First Total Synthesis of (±)-Melinonine-E and (i)-Strychnoxanthine Using a Radical Cyclization Process as the Core Ring-Forming Step

Article abstract of DOI:10.1021/jo971148c

The first total synthesis of (±)-melinonine-E and (±)-strychnoxanthine is described. The key common step for the synthesis of both alkaloids is the elaboration of the 2-azabicyclo[3.3.1]nonane nucleus (D and E rings) by a radical carbocyclization, using an α-carbamoyldichloromethyl radical as a donor. The closure of the C ring by a Bischler-Napieralski cyclization, followed by an epimerization process to gain the axial nitrile 20, and appropriate reduction transformations afforded pentacyclic alcohol 23. This alcohol was converted into either (±)-melinonine-E (1) or (±)-strychnoxanthine (2) by means of a palladium black dehydrogenation of the C ring or a SeO₂ oxidation of the corresponding acetate 25, respectively.

Full text of DOI:10.1021/jo971148c

968
J . Org. Chem. 1998, 63, 968-976
F ir st Tota l Syn th esis of (()-Melin on in e-E a n d
(()-Str ych n oxa n th in e Usin g a Ra d ica l Cycliza tion P r ocess a s th e
Cor e Rin g-F or m in g Step
J osefina Quirante, Carmen Escolano, Alma Merino, and J osep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Farmacy, University of Barcelona, 08028-Barcelona, Spain
Received J une 24, 1997
The first total synthesis of (()-melinonine-E and (()-strychnoxanthine is described. The key
common step for the synthesis of both alkaloids is the elaboration of the 2-azabicyclo[3.3.1]nonane
nucleus (D and E rings) by a radical carbocyclization, using an R-carbamoyldichloromethyl radical
as a donor. The closure of the C ring by a Bischler-Napieralski cyclization, followed by an
epimerization process to gain the axial nitrile 20, and appropriate reduction transformations afforded
pentacyclic alcohol 23. This alcohol was converted into either (()-melinonine-E (1) or (()-
strychnoxanthine (2) by means of a palladium black dehydrogenation of the C ring or a SeO2
oxidation of the corresponding acetate 25, respectively.
In tr od u ction
In this paper, we describe the first synthesis of
alkaloids 1 and 2, using a common precursor. The
strategy we have developed for assembling the pentacy-
clic ring system of these alkaloids involves the construc-
tion of an appropriately substituted and functionalized
2-azabicyclo[3.3.1]nonane II, incorporating rings D and
E, and the final closure of the C ring by a Bischler-
Napieralski cyclization.9 The required 2-azabicyclo[3.3.1]-
nonane10 II was prepared from radical precursor I, which
incorporates all carbon atoms of targets 1 and 2, in a
process involving the closure of the piperidine ring by
attack of an R-carbamoylmethyl radical upon an R,â-
unsaturated nitrile moiety11 (Scheme 1). This process
affords a δ-lactam unit that enables the next ring closure
to achieve pentacycle III.
Melinonine-E (1) and strychnoxanthine (2) are two
quaternary alkaloids with a pentacyclic ring system
unprecedented among natural or synthetic products,
consisting of a â-carbolinium moiety fused to a 2-aza-
bicyclo[3.3.1]nonane nucleus.1 Furthermore, these two
alkaloids are rare examples of the relatively small
collection of biogenetically and theoretically interesting
zwitterionic alkaloids with a core of indolo[2,3-a]quino-
lizidine.2 The isolation of melinonine-E from the bark
of Strychnos melinoniana was reported for the first time
in 1957,3 but its structural elucidation was not carried
out until 1984.4 Strychnoxanthine is the 14-oxo deriva-
tive of melinonine-E isolated from the root bark of
Strychnos gossweileri.5 Biogenetically, it can be envis-
aged that both alkaloids might arise from the tetracyclic
bases of the antirhine group,6 which have an unusual
â-configuration at C-15, by closure of the E ring (bond
formed C-17/C-18)7 and aromatization of the C ring.
Consequently, these alkaloids can be classified as a new
group of the Vallesiachotaman class of monoterpenoid
indole alkaloids characterized by both the presence of a
bond between N-4 and C-17 and the unit C-2/C-3/C-14.8
Resu lts a n d Discu ssion
P r elim in a r y Stu d ies. Our initial attention was
focused on the preparation of acetamides 5a ,b (Scheme
2). According to our plan, they should be converted into
cyclohexene derivatives, precursors of type I radicals, in
which an additional carbon (C-21 atom in the target
alkaloids) has been incorporated. Model studies using
an N-benzyl derivative analogue of I, such as cyclohex-
enecarbonitrile 6, showed that monohaloacetamides are
incapable of carrying out the cyclization process to
(1) For a preliminary report of part of this work, see: Quirante, J .;
Escolano, C.; Bosch, J .; Bonjoch, J . J . Chem. Soc., Chem. Commun.
1995, 2141-2142.
(2) Gribble, G. W. Synthesis of Zwitterionic Indolo[2,3-a]quinolizine
Alkaloids. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1988; Vol. 1, pp 123-162.
(3) Ba¨chli, E.; Vamvacas, C.; Schmid, H.; Karrer, P. Helv. Chim.
Acta 1957, 40, 1167-1187. A yohimbine-type structure had been
proposed earlier but not verified later by synthesis: Albright, J . D.;
Mitscher, L. A.; Goldman, L. J . Heterocycl. Chem. 1970, 7, 623-627.
(4) Borris, R. P.; Guggisberg, A.; Hesse, M. Helv. Chim. Acta 1984,
67, 455-460.
(9) For some recent syntheses of indole alkaloids involving
a
Bischler-Napieralski process in the elaboration of the tetrahydro-â-
carboline unit, see: (a) Lo¨gers, M.; Overman, L. E.; Welmaker, G. S.
J . Am. Chem. Soc. 1995, 117, 9139-9150. (b) Aube´, J .; Ghosh, S.;
Tanol, M. J . Am. Chem. Soc. 1994, 116, 9009-9018. (c) Hanessian,
S.; Faucher, A.-M. J . Org. Chem. 1991, 56, 2947-2949.
(10) For previous synthetic approaches to 2-azabicyclo[3.3.1]nonanes
starting from carbocyclic compounds involving the formation of C-4/
C-5 bond in the ring closure, see: (a) Alkylation of an enolate, Boger,
D. L.; Patel, M.; Mullican, M. D. Tetrahedron Lett. 1982, 23, 4559-
4562. (b) Aldol condensation, Teuber, H.-J .; Tsaklakidis, C.; Bats, J .
W. Liebigs Ann. Chem. 1990, 781-787. (c) Pummerer rearrangement
followed by cationic cyclization, Magnus, P.; Coldham, I. J . Am. Chem.
Soc. 1991, 113, 672-673. (d) Heck reaction, Rawal, V. H.; Michoud,
C. Tetrahedron Lett. 1991, 32, 1695-1698.
(5) Coune, C.; Tavernier, D.; Caprasse, M.; Angenot, L. Planta Med.
1984, 50, 93-95.
(6) Lounasmaa, M.; Tolvanen, A. The Corynantheine-Heteroyohim-
bine Group. In Monoterpenoid Indole Alkaloids, supplement to part
4; Saxton, J . E., Ed.; In The Chemistry of Heterocyclic Compounds;
Taylor, E. C., Ed.; Wiley: Chichester, 1994; Vol. 25, pp 57-159.
(7) Biogenetic numbering is used throughout this paper for tetra-
cyclic and pentacyclic compounds. Le Men, J .; Taylor, W. I. Experientia
1965, 21, 508-510.
(8) Kisaku¨rek, M. V.; Leeuwenberg, A. J . M.; Hesse, M. In Alka-
loids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1983; pp 211-376.
(11) Before our work in this area,1,12 there was only one precedent
for the synthesis of six-membered nitrogen heterocycles from R-car-
bamoyl radicals:13 Hirai, Y.; Hagiwara, A.; Terada, T.; Yamazaki, T.
Chem. Lett. 1987, 2417-2418. See also: Stork, G.; Mah, R. Hetero-
cycles 1989, 28, 723-727.
S0022-3263(97)01148-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/27/1998

Total Synthesis of Melinonine-E and Strychnoxanthine
J . Org. Chem., Vol. 63, No. 4, 1998 969
Sch em e 1. Syn th etic Str a tegy
Sch em e 3
azabicyclo nucleus through an ionic cyclization (Scheme
3). Nevertheless, treatment of 8 with K-t-BuO furnished
azabicyclic derivative 10 in low yield,16,17 and its ap-
plicability to the synthesis of melinonine-E was dis-
carded.
Syn th esis of 2-Aza bicyclo[3.3.1]n on a n e II by a
Ra d ica l Cycliza tion P r ocess. At this point we turned
our attention to trichloroacetamide 5a , which was pre-
pared in good yield by reductive amination of tryptamine
and 1,4-cyclohexanedione monoethylene acetal in the
presence of sodium triacetoxyborohydride,18 followed by
trichloroacetylation and further chemoselective hydroly-
sis of 4a . The existence of two rotational isomers around
the acyl-nitrogen bond in trichloroacetamides 4a and 5a
Sch em e 2
1
caused line broadening of some peaks in the H NMR,
but two separate signals in the 13C NMR specta were not
observed, thus indicating that the coalescence tempera-
ture is close to that of the registration of NMR spectra.19
For the purpose of the one-carbon homologation (C-
21), ketone 5a was converted to cyanohydrin 12 by
treatment of 5 with trimethylsilyl cyanide and ZnI2,
followed by hydrolysis of O-silylcyanohydrin intermediate
11.20 The reaction was stereoselective, only the trans
isomer being formed, whereas when acetone cyanohydrin
and base were used, a mixture of cis-trans isomers of
12 was isolated. R,â-Unsaturated nitrile 13, the precursor
of radical I, was obtained by dehydration of 12 at room
temperature or in a more straightforward manner by
treatment of the intermediate 11 with POCl3 at benzene
reflux temperature21 (Scheme 4).
Our synthetic approach to azabicyclo II implies an
intramolecular alkylation of the suitably 4-substituted
cyclohexenecarbonitrile 13 by means of a reductive
radical cyclization, using an R-carbamoyldichloromethyl
radical (I, R ) Cl) as a promoter.22 When compound 13
was treated with tris(trimethylsilyl)silane (TMS3SiH)23
(3.5 equiv), as the radical mediator, and 0.2 equiv of
AIBN in refluxing benzene (0.12 M), the expected cy-
clization to the 2-azabicyclo[3.3.1]nonane ring system
took place to give a mixture of 16 (44%) and its C-14
chloro- and dichloro-substituted derivatives 15 (14%) and
14 (11%), respectively. From the synthetic standpoint,
the best results were achieved when the above crude
bridged DE ring systems,12 and consequently, compound
5b was discarded for this purpose. An experiment on
iodoacetamide 6, using Bu3SnD as a radical process
promoter, resulted in the isolation of deuterated aceta-
mide 7,14 showing that the inefficiency in the cyclization
is due to a direct reduction of the carbamoylmethyl
radical, not to a 1,5-hydrogen atom transfer followed by
reduction.15
Next, we examined the possibility that chloroacetamide
5b, after protection of indole as its N-Boc derivative 8,
might prove useful in gaining access to the bridged
(12) Quirante, J .; Escolano, C.; Massot, M.; Bonjoch, J . Tetrahedron
1997, 53, 1391-1402.
