Formal synthesis of valienamine using ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2005.07.054

(1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxymethyl)-cyclohex-5-ene-1,2,3, 4-tetrol, a precursor of the α-glucosidase inhibitor, valienamine, was synthesised in eight steps from tetrabenzyl glucose. The key steps were the selective protection of an open-c

Full text of DOI:10.1016/j.tetlet.2005.07.054

Tetrahedron
Letters
Tetrahedron Letters 46 (2005)6257–6259
Formal synthesis of valienamine using ring-closing metathesis
Ian Cumpstey*
Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, 10691 Stockholm, Sweden
Received 22 April 2005; revised 28 June 2005; accepted 14 July 2005
Abstract—(1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxymethyl)-cyclohex-5-ene-1,2,3,4-tetrol, a precursor of the a-glucosidase
inhibitor, valienamine, was synthesised in eight steps from tetrabenzyl glucose. The key steps were the selective protection of an
open-chain diol, and the formation of the cyclohexene ring by ring-closing metathesis with the trisubstituted olefin of valienamine
correctly in place.
Ó 2005 Elsevier Ltd. All rights reserved.
Valienamine 1 is an unsaturated carbasugar that is
found in Nature as a component of glucosidase inhibi-
tors such as acarbose 21 or the antibiotic validamycin
A 32 (Fig. 1). The glucosidase-inhibitory properties of
valienamine stem from its distorted ring structure and
positive charge, which means that it resembles the tran-
sition state of the hydrolysis reaction of an a-glucoside. I
was keen to synthesise this molecule as part of a project
towards the synthesis of novel glycosidase-specific
inhibitors.
Several syntheses of valienamine 1 have been reported,
and these have recently been reviewed.3 Of the various
methods reported, I was attracted by the ring-closing
metathesis approach of Vasella and co-workers.4 How-
ever, this method makes use of GrubbsÕ first generation
catalyst to close the ring with a disubstituted double
bond between C-1 and C-5a, and relies on a rearrange-
ment to obtain the C-5@C-5a double bond and the sub-
stituent at C-1. It has been shown by Callam and
Lowary5 and by Seepersaud and Al-Abed6 in the synthe-
sis of carbaarabinofuranose derivatives such as 4 (Fig. 2)
that it is possible to achieve ring-closing metathesis to
form a trisubstituted double bond in the analogous
position to that in valienamine, using the Shrock or
GrubbsÕ second generation catalysts. Now with GrubbsÕ
second generation catalyst commercially available, I
wondered whether it would be possible to apply the
same approach to the synthesis of the equivalent glu-
cose-derived compound 5, which could then be trans-
formed into valienamine 1 as described by Fukase and
Horii.7 During the course of this work, a paper describ-
ing a similar approach has appeared.8
OH
OH
5a
H
N
6
1
NH2
OH
O
OH
OH
HO
HO
5
HO
HO
2
O
4
3
OH
OH
OH
OH
OH
OH
1
3
HO
HO
O
HO
NH
HO
OH
O
OH
HO
Thus, treatment of commercially available tetrabenzyl
glucose 6 with vinylmagnesium bromide gave 7 and 8
O
OH
O
HO
HO
O
HO
2
HO
OH
BnO
BnO
BnO
HO
HO
Figure 1. Structures of valienamine 1, acarbose 2, and validamycin A
3.
OR
OBn
OR
OBn
10
OR
OBn
BnO
BnO
BnO
Keywords: Valienamine; Ring-closing metathesis; Selective protection;
Glucosidase inhibitors.
4
9
*
Figure 2. Structures of carbaarabinose derivatives 4, and of the
substrates of reported selective protection of allylic alcohols, 9 and 10.
Tel.: +46 (0)8 674 7263; fax: +46 (0)8 15 49 08; e-mail: cumpstey@
organ.su.se
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.054

