Concise total synthesis of (±)-cephalotaxine via a transannulation strategy: Development of a facile reductive oxy-Nazarov cyclization

Article abstract of DOI:10.1021/ol201390r

A concise total synthesis of (±)-cephalotaxine (1) has been achieved from dioxolanone derivative 15 via a transannulation strategy. The key transformation is a facile reductive oxy-Nazarov cyclization as illustrated above, involving presumably a tethered 1,2-oxidopentadienyl cation species 7a or 7b, which represents a new variant of the oxy-Nazarov cyclization and constitutes an effective, regio- and stereospecific 5-hydroxy cyclopentenone annulation protocol under mild hydride reduction conditions.

Full text of DOI:10.1021/ol201390r

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3538–3541
Concise Total Synthesis of (()-Cephalotaxine
via a Transannulation Strategy:
Development of a Facile Reductive
oxy-Nazarov Cyclization
Wei-Dong Z. Li,* Wei-Guo Duo, and Cheng-Han Zhuang
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071,
P. R. China
wdli@nankai.edu.cn
Received May 23, 2011
ABSTRACT
A concise total synthesis of (()-cephalotaxine (1) has been achieved from dioxolanone derivative 15 via a transannulation strategy. The key
transformation is a facile reductive oxy-Nazarov cyclization as illustrated above, involving presumably a tethered 1,2-oxidopentadienyl cation
species 7a or 7b, which represents a new variant of the oxy-Nazarov cyclization and constitutes an effective, regio- and stereospecific 5-hydroxy
cyclopentenone annulation protocol under mild hydride reduction conditions.
The Nazarov reaction is a unique electrocyclization of
a formal oxidopentadienyl cation species leading to cyclo-
pentenone derivatives.1 This mechanistically interesting
and synthetically valuable cyclopentannulation has enjoyed
ever-increasing attention.2 Despite recent advances in
directed control and catalysis,3 it is still desirable to explore
new variants of this reaction under mild conditions. We
present here the development of a facile reductive oxy-
Nazarov (RON) cyclization4 in conjunction with our
(1) (a) Denmark, S. E. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991,
pp 751À784. (b) Habermas, K. L.; Denmark, S. E; Jones, T. K. Org.
React. 1994, 45, 1.
(2) For recent reviews, see: (a) Tius, M. A. Eur. J. Org. Chem. 2005,
2193. (b) Pellissier, H. Tetrahedron 2005, 61, 6479. (c) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577. For notable recent advance-
ments, see:(d) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133.
(e) He, W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.; Kellenberger,
C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003. (f) De Simone,
F.; Andres, J.; Torosantucci, R.; Waser, J. Org. Lett. 2009, 11, 1023.
(g) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009,
131, 7504. (h) Malona, J. A.; Cariou, K.; Frontier, A. J. J. Am. Chem.
I. R.; Frontier, A. J.; Eisenberg, R. Angew. Chem., Int. Ed. 2010, 49,
3363. (m) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010, 132, 1685.
(n) Kerr, D. J.; White, J. M.; Flynn, B. L. J. Org. Chem. 2010, 75, 7073.
(o) Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org.
Lett. 2010, 12, 440. (p) Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic,
D. A.; Tius, M. A. J. Am. Chem. Soc. 2010, 132, 8266. (q) Cao, P.; Deng,
C.; Zhou, Y.-Y.; Sun, X.-L.; Zheng, J.-C.; Xie, Z.; Tang, Y. Angew.
Chem., Int. Ed. 2010, 49, 4463. (r) Patil, D. V.; Phun, L. H.; France, S.
Org. Lett. 2010, 12, 5684. (s) De Simone, F.; Gertsch, J.; Waser, J.
Angew. Chem., Int. Ed. 2010, 49, 5767. (t) Spencer, W. T., III; Levin,
M. D.; Frontier, A. J. Org. Lett. 2011, 13, 414. (u) Scadeng, O.;
Ferguson, M. J.; West, F. G. Org. Lett. 2011, 13, 114. (v) Huang, J.;
Leboeuf, D.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 6307.
ꢀ
ꢀ
Soc. 2009, 131, 7560. (i) Faza, O. N.; Lopez, C. S.; Alvarez, R.; de Lera,
ꢀ
A. R. Chem.;Eur. J. 2009, 15, 1944. (j) Wu, Y.-K.; West, F. G. J. Org.
Chem. 2010, 75, 5410. (k) Wender, P. A.; Stemmler, R. T.; Sirois, L. E.