(13) For some recent examples of synthesis of six-membered rings
using nitrogen-containing radicals, see: (a) Esch, P. M.; Hiemstra, H.;
de Boer, R. F.; Speckamp, W. N. Tetrahedron 1992, 48, 4659-4676.
(b) Martin, S. F.; Tso, H.-H. Heterocycles 1993, 35, 85-88. (c)
Beckwith, A. L. J .; J oseph, S. P.; Mayadunne, R. T. A. J . Org. Chem.
1993, 58, 4198-4199. (d) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi,
N.; Tokunaga, Y.; Fukumoto, K. J . Org. Chem. 1994, 59, 5317-5323.
(e) Lee, E.; Kang, T. S.; J oo, B. J .; Tae, J . S.; Li, K. S.; Chung, C. K.
Tetrahedron Lett. 1995, 36, 417-420. (f) Bowman, W. R.; Stephenson,
P. T.; Young, A. R. Tetrahedron Lett. 1995, 36, 5623-5626. (g) Khim,
S.-K.; Cederstrom, E.; Ferri, D. C.; Mariano, P. S. Tetrahedron 1996,
52, 3195-3222. (h) Sibi, M. P.; J i, J . J . Am. Chem. Soc. 1996, 118,
3063-3064.
(16) (a) An analogous cyclization in the decahydroisoquinolone series
proceeds with good yield,16b but in the bridged 2-azabicyclo[3.3.1]-
nonane series, a related intramolecular alkylation occurs in low yield.10a
(b) Sapi, J .; Dridi, S.; Laronze, J .; Sigaut, F.; Patigny, D.; Laronze,
J .-Y.; Le´vy, J . Tetrahedron 1996, 52, 8209-8222.
(17) All synthetic compounds are racemic. The schemes depict only
the enantiomer bearing the natural configuration at C-15.
(18) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849-3862.
(14) N-Benzyl-N-(4-cyano-3-cyclohexenyl)-2-deuterioethanamide (7)
was the only product isolated (62%) when iodoacetamide 6 (52 mg,
0.13 mmol) was treated with tributyltin deuteride (0.08 mL, 0.3 mmol)
and AIBN (4 mg, 0.026 mmol) in benzene (1 mL) at 80 °C for 8 h.
(19) The same behavior was observed in the other trichloroaceta-
mides (11-13) synthesized in this work. In contrast, chloroacetamides
4b and 5b showed by NMR two sets of signals corresponding to both
rotamers at this temperature. For the influence of steric factors on
the energy barrier to rotation about the C-N amide bonds, see:
J ohnson, R. A. J . Org. Chem. 1968, 33, 3627-3632.
(20) Gassman, P. G.; Talley, J . J . Org. Synth. 1981, 60, 14-18.
(21) Oda, M.; Yamamuro, A.; Watabe, T. Chem. Lett. 1979, 1427-
1430.
(15) For 1,5-hydrogen-transfer reactions, see: Curran, D. P.; Shen,
W. J . Am. Chem. Soc. 1993, 115, 6051-6059.

970 J . Org. Chem., Vol. 63, No. 4, 1998
Quirante et al.
Sch em e 4
The radical cyclization which allows the preparation
of the valuable intermediate 16 is stereoselective. The
relative configuration at C-20 in compound 16 (equatorial
1
cyano group) was deduced from its H NMR spectrum,
in which the multiplicity (qd, J ) 13.5, 4 Hz) of H-19ax
indicates the axial disposition for the proton at C-20. On
the other hand, the equatorial disposition of the chlorine
atom at C-14 in azabicyclo 15 was revealed by comparing
13C NMR chemical shifts of C-16 in compounds 14 and
15 (see Table 1), which shows the lack of compression at
C-16 in the monochloro derivative 15.25 The relative
configuration at C-20 in compounds 14-16 and at C-14
in 15 is the expected one, taking into account that
hydrogen abstraction by radicals in cyclic systems occurs
from the most accessible face.26
The above cyclization of trichloroacetamidocyclohexene
13 not only provides a new synthetic entry to the
2-azabiciclo[3.3.1]nonane ring system10,12 but also con-
stitutes one of the scarce examples of synthetically useful
6-exo-trig cyclization from 3-aza-6-heptenyl radicals.11,27
The success of the cyclization using trichloroacetamides
(i.e., 13) can be explained by the presence of bulky
substituents on the nitrogen, which prevent a restricted
rotation around the carbonyl group of the amide, and
three chloro atom substituents R to the carbonyl group,
which increase the stability of the radical intermediate.
These factors change the course of the reaction as
compared with the process that uses monohaloaceta-
mides, in which premature irreversible hydrogen ab-
straction from the stannane by the R-carbamoylmethyl
radical is the preferred pathway (see, for example, the
failure in cyclization of iodoacetamide 6). To gain more
knowledge, the radical cyclization of 13 was also carried
out using 1.1 equiv of tributyltin deuteride. Monodeu-
terated compound 17 and dideuterated monochloro de-
rivative 18 were isolated, and no uncyclized reduced
product was detected. These results indicate that the
cyclizing ability of trichloroacetamides to give six-
membered lactams does not lie in the three opportunities
of carbamoylmethyl radicals to cyclize but in the stability
that the two additional chlorine atoms confer to the
initially generated R-carbamoyldichloromethyl radical,28
whose lifetime is long enough to allow it to undergo
cyclization even upon a deactivated double bond.29
Syn th esis of (()-Melin on in e-E a n d (()-Str ych -
n oxa n th in e. With an efficient procedure for the elabo-
mixture, without isolation of components, was treated in
situ with Bu3SnH-AIBN, which brought about the
hydrogenolysis of the remaining C-Cl bonds and allowed
the isolation of lactam 16 in 64% overall yield. Attempts
to obtain the all-dechlorinated compound 16 using only
TMS3SiH were unsuccessful.24 On the other hand, when
the cyclization was conducted in the presence of 3.2 equiv
of Bu3SnH, the cyclized product 16 was obtained directly
but in lower yield (46%).
(22) (a) Radical cyclizations of trichloroacetamides leading to five-
membered lactams have been accomplished using ruthenium-22b or
copper-catalyzed22c processes, nickel-acetic acid,22d or tributyl-
stannane.22e In contrast, few processes of this type leading to six-
membered lactams have been reported so far.11 (b) Nagashima, H.;
Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe, M.; Tajima, T.; Itoh,
K. J . Org. Chem. 1992, 57, 1682-1689. (c) Nagashima, H.; Ozaki, N.;
Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J . Org. Chem. 1993, 58,
464-470. Seijas, J . A.; Va´zquez-Tato, M.-P.; Castedo, L.; Este´vez, R.
J .; OÄ nega, M.-G.; Ru´ız, M. Tetrahedron 1992, 48, 1637-1642. (d)
Boivin, J .; Yousfi, M.; Zard, S. Z. Tetrahedron Lett. 1994, 35, 5629-
5632. (e) Goodall, K.; Parsons, A. F. Tetrahedron 1996, 52, 6739-
6758.
(23) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
(24) For runs with long reaction times (6 h), adding AIBN every 2
h gave 16 (56%) and 15 (14%). Moreover, treatment of monochloro
derivative 15 with TTMSS (1.5 equiv) and AIBN (0.2 equiv) gave 48%
of reduced compound 16 and 36% of the starting material, whereas
the same process using Bu3SnH (1.1 equiv) and AIBN (0.2 equiv)
furnished exclusively 16 in 80% yield.
(25) For 13C NMR assignments of 2-azabicyclo[3.3.1]nonanes, see:
Casamitjana, N.; Bonjoch, J .; Gra`cia, J .; Bosch, J . Magn. Reson. Chem.
1992, 30, 183-185.
(26) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996. (b) Apeloig, Y.; Nakash,
M. J . Am. Chem. Soc. 1994, 116, 10781-10782. (c) Damm, W.; Giese,
B.; Hartung, J .; Hasskerl, T.; Houk, K. N.; Hu¨ter, O.; Zipse, H. J . Am.
Chem. Soc. 1992, 114, 4067-4079.
(27) For reviews about radical cyclization reactions, see: (a) Curran,
D. P. Radical cyclization reactions and sequential radical reactions.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, pp 779-831. (b) Giese, B.;
Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach,
F. Org. React. 1996, 48, 301-856.
(28) For radical stabilization energies, see: Bordwell, F. G.; Lynch,
T.-Y. J . Am. Chem. Soc. 1989, 111, 7558-7562.

Total Synthesis of Melinonine-E and Strychnoxanthine
Ta ble 1. 13C NMR Da ta (δ) of Tetr a - a n d P en ta cyclic Der iva tivesa -c
14 15 16 19 20 23 24 25 26
21f 22f
136.0 135.9 122.1 122.5 122.3 122.1 135.8 135.8 135.9 135.9 135.9 135.9 135.9 135.9 135.0 135.9 135.7 135.6
J . Org. Chem., Vol. 63, No. 4, 1998 971
carbon
1d,e
2d,e
10
27d,e
28d
29d
30d,e
C-2
C-3
C-5
C-6
131.9 127.7 168.1 163.5 165.8 169.7 49.1 49.1 49.6 49.1 50.1 49.4 49.9
132.5 134.7 47.8 48.6 48.5 47.7 51.5 51.2 51.3 51.5 51.6 51.7 51.5
116.5 121.9 23.6 22.9 23.2 23.3 22.9 22.8 22.9 22.9 22.9 23.0 22.9
49.4 132.0 127.4 127.6 127.8
51.7 133.5 134.5 134.5 134.8
23.0 117.0 122.1 122.1 122.0
C-7
C-8
C-9
142.4 139.5 113.0 112.3 112.9 112.0 108.5 108.3 108.1 108.1 108.2 108.4 108.2 108.3 142.3 139.6 139.6 139.5
121.5 120.6 127.4 127.0 127.3 127.1 127.1 127.0 127.1 127.1 127.3 127.3 127.3 127.3 121.3 120.5 120.5 120.5
123.8 124.7 118.7 118.5 118.6 118.2 118.0 117.9 117.8 117.8 117.9 117.9 118.0 117.9 123.9 124.7 124.7 124.7
122.4 124.1 119.4 119.6 119.6 118.8 119.4 119.3 119.1 119.1 119.2 119.2 119.3 119.2 122.9 124.1 124.1 124.1
132.0 134.5 121.9 122.2 121.9 121.5 121.4 121.1 121.0 121.0 121.0 121.1 121.1 121.1 132.5 134.5 134.5 134.5
114.5 114.7 111.2 111.3 111.3 111.2 110.8 110.6 110.7 110.7 110.7 110.6 110.6 110.6 113.9 114.7 114.7 114.6
146.7 147.6 136.2 136.3 136.2 136.1 136.0 135.9 136.4 136.4 135.9 136.9 136.8 136.8 145.2 147.5 147.5 147.5
C-10
C-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
C-21
33.0g 196.9 35.1 84.2 57.2 33.4 31.2 33.7 34.6 31.2 35.7 28.7 35.6
28.9
26.2
29.0
54.4
31.9
19.9
40.3
26.5 196.0 195.0 195.3
25.8
25.6
62.4
29.3
18.5
h
42.8 44.1 46.7 36.0 29.2 27.9 28.2 24.4 25.2 25.9 25.9 23.4
25.9 31.9 29.9 32.4 30.3 27.7 24.6 25.2 28.2 28.3 29.1 26.4
64.3 52.0 52.8 52.3 51.5 52.7 53.1 53.8 54.1 54.6 54.6 54.3
27.7 30.4 28.3 28.3 27.7 30.9 28.5 29.3 30.9 29.7 32.0 28.0
19.3 33.9 20.1 20.2 20.1 20.8 19.5 16.3 17.1 18.2 19.9 18.1
39.7 211.1 32.8 31.3 32.6 33.3 32.5 53.7 53.9 43.2 43.8 39.2
h
36.5
39.4
31.6
63.8
32.3
21.7
43.7
43.6
31.9
64.2
32.6
21.9
43.1
31.3 26.0
62.6 64.0
33.9 27.7
20.7 19.5
44.1 43.0
63.3
62.4
120.0 119.6 120.7 122.1 122.6 205.4 205.3 64.3 65.3 65.9i 66.5i 65.1 64.6i 66.8i 64.6
a
b
d
In CDCl3 (75.5 MHz). Biogenetic numbering is used in this table. c Assignments were aided by HMQC spectrum. In CD3OD.
e Assignments were aided by HMBC spectrum. f Registered from a mixture of equatorial and axial aldehydes (21 and 22) in a 7:3 ratio.
