Synthesis of 8,9-(1,3-benzodioxolo-5,6)-5-azatricyclo[8.2.1.0 1,5]tridec-11-en-6-one. A convenient route to structural analogs of the alkaloid cephalotaxine

Article abstract of DOI:10.1007/s11172-006-0103-8

A synthetic route to 8,9-(1,3-benzodioxolo-5,6)-5-azatricyclo[8.2.1.0 ^1,5]tridec-11-en-6-one structurally isomeric to the pentacyclic cephalotaxine nucleus is suggested. The route is based on the sequence including diallylboration of 2-pyrrolidinone and intramolecular meta-thesis of the resulting 2,2-diallylpyrrolidine, giving rise to 1-azaspiro[4.4]non-7-ene. This product was N-acylated with 6-bromohomopiperonylic acid chloride and then subjected to intramolecular cyclization according to the Heck reaction.

Full text of DOI:10.1007/s11172-006-0103-8

Russian Chemical Bulletin, International Edition, Vol. 54, No. 9, pp. 2229—2232, September, 2005
2229
Synthesis of 8,9ꢀ(1,3ꢀbenzodioxoloꢀ5,6)ꢀ
5ꢀazatricyclo[8.2.1.01,5]tridecꢀ11ꢀenꢀ6ꢀone.
A convenient route to structural analogs of the alkaloid cephalotaxine*
N. Yu. Kuznetsov, I. V. Zhun´, V. N. Khrustalev, and Yu. N. Bubnovꢀ
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation
Fax: +7 (495) 135 5085. Eꢀmail: bubnov@ineos.ac.ru
A synthetic route to 8,9ꢀ(1,3ꢀbenzodioxoloꢀ5,6)ꢀ5ꢀazatricyclo[8.2.1.01,5]tridecꢀ11ꢀenꢀ6ꢀ
one structurally isomeric to the pentacyclic cephalotaxine nucleus is suggested. The route is
based on the sequence including diallylboration of 2ꢀpyrrolidinone and intramolecular metaꢀ
thesis of the resulting 2,2ꢀdiallylpyrrolidine, giving rise to 1ꢀazaspiro[4.4]nonꢀ7ꢀene. This
product was Nꢀacylated with 6ꢀbromohomopiperonylic acid chloride and then subjected to
intramolecular cyclization according to the Heck reaction.
Key words: cephalotaxine, Heck reaction, palladacycles, polycyclic compounds, 1ꢀazaꢀ
spiro[4.4]nonꢀ7ꢀene, intramolecular metathesis, XꢀRay diffraction analysis.
sis is the design of 1ꢀazaspiro[4.4]nonꢀ7ꢀene (2). This
product was prepared by reductive diallylation of 2ꢀpyrꢀ
rolidinone with triallylborane4 followed
by intramolecular metathesis of the
Nꢀtrifluoroacetyl derivative 3 in the
presence of the Grubbs catalyst (A)
(0.5 mol.%, CH2Cl2)5 (Scheme 1). The
protective group in 4 was removed by
treatment with alkali in methanol, and
In recent years, a large number of alkaloids whose
molecules contain spiroꢀcoupled (hetero)cycles have been
isolated from various natural objects.1 Among these alkaꢀ
loids, a special part belongs to pentacyclic cephalotaxine
and a number of its esters (harringtonine, homoharringꢀ
tonine, isoharringtonine, and deoxyharringtonine). All
these alkaloids are produced by yew trees (Cephalotaxus
harrigtonia var. drupacae), which grow in China and in
Japan. Cephalotaxine esters possess high antileucaemia
(myeloid leucaemia)2a and antimalarial activities;2b pharꢀ
maceuticals based on them are now under clinical trials.2
Previously, several research groups have synthesized the
parent cephalotaxine and some of its close analogs (see,
for example, Ref. 3).
bicyclic amine 2 was isolated by distillation in 74% yield.
