Stereoselective synthesis of (-)-gabosine C using a Nozaki-Hiyama-Kishi reaction and RCM

Article abstract of DOI:10.1016/j.tetlet.2005.03.018

An efficient synthesis of (-)-gabosine C 3 and a formal synthesis of (-)-COTC 4 are described using the Nozaki-Hiyama-Kishi (NHK) reaction and RCM as the key steps.

Full text of DOI:10.1016/j.tetlet.2005.03.018

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3049–3051
Stereoselective synthesis of (ꢀ)-gabosine C using a
Nozaki–Hiyama–Kishi reaction and RCMI
G. Venkata Ramana and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 November 2004; revised 21 February 2005; accepted 3 March 2005
Available online 22 March 2005
Abstract—An efficient synthesis of (ꢀ)-gabosine C 3 and a formal synthesis of (ꢀ)-COTC 4 are described using the Nozaki–
Hiyama–Kishi (NHK) reaction and RCM as the key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
The gabosines, a class of carbasugars, have been isolated
from Streptomyces strains. The majority contain tri-
hydroxylated hydroxymethyl cyclohexenone structures
as their common skeleton.1 These unsaturated carba-
sugars present structural diversity due to variations at
three asymmetric centers and differing substitutions at
C-2 or C-3 as in structures 1 and 2.2 Gabosines and re-
lated natural products are known to exhibit a variety of
biological activities such as antiprotozoal activity, DNA
binding properties, and inhibition of glyoxalase-I and
glycosidases.3 Gabosine related derivatives have been
used as intermediates for the synthesis of biologically
active compounds such as a L-fucosyltransferase inhibi-
tor, valienamine and derivatives, and a pseudosugar
C-disaccharide.2
crotonic acid and BF3ÆOEt2.5 (ꢀ)-COTC, (2-crotonyloxy-
methyl-(4R,5R,6R)-trihydroxycyclohex-2-enone) 4 was
isolated from the culture broth of Streptomyces griseo-
sporeus by Umezawa and co-workers6 as cytotoxic and
potentially cancerostatic with low toxicity and has been
shown to act synergistically with aclarubicin, an anti-
cancer drug.6,7
Considering their fascinating structures, biological
activities, and versatility as synthons, we are interested
in developing a new general access to the gabosine skele-
ton and have focused on the preparation of (ꢀ)-gabo-
sine C 3 using the Nozaki–Hiyama–Kishi reaction8
and RCM as the key steps. Although there are several
reports of the synthesis of 3 and 4,9 our strategy is short
and straightforward and is also useful for making other
gabosine skeletons from carbohydrates.
(ꢀ)-Gabosine C 3, identical to the antibiotic (ꢀ)-KD16-
U1, was isolated in 1974 from the culture broth of Strep-
tomyces filipensis.4 It has been transformed into
(ꢀ)-COTC 4 a glyoxalase-I inhibitor, by treatment with
Our approach to the synthesis of (ꢀ)-gabosine C 3 is
shown in Scheme 1. 2,3-O-Isopropylidene-D-ribose was
O
O
O
O
O
OH
OH
OH
OH
OH
OH
OH
OH
HO
O
R
R
OH
OH
OH
OH
(-)-Gabosine C
3
R= OH
2
R= OH
(-)-COTC
4
1
q IICT communication number: 041116.
*
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40 27160512; e-mail: venky@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.018

