Novel formal synthesis of cephalotaxine via a facile friedel - Crafts cyclization

Article abstract of DOI:10.1021/ol070024b

Figure presented A novel formal synthesis of cephalotaxine (CET), the parent structure of the antileukemia Cephalotaxus alkaloids, was achieved via a facile Friedel-Crafts cyclization of the amino (or amido) spiro-cyclopentenone precursor (A) mediated by

Full text of DOI:10.1021/ol070024b

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1211-1214
Novel Formal Synthesis of
Cephalotaxine via a Facile
Friedel−Crafts Cyclization
Wei-Dong Z. Li*,†,‡ and Xin-Wei Wang†
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, China, and State Key Laboratory of Elemento-organic Chemistry,
Nankai UniVersity, Tianjin 300071, China
wdli@nankai.edu.cn
Received January 5, 2007
ABSTRACT
A novel formal synthesis of cephalotaxine (CET), the parent structure of the antileukemia Cephalotaxus alkaloids, was achieved via a facile
Friedel Crafts cyclization of the amino (or amido) spiro-cyclopentenone precursor (A) mediated by a protic acid leading to tetracyclic ketone
B. A remarkable stereoelectronic effect of the methylenedioxy substituent (R) and an interesting skeletal isomerization of the CET core ring
system (B, X H2) were observed.
−
)
Cephalotaxine (CET) is the parent structure of a rare family
of plant antileukemia Cephalotaxus alkaloids,1 possessing a
unique spiro-annulated polycyclic ring system. The structural
characteristics of CET and the clinically proven yet intriguing
antitumor therapeutic potentials of its naturally occurring
ester derivatives (i.e., harringtonine and homoharringtonine)
have attracted a long-standing interest in their chemical
synthesis.1b,2 A variety of innovative synthetic strategies have
been developed since the landmark total synthesis of CET
by Weinreb and Semmelheck in the 1970s,3 by focusing on
the construction of the tetracyclic core ring system (ABCD,
Figure 1).
One of the most commonly employed strategic approaches
is the B-ring closure of a spirocyclic precursor (A-CD)
leading to the formation of the central benzazepine system
(bond highlighted in red in Figure 1). Some typical B-ring
closure approaches used in previous CET synthesis (or a
relevant model study) include: (1) Lewis (or protic) acid
mediated Friedel-Crafts-type cyclization as employed by
the Kuehne,4 Royer,5 Sha,6 and Mori7 groups (Figure 2),8
among which a remarkable stereoelectronic effect of the
* To whom correspondence should be addressed. Fax/Phone:
0086-(0)22-23494613.
† Lanzhou University.
‡ Nankai University.
(1) 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) 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.
(2) For a recent total synthesis, see: Eckelbarger, J. D.; Wilmot, J. T.;
Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370 and references therein.
Figure 1. Cephalotaxine (CET) and its core ring system.
10.1021/ol070024b CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/10/2007