This signal appears as a triplet in the proton noise-decoupled 13C NMR spectrum due to a partial deuteration of the methylene at C-14
g
h
(see ref 4). The resonances for C-15 (δ 26.3 and 26.4) in 27 and C-20 (δ 43.1 and 43.2) in 1 appear as two lines, indicating the presence
of two rotamers about C-20/C-21 bond (see ref 4). Ac: δ 21.1 and 171.0 for 25 and 26; δ 20.8 and 172.6 for 28 and 29.
i
ration of the ABDE tetracyclic framework of the target
alkaloids, we proceeded to the closure of the C ring
(Scheme 4). Cyclization to the desired pentacyclic system
was achieved by the Bischler-Napieralski reaction.
Thus, treatment of lactam 16 with phosphorus oxychlo-
ride, followed by NaBH4 reduction, stereoselectively led
to the pentacyclic amine 19, which showed spectroscopic
data in agreement with both a 3-Hâ relative configura-
tion and a trans C/D ring conformation for the quinolizi-
dine system30 (δ 22.9 for C-6 and δ 3.95, dd, J ) 12, 4 Hz
for H-3). It is noteworthy that the cis relationship
between H-3 and H-15 implies a boat conformation for
the D ring. This feature was made evident by the 1H
NMR spectrum of 19, in which the vicinal coupling
between protons H-14eq and H-15eq (J ∼ 12 Hz) corre-
sponds to a dihedral angle near 0°.
At this point, three operations were required to com-
plete the synthesis: epimerization of the C-20 equatorial
cyano group to the axial position, adjustment of the
functionalization at C-21, and aromatization of the
â-carboline unit. The epimerization at C-20 was partially
accomplished by deprotonation of nitrile 19 with LDA,
followed by quenching of the resulting stabilized anion
with diluted hydrochloric acid at -78 °C.31 A mixture of
pentacyclic nitriles 19 and 20 (2:3 ratio), the latter with
the natural relative stereochemistry at C-20, was ob-
tained.32 It is worth mentioning that the major epimer
20 arises from the equatorial protonation of the exocyclic
R-cyano carbanion to leave an axial cyano substituent.33
Both isomers were separated by column chromatography,
and the wrong minor epimer 19 was reused. The relative
configuration at C-20 in nitriles 19 and 20 was estab-
lished from their 13C NMR data by considering the
existence or absence of γ-effects upon C-14, C-16, or
C-18.25
DIBALH reduction of nitrile 20, followed by hydrolysis
of the intermediate imine, afforded the corresponding
aldehyde 21 without appreciable epimerization.34 This
aldehyde was immediately reduced (NaBH4) to the
alcohol 23, which is stereochemically homogeneous.
Finally, treatment of 23 with palladium black and maleic
acid35 in boiling water for 20 h caused the dehydrogena-
tion of the C ring to give melinonine-E (1) in 63% yield.
The 1H and 13C NMR data of our synthetic (()-meli-
nonine-E chloride were shown to be virtually superim-
posable on those recorded for the natural product.4 The
Rf values of the corresponding picrates were also coinci-
dent.36
Strychnoxanthine (2) possesses a greater oxidation
level than melinonine-E (1), incorporating a ketone group
at C-14. Therefore, it was of interest to introduce this
functionality at the same time in which the aromatization
process takes place, using the pentacyclic alcohol 23 as
the precursor as above. For this purpose, after protection
of the hydroxyl group of 23, the acetate 25 was oxidized
with SeO2.37 In this manner, acetate 28 was obtained,
and after saponification, (()-strychnoxanthine (2) was
isolated. The IR, UV, 1H and 13C NMR, and Rf values of
(32) Attempts to induce the epimerization of nitrile 19 using LDA
and quenching with tert-butyl bromide or 2,6-di-tert-butyl-4-meth-
ylphenol, or using KHMDS and quenching with HCl (0.5 N), were less
fruitful.
(33) For protonation of cyclohexyl anions, see: Lu¨ning, U.; Baum-
gartner, H.; Manthey, C.; Meynhardt, B. J . Org. Chem. 1996, 61, 7922-
7926. See also: Klein, J . Tetrahedron 1974, 30, 3349-3353. Hoz, S.;
Azran, C.; Sella, A. J . Am. Chem. Soc. 1996, 118, 5456-5461.
(34) Aldehydes 21 and 22 (coming from nitrile 19) epimerized either
in CDCl3 solution or by column chromatography (SiO2) to a 3:7 mixture
of 21 and 22, respectively. The reduction of this mixture afforded
alcohols 23 and 24, which we could not separate.
(35) Fujii, T.; Ohba, M.; Ohashi, T. Tetrahedron 1993, 49, 1879-
1890.
(36) We thank Professor M. Hesse (Universita¨t Zu¨rich) for a sample
of natural melinonine-E (picrate form).
(37) Cain, M.; Campos, O.; Guzman, F.; Cook, J . M. J . Am. Chem.
Soc. 1983, 105, 907-913.
(29) It is noteworthy that dichloromethylcarbamoyl radicals, gener-
ally considered to have an electrophilic nature, undergo cyclization on
electron-poor double bonds with good yields. Recently, we have noted
that these radicals also undergo cyclization on simple alkenes and
alkenes with electron-donating groups: Quirante, J .; Escolano, C.;
Bonjoch, J . XVI Spanish Symposium on Organic Chemistry, Ciudad
Real, Spain, 1997.
(30) (a) Gribble, G. W.; Nelson, R. B.; J ohnson, J . L.; Levy, G. C. J .
Org. Chem. 1975, 40, 3720-3725. (b) Tourwe´, D.; Van Binst, G.
Heterocycles 1978, 9, 507-533. (c) Lounasmaa, M.; J okela, R.; Han-
hinen, P.; Miettinen, J .; Salo, J . Tetrahedron 1994, 50, 9207-9222 and
references therein.
(31) For a review on kinetic protonation of enols, enolates, and
analogues, see: Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-
268.

972 J . Org. Chem., Vol. 63, No. 4, 1998
Quirante et al.
H), 7.02 (d, J ) 2.5, 1 H), 7.10 (td, J ) 7, 1.5, 1 H), 7.19 (td, J
) 7, 1.5, 1 H), 7.34 (d, J ) 7.5, 1 H), 7.62 (dt, J ) 7.5, 1 H),
8.30 (br s, 1 H); 13C NMR 26.0 (t), 30.2 (t, 2C), 33.0 (t, 2C),
47.1 (t), 55.2 (d), 64.2 (t, 2C), 108.7 (s), 111.1 (d), 113.7 (s),
118.8 (d), 119.1 (d), 121.1 (d), 121.9 (d), 127.4 (s), 136.4 (s);
MS (EI) m/z 170 (100), 171, 144, 143, 141, 131, 130, 108, 99,
97, 56, 55. Anal. Calcd for C18H24N2O2: C, 72.00; H, 8.05; N,
9.33. Found: C, 72.23; H, 8.10; N, 9.35.
synthetic (()-2 proved to be virtually identical with those
obtained with a natural sample of strychnoxanthine.5,38
The NMR spectra data for alkaloids 1 and 2 have been
unambiguously assigned, aided by HMQC, HMBC, and
NOESY experiments.
On the other hand, in a parallel sequence of reactions,
the nitrile 19 was converted into (()-20-epimelinonine-E
(27) and (()-20-epistrychnoxanthine (30) (see the Ex-
perimental Section).
N-[4,4-(Eth ylen ed ioxy)cycloh exyl]-N-(tr ich lor oa cetyl)-
tr yp ta m in e (4a ). To a solution of 3 (9.20 g, 30.7 mmol) in
CH2Cl2 (45 mL) were added pyridine (2.60 mL, 32.2 mmol)
and dropwise trichloroacetyl chloride (5.3 mL, 47 mmol) in
CH2Cl2 (4.5 mL). The mixture was stirred at rt for 12 h and
then concentrated. The residue was dissolved in CH2Cl2 and
washed with aqueous HCl (1 N), saturated aqueous Na2CO3,
and brine. The organic phase was dried and concentrated, and
the residue was chromatographed (CH2Cl2) to give trichloro-
acetamide 4a (12.1 g, 88%) as a yellow solid: mp 163-165 °C
(CH2Cl2); IR (KBr) 3357, 1663, 1103; 1H NMR (200 MHz) 1.5-
2.1 (m, 8 H), 3.06 and 3.57 (2m, AA′BB′ system, 4 H), 3.95 (s,
4 H), 4.45 (m, 1 H), 7.03 (d, J ) 2, 1 H), 7.13 (td, J ) 7, 1.5, 1
H), 7.20 (td, J ) 7, 1.5, 1 H), 7.35 (dd, J ) 7, 1.5, 1 H), 7.81
(dd, J ) 7, 1.5, 1 H), 8.13 (br s, 1H); 13C NMR 24.0 (t), 27.2 (t,
2C), 33.8 (t, 2C), 46.1 (t), 57.5 (d), 64.3 (t), 64.5 (t), 93.8 (s),
107.0 (s), 111.0 (d), 112.9 (s), 119.2 (d), 119.4 (d), 122.0 (d, 2C),
127.3 (s), 136.2 (s), 159.9 (s); MS (EI) m/z 446 (2, M+), 168,
144, 143 (100), 131, 130, 115, 99, 97, 86, 77, 55. Anal. Calcd
for C20H23Cl3N2O3: C, 53.88; H, 5.20; N, 6.28. Found: C, 53.47;
H, 5.19; N, 6.26.
In summary, the first synthesis of (()-melinonine-E
and (()-strychnoxanthine from an advanced common
intermediate (i.e., alcohol 23) has been accomplished. The
synthesis starts from tryptamine and, in the key steps,
makes use of a radical cyclization process to generate the
2-azabicyclo[3.3.1]nonane DE ring system and a Bis-
chler-Napieralski cyclization to achieve the pentacyclic
skeleton. The final steps require the adjustment of the
stereochemistry and functionality at C-20/C-21 and the
oxidation of the C ring.
