A facile total synthesis of hainanensine via an unusual rearrangement-annulation cascade

Article abstract of DOI:10.1021/ol1003324

A facile total synthesis of hainanensine (1), a structurally unique Cephalotaxus alkaloid, via an effective acid-mediated rearrangement/Friedel- Crafts annulation cascade (7a/7b → 8a/8b), is described.

Full text of DOI:10.1021/ol1003324

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1649-1651
A Facile Total Synthesis of
Hainanensine via an Unusual
Rearrangement-Annulation Cascade
Zhi-Wei Zhang† and Wei-Dong Z. Li*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersty,
Lanzhou 730000, China, and State Key Laboratory of Elemento-organic Chemistry,
Nankai UniVersity, Tianjin 300071, China
wdli@nankai.edu.cn
Received February 8, 2010
ABSTRACT
A facile total synthesis of hainanensine (1), a structurally unique Cephalotaxus alkaloid, via an effective acid-mediated rearrangement/
Friedel-Crafts annulation cascade (7a/7b f 8a/8b), is described.
Hainanensine (1, racemic, Figure 1) is a structurally unique
minor alkaloidal component identified from the antileukemia
plant Cephalotaxus hainanensis and C. fortunei by Liang
and Sun in 1981.1 Preliminary pharmacological studies
indicated that 1 possesses marginal antitumor activity.1 Later,
Liang and co-workers reported that saturated derivatives and
other structural analogues of 1 have shown a range of
interesting biological activity.2 For further structural confir-
mation, Liang and Sun have synthesized 1 from a benza-
zepine derivative 2 by an acid-mediated cyclization.1,3
Compound 2 is the key intermediate in the classic Weinreb
synthesis of cephalotaxine (CET),4 the parent member of the
Cephalotaxus alkaloid family.5 Liang thus postulated that 1
and CET might share a common biosynthetic origin.1
In connection with our continued studies6 on the novel
chemical synthesis of CET and its potent antileukemia ester
derivatives (i.e., homoharringtonine), we report herein a fac-
ile total synthesis of 1 via an unusual acid-mediated rearrange-
ment-annulation cascade of enone derivative 7a/7b.
Figure 1. Hainanensine (1) and cephalotaxine (CET).
† Lanzhou University.
‡ Nankai University.
(1) Sun, N. J.; Liang, X. T. Acta Pharmacol. Sin. 1981, 16, 24; Chem.
Abstr. 1981, 95, 175622t.
For the synthesis of enone 7, an effective isoquinoline
annulation approach (3 f 4) previously developed in our
10.1021/ol1003324  2010 American Chemical Society
Published on Web 03/17/2010

Scheme 3
Scheme 1. Isoquinoline Annulation Approach to 6
trimethoxy enone derivative 1010 was found to give the
corresponding ring-expansion product 11 in good yield.
As depicted in Scheme 4, a sequence of functional group
transformations was developed for the facile assembling of
laboratory7 was employed. As shown in Scheme 1, isoquino-
line aldehyde derivative 6 was prepared from readily
available 3,4-dihydroisoquinoline 3 in 70% overall yield. As
illustrated in Scheme 2, enone 7a was elaborated by the
Horner-Wadsworth-Emmons olefination8 of aldehyde 6a.
Scheme 4. Synthesis of Dimethyl Analogue 16
Scheme 2. Rearrangement-Annulation Cascade of 7a f 8a
With readily available enone 7a in hand, we anticipated
an acid-promoted ring-expansion process as indicated (ar-
rows, Scheme 2) leading to the benzazepine ring system of
1. Upon refluxing enone 7a in formic acid for 6 h, a
crystalline product (mp 152-154 °C) was isolated in 92%
yield, which was characterized spectroscopically as com-
pound 8a, bearing the exact ring skeleton of 1. Apparently,
the formation of rearranged annulation product 8a is resulted
from further Friedel-Crafts-type cyclization-dehydration of
the initial ring-expansion intermediates i and ii (Scheme 2).9
Further confirmation of the above rearrangement-annulation
pathway (7a f 8a) was provided by the clean transformation
of a previously synthesized benzazepine ketone 97 into 8a
in refluxing formic acid (Scheme 3). Furthermore, the
the dimethyl analogue 16 of hainanensine (1) from readily
available 8a, which involves (1) converting 8a into the
corresponding thiocarbonyl derivative 12a; (2) regioselective
dihydroxylation to diol 13a; (3) acid-mediated pinacol-type
rearrangement of diol 13a to ketone 14a facilitated via a
(2) (a) Yin, D. L.; Xu, C. X.; Gao, Y. S.; Liu, D. K.; Wen, S. Y.; Guo,
J. Y. Acta Pharmacol. Sin. 1992, 27, 824; Chem. Abstr. 1993, 118, 160544p.
(b) Guo, J. Y.; Yin, D. L.; Gao, Y. S.; Liu, D. K.; Liang, X. T. Youji Huaxue
1993, 13, 195; Chem. Abstr. 1993, 119, 72895. (c) Ye, Y. M.; Xu, C. X.;
Sui, R. H.; Guo, J. Y.; Cui, G. J. Acta Pharmacol. Sin. 1995, 30, 12; Chem.
Abstr. 1995, 123, 414w. (d) Zhang, W. J.; Zhou, T. H. Acta Pharmacol.
Sin. 1998, 33, 212; Chem. Abstr. 1998, 129, 269913m.
1650
Org. Lett., Vol. 12, No. 8, 2010

