A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions.

Article abstract of DOI:10.1021/ol017114f

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrr

Full text of DOI:10.1021/ol017114f

ORGANIC
LETTERS
2002
Vol. 4, No. 6
885-888
A Formal Total Synthesis of
(±)-Cephalotaxine Using Sequential
N-Acyliminium Ion Reactions
Yuji Koseki, Hiroto Sato, Yumi Watanabe, and Tatsuo Nagasaka*
Tokyo UniVersity of Pharmacy and Life Science, School of Pharmacy,
1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan
nagasaka@ps.toyaku.ac.jp
Received November 24, 2001
ABSTRACT
Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps
include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12,
and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.
Cephalotaxine 1, a representative Cephalotaxus alkaloid,1
possesses the unique structure of a pentacyclic ring system
with a spiro-fused five-membered ring. Because of its unique
structural features and the antileukemic activity of its
2-alkylhydroxysuccinates such as harringtonine 1a,2,3 many
have reported4 about the total synthesis of cephalotaxine 1.
However, it is known that cephalotaxine itself displays no
significant antileukemic activity.
such as lennoxamine and chilenine, utilizing the ring-
expansion reaction of isoindoloisoquinoline to isoindolo-
benzazepine has also been reported.6 The utility of these
methods via N-acyliminium ion reactions7 directed us to the
(2) For reviews, see: (a) Huang, L.; Xue, Z. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1984; Vol. 23, p 157. (b) Hudlicky,
T.; Kwart, L. D.; Reed, J. W. In Alkaloids; Pelletier, S. W., Ed.; John Wiley
and Sons: New York, 1987; Vol. 5, p 639. (c) Miah, M. A. J.; Hudlicky,
T.; Reed, J. W. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 1998; Vol. 51, p 199. (d) Smith, C. R., Jr.; Mikolajczak, K. L.;
Powell, R. G. In Anticancer Agents Based on Natural Product Models;
Cassady, J. M., Douros, J. D., Eds.; Academic Press: New York, 1980; p
391.
(3) For an isolation of new alkaloids, cephalezomines, see: Morita, H.;
Arisaka, M.; Yoshida, N.; Kobayashi, J. Tetrahedron 2000, 56, 2929.
(4) For recent total synthesis of 1, see: (a) 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. (b) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264 and
references therein.
(5) (a) Koseki, Y.; Kusano, S.; Nagasaka, T. Tetrahedron Lett. 1998,
39, 3517. (b) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T.
Tetrahedron 2000, 56, 8855.
(6) Koseki, Y.; Kusano, S.; Sakata, H.; Nagasaka, T. Tetrahedron Lett.
1999, 40, 2169.
(7) For reviews, see: (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817. (b) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, p 1047. (c) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367.
In our laboratory, the alkylidenelactams obtained by the
AgOTf-(TMS)2NLi-catalyzed cyclization of alkynylamides
have been converted into N-acyliminium ion precursors for
the synthesis of 5-substituted 2-pyrrolidinone derivatives.5
Furthermore, the synthesis of isoindolobenzazepine alkaloids,
(1) For a first isolation of 1, see: Paudler, W. W.; Kerley, G. I.; McKay,
J. J. Org. Chem. 1963, 28, 2194.
10.1021/ol017114f CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/22/2002

