Synthesis of a potent aminocyclitol α-mannosidase inhibitor, 1L-(1,2,3,5/4)-5-amino-4-O-methyl-1,2,3,4-cyclopentanetetrol

Article abstract of DOI:10.1016/S0960-894X(00)00162-1

Demethylthio-, de-S-methyl-, and ethylthio-derivatives of the α-mannosidase inhibitor, mannostatin A, have been synthesized and evaluated for their inhibition of Jack bean α-mannosidase in order to elucidate the roles of the methylthio group. All derivati

Full text of DOI:10.1016/S0960-894X(00)00162-1

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1047±1050
Synthesis of a Potent Aminocyclitol ꢀ-Mannosidase Inhibitor,
1L-(1,2,3,5/4)-5-amino-4-O-methyl-1,2,3,4-cyclopentanetetrol
Seiichiro Ogawa* and Takayuki Morikawa
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku,
Yokohama, 223±8522 Japan
Received 31 January 2000; accepted 3 March 2000
AbstractÐDemethylthio-, de-S-methyl-, and ethylthio-derivatives of the a-mannosidase inhibitor, mannostatin A, have been syn-
thesized and evaluated for their inhibition of Jack bean a-mannosidase in order to elucidate the roles of the methylthio group. All
derivatives had lowered inhibitory potentials. However, a mannostatin A analogue with a methoxyl instead of the methylthio,
exhibited about 2-fold enhancement of the activity, indicating an importance for the methyl group rather than the sulfur atom.
# 2000 Elsevier Science Ltd. All rights reserved.
Identi®cation of potent and speci®c a-mannosidase
inhibitor mannostatin A1,2 (1), 1d-(1,2,3,4/5)-4-amino-
5-methylthio-1,2,3-cyclopentanetriol,3 has stimulated us
to develop new glycosidase inhibitors of 5-amino-
1,2,3,4-cyclopentanetetrol type. Recently, synthesis and
evaluation of a-mannosidase inhibitory activity of three
deoxy derivatives of 1 have been carried out4 to eluci-
date the signi®cance of each hydroxyl groups. The 3-
hydroxyl group was thereby found to be the most
important, conceivably correlating with the 2-hydroxyl
group of the mannopyranosyl cation5 and the amino group
located around the carbocation atom. We have shown6
that, among twenty four stereoisomers of 5-amino-1,2,3,4-
cyclopentanetetrols, only 1l-(1,2,3,5/4)- and (1,2,3,4,5/0)-
isomers, and the corresponding 5-C-methyl derivatives7
are moderate inhibitors of Jack bean a-mannosidase.
In the present study chemical modi®cation concerning
the methylthio function of mannostatin A 1 was carried
out. Demethylthio- 2, de-S-methyl- 3, and ethylthio-
derivative 4 were ®rst synthesized. Secondly, in order to
assess the roles of the sulfur atom of 1, attempts were
made to replace the methylthio group by a methoxyl
group by preparation of 5-amino-4-O-methyl-,-1,4-di-
O-methyl-, and-epi-4-O-methyl-1,2,3,4-cyclopentanete-
trols (5, 6 and 7).1
Reaction of the 2,3-O-cyclohexylidene derivative8 of
(1,2,3,4,5/0)-5-acetamido-1,2,3,4-cyclopentanetetrol with
(R)-O-acetylmandelic acid in the presence of DCC and
DMAP in CH2Cl2 a€orded rather diastereoselectively the
1R-(R)-O-acetylmandelate9 L-8, (56%) an major product,
together with the 1S-ester D-8 (8%). Compound L-8 was
*Corresponding author. Tel.: +81-45-566-1559; fax: +81-45-566-
1551; e-mail: ogawa@applc.keio.ac.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00162-1