J. Am. Chem. Soc. 2010, 132, 2532. (l) Vaidya, T.; Atesin, A. C.; Herrick,
r
10.1021/ol201390r
Published on Web 06/08/2011
2011 American Chemical Society

its optical lability.9 An appealing mechanistic speculation
concerning the racemization of 1 was invoked by Liang in
1980 (Figure 1)10 in which seco-CET (6) was proposed as a
transient structure in a reversible addition of the amine to
the aldehyde function across the macrocyclic olefin. In-
spired by this hypothesis,11 we reasoned that a tethered
oxonium species 7 could serve as a functional equivalent of
6 that might undergo a formal electrocyclization to give
the cyclopentenone species 8. Subsequent transannular
cyclization would lead to the core ring system of 1. In con-
tinuation of our strategic exploration of CET synthesis,12
we envisioned a transannulation approach13 starting from
an equivalent macrocyclic dioxolanone derivative 6a
(Figure1). Itwas ourassumption thatthe fragmentation of
1 to 6 might involve a formal retro-Nazarov process14 of a
cationic species 9,11 which could shed light on the puzzling
racemization mechanism of CET.15
Figure 1. Liang’s hypothesis and transannulation strategy.
To explore the above transannulation strategy, condensa-
tion16 of norhydrastinine (10)17 with iodo enolsilane 11 in
DMF afforded the annulation product 12 (mp 92À93 °C)18
in 45% yield (Scheme 1).19 Upon exposure of aldehyde
12 to a mixture of 10 equiv of 2,2,2-trichloroethyl chloro-
formate (TrocCl) and 8 equiv of KHCO3 in CHCl3,
macrocyclic aldehyde 13 (mp 156À158 °C)18 was obtained
in 91% yield.20 Wittig olefination19 of 13 with triphenyl-
phosphoranylidene dioxolanone (14) in toluene at reflux
furnished the (E)-dioxolanone 15(mp 122À123 °C) in68%
isolated yield, along with the separable (Z)-isomer (14%).
This convergent three-step procedure produced the desig-
nated macrocyclic dioxolanone derivative 15 (cf. 6a) in a
synthetic studies toward cephalotaxine (1, CET, Figure 1).
This transformation (eq 1) constitutes an effective, regio-
and stereospecific cyclopentannulation of vinylalkylidene
dioxolanone 2 to 5-hydroxy cyclopentenone 5 under mild
hydride reduction conditions,5 which is formulated tenta-
tivelyasthe thermallyconrotatory ring closureofatethered
1,2-oxidopentadienyl cation species 3 or resonance hybrid
form 4.6 An expedient total synthesis of (()-1 was achieved
by employing this RON cyclization as a key step.
(9) (a) Hudlicky, T.; Kwart, L. D.; Reed, J. W. In The Alkaloids:
Chemical and Biological Perspectives, Vol. 5; Pelletier, S. W., Ed.; John
Wiley & Sons: New York, 1987; pp 639À690. (b) Isono, N.; Mori, M.
J. Org. Chem. 1995, 60, 115.
CET (1) is the parent structure of the Cephalotaxus
alkaloids.7 The unusual cyclic architecture and potent anti-
leukemic activity of its ester derivatives (i.e., homoharring-
tonine) render 1 an attractive target for total synthesis.7b,8
An intriguing stereochemical problem associated with 1 is
(10) Liang, X.-T. In Chemistry of Natural ProductsÀThe Proceedings
of Sino-American Symposium on Chemistry of Natural Products
(Shanghai, October 1980); Wang, Y., Ed.; Science Press: Beijing, 1982;
pp 19À28.
ꢀ
(11) For a similar mechanistic suggestion, see: Planas, L.; Perard-Viret,
J.; Royer, J. J. Org. Chem. 2004, 69, 3087.
(12) (a) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. (b) Li,
W.-D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (c) Li, W.-D. Z.;
Wang, X.-W. Org. Lett. 2007, 9, 1211.
(3) For a recent review, see: Harmata, M. ChemtractsÀOrg. Chem.
2004, 17, 416.
(4) For a variant of the intercepted Nazarov cyclization by hydride
transfer reduction which was termed also as the Reductive Nazarov
Cyclization, see: Giese, S.; West, F. G. Tetrahedron Lett. 1998, 39, 8393.
idem, Tetrahedron 2000, 56, 10221.
