Enantioselective synthesis of the papulacandin ring system: conversion of the mannose diastereoisomer into a glucose stereoisomer.

Article abstract of DOI:10.1021/ol006662a

[structure] An enantioselective synthesis of three diastereoisomers of the C-arylglycoside tricyclic spiroketal nucleus of the papulacandins has been achieved, in which the initial asymmetry was introduced via a Sharpless dihydroxylation of substituted 5-

Full text of DOI:10.1021/ol006662a

ORGANIC
LETTERS
2
000
Vol. 2, No. 25
033-4036
Enantioselective Synthesis of the
Papulacandin Ring System: Conversion
of the Mannose Diastereoisomer into a
Glucose Stereoisomer
4
Devan Balachari and George A. O’Doherty*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
odoherty@chem.umn.edu
Received September 26, 2000
ABSTRACT
An enantioselective synthesis of three diastereoisomers of the C-arylglycoside tricyclic spiroketal nucleus of the papulacandins has been
achieved, in which the initial asymmetry was introduced via a Sharpless dihydroxylation of substituted 5-aryl-2-vinylfurans. A selective oxidation−
reduction sequence converted the mannose isomer into the glucose isomer. This sequence can conveniently produce both the papulacandin
ring system along with its enantiomer and diastereomers in only 10−14 steps from 3,5-dimethoxybenzyl alcohol in 5−8% overall yield.
4
The discovery of antifungal agents that possess a high degree
of selective toxicity against fungal cells remains an important
scientific challenge. The need for antifungal agents is evident
in that Pneumocystis carinii pneumonia is the most prevalent
opportunistic infection in AIDS patients worldwide and a
plex. There are various members in this family, which differ
in acyl side chain substitution at C-3 and C-6′. The
5
,6
papulacandins A-D (Figure 1) and the more recently
isolated new members Mer-WF3010, L-687-781, Bu-
4794F, and BE-29602 all share a common spiroketal
residue. The simplest member, papulacandin D, lacks the
C-4 galactose with the C-6′ acyl group. All the isolated
papulacandins have shown antifungal activity.
7
8
9
10
1
frequent cause of death. An attractive enzyme target for the
development of new antifungal agents is 1,3-â-glucan
synthase, which is necessary for cell wall construction in
fungi but not humans.2 Several proposed 1,3-â-glucan
synthase inhibitors were evaluated for their ability to control
The papulacandin’s high degree of selective toxicity and
(
4) (a) Van Middlesworth, F.; Omstead, M. N.; Schmatz, D.; Bartizal,
1a
P. carinii pneumonia in vivo. Emerging from these studies
K.; Fromtling, R.; Bills, G.; Nollstadt, K.; Honeycutt, S.; Zweerink, M.;
Garrity, G.; Wilson, K. J. Antibiot. 1991, 44, 45. (b) Jabri, E. D. R.; Quigley,
M.; Alders, M.; Hrmova, M.; Taft, C. S.; Phelps, P.; Selitrennikoff, C. P.
Curr. Microbiol. 1989, 19, 153. (c) Bartizal, K.; Abruzzo, G.; Trainor, C.;
Krupa, D.; Nollstadt, K.; Schmatz, D.; Schwartz, R.; Hammond, M.;
Balkovec, J.; Van Middlesworth, F. L. Antimicrob. Agents Chemother. 1992,
was a class of spiroketal mono- or disaccharide natural
products, the papulacandins.3
The papulacandins are a group of naturally occurring
glycolipid antifungal agents isolated from the fermentation
3
6, 1648.
3
broths of Papularia spherosperma and Dictyochaeta sim-
(
5) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. Antibiot. 1980, 33,
9
67.
(
1) (a) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz,
(6) Rihs, V. G.; Traxler, P. HelV. Chim. Acta 1981, 64, 1533.
(7) Chiba, H.; Kaneto, R.; Agematu, H.; Shibamoto, N.; Yoshioka, T.;
R. E.; Fromtling, R. A.; Nollstadt, K. H.; Van Middlesworth, F. L.; Wilson,
K. E.; Turner, M. J. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 5950. (b) Kovacs,
J.; Masur, H. J. Infect. Dis. 1988, 158, 254.
Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 356.
(8) VanMiddlesworth, F.; Olmstead, M. N.; Schmatz, D.; Bartizal, K.;
Fromtling, R.; Bills, G.; Nolstadt, K.; Honeycutt, S.; Zweerink, M.; Garrity,
G.; Wilson, K. J. Antibiot. 1991, 44, 45.
(9) Aoki, M.; Tsutomu; Ueki, T.; Masuyoshi, S.; Sugawara, K.; Oki, T.
J. Antibiot. 1993, 46, 952.
(2) (a) Baguley, B. C.; Rommele, G.; Gruner, J.; Wehrli, W. Eur. J.
Biochem. 1979, 97, 345. (b) Perez, P.; Varona, R.; Garcia-Acha, I.; Duran,
A. FEBS Lett. 1981, 129, 249. (c) Varona, R.; Perez, P.; Duran, A. FEMS
Microbiol. Lett. 1983, 20, 243. (d) Rommele, G.; Traxler, P.; Wehrli, W.
J. Antibiot. 1983, 36, 1539.
(10) Okada, H.; Nagashima, M.; Masao, S.; Suzuki, H.; Nakajima, S.;
Suda, H. Japanese Patent, 5-170784, July 9, 1993.
(3) Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977, 30, 289.
1
0.1021/ol006662a CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/21/2000