synthesis of cephalotaxine 1 having a pentacyclopyrrolo-
benzazepine skeleton. In this paper, the synthesis of 1 based
on tertiary N-acyliminium ions8 from alkynylamide 2 is
reported (Figure 1).
O-silylated 7 with 2-(benzyloxy)ethyl iodide proceeded in
HMPA-THF and was followed by deprotection with 45%
HF-CH3CN to give alcohol 8. Oxidation of 8 was carried
out according to Zhao’s method10 to give carboxylic acid 9,
which was condensed with 2-(3,4-methylenedioxyphenyl)-
ethylamine11 by DEPC to alkynylamide 2.
The synthesis of key building block 10 as a tertiary
N-acyliminium ion equivalent from alkynylamide 2 was
accomplished by utilizing successive methods previously
reported by us (Scheme 2).5b
Scheme 2a
Figure 1. Retrosynthesis of cephalotaxine 1.
Our synthetic plan relied on the construction of penta-
cyclopyrrolobenzazepine cis-6 (cis-fused 7/5 ring system),
an important intermediate in Hanaoka’s synthesis,9 from
â-keto-ester 5, which would be obtained by the ring ex-
pansion of 4 to the pyrrolobenzazepine skeleton (Figure 1).
Initially, we synthesized alkynylamide 2 from 4-pentyn-
1-ol 7 (Scheme 1). Alkylation of the lithium salt of
a (a) LHMDS (0.3 equiv), AgOTf (0.15 equiv), toluene, 65-70
°C, 94%; (b) DMD (excess), MeOH, -78 to -30 °C; (c) BF3‚OEt2
(2.1 equiv), CH2Cl2, -45 to 0 °C, 80% (from 3); (d) SO2Cl2 (2.1
equiv), Et3N, (5 equiv), CHCl3-Py (4:1), -78 to 0 °C, 76%.
Alkynylamide 2 was treated with a catalytic AgOTf-
(TMS)2NLi (1:2) system5a to afford alkylidenelactam 3 in
only a Z-form, which was oxidized with dimethyldioxirane
(DMD) in the presence of MeOH6 to give unstable meth-
oxylactam 10 as a diastereomer mixture (1.8:1). When this
crude material 10 was immediately treated with BF3‚OEt2,
cyclization of 10 via acyliminium ion 11 proceeded smoothly
to give pyrroloisoquinoline 4 in excellent yield as a dia-
stereomer mixture (2:1).12
Scheme 1a
(8) (a) Ollero, L.; Mentink, G.; Rutjes, F. P. J. T.; Speckamp, W. N.;
Hiemstra, H. Org. Lett. 1999, 1, 1331 and references therein. (b) Kim, S.-
H.; Cha, J. K. Synthesis 2000, 2113. (c) Kende, A. S.; Martin Hernando, J.
I.; Milbank, J. B. J. Org. Lett. 2001, 3, 2505.
(9) Yasuda, S.; Yamamoto, Y.; Yoshida, S.; Hanaoka, M. Chem. Pharm.
Bull. 1988, 36, 4229.
(10) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564.
(11) (a) Ho, B. T.; McIsaac, W. M.; An, R.; Tansey, L. W.; Walker, K.
E.; Englert, L. F., Jr.; Noel, M. B. J. Med. Chem. 1970, 13, 26. (b) Kihara,
M.; Kobayashi, S. Chem. Pharm. Bull. 1978, 26, 155.
a (a) (i) TBDMSCl, imidazole, DMF, rt, 95%; (ii) n-BuLi (1.1
equiv), THF, -5 °C, then BnOCH2CH2I (1.3 equiv), HMPA, 0
°C; (iii) 45% HF-CH3CN, rt, 79% in 2 steps; (b) NaClO2, cat.
NaClO, cat. TEMPO, pH 6.86 phosphate buffer-CH3CN,10 35 °C,
84%; (c) 2-[3,4-(methylenedioxy)phenyl]ethylamine (1 equiv),
DEPC (1 equiv), Et3N (1.1 equiv), rt, THF, 88%.
886
Org. Lett., Vol. 4, No. 6, 2002

