Enantioselective synthesis and absolute configuration assignment of gabosine O. synthesis of (+)- and (-)-gabosine N and (+)- and (-)-epigabosines N and O

Article abstract of DOI:10.1021/ol060173e

A rational approach to the synthesis of gabosines and other related carba-sugars starting from a masked p-benzoquinone has been designed. The enantioselective acetylation of the hydroxyketal 2 provides a practical entry to either enantiomer of the target

Full text of DOI:10.1021/ol060173e

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1617-1620
Enantioselective Synthesis and Absolute
Configuration Assignment of Gabosine
O. Synthesis of (
+)- and (−)-Gabosine N
and ( )- and ( )-Epigabosines N and O
+
−
Ramo´n Alibe´s, Pau Bayo´n, Pedro de March, Marta Figueredo,* Josep Font, and
Georgina Marjanet
UniVersitat Auto`noma de Barcelona, Departament de Qu´ımica,
08193 Bellaterra, Spain
marta.figueredo@uab.es
Received January 20, 2006
ABSTRACT
A rational approach to the synthesis of gabosines and other related carba-sugars starting from a masked p-benzoquinone has been designed.
The enantioselective acetylation of the hydroxyketal 2 provides a practical entry to either enantiomer of the target products. The strategy has
been applied to the synthesis of (+)- and (−)-gabosines N and O and (+)- and (−)-epigabosines N and O. The absolute configuration of natural
gabosine O has been established.
The gabosine family comprises a group of secondary
metabolites isolated from various Streptomyces strains with
a closely related carba-sugar structure.1 All the gabosines
present a polyoxygenated methyl cyclohexane system as the
common constitutional feature (Figure 1). Their structural
diversity is originated by differences in the substituent
positions, unsaturation degree, and/or relative and absolute
configuration of their stereogenic centers. The absolute
configurations of natural gabosines A,1b B,2 C,1a D,1b E,1b
F,1b I,3 L,1d and N1d were already determined, whereas those
of gabosines G, H, J, and O have not been established yet.
A variety of biological activities have been reported for
some of the gabosines. For instance, gabosine C is the known
(1) First isolation of gabosine C, named KD16-U1: (a) Tatsuta, K.;
Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H.; Naganawa, H. J.
Antibiot. 1974, 27, 579. Isolation and structural assignment of gabosines
A-K: (b) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hammann, P.; Hu¨tter,
K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993,
241. Synthetic studies indicate that the structure of gabosine K needs to be
revised: (c) Metha, G.; Lakshminath, S. Tetrahedron Lett. 2000, 41, 3509.
Isolation and structural assignment of gabosines L, N, and O: (d) Tang,
Y.-Q.; Maul, C.; Hoefs, R.; Sattler, I.; Grabley, S.; Feng, X.-Z.; Zeeck, A.;
Thiericke, R. Eur. J. Org. Chem. 2000, 149.
(2) Mu¨ller, A.; Keller-Schierlein, W.; Bielecki, J.; Rak, G.; Stu¨mpfel,
J.; Za¨hner, H. HelV. Chim. Acta 1986, 69, 1829.
(3) Lubineau, A.; Billault, I. J. Org. Chem. 1998, 63, 5668.
10.1021/ol060173e CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/22/2006