L-sugars as well as manno- and allo-isomers). Because of
the difficulties Barrett encountered in introducing the acyl
1
3
side chain on the C-3 hydroxyl group, we decided to
synthesize a mannopyranoside isomer of papulacandin D,
which may allow for simple acylation of C-3 and then
inversion at C-2.
In the context of a research program aimed at the synthesis
and study of the mechanism of action of the papulacandins,
we targeted three [4.5]spirocyclic ketal containing papula-
candin stereoisomers 1, 2, and 3 for synthesis and study as
glycosidase inhibitors (Figure 2). A key aspect to our study
Figure 1.
the fascinating molecular structure have stimulated a sig-
nificant amount of both biological5,7,9,11 and synthetic inves-
12
tigations by a number of research groups. So far, only one
member of the papulacandins has succumbed to total
1
3
synthesis, that being papulacandin D by the Barrett group.
Hitchcock and his group at Eli Lilly have completed a
semisynthesis of papulacandin D by attaching the more
readily available papulacandin A side chain to the papula-
candin D ring system.14 These two routes both correlated
and assigned the C-3 acyl side chain absolute stereochemistry
of papulacandins A and D.
Figure 2.
is to test the hypothesis that an iminosugar will nicely mimic
the spiroketal ring system of the papulacandins. Crucial
With the exception of the work from the Danishefsky
17
group1 and our own, all other routes to the papulacandins
derive their asymmetry from D-glucose. Danishefsky used a
Diels-Alder strategy to construct the spiroketal portion of
the papulacandins, in which the asymmetry was derived from
2a
15
for testing this hypothesis is the development of a synthetic
sequence to diastereomers of the papulacandin ring system
that will allow for testing against their corresponding
glycosidase enzymes and comparison with their analogous
iminosugar analogues. Herein we would like to report our
achievement of the enantioselective synthesis of three
papulacandin spiroketal diastereoisomers, glucose 1, mannose
1
2a
a combination of chiral auxiliary and chiral Lewis acid.
Our group has developed an approach to the mannose
stereoisomers of the papulacandin ring system via an
asymmetric dihydroxylation of 5-aryl-2-vinylfurans (vide
infra).1 In addition to potentially improved routes to the
papulacandins, a synthetic route from achiral starting materi-
als will allow for the preparation of analogues (i.e., D- and
2
, and allose 3.
5,16
Previously, we have reported the Sharpless asymmetric
dihydroxylation reaction on vinylfurans and have applied this
methodology to synthesize various D- or L-hexoses.
18,19
More
recently, we have described an asymmetric dihydroxylation
of 5-substituted vinylfuran for the synthesis of enantio-
(
11) (a) Kaneto, R.; Chiba, H.; Agematu, H.; Shibamoto, N.; Yoshioka,
T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 247. (b) Okada, H.;
Nagashima, M.; Suzuki, H.; Nakajima, S.; Kojiri, K.; Suda, H. J. Antibiot.
1
5
enriched furyl alcohols such as 4, which were converted
1
996, 49, 103.
12) For other approaches to the papulacandin ring system, see: (a)
Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydr. Res. 1987, 171, 317.
b) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163. (c) Friesen, R.
20
21
via an Achmatowicz oxidation/Luche reduction sequence
(
(
(17) It has been proposed that the spiroketal ring system inhibits the
enzyme â(1-3)glucan synthases as a transition state inhibitor analogously
with iminosugars; in fact, Urbina has found some simple arylamines inhibit
fungal cell wall synthesis. See: Urbina, J. M.; Cortes, J. C. G.; Palma, A.
Bioorg. Med. Chem. 2000, 8(4), 691.
(18) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
W. Sturino, C. F. J. Org. Chem. 1990, 55, 5808. (d) Friesen, R. W.; Loo,
R. W.; Sturino, C. F. Can. J. Chem. 1994, 72, 1262. (e) Friesen, R. W.;
Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133. (f) Dubois, E.; Beau, J.-
M. Tetrahedron Lett. 1990, 31, 5165. (g) Dubois, E.; Beau, J.-M. Carbohydr.
Res. 1992, 223, 157. (h) Rosenblum, S.; Bihovsky, M. J. Am. Chem. Soc.
1
990, 112, 2746. (i) Czernecki, S.; Perlat, M. C. J. Org. Chem. 1991, 56,
6
289. (j) Barrett, A. G. M.; Dhanak, D.; Lebold, S. A.; Pena, M.; Pilipauskas,
(19) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V.
G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328(1), 17.
(20) (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
(b) Grapsas, I.; K.; Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem.
1990, 64, 823.
D. Pest. Sci, 1991, 31, 581. (k) McDonald, F. E.; Zhu, H. Y. H.; Holmquist,
C. R. J. Am. Chem. Soc. 1995, 117, 6605. (l) Parker, K. A.; Georges, A. T.
Org. Lett. 2000, 2(4), 497-499.
(13) For a synthesis of a papulacandin D and for relevant references,
see: Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org. Chem. 1996,
1, 1082.
14) Hitchcock, S. A.; Gregory, G. S.; Kraynack, E. A.; Mayhugh, D.
6
(21) Luche, J.-L. J. Am. Chem. Soc. 1978, 110, 2226.
(
(22) For other Achmatowicz oxidation approaches to spiroketals, see:
(a) DeShong, P.; Waltermire, R. E.; Ammon, H.; L. J. Am. Chem. Soc.
1988, 110, 1901. (b) Perron, F. Albizati, K.; F. J. Org. Chem. 1989, 54,
2047. For a review on the synthesis of spiroketals, see: (c) Perron, F.;
Albizati, K.; F. Chem. ReV. 1989, 89, 1617. (d) Brimble, M. A.; Fares, F.
A. Tetrahedron 1999, 55, 7661.
R. Presented at the 218th National Meeting of the American Chemical
Society, New Orleans, Aug 22-26, 1999.
(
15) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863.
(16) Balachari, D.; Quim, L.; O’Doherty, G. A. Tetrahedron Lett. 1999,
4
0, 4769.
4034
Org. Lett., Vol. 2, No. 25, 2000