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S. Ogawa, T. Morikawa / Bioorg. Med. Chem. Lett. 10 (2000) 1047±1050
converted into the phenylthiocarbonyl ester 9 (27%) by
treatment in turn with DMAP (6 molar equiv) and
phenyl chlorothionocarbonate (5 molar equiv) in
CH3CN at room temperature. Reaction of 9 with tri-
butyltinhydride in the presence of AIBN gave the deoxy
derivative 11 (43%). Deprotection of 11 with 2 M HCl
at 80 ꢀC followed by conventional acetylation gave the
tetra-N,O-acetyl derivative10 2a (ꢁ100%), the structure
1,2,3,4-cyclopentanetetrol with (S)-O-acetylmandelic acid
(!ca. 4:1 mixture of L-15 and D-15), followed by treat-
ment with triethylsilyltri¯ate in CH2Cl2 gave a separable
mixture of L-16 (77%) and D-16 (23%). Compound L-16
was de-O-acylated under Zemplen conditions (!17),
and subsequently treated with iodomethane-Ag2O in
MeCN to give the methyl ether 18 (ꢁ100%). Desilylation
of 18 with tributylammonium¯uoride in THF (!19,
69%), conventional transformation into the mesylate
(!20), and heating in 80% aq DMF at 110 ꢀC gave
through neighboring participation the 4-epimeric alcohol
21 (76%). Acid hydrolysis of 21 and successive acety-
lation gave the tetra-N,O-acetyl derivative13 5a (53%).
1
of which was characterized on the basis of its H NMR
spectrum.
Compound L-8 was treated with tri¯uoroacetic anhy-
dride in pyridine-CH2Cl2 ( 15 ꢀC) and the resulting tri-
¯ate 10 was then subjected to a nucleophilic substitution
with potassium thioacetate-18-crown 6-ether in dry
benzene to give the acetylthio derivative 12 (61%). Acid
hydrolysis of 12 followed by acetylation gave the penta-
N,O,S-acetyl derivative11 3a (ꢁ100%). In addition, 12
was de-S-acetylated with methanolic sodium methoxide
and then treated with iodoethane to give the ethylthio
derivative 13 (ꢁ100%), which was converted into the
tetra-N,O-acetyl derivative12 4a (ꢁ100%).
The alcohol 22 derived from D-16 was mesylated and
the sulfonate was treated with sodium acetate in aq
DMF to give the 4-epimer 23 (80%). Compound 23 was
methylated in the usual manner to the dimethyl ether 24
(68%), which was converted into the tri-N,O-acetyl
derivative14 6a (86%).
Compound D-8 was silylated, deacylated (!25, 68%)
and then methylated to give the methyl ether 26 (97%).
Deprotection of 26 followed by acetylation gave the
tetra-N,O-acetyl derivative15 7a (87%).
Moderate diastereoselective acylation of the 2,3-O-cyclo-
hexylidene derivative8 14 of (1,4/2,3,5)-5-acetamido-