Scheme 3a
a (a) 5% Pd-C, H2 (1 atm), THF-H2O (15: 87%, 16: 11%); (b) Dess-Martin periodinane, CHCl3, rt, 80%; (c) (i) LiCH2COOBn (1.7
equiv), THF, -78 °C, 93%; (ii) Dess-Martin periodinane, CHCl3, rt, 80%; (d) TiCl4 (1.1 equiv), AcOH-CH2Cl2 (1:10), rt, 97% (19a +
19b); (e) (i) 5% Pd-C, H2 (1 atm), MeOH; (ii) 100 °C, toluene, 87% (from 19a to cis-6), 95% (from 19b to trans-6); (f) N-iodosuccinimide
(3 equiv), TiCl4 (1.2 equiv), MeOH-CH2Cl2 (1:30), rt, 71%; (g) (i) 5% Pd-C, H2 (1 atm), THF-MeOH (1:1); (ii) 100 °C, toluene; (iii)
20% Pd(OH)2, H2 (1 atm), AcOEt, 73%; (h) (i) L-selectride (2 equiv), THF-CH2Cl2, -78 °C, quant; (ii) p-NO2C6H4COCl (2 equiv), Et3N
(2.2 equiv), Py, rt, 86%.
In a key step concerning the approach to pyrrolobenz-
azepine, our successful ring-expansion reaction of the six-
membered ring (isoindoloisoquinoline) to a seven-membered
ring6,13 was applied to 4, which possessed the secondary
hydroxy group at the 10b-position of the pyrroloisoquinoline
ring. When compound 4 was submitted to 2.1 equiv of
SO2Cl2 in a mixed solvent (CHCl3-pyridine ) 4:1) contain-
ing 5 equiv of Et3N, pyrrolobenzazepine 12 was isolated in
76% yield.
A plausible mechanism for this ring-expansion reaction
is shown below. At the first step, chlorosulfonylation of a
hydroxy group with SO2Cl2 afforded 13,14 which underwent
the migration of an aromatic ring to give 12 via acyliminium
ion 14.
In 10%Pd-C under 2 atm of pressure for 8 h, the
undesired product 16 was the major product.15 The use of
aqueous THF (1:5) solvent containing 5%Pd-C led to
dramatic improvement of the isolated yield of 15 (87%, along
with 16 in 11%), even under atmospheric pressure for 5 h.
Oxidation of alcohol 15 with Dess-Martin periodinane
afforded aldehyde 17 followed by an aldol reaction with the
lithium enolate of benzyl acetate in THF, and oxidation of
the resulting alcohol with Dess-Martin periodinane again
afforded â-keto-ester 5.
In the final key step, the cyclization of â-keto-ester 5 via
acyliminium ion 18 to pentacyclic compound 19 was
examined.8 For the intramolecular cyclization of 5 to 19,
some acidic conditions were attempted, e.g., BF3‚OEt2,
(12) For a similar intramolecular cyclization via an N-acyliminium ion,
see for some examples: (a) Garc´ıa, E.; Arrasate, S.; Ardeo, A.; Lete, E.;
Sotomayor, N. Tetrahedron Lett. 2001, 42, 1511. (b) Cid, M. M.;
Dom´ınguez, D.; Castedo, L.; V.-Lo´pez, E. M. Tetrahedron 1999, 55, 5599.
(c) Heancy, H.; Simcox, M. T.; Slawin, A. M. Z.; Giles, R. G. Synlett 1998,
640. (d) Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E.
J. Org. Chem. 1997, 62, 2080.
(13) Recently, synthesis of pyrrolo[3]benzazepines utilizing Stevens [1,2]-
rearrangement of tetrahydroisoquinilines has been reported, see: (a) Padwa,
A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K. J. J. Org. Chem. 2001, 66,
2414. For reviews on other ring expansion reactions, see: (b) Weinstock,
J.; Hieble, J. P.; Wilson, J. W. Drugs Future 1985, 10, 645. (c) Kametani,
T.; Fukumoto, K. Heterocycles 1975, 3, 931.
(14) Yamauchi, T.; Hattori, K.; Nakao, K.; Tamaki, K. Bull. Chem. Soc.
Jpn. 1987, 60, 4015.
(15) For example, the similar result has been obteined by Kende et al.,
see: ref 8c.
Next, we examined the removal of the benzyl protecting
group of 12 by catalytic hydrogenation in order to create
the â-keto-ester moiety in 5 (Scheme 3).
Initially, use of 5%Pd-C under atmospheric pressure
hydrogen in MeOH for 1 day afforded the desired product
15 in low yield (5%<).
Org. Lett., Vol. 4, No. 6, 2002
887