N-(Ch lor oa cet yl)-N-[4,4-(et h ylen ed ioxy)cycloh exyl]-
tr yp ta m in e (4b). A suspension of 3 (0.5 g, 1.66 mmol),
magnesium oxide (0.17 g, 4.16 mmol), and chloroacetyl chloride
(0.13 mL, 1.66 mmol) in dioxane was stirred at rt for 24 h.
After filtration of the magnesium oxide, the solvent was
evaporated and the residue was dissolved in CH2Cl2 and
washed with saturated aqueous NaHCO3. The dried extracts
were concentrated to give 4b (0.41 g, 68%) as a pale yellow
Exp er im en ta l Section
Gen er a l. All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhy-
drous conditions. Unless otherwise noted, 1H and 13C NMR
spectra were recorded in CDCl3 solution, using Me4Si as
internal standard. Chemical shifts are reported in ppm (δ)
downfield from Me4Si, and coupling constants are expressed
in hertz (Hz). NMR peak assignments are given only when
they are derived from definitive two-dimensional NMR experi-
ments (500 MHz). The 13C NMR spectra (50 or 75 MHz), when
an unambiguous assignation is not available, are reported as
follows: chemical shift (multiplicity determined from DEPT
spectra). Only noteworthy IR absorptions (cm-1) are listed.
Melting points were determined in a capillary tube. TLC was
carried out on SiO2 (silica gel 60 F254, Merck), and the spots
were located with iodoplatinate reagent or 1% aqueous KM-
nO4. Chromatography refers to flash chromatography and was
carried out on SiO2 (silica gel 60, SDS, 230-240 mesh ASTM).
Drying of organic extracts during workup of reactions was
performed over anhydrous Na2SO4. Evaporation of solvent
was accomplished with a rotatory evaporator. Microanalyses
and HRMS were performed by the Centro de Investigacio´n y
Desarrollo (CSIC), Barcelona, Spain.
1
solid: IR (KBr) 3258, 1644; H NMR (200 MHz) (3:2 mixture
of E and Z rotamers) 1.50-2.20 (m, 8 H), 3.05 and 3.55 (2m,
AA′BB′ system, 4 H), 3.65 (m, 0.6 H), 3.88 (s, 0.8 H), 3.96 and
3.97 (2s, 4 H), 4.17 (s, 1.2 H), 4.45 (m, 0.4 H), 7.0-7.9 (m, 5
H), 8.15, 8.30 (2br s, 1 H); 13C NMR (E rotamer) 28.3 (t), 27.3
(t, 2C), 33.8 (t, 2C), 41.8 (t), 43.6 (t), 56.8 (d), 64.2 (t, 2C), 107.1
(s), 111.0 (d), 113.0 (s), 119.4 (d), 119 (d), 122.1 (d), 121.7 (d),
127.3 (s), 136.2 (s), 166.2 (s); 13C NMR (Z rotamer) 24.7 (t),
27.3 (t, 2C), 33.8 (t, 2C), 41.4 (t), 44.6 (t), 53.5 (d), 64.2 (t, 2C),
107.6 (s), 111.5 (d), 113.0 (s), 118.0 (d), 119.0 (d), 122.1 (d),
122.2 (d), 126.7 (s), 136.2 (s), 167.0 (s). Anal. Calcd for
C
20H25ClN2O3‚3/4H2O: C, 61.53; H, 6.84; N, 7.18. Found: C,
61.30; H, 6.51; N, 7.21.
N-(4-Oxocycloh exyl)-N-(tr ich lor oacetyl)tr yptam in e (5a).
To a solution of 4a (5 g, 12.4 mmol) in THF (5 mL) was added
aqueous HCl (3 N, 30 mL), and the mixture was heated at 65
°C for 5 h. After THF evaporation, the aqueous phase was
extracted with CH2Cl2. The dried extracts were concentrated
and chromatographed (CH2Cl2) to give cyclohexanone 5a (3.8
g, 85%) as a white solid and starting material 4a (0.3 g, 6%).
1
5a : mp 170-171 °C (CH2Cl2); IR (KBr) 3370, 1718, 1664; H
NMR (COSY) 1.93-2.03 (m, 2 H, H-2ax and H-6ax), 2.15 (dm,
J ) 13, 2 H, H-2eq and H-6eq), 2.41-2.48 (m, 4 H), 3.08 (ddd,
J ) 8, 7, 1, 2 H, CH2Ar), 3.52 (ddd, J ) 8, 7, 1, 2 H, CH2N),
4.88 (tt, J ) 12, 3.5, 1 H, H-1ax), 7.03 (d, J ) 2.5, 1 H, H-2),
7.13 (td, J ) 7.5, 1, 1 H, H-5), 7.19 (td, J ) 7.5, 1, 1 H, H-6),
7.35 (d, J ) 8.5, 1 H, H-7), 7.70 (d, J ) 8, 1 H, H-4), 8.00 (br
s, 1 H, NH); 13C NMR (HMQC) 23.8 (CH2), 29.1 (C-2′, C-6′),
39.6 (C-3′, C-5′), 46.2 (CH2N), 56.6 (C-1′), 93.7 (CCl3), 111.2
(C-7), 112.4 (C-3), 118.8 (C-4), 119.6 (C-5), 122.1 (C-2 and C-6),
127.1 (C-3a), 136.1 (C-7a), 159.9 (CO), 208.1 (CO); MS (EI) m/z
199, 144, 143, 131, 130 (100), 115, 77, 69, 55. Anal. Calcd for
N-[4,4-(Eth ylen ed ioxy)cycloh exyl]tr yp ta m in e (3). To
a solution of tryptamine (13.2 g, 82.4 mmol) in 1,2-dichloro-
ethane (1.5 L) at rt were added 1,4-cyclohexanedione mono-
ethylene acetal (12.1 g, 77.5 mmol), sodium triacetoxyborohy-
dride (25.0 g, 117.9 mmol), and glacial acetic acid (4.4 mL, 77.1
mmol). After stirring for 24 h, the mixture was concentrated
and the residue was taken up with CH2Cl2 (700 mL). The
organic solution was washed with saturated aqueous Na2CO3
and water, dried, and concentrated. The resulting crude was
recrystallized from CH2Cl2 to give 3 (20.2 g, 87%) as a white
solid: mp 138-139 °C; IR (KBr) 3167, 1105; 1H NMR (200
MHz) 1.45 (qd, J ) 12, 3, 2 H), 1.54 (td, J ) 12, 3, 2 H), 1.67-
1.90 (m, 4 H), 2.55 (tt, J ) 10, 3, 1 H), 2.98 (s, 4 H), 3.91 (s, 4
C
18H19Cl3N2O3: C, 53.82; H, 4.77; N, 6.97; Cl, 26.48. Found:
C, 53.85; H, 4.88; N, 6.82; Cl, 26.95.
N-(Ch lor oa cetyl)-N-(4-oxocycloh exyl)tr yp ta m in e (5b).
To a cold (0 °C) solution of 4b (100 mg, 0.28 mmol) in THF
(0.64 mL) were added TFA (0.68 mL, 8.8 mmol) and water (0.6
mL). The reaction mixture was stirred at rt for 24 h. THF
(38) We thank Professor L. Angenot (Universite´ de Lie`ge) for a
sample of natural strychnoxanthine (chloride form). The NMR spectra
of (()-2‚HCl were recorded in either D2O or CD3OD.

Total Synthesis of Melinonine-E and Strychnoxanthine
J . Org. Chem., Vol. 63, No. 4, 1998 973
was evaporated, and the residue was taken up with CH2Cl2.
The organic solution was washed with brine, dried, and
concentrated. Chromatography (1% MeOH in CH2Cl2) gave
ketone 5b (60 mg, 64%): mp 110-111 °C (EtOAc); IR (film)
3400, 1715, 1642; 1H NMR (300 MHz) (3:2 mixture of Z and E
rotamers) 1.9-2.2 (m, 4 H), 2.49 (t, J ) 5.5, 4 H), 3.05 (dd, J
) 8, 7, 2 H), 3.49 (m, 1 H), 3.58 (t, J ) 7, 1 H), 3.91 (s, 1.2 H),
4.15 (m, 0.4 H), 4.24 (s, 0.8 H), 4.64 (quint, J ) 7.5, 0.6 H),
7.02 (d, J ) 2, 1H), 7.11-7.25 (m, 2 H), 7.36 (d, J ) 8, 0.4 H),
7.40 (d, J ) 8, 0.6 H), 7.55 (d, J ) 8, 0.6 H), 7.72 (d, J ) 8, 0.4
H), 8.25 (br, 0.4 H), 8.45 (br, 0.6 H); 13C NMR (Z rotamer) 27.2
(t), 29.2 (t, 2C), 39.9 (t, 2C), 41.5 (t), 45.8 (t), 53.7 (d), 111.3
(s), 111.6 (d), 118.0 (d), 119.8 (d), 122.0 (d), 122.2 (d), 126.6
(s), 136.2 (s), 167.1 (s), 209.4 (s); 13C NMR (E rotamer) 24.6
(t), 30.3 (t, 2C), 39.7 (t, 2C), 41.8 (t), 43.8 (t), 55.9 (d), 111.2
(d), 112.8 (s), 118.4 (d), 118.8 (d), 121.4 (d), 121.9 (d), 127.2
(s), 136.1 (s), 166.2 (s), 208.2 (s). Anal. Calcd for
C18H21ClN2O2‚3/4H2O: C, 62.42; H, 6.55; N, 8.08. Found: C,
62.29; H, 6.19; N, 7.98.
1-(ter t-Bu toxyca r bon yl)-N-(ch lor oa cetyl)-N-(4-oxocy-
cloh exyl)tr yp ta m in e (8). To a solution of ketone 5b (604
mg, 1.8 mmol) in CH2Cl2 (6 mL) at rt were added DMAP (24.1
mg, 0.19 mmol) and di-tert-butyl dicarbonate (475 mg, 2.17
mmol). After stirring for 18 h, the solvent was evaporated and
the residue was dissolved in CH2Cl2 and extracted with
aqueous KHSO4 (1 M). The combined organic extracts were
washed with water, saturated aqueous NaHCO3, and brine.
The dried organic extracts were concentrated to give 8 (580
mg, 77%) as a white solid: mp 130-131 °C (EtOAc); IR
(CHCl3) 1725, 1640; 1H NMR (200 MHz) (3:2 mixture of E and
Z rotamers) 1.68 and 1.70 (2s, 9 H), 1.95-2.25 (m, 4 H), 2.4-
2.6 (m, 4 H), 3.0 and 3.55 (2m, AA′BB′ system, 4 H), 3.65 (m,
0.6 H), 4.06 (s, 0.8 H), 4.25 (s, 1.2 H), 4.60 (m, 0.4 H), 7.10-
7.80 (m, 5 H), 8.15 (br s, 1 H); 13C NMR (E rotamer) 24.3 (t),
28.0 (q), 30.2 (t, 2C), 39.5 (t, 2C), 41.7 (t), 42.7 (t), 55.8 (d),
83.4 (s), 115.0 (d), 117.5 (s), 119.1 (d), 122.5 (d), 122.9 (d), 124.3
(d), 129.5 (s), 135.3 (s), 149.4 (s), 166.1 (s), 207.9 (s); 13C NMR
(Z rotamer) 26.9 (t), 28.0 (q), 29.0 (t, 2C), 39.7 (t, 2C), 41.4 (t),
44.8 (t), 53.5 (d), 83.8 (s), 115.4 (d), 116.0 (s), 118.1 (d), 122.7
(d), 122.9 (d), 124.7 (d), 130.1 (s), 135.3 (s), 149.4 (s), 166.6 (s),
209.0 (s). Anal. Calcd for C22H29ClN2O4: C, 62.78; H, 6.94;
N, 6.66. Found: C, 62.89; H, 6.95; N, 6.67.
g, 9.96 mmol) in CH2Cl2 (28 mL) were added anhydrous
(freshly sublimed) zinc iodide (260 mg, 0.8 mmol) and trim-
ethylsilyl cyanide (1.46 mL, 19.9 mmol). The mixture was
heated at 65 °C for 2 h and concentrated to give 11 (3.47 g,
74%) which was pure enough for further transformations.