6258
I. Cumpstey / Tetrahedron Letters 46 (2005) 6257–6259
HO OH
HO OH
O
OH
7
1
BnO
BnO
6
2
8
BnO
BnO
BnO
BnO
(i)
5
3
+
OBn
4
OBn
OBn
OBn
OBn
OBn
6
8
7
Scheme 1. Reagents and conditions: (i)CH 2@CHMgBr, THF, 0 °C; 8, 29%; 7, 65%.
as a 2.2:1 mixture in favour of the desired R diastereo-
mer 7 (vide infra)( Scheme 1).9
Pivaloylation of the alcohols 11 and removal of the
DMB protecting groups gave the alcohols 14a and
14b, still as an inseparable mixture. Swern oxidation of
the alcohols 14a and 14b gave the ketones 15 and 16,
which were easily separated by flash column chromato-
graphy, in 81% and 7% yields, respectively. Wittig meth-
ylenation of the ketone 15 gave the diene 17, which
smoothly underwent ring-closing metathesis mediated
by GrubbsÕ second generation catalyst to give the carba-
sugar 18.5 The stereochemistry at the pseudoanomeric
centre could then be assigned as R, based on the cou-
It was necessary to differentiate the two alcohol func-
tionalities of the resulting diol 7. Success in similar sys-
tems has been reported previously: Martin selectively
protected the allylic alcohol of 9 using benzoyl chloride
under phase-transfer conditions,10 whereas Al-Abed
selectively protected the allylic alcohol of the epimeric
mixture 10 using para-methoxybenzyl chloride and
sodium hydride (Fig. 2).6
3
pling constant J1,2 of 7.9 Hz.12 Straightforward deacyl-
Unfortunately, these conditions could not be generally
applied, as in my system, treatment of 7 with benzoyl
chloride under the reported conditions gave a 2.8:1 mix-
ture of the regioisomeric monobenzoates in favour of
the 2-O-benzoate; attempted para-methoxybenzylation
of 8 under the reported conditions gave a 1:1 mixture
of the regioisomeric products. However, I found
that excellent regioselectivity could be achieved using
3,4-dimethoxybenzyl chloride (DMBCl)11 with sodium
hydride at 0 °C in DMF, and 11a and 11b were obtained
as an inseparable 10:1 mixture of regioisomers in favour
of the 2-O-dimethoxybenzyl derivative 11a, along with
the diprotected compound 12 (Scheme 2). As an alterna-
tive solution to this problem, the dithioacetal route
described by Jeon and Kim avoids the need for differen-
tiation of the two secondary alcohols, but has the
disadvantages of using ethanethiol as solvent during
dithioacetal formation, and mercury salts for its
removal.8
ation of the pseudoanomeric protecting group gave the
alcohol 5, which may be transformed into valienamine
1 in three steps using FukaseÕs procedure.7
In summary, I have demonstrated a new synthesis of the
precursor 5 to valienamine 1 in eight steps from com-
mercially available tetrabenzyl glucose 6 and in 7.7%
overall yield. The key steps were the selective protection
of one of two secondary alcohols in the acyclic deriva-
tive 7 and the formation of the cyclohexene ring using
ring-closing metathesis mediated by GrubbsÕ second
generation catalyst, with the double bond being in the
correct position for valienamine. Further investigations,
including the synthesis of mannose- and galactose-
derived valienamine analogues using this methodology,
the introduction of nitrogen at the pseudoanomeric
position before ring closure and the conjugation of
valienamine to other sugars, is in progress, and the
results will be reported in due course.
RO OR'
BnO
HO OH
PivO
O
O
OPiv
BnO
OBn
(iv)
(i)
BnO
BnO
BnO
BnO
BnO
OBn
+
OBn
OBn
BnO
OBn
11a R=DMB, R'=H
11b R=H, R'=DMB
+
OBn
OBn
OBn
15
16
7
(ii)
12 R=R'=DMB
13a R=DMB, R'=Piv
13b R=Piv, R'=DMB
(v)
(iii)
14a R=H, R'=Piv
14b R=Piv, R'=H
OPiv
OPiv
OBn
OH
OBn
BnO
BnO
BnO
BnO
(vi)
(vii)
BnO
BnO
OBn
OBn
OBn
OBn
17
5
18
Scheme 2. Reagents and conditions: (i)DMBCl, DMF, NaH, 0 °C; 57%; 11a/11b, 10:1; (ii)PivCl, pyridine, DMAP, 93%; (iii)CAN, MeCN, H 2O,
0 °C ! rt; 74%; (iv)oxalyl chloride, DMSO, Et N, DCM, ꢀ60 °C; 16, 7%; 15, 81%; (v)PPh CH3Br, THF, NaHMDS, ꢀ78 °C; 63%; (vi)Grubbs Õ
3
3
2nd gen. cat., toluene, 60 °C, 65%; (vii)NaOMe, MeOH, 40 °C, >99% (DMB = 3,4-dimethoxybenzyl).

I. Cumpstey / Tetrahedron Letters 46 (2005) 6257–6259
6259
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2000, 2, 167–169.
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7. Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3651–3658.
8. During the preparation of this manuscript, the following
article appeared: Chang, Y.-K.; Lee, B.-Y.; Kim, D. J.;
Lee, G. S.; Jeon, H. B.; Kim, K. S. J. Org. Chem. 2005, 70,
3299–3302.
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.07.054.
References and notes
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