Formal stereoselective synthesis of (±)-akagerine

Article abstract of DOI:10.1039/a807868h

A stereoselective synthesis of pentacyclic dilactam 1, a known precursor of the indole alkaloid akagerine, involving addition of the enolate of 1-acetylindole 2 to 3-acetyl-2-fluoropyridinium salt 3, cyclization of the resultant 1,4-dihydropyridine, elabo

Full text of DOI:10.1039/a807868h

Formal stereoselective synthesis of (±)-akagerine
M.-Lluïsa Bennasar,* Bernat Vidal, Bilal A. Sufi and Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain.
E-mail: jbosch@farmacia.far.ub.es
Received (in Cambridge, UK) 9th October 1998, Accepted 30th October 1998
A stereoselective synthesis of pentacyclic dilactam 1, a
known precursor of the indole alkaloid akagerine, involving
addition of the enolate of 1-acetylindole 2 to 3-acetyl-
2-fluoropyridinium salt 3, cyclization of the resultant
1,4-dihydropyridine, elaboration of the (E)-ethylidene sub-
stituent and closure of the C ring by Pummerer reaction, is
reported.
followed by Pd0 catalyzed reduction with Bu3SnH.13 Following
this protocol 6 was obtained in 45% overall yield from 5.
MCPBA oxidation of tetracyclic sulfide 6 gave the corre-
sponding sulfoxide (mixture of stereoisomers), which smoothly
underwent Pummerer rearrangement with TFAA in CH2Cl2 in
the presence of 2,6-di(tert-butyl)pyridine at room tempera-
ture.14 When the presumed acyloxy sulfide intermediate was
refluxed in CH2Cl2 the desired pentacyclic sulfide 7 (a single
diastereomer, undetermined configuration at C-6) was obtained
in 71% overall yield from 6.
Finally, desulfurization of 7 with Bu3SnH–AIBN gave the
desired pentacyclic dilactam 1 in 72% yield. The 1H NMR data
of 1 are in agreement with those previously reported.5,15 Taking
into account the previous work by Winterfeldt,5 the synthesis of
1 represents a formal total synthesis of (±)-akagerine.
Financial support from the DGICYT, Spain (project PB94-
0214) is gratefully acknowledged. Thanks are also due to the
Akagerine is a tetracyclic indole alkaloid isolated in 1975 from
Strychnos usambarensis1 and later from several Strychnos
species.2 This Corynanthean3 alkaloid has a peculiar skeleton
lacking the characteristic piperidine (D) ring and containing an
additional link between N-1 and C-17 (biogenetic numbering);4
consequently, it incorporates a perhydroazepine ring fused to a
tetrahydro-b-carboline unit. Akagerine has received little
attention from the synthetic standpoint: only one total synthesis
in the racemic series via dilactam 15 (Scheme 1) and one
enantioselective synthesis of (2)-akagerine6 through a com-
pletely different route have been reported to date.
We present here a short, stereoselective route to pentacyclic
dilactam 1. Our approach takes advantage of our previously
developed methodology for the synthesis of bridged indole
alkaloids, based on the addition of indole-containing enolates to
N-alkyl-3-acylpyridinium salts, with subsequent acid-promoted
cyclization of the resultant 1,4-dihydropyridine.7 Taking into
account the easy hydrolysis of the C–F bond in 2-fluoropyr-
idines,8 we thought that the use of a pyridinium salt bearing a
fluorine atom at the 2-position in the above two-step sequence
would lead to a bridged tetracyclic intermediate embodying the
required 2-piperidone moiety present in 1. On the other hand,
the closure of the C ring would be effected by electrophilic
cyclization of a thionium ion generated by Pummerer rearrange-
ment,9 taking advantage of the functionalized two-carbon
substituent present at the piperidone nitrogen.
N
SPh
O
+
2
i
N
N
SPh
F
TfO–
O
+
N
F
O
ii
4
3
O
SPh
SPh
The synthetic sequence is outlined in Scheme 2. Thus,
reaction of the enolate derived from 1-acetylindole 2 with
3-acetyl-2-fluoropyridinium salt 3 gave (25%) 1,4-dihydropyr-
idine 4,10 which underwent cyclization (58% yield) upon the
indole 2-position with concomitant cleavage of the C–F bond by
treatment with TsOH in the presence of LiI.11 The spectroscopic
data of the resulting tetracyclic lactam 512 clearly showed that
the acetyl carbonyl group was in an enolized form, presumably
with a Z double bond configuration.
H
H
N
N
O
O
N
N
iii,iv
O
O
OH
H
H
5
6
The elaboration of the C-20 (E)-ethylidene double bond was
effected in a stereoselective fashion by conversion of the
1-hydroxyethylidene group of 5 into the corresponding triflate,
v,vi
SPh
H
H
N
N
O
O
N
N
vii
9
A
12
6
O
O
8
7
2
10
11
5
H
H
C
B
N
4
H
H
N
4
N
Me
21
1
O
ref. 5
N
7
13
3
D
21
17
17 E
14 CHO
Scheme 2 Reagents and conditions: i, LDA, THF, 230 °C, 1.5 h; ii, C6H6,
TsOH, MeOH, LiI, room temp., 2 h; iii, Tf2O, 1,8-bis(dimethylamino)na-
phthalene, 230 to 210 °C, 1 h; iv, Bu3SnH, Pd(Ph3P)4, LiCl, THF, reflux,
1 h; v, MCPBA, CH2Cl2, 270 °C, 30 min; vi, TFAA, 2,6-di(tert-
butyl)pyridine, CH2Cl2, room temp., 30 min, then reflux, 1.5 h; vii,
Bu3SnH, AIBN, benzene, reflux, 1 h.
HO
O
20
16
15
19
18
H
H
Akagerine
1
Scheme 1
Chem. Commun., 1998, 2639–2640
2639

