Synthesis of statine employing a general syn-amino alcohol building block

Article abstract of DOI:10.1016/S0040-4039(01)02206-7

An orthogonally protected syn-2-amino-1,3,4-butanetriol has been employed as a general syn-amino alcohol building block in the synthesis of statine. This synthesis demonstrates the utility of the building block in the synthesis of any syn-amino alcohol co

Full text of DOI:10.1016/S0040-4039(01)02206-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 639–641
Synthesis of statine employing a general syn-amino alcohol
building block
Soon Ji Kwon and Soo Y. Ko*
Department of Chemistry and Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, South Korea
Received 17 October 2001; accepted 16 November 2001
Abstract—An orthogonally protected syn-2-amino-1,3,4-butanetriol has been employed as a general syn-amino alcohol building
block in the synthesis of statine. This synthesis demonstrates the utility of the building block in the synthesis of any syn-amino
alcohol compound. © 2002 Elsevier Science Ltd. All rights reserved.
Amino alcohols are an important class of compounds.
In addition to their use as chiral auxiliaries and ligands,
the biological activities associated with this functional
group have attracted intense interests among organic
and medicinal chemists in these compounds.1 Accord-
ingly, several useful synthetic strategies have been
developed. Take, for example, statine, the key compo-
nent of the naturally occurring pepstatin, which is the
prototype of the amino alcohols with the protease
inhibitory activities.2 A number of reported syntheses
of statine attest the importance of amino alcohol com-
pounds, while at the same time, highlight the critical
issues in the synthesis of this important functional
group.
Among the key issues in the synthesis of amino alcohol
compounds are the stereo- and regiochemical controls.
Various strategies have been devised to address these
issues, including 1,2-asymmetric inductions,3 chiral aux-
iliary-induced asymmetric aldol-type reactions,4 cata-
lytic asymmetric reactions,5 and the chiron approach.6
A rather conspicuous and seemingly surprising omis-
sion might be a synthesis based on the asymmetric
aminohydroxylation strategy; however, the Sharpless
NHBoc
Pd/C
H2
HO
BnO
BnO
OTBDMS
87%
OBz
3
NHBoc
OH
NHBoc
O
aq.HF
78%
BnO
O
OTBDMS
O
OH
ref. 8
OBz
O
OH
OBz
2
1
4
NHBoc
PhLi
86%
OTBDMS
OH
5
Scheme 1.
Keywords: statine; synthesis; syn-amino alcohol; building block.
* Corresponding author. Tel.: +822-3277-3283; fax: +822-3277-2384; e-mail: sooyko@mm.ewha.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All right reserved.
PII: S0040-4039(01)02206-7

640
S. J. Kwon, S. Y. Ko / Tetrahedron Letters 43 (2002) 639–641
NHBoc
NHBoc
Boc
N
1. Pd/C, H2, 87%
BnO
NaH
85%
TsO
OTBDMS
OTBDMS
OTBDMS
MgCl
2. TsCl, pyr, 92%
OBz
OBz
OBz
7
6
2
78%
CuBr SMe2
NHBoc
OBz
NHBoc
O
NHBoc
1.aq.HF/CH3CN, 76%
2. TsCl, pyr, 83%
Cs2CO3
OTs
OTBDMS
CH3OH
99%
OBz
9
10
8
MgBr
CuI, 86%
NHBoc
OH
NHBoc
OH
NaOH/CH3OH
O3, 79%
CO2CH3
11
12
Scheme 2.
one-carbon extension, a reported difficulty in hydrolyz-
ing the resulting nitrile forced us to opt for an alterna-
tive method.10 Thus, after treating the tosylate 9 with
Cs2CO3 in methanol to yield the corresponding epoxide
(10), a two-carbon extension was carried out by a
ring-opening of the epoxide 10 using a vinyl Grignard
reagent-CuI to give 11. The extra carbon was then
cleaved off by ozonolyzing 11 in the presence of
MeOH/NaOH to afford the desired N-Boc protected
statine methyl ester 12.11
process has a problem of regiochemistry to overcome
when applied on an isolated olefin substrate.7
Our interest in the amino alcohol synthesis has led us to
propose
O(1)-benzyl-N(2)-Boc-O(3)-benzoyl-O(4)-
TBDMS-protected 2-amino-1,3,4-butanetriol (2) as a
general building block for syn-amino alcohol com-
pounds.8 Unique features of this tartrate-derived four-
carbon unit include: the syn-relative stereochemistry of
the amino alcohol function—particularly so, originating
from the syn-dihydroxy starting material9—as well as
the rich functionalities and their orthogonal protections
that would enable one to regioselectively transform the
building block to the desired target molecules (Scheme
1). As a demonstration of the synthetic utility of the
building block 2 for syn-amino alcohol compounds, a
formal synthesis of statine has been undertaken, as
presented herein.
In conclusion, we have employed O(1)-Benzyl-N(2)-
Boc-O(3)-benzoyl-O(4)-TBDMS-protected
2-amino-
1,3,4-butanetriol (2) as a building block in a formal
synthesis of statine. Its orthogonal protecting groups
enabled us to regioselectively transform the four-carbon
unit to the desired target compound. The strategy
employed in the present synthesis is generally applicable
to other syn-amino alcohol compounds, demonstrating
the utility of the compound 2 as a general building
block for this important functional group.
The C(1)–C(4) of the building block, O(1)-Benzyl-N(2)-
Boc-O(3)-benzoyl-O(4)-TBDMS-protected
2-amino-
1,3,4-butanetriol (2), corresponds to the C(5)–C(2) of
statine (statine numberings). Attachments of an isopro-
pyl group and a carboxyl group at the C(1) and C(4) of
the building block, respectively, would therefore accom-
plish the synthesis of statine (Scheme 2).
Acknowledgements
This work was supported by the KRF (2000-015-
DP0271). S.J.K. is grateful to the Brain Korea 21
project for a graduate fellowship.
In order to attach the isopropyl group, the C(1)-
hydroxyl group was selectively unveiled (H2, Pd/C),
which was then activated as tosylate (6). The carbon-
chain extension was best accomplished first by convert-
ing the tosylate 6 to the N-Boc-aziridine 7, which was
then ring-opened using an isopropyl Grignard reagent
in the presence of CuBr catalyst (to give 8). For the
one-carbon extension at the other end, an electrophilic
site was similarly introduced at the C(4), i.e. by depro-
tection of the O(4) of 8 (aq. HF) followed by tosylation
(to give 9). While a nucleophilic substitution by cyanide
anion would have been an easy choice for the required
References
1. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835; (b) Cardillo, G.; Tomasini, C. Chem. Soc.
Rev. 1996, 25, 117; (c) Juaristi, E. Enantioselective Syn-
thesis of i-Amino Acids; Wiley-VCH: New York, 1997;
(d) Juraristi, E.; Quintana, D.; Escalante, J. Aldrichim.
Acta 1994, 27, 3; (e) Cole, D. C. Tetrahedron 1994, 50,
9517.

