Short synthesis of (-)-cephalotaxine using a radical cascade

Article abstract of DOI:10.1021/ol801747m

(Chemical Equation Presented) The short total synthesis of (-)-cephalotaxine is described. The concise construction of the pentacyclic core of this alkaloid was achieved by a radical cascade involving 7-endo and 5-endo cyclizations.

Full text of DOI:10.1021/ol801747m

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4129-4131
Short Synthesis of (-)-Cephalotaxine
Using a Radical Cascade
Tsuyoshi Taniguchi and Hiroyuki Ishibashi*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
isibasi@p.kanazawa-u.ac.jp
Received July 30, 2008
ABSTRACT
The short total synthesis of (-)-cephalotaxine is described. The concise construction of the pentacyclic core of this alkaloid was achieved by
a radical cascade involving 7-endo and 5-endo cyclizations.
Cephalotaxus alkaloids are a class of cytotoxic natural
products first isolated from Asian plum yews Cephalotaxus
drupacea and Cephalotaxus fortunei.1,2 Cephalotaxine (1)
has attracted much attention from many chemists due to a
combination of its fascinating pentacyclic structure (ABCDE
ring system in Figure 1) and the antileukemic activity of its
ester derivatives such as harringtonine (2)3 and homohar-
ringtonine (3).3 Since the first total synthesis of (()-
cephalotaxine by Weinreb4 and Semmelhack,5 a number of
approaches to the synthesis of this compound have been
reported, and several efforts have culminated in a total
synthesis of a racemic mixture6 of optically active7 cepha-
Figure 1. Cephalotaxine and its ester derivatives.
(1) Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem. 1963, 28,
2194
.
(2) For reviews on the Cephalotaxus alkaloids, see: (a) Weinreb, S. M.;
Semmelhack, M. F. Acc. Chem. Res. 1975, 8, 158–164. (b) Huang, L.; Xue,
Z. The Alkaloids; Academic Press: New York, 1984; Vol. 23, pp 157-226.
(c) Jalil Miah, M. A.; Hudlicky, T.; Reed, J. W. The Alkaloids; Academic
Press: San Diego, 1998; Vol. 51, pp 199-269.
lotaxines. One of the most frequently used strategies is
C4-C13 bond formation, i.e., formation of the C-ring of the
cephalotaxine structure.
(3) (a) Powell, R. G.; Weisleder, D.; Smith, C. R., Jr. J. Pharm. Sci.
1972, 61, 1227. (b) Corbett, T. H.; Griswold, D. P., Jr.; Roberts, B. J.;
Peckham, J. C.; Schabel, F. M. Cancer 1977, 40, 2660. (c) Smith, C. R.,
Jr.; Mikolajczak, K. l.; Powell, R. G. Anticancer Agents Based on Natural
Product Models; Cassady, J. M., Douros, J. D., Eds.; Academic Press: New
York, 1980; Chapter 11. (d) Hudlicky, T.; Kwart, L. D.; Reed, J. W.
Alkaloids, Chemical and Biological PerspectiVes; Pelletire, S. W. J., Ed.;
Wiley: New York, 1987; Vol. 5, Chapter 5. (e) Kantarjian, H. M.; Talpaz,
M.; Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92,
1591. See also ref 2b and 2c.
In a previous paper, we reported the concise construction
of a cephalotaxine skeleton 6 using a radical cascade8,9 that
involved Bu3SnH-mediated 7-endo-selective aryl radical
cyclization of enamide 4 followed by a 5-endo-trig cycliza-
tion of the resultant R-amidoyl radical intermediate 5
(Scheme 1).10 A characteristic feature of the reaction is
simultaneous construction of the C and D rings of the
caphalotaxine skeleton. Herein, we report an application of
this method to a short synthesis of (-)-cephalotaxine.
(4) Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972, 94, 7172.
(5) Semmelhack, M. F.; Chong, B. P.; Jones, I. D. J. Am. Chem. Soc.
1972, 94, 8629.
10.1021/ol801747m CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society