borate intermediate iii;11 (4) reductive desulfurization of 14a
to ketone 15a; and (5) basic autoxidation12 of 15a to the
hydroxyl ketone 16. The structure of 16 was established by
X-ray crystallographic analysis (Figure 2).13 It is worthy to
note that attempted direct oxidation of diol 13a led to the
corresponding dicarbonyl product (C-C cleavage) exclu-
sively.
Scheme 5. Synthesis of Hainanensine (1) from 6b
In summary, we have achieved a facile total synthesis of
unique natural alkaloid 1 via an unusually effective
rearrangement-annulation cascade, which may facilitate the
synthesis of structural analogues of 1 and further biological
evaluation.
Figure 2. X-ray structure of compound 16 (ORTEP drawing).
Hainanensine (1) was analogously synthesized from al-
dehyde 6b via the enone intermediate 7b and rearranged
annulation product 8b as shown (Scheme 5).14 The synthetic
product 1 (racemic) is identical spectroscopically with the
natural hainanensine reported.1,15
Acknowledgment. We are grateful to Dr. Hua Yang
(Lanzhou University) for his earlier exploratory study on this
subject. We thank the National Natural Science Foundation
(QT 20021001 and 20572047) for financial support. The
Cheung Kong Scholars program and the Outstanding Schol-
ars program of Nankai University are gratefully acknowl-
edged.
(3) For a similar synthetic method, see also: Japanese Patent JP58059984,
1983; Chem. Abstr. 1983, 99, 140218w.
(4) (a) Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972, 94, 7172.
(b) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc. 1975, 97, 2503.
(5) For reviews, see: (a) Huang, L.; Xue, Z. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1984; Vol. 23, pp 157-226. (b)
Hudlicky, T.; Kwart, L. D.; Reed, J. W. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; John Wiley and Sons: New
York, 1987; Vol. 5, pp 639-690. (c) Jalil Miah, M. A.; Hudlicky, T.; Reed,
J. W. In The Alkaloids; Brossi, A.; Ed.; Academic Press: New York, 1998;
Vol. 51, pp 199-269. (d) Hudlicky, T.; Reed, J. W. The Way of Synthesis:
EVolution of Design and Methods for Natural Products; Wiley-VCH:
Weinheim, Germany, 2007; pp 655-687.
Supporting Information Available: Experimental pro-
cedures; spectral data; copies of spectra for compounds
3b-8b, 7a, 8a, 10, 11, 12a/b-15a/b, 16, and 1; and CIF
file for 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL1003324
(6) (a) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931; 2009, 11,
1865 (Erratum). (b) Li, W.-D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277.
(c) Ma, B.-C.; Wang, Y.-Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528.
(d) Li, W.-D. Z.; Wang, X.-W. Org. Lett. 2007, 9, 1211.
(11) (a) Malan, C.; Morin, C.; Preckher, G. Tetrahedron Lett. 1996, 37,
6705. For a review, see: (b) Matteson, D. S. Tetrahedron 1989, 45, 1859.
(12) (a) Bailey, E. J.; Barton, D. H. R.; Templeton, J. F. J. Chem. Soc.
1962, 1578. (b) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968,
38, 3294.
(7) Li, W.-D. Z.; Yang, H. Tetrahedron 2005, 61, 5037.
(8) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber.
1959, 92, 2499. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc.
196162, 1733.
(9) Other protic or Lewis acid conditions led to decomposition of 7 or
very sluggish reaction.
(13) For detailed data, see Supporting Information.
(14) For experimental details, see Supporting Infromation.
(15) No authentic sample available for direct comparison.
(10) For preparation, see Supporting Information.
Org. Lett., Vol. 12, No. 8, 2010
1651