A Synthesis of (+)-Cyclophellitol from D-Xylose

Full text of DOI:10.1021/jo971998s

426
J . Org. Chem. 1998, 63, 426-427
Sch em e 1
A Syn th esis of (+)-Cyclop h ellitol fr om
D-Xylose†
Frederick E. Ziegler* and Yizhe Wang
Sterling Chemistry Laboratory, Yale University,
New Haven, Connecticut 06511-8118
Received October 31, 1997
Sch em e 2a
(+)-Cyclophellitol (1), a â-glucosidase inhibitor, originally
isolated from the culture broth of the mushroom Phellinus
sp.,1 has been a popular target of synthetic chemists2-7 owing
to its potential inhibitor activity against human immuno-
deficiency virus (HIV).8 Apart from its biological activity,
this naturally occurring epoxide provided an opportunity to
explore the formation of six-membered rings via the cycliza-
tion of oxiranyl radicals9,10 using D-xylose (2) as the chiral
pool (Scheme 1). During the course of our study, it became
necessary to acquire the product of oxiranyl radical cycliza-
tion (13, Scheme 4) by an independent pathway. To this
end, we utilized intermediates prepared from D-xylose to
achieve an independent synthesis of (+)-cyclophellitol.
The primary hydroxyl of D-xylose diethyl thioacetal 311
was silylated selectively, and the three secondary hydroxyl
groups were benzylated without incident (Scheme 2). Thio-
acetal 4b has served in our studies as a bidirectional
synthetic intermediate, which in this instance called for the
initial removal of the dithioacetal.
a
Key: (a) TBDMSCl, imidazole, CH2Cl2, 25 °C; 90%; (b) NaH, BnBr,
Bu4NI (cat.), THF, 0 f 25 °C; 80%; (c) HgO/HgCl2, aqueous acetone,
reflux; 80%.
Sch em e 3a
Methylenation of the aldehyde group of 5 under Wittig
conditions provided the desired olefin (55-60% yield) in
addition to the unsaturated aldehyde, and its diene, derived
from â-elimination of benzyl alcohol from aldehyde 5. To
avoid the alkaline conditions of the Wittig reaction, Tebbe’s
reagent was employed. The yield of olefin 6 was increased
to 80% without the appearance of elimination product
(Scheme 3).
a
Key: (a) Cp2TiClAlMe3, pyridine, toluene/THF, -78 °C; 80%; (b)
TBAF, THF, 25 °C; 88%; (c) DMSO, COCl2, Et3N, CH2Cl2, -78 °C; (d)
Ph3PCHCO2Me, CH2Cl2, -30 f 25 °C; 89% (two steps).
Sch em e 4a
The synthetic approach now required stereoselective 1,4-
addition, or the equivalent thereof, of a vinyl anion to R,â-
unsaturated ester 8 (Scheme 4). Neither literature prece-
dent12,13 nor our own experience in a closely related system
augured well for an Ireland-Claisen rearrangement route
(8 f 11 f 9). Alternatively, the conjugate addition of
cuprates to R,â-unsaturated esters bearing γ-alkoxy groups
has been reported,14,15 in particular, the addition of vinyl
cuprates to these substrates.16-18 These studies established
† This Communication is dedicated to the memory of Professor R. H.
Schlessinger. Deceased Dec 11, 1997.
(1) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.; Nakamura, H.;
Iitaka, Y.; Takeuchi, T. J . Antibiot. 1990, 43, 49.
(2) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata, M.
Tetrahedron Lett. 1990, 31, 1171.
(3) Fraser-Reid, B.; McDevitt, R. E. J . Org. Chem. 1994, 59, 3250.