(5) To the best of our knowledge, the only documentation on the
reduction of a geometric mixture of cinnamylidene dioxolanones by
Dibal-H (Toluene, À78 °C) was recorded to give a product mixture of
hydroxyl aldehyde and stereochemically unspecified hydroxyl cyclopen-
tenone in an attempted synthesis of R-keto aldehyde, see: Ramage, R.;
Griffiths, G. J.; Shutt, F. E.; Sweeney, J. N. A. J. Chem. Soc., Perkin
Trans. 1 1984, 1531.
(6) For a recent synthesis of 5-hydroxycyclopent-2-enones via an
interrupted Nazarov cyclization, see: Marx, V. M.; Burnell, D. J. Org.
Lett. 2009, 11, 1229.
(13) For a conceptually different transannular strategy for CET
synthesis, see: Lin, X.-D.; Kavash, R. W.; Mariano, P. S. J. Am. Chem.
Soc. 1994, 116, 9791. idem, J. Org. Chem. 1996, 61, 7335.
(14) (a) Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328.
(b) Harmata, M.; Schreiner, P. R.; Lee, D. R.; Kirchhoefer, P. L. J. Am.
Chem. Soc. 2004, 126, 10954. (c) Harmata, M.; Lee, D. R.; Barnes, C. L.
Org. Lett. 2005, 7, 1881. (d) Etheridge, Z. C.; Caddick, S. Tetrahedron:
Asymmetry 2004, 15, 503.
(15) Studies are underway in our laboratory to verify this mechanistic
reasoning.
(16) (a) Skold, C. N. Synth. Commun. 1976, 6, 119. (b) Oppolzer, W.;
Hauth, H.; Pfaffli, P. Helv. Chim. Acta 1977, 60, 1801.
(17) Cushman, M.; Dekow, F. W. J. Org. Chem. 1979, 44, 407.
(18) Structure characterized by single crystal X-ray analysis.19
CCDC 735679, 735678, 735677, 735680, 735707, and 735676 contain
the supplementary crystallographic data for compounds 12, 13, 17, 20a,
23a, and s-5 (SI-1), respectively. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(7) For reviews: (a) Huang, L.; Xue, Z. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1984; Vol. 23, pp 157À226. (b) Jalil Miah,
M. A.; Hudlicky, T.; Reed, J. W. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1998; Vol. 51, pp 199À269.
(8) For recent reports, see: (a) Eckelbarger, J. D.; Wilmot, J. T.; Gin,
D. Y. J. Am. Chem. Soc. 2006, 128, 10370. (b) Zhao, Z.; Mariano, P. S.
Tetrahedron 2006, 62, 7266. (c) Liu, Q.; Ferreira, E. M.; Stiltz, B. M.
J. Org. Chem. 2007, 72, 7352. (d) Taniguchi, T.; Ishibashi, H. Org. Lett.
2008, 10, 4129. (e) Hameed, A.; Blake, A. J.; Hayes, C. J. J. Org. Chem.
2008, 73, 8045. (f) Zhao, Y.-M.; Gu, P.; Zhang, H.-J.; Zhang, Q.-W.;
Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M. J. Org. Chem. 2009, 74, 3211.
(19) See Supporting Information (SI-1) for details.
(20) (a) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.;
Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403. (b) Magnus,
P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.;
Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116.
Org. Lett., Vol. 13, No. 13, 2011
3539

Scheme 1. Concise Total Synthesis of (()-Cephalotaxine (1)
Scheme 2. Reductive oxy-Nazarov (RON) Cyclization
and 20c22 were obtained from the respective geometric
isomers 19b and 19c. Cyclopentenone 20d with a quatern-
ary carbon and spiro-cyclopentenone20e were constructed
effectively. Reductive deoxygenation23 of 20a and 20b to
21a and 21b was realized via the corresponding acetates
with metallic zinc in glacial acetic acid.19
multigram quantity from readily available components 10,
11, and 14.
