Concise synthesis of the tricyclic skeleton of cylindricines using a radical cascade involving 6-endo selective cyclization

Article abstract of DOI:10.1055/s-2005-865236

On treatment with Bu₃SnH and azobis(cyclohexanecarbonitrile) (ACN), enamide 19 underwent a 6-endo-trig/5-endo-trig radical cascade to afford perhydropyrrolo[2,1-j]quinoline derivative 21, a cylindricine skeleton.

Full text of DOI:10.1055/s-2005-865236

LETTER
1179
Concise Synthesis of the Tricyclic Skeleton of Cylindricines Using a Radical
Cascade Involving 6-Endo Selective Cyclization
C
oncise Synthe
s
sis of Cyli
u
ndricine Ske
y
leton oshi Taniguchi,a Osamu Tamura,a Masahiko Uchiyama,a Osamu Muraoka,b Genzoh Tanabe,b
Hiroyuki Ishibashi*a
a
Division of Phamaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192,
Japan
Fax +81(76)2344476; E-mail: isibasi@p.kanazawa-u.ac.jp
b
Faculty of Pharmaceutical Sciences, Kinki University, Higashi-osaka, Osaka 577-0818, Japan
Received 22 February 2005
gave O-TBS enamide, which was deprotected with TBAF
Abstract: On treatment with Bu3SnH and azobis(cyclohexanecar-
to give alcohol 4. Mesylation of the hydroxyl group of 4
bonitrile) (ACN), enamide 19 underwent a 6-endo-trig/5-endo-trig
followed by treatment with lithium bromide afforded
bromide 6.
radical cascade to afford perhydropyrrolo[2,1-j]quinoline deriva-
tive 21, a cylindricine skeleton.
Key words: cyclizations, cylindricine, regioselectivity, radical
cascade, acyl radical
OH
a,b,c
H2N
OTBS
R
N
Cylindricines A–K were isolated from the Tasmanian as-
cidian Clavelina cylindrica by Blackman and co-workers
in 1993.1 Among this class of alkaloids, cylindricines
A,C–F (1a–e) possess a tricyclic perhydropyrrolo[2,1-
j]quinoline framework, which is intimately related to the
marine tricyclic alkaloid lepadiformine (2) isolated from
Clavelina lepadiformi by Biard and co-workers in 1994.2
Cylindricines cause mortality in a brine shrimp bioassay,1
and lepadiformine is cytotoxic toward KB, HT29, and
P388 cell lines.2 Their unique structure and biological ac-
tivities make them intriguing targets for total synthesis.3,4
Herein we describe the concise synthesis of a cylindricine
skeleton by an acyl radical-induced 6-endo-trig/5-endo-
trig cascade.5,6
3
O
4 R = Me
5 R = CH=CH2
Br
d,e
R
N
O
6 R = Me
7 R = CH=CH2
Scheme 1 Reaction conditions: a) cyclohexanone, benzene, reflux;
b) CH3COCl or CH2=CHCOCl, Et3N, CH2Cl2, 0 °C; c) TBAF, THF,
54% for 4 from 3, 82% for 5 from 3; d) MsCl, Et3N, DMAP, toluene;
e) LiBr, DMF, 60% for 6 from 4, 80% for 7 from 5.
Treatment of enamide 6 with Bu3SnH in the presence of
azobis(cyclohexanecarbonitrile) (ACN) in boiling toluene
caused alkyl radical cyclization to afford the 6-endo cy-
clization product 8 (73%) as a 1.5:1 mixture of trans- and
cis-isomers,8 along with a small amount of 5-exo cycliza-
tion product 9 (15%, Scheme 2).9,10
O
7
N
N
X
HO
C6H13
C6H13
X = Cl: cylindricine A (1a)
X = OH: cylindricine C (1b)
X = OMe:cylindricine D (1c)
X = OAc: cylindricine E (1d)
X = SCN: cylindricine F (1e)
lepadiformine (2)
Bu3SnH
Br
ACN
O
Me
N
Me
N
toluene
reflux
N
Figure 1 Cylindricines and lepadiformine.
Me
O
O
9 (15%)
6
8 (73%)
trans/cis = 1.5:1
We initiated our investigation by examining the mode of
cyclization of alkyl radical generated from 6, which was
prepared as shown in Scheme 1. Condensation of amine
37 with cyclohexanone followed by treatment of the re-
sulting imine with acetyl chloride in the presence of Et3N
Bu3SnH
ACN
Br
Et
N
toluene
reflux
N
Et
O
O
SYNLETT 2005, No. 7, pp 1179–1181
Advanced online publication: 14.04.2005
0
2.