(4) Shing, T. K. M.; Tai, V. W. F. J . Chem. Soc., Perkin Trans. 1 1994,
2017.
a
Key: (a) (CH2dCH)2CuMgBr, TMSCl, THF, -78 °C; 90%; (b) 15
mol % (Cy3P)2RuCl2(CHPh), 0.02 M CH2Cl2, 25 °C, 60 h; 92%; (c) LiOH,
aq THF, 25 °C; (d) KI, I2, KHCO3, aq THF, 25 °C; 92% (two steps); (e)
Na2CO3, MeOH, 98%.
(5) Tai, V. W. F.; Fung, P. H.; Wong, Y. S.; Shing, T. K. M. Tetrahedron:
Asymmetry 1994, 5, 1353.
(6) For leading references to syntheses of cyclophellitol, see: J ung, M.
E.; Choe, S. W. T. J . Org. Chem. 1995, 60, 3280.
(7) Schlessinger, R. H.; Bergstrom, C. P. J . Org. Chem. 1995, 60, 16.
(8) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K. J . Antibiot. 1990,
43, 1579.
(9) Ziegler, F. E.; Harran, P. G. Tetrahedron Lett. 1993, 34, 4505.
(10) Ziegler, F. E.; Wang, Y. Tetrahedron Lett. 1996, 37, 6299.
(11) Rollin, P.; Pougny, J . Tetrahedron 1986, 42, 3479.
(12) Cha, J . K.; Lewis, S. C. Tetrahedron Lett. 1984, 25, 5263.
(13) Suzuki, T.; Sato, E.; Kamada, S.; Tada, H.; Unno, K.; Kametani, T.
J . Chem. Soc., Perkin Trans. 1 1986, 387.
(14) Ziegler, F. E.; Gilligan, P. J . J . Org. Chem. 1981, 46, 3874.
(15) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J . Am. Chem. Soc. 1982,
104, 2027.
the high diastereoselectivity of the conjugate addition, whose
high diastereoselectivity is ascribed to a vinylogous, nonch-
elation Felkin-Anh transition state.16,17 Although we ex-
perienced high stereoselective addition of several lithium-
based vinyl cuprates, these experiments were capricious and,
as had been observed by Roush,16 variable in yield. On the
other hand, magnesium-based vinyl cuprates, employed
under the protocol reported by Hanessian,18 gave both high
yields and high selectivity (Scheme 4).
(16) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B. M.; Chong,
W. K. M.; Harris, D. J . J . Am. Chem. Soc. 1989, 111, 2984.
(17) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J .
Am. Chem. Soc. 1992, 114, 7652.
(18) Hanessian, S.; Gai, Y.; Wang, W. Tetrahedron Lett. 1996, 37, 7473.
(19) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039.
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Published on Web 01/13/1998

Communications
J . Org. Chem., Vol. 63, No. 3, 1998 427
Sch em e 5a
Sch em e 6a
a
Key: (a) DIBALH, CH2Cl2-Et2O, -78 f -30 °C; 85%; (b) PhI-
(OAc)2, I2, cyclohexane, 500 W W-lamp, 10-30 °C; 78%; (c) KOH, aq
THF; 76%.
a
Key: (a) Bu3SnH, AIBN, O2, toluene, 3 h, 60 °C; (b) Pd(OH)2/C,
H2, MeOH, 12 h; 85%.
debenzylation presumably occurred via the intermediate
hydroperoxy radical 20b and not the carbon radical because
none of the deoxygenated product 19c was detected.29 That
debenzylation occurred proximate to the radical site was
confirmed by the formation of cyclic carbonate 18 (triphos-
The application of ring-closing metathesis (RCM) using
Grubbs’s catalyst19 delivered the cyclohexene 10 efficiently.