Chromatography (CH2Cl2) followed by recrystallization from
CH2Cl2 yielded a highly pure sample of 11 as white crystals:
mp 209-210 °C; IR (KBr) 3403, 1668; 1H NMR (300 MHz) 0.26
(s, 9 H), 1.60-2.07 (m, 6 H), 2.25 (d, J ) 12, 2 H), 3.08 and
3.58 (2m, AA′BB′ system, 4 H), 4.40 (m, 1 H), 7.05 (d, J ) 1.5,
1 H), 7.15 (td, J ) 7, 1, 1 H), 7.20 (td, J ) 7, 1, 1 H), 7.36 (d,
J ) 7.5, 1 H), 7.80 (d, J ) 7.5, 1 H), 8.04 (br s, 1 H); 13C NMR
1.38 (q), 24.0 (t), 26.7 (t, 2C), 38.4 (t, 2C), 46.3 (t), 56.7 (d),
70.2 (s), 93.6 (s), 111.1 (d), 112.6 (s), 119.2 (d), 119.7 (d), 120.6
(s), 122.1 (d), 122.2 (d), 127.2 (s), 136.2 (s), 159.9 (s). Anal.
Calcd for C22H28Cl3N3O2Si‚2/3H2O: C, 51.51; H, 5.76; N, 8.19.
Found: C, 51.27; H, 5.46; N, 8.16. HRMS calcd for C22H28
Cl3N3O2Si 499.1016, found 499.1029.
-
N -(4-Cya n ocycloh e x-3-e n -1-yl)-N -(t r ich lor oa ce t yl)-
tr yp ta m in e (13). Meth od A. To a solution of crude 11 (7.5
g, 14.9 mmol) in benzene (6 mL) were added pyridine (23 mL)
and POCl3 (4 mL, 43.8 mmol), and the mixture was heated at
reflux for 5 h. The mixture was concentrated, and the residue
was taken up with CH2Cl2. The organic solution was washed
with aqueous HCl (1 N) and brine, dried, and concentrated.
Chromatography (CH2Cl2) gave R,â-unsaturated nitrile 13 (3.4
g, 46% overall yield from ketone 5a ) as a white power: mp
192-194 °C (CHCl3); IR (KBr) 3383, 2325, 1674; 1H NMR (200
MHz) 1.70-2.60 (m, 6 H), 3.12 and 3.52 (2m, AA′BB′ system,
4 H), 4.61 (m, 1 H), 6.51 (br s, 1 H), 7.04 (d, J ) 2.5, 1 H),
7.10-7.30 (m, 2 H), 7.38 (d, J ) 7, 1 H), 7.71 (d, J ) 7, 1 H),
8.02 (br s, 1 H); 13C NMR 23.7 (t), 25.8 (t), 27.0 (t), 29.1 (t),
46.1 (t), 53.5 (s), 93.3 (s), 111.2 (d), 112.2 (s), 112.5 (s), 118.5
(s), 118.8 (d), 119.6 (d), 120.0 (d), 122.2 (d), 127.2 (s), 136.2
(s), 142.2 (d), 160.1 (s); MS (EI) m/z 144, 143, 131, 130 (100),
103, 77, 69, 57, 55. Anal. Calcd for C20H21Cl3N2O3: C, 55.56;
H, 4.42; N, 10.23; Cl, 25.90. Found: C, 55.29; H, 4.34; N,
10.06; Cl, 26.17.
Meth od B. To a solution of crude 11 in THF (4 mL) was
added aqueous HCl (3 N, 2.5 mL). The resulting solution was
heated at 65 °C for 1 h. After separation of the two phases,
the aqueous one was extracted with Et2O. The combined
organic extracts were dried and concentrated, and the residue
was chromatographed (CH2Cl2) to give N-(tr a n s-4-cya n o-4-
h yd r oxycycloh exyl)-N-(tr ich lor oa cetyl)tr yp ta m in e (12;
3.0 g, 70%)39 as a white solid: mp 210 °C dec; IR (KBr) 3476,
2-[2-(3-In d olyl)eth yl]-2-a za bicyclo[3.3.1]n on a n e-3,6-d i-
on e (10). To a solution of chloroacetamide 8 (100 mg, 0.23
mmol) in toluene (2 mL) was added freshly sublimed potassium
tert-butoxide (52 mg, 0.46 mmol), and the reaction mixture was
stirred at reflux for 3 h. Then, CH2Cl2 (13 mL) and aqueous
HCl (2 N, 5 mL) were added. The aqueous layer was extracted
with CH2Cl2, and the combined organic extracts were dried
and concentrated. Chromatography (EtOAc) gave 2-[2-[1-
(ter t-bu toxycar bon yl)-3-in dolyl]eth yl]-2-azabicyclo[3.3.1]-
n on a n e-3,6-d ion e (9) (10 mg, 11%): IR (NaCl) 1712, 1650,
1638; 1H NMR (300 MHz) 1.56 (s, 9 H), 1.5-2.7 (m, 8 H), 2.75
(br s, 1 H), 2.90-3.25 (m, 3 H), 3.40 (br s, 1 H), 4.15-4.35 (m,
1 H), 7.00-7.35 (m, 3 H), 7.37 (d, J ) 7, 1 H), 7.70 (d, J ) 7,
1 H).
1
3356, 1670; H NMR (200 MHz, CD3OD) 1.60-2.40 (m, 8 H),
3.10 and 3.58 (2m, AA′BB′ system, 4 H), 4.40 (m, 1 H), 7.07
(d, J ) 2, 1 H), 7.14 (td, J ) 7, 1.5, 1 H), 7.20 (td, J ) 7, 1.5,
1 H), 7.36 (dd, J ) 7, 1.5, 1 H), 7.79 (d, J ) 7, 1 H), 8.00 (br s,
1 H); 13C NMR 24.8 (t), 27.6 (t, 2C), 37.7 (t, 2C), 47.5 (t), 58.3
(d), 69.8 (s), 94.7 (s), 112.2 (d), 112.5 (s), 119.6 (d), 119.9 (d),
121.0 (s), 122.4 (d), 123.7 (d), 128.6 (s), 138.0 (s), 161.4 (s);
MS m/z 199, 198, 170, 144, 143, 131, 130 (100), 115, 97, 77,
69, 57, 55. Anal. Calcd for C19H20Cl3N3O2‚1/3H2O: C, 52.50;
H, 4.79; N, 9.67. Found: C, 52.66; H, 4.71; N, 9.44. HRMS
calcd for C19H20Cl3N3O2 427.0621, found 427.0632.
TFA (0.01 mL, 0.14 mmol) was added to a stirred solution
of 9 (10 mg, 0.02 mmol) in CH2Cl2 (0.5 mL) at rt. After 6 h,
the mixture was poured into saturated aqueous NaHCO3 (2
mL) and extracted with CH2Cl2. The dried organic extracts
were concentrated, dried, and purified by chromatography (1%
MeOH in CH2Cl2) to give dione 10 (6 mg, 80%): IR (KBr) 3404,
1712, 1620; 1H NMR7 (COSY) 1.72 (tdd, J ) 13.5, 5.5, 2, 1 H,
H-18ax), 1.86 (apparent 2s, 2 H, H-16), 2.16 (dm, J ) 13, 1 H,
H-18eq), 2.31 (dd, J ) 16, 5, 1 H, H-19eq), 2.41 (ddd, J ) 16,
13, 7, 1 H, H-19ax), 2.44 (d, J ) 17.5, 1 H, H-14eq), 2.70 (dd, J
) 18, 8, 1 H, H-14ax), 2.73 (br s, 1 H, H-15eq), 3.06-3.23 (m, 3
H), 3.39 (m, W1/2 ) 8, 1 H, H-17eq), 4.25 (m, 1 H, H-5), 7.07 (d,
J ) 2, 1 H, H-2), 7.13 (td, J ) 8, 1, 1 H, H-10), 7.20 (td, J )
8, 1, 1 H, H-11), 7.37 (d, J ) 8, 1 H, H-12), 7.66 (d, J ) 8, 1 H,
H-9), 8.08 (br s, 1 H, NH); 13C NMR, Table 1. Anal. Calcd for
To a cold (0 °C) solution of 12 (2.8 g, 6.6 mmol) in pyridine
(17 mL) was slowly added POCl3 (4 mL, 43.8 mmol), and the
mixture was stirred at rt for 5 h. The mixture was concen-
trated, and the residue was taken up with CH2Cl2. The
organic solution was washed with aqueous HCl (1 N) and
brine, dried, and concentrated. Chromatography (CH2Cl2)
gave 13 (1.7 g, 63%, 44% overall yield from 5a ).
(1RS,5SR,6SR)-2-[2-(3-In dolyl)eth yl]-3-oxo-2-azabicyclo-
[3.3.1]n on a n e-6-ca r bon itr ile (16). To a boiling solution of
13 (1.6 g, 3.9 mmol) and AIBN (200 mg, 1.2 mmol) in benzene
(32 mL) was added TMS3SiH (4.2 mL, 13.6 mmol) dropwise,
and the mixture was heated under reflux for 3 h. Bu3SnH
(39) This compound was also obtained from 5a , but as a mixture of
cis-trans isomers, when using acetone cyanohydrin and aqueous K2-
CO3: 13C NMR (CDCl3) (cis isomer) 23.4 (t), 29.7 (t, 2C), 35.4 (t, 2C),
46.0 (t), 56.7 (d), 64.7 (s), 93.4 (s), 111.2 (d), 112.1 (s), 118.8 (d), 119.4
(d), 120.8 (s), 122.1 (d), 122.2 (d), 127.1 (s), 136.0 (s), 160.0 (s).
C
18H20N2O2‚3/4H2O: C, 69.77; H, 6.91; N, 9.04. Found: C,
69.53; H, 6.89; N, 9.02.
N-[tr a n s-4-Cya n o-4-[(t r im et h ylsilyl)oxy]cycloh exyl]-
N-(tr ich lor oa cetyl)tr yp ta m in e (11). To a solution of 5a (4.0

974 J . Org. Chem., Vol. 63, No. 4, 1998
Quirante et al.