Figure 4. Alternative radical cyclization approaches.
directly, which is known to be readily transformed into
CET.16
Figure 2. Typical Friedel-Crafts cyclization approaches.
Scheme 1. Enone Friedel-Crafts Cyclization Approach (?)
methylenedioxy substituent (R) was first noticed by Sha
and co-workers;6 (2) Pd(0)-catalyzed Heck-type coupling of
an unsaturated spirocyclic aryl halide precursor as exempli-
fied by the Tietze,9 Ikeda,10 Suga-Yoshida,11 and Hayes12
groups (Figure 3); and (3) radical cyclization approaches as
used by the Semmelheck13 and Taniguchi14 groups (Figure
4).
To test the feasibility of this B-ring closure approach, the
amido spiro-cyclopentenone 4a (or 4b) was prepared17
conveniently from proline-derived spirocyclic amino enone
2 and acid chloride 3 in good yield (Scheme 2) by following
procedures reported by Ikeda et al.10b Although the methyl-
enedioxy-substituted precursor 4a did not cyclize under
various Lewis or protic acid conditions, we found that a
(8) For an alternative B-ring cyclization approach involving a cationic
intermediate, see: Ishibashi, H.; Okano, M.; Tamaki, H.; Maruyama, K.;
Yakura, T.; Ikeda, M. J. Chem. Soc., Chem. Commun. 1990, 1436.
(9) (a) Tietze, L. F.; Shirok, H. Angew. Chem., Int. Ed. 1997, 36,
1124. (b) Tietze, L. F.; Shirok, H. J. Am. Chem. Soc. 1999, 121,
10264.
Figure 3. Typical Pd0-catalyzed Heck-type coupling approaches.
(10) (a) Ikeda, M.; Hirose, K.; El Bialy, S. A. A.; Sato, T.; Yakura, T.;
Bayomi, S. M. M. Chem. Pharm. Bull. 1998, 46, 1084. (b) 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.
(11) Suga, S.; Watanabe, M.; Yoshida, J. I. J. Am. Chem. Soc. 2002,
124, 14824.
As a continuation of our study toward CET synthesis,15
we envisioned that an alternative Friedel-Crafts-type cy-
clization (Scheme 1, arrows) of a spiro-cyclic enone precur-
sor I would produce the tetracyclic ring structure II of CET
(12) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 6011.
(13) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T.
D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507.
(14) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.;
Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922.
(15) (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) Ma, B.-C.; Wang,
Y.-Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528.
(16) Yasuda, S.; Yamada, T.; Hanaoka, M. Tetrahedron Lett. 1986, 27,
2023.
(3) For an account, see: Weinreb, S. M.; Semmelhack, M. F. Acc. Chem.
Res. 1975, 8, 158.
(4) Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.;
Blount, J. F.; Zubieta, J. J. Org. Chem. 1988, 53, 3439.
(5) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69,
3087.
(6) Sha, C. K.; Young, J. J.; Yeh, C. P.; Chang, S. C.; Wang, S. L. J.
Org. Chem. 1991, 56, 2694.
(7) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115.
(17) See Supporting Information for experimental details.
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Org. Lett., Vol. 9, No. 7, 2007

Scheme 2. Novel Formal Synthesis of Cephalotaxine
Scheme 3. Friedel-Crafts Enone Cyclization of 8
derivative 8a failed to cyclize under the same or forcing
acidic conditions.20
This Friedel-Crafts enone cyclization is equally applicable
for the six-membered ring formation from various spirocyclic
enone substrates 10-13 as summarized in Figure 5 under
smooth (conjugate) Friedel-Crafts-type enone cyclization
of an analogous dimethoxy derivative 4b occurred on
treatment with triflic acid (2.5 equiv, as a slurry mixture in
CH2Cl2) at ambient temperature and the cyclization product
5b (mp 222-224 °C) was obtained in 93% yield.18 It is
obvious that the remarkable stereoelectronic effect of the
methylenedioxy substituent6 is responsible for the deactiVa-
tion of the aryl group (leading to an electron-deficient arene
system). It is noteworthy that the corresponding iodo
analogue of 4a used by the Ikeda group10 in their Heck
cyclization approach (Figure 3) gave the corresponding
cyclization product in quite low yield (ca. 7%) as well, which
may underline the significance of a stereoelectronic effect
similar to that above.
The spectroscopic features of 5b are identical to those
reported by Hanaoka et al.16 and its cis-cyclopentanone
configuration was further confirmed by a single-crystal X-ray
diffraction analysis.19 A simple yet effective formal synthesis
of CET via a facile Friedel-Crafts enone cyclization was
thus realized.
As shown in Scheme 3, the amino spiro-cyclopentenone
8a (or 8b) was prepared analogously via N-alkylation of spiro
amino alcohol 6 derived from enone 1 and followed by IBX
oxidation.17 Similarly, the protic acid mediated Friedel-
Crafts cyclization of the dimethoxy enone 8b (R ) Me)
proceeded cleanly to give tetracyclic ketone 9b in 90%
isolated yield, whereas the corresponding methylenedioxy
Figure 5. Friedel-Crafts cyclization of spiro enones 10-13.
similar acidic conditions.21 The deactivation of the aryl
system by the methylenedioxy substituent is obvious in the
cases of 10b vs 11b. The electron-deficient aryl system (i.e.,
13b) is very reluctant to participate in the conjugated
arylative enone cyclization.
(18) During the preparation of this manuscript, we have noticed a recent
report by Trauner et al. (Grundl, M. G.; Kaster, A.; Beaulieu, E. D.; Trauner,
D. Org. Lett. 2006, 8, 5429.) on a similar triflatiVe Friedel-Crafts cyclization
of an aryl enone precursor:
(20) For example, enlongated refluxing of 8a with triflic acid in CH2Cl2
led to gradual decomposition.
(21) Mediated by triflic acid in a slurry mixture of CH2Cl2, see Supporting
Information for detailed spectral data of the corresponding cyclization
products with a general structure of
(19) X-ray crystallographic data of 5b: C18H21NO4, FW 315.36, mono-
clinic, space group P2(1)/c, a ) 8.576(2) Å, b ) 7.6040(18) Å, c )
24.573(6) Å, â ) 99.323(4), Z ) 4, dcalcd ) 1.325 g/cm3, R1 (I > 2σ(I)) )
0.0454, wR2 (all data) ) 0.0903. See Supporting CIF file for more details.
Org. Lett., Vol. 9, No. 7, 2007
1213