22
into spiroketals such as 5 (Scheme 1). Finally the spiroketal
5
was converted into the manno-papulacandin 2 via a
Scheme 3
Scheme 1
dihydroxylation/deprotection sequence. Herein we would like
to disclose the synthesis of the allose and glucose diastere-
oisomers 1 and 3 from the spiroketal 5.
Exposure of 4 to aqueous NBS conditions oxidatively
rearranges the furyl alcohol into a 4:1 mixture of spiroketals
In contrast to the axial alcohol of 9, the equatorial C-2
alcohol of 12 was easily oxidized to the C-2 ketosugar 13;
however no C-3 epimer was found under various acid or
basic epimerization conditions (e.g., TsOH/MeOH, DABCO/
6
(47% yield) after treatment with aqueous acid (Scheme
2). Both anomers of the enone 6 were stereoselectively
3
THF, Et N/MeOH).
Scheme 2
Although we were unsuccessful at converting the allose
isomers 8 into the glucose stereochemistry, success was
achieved at converting the mannose isomer 7 into the gluco-
isomer 17 (Scheme 4). By taking advantage of the hydrogen
Scheme 4
reduced with aqueous NaBH
give a single stereoisomer of 5 (64% yield). Treating a
t-BuOH/H O solution of 5 with OsO /NMO at 80 °C resulted
4
and protected with TBSCl to
2
4
in a 3:1 ratio of diols 7 and 8 in a 94% combined yield. The
relative stereochemistry of the manno-diol 7 was assigned
by examination of coupling constants and confirmed by
single crystal X-ray analysis. The allose stereochemistry for
diol 8 was assigned by examination of analogous coupling
constants. With a rapid and convenient route to the mannose
and allose isomers 7 and 8, we turned our attention toward
the conversion of the less desirable allose isomer 8 into the
glucose isomer 10 (Scheme 3). The diol 8 was easily
differentiated to form the C-2 acetate 9 and C-3 TBS-ether
bond that exists between the C-2 axial alcohol and the C-12
methoxy group in 7, the diols were easily differentiated with
excess TBSCl, affording 15 in good yields (95%). The axial
C-2 alcohol of 15 was cleanly oxidized to the 2-ketosugar
14 under Dess-Martin conditions (98% yields). All that
remained was to find a suitable reducing agent that would
reduce the ketone functionality of 14 to the desired equatorial
alcohol. Various borohydride reagents were examined to no
2
12 by selective protections with Ac O and TBSCl, respec-
tively. Unfortunately, we were unsuccessful in uncovering
avail; no reaction occurred even with excess NaBH
4
in
conditions for the inversion of the C-3 axial alcohol of 8 or
refluxing MeOH. Switching to LiAlH at room temperature
4
9
into the glucose isomer 10 or 11. These efforts included
provided sufficient reactivity to reduce the C-2 ketone,
providing a 1:1 mixture of the depivolated glucose isomer
17 in addition to its mannose isomer. Selective reduction
Mitsunobu conditions, mesylate and triflate formation, and
various oxidation conditions (e.g., Swern and Dess-Martin).
Org. Lett., Vol. 2, No. 25, 2000
4035