(2.3 mL, 8.5 mmol) and AIBN (139 mg, 0.84 mmol) were added
to the reaction mixture, and the solution was again refluxed
for 3 h. After the solvent had been evaporated off, CH2Cl2 was
added to the residue and the solution was washed several
times with aqueous KF (1 M). The mixture was filtered
through Celite and chromatographed (3% MeOH in CH2Cl2)
to give 16 (764 mg, 64%) as white crystals: mp 196-197 °C
(2RS,3RS,6SR,14bSR)-2,3,4,5,6,7,8,9,14,14b-Deca h yd r o-
2,6-m et h a n o-1H -a zocin o[1′,2′:1,2]p yr id o[3,4-b]in d ole-3-
ca r bon itr ile (19). To a solution of nitrile 16 (1.7 g, 5.5 mmol)
in benzene (44 mL) was added POCl3 (7 mL, 74.8 mmol)
dropwise very slowly. The reaction mixture was heated at
reflux for 75 min. The solvent was evaporated, and the residue
was taken up with MeOH (41 mL). To the cooled (0 °C)
solution was added NaBH4 (1 g, 26.5 mmol), and it was stirred
at this temperature for 1.5 h. Acetone (8.5 mL) was added,
and stirring was maintained 10 min. The mixture was
concentrated, and the residue was taken up with CH2Cl2. The
organic solution was washed with water, dried, and concen-
trated. Chromatography (CH2Cl2) gave 19 (850 mg, 53%) as
a yellow solid: mp 175-177 °C (CH2Cl2); IR (KBr): 3358, 2240;
1H NMR (COSY)7 1.16 (tdd, J ) 13, 4, 2, 1 H, H-18ax), 1.21
(dm, J ) 13.5, 1 H, H-16), 1.61-1.66 (m, 2H, H-19eq), 1.72 (td,
J ) 12, 2, 1 H, H-14ax), 2.23 (dm, J ) 13.5, 1 H, H-16), 2.35
(qd, J ) 13, 5, 1 H, H-19ax), 2.39 (td, J ) 12, 4, 1 H, H-14eq),
2.46 (dm, J ) 11.5, 1 H, H-15eq), 2.54 (dt, J ) 12.5, 3.5, 1 H,
H-20ax), 2.57-2.63 (m, 1 H, H-6), 2.78-2.88 (m, 3 H, H-6, H-5,
and H-17eq), 2.89-2.96 (m, 1 H, H-5), 3.95 (dd, J ) 12, 4, 1 H,
H-3ax), 7.02 (td, J ) 7, 1, 1 H, H-10), 7.07 (td, J ) 7, 1, 1 H,
H-11), 7.25 (d, J ) 8, 1 H, H-12), 7.40 (d, J ) 8, 1 H, H-9),
7.65 (br s, 1 H, NH); 13C NMR, Table 1. Anal. Calcd for
1
(CH2Cl2); IR (KBr) 3429, 2240, 1612; H NMR7 (COSY) 1.32
(tq, 1 H, J ) 13.5, 2, 1 H, H-18ax), 1.51 (dm, J ) 13, 1 H, H-16),
1.66 (masked, 1 H, H-16), 1.69 (qd, J ) 14, 4, 1 H, H-19ax),
1.79 (dm, J ) 14, 1 H, H-18eq), 1.87 (dm, J ) 14.5, 1 H, H-19eq),
2.40 (br s, 1 H, H-15eq), 2.64-2.70 (m, 3 H, H-14 and H-20ax),
2.97-3.14 (m, 3 H, H-5 and H-6), 3.24 (br s, 1 H, H-17eq), 4.15
(m, 1 H, H-5), 7.03 (s, 1H, H-2), 7.10 (td, J ) 8, 1, 1 H, H-10),
7.17 (td, J ) 7, 1, 1 H, H-11), 7.35 (d, J ) 8.5, 1 H, H-12), 7.61
(d, J ) 8, 1 H, H-9), 8.08 (br s, 1 H, NH); 13C NMR, Table 1.
Anal. Calcd for C19H21N3O: C, 74.23; H, 6.89; N, 13.68.
Found: C, 74.11; H, 6.89; N, 13.56.
Ra d ica l Cycliza tion of 13 w ith TMS3SiH. To a boiling
solution of 13 (500 mg, 1.21 mmol) and AIBN (210 mg, 1.28
mmol) in benzene (10 mL) was added TMS3SiH (1.30 mL, 4.23
mmol) dropwise, and the mixture was heated under reflux for
3 h. After the solvent had been evaporated off, the residue
was chromatographed (1-3% MeOH in CH2Cl2). The first
eluate gave (1RS,5RS,6SR)-4,4-d ich lor o-2-[2-(3-in d olyl)-
eth yl]-3-oxo-2-azabicyclo[3.3.1]n on an e-6-car bon itr ile (14)
(50 mg, 11%): white solid; mp 207-208 °C (CH2Cl2); IR (KBr)
3350, 2247, 1666; 1H NMR7 (COSY) 1.40 (tm, J ) 12, 1 H,
H-18ax), 1.56 (dt, J ) 14.5, 3, 1 H, H-16), 1.82 (qd, J ) 14, 4,
1 H, H-19ax), 1.85 (masked, 1 H, H-18eq), 1.93 (dm, J ) 13, 1
H, H-19eq), 2.41 (dm, J ) 13, 1 H, H-16), 2.90 (dt, J ) 12, 3, 1
H, H-20ax), 3.07 (br s, 1 H, H-17), 3.15 (m, 1 H, H-15), 3.02-
3.23 (m, 3 H, H-6 and H-5), 4.21 (m, 1 H, H-5), 7.08 (d, J ) 2,
1 H, H-2), 7.13 (td, J ) 7, 1, 1 H, H-10), 7.20 (td, J ) 7, 1, 1
H, H-11), 7.37 (d, J ) 8, 1 H, H-12), 7.65 (d, J ) 7.5, 1 H,
H-9), 8.01 (br s, 1 H, NH); 13C NMR, Table 1. Anal. Calcd for
C
19H21N3: C, 78.36; H, 7.21; N, 14.42. Found: C, 78.21; H,
7.30; N, 14.40.
Ep im er iza tion of Equ a tor ia l Nitr ile 19 to Axia l Nitr ile
20. To a solution of 19 (1 g, 3.4 mmol) in THF (90 mL) at -78
°C was added dropwise LDA (7.6 mL, 1.5 M in cyclohexane,
11.3 mmol). After the mixture stirred for 2 h at this temper-
ature, aqueous HCl (0.5 N, 20 mL) was added and the reaction
mixture was allowed to warm to rt. THF was evaporated, and
the aqueous phase was extracted with CH2Cl2. The dried
extracts were concentrated and chromatographed (EtOAc). A
partial separation afforded 180 mg of nitrile 20, 352 mg of a
mixture of nitriles 20 and 19 (2:1 ratio, from 1H NMR), and
260 mg of nitrile 19. After a further column of the mixture,
20 was isolated in 41.5% yield, and the starting material 19
was recovered in 37% yield, the latter being submitted to
further epimerization reactions.
C
19H19Cl2N3O: C, 60.63; H, 5.05; N, 11.17. Found: C, 60.57;
H, 5.03; N, 11.03.
The second eluate gave (1RS,4SR,5RS,6SR)-4-ch lor o-2-
[2-(3-in d olyl)et h yl]-3-oxo-2-a za b icyclo[3.3.1]n on a n e-6-
ca r bon itr ile (15) (58 mg, 14%): white crystals; mp 211-212
°C (CH2Cl2); IR (KBr) 3306, 2242, 1644; 1H NMR7 (COSY) 1.38
(tm, J ) 12, 1 H, H-18ax), 1.63 (dt, J ) 14, 3.5, 1 H, H-16),
1.71 (dm, J ) 14.5, 1 H, H-16), 1.82 (dm, J ) 15, 1 H, H-18eq),
1.91 (qd, J ) 14, 4, 1 H, H-19ax), 1.93 (masked, 1 H, H-19eq),
2.77-2.83 (m, 2 H, H-15 and H-20ax), 2.99-3.21 (m, 4 H), 4.18
(m, 1 H, H-5), 4.64 (d, J ) 6.5, 1 H, H-14ax), 7.02 (d, J ) 2, 1
H, H-2), 7.10 (td, J ) 7, 1, 1 H, H-10), 7.18 (td, J ) 7, 1, 1 H,
H-11), 7.34 (d, J ) 8, 1 H, H-12), 7.60 (d, J ) 8, 1 H, H-9),
8.00 (br s, 1 H, NH); 13C NMR, Table 1; MS (EI) m/z 341 (2,
M+), 144, 143 (100), 130, 98, 97, 85, 83, 81, 73, 71, 69, 67, 57,
55. Anal. Calcd for C19H20ClN3O: C, 66.76; H, 5.85; N, 12.29;
Cl, 10.39. Found: C, 66.80; H, 5.83; N, 12.30; Cl, 9.99.
The third eluate gave 16 (164 mg, 44%) which was identical
with that obtained above.
Dichlorinated lactam 14 (200 mg, 0.53 mmol) was treated
with Bu3SnH (0.32 mL, 1.2 mmol) and AIBN (59 mg, 0.36
mmol) in benzene (4 mL) at reflux temperature for 5 h. After
removal of tin products by chromatography (1% MeOH in CH2-
Cl2), lactam 16 (116 mg, 71%) was isolated. Operating as
above from monochlorinated lactam 15 (200 mg, 0.58 mmol),
Bu3SnH (0.16 mL, 0.63 mmol), and AIBN (30 mg, 0.18 mmol),
lactam 16 (172 mg, 78%) was isolated.
(2RS,3SR,6SR,14bSR)-2,3,4,5,6,7,8,9,14,14b-Deca h yd r o-
2,6-m et h a n o-1H -a zocin o[1′,2′:1,2]p yr id o[3,4-b]in d ole-3-
ca r bon itr ile (20): mp 176-178 °C (CH2Cl2); IR (KBr) 3409,
1
2232; H NMR7 (COSY) 1.39 (m, 1 H, H-14ax), 1.59 (tdd, J )
14, 3.5, 2, 1 H, H-18ax), 1.65 (m, 2 H, H-19eq), 1.78 (dm, J )
14, 1 H, H-16), 2.20 (dm, J ) 15.5, 1 H, H-16), 2.49 (m, 2 H,
H-14eq and H-15), 2.53 (tm, J ) 14, 1 H, H-19ax), 2.60 (m, 1 H,
H-20eq), 2.66 (m, 1 H, H-6), 2.88 (m, 2 H, H-5 and H-6), 3.00
(m, 2 H, H-5 and H-17), 4.04 (dm, J ) 12, 1 H, H-3ax), 7.09
(td, J ) 7, 1, 1 H, H-10), 7.13 (td, J ) 7, 1, 1 H, H-11), 7.30 (d,
J ) 8, 1 H, H-12), 7.47 (d, J ) 7.5, 1 H, H-9), 7.70 (br s, 1 H,
NH); 13C NMR, Table 1. Anal. Calcd for C19H21N3‚1/2H2O: C,
76.01; H, 7.39; N, 13.99. Found: C, 75.95; H, 7.37; N, 13.60.
HRMS calcd for C19H21N3 291.1735, found 291.1725.
(2RS,3SR,6SR,14bSR)- a n d (2RS,3RS,6SR,14bSR)-
2,3,4,5,6,7,8,9,14,14b-Deca h yd r o-2,6-m eth a n o-1H-a zocin o-
[1′,2′:1,2]p yr id o[3,4-b]in d ole-3-ca r ba ld eh yd e (21 a n d 22).