0
5.
2
0
0
5
11 (quant.)
10
DOI: 10.1055/s-2005-865236; Art ID: U04605ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1180
T. Taniguchi et al.
LETTER
On the other hand, treatment of enamide 1011 with clohexanone followed by treatment with acetyl chloride
Bu3SnH-ACN exclusively afforded 5-exo cyclization afforded ester 16. After hydrolysis of the ester 16, the re-
product 11 in quantitative yield.12,13 These results clearly sulting carboxylic acid was transformed into phenylsele-
indicate that the mode of cyclization of enamides 6 and 10 no ester 18 by using the known method (Scheme 4).18
can be shifted by the difference in the position of the
carbonyl group of amide.14
O
The cyclization of 7, which was prepared in a manner sim-
ilar to that for 6 (Scheme 1), was next examined for the
O
a
OEt
Cl
H2N
OEt
R
N
synthesis lepadiformine skeleton 14. Treatment of en-
amide 7 with Bu3SnH-ACN, however, gave cis-fused tri-
cyclic compound 1215 as a sole cascade product. No trans-
fused tricyclic compound 14 was detected (Scheme 3).
15
O
16 R = Me
17 R = CH=CH2
O
b, c
SePh
Bu3SnH
R
N
Br
ACN
O
toluene
reflux
N
N
18 R = Me
19 R = CH=CH2
O
O
12 (30%)
7
Scheme 4 Reaction conditions: a) cyclohexanone, benzene, reflux,
then CH3COCl or CH2=CHCOCl, Et3N, CH2Cl2, 0 °C, 44% for 16,
47% for 17; b) 10% NaOH, aq EtOH; c) (PhSe)2, Bu3P, THF, 95% for
18 from 16, 40% for 19 from 17.
O
O2N
NO2
1) BH3·THF
2) picric acid
N
N
H
NO2
O
Treatment of the enamide 18 with Bu3SnH-ACN in
boiling toluene exclusively afforded 6-endo cyclization
product 20 (97%) as a 1:1.5 mixture of trans- and cis-
isomers.19 No 5-exo cyclization product was detected
(Scheme 5).
14
13 (quant.)
not detected
Scheme 3
The stereochemistry of 12 was unequivocally established
by an X-ray crystallographic analysis of the amine-picrate
13,16 prepared by reduction of the lactam 12 with borane–
THF complex followed by treatment with picric acid. For-
mation of 12 from 7 can be explained by the following
mechanistic consideration. As depicted in Figure 2 the
transition states of the formation of 12 and 14 might be I
and II, the A rings of which are chair and boat forms, re-
spectively. Therefore, the 5-endo-trig cyclization may
proceed through transition state I, in which the A ring has
a more favorable chair form (Figure 2).
O
O
Bu3SnH, ACN
toluene, reflux
SePh
Me
N
Me
N
O
O
18
20 (97%)
trans/cis = 1:1.5
O
O
Bu3SnH, ACN
toluene, reflux
SePh
N
N
O
O
H
12
14
21 (37%)
19
N
A
A
O
N
O
H
Scheme 5
I cis (favor)
II trans (disfavor)
Figure 2 Transition state of the formation of cis and trans tricyclic
compound 12 and 14.
Being encouraged by the success of obtaining 20 from 18,
we next examined the cyclization of 19, which was pre-
pared by a similar sequence of the reactions for 18. When
the enamide 19 was treated with Bu3SnH-ACN, the cis-
fused tricyclic compound 2120 (37%), a cylindricine skel-
eton, was obtained (Scheme 5). The stereochemistry of 21
was established by its X-ray crystallographic analysis.16
The stereostructure of tricyclic system 12 obtained by the
alkyl radical-induced 6-endo-trig/5-endo-trig radical cas-
cade was found to be in accord with that of cylindricines
(Figure 1), and we therefore turned our attention to the use
of acyl radical17 for the radical cascade to introduce oxo-
functionality at C7 into the tricyclic system.