Chiral dioxolanone derivative 22, readily prepared from
(S)-perillaldehyde, underwent smooth RON annulation
(eq 2) to give the bicyclic diastereomers 23a (mp 108À
109 °C)18 and 23b in a ratio of 5:1, which implies a substantial
torquoselective control by the isopropenyl group.24
Various reductive conditions were next examined on
dioxolanone 15. To our delight, upon exposure to Dibal-H
(1.2 equiv) in toluene at À78 °C and subsequent aqueous
workup with an aqueous Rochelle salt solution, hydroxy
cyclopentenone 16 (mp 177À179 °C)21 was isolated (55%
borsm) as the sole product (Scheme 1). The facile and
stereospecific transformation of 15 f 16 indicated that
an oxy-Nazarov cyclization took place effectively under
mild hydride reduction conditions, presumably via the
tethered 1,2-oxidopentadienyl cation species 7a. Notably,
the carbamate function in 15 was not affected by the action
of Dibal-H. Acetylation of hydroxy enone 16 followed
by selective cleavage of the N-Troc group by zinc reduc-
tion afforded the corresponding transannular cyclization
product 17 (mp 156À158 °C)18 as a single diastereomer.
Demethylcephalotaxinone (18) was prepared by oxidation
of 17 in 57% yield, and this was converted to (()-CET
via a well-established two-step procedure.9b,12a Thus an
expedient total synthesis of (()-CET has been achieved
from dioxolanone 15 via a 5-step sequence.
To delineate the general scope of this novel RON cycliza-
tion, we examined a range of vinylalkylidene dioxolanones
19aÀe (Scheme 2). Cyclization proceeded smoothly with
Dibal-H (1.2 equiv) in toluene at À78 °C to give the corres-
ponding 5-hydroxy cyclopentenones 20aÀestereospecifically
in satisfactory yield. Diastereomeric cyclopentenones 20b
(22) (a) Hughes, C. C.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7,
3425. (b) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl,
S. N.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 17057. (c) Li, C.-C.;
Wang, C.-H.; Liang, B.; Zhang, X.-H.; Deng, L.-J.; Liang, S.; Chen, J.-H.;
Wu, Y.-D.; Yang, Z. J. Org. Chem. 2006, 71, 6892.
(23) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.;
McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223.
(24) (a) Kallel, E. A.; Houk, K. N. J. Org. Chem. 1989, 54, 6606.
(b) Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990,
55, 5543. (c) Hu, H.; Smith, D.; Cramer, E.; Tius, M. A. J. Am. Chem.
Soc. 1999, 121, 9895. (d) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello,
P.; Occhiato, E. G. J. Org. Chem. 2004, 69, 7705.
(21) Stereostructure characterized by an X-ray analysis of the corre-
sponding p-nitrobenzoate of an analogously cyclized N-Eoc derivative
s-5.18,19
3540
Org. Lett., Vol. 13, No. 13, 2011

Other mechanistically relevant variants of the general
oxy-Nazarov cyclization include those of R-ketoenone
or functional equivalents (eq 3),2e,p,27 2-furyl carbinol
(Piancatelli rearrangement, eq 4),28 and vinylallene oxide
(eq 5),2h,29 in which the oxy-substituents at C(2) or C(4) of
the corresponding pentadienyl cations facilitate their re-
spective pericyclic ring-closure process.30 Thus, the RON
cyclization (eq 1) developed in this work represents a new
variant of the typical oxy-Nazarov reaction, featuring the
incorporation of a tethered oxy-substituent at C(2) in the
presumably bis-oxidopentadienyl cation species 3 and 4,
which might explain the rapid and effective 4π electro-
cyclization of dioxolanone 2 under mild hydride reduction
conditions.
Scheme 3. Dibal-H Reduction of 24 and 26(a,b) (Ar = 2-BrPh)
It is evident that the alkylidene geometry of the dioxo-
lanone 2 must be (E)-configured. Hydride reduction of the
(Z)-isomer 24 resulted in a moderate yield of the hydroxy
aldehyde 25 (Scheme 3) as the sole isolable product (Ar =
(2-Br)Ph).19 Furthermore, the tethered acetal function in
2 facilitates the RON cyclization significantly as the
hydride reduction of dienyl esters 26a and 26b afforded
the corresponding alcohols 27a and 27b in moderate
yield, respectively (Scheme 3). Oxidation of 27a with
IBX led to the cyclopentenone 20a in 36% yield, which
corresponds to the iso-Nazarov cyclization25 of an alde-
hyde intermediate 28a. In contrast, the IBX oxidation of
28b produced the corresponding aldehyde 27b as the sole
product.26
In summary, a facile RON cyclization of vinylalkylidene
dioxolanones of type 2 has been developed which provides
an efficient, regio- and stereospecific oxy-cyclopentannu-
lation protocol,31 as demonstrated in an expedient synthe-
sis of (()-CET. Further investigations on the scope,
mechanistic details, asymmetric variant, and synthetic
applications of this reaction is ongoing in our laboratory
and will be reported in due course.