Scheme 1
In this communication we propose a route to polyꢀ
cyclic amide 1. This compound can be used to prepare the
previously unknown pentacyclic system, which is isomeric
to the alkaloid cephalotaxine. The key step of the syntheꢀ
The other fragment of the molecule was prepared
according to Scheme 2. Commercially available homoꢀ
piperonylic acid was brominated into position 6 with
Nꢀbromosuccinimide6a in dichloromethane for 2 h; the
use of this reagent proved to be more convenient than
* Dedicated to Academicians A. L. Buchachenko and
N. S. Zefirov on the occasion of their 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2160—2163, September, 2005.
1066ꢀ5285/05/5409ꢀ2229 © 2005 Springer Science+Business Media, Inc.

2230
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 9, September, 2005
Kuznetsov et al.
Scheme 2
treatment with bromine (this has been described preꢀ
viously6b). The resulting bromo acid 5 was heated with
oxalyl chloride in dichloromethane, which gave acyl chloꢀ
ride 6 in a quantitative yield.3b
The acylation of bicyclic amine 2 with chloride 6 was
carried out in the presence of triethylamine; the amide 7
thus formed was isolated by chromatography on silica gel.
The final step made use of the Heck cyclization (cf.
Ref. 3b, in which the double bond in the product of simiꢀ
lar cyclization is also nonconjugated with the aromatic
nucleus). Heating of amide 7 with palladium complex B
as the catalyst for 13 h at 140 °C affords compound 1
(85%) (see Scheme 2).
C(19)
C(18)
C(17)
C(11)
C(12)
C(1)
N(13)
C(10)
C(20)
C(2)
Fig. 2. Conformation of the tricyclic fragment in compound 1.
The structure of pentacyclic compound 1 was deterꢀ
mined by Xꢀray diffraction analysis (Fig. 1). Compound 1
has two asymmetric centers, C(1) and C(17). The crystal
of 1 is racemic, the relative configuration of these centers
being (1S*, 17R*). The structure of the nitrogenꢀcontainꢀ
ing tricyclic fragment is shown in Fig. 2: the 9ꢀmembered
ring has a boat conformation (the C(11), C(18), and C(19)
atoms deviate from the mean plane of the other atoms of
the ring by –0.909, –1.493, and –1.468 Å, respectively),
the 8ꢀmembered ring has a chair conformation (the C(11)
and C(20) atoms deviate from the mean plane of the other
ring atoms by –0.909 and +0.798 Å, respectively), and
the 5ꢀmembered ring has an envelope conformation (the
C(20) atom deviates from the plane of the other ring
atoms by 0.405 Å).
Thus, using the sequence including diallylboration of
2ꢀpyrrolidinone, intramolecular metathesis, and the Heck
cyclization, we synthesized pentacyclic compound 1
whose further transformations allow the synthesis of a
structural isomer of the alkaloid cephalotaxine. The
change in the size of the nitrogenꢀcontaining fragment of
the spiroꢀcoupled heterocycle, which may take place in
our method, allows one to prepare a number of new
cephalotaxine analogs.
O(12)
C(14)
C(12)
O(7)
C(9)
C(10)
C(8)
C(4)
C(6)
C(15)
C(16)
C(11)
N(13)
O(5)
C(20)
C(2)
C(1)
C(17)
C(3)
C(18)
C(19)
Experimental
Fig. 1. Molecular structure of compound 1 (ellipsoids of thermal
vibrations are given with 50% probability).
The reactions were carried out in an atmosphere of pure
argon. All solvents were purified and dried according to stanꢀ

Cephalotaxine analog
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 9, September, 2005
2231
dard procedures. The NMR spectra were recorded on Bruker
AМХꢀ400 and Avanceꢀ300 spectrometers. Column chromatoꢀ
graphy was carried out using silica gel 60—230 mesh (Merck).
Aluminum plates with silica gel 60 F254 (Merck) were used for
thin layer chromatography. Catalyst A was received from Fluka.
