Total synthesis of the Strychnos alkaloids (±)-akuammicine and (±)-norfluorocurarine from 3a-(o-nitrophenyl)hexahydroindol-4-ones by nickel(0)-promoted double cyclization

Full text of DOI:10.1021/jo960588l

4194
J . Org. Chem. 1996, 61, 4194-4195
Sch em e 1a
Tota l Syn th esis of th e Str ych n os Alk a loid s
(()-Ak u a m m icin e a n d
(()-Nor flu or ocu r a r in e fr om
3a -(o-Nitr op h en yl)h exa h yd r oin d ol-4-on es
by Nick el(0)-P r om oted Dou ble Cycliza tion
Daniel Sole´, J osep Bonjoch,* and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, 08028 Barcelona, Spain
Received April 3, 1996
One of the most flexible approaches for the synthesis
of Strychnos alkaloids1 consists of the use of nonindolic
starting materials, with elaboration of the indole moiety
in the last synthetic steps from azapolycyclic intermedi-
ates with the appropriate functionality and stereochem-
istry. Efforts in this direction have culminated in the
total synthesis of several pentacyclic Strychnos alka-
loids2,3 and in the first, and so far only, enantioselective
total synthesis of Wieland-Gumlich aldehyde and strych-
nine.4 In this context, we have recently reported the use
of cis-3a-(o-nitrophenyl)hexahydroindol-4-ones as build-
ing blocks for assembling the pentacyclic ABCDE ring
system of Strychnos alkaloids.5 Treatment of vinyl halide
2 with nickel-bis(cyclooctadiene) [Ni(COD)2]6 in the
presence of lithium cyanide brought about both the
closure of the piperidine ring (bond formed C15-C20)7 and
the reductive cyclization of the R-(o-nitrophenyl) ketone
moiety to afford (40%) the norcuran type pentacycle (()-
dehydrotubifoline (3) in a single synthetic step.5
The synthesis of Strychnos alkaloids of the curan type
requires the introduction of the oxidized one-carbon
substituent (C-17) linked at C-16 in these alkaloids.
Initially, this transformation was accomplished from the
pentacyclic indolenine 3. Thus, treatment of 3 with
methyl chloroformate in the presence of NaH gave (36%)8
the N-methoxycarbonyl derivative 4, which was then
photoisomerized (30%) to (()-akuammicine (pseudo-
akuammicine)9 upon irradiation with a low-pressure
mercury lamp.10 Akuammicine was identified by com-
parison of its 1H NMR (300 MHz) spectral data with those
reported for the natural product.11 The Rf values of our
synthetic akuammicine in several solvent mixtures were
also coincident with those of an authentic sample of the
alkaloid12 (Scheme 1).
a
Key: (i) (Z)-BrCH2CIdCHCH3, anhyd K2CO3, CH3CN, rt, 3h,
70%; (ii) Ni(COD)2 (6.6 equiv), Et3N, LiCN (10 equiv), 2.5:1
CH3CN-DMF, rt, 2.5 h, 40%; (iii) ClCOOMe, NaH, DME, 60 °C,
4 h, 36%; (iv) hν, CH3OH, 30%; (v) Ni(COD)2 (6.6 equiv), Et3N,
LiCN (10 equiv), 2.5:1 CH3CN-DMF, rt, 2.5 h, then (CH3)2-
N+dCHCl Cl- (20 equiv), rt, 2 h, 15%; (vi) hν, CH3OH, 15%.
A more straightforward method for the introduction
of C-17 was the treatment of vinyl iodide 2 with Ni-
(COD)2/LiCN, followed by trapping of the resulting
intermediate with (chloromethylene)dimethyliminium
chloride in a one-pot reaction. Under these conditions,
the N-formyl derivative 5 was directly obtained in 15%
yield from 2. Probably, formylation occurs from a met-
alloenamine intermediate because dehydrotubifoline (3)
was recovered unchanged after treatment with the above
formylating agent (DMF, 80 °C, 15 h).13
(1) For recent reviews, see: (a) Sapi, J .; Massiot, G. Monoterpenoid
Indole Alkaloids; Saxton, J . E., Ed. In The Chemistry of Heterocyclic
Compounds; Taylor, E. C., Ed.; Wiley: New York, 1994; Suppl. to Vol.