Scheme 1. Conversion of the Masked p-Benzoquinone 1 to
Ketone 3
utility. Compound 1 (Scheme 1) is a p-benzoquinone equiva-
lent, with one of the carbonyl groups protected by ketalization
and one of the carbon-carbon double bonds masked by
addition of thiophenol. The racemate of 1 is easily available,
and its chromatographic resolution can be efficiently per-
formed.7 The absolute configuration of (+)- and (-)-1 was
unequivocally established by chemical correlation.8 Treat-
ment of 1 with NaBH4 exclusively furnishes the cis alcohol
2, which can be converted to ketone 3 in good overall yield.8,9
We visualized ketone 3 as a very suitable starting material
to undertake a systematic synthesis of gabosines and other
related compounds through the strategy depicted in Scheme
2, which involves three main transformations: (i) alkylation
Figure 1. Gabosine family of secondary metabolites: structural
classification.
Scheme 2. Diversity-Oriented Synthetic Strategy to Gabosines
and Related Compounds
antibiotic KD16-U1 and its crotonyl ester, named COTC, is
a potent glyoxylase-I inhibitor that is potentially cytotoxic.4,5
Gabosine E is a weak inhibitor of cholesterol biosynthe-
sis,1b and the antibacterial activity1a and DNA-binding
properties1d of several gabosines have also been described.
Their peculiar structure and promising biological activity
have motivated synthetic studies directed at these targets.
As a result, syntheses of several gabosines have already been
accomplished,6 but a synthetic strategy suitable for a large
number of these compounds from common synthetic inter-
mediates has not been described hitherto. We have designed
a rational, diversity-oriented approach to these compounds,
completed the synthesis of each enantiomer of gabosines O
and N and their C4 epimers, and established the previously
unknown absolute configuration of natural gabosine O. These
studies are described herein.
In previous investigations, we prepared a series of chiral
p-benzoquinone derivatives and explored their synthetic
(4) Chimura, H.; Nakamura, H.; Takita, T.; Takeuchi, T.; Umezawa,
H.; Kato, K.; Saito, S.; Tomisawa, T.; Iitaka, Y. J. Antibiot. 1975, 28, 743.
(5) ) Sugimoto, Y.; Suzuki, H.; Yamaki, H.; Nishimura, T.; Tanaka, N.
J. Antibiot. 1982, 35, 1222.
of the doubly activated C6 position of 3 to introduce the
methyl or hydroxymethyl substituent; (ii) dihydroxylation
or epoxidation of the double bond to provide the cis or trans
C2-C3 glycol unit, respectively; and (iii) reduction of the
C6-S bond or oxidation to the sulfoxide followed by
(6) Gabosines ent-C and E: (a) Lygo, B.; Swiatyj, M.; Trabsa, H.; Voyle,
M. Tetrahedron Lett. 1994, 35, 4197; gabosine C and COTC: (b) Tatsuta,
K.; Yasuda, S.; Araki, N.; Takahashi, M.; Kamiya, Y. Tetrahedron Lett.
1998, 39, 401. (c) Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron
Lett. 2000, 41, 2031. (d) Takahashi, T.; Yamakoshi, Y.; Okayama, K.;
Yamada, J.; Ge, W.-Y.; Koizumi, T. Heterocycles 2002, 56, 209. (e)
Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049. Gabosine I:
ref 3. (()-Gabosine B and putative structure of (()-gabosine K: ref 1c.
Gabosine A: (f) Banwell, M. G.; Bray, A. M.; Wong, D. J. New J. Chem.
2001, 25, 1351. Gabosines A, B, ent-D, and ent-E: (g) Shinada, T.; Fuji,
T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341.
(7) (a) de March, P.; Escoda, M.; Figueredo, M.; Font, J. Tetrahedron
Lett. 1995, 36, 8665. (b) de March, P.; Escoda, M.; Figueredo, M.; Font,
J.; Medrano, J. An. Quim. Int. Ed. 1997, 93, 81.
(8) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Garc´ıa-Garc´ıa,
E.; Rodr´ıguez, S. Tetrahedron: Asymmetry 2000, 15, 4473.
1618
Org. Lett., Vol. 8, No. 8, 2006

