Reductive aromatization of quinols: Synthesis of the C-arylglycoside nucleus of the papulacandins and chaetiacandin

Article abstract of DOI:10.1021/ol991346l

(Formula presented) Nucleophilic 1,2-addition of lithiated glycal 9b to functionalized quinone 7 provided, after reductive aromatization, C-arylglycoside 11b. Treatment with mCPBA afforded the tricyclic papulacandin framework. Alternatively, hydroboration

Full text of DOI:10.1021/ol991346l

ORGANIC
LETTERS
2000
Vol. 2, No. 4
497-499
Reductive Aromatization of Quinols:
Synthesis of the C-Arylglycoside
Nucleus of the Papulacandins and
Chaetiacandin
Kathlyn A. Parker* and Asimina T. Georges
Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
kathlyn_parker@brown.edu
Received December 14, 1999
ABSTRACT
Nucleophilic 1,2-addition of lithiated glycal 9b to functionalized quinone 7 provided, after reductive aromatization, C-arylglycoside 11b. Treatment
with mCPBA afforded the tricyclic papulacandin framework. Alternatively, hydroboration gave the chaetiacandin nucleus.
Papulacandins A-D, 1 and 2,1 are antifungal antibiotics
isolated from Papularia sphaerosperma.
sible for P. carinii-induced pneumonia in AIDS patients.3
Chaetiacandin 3, more recently isolated from Monochaetia
dimorphospora,4 demonstrates similar biological activity.
Although their structures were fully elucidated more than
20 years ago, serious attention to these compounds as
synthetic targets only followed the more recent discovery
of their strong activity against clinical isolates of Candida
albicans and other fungi. Papulacandins inhibit the enzymes
involved in the biosynthesis of 1,3-â-D-glucan, a vital
constituent of fungal cell walls.2 By inhibiting these syn-
thases, the papulacandins pose a major threat to the life cycle
of Pneumocystis carinii, an opportunistic infection respon-
Successful preparations of the C-arylglycosidic nuclei of
the papulacandins and chaetiacandin include as key steps a
(2) (a) Baguley, B. C.; Rommele, G.; Gruner, J.; Wehrli, W. Eur. J.
Biochem. 1979, 97, 345-351. (b) Perez, P.; Varona, R.; Garcia-Acha, I.;
Duran, A. FEBS Lett. 1981, 129, 249-252. (c) Varona, R.; Perez, P.; Duran,
A. FEMS Microbiol. Lett. 1983, 20, 243-247. (d) Rommele, G.; Traxler,
P.; Wehrli, W. J. Antibiot. 1983, 36, 1539-1542.
(3) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz, R.
E.; Fromtling, R. A.; Nollstadt, K. H.; Vanmiddlesworth, F. L.; Wilson, K.
E.; Turner, M. J. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 5950-5954.
Debono, M.; Gordee, R. S. Annu. ReV. Microbiol. 1994, 48, 471-497.
(4) Komori, T.; Yamashita, M.; Tsurumi, Y.; Kohsaka, M. J. Antibiot.
1985, 38, 455-459. Komori, T.; Hoh, Y. J. Antibiot. 1985, 38, 544-546.
(1) Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977, 30, 289-
296.
10.1021/ol991346l CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/29/2000

Scheme 1a
Lewis acid-catalyzed hetero Diels-Alder reaction,5 a Stille-
of this type (see 11a) might serve as the common synthetic
intermediate to both the papulacandins and chaetiacandin.
Our umpolung approach provides an attractive alternative
to coupling procedures which rely on tin reagents as it does
not lead to toxic or environmentally problematic byproducts.
type coupling of a stannylglycal with an aryl bromide,6 and
an aryllithium condensation with a D-glucose precursor7 or
a protected gluconolactone.8 The stereochemistry of the chiral
centers in the papulacandin D side chain was established by
Barrett9 who then completed a total synthesis of papulacandin
D, the simplest member of the series.
Synthesis of the C-arylglycoside intermediate 11a began
with the construction of the functionalized quinone 7
(Scheme 1). Regioselective benzylation (BnBr, 2.5 equiv of
NaH, THF, 25 °C, 10 h)12 of commercially available 2,3-
dihydroxybenzaldehyde (4) followed by hydride reduction
(NaBH4, MeOH) of monobenzylated aldehyde 4b afforded
alcohol 5. A second regioselective benzylation (BnBr, 3
equiv of NaH, DMSO) yielded phenol 6. Catalytic salcomine
oxidation13 (O2, N,N′-bis(salicylidene)ethylenediiminocobalt-
(II), DMF, 48 h) furnished the appropriately substituted
quinone 7.
The papulacandins and chaetiacandin are ideal candidates
for illustrating our “reverse polarity” strategy for the synthesis
of C-arylglycosides of the group I substitution pattern.10 In
this methodology, a 1,2-addition of a protected nucleophilic
glycal to an electrophilic quinone followed by reductive
aromatization of the resulting quinol affords phenols that bear
glycals in the para position.11 A glycal-substituted phenol
(5) Danishefsky, S.; Phillips, G.; Ciufolini, M. Carbohydr. Res. 1987,
171, 317-327.
(6) (a) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 5808-
5810. (b) Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994,
72, 1262-1272. (c) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett. 1990,
31, 6133-6136. (d) Dubois, E.; Beau, J.-M. Tetrahedron Lett. 1990, 31,
5165-5168. (e) Dubois, E.; Beau, J.-M. Carbohydr. Res. 1992, 223, 157167.
(7) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163-7169.
(8) (a) Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc. 1990, 112,
2746-2748. (b) Czernecki, S.; Perlat, M.-C. J. Org. Chem. 1991, 56, 6289-
6292.
Preparation of differentially protected glycal 9 began with
commercially available tri-O-acetyl-D-glucal. Removal of the
acetyl groups by methanolysis (K2CO3, MeOH, 25 °C)
followed by silylation, first with di-tert-butylsilyl ditriflate
(2,6-lutidine, DMF, -50 °C, 10 h) and then with triisopro-
(9) (a) Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Chem. Soc.,
Chem Commun. 1995, 1145-1146, (b) Barrett, A. G. M.; Pena, M.;
Willardsen, J. A. J. Chem. Soc., Chem Commun. 1995, 1147-1148. (c)
Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org. Chem. 1996, 61,
1082-1100.
(11) Parker, K. A.; Coburn, C. A. J. Org. Chem. 1992, 57, 5547-5550.
(12) van Doorn, A. R.; Bos, M.; Harkema, S.; van Eerden, J.; Verboom,
W.; Reinhoudt, D. N. J. Org. Chem. 1991, 56, 2371-2380.
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N.; Liu, Y.-X. J. Org. Chem. 1986, 51, 4347-4353.
(10) Parker, K. A. Pure Appl. Chem. 1994, 66, 2135-2138.
498
Org. Lett., Vol. 2, No. 4, 2000