Interestingly, we found that the cis-tetracyclic ketone 9b
readily underwent a ring skeletal isomerization (Scheme 4)
Scheme 5. Dolby Rearrangement24 Proposal to Cyclic
Ketones 14a and 14b
Scheme 4. Ring Skeletal Isomerization of 9b
equilibration with macrocyclic enone intermediates iii and
iv and ring skeletal rearrangement product 14a was identified
as the sole isolable product. The presence of an R-ethoxy-
carbonyl group on the cyclopentanone ring and the relatively
electron-deficient aryl system with the methylenedioxy
substituent in 15 may be responsible for the extremely facile
isomerization to 14a and 14b.
In summary, we have accomplished a simple and effective
formal synthesis of cephalotaxine via a facile Friedel-Crafts-
type enone cyclization of a spiro-cyclopentenone precursor.
The remarkable stereoelectronic effect of the aryl methyl-
enedioxy substituent demonstrated in this work implies the
π-electronic demanding character for the above cyclization
reaction. This facile Friedel-Crafts enone cyclization may
be applicable in other heterocyclic syntheses of potential
medicinal use.
upon exposure to mild acidic conditions (i.e., long-standing
in a CHCl3 solution), from which a more polar major isomer
(67%, monohydrate of hydrochloride salt, mp. 223-225 °C)
was identified by single-crystal X-ray diffraction analysis
as the trans-isomer 9b′22 and a less polar isomer (ca. 15%,
mp 171-172 °C) was found to be the known ketone 14.23
Apparently, an acid-mediated equilibration between cis-9b
and macrocyclic enones i and ii via retro-Michael and
cyclopentenone isomerization is attributed to the observed
skeletal rearrangement. It was noted that the crystalline trans-
isomer 9b′ was more stable and less prone toward isomer-
ization than the corresponding cis-isomer 9b. This skeletal
isomerization can be accelerated under some forcing condi-
tions (i.e., refluxing in toluene with a catalytic amount of
PPTs).
Acknowledgment. Dedicated to Dr. L. J. Dolby of
Organic Consultants, Inc. (Eugene, Oregon 97401). We thank
the National Natural Science Foundation (QT 20021001 and
20572047) for financial support. The Cheung Kong Scholars
program and the Outstanding Scholars program of Nankai
University are gratefully acknowledged.
These observations are coincident with an intriguing ring
system isomerization process proposed previously by Dolby
and co-workers (Scheme 5)24 during their pioneering syn-
thetic study on CET, in which the Dolby-Weinreb enamine
alkylation product 15 was assumed to undergo a fast
Supporting Information Available: Experimental pro-
cedures, spectral data, copies of spectra for compounds 4a,
4b, 5b, 8a, 8b, 9b, 9b′, and 10-13, the corresponding
cyclization products of 10-13, and crystallographic informa-
tion files (CIFs) for compounds 5b and 9b′. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) X-ray crystallographic data for the monohydrate of the hydrochloride
salt of 9b′: C18H26NClO4, FW 355.85, triclinic, space group P1, a )
7.477(9) Å, b ) 10.370(13) Å, c ) 11.376(14) Å, R ) 92.785(14), â )
94.308(16), γ ) 92.272(15), Z ) 2, dcalcd ) 1.348 g/cm3, R1 (I > 2σ(I)) )
0.0484, wR2 (all data) ) 0.0714. See Supporting CIF file for more details.
(23) For an alternative preparation and X-ray structure, see ref 15b.
(24) Dolby, L. J.; Nelson, S. J.; Senkovich, D. J. Org. Chem. 1972, 37,
3691.
OL070024B
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Org. Lett., Vol. 9, No. 7, 2007