acylated with acryloyl chloride to give enamide 14in 50%
yield (Scheme 3). When enamide 14 was treated with
Scheme 1
Scheme 3
Scheme 2 shows the preparation of the key, optically active
cyclopentanone 12. Diethyl D-(-)-tartrate was converted into
Scheme 2
Bu3SnH in the presence of 1,1′-azobiscyclohexanecarbonitrile
(ACN) in boiling chlorobenzene, a radical cascade reaction
occurred to give desired pentacyclic compound 15 in 27%
yield. The 1H NMR spectrum of 15 [δ 2.81 (1H, d, J ) 9.8
(7) For synthesis of (-)-cephalotaxine, see: (a) Isono, N.; Mori, M. J.
Org. Chem. 1995, 60, 115. (b) Nagasaka, T.; Sato, H.; Saeki, S. Tetrahedron:
Asymmetry 1997, 8, 191. (c) Ikeda, M.; El Bialy, S. A. A.; Hirose, K.;
Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.;
Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47, 983. (d) Tietze, L. F.;
Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264. (e) Planas, L.; Perard-
Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087. (f) Eckelbarger, J. D.;
Wilmot, J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370. (g) Zhao,
Z.; Mariano, P. S. Tetrahedron 2006, 62, 7266. (h) Liu, Q.; Ferreira, E. M.;
Stoltz, B. M. J. Org. Chem. 2007, 72, 7352. (i) Esmieu, W. R.; Worden,
S. W.; Catterick, D.; Wilson, C.; Hayes, C. J. Org. Lett. 2008, 10, 3045.
(8) For reviews on radical cascades, see: (a) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. (b) McCarroll, A. J.; Walton,
J. C. J. Chem. Soc., Perkin Trans. 1 2001, 3215.
trifrate 811 via tosylate 7,12 and the reaction of 8 with lithium
phenylacetylide afforded compound 9. Bromination of to-
sylate 9 with lithium bromide followed by removal of the
acetonide group afforded compound 10. Compound 10 was
then subjected to Bu3SnH-mediated radical cyclization to
give five-membered product 11 in 53% yield from 7.
Protection of two hydroxyl groups of compound 11 with
TBDPSCl followed by ozonolysis afforded the desired
cyclopentanone 12.13
(9) For reviews on the synthesis of heterocyclic compounds and natural
products using radical cyclization, see: (a) Jasperse, C. P.; Curran, D. P.;
Fevis, T. L. Chem. ReV. 1991, 91, 1237. (b) Li, J. J. Alkaloids: Chemical
PerspectiVes; Pelletire, S. W., Ed.; Wiley: New York, 2001; Vol. 5, Chapter
4. (c) Renaud, P.; Sibi, M. P. Radical in Organic Synthesis; Wiley-VCH:
Weinheim, 2001. (d) Majumdar, K. C.; Mukhopadhyay, P. P.; Basu, P. K.
Heterocycles 2004, 63, 1903.
Condensation of amine 1315 with cyclopentanone 12 in
the presence of Ti(OiPr)4 afforded an imine, which was
(6) For recent examples of the synthesis of (()-cephalotaxine, see: (a)
Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 9601. (b)
Ishibashi, H.; Okano, M.; Tamaki, H.; Maruyama, K.; Yakura, T.; Ikeda,
M. J. Chem. Soc., Chem. Commun. 1990, 1436. (c) Ikeda, M.; Okano, M.;
Kosaka, K.; Kido, M.; Ishibashi, H. Chem. Pharm. Bull. 1993, 41, 276. (d)
Lin, X.; Kavash, R. W.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 9791.
(e) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Org. Chem. 1996, 61, 7335.
(f) Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1124.
(g) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T. Org. Lett. 2002, 4,
885. (h) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. (i) Li, W.-
D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (j) Ma, B.-C.; Wang, Y.-
Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528. (k) Li, W.-D. Z.; Wang,
X.-W. Org. Lett. 2007, 9, 1211.
(10) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka,
O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922.
(11) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417.
(12) Tosylate 7 was prepared by reaction of the corresponding diol,
which, in turn, was readily prepared from diethyl D-tartrate, with p-
toluenesulfonyl chloride. Diol is now commercially available.
(13) (3S,4S)-3,4-Dihydroxycyclopentane, whose protection with TB-
DPSCl would give the enantiomer of 12, was reported to be prepared from
diethyl L-tartrate using FAMSO,14 but, in our hand, only a very low yield
of (3R,4R)-congener was obtained from diethyl D-tartrate.
(14) Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J.-J.; Rokach, J. J.
Org. Chem. 1995, 60, 7548.
(15) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264.
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Org. Lett., Vol. 10, No. 18, 2008

Hz, H-4), 4.41 (1H, td, J ) 11.6, 7.3 Hz, H-2), and 4.56
(1H, dd, J ) 9.8, 7.3 Hz, H-3)] showed it to be a single
isomer having the stereochemistry depicted in Scheme 3.
Removal of the two TBDPS groups of 15 with TBAF gave
diol 16 in 96% yield. A successive oxidation of 16 with
TFAA, DMSO, and triethylamine afforded compound 177e
in 55% yield. At this stage, a formal total synthesis of (-)-
cephalotaxine (1) from compound 17 was accomplished,
whereas, since a specific rotation of 17 was not indicated in
the literature, ketone 17 was treated with methoxytrimeth-
ylsilane to give methoxy ketone 18 by using the known
procedure.7e Finally, two carbonyl groups of 18 were reduced
with alane to give (-)-cephalotaxine (1), [R]D -185 (c )
0.175, CHCl3) [lit.3a [R]D -188 (c ) 0.5, CHCl3), lit.7e [R]D
-182 (c ) 0.21, CHCl3)]. The other spectral data were in
accord with the literature values.
The use of a radical cascade involving two endo-selective
cyclizations allowed us to create the pentacyclic skeleton of
1 in one step. Further studies directed toward improvement
of the yield of the radical cascade product and toward the
synthesis of other cephalotaxus alkaloids using this strategy
are now in progress in our laboratory.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Sciences and Technology of
Japan.
Supporting Information Available: Experimental pro-
cedure and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we achieved a rapid total synthesis of (-)-
cephalotaxine (1) using a radical cascade as the key step.
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