pylsilyl chloride (DMF, 50 °C, 24 h),14 delivered the fully
protected glycal 9a.
benzylated (BnBr, NaH, THF) to give the more stable
C-arylglycoside 11b.15
The papulacandin nucleus was elaborated by oxidation of
the glycal olefin with mCPBA.9a Oxidation of intermediate
11b occurred cleanly from the R-face, a result consistent with
studies on similar compounds.20 Removal of the benzyl
ethers10 and selective silyl protection of the phenolic hydroxyl
groups gave the papulacandin intermediate 12 appropriately
functionalized for further elaboration to the natural product.
Alternatively, hydroboration of the glycal double bond of
11b, also from the R-face, with oxidative workup under basic
conditions (H2O2, aqueous NaOH)6c yielded the chaetiacandin
nucleus 13. Like papulacandin intermediate 12, the differ-
entially protected chaetiacandin nucleus 13 is set up for the
appending of the side chains in preparation for total synthesis.
As described, key intermediates 12 and 13 are available
by short schemes that do not employ noxious or ecologically
unfriendly reagents. The stage is therefore set for the
completion of a practical synthesis of one or more of the
papulacandin/chaetiacandin class of natural products. Efforts
to effect a fully convergent total synthesis of papulacandin
D are currently underway.
With the two C-arylglycoside precursors in hand, we were
now prepared to apply our umpolung methodology to the
papulacandin and chaetiacandin nuclei. Lithiation of silylated
glycal15 9a with t-BuLi (2 equiv of t-BuLi, THF, -78 °C,
then 0 °C, 2 h) and addition of 9b in THF at -100 °C to
quinone 7 in THF at -78 °C afforded quinol 10 with a
disappointing yield of 9%. Attempts to improve this key
reaction by the addition of chelating ligands were unsuc-
cessful.16 Likewise, use of the transmetalated organocerium17
or organocadmium18 reagent did not lead to improvement.
Examination of the effect of Lewis acids revealed that while
LiCl, LiBr, and ZnCl2 were ineffective, the presence of 1
equiv of BF3‚Et2O provided a useful procedure. Chroma-
tography of the crude reaction product afforded 33% of
quinol 10. This yield is somewhat shy of those obtained in
similar systems.19 However, 58% of quinone 7, pure enough
for use in subsequent reactions, was also recovered from the
chromatography, somewhat offsetting the modest conversion.
Reductive aromatization of intermediate 10 with Na2S2O4
(5:2 THF/ H2O, 8 h) afforded phenol 11a which proved to
be unstable even for short periods of time at ambient
temperature. Therefore, the crude 11a was immediately
Acknowledgment. This work was supported in part by
the National Science Foundation (NSF CHE-9521055).
A.T.G. is a fellow of the Graduate Assistance in Areas of
National Need program of the U.S. Department of Education.
(14) Jeanneret, V.; Meerpoel, L.; Vogel, P. Tetrahedron Lett. 1997, 38,
543.
(15) Lesimple, P.; Beau, J.-M.; Jaurand, G.; Sinay, P. Tetrahedron Lett.
1986, 51, 6201.
(16) Fraser, R. R.; Mansour, T. S. Tetrahedron Lett. 1986, 27, 331-
334. Tetramethylethylenediamine (TMEDA) and hexamethylphosphoramide
(HMPA) were used but had no beneficial effect on the yield.
(17) Furstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 0, 2817-
2825.
Supporting Information Available: Full experimental
and analytical data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991346L
(18) Aponick, A.; McKinley, J. D.; Raber, J. C.; Wigal, C. T. J. Org.
Chem. 1998, 63, 2676-2678.
(19) Parker, K. A.; Koh, Y.-h. J. Am. Chem. Soc. 1994, 116, 11149-
11150. See also ref 11.
(20) (a) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J. Chem. Soc.,
Chem. Commun. 1986, 925-926. (b) Hanessian, S.; Martin, M.; Desai, R.
C. J. Chem. Soc., Chem. Commun. 1986, 926-927.
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