8366
J . Org. Chem. 1996, 61, 8366-8367
Sch em e 1a
Tota l Syn th esis of en t-Lycor icid in e via a
Th iyl Ra d ica l Ad d ition -Cycliza tion
Sequ en ce†
Gary E. Keck* and Travis T. Wager
Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112
Received August 20, 1996
Pancratistatin (1) and structurally related naturally
occurring materials such as 7-deoxypancratistatin (2),
narciclasine (3), and lycoricidine (4) have attracted
considerable synthetic attention because of interest in the
biological activity of these compounds and their novel
structural aspects.1 In particular, three recent total
syntheses of 1 have been recorded2 as have five total
syntheses of 4.3 Our own efforts in this area have led to
a recently reported synthesis of 2 via a radical cyclization-
based strategy.4 We now report the development of a
rather different radical based approach to 4. Although
the approach is capable of providing either enantiomer
of 4, we chose to pursue the synthesis of ent-4 to allow
for biological assay of this material.
a
Key: (a) BnOH, p-TsOH, 81%; (b) DMP, acetone, p-TsOH, 90%;
(c) TBS-Cl, imidazole, 95%; (d) (i) Li, NH3, (ii) BnONH2‚HCl,
pyridine, 93% over two steps; (e) (i) TPAP, NMO, 4 Å MS, (ii) CBr4,
PPh3, NEt3, 55% over two steps; (f) n-BuLi, 91%; (g) HF‚pyridine,
88%; (h) MnO2, NaCN, HOAc, MeOH, 81%.
followed by reaction of the crude lactol with O-benzyl-
hydroxylamine hydrochloride in pyridine gave a 93%
isolated yield of the O-benzyloxime 7 as a 2.5:1 mixture
of E/ Z oxime isomers.7 This material was then converted
to the terminal alkyne 8 via oxidation using the general
procedure of Ley8 followed by application of the Corey-
Fuchs protocol9 to the resulting aldehyde. Coupling with
the aromatic subunit was achieved in excellent yield by
reaction of the terminal alkyne 8 with bromopiperonal10
using the palladium-catalyzed process developed by
Sonogashira and co-workers,11 affording the alkynealde-
hyde 9. This material was also processed (vide supra)
to afford two additional radical cyclization substrates:
removal of the TBS group afforded hydroxy aldehyde 10,
which was converted (81% isolated yield) to the hydroxy
ester 11 using the Corey-Gilman-Ganem oxidation.12
The critical reaction envisioned for establishing the
functionalized cyclohexene moiety present in 4 was
addition of a radical X• to the alkyne moiety in a substrate
such as 12, followed by cyclization of the resulting vinyl
radical onto the pendant oxime moiety. Although the
relative amounts of the potential products of this reaction
are a function of a fairly complex kinetic scheme, clearly
regiochemistry in the addition of X• to the alkyne is an
issue here. We anticipated that the regiochemical issue
should be dominated by benzylic stabilization13 of the
vinyl radical intermediate, thus leading to the vinyl
radical desired for our purposes. As candidates for X•,
we focused our attention on tri-n-butylstannyl and phenyl
thiyl radicals.
The strategy chosen for experimental scrutiny was
based on establishing the C4a-C10b bond late in the
synthesis, via radical cyclization using an O-benzyloxime
as the radical acceptor.5 The synthesis of potential
substrates for this reaction is outlined in Scheme 1. The
route began with D-lyxose (5), which was converted to
the O-benzyl-3,4-isopropylidenelyxopyranoside via known6
procedures; silyation of the remaining hydroxyl afforded
6. Reduction of 6 with lithium in liquid ammonia
† The synthesis described herein has been previously disclosed:
Keck, G. E.; Wager, T. T. Abstracts of Papers; 212th National Meeting
of the American Chemical Society, Orlando, FL, Aug 1996; American
Chemical Society: Washington, DC, 1996; ORGN 317.
(1) Polt, R. L. In Amaryllidaceae Alkaloids with Antitumor Activity;
Hudlicky, T., Ed.; Organic Synthesis: Theory and Application: J AI
Press, Inc.: Greenwich, 1996; Vol. 3, pp 109-148.
(2) (a) Danishefsky, S.; Lee, J . Y. J . Am. Chem. Soc. 1989, 111, 4829.
(b) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J . Am. Chem. Soc. 1995,
117, 3643. (c) Trost, B. M.; Pulley, S. R. J . Am. Chem. Soc. 1995, 117,
10143.
(3) (a) Ohta, S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2977. (b)
Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535. (c) Martin, S.
F.; Tso, H.-H. Heterocycles 1993, 35, 85. (d) Ogawa, S.; Ohtsuka, M.;
Chida, N. J . Org. Chem. 1993, 58, 4441. (e) Hudlicky, T.; Olivo, H. F.;
McKibben, B. J . Am. Chem. Soc. 1994, 116, 5108.
(4) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Am. Chem. Soc.
1995, 117, 7289.
(7) For purposes of characterization, the major oxime isomer of all
synthetic intermediates en route to ent-4 was isolated and character-
ized; for preparative purposes the mixture of oxime isomers was carried
through the sequence.
(8) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(9) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(10) Dallacker, F. Liebigs Ann. Chem. 1960, 14.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(12) Corey, E. J .; Gilman, N .W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5618.
(5) For additional earlier examples see ref 4 and references cited
therein. (a) Marco-Contelles, J .; Destabel, C.; Chiara, J . L.; Bernabe,
M. Tetrahedron Asymmetry 1995, 6, 1547. (b) Naito, T.; Ninomiya, I.;
Tajiri, K.; Kiguchi, T.; Hiramatsu, H. Tetrahedron Lett. 1995, 36, 253.
(c) Marco-Contelles, J .; Chiara, J . L.; Khiar, N.; Gallego, P.; Destabel,
C.; Bernabe, M. J . Org. Chem. 1995, 60, 6010. (d) Parker, K. A.; Fokas,
D. J . Org. Chem. 1994, 59, 3927. (e) Booth, S. E.; J enkins, P. R.; Swain,
C. J .; Sweeney, J . B. J . Chem. Soc., Perkin Trans. 1 1994, 3499. (f)
Parker, K. A.; Fokas, D. J . Org. Chem. 1994, 59, 3933. (g) Grissom, J .
W.; Klingberg, D. J . Org. Chem. 1993, 58, 6559. (h) Pattenden, G.;
Schulz, D. J . Tetrahedron Lett. 1993, 34, 6787.
(13) Aryl-substituted vinyl radicals appear to be linear: (a) Dolbier,
W. R., J r.; Bartberger, M. D. J . Org. Chem. 1995, 60, 4984. (b) Bennett,
J . E.; Howard, J . A. Chem. Phys. Lett. 1971, 9, 460.
(6) Keck, G. E.; Kachensky, D. F.; Enholm, E. J . J . Org. Chem. 1985,
50, 4317.
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