10 All yields are from material purified by column chromatography.
Satisfactory spectral, analytical and/or HRMS data were obtained for all
new compounds.
‘Comissionat per a Universitat i Recerca’ (Generalitat de
Catalunya) for Grant 1997SGR0018.
11 M.-L. Bennasar, J.-M. Jiménez, B. A. Sufi and J. Bosch, Tetrahedron
Lett., 1996, 37, 7653.
Notes and references
12 Selected data for 5: dH(300 MHz, CDCl3) 2.09 (s, 3H, 18-H), 2.32 (dm,
J 14, 1H, 14-H), 2.44 (m, 1H, 14-H), 2.81 (m, 1H, 5-H), 2.96 (br d, J
12.8, 1H, 16-H), 3.15 (m, 4H, 6-H, 15-H, 16-H), 3.60 (m, 1H, 5-H), 4.80
(d, J 5.1, 1H, 3-H), 6.16 (s, 1H, 7-H), 7.26–7.33 (m, 7H, Ar), 7.42 (d, J
7.6, 1H, 9-H), 8.13 (d, J 8.2, 1H, 12-H); dC(75 MHz, CDCl3) 18.4 (C-
18), 29.3 (C-15), 30.7 (C-6), 32.3 (C-14), 44.4 (C-5), 47.7 (C-16), 56.9
(C-3), 96.7 (C-20), 112.5 (C-7), 115.5 (C-12), 120.6 (C-9), 123.7 (C-
10), 125.8 (C-11), 126.3 (Ph), 129.2 (Ph), 129.5 (C-8), 135.0 (Ph), 135.2
(C-2), 138.4 (C-13), 168.9 (C-19), 171.7, 172.7 (C-17, C-21).
13 K. Ritter, Synthesis, 1993, 735.
14 K. Cardwell, B. Hewitt, M. Ladlow and P. Magnus, J. Am. Chem. Soc.,
1988, 110, 2242.
15 Selected data for 1: dC(75 MHz, CDCl3) 14.3 (C-18), 20.0 (C-6), 27.6
(C-15), 27.3 (C-14), 42.4 (C-5), 47.0 (C-16), 51.9 (C-3), 115.2 (C-12),
117.8 (C-9), 120.1 (C-7), 123.9 (C-10), 125.2 (C-11), 132.6 (C-20),
135.8 (C-2), 136.8 (C-13), 138.1 (C-19), 166.1 (C-21), 172.1 (C-17).
1 L. Angenot, O. Dideberg and L. Dupont, Tetrahedron Lett., 1975,
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Synthesis, 1997, 1353 and references cited therein.
Communication 8/07868H
2640
Chem. Commun., 1998, 2639–2640