In conclusion, we revealed that treatment of enamide 6
with Bu3SnH-ACN gave the 6-endo cyclization product 8,
whereas a similar treatment of enamide 10 gave the 5-exo
cyclization product 11. The former reaction could be
applied to a concise synthesis of a cylindricine skeleton 21
We first examined the mode of cyclization of acyl radical
generated from 18. Condensation of the commercially
available b-alanine ethyl ester hydrochloride 15 with cy-
Synlett 2005, No. 7, 1179–1181 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of a Cylindricine Skeleton
1181
(11) Enamide 10 was synthesized by treatment of the imine,
prepared from ethylamine and cyclohexanone, with 3-
bromopropionyl chloride in the presence of NaHCO3.
(12) 13C NMR spectrum of compound 11 showed the presence of
a quaternary carbon atom (d = 64.0 ppm) and the IR
spectrum of 11 exhibited absorption at 1665 cm–1 due to the
five-membered lactam.
from 19 that consisted of a radical cascade involving 6-
endo-trig cyclization of acyl radical and 5-endo-trig
cyclization of a-amidoyl radical. Further studies directed
toward total synthesis of cylindricines using this method-
ology are now in progress.
(13) Radical reactions of some sterically fixed 3-bromo-N-
(cyclohex-1-enyl)propionamides, which are closely related
to compound 8, leading to the formation of 6-endo
cyclization product or a mixture of 6-endo and 5-exo
cyclization products have been reported. See: Schultz, A. G.;
Guzzo, P. R.; Nowak, D. M. J. Org. Chem. 1995, 60, 8044.
(14) An analogous example on the aryl radical cyclization:
Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O.
J. Chem. Soc., Chem Commun. 2000, 1527.
Acknowledgment
1
We are grateful to Professor Roger Hunter for giving us the H
NMR and 13C NMR spectra of compounds 12 and 14. We also thank
Professor Jeffrey Aubé for the useful discussion for the formation
of compound 12. This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
(15) (a) Aubé, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113,
8965. (b) Hunter, R.; Richards, P. Synlett 2003, 271.
(16) Crystallographic data of 13 and 21 have been deposited with
the Cambridge Crystallographic Data Centre as
References
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data_request@ccdc.cam.ac.uk, or by contacting The
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Cambridge CB2 1EZ, UK; fax: +44(1223)336033.
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(19) The structure of compound 20 was confirmed by
transforming it to compound 8 by removal of the carbonyl
group of the ketone.
(20) (7aS*,11aS*)-Octahydro-3H-pyrrolo[2,1-j]quinoline-3,7
(7aH)-dione (21).
To a boiling solution of 19 (530 mg, 1.46 mmol) in toluene
(70 mL) was added dropwise a solution of Bu3SnH (649 mg,
2.20 mmol) and ACN (71.5 mg, 0.292 mmol) in toluene (70
mL) over 3 h using a syringe pump. The reaction mixture
was cooled to r.t. and the solvent was removed under
reduced pressure. The residue was purified by flash
chromatography on silica gel (hexane–EtOAc, 1:1) to give
21 (113 mg, 37%) as colorless crystals; mp 106–107 °C
(hexane). IR (CHCl3): n = 1715, 1680 cm–1. 1H NMR (270
MHz, CDCl3): d = 1.19–1.79 (m, 9 H), 2.00 (td, J = 8.3, 13.5
Hz, 1 H), 2.16 (ddd, J = 6.6, 8.3, 13.5 Hz, 1 H), 2.25–2.31
(m, 1 H), 2.33–2.53 (m, 3 H), 3.04 (ddd, J = 6.3, 10.2, 13.5
Hz, 1 H), 4.38 (ddd, J = 2.3, 6.3, 13.5 Hz, 1 H). 13C NMR
(67.8 MHz, CDCl3): d = 20.5, 21.7, 22.3, 29.0, 29.4, 32.4,
35.0, 39.7, 55.2, 64.6, 173.1, 207.3. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.31; H,
8.42; N, 6.61.
(5) We previously reported that radical-induced 7-endo-trig/5-
endo-trig radical cascade gave a cephalotaxine skeleton.
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111.
(9) The structure of compound 9 was determined by its 13
C
NMR spectrum, which showed the presence of a quaternary
carbon atom (d = 66.3 ppm).
(10) Reviews on the synthesis of five- and six-membered
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(a) Majumdar, K. C.; Mukhopadhyay, P. P.; Basu, P. K.
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Synlett 2005, No. 7, 1179–1181 © Thieme Stuttgart · New York