Complex B was prepared from palladium acetate and triꢀ
оꢀtolylphosphine according to a published procedure.7 Homoꢀ
piperonylic acid was purchased from Acros. Compound 4 was
prepared according to a reported procedure.4,5
1ꢀAzaspiro[4.4]nonꢀ7ꢀene (2). Bicyclic amide 4 4 (12.3 g,
56.0 mmol) was dissolved in МеOH (60 mL), a solution of
NaOH (10 M, 20 mL, 0.2 mol) was added, and the mixture was
refluxed for 2 h, the course of the reaction being monitored by
TLC (hexane—AcOEt, 4 : 1). Methanol was removed in vacuo,
the residue was extracted with ether (3×20 mL), and the comꢀ
bined extracts were dried with К2CO3 and concentrated on a
rotary evaporator. Distillation gave amine 2 (5.1 g, 74%) as a
colorless liquid, b.p. 69—70 °C (12 Torr). 1H NMR (400 МHz,
CDCl3), δ: 5.54 (s, 2 H); 2.87 (t, 2 H, J = 7.0 Hz); 2.25 (s, 4 H);
1.71 (m, 2 H); 1.60 (m, 3 H). 13C NMR (100 МHz, CDCl3), δ:
125.13 (2 CH=); 65.22 (C); 41.89 (2 CH2); 41.20 (CH2); 34.65
(CH2); 20.75 (CH2).
(5 mL), DMF (5 mL), and water (1 mL) were added. The
mixture was degassed through three freezing—evacuation—arꢀ
gon filling—thawing cycles. The flask was plugged with stoppers
secured by springs and heated on an oil bath for 13 h at 140 °C.
The solvents were evaporated in vacuo, the residue was diluted
with water, and the resulting mixture was extracted with CH2Cl2
(3×10 mL). After concentrating the extracts, the residue was
purified by chromatography on silica gel with a AcOEt—hexane
system, 2 : 1 (Rf = 0.23) to give compound 1 (0.24 g, 85%) as a
white crystalline powder, m.p. 149—150 °C. 1H NMR (300 МHz,
CDCl3), δ: 6.77, 6.63 (both s, 1 H each); 6.11 (dd, 1 H, J = 2.9,
J = 5.3 Hz); 5.91, 5.88 (both d, 1 H, J = 1.3 Hz); 5.81 (d,
1 H, J = 5.4 Hz); 4.94 (d, 1 H, J = 13.1 Hz); 3.82 (dd, 1 H,
J = 2.1 Hz, J = 8.8 Hz); 3.73 (ddd, 1 H, J = 3.4 Hz, J = 8.4 Hz,
J = 12.2 Hz); 3.47 (ddd, 1 H, J = 7.4 Hz, J = 9.1 Hz, J =
12.2 Hz); 3.15 (d, 1 H, J = 13.1 Hz); 2.32 (m, 1 H); 3.27
(dd, 1 H, J = 8.8 Hz, J = 13.0 Hz); 1.98—1.72 (m, 4 H).
13C NMR (75 МHz, CDCl3), δ: 171.36, 146.59, 146.15,
134.98, 134.78, 134.42, 128.16, 113.85, 110.21, 101.00, 73.65,
52.99, 49.09, 47.78, 40.88, 40.76, 21.42. Found (%): C, 72.04;
H, 5.94; N, 4.94. C17H17NO3. Calculated (%): C, 72.07;
H, 6.05; N, 4.94.
(6ꢀBromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetic acid (5). NꢀBromoꢀ
succinimide (5.3 g, 30 mmol) was added in portions at +5 °C
over a period of 15 min (see Ref. 7) to a solution of homoꢀ
piperonylic acid (5 g, 27.7 mmol) in CH2Cl2 (80 mL). The
mixture was stirred for 2 h at room temperature. Water (100 mL)
was added, the organic layer was separated, and the solvent was
evaporated on a rotary evaporator. The resulting precipitate was
filtered off, washed with hexane and water, and dried in air for
~12 h to give brominated acid 5 (6.6 g, 92%) as a white powder,
m.p. 190—191 °C. 1H NMR (400 МHz, DMSOꢀd6), δ: 12.45,
7.17, 6.98 (all s, 1 H each); 6.04, 3.62 (both s, 2 H each).