To a solution of equatorial nitrile 19 (430 mg, 1.6 mmol) in
toluene (6 mL) at -20 °C was added dropwise DIBALH (2 mL,
1 M in toluene). After the mixture stirred for 1 h, 5% aqueous
H2SO4 (13 mL) was added and then the mixture was allowed
to warm to rt over 2 h. The mixture was basified with aqueous
NaOH (2 N) and extracted with CH2Cl2. The dried extracts
were concentrated to give a residue which was chromato-
graphed (from CH2Cl2 to 1% MeOH in CH2Cl2) to give aldehyde
22 along with its axial C-3 epimer 21 (175 mg, 40%) in a 7:3
ratio, estimated by 1H NMR. It is worth mentioning that
without the chromatographic process the reduction yield is
much better, as indicated by the overall yield of reduction to
the corresponding alcohol (vide infra). Recrystallization from
CHCl3 provided an analytical sample: mp 180 °C dec; IR (KBr)
Cycliza tion of 13 w ith Bu 3Sn D. To a boiling solution of
13 (300 mg, 0.73 mmol) and AIBN (24 mg, 0.14 mmol) in
benzene (6 mL) was added Bu3SnD (0.2 mL, 0.8 mmol)
dropwise, and the mixture was heated under reflux for 8 h.
After the solvent had been evaporated off, the residue was
chromatographed (1% CH3OH in CH2Cl2). The first eluate
1
gave 17 (89 mg, 32%). In its H NMR spectrum the signal at
δ 2.86 of analogue 14 is missing, and in its 13C NMR spectrum
the signal at δ 32.2 appears as a triplet (J ) 20 Hz). The
second eluate gave the monochlorinated derivative 18 (57 mg,
23%), in which the incorporation of deuterium on C-14 and
C-20 was observed.
3500, 1720; 1H NMR7 (COSY) 1.18-1.38 (m, 2.7 H, H-14ax
,
H-16, H-18ax, 22 and H-16, H-18ax, 21), 1.51 (td, J ) 12, 2.5,
0.3 H, H-14ax, 21), 1.61 (dm, J ) 12.5, 0.3 H, H-18eq, 21), 1.70
(dm, J ) 12.5, 0.7 H, H-19eq, 22), 1.77 (dm, J ) 12.5, 0.7 H,

Total Synthesis of Melinonine-E and Strychnoxanthine
J . Org. Chem., Vol. 63, No. 4, 1998 975
H-18eq, 22), 1.86 (dm, J ) 12.5, 0.3 H, H-19eq, 21), 2.11 (dm, J
) 12.5, 0.3 H, H-16, 21), 2.16 (masked, 0.3 H, H-20ax, 21), 2.18
(qd, J ) 13, 4.5, 0.7 H, H-19ax, 22), 2.28 (dt, J ) 10, 3.5, 0.7 H,
H-20ax, 22), 2.28-2.38 (m, 1.4 H, H-16 and H-14eq, 22), 2.44
(m, 0.3 H, H-19ax, 21), 2.56 (ddd, 0.3 H, J ) 13, 11, 5, H-14eq,
21), 2.60-2.75 (m, 1H, H-6), 2.70 (m, W1/2 ) 20, 1 H, H-15eq),
2.95 (m, 0.7 H, H-17eq, 22), 3.2-3.8 (m, 3.3 H, H-5, H-6, and
H-17eq, 21), 3.99 (dm, J ) 12, 0.7 H, H-3ax, 22), 4.06 (dm, J )
12, 0.3 H, H-3ax, 21), 7.05 (td, J ) 7.25, 1.5, 0.7 H, H-10, 22),
7.06 (td, J ) 7.25, 1.5, 0.3 H, H-10, 21), 7.09 (td, J ) 7.25, 1.5,
0.7 H, H-11, 22), 7.11 (td, J ) 7.25, 1.5, 0.3 H, H-11, 21), 7.25
(d, J ) 8, 0.7 H, H-12, 22), 7.29 (d, J ) 8, 0.3 H, H-12, 21),
7.43 (d, J ) 8, 0.7 H, H-9, 22), 7.45 (d, J ) 8, 0.3 H, H-9, 21),
7.59 (br s, 0.7 H, NH, 22), 7.63 (br s, 0.3 H, NH, 21), 9.56 (s,
0.7 H, CHO, 22), 9.75 (s, 0.3 H, CHO, 21);13C NMR, Table 1.
Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.53; H, 7.63; N, 9.45.
9 h. The catalyst was filtered through a short pad of Celite
and washed with hot MeOH. The combined filtrate and
washings were concentrated to leave a yellowish solid, which
was mixed with water (1.5 mL). The resulting aqueous
suspension was neutralized with saturated aqueous NaHCO3,
and then a solution of NaClO4‚H2O (56 mg, 0.40 mmol) in
water (1 mL) was added. The precipitate was filtered off and
washed with water (1 mL) to give 1 perchlorate (58 mg, 63%).
Recrystallization from MeOH-Et2O (1:1) provided an analyti-
cal sample as a yellow solid: mp 254-256 °C; IR (KBr) 3425,
1
2926, 1635, 623; H NMR (CD3OD, COSY and ROESY) 1.30
(m, 1 H, H-19ax), 1.74 (dm, J ) 15, 1 H, H-19eq), 2.02 (dm, J )
14.5, 1 H, H-18eq), 2.12 (m, 1 H, H-20eq), 2.28 (tm, J ) 14, 1 H,
H-18ax), 2.32 (dm, J ) 14, 1 H, H-16syn), 2.52 (dt, J ) 14.5,
2.5, 1 H, H-16anti), 2.79 (br s, 1 H, H-15eq), 3.83 (dd, J ) 11,
7.5, 1 H, H-21), 3.92 (dd, J ) 11, 8, 1 H, H-21), 5.19 (br s, 1 H,
H-17eq), 7.55 (m, 1 H, H-10), 7.84-7.92 (m, 2 H, H-11 and
H-12), 8.44 (m, 1 H, H-5), 8.48 (m, 1 H, H-9), 8.60 (d, J ) 6.5,
1 H, H-6); 13C NMR, Table 1. Anal. Calcd for C19H21ClN2O5:
C, 58.15; H, 5.40; N, 7.14. Found: C, 58.11; H, 5.76; N, 6.97.
1 Perchlorate (40 mg) was loaded on a basic anion-exchange
resin (Amberlite IRA-400, chloride form) and eluted with
MeOH. Evaporation of the solvent quantitatively afforded
melinonine-E (1) chloride (47 mg), which was identical (mp,
IR, UV, 1H NMR, and 13C NMR) with the natural melinonine-E
chloride form.4,36 Melinonine-E (1) picrate was prepared from
1 chloride (20 mg, 0.06 mmol) by initial conversion to the
corresponding betaine on a basic anion-exchange resin (Am-
berlite IRA-401, hydroxide form) and elution with MeOH.
Treatment of the resulting betaine (13 mg, 0.04 mmol) with
an equivalent amount of picric acid (9.5 mg, 0.04 mmol)
quantitatively afforded 1 picrate as a yellow solid. Rf values
of synthetic picrate and an authentic sample36 were also
coincident.
(2R S ,3S R ,6S R ,14b S R )-3-(H y d r o x y m e t h y l)-2,3,4,
5,6,7,8,9,14,14b-d eca h yd r o-2,6-m eth a n o-1H-a zocin o[1′,2′:
1,2]p yr id o[3,4-b]in d ole (23). To a solution of nitrile 20 (500
mg, 1.71 mmol) in toluene (6.6 mL) at -20 °C was added
dropwise DIBALH (2.38 mL, 1 M in toluene). After the
mixture stirred at -20 °C for 1 h, 5% aqueous H2SO4 (13 mL)
was added. The resulting mixture was allowed to warm to rt
over 2 h. The reaction mixture was basified with aqueous
NaOH (2 N) and extracted with CH2Cl2. The dried extracts
were concentrated to give aldehyde 21 (430 mg), which was
immediately reduced to avoid an epimerization process. To a
solution of 21 (430 mg, 1.46 mmol) in MeOH (67 mL) at 0 °C
was added NaBH4 (116 mg, 3.07 mmol), and the reaction
mixture was stirred at rt for 4 h. Water (6.7 mL) was added,
MeOH was evaporated, and the organic phase was extracted
with CH2Cl2. The dried extracts were concentrated, and the
residue was chromatographed (CH2Cl2) to give alcohol 23 (332
mg, 67% overall yield from nitrile 20) as a yellow solid: mp
3-Ep im elin on in e-E (27) P er ch lor a te.40 Operating as in
the above axial series, from equatorial alcohol 24 (60 mg, 0.20
mmol), maleic acid (116 mg, 1 mmol), and Pd black (80 mg,
0.75 mmol) in water (7 mL) was prepared 3-epimelinonine-E
(27) perchlorate (50 mg, 63%) as a yellow solid. Recrystalli-
zation from MeOH-Et2O (1:1) provided an analytical
1
168-169 °C (EtOAc); IR (KBr) 3418, 2928; H NMR (COSY)
1.24-1.36 (m, 2 H, H-18ax and H-19eq), 1.42 (dm, J ) 13.5, 1
H, H-16), 1.45-1.62 (m, 3 H, H-14ax, H-18eq, and H-20eq), 2.00
(dm, J ) 12.5, 1 H, H-16), 2.25 (apparent dm, J ) 10.5, 1 H,
H-15eq), 2.36 (tm, J ) 13, 1 H, H-19ax), 2.53 (td, J ) 12, 5.5, 1
H, H-14eq), 2.65 (dm, J ) 11.5, 1 H, H-6), 2.87 (m, 3 H, H-5,
H-6, and H-17eq), 3.00 (m, 1 H, H-5), 3.68 (dd, J ) 11, 7.5, 1
H, H-21), 3.73 (dd, J ) 11, 8, 1 H, H-21), 4.06 (dm, J ) 12.5,
1 H, H-3ax), 7.03 (td, J ) 7.5, 1, 1 H, H-10), 7.11 (td, J ) 7.5,
1.5, 1 H, H-11), 7.31 (d, J ) 8, 1 H, H-12), 7.46 (d, J ) 7.5, 1
H, H-9), 7.75 (br s, 1 H, NH); 13C NMR, Table 1. Anal. Calcd
for C19H24N2O‚2/3H2O: C, 73.98; H, 8.28; N, 9.08. Found: C,
73.98; H, 8.00; N, 9.26. HRMS calcd for C19H24N2O 296.1888,
found 296.1878.
1
sample: mp 260-265 °C; IR (KBr) 3429, 2924, 1635, 625; H
NMR (CD3OD, COSY and ROESY) 0.57 (m, 1 H, H-19ax), 1.64
(dm, J ) 15, 1 H, H-19eq), 2.09 (br s, 1 H, H-20ax), 2.16 (m, 2
H, H-18), 2.31 (dm, J ) 14, 1 H, H-16anti), 2.49 (dm, J ) 14.5,
1 H, H-16syn), 2.76 (br s, 1 H, H-15eq), 3.59 (d, J ) 7, 2 H,
CH2O), 3.73-3.79 (m, 1 H, H-14), 5.25 (br s, 1 H, H-17eq), 7.54
(td, J ) 6, 2, 1 H, H-10), 7.86 (m, 2 H, H-11 and H-12), 8.45
(m, 2 H, H-5 and H-9), 8.57 (d, J ) 6.5, 1 H, H-6); 13C NMR,
Table 1. Anal. Calcd for C19H21N2O5Cl: C, 58.02; H, 5.55; N,
7.13; Cl, 9.02. Found: C, 58.02; H, 5.55; N, 7.13; Cl, 8.91.