Subsequent iodolactonization afforded iodide 12, which was
to serve as the genesis of the â-epoxide and â-hydroxymethyl
group present in cyclophellitol.
gene, pyr, 25 °C), whose 1H NMR coupling pattern (J ab
)
Iodo lactone 12 required oxidative decarboxylation to
realize our goal. To this end, several approaches, which
proved to be unsuccessful, were attempted: (a) ozonolysis
of the TMS silyl ketene acetal; (b) Tebbe methylenation,
double-bond isomerization, ozonolysis; (c) alkoxy hydroper-
oxide rearrangement.20,21 The degradation was accom-
plished through the Sa´urez procedure (Scheme 5).22,23 Lactol
14, readily derived from lactone 12 by DIBALH reduction,
efficiently afforded diiodoformate 15 upon irradiation in the
presence of PhI(OAc)2/I2.24 Subsequent base treatment gave
iodo epoxide 16 without compromising the alkyl iodide
portion of the molecule. On the other hand, treatment of
diiodoformate 15 with Na2CO3/MeOH or KOH/DMF/H2O led
exclusively to epoxyolefin 17, a compound that had been
converted to benzylated cyclophellitol 20a . The reaction of
iodo epoxide 16 with KO2/DMSO25 as an oxygen nucleophile
led to a 1:1 mixture of the desired alcohol 20a and olefin
17.
J bc )10.2 Hz; J ae ) 10.3 Hz) confirmed the stereochemistry
of the vinyl cuprate addition and, ultimately, the stereo-
chemistry of the epoxide through the known mechanism of
iodolactone formation. Finally, hydrogenolysis of the benzyl
groups in epoxy alcohols 19a and 20a afforded (+)-cycloph-
ellitol in 85% yield [[R]20 +97° (c 0.35, H2O) (lit.1 [R]27
D
D
+103° (c 0.5, H2O))], whose 500 MHz 1H NMR spectrum was
identical with that of an enantiomerically pure synthetic
sample provided by Professor Tatsuta.
Ack n ow led gm en t. This work was supported by grants
from the National Science Foundation and the Institute of
General Medical Sciences of the National Institutes of
Health. We are grateful to Professor Hanessian (University
of Montreal) for experimental details regarding cuprate
preparation and to Professor Tatsuta (Waseda University)
for spectra and a sample of synthetic (+)-cyclophellitol. We
are grateful to a reviewer and Dr. Stuart McCombie for
their thoughts on the mechanism of formation of epoxy diol
19a .
Su p p or tin g In for m a tion Ava ila ble: Experimental details
and 1H NMR spectra of 4b, 5, 8, 15, 16, 18, 19a , 20a , 1, and 1
(authentic) for which combustion analyses were not obtained (23
pages).
J O971998S
The iodine to hydroxyl transformation was accomplished
by radical oxygenation,26-28 affording a mixture of epoxy
alcohol 20a (70%) and epoxy diol 19a (10%). Selective
(24) For a related case see: Oh, J . Tetrahedron Lett. 1997, 38, 3249.
(25) Corey, E. J .; Nicoloau, K. C.; Shibasaki, M.; Machida, Y.; Shiner, C.
S. Tetrahedron Lett. 1975, 37, 3183.
(26) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J . Am. Chem. Soc.
1991, 113, 8980.
(20) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363.
(21) Ziegler, F. E.; Kneisley, A.; Thottathil, J . K.; Wester, R. T. J . Am.
Chem. Soc. 1988, 110, 5434.
(22) Sua´rez, E.; Freire, R.; Marrero, J . J .; Rodriguez, M. S. Tetrahedron
Lett. 1986, 27, 383.
(27) Prandi, J .; Moutel, S. Tetrahedron Lett. 1994, 35, 8163.
(28) Prandi, J .; Mayer, S. Tetrahedron Lett. 1996, 37, 3117.
(29) A reviewer has offered the pausible suggestion that debenzylation
may occur in 20a by hydroperoxy radical abstraction of the methine site
via a six-membered transition state followed by loss of a benzyl radical.
(23) Sua´rez, E.; Armas, P.; Francisco, C. G. Angew. Chem., Int. Ed. Engl.
1992, 31, 772.
The resultant ketone could then undergo reduction. Alternatively, a
nucleophilic debenzylation may occur through chelation in 20d .