13C NMR (100 МHz, DMSOꢀd6), δ: 171.58, 147.22, 146.99,
128.09, 114.87, 112.04, 111.60, 101.92, 40.83. Acid 5 was conꢀ
verted into the corresponding acyl chloride 6 by a reported
procedure.3b
1ꢀ(1ꢀAzaspiro[4.4]nonꢀ7ꢀenꢀ1ꢀyl)ꢀ2ꢀ(6ꢀbromoꢀ1,3ꢀbenzoꢀ
dioxolꢀ5ꢀyl)ethanꢀ1ꢀone (7). Solid chloride 6 (4.85 g, 17.5 mmol)
was added with stirring and waterꢀbath cooling (~20 °C) to a
solution of amine 2 (2.0 g, 16.2 mmol) and triethylamine (2.0 g,
2.78 mL, 20.0 mmol) in CH2Cl2 (40 mL). The mixture was
stirred for 2 h and treated with water (40 mL). The organic layer
was separated, washed with a solution of NaHCO3, water, and
a solution of 3 M HCl (10 mL), and dried with Na2SO4.
The solvent was evaporated and the oil thus formed was
chromatographed on silica gel with a hexane—AcOEt (2 : 1)
system to give amide 7 (5.07 g, 86%) as a white crystalline
powder, m.p. 102—103 °C. 1H NMR (400 МHz, CDCl3), δ:
6.96, 6.80 (both s, 1 H each); 5.91, 5.62, 3.60, 3.56 (all s,
2 H each); 3.19 (d, 2 H, J = 15.2 Hz); 2.09 (d, 2 H, J = 15.0 Hz);
1.89 (br.s, 4 H). 13C NMR (100 МHz, CDCl3), δ: 167.74, 147.34,
147.26, 128.76 (2 CH), 128.49, 115.04, 112.42, 110.93, 101.66,
69.82, 48.65, 43.97 (2 CH2), 43.14, 42.95, 23.37. Found (%):
C, 56.07; H, 4.94; N, 3.82. C17H18BrNO3. Calculated (%):
C, 56.06; H, 4.98; N, 3.85.
XꢀRay diffraction analysis of compound 1 (C17H17NO3,
M = 283.32). The crystals of 1 are monoclinic, space group
P21/n; at T = 120 K: a = 7.1808(13), b = 18.046(3), c =
10.3917(18) Å, β = 99.352(3)°, V = 1328.7(4) Å3, Z = 4, dc
=
1.416 g cm–13, F(000) = 600, µ = 0.097 mm–1. The unit cell
parameters and the intensities of 12317 reflections (Rint = 0.026)
were measured on a Bruker SMART 1000 CCD automated
diffractometer equipped with a Oxford CryoSystem lowꢀtemꢀ
perature unit (T = 120 K, MoꢀKα radiation, graphite monoꢀ
chromator, ϕ and ω scan mode, 2θmax = 54°). The structure was
solved by the direct method and refined by the fullꢀmatrix leastꢀ
squares calculations in the anisotropic approximation for
nonhydrogen atoms. The hydrogen atoms were located in the
difference Fourier syntheses and refined isotropically. The final
Rꢀfactors: R1 = 0.044 for 2196 independent reflections with
I > 2σ(I ) and wR2 = 0.115 for all 2898 independent reflections.
All calculations were performed using the SHELXTL PLUS
software (Version 5.10).8
This work was financially supported by the Rusꢀ
sian Foundation for Basic Research (Projects No. 02ꢀ03ꢀ
32248 and No. 05ꢀ03ꢀ33268), the Council for Grants
at the President of the Russian Federation (Program for
the State Support of Leading Scientific Schools of the
Russian Federation, grant NSh 1917.2003.3), and the
Presidium of the Russian Academy of Sciences (Proꢀ
gram "Targeted Synthesis of Substances with Specified
Properties and Design of Functional Materials Based
on Them").
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AcONa (0.21 g, 2.6 mmol), and amide 7 (0.36 g, 1 mmol) were
charged into a 25ꢀmL twoꢀnecked flask under argon, and CH3CN
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Received June 15, 2005;
in revised form September 12, 2005