3-Epimelinonine-E (27) chloride was obtained from 27
perchlorate using the preceding procedures described for
melinonine-E (1) chloride: UV (MeOH), λ (nm) 364, 306, 252,
204; HRMS (FAB) calcd for C19H21N2O+ 293.1653, found
293.1649. 3-Epimelinonine-E (27) picrate was prepared from
27 chloride using the preceding procedures described for
melinonine-E (1) picrate.
(2R S ,3R S ,6S R ,14b S R )-3-(H y d r o x y m e t h y l)-2,3,4,
5,6,7,8,9,14,14b-d eca h yd r o-2,6-m eth a n o-1H-a zocin o[1′,2′:
1,2]p yr id o[3,4-b]in d ole (24). Operating as above, nitrile 19
(700 mg, 2.40 mmol) was converted by reduction with DIBALH
(3.3 mL, 1 M in toluene) into aldehyde 22 (570 mg). Further
reduction with NaBH4 (116 mg, 4.3 mmol) in MeOH (95 mL)
gave alcohol 24 (483 mg, 69%) as a yellow solid after chroma-
tography (CH2Cl2): mp 161-164 °C (EtOAc); IR (KBr) 3252,
1
2928; H NMR (COSY) 1.15-1.25 (m, 3 H, H-16, H-18ax and
(()-Str ych n oxa n th in e (2) Ch lor id e. To a solution of
alcohol 23 (45 mg, 0.15 mmol) in pyridine (5 mL) was added
Ac2O (3 mL). The mixture was stirred at rt overnight.
Removal of excess reagent afforded a residue which was taken
up with CH2Cl2 and washed with water. The dried extracts
were concentrated to give a dark solid which was chromato-
graphed (EtOAc) to afford acetate 25 (28 mg, 55%): IR (KBr)
3373, 2928, 1718; 1H (300 MHz) 1.27 (dm, J ) 12.5, 1 H), 1.47
(tm, J ) 13, 1 H), 1.71 (m, 1 H), 1.94-2.20 (m, 2 H), 2.07 (s,
3 H), 2.36 (tm, J ) 13, 1 H), 2.49 (ddd, J ) 13, 11, 4.5, 1 H),
2.65 (dm, J ) 11, 1 H), 2.89 (m, 3 H), 2.98 (m, 1 H), 4.04 (dm,
J ) 12, 1 H), 4.11 (dd, J ) 11, 7.5, 1 H), 4.18 (dd, J ) 11, 8,
1 H), 7.07 (td, J ) 7, 1.5, 1 H), 7.12 (td, J ) 7, 1.5, 1 H), 7.30
(dd, J ) 7, 1.5, 1 H), 7.47 (dd, J ) 7, 1.5, 1 H), 7.72 (br s, 1 H);
13C NMR, Table 1.
H-19eq), 1.42 (td, J ) 12, 2, 1 H, H-14ax), 1.58-1.85 (m, 2 H,
H-18 and H-20ax), 2.10 (ddd, J ) 13, 11, 5, 1 H, H-14eq), 2.23-
2.30 (m, 3 H, H-15, H-16, and H-19ax), 2.62 (m, 1 H, H-6), 2.75-
2.87 (m, 2 H, H-6 and H-5), 2.85 (br s, 1 H, H-17eq), 2.92 (m,
1 H, H-5), 3.34 (dd, J ) 10.5, 6, 1 H, H-21), 3.37 (dd, J ) 10.5,
8, 1 H, H-21), 3.95 (dm, J ) 10, 1 H, H-3ax), 7.01 (td, J ) 7.5,
1, 1 H, H-10), 7.04 (td, J ) 7, 1, 1 H, H-11), 7.22 (d, J ) 8, 1
H, H-12), 7.38 (d, J ) 7.5, 1 H, H-9), 7.63 (br s, 1 H, NH); 13
C
NMR, Table 1. Anal. Calcd for C19H24N2O‚2/3H2O: C, 73.98;
H, 8.28; N, 9.08. Found: C, 73.97; H, 8.31; N, 8.85. HRMS
calcd for C19H24N2O 296.1888, found 296.1880.
(()-Melin on in e-E (1) P er ch lor a te. A stirred mixture of
alcohol 23 (70 mg, 0.23 mmol), maleic acid (135 mg, 1.16
mmol), and palladium black (80 mg, 0.75 mmol) in water (7
mL) was heated at reflux for 8.5 h. After cooling (5-10 °C)
overnight, a further portion of Pd black (50 mg, 0.46 mmol)
was added and the reaction mixture was heated at reflux for
To a solution of acetate 25 (28 mg, 0.08 mmol) in dioxane
(1.5 mL) was added SeO2 (73.5 mg, 0.66 mmol), and the
mixture was stirred for 45 h at reflux. The selenium that

976 J . Org. Chem., Vol. 63, No. 4, 1998
Quirante et al.
precipitated from the reaction was filtered through Celite and
washed with MeOH. The filtrate and washings were combined
and concentrated to give 28 as a yellow solid: 1H NMR (CD3-
OD) 1.40 (m, 1 H), 1.63 (dm, J ) 15, 1 H), 1.95 (m, 1 H), 2.03
(s, 3 H), 2.33 (m, 1 H), 2.66 (m, 1 H), 3.10 (br s, 1 H), 4.46 (m,
1 H), 4.56 (m, 1 H), 5.30 (br s, 1 H), 7.50-9.20 (m, ArH); 13C
NMR, Table 1. HRMS calcd for C21H21N2O3 349.1539, found
349.1541.
Treatment of 26 (50 mg, 0.14 mmol) with SeO2 (128 mg,
1.16 mmol) as above afforded 29:42 1H NMR (CD3OD) 1.20 (m,
1 H), 1.95 (dm, J ) 15, 1 H), 2.16 (s, 3 H), 2.15 (m, 1 H), 2.30-
2.75 (m, 4 H), 3.10 (dm, J ) 14, 1 H), 4.13 (m, 2 H), 5.52 (br
s, 1 H), 7.60-9.10 (ArH); 13C NMR, Table 1; HRMS calcd for
C
21H21N2O3 349.1552, found 349.1551.
From 3-epistrychnoxanthine (29) was obtained 3-epistrych-
noxanthine chloride (30) (40 mg, 77%) as an orange solid: mp
280 °C dec; IR (KBr) 3425, 1690, 1626; 1H NMR (CD3OD,
COSY) 0.92 (qd, J ) 14.5, 4.5, 1 H, H-19ax), 1.86 (dm, J ) 14.5,
1 H, H-19eq), 2.22-2.23 (m, 2 H, H-18eq and H-20), 2.37 (tdd,
J ) 14.5, 5, 3, 1 H, H-18ax), 2.54 (dt, J ) 14.5, 2.5, 1 H, H-16),
3.00 (dm, J ) 14.25, 1 H, H-16), 3.30 (masked, 1 H, H-15),
3.45 (dd, J ) 11.5, 7.5, 1 H, H-21), 3.59 (dd, J ) 11.25, 7, 1 H,
H-21), 5.41 (br s, 1 H, H-17), 7.53 (td, J ) 7.5, 1, 1 H, H-10),
7.82-7.91 (m, 2 H, H-11 and H-12), 8.48 (d, J ) 8, 1 H, H-9),
8.76 (d, J ) 6.5, 1 H, H-5), 8.93 (d, J ) 6.5, 1 H, H-6); 13C
NMR, Table 1; HRMS calcd for C19H19N2O2 307.1446, found
307.1444.
A solution of acetate 28 in EtOH (1 mL) was treated with
aqueous NaOH (2 N, 1 mL), EtOH was evaporated, and the
aqueous phase was extracted with CH2Cl2. The dried extracts
were concentrated to afford a violet residue to which HCl (2.5
N) in MeOH was added. The resulting precipitate was filtered
off, washed with MeOH, and dried to give 2 chloride (22 mg,
78%), which was identical (Rf values, IR, UV, 1H NMR, and
13C NMR) with an authentic sample,5,38 as an orange solid:
1
mp 280 °C dec; H NMR (CD3OD, COSY and NOESY) 1.36-
1.45 (m, 1 H, H-19ax), 1.73 (dm, J ) 15, 1 H, H-19eq), 2.06 (dm,
J ) 15, 1 H, H-18eq), 2.22 (m, 1 H, H-20eq), 2.38 (tdd, 1 H, J )
14.5, 9, 3, H-18ax), 2.66 (dt, 1 H, J ) 15, 2.5, H-16anti), 2.67-
2.81 (m, 1 H, H-16syn), 3.27 (br s, 1 H, H-15), 3.80 (dd, J ) 11,
6.5, H-21), 3.94 (dd, J ) 11, 9, H-21), 5.28 (br s, 1 H, H-17),
7.55 (td, J ) 7, 1, 1 H, H-10), 7.88 (td, J ) 8.5, 1.5, 1 H, H-11),
7.92 (d, J ) 8, H-12), 8.49 (d, J ) 8, 1 H, H-9), 8.75 (d, J )
6.5, 1 H, H-5), 8.94 (d, J ) 6.5, 1 H, H-6); 13C NMR, Table 1;
HRMS calcd for C19H19N2O2 307.1446, found 307.1450.
20-Ep istr ych n oxa n th in e Ch lor id e (30).41 Operating as
in the above axial series, acetoxy derivative 26 was prepared
from equatorial alcohol 24 by the foregoing procedure in 49%
yield on an identical molar scale: IR (KBr) 3373, 2928, 1718;
1H NMR (300 MHz) 1.16-1.40 (m, 3 H), 1.48 (td, J ) 12, 2, 1
H), 1.60-1.85 (m, 2 H), 2.04 (s, 3 H), 2.13 (ddd, J ) 13, 11, 5,
1 H), 2.29-2.36 (m, 2 H), 2.64 (m, 1 H), 2.78-3.04 (m, 3 H),
2.98 (br s, 1 H), 3.81 (dd, J ) 11, 5.5, 1 H), 3.92 (dd, J ) 11,
8, 1 H), 3.99 (dm, J ) 11, 1 H), 7.07 (td, J ) 7, 1, 1 H), 7.12
(td, J ) 7, 1, 1 H), 7.28 (d, J ) 7, 1 H), 7.45 (d, J ) 7, 1 H),
7.71 (br s, 1 H); 13C NMR, Table 1.
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (Project PB94-0858), is gratefully acknowl-
edged. Thanks are also due to the Comissionat per a
Universitats i Recerca (Generalitat de Catalunya) for
Grant SGR95-00045 and a fellowship to C.E.
J O971148C
(40) Systematic name: (2RS,3RS,6SR)-3-(hydroxymethyl)-2,3,4,5,
6,14-hexahydro-2,6-methano-1H-azocino[1′,2′:1,2]pyrido[3,4-b]indol-7-
ium perchlorate.
(41) Systematic name: (2RS,3SR,6RS)-3-(hydroxymethyl)-1-oxo-
2,3,4,5,6,14-hexahydro-2,6-methano-1H-azocino[1′,2′:1,2]pyrido[3,4-b]-
indol-7-ium chloride.
(42) Compound 29 was also prepared, but in a less satisfactory
manner, from 3-epimelinonine E perchlorate (27) by acetylation (Ac2O)
followed by oxidation (SeO2) of crude acetate 26.