S. J. Kwon, S. Y. Ko / Tetrahedron Letters 43 (2002) 639–641
641
2. Umezawa, H.; Aoyagi, T.; Morishita, H.; Matsuzaki,
M.; Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23,
259.
Lett. 1999, 1, 1831; (b) Nishi, T.; Kitamura, M.;
Ohkuma, T.; Noyori, R. Tetrahedron Lett. 1988, 29,
6327; (c) See also Refs. 10b and c.
3. Selected examples of recent syntheses of statine: (a)
Veeresha, G.; Datta, A. Tetrahedron Lett. 1997, 38,
5223; (b) Sengupta, S.; Sarma, D. S. Tetrahedron:
Asymmetry 1999, 10, 4633; (c) Hoffman, R. V.; Tao, J.
J. Org. Chem. 1997, 62, 2292; (d) Reddy, G. V.; Rao,
G. V.; Iyengar, D. S. Tetrahedron Lett. 1999, 40, 775.
4. Selected examples of recent syntheses: (a) Gennari, C.;
Pain, G.; Moresca, D. J. Org. Chem. 1995, 60, 6248;
(b) Ender, D.; Reinhold, U. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1219; (c) Meunier, N.; Veith, U.; Ja¨ger,
V. Chem. Commun. 1996, 331; (d) Neibois, P.; Greene,
A. E. J. Org. Chem. 1996, 61, 5210; (e) Okamoto, S.;
Fukuhara, K.; Sato, F. Tetrahedron Lett. 2000, 41,
5561; (f) Pesenti, C.; Bravo, P.; Corradi, E.; Frigerio,
M.; Meille, S. V.; Panzeri, W.; Viani, F.; Zanda, M. J.
Org. Chem. 2001, 66, 5637.
6. (a) Yanagisawa, H.; Kanazaki, T.; Nishi, T. Chem.
Lett. 1989, 687; (b) Shinozaki, K.; Mizuno, K.; Oda,
H.; Masaki, Y. Bull. Chem. Soc. Jpn. 1996, 69, 1737;
(c) Kinoshita, M.; Hagiwara, A.; Aburaki, S. Bull.
Chem. Soc. Jpn. 1975, 48, 570.
7. (a) Reiser, O. Angew. Chem., Int. Ed. Engl. 1996, 35,
1308; (b) O’Brien, P. Angew. Chem., Int. Ed. Engl.
1999, 38, 326 and references cited therein.
8. Kwon, S. J.; Ko, S. Y. J. Org. Chem. 2001, 66, 6833.
9. Cho, G. Y.; Ko, S. Y. J. Org. Chem. 1999, 64, 8745.
10. (a) Castejon, P.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron 1996, 52, 7063; (b) Bessodes, M.; Saiah,
M.; Antonakis, M. J. Org. Chem. 1992, 57, 4441; (c)
Bessodes, M.; Saiah, M.; Antonakis, M. Tetrahedron:
Asymmetry 1991, 2, 111.
11. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993,
58, 3675.
5. (a) Alemany, C.; Bach, J.; Farras, J.; Garcia, J. Org.