BF3‚2AcOH,16 and catalytic or stoichiometric amount of
TiCl4, but these conditions afforded no pentacyclic ring
system compounds. Conversely, on exposure to 1.2 equiv
of TiCl4 in the presence of AcOH in CH2Cl2 at room
temperature, the intramolecular cyclization of 5 proceeded
smoothly through the formation of acyliminium ion 18 to
give the pentacyclic system compound 19 as a diastereomer
mixture of cis- and trans-fused 7/5 ring system in the ratio
of 1:4.3 (19a-cis:19b-trans)17 in 18% and 79% isolated yield,
respectively. The debenzylation of 19a (enolic form) and 19b
(as a 2:1 mixture of two epimers at the 3-position) on 5%
Pd-C followed by heating at 100 °C in toluene afforded
proceeded to afford iodospiro-ketone 21, which was easily
converted into enone 22 as a 1:1 mixture of two epimers in
71% yield under these reaction conditions. In this cyclization
of 5 to 19 or 22, the absence of cosolvents (AcOH or MeOH,
respectively) caused the cleavage of methylenedioxy function
on aromatic rings. The decarbobenzyloxylation of 22 fol-
lowed by catalytic reduction afforded spiro-ketone cis-69,18
in 73% isolated yield.
In summary, a formal total synthesis of cephalotaxine 1
using the sequential N-acyliminium ion reactions, the oxida-
tion of alkylidenelactam to N-acyliminium ion precursors,
and the ring expansion of a six-membered ring to a seven-
membered ring via N-acyliminium ions was achieved. The
synthetic method reported herein was done in many steps
(17 steps from 7 to cis-6) compared with those described by
other authors.4b However, in the final key step, this result
shows that the cyclization of the â-keto-ester moiety to the
enamide through the formation of tertiary N-acyliminium ion
intermediate by the combined use of a TiCl4-AcOH or
TiCl4-NIS-MeOH system is an efficient method for the
construction of N-heterocyclic rings. Investigation of the
enantiotopic face-selective cyclization against the double
bond of enamide of compound 5 for the asymmetric synthesis
of 1 is now underway.
1
the target compound 6, respectively. However, both the H
NMR spectra and the melting point (268-271 °C) of
the major isomer 6 were not identical with those of an
authentic sample cis-6 (cis-fused 7/5 ring system, mp
192-193 °C).18
The stereochemistry of major isomer 6 in this study was
confirmed to be a trans-fused 7/5 ring system by X-ray
analysis of nitrobenzoate 23 derived from ketone 6 in two
steps.
Next, the iodonium-mediated generation of N-acyliminium
ion 20 from enamide 5 for the construction of the cis-fused
7/5 ring was examined. When 5 was treated with 3 equiv of
N-iodosuccinimide (NIS) in a TiCl4-MeOH system, the
iodocarbocyclization via an N-acyliminium ion intermediate
Acknowledgment. The authors are grateful to Professor
M. Hanaoka of Kanazawa University for kindly providing
spectral data of compound cis-6.
(16) Brodney, M. A.; Padwa, A. J. Org. Chem. 1999, 64, 556.
(17) The intermolecular nucleophilic addition of silyl enol ether to the
enamide through the formation of N-acyliminium ion by HCl-TiCl4 was
reported; see: (a) Wanner, K. T.; Ka¨rtner, A.; Wadenstorfer, E. Heterocycles
1988, 27, 2549. The examples of the â-keto-ester ring closure to N-
acyliminium ion imtermediate, see: (b) Mori, M.; Watanabe, Y.; Kagechica,
K.; Shibasaki, M. Heterocycles 1989, 29, 2089. (c) Tsuda, Y.; Ishiura, A.;
Hosoi, S.; Isobe, K. Chem. Pharm. Bull. 1992, 40, 1697. (d) Kigoshi, H.;
Hayashi, N.; Uemura, D. Tetrahedron Lett. 2001, 42, 7469.
Supporting Information Available: Experimental pro-
cedure of 3, 4, 12, 15, 19a,b, 22, and cis-6; full characteriza-
tion data for compounds 3, 12, 15, 17, 5, cis-/trans-6, 22,
and 23; and X-ray data for 23 are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
(18) The H NMR spectra data and melting point (mp 204-205 °C) of
minor isomer 6 was identical with those of cis-6 in the literature (mp 192-
193 °C); see ref 9.
OL017114F
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Org. Lett., Vol. 4, No. 6, 2002