyagi, T.; Takeuchi, T. J. Antibiot. 1997, 50, 82.
8. Aoyagi, T.; Yoshida, S.; Nakamura, Y.; Shigihara, Y.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1990, 43, 143.
9. Harbeson, S. L.; Rich, D. H. Biochemistry 1988, 27, 7301.
10. (a) Kudyba, I.; Raczko, J.; Jurczak, J. J. Org .Chem. 2004,
69, 2844; (b) Lee, J. H.; Lee, B. W.; Jang, K. C.; Jeong,
I.-Y.; Yang, M. S.; Lee, S. G.; Park, K. H. Synthesis 2003,
829; (c) Righi, G.; DÕAchille, C.; Pescatore, G.; Bonini, C.
Tetrahedron Lett. 2003, 44, 6999; (d) Nemoto, H.; Ma, R.;
Suzuki, I.; Shibuya, M. Org. Lett. 2000, 26, 4245; (e)
Palomo, C.; Aizpurua, J. M.; Cuevas, C. J. Chem. Soc.,
Chem. Commun. 1994, 1957; (f) Herranz, R.; Vinuesa, S.;
Castro-Pichel, J.; Perez, C. J. Chem. Soc., Perkin Trans. 1
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Chem. 1989, 54, 4235.
tried the reaction with NaBH4 in the presence of
Cu(OAc)2,16 but we observed only decomposition of
the starting material. Therefore, the nitroaldol product
was acetylated under standard conditions and the result-
ing nitroacetate hydrogenated with 10% Pd–C at 1 atm
H2 in methanol in the presence of NaBH4 (0.5 equiv)
furnished the aminoacetate (2S,3R)-5 in 60% yield.
Boc-protection of the amino group provided (2S,3R)-6
in 92% yield. Coupling of the protected b-amino a-hy-
droxy acid (2S,3R)-6 with the benzyl ester of L-leucine
and subsequent hydrogenation delivered (2S,3R)-7 in
77% yield over two steps. Finally, deprotection of both
the protecting groups in two-steps furnished the target
molecule, which had physical and spectral properties
identical with those reported in the literature.3a
In conclusion, we have demonstrated a short and effi-
cient route to (À)-bestatin, which may also be applicable
to several other substituted analogues such as phebestin
and probestin, or molecules like statin, norstatin,
microgenin, etc.
11. Borah, J. C.; Gogoi, S.; Boruwa, J.; Kalita, B.; Barua, N.
C. Tetrahedron Lett. 2004, 45, 3689, and references cited
therein.
Acknowledgements
The authors are thankful to the Director, RRL Jorhat,
for providing facilities. J.B. also thanks CSIR, New
Delhi, for the Research Fellowship.
12. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J.
Am. Chem. Soc. 1992, 114, 4418.
13. Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 851.
14. The enantiomeric excess (ee) was measured by HPLC
analysis carried out using a Waters 510 HPLC system.
References and notes
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a mobile phase consisting of n-hexane 90% and isopropa-
nol 10% at a flow rate of 0.8 mL/min and a pressure of
125 psi with UV detection at 243 nm.
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