(25) For examples of iso-Nazarov cyclization involving a 1-oxido-
pentadienyl cation or equivalents, see: (a) Jung, M. E.; Yoo, D. J. Org.
Chem. 2007, 72, 8565. (b) Miller, A. K.; Banghart, M. R.; Beaudry,
C. M.; Suh, J. M.; Trauner, D. Tetrahedron 2003, 59, 8919. (c) de Lera,
A. R.; Rey, J. G.; Hrovat, D.; Iglesias, B.; Lopez, S. Tetrahedron Lett.
1997, 42, 7425. (d) Denmark, S. E.; Hite, G. A. Helv. Chim. Acta 1988,
71, 195. (e) Tius, M. A.; Astrab, D. P. Tetrahedron Lett. 1984, 25, 1539.
(26) For analogous dienal cyclization, see: (a) Kuroda, C.; Honda, S.;
Nagura, Y.; Koshio, H.; Shibue, T.; Takeshita, T. Tetrahedron 2004, 60,
319. (b) Porter, M. J.; White, N. J.; Howells, G. E.; Laffan, D. D. P.
Tetrahedron Lett. 2004, 45, 6541.
Acknowledgment. In memory of Professor Xiao-Tian
Liang. Financial support was provided by the National
Natural Science Foundation (20572047). The Cheung Kong
Scholars program and the Outstanding Scholars program
of Nankai University are gratefully acknowledged.
ꢀ
ꢀ
Supporting Information Available. Experimental pro-
1
cedures, spectral data, and copies of H and 13C NMR
(27) For examples, see: (a) Muxfeldt, H.; Weigele, M.; Van Rheenen,
V. J. Org. Chem. 1965, 30, 3573. (b) Weinreb, S. M.; Auerbach, J. J. Am.
Chem. Soc. 1975, 97, 2503. (c) Kim., S. H.; Cha, J. K. Synthesis 2000, 14,
2113. (d) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4972.
(e) Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005, 127, 12472.
(f) Prandi, C.; Deagostino, A.; Venturello, P.; Occhiato, E. G. Org.
Lett. 2005, 7, 4345.
spectrum for compounds 12, 13, 15À18, 19aÀe, 20aÀe,
21(a,b), 22, 23a, 24, 25, 26(a,b), 27(a,b), 28b. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(30) For general accounts: (a) Carpenter, B. K. Tetrahedron 1978, 34,
1877. (b) Davis, R. L.; Tantillo, D. J. Curr. Org. Chem. 2010, 14, 1561.
(31) For a review, see: (a) Ramaiah, M. Synthesis 1984, 529. For
recent methodology developments, see: (b) Davie, C. P.; Danheiser,
R. L. Angew. Chem., Int. Ed. 2005, 44, 5867 and references therein.
(c) Pujanauski, B. G.; Bhanu, B. A.; Sarpong, R. J. Am. Chem. Soc. 2006,
128, 6786. (d) Shi, X.-D.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 5802. (e) Oh, C. H.; Karmakar, S. J. Org. Chem. 2009, 74, 370.
(f) Lin, C.-C.; Teng, T.-M.; Tsai, C.-C.; Liao, H.-Y.; Liu, R.-S.
J. Am. Chem. Soc. 2008, 130, 16417.
(28) For seminal studies, see: (a) Piancatelli, G.; Scettri, A.; Barbadoro,
S. Tetrahedron Lett. 1976, 39, 3555. (b) Piancatelli, G.; Maurizio, D.;
Franco, D. Synthesis 1994, 867.
(29) For a relevant review, see: (a) Beaudry, C. M.; Malerich, J. P.;
Trauner, D. Chem. Rev. 2005, 105, 4757. For examples, see: (b) Corey,
E. J.; Ritter, K.; Yus, M.; Najera, C. Tetrahedron Lett. 1987, 28, 3547.
(c) Kim, S. J.; Cha, J. K. Tetrahedron Lett. 1988, 29, 5613. (d) Hess,
B. A., Jr.; Smentek, L.; Brash, A. R.; Cha, J. K. J. Am. Chem. Soc. 1999,
ꢀ
ꢀ
121, 5603. (e) Lopez, C. S.; Faza, O. N.; York, D. M.; De Lera, A. R.
J. Org. Chem. 2004, 69, 3635.
Org. Lett., Vol. 13, No. 13, 2011
3541