S. Ogawa, T. Morikawa / Bioorg. Med. Chem. Lett. 10 (2000) 1047±1050
1049
Table 1. Inhibitory activitya of mannostatin A 1 and six analogues 2±
7 against a-mannosidaseb (Jack bean)
K.; Yamamoto, T.; Aoyagi, T.; Nakamura, H.; Iitaka, Y. J.
Antibiot. 1989, 42, 1008.
2. Total synthesis: (a) Ogawa, S.; Yuming, Y. J. Chem. Soc.,
Chem. Commun. 1991, 890; Biorg. Med. Chem. 1995, 3, 939.
(b) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1991, 113, 5089;
J. Am. Chem. Soc. 1994, 116, 562. (c) Knapp, S.; Murali Dhar,
T. G. J. Org. Chem. 1991, 56, 4096. d) Trost, B. M.; Van
Vranken, D. L., J. Am. Chem. Soc. 1991, 113, 5089. For a
review article, see Ganem, B. In Carbohydrate Mimics; Cha-
pleur, Y., Ed.; Wiley-VCH: Weinheim, 1998, pp 239.
3. In this paper, nomenclature of cyclitols follows IUPAC-
IUB 1973 Recommendations for Cyclitols (Pure Appl. Chem.
1974, 37, 285).
Compound
1c
2
3
4
5
6
7
IC50 (mM)
0.35
11
36
5.0
0.16
NId
NI
a2.0 mM p-nitrophenyl a-d-mannopyranoside, 0.1 M acetate bu€er,
pH 4.5.16
ba-Mannosidase and nitrophenyl mannopyranoside were purchased
from SIGMA.
cRef. 9.
dNo inhibition <10 M.
3
4. Ogawa, S.; Morikawa, T. Bioorg. Med. Chem. Lett. 1999, 9,
1499.
5. Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res.
1993, 26, 182.
6. Uchida, C.; Kimura, H.; Ogawa, S. Bioorg. Med. Chem.
1997, 5, 921.
7. Ogawa, S.; Washida, K. Eur. J. Org. Chem. 1929, 1998
8. Suami, T.; Tadano, K.; Nishiyama, S.; Lichtenthaler, F. W.
J. Org. Chem. 1973, 38, 3691. Uchida, C.; Yamagishi, T.;
Ogawa, S. J. Chem. Soc., Perkin Trans 1 1994, 589.
9. Ogawa, S.; Kimura, H.; Uchida, C.; Ohashi, T. J. Chem.
Soc. Perkin Trans 1, 1995, 1695.
Mannostain A analogues 2±4 were prepared by treat-
ment of the corresponding peracetyl derivatives 2a±4a
with 2 M hydrochloric acid at 80 ꢀC, and puri®ed over a
column of Dowex 50WÂ2 (H+) resin with 1% aq
ammonia as the eluent. The analogues 3±7 were
obtained by hydrolysis of 3a±7a with 1 M aq Ba(OH)2
at 90 ꢀC, followed by similar puri®cation. The free bases
thus obtained were directly subjected to assay of Jack
bean a-mannosidase inhibition (Table 1).
Thus we ®nally succeeded in obtaining a compound 5
which was two times stronger than the parent 1, which
should provide a lead compound for further develop-
ment of new a-mannosidase inhibitors. The con®gura-
tion of the S or O-methyl function was shown to be very
important. Introduction of the 1-methoxyl group at C-1
of 5 resulted in complete loss of the activity, establishing
again the importance of the 1-hydroxyl group of the
mannostatin family. Inhibitory activity was demon-
strated to be generated by the essential core structure
composed of the O-(or S-)methyl function trans to the
consecutive 1- or 2-, and 3-hydroxyl and 4-amino
groups in a cis-relationship on a cyclopentane ring.
10. 1d-(1,2,3,4/0)-1,2,3-Tri-O-acetyl-4-acetamido-1,2,3-cyclo-
pentanetriol (2a): [a]2d5 +16ꢀ (CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.74 (1H, d, J4,MH 8.5 Hz, NH), 5.28±5.20 (3H, m,
1-H, 2-H, 3-H), 4.57 (1H, m, 4-H), 2.66 (1H, m, 5a-H), 2.13,
2.07, 2.05, and 2.01 (each 3 H, 4 s, 4ÂAc), 1.77 (1H, m, 5b-H).
-HRMS: C13H20NO7 (MH+, 302.1239): found 302.1229.
11. 1d-(1,2,3,4/5)-1,2,3-Tri-O-acetyl-4-acetamido-5-acetylthio-
1,2,3-cyclopentanetriol (3a): [a]2d5 +26ꢀ (CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.79 (1H, d, J4,NH 8.5 Hz, NH), 5.42
(1H, dd,J2,3=3.9, J3,4=4.4 Hz, 3-H), 5.40 (1H, dd, J1,2 7.1 Hz,
2-H), 5.26 (1H, dd, J1,5 6.8 Hz, 1-H), 4.52 (1H, ddd, J4,5 10.5
Hz, 4-H), 3.91 (1 H, dd, 5-H), 2.37, 2.15, 2.07, 2.03 and 1.99
(each 3H,
376.1066): found 376.1068.
5
s, 5ÂAc). -HRMS: C15H22NO8S (MH+,
12. 1d-(1,2,3,4/5)-1,2,3-Tri-O-acetyl-4-acetamido-5-ethylthio-
1,2,3-cyclopentanetriol (4a): [a]2d5 +15ꢀ (CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.70 (1H, d, J4,NH 8.8 Hz, NH), 5.42
(1H, dd, J1,2 5.6, J2,3 4.4 Hz, 2-H), 5.35 (1H, dd, J3,4 5.6 Hz, 3-
H), 5.16 (1H, t, J1,5 5.6 Hz, 1-H), 4.53 (1H, ddd, J4,5 7.6 Hz, 4-
H), 3.17 (1H, dd, 5-H), 2.73.16 (each 1 H, ABq, J 7.3, Jgem
14.9 Hz, SCH2CH3), 2.11, 2.08, 2.06, and 2.04 (each 3H, 4 s,
References and Notes
1. Isolation: Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Mori-
shima, H.; Nagai, M.; Hamada, M.; Takeuchi, T.; Umezawa,
H. J. Antibiot. 1989, 42, 883. Structure: Morishima, H.; Kojiri,