25, Part 4, pp 279-355. (b) Bosch, J .; Bonjoch, J .; Amat, M. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1996; Vol.
48, pp 75-189.
Photoisomerization14 of the N-formyl derivative 5 gave
(()-norfluorocurarine (vinervidine) in 15% yield,15 the
major product (69%) formed in this process being the
(2) Bonjoch, J .; Sole´, D.; Bosch, J . J . Am. Chem. Soc. 1993, 115,
2064-2065.
(3) Angle, S. R.; Fevig, J . M.; Knight, S. D.; Marquis, R. W., J r.;
Overman, L. E. J . Am. Chem. Soc. 1993, 115, 3966-3977.
(4) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J . Am. Chem. Soc.
1995, 117, 5776-5788.
(10) For the use of this photoisomerization in the synthesis of
Strychnos alkaloids, see: (a) Amat, M.; Linares, A.; Bosch, J . J . Org.
Chem. 1990, 55, 6299-6312. (b) Gra`cia, J .; Casamitjana, N.; Bonjoch,
J .; Bosch, J . J . Org. Chem. 1994, 59, 3939-3951. For the use of this
process in the construction of the anilinoacrylate moiety present in
other groups of indole alkaloids, see: (c) Overman, L. E.; Sworin, M.;
Burk, R. M. J . Org. Chem. 1983, 48, 2685-2690. (d) Wenkert, E.;
Porter, B.; Simmons, D. P. J . Org. Chem. 1984, 49, 3733-3742.
(11) Hu, W.-L.; Zhu, J .-P.; Hesse, M. Planta Med. 1989, 55, 463-
466. See also ref 9b.
(5) Bonjoch, J .; Sole´, D.; Bosch, J . J . Am. Chem. Soc. 1995, 117,
11017-11018.
(6) For the use of Ni(COD)2 in cyclizations of vinyl halides with
alkenes, see: Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J . M.; Delgado,
A. J . Am. Chem. Soc. 1994, 116, 12133-12134.
(7) The biogenetic numbering and ring labeling is used throughout
this paper: Le Men, J .; Taylor, W. I. Experientia 1965, 21, 508-510.
(8) All yields are after purification by chromatography. New com-
pounds were characterized by IR, 1H NMR, 13C NMR, and/or mi-
croanalysis.
(12) We are indebted to Professor Georges Massiot (University of
Reims) for providing us with an authentic sample of natural akuam-
micine.
(9) (a) For the isolation of (()-akuammicine, see: Edwards, P. N.;
Smith, G. F. Proc. Chem. Soc. (London) 1960, 215. (b) For previous
syntheses of this racemic alkaloid, see: Kuehne, M. E.; Xu, F.; Brook,
C. S. J . Org. Chem. 1994, 59, 7803-7806. See also ref 3.
(13) Formylation (POCl3, DMF, 50-60 °C) of dehydrotubifoline 3
to the N-formyl derivative 5 has been previously reported (no yield
indicated): see ref 3.
(14) Lenz, G. R. Synthesis 1978, 489-518.
S0022-3263(96)00588-9 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 13, 1996 4195
Sch em e 2a
[vinyl halide/alkene-R-(o-nitrophenyl) ketone] but also
an alkene isomerization20 to the natural E configuration
for the ethylidene substituent21 occurs in a single syn-
thetic step in more than acceptable yield (53%). The
formation of nitrone 8, which was identical to that formed
from 2 when the cyclization was carried out in the
absence of lithium cyanide,5 further illustrates the effect
of LiCN in modulating the Ni(COD)2-promoted reductive
cyclization of R-(o-nitrophenyl) ketones either to the
nitrone or the imine (indolenine) functionality. Interest-
ingly, a further treatment of nitrone 8 with Ni(COD)2 in
the presence of LiCN afforded the pentacyclic indoline 9
(19,20-didehydrotubifolidine) in 40% yield.22
In conclusion, the Ni(COD)2-promoted double cycliza-
tion of 3a-(o-nitrophenyl)hexahydroindol-4-ones consti-
tutes a straightforward and flexible method for assem-
bling the pentacyclic ABCDE ring system of Strychnos
alkaloids that may be applicable to the synthesis of the
most complex alkaloids of this group.