3050
G. V. Ramana, B. V. Rao / Tetrahedron Letters 46 (2005) 3049–3051
OMOM
OH
OMOM
O
OR1
OR1
O
HO
a
f
e
c
O
O
h
O
O
O
O
O
O
1 = Piv
1= H
10
8
9
R
R
6
7
5
R
R
d
1 = H
b
1
Piv
=
OH
O
MOMO
O
OH
O
O
O
O
OTHP
THPO
THPO
g
i
O
OMOM
13
OMOM
12
11
O
O
O
N
N
OH
OH
HO
OH
OH
ref.5
O
C l
Ru
C l
Ph
OH
PCy3
OH
4
3
I
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, ꢀ78 °C to 0 °C, 2 h, 70%; (b) Piv-Cl, 2,6-lutidine, DMAP, CH2Cl2, 0 °C to
rt, 12 h, 74%; (c) MOM-Cl, DIPEA, TBAI, CH2Cl2, 0 °C to rt, 24 h, 83%; (d) NaOMe, MeOH, 0 °C to rt, 5 h, 75%; (e) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 °C, 3 h, (f) 16, CrCl2, NiCl2, DMF, rt, 24 h, 84% (for the two steps); (g) Grubbsꢀ second-generation olefin metathesis catalyst
(I, 0.1 equiv), CH2Cl2, 80 °C, 48 h, 56% (86% yield based on recovered starting material 11 as a 1:1 diastereomeric mixture); (h) PDC, CH2Cl2, 0 °C
to rt, 24 h, 78%; (i) AmberlystÒ 15, THF:H2O (2:1), 70 °C, 5 h, 50%.
converted to 2,3-O-isopropylidene-L-erythronolactol 5
using a known procedure.10 A Grignard reaction on 5
yielded the required compound 13. Finally, removal of
the MOM, THP, and acetonide protecting groups
occurred in one step with AmberlystÒ 15 in THF:H2O
(2:1) at 80 °C to afford (ꢀ)-gabosine C 3 which was puri-
fied by column chromatography and then crystallized
using a reported protocol afforded diol 611 as the major
25
isomer with high stereoselectivity (½aꢁ +41.6 (c 1.4,
D
CHCl3) lit.11 [a]D ꢀ42.2 (c 1.8, CHCl3) for its enantio-
mer). Selective protection of the primary hydroxyl group
in 6 with Piv-Cl, in the presence of 2,6-lutidine gave 7
and then the secondary hydroxyl group was protected
as the MOM ether to give 8. Deprotection of the Piv
from EtOAc to give a white solid whose physical (mp:
25
D
113–114 °C lit.1b,4 113–114 °C; ½aꢁ ꢀ166 (c 0.13, H2O)
28
D
lit.9a ½aꢁ ꢀ166 (c 0.17, H2O)) and spectral data were
in agreement with the reported values. Conversion of
(ꢀ)-gabosine C 3 to its crotyl ester derivative (ꢀ)-COTC
4 has been reported previously by the Umezawa et al.5
group in
8 with NaOMe gave the alcohol 9
25
D
(½aꢁ ꢀ48.5 (c 1.18, CHCl3)). Oxidation of the alcohol
9 under Swern conditions yielded the aldehyde 10. Using
a Nozaki–Hiyama–Kishi reaction,8 aldehyde 10 was
treated with the iodo compound 16 (prepared from
propargyl alcohol in two steps12 Scheme 2), CrCl2 and
NiCl2 in DMF to afford a diastereomeric mixture of
dienes 11 (as a 1:1 diastereomeric mixture at the newly
created stereogenic center). Treatment of these dienes
11 with Grubbsꢀ second-generation olefin metathesis cat-
alyst I13 in CH2Cl2 at 80 °C furnished the cyclohexene
12 in 56% yield. Oxidation of alcohol 12 with PDC
In summary we have synthesized (ꢀ)-gabosine C, 3
using a Nozaki–Hiyama–Kishi reaction and RCM as
the key steps. This strategy is suitable for synthesizing
polyhydroxylated cyclohexene systems in general.
Acknowledgements
G.V.R. thanks the CSIR New Delhi for a research
fellowship (SRF). We also thank Dr. J. S. Yadav and
Dr. A. C. Kunwar for their support and encouragement.
OH
I
I
a
b
OTHP
OH
References and notes
14
15
16
1. (a) Yuan-Qing, T.; Corinna, M.; Regina, H.; Isabell, S.;
Susanne, G.; Xiao-Zhang, F.; Axel, Z.; Ralf, T. Eur.
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0 °C to rt, 90 min, 61%; (b) DHP, PTSA (0.1 equiv), CH2Cl2, 0 °C to
rt, 2 h, 86%.

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