1050
S. Ogawa, T. Morikawa / Bioorg. Med. Chem. Lett. 10 (2000) 1047±1050
4ÂAc), 1.25 (3 H, t, SCH2CH3). -HRMS: C15H24NO7S
(MH+, 362.1273): found 362.1270.
(1H, dd, J1,2 3.6, J2,3 5.6 Hz, 2-H), 5.02 (1H, t, J3,4 5.6 Hz, 3-
H), 4.44 (1H, dd, J1,5 6.8, J4,5 3.7 Hz, 5-H), 3.89 (1 H, dd, 1-
H), 3.72 (1H, dd, 4-H), 3.45 and 3.37 (each 3H, 2 s, 2 Me),
2.14, 2.09, 2.08, and 2.05 (each 3H, 4 s, 4ÂAc). -HRMS:
C13H22NO7 (MH+, 304.1396): found 304.1402.
13. 1l-(1,2,3,5/4)-1,2,3-Tri-O-acetyl-5-acetamido-4-O-methyl-
1,2,3,4-cyclopentanetetrol (5a): [a]2d3 3ꢀ (CHCl3); H NMR
1
(300 MHz, CDCl3): d=5.82 (1H, d, J5,NH 9.0 Hz, NH), 5.46
(1H, dd, J1,2 3.9, J2,3 4.6 Hz, 2-H), 5.34 (1H, dd, J1,5 6.1 Hz, 1-
H), 5.14 (1H, t, J3,4 4.6 Hz, 3-H), 4.57 (1H, ddd, J4,5 4.6 Hz, 5-
H), 3.77 (1H, t, 4-H), 3.42 (3H, s, Me), 2.10, 2.08, and 2.04 (3,
6, 3 H, 3 s, 4ÂAc). -HRMS: C14H22NO8 (MH+, 332.1345):
found 332.1371.
15. 1l-(1,2,3,4,5/0)-1,2,3-Tri-O-acetyl-5-acetamido-4-O-methyl-
ꢀ
1,2,3,4-cyclopentanetetrol (7a): [a]2d2 +36 (CHCl3); H NMR
1
(300 MHz, CDCl3): d=5.97 (1H, d, J5,NH 9.0 Hz, NH),
5.29.22 (3H, m, 2-H, 3-H, 4-H), 4.74 (1H, m, 5-H), 3.86 (1H,
m, 1-H), 3.40 (3H, s, Me), 2.14, 2.09, 2.08, and 2.05 (each 3H,
4 s, 4ÂAc). -HRMS: C14H22NO8 (MH+, 332.1345): found
332.1331.
14. 1l-(1,2,3,5/4)-2,3-Di-O-acetyl-5-acetamido-1,4-di-O-methyl-
1,2,3,4-cyclopentanetetrol (6a): [a]2d2 44ꢀ (CHCl3); H NMR
1
(300 MHz, CDCl3): d=6.05 (1H, d, J5,NH 8.5 Hz, NH), 5.48
16. Suzuki, H.; Li, S.-C.; Li, Y.-T. Biol. Chem. 1970, 245, 781.