pyrolysis to generate the C5-C6 double bond, depending
on the target gabosine.
The synthetic studies were first undertaken starting from
racemic 3. Treatment of 3 with potassium tert-butoxide and
an excess of methyl iodide furnished a 1:2.2 mixture of
ketones 4 and 5 in 97% total yield (Scheme 3). The epimeric
These new enones are likely to be formed via various keto-
enolic equilibria, which favor the elimination of thiophenol.
During the chromatographic purification of dihydroxyketone
8, enones 9 and 10 were also detected; however the degra-
dation process was less important in this case, and ketone 8
could be isolated in 70% yield. Therefore, the synthetic
pathway was first continued with this intermediate.
Standard desulfurization of 8, followed by O-desilylation
gave a new compound, the C4 epimer of gabosine O, which
we have named epigabosine O, whereas sulfide oxidation
followed by pyrolysis of the sulfoxide and desilylation
furnished the hitherto unknown epigabosine N (Scheme 5).
Scheme 3. Partial Synthetic Sequence to Gabosines O and N:
The Alkylation and Dihydroxylation Steps
Scheme 5. Final Steps of the Synthesis of Epigabosines O
and N
ketones were chromatographically separated, and their rela-
tive stereochemistry was assigned by 1H NMR, with the help
of nOe experiments. By changing the base to sodium hydride,
ketones 4 and 5 could be obtained in ca. 1:1 ratio, although
in slightly lower yield. The reaction of ketone 4 with N-meth-
ylmorpholine N-oxide in the presence of osmium tetroxide
delivered diols 6 and 7 in a 2.8:1 ratio and 62% total yield.
Dihydroxylation of ketone 5 under the same reaction condi-
tions furnished exclusively diol 8. These results suggest that
the stereoselectivity of the reaction is directed by steric fac-
tors, with the oxidant reagent approaching the enone mainly
on the face opposite to the bulky phenylsulfenyl group.10
Intended chromatographic separation of 6 and 7 led to the
isolation of significant quantities of enones 9 and 10 (Scheme
4), in detriment of the initially produced sulfenyl ketones.
We next assessed the same transformations starting from
a 2.8:1 mixture of diastereomeric ketones 6 and 7 (Scheme
6). Desulfurization provided the expected ketone 13 derived
from 6 as the major product, along with a minor quantity of
ketone 11, presumably formed by reduction of 7 and C6
epimerization. The major isomer 13 was isolated in 53%
yield and converted to gabosine O by desilylation. The
oxidation-pyrolysis protocol applied to a 3.3:1 mixture of
6 and 7 furnished a mixture of enones 14 and 12, from where
the major isomer 14 was separated in 60% yield and
converted to gabosine N.
Having completed the aforementioned syntheses, our
preparation of enantiopure gabosines required us to repeat
the former sequences, starting from enantiopure (+)- and/or
(-)-2. This endeavor was particularly interesting in the case
of gabosine O, for which the absolute configuration of the
levorotatory natural antipode was still unknown.
As already mentioned, the enantiomers of 2 were available
by reduction of the precursor ketone (+)- or (-)-1, which
can be resolved by liquid chromatography on cellulose
triacetate on a scale of several hundred milligrams.8 Nev-
ertheless, to avoid tedious chromatographic separations,
we decided to investigate an alternative route to (+)- and
(-)-2. We found that treatment of (()-2 with vinyl acetate
Scheme 4. Proposed Mechanism for the Formation of 9 and
10 during the Chromatographic Purification (Silica Gel) of 6
and 7
(9) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Marjanet, G.
Tetrahedron: Asymmetry 2004, 15, 1151.
(10) For sterically controlled facial selectivity in dihydroxylation reactions
of related systems, see: Kwon, Y.-U.; Lee, C.; Ghung, S.-K. J. Org. Chem.
2002, 67, 3327.
Org. Lett., Vol. 8, No. 8, 2006
1619

Scheme 6. Final Steps of the Synthesis of Gabosines O and N
Scheme 7. Enzymatic Resolution of (()-2
osine O ([R]D ) -10.5° (c 0.38, MeOH)), (-)-epigabosine
N ([R]D ) -92° (c 0.26, MeOH)), and (-)-epigabosine O
([R]D ) -8.2° (c 0.49, MeOH)). Starting from (-)-2,
we synthesized (+)-gabosine N ([R]D ) +180° (c 0.15,
MeOH)),13 (+)-gabosine O ([R]D ) +20° (c 0.30, MeOH)),13
(+)-epigabosine N ([R]D ) +120° (c 0.40, MeOH)), and
(+)-epigabosine O ([R]D ) +12.2° (c 0.49, MeOH)). The
absolute configuration of natural gabosine O was thus
established as 2R,3R,4R,6S.
In summary, a general strategy has been designed for the
synthesis of gabosines and other related compounds which
has been successfully applied to several carba-sugars with
cis C2/C3 relative configuration. Work is in progress to
complete the synthesis of other related targets, including
those with trans C2/C3 relative configuration.
and a catalytic amount of Novozyme 435 in diisopropyl
ether11 furnished the acetate (-)-15 in 43% yield and 90%
ee and the unreacted alcohol (+)-2 in 45% yield and 98%
ee12 (Scheme 7). Methanolysis of the acetate (-)-15 led to
the recovery of (-)-2 whose ee was raised to 97% by
repeated crystallization from dichloromethane/pentane with
75% chemical yield.
Acknowledgment. We acknowledge financial support
from DGES (BQU2001-2600) and CIRIT (2001SGR00178)
and a grant from DGR (to G.M.).
Starting from (+)-2, we completed the synthesis of
(-)-gabosine N ([R]D ) -142° (c 0.16, MeOH)),13 (-)-gab-
Supporting Information Available: Experimental pro-
cedures, a listing of spectral data of new compounds,
(11) See related resolutions in: (a) Morgan, B. S.; Hoenner, D.; Evans,
P.; Roberts, S. M. Tetrahedron: Asymmetry 2004, 15, 2807. (b) Raminelli,
C.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L. M. Tetrahedron:
Asymmetry 2004, 15, 3117.
1
significant H- and 13C NMR spectra, and CHPLC chro-
matograms of 2 and 15. This material is available free of
(12) Enantiomeric excesses were determined by CHPLC analyses.
(13) Gabosine N: lit.1d -152° (c 0.89, H2O). Gabosine O: lit.1d -21.0°
(c 0.1, MeOH).
charge via the Internet at http://pubs.acs.org.
OL060173E
1620
Org. Lett., Vol. 8, No. 8, 2006