was achieved by switching to the more hindered reducing
agent, Dibal-H. This greater selectivity was proven in that
the C-6 pivolate group could be selectively deprotected upon
the addition at -78 °C of 2 equiv of Dibal-H, affording the
ketosugar 16 in >95% yield. The C-2 ketone of 16 was
selectively reduced upon exposure at -78 °C of 2 equiv of
deprotected glucose sugar 1 was produced from 17 in a
similar manner (Scheme 5). Treatment of a THF solution of
17 with TBAF provided 1 in a 67% yield.
Finally, the deprotected allose sugar 3 was produced from
12 by a similar Dibal-H/TBAF deprotection sequence. The
C-6 pivolate of 12 was removed with Dibal-H, affording the
diol 19 in excellent yield (81%), and exposure of 19 to TBAF
cleanly removed the C-2 and C-3 TBS groups, producing
LiAlH
4
, providing 17 in an 88% yield as a single stereoi-
somer.
2
4
With access to protected forms of the allose, glucose, and
mannose sugars, we decided to investigate the deprotection
of 7, 12, and 17 to form the unprotected hexoses 1, 2, and
the allose spiroketals 3 (93%).
In summary, we have synthesized the three stereoisomeric
papulacandin derivatives 1, 2, and 3 from the furyl alcohol
4. This sequence can conveniently produce for the first time
both the papulacandin ring system and its enantiomer and
diastereomers in only 10-14 steps from 3,5-dimethoxybenzyl
alcohol and 5-8% overall yield. The strategy disclosed
herein allows access to significant quantities (∼50-100 mg
from several runs) of these diastereomeric papulacandin
analogues for evaluation as glycosidase and glycosyl trans-
ferase inhibitors as well as further biological analysis.
Currently, we are applying the same sequence on the 3,5-
dibenzyloxybenzyl alcohol to produce the free resorcinol
forms of 1, 2, and 3. The results of such investigations will
be reported in due course.
3
. Selection of the appropriate deprotected sequence was
crucial, because purification of the crude reaction mixture
proved to be quite difficult. After some experimentation, it
was discovered that TBAF-mediated TBS removal followed
by Florisil chromatography provides access to substantial
23
amounts of pure materials. The deprotected mannose isomer
2
was produced from 7 in a straightforward manner (Scheme
5). The C-6 pivolate of was removed upon the treatment of
Scheme 5
Acknowledgment. We thank the University of Minnesota
(grant in aid program), the American Cancer Society for an
Institutional Research Grant (IRG-58-001-40-IRG-19, the
donors of the Petroleum Research Fund (ACS-PRF#33953-
G1), administered by the American Chemical Society, and
the Arnold and Mabel Beckman Foundation for their
generous support of our program.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds as well as experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006662A
(
23) The significance of this procedure is evident in that previous
Dibal-H, affording the triols 18 in excellent yield (93%). The
C-4 TBS ether of 18 were removed upon treatment with a
THF solution of TBAF, providing the deprotected manno-
papulacandin 2 in good yield (93%). The partially and fully
synthetic routes to the glucose paplulacandin isomer 1 only provided impure
materials, which were characterized as their tetraacetates: see ref 12i.
(
sequence; however, the intermediate triol was difficult to characterize
because of TBS group migration.
24) The allose papulacandin 3 was also prepared from 8 by this
4036
Org. Lett., Vol. 2, No. 25, 2000