a
Key: (i) (E)-BrCH2CIdCHCH3, anhyd K2CO3, CH3CN, rt, 3h,
60%; (ii) Ni(COD)2 (6.6 equiv), Et3N, LiCN (10 equiv), 2.5:1
CH3CN-DMF, rt, 2.5 h, then (CH3)2N+dCHCl Cl- (20 equiv), rt,
2 h, 20%; (iii) Ni(COD)2 (6.6 equiv), Et3N, CH3CN, rt, 2.5 h, 53%;
(iv) Ni(COD)2 (4 equiv), Et3N, LiCN (8 equiv), 3.5:1 CH3CN-DMF,
rt, 2.5 h, 40%.
Ack n ow led gm en t. This work was supported by the
DGICYT, Spain (projects PB94-0214 and PB94-0858).
Thanks are also due to the Comissionat per a Univer-
sitat i Recerca (Generalitat de Catalunya) for Grant
SGR95-00428.
1
deformylated indolenine 3. The H NMR spectrum (300
MHz) of our synthetic (()-norfluorocurarine was identical
to that reported for the alkaloid.16
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of all new compounds and copies of
their 1H and 13C NMR spectra (18 pages).
The potential and flexibility of this methodology for the
construction of the pentacyclic curan skeleton was evi-
dent when the above one-pot treatment [Ni(COD)2/LiCN/
Me2N+dCHCl Cl-] was applied to the (E)-vinyl iodide 6
to give the pentacyclic N-formylenamine 7 in 20% yield
(Scheme 2). The constitution and relative configuration
J O960588L
(17) Compound 7: IR (film) 1685, 1656, 1462, and 1385 cm-1 1H
;
NMR (acetone-d6, 300 MHz) 1.43 (dm, 1H, J ) 11.8 Hz, H-14), 1.64
(d, 3H, J ) 7.7 Hz, H-18), 1.72 (ddd, 1H, J ) 12.8, 6.9, 5.9 Hz, H-6),
2.12 (m, 1H, H-14), 2.75 (dt, 1H, J ) 10.7, 6.6 Hz, H-6), 2.84-3.04 (m,
1H, H-5), 3.02 (dt, 1H, J ) 11.2, 7 Hz, H-5), 3.13 (m, 1H, H-15), 3.18
(d, 1H, J ) 14.6 Hz, H-21), 3.63 (d, 1H, J ) 14.6 Hz, H-21), 4.03 (m,
1H, H-3), 5.49 (qd, 1H, J ) 6.8, 1.2 Hz, H-19), 6.07 (dm, 2/3H, J ) 6
Hz, H-16), 6.73 (broad, 1/3H, H-16), 7.18 (td, 1H, J ) 7.5, 1.1 Hz, H-10),
7.28 (td, 1H, J ) 7.7, 1.4 Hz, H-11), 7.39 (d, 1H, J ) 7.7 Hz, H-9), 7.50
and 8.06 (2 broad, 1H, H-12), 8.92 and 9.26 (2 broad, 1H, H-17); 13C
NMR (acetone-d6, 75 MHz, major rotamer) 13.0 (C-18), 29.1 (C-14),
36.2 (C-14), 41.8 (C-6), 46.7 (C-21), 53.4 (C-5), 54.2 (C-7), 59.7 (C-3),
114.4 (C-16), 116.3 (C-12), 120.3 (C-9), 121.4 (C-19), 125.7 (C-10), 128.2
(C-11), 137.0 (C-20), 141.3 (C-13), 146.2 (C-2), 157.8 (C-17); 1H NMR
(CDCl3, 500 MHz) 1.50 (d, 1H, J ) 8 Hz, H-14), 1.65 (d, 3H, J ) 7 Hz,
H-18), 1.96 (broad s, 1H, H-6), 2.21 (dt, 1H, J ) 13.5, 3 Hz, H-14),
2.30 (broad s, 1H, H-6), 2.83 (broad s, 1H, H-5), 3.25 (broad s, 1H,
H-15), 3.30-3.50 (m, 2H, H-5 and H-21), 3.75 (d, 1H, J ) 15 Hz, H-21),
4.35 and 4.53 (2 broad s, 1H, H-3), 5.63 and 5.74 (2 broad s, 1H, H-19),
5.96 and 6.88 (2 broad s, 1H, H-16), 7.15 (t, 1H, J ) 7.5 Hz, H-10),
7.26 (td, 1H, J ) 7.5, 1 Hz, H-11), 7.34 (m, 1H, H-9), 7.30 and 8,07 (2
broad s, 1H, H-12), 8.83 and 9.09 (2 broad s, 1H, H-17); 13C NMR
(CDCl3, 75 MHz, major rotamer) 13.1 (C-18), 28.1 (C-14), 34.2 (C-15),
40.4 (C-6), 46.0 (C-21), 52.6 (C-5), 53.3 (C-7), 58.9 (C-3), 114.1 (C-16),
116.2 (C-12), 120.4 (C-9), 125.3 (C-10 and C-19), 128.0 (C-11), 133.5
(C-8), 135.0 (C-20), 139.9 (C-13), 145.1(C-2), 156.7 (C-17); HRMS Calcd
for C19H20N2O 292.1582, found 292.1577.
of 7 was unambiguously established from its H and 13C
1
NMR data,17 with the aid of 2D-NMR experiments and
ROESY. These data are clearly different from those
reported for bharhingine, an alkaloid isolated from
Rhazya stricta,18 for which the structure 7 had been
proposed. So, a revised structure for the alkaloid is
needed.19
However, when vinyl iodide 6 was treated with Ni-
(COD)2 under the conditions satisfactorily used for the
cyclization of 2 to 3 [Ni(COD)2 (6.6 equiv), Et3N, LiCN
(10 equiv), 2.5:1 CH3CN-DMF, rt, 2.5 h], a complex
mixture was obtained instead of the expected pentacyclic
indolenine. The crude reaction mixture (TLC) showed
the clean formation of a new product, but after the
workup a complex mixture was formed. In contrast,
indicating that the above result is a consequence of the
instability of the pentacyclic indolenine rather than to a
failure of the cyclization, when the Ni(COD)2-promoted
double cyclization of 6 was performed in the absence of
LiCN, the pentacyclic nitrone 8 was isolated in 53% yield.
Under these conditions, not only the double cyclization
(18) Atta-ur-Rahman; Habib-ur-Rehman; Ahmad, Y.; Fatima, K.;
Badar, Y. Planta Med. 1987, 53, 256-259.
(19) We thank Professor Atta-ur-Rahman for sending us detailed
spectroscopic data of bharhingine.
(15) (a) For the isolation of (()-norfluorocurarine, see: Rakhimov,
D. A.; Malikov, V. M.; Yusunov, C. Y. Khim. Prir. Soedin 1969, 5, 461-
462; Chem. Abstr. 1970, 72, 67165n. (b) For the only previous synthesis
of this racemic alkaloid, see: Crawley, G. C.; Harley-Mason J . J . Chem.
Soc., Chem. Commun. 1971, 685-686.
(16) Clivio, P.; Richard, B.; Deverre, J .-R.; Sevenet, T.; Zeches, M.;
Le Men-Oliver, L. Phytochemistry 1991, 30, 3785-3792.
(20) For alkene isomerizations in intramolecular palladium-cata-
lyzed vinylations of olefins, see: (a) Owezarczyk, Z.; Lamaty, F.;
Vawter, E. J .; Negishi, E. J . Am. Chem. Soc. 1992, 114, 10091-10092.
(b) Rawal, V. H.; Michoud, C. J . Org. Chem. 1993, 58, 5583-5584.
(21) Bosch, J .; Bennasar, M. L. Heterocycles 1983, 20, 2471-2511.
(22) For a previous synthesis of 19,20-didehydrotubifolidine (9),
see: Smith, G. F.; Wro´bel, J . T. J . Chem. Soc. 1960, 792-795.