1650

tion of 20 with selenium dioxide in aqueous dioxane 8 7

provided the known63 diosphenol 21 in 30% yield. The

diosphenol 21 was heated to 155° for 1 hr with hydrazine
hydrate in diethylene glycol. The product, separated
on alumina, consisted of lycopodine (1, 26%), anhydro-
dihydrolycopodine (22, 40%), which is also a naturally
occurring Lycopodium alkaloid,8 and dihydrodeoxyly-
copodine63 (1, C=0 replaced by CH2, ~10%). Since
lycopodine has been transformed into annofoline9 and
into alkaloid L.206b this synthesis also represents, in a
formal sense, a synthesis of these alkaloids.10
Acknowledgment. We wish to express our thanks to
the National Research Council of Canada for supporting
this study. We also thank J. F. McCutcheon and 2a 3a
4a( R ß- =

A. C. Soper for their help in various phases of this work. b b bJ indolyl-

acetyl
a, Ri =
C2H5; R- = H
(8) B. Douglas, D. G. Lewis, and L. Marion, Can. J. Chem., 31, b, Ri =
H; R2 =
C2H5
272 (1953).
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(9) W. A. Ayer, D. A. Law, and K. Piers, Tetrahedron Letters, 2959 hyde 7a. The crude 7a underwent the Fluang-Minlon
(1964).
(10) G. Stork, R. A. Kretchmer, and R. H. Schlessinger, J. Am.
reduction giving 7b (69% over-all yield from 6b), bp
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Chem. Soc., 90, 1647 (1968), have also completed a synthesis of dl-ly- 123-130° (6 mm), which on hydrolysis [7c, bp 97-100°
copodine. Simultaneous publication has been arranged. (6 mm)] followed by tosylation (7d) and the Gabriel
William A. Ayer, W. Russell Bowman, T. C. Joseph, Peter Smith amination was transformed into pure 2a in 67 % over-all
Department of Chemistry, University of Alberta yield[2a, bp 104-106° (34 mm); picrate mp 153-154.5°].
Edmonton, Alberta, Canada The cis configuration in 2a was based on the following
Received December 22, 1967 evidence. On careful oxidation9 followed by oximina-
tion and dehydration, 7c was converted into the olefinic
cis-nitrile 7e,10 bp 115-118° (32 mm), which was
A Stereochemically Controlled Total Synthesis of hydrogenated to c/s-3-ethylcyclohexane-l-carbonitrile,
¿//-Ibogamine and ¿//-Epiibogamine bp 130° (bath temperature, 38 mm), identical with an
authentic sample,11 and reduced with L1A1H4 to the
Sir: amine 2a identical with that prepared as described
A recent communication1 on the stereocontrolled earlier. For the preparation of 2b, the known com-
total synthesis of ¿//-ibogamine prompted us to disclose pound 8a12 was reduced (L1A1H4) giving 8b (84%, p-
our own total synthesis of dl-ibogamine (la) and dl-
epiibogamine (lb).2,3 Our synthesis is also stereo-
chemically controlled, proving the assigned configura-
tions of the ethyl side chains as depicted in la and lb.
As was the case in our previous synthesis1 5of the 234

5a, R = H 6a, R =
H 7a, Ri CH2OTHP; =

alkaloid skeleton (desethylibogamine), the key reaction b, R = THP b, R =

CH=CH2 R2 CHO =

steps of the present synthesis comprise one-step con- b, Ri =

CH2OTHP;
R2 =
CH3
version of cis- and DwM-3-ethyl-5-aminomethylcyclo- c, Ri =
CH2OH; R2 =

hexenes (2a,b) into the bridged aziridines 3a,b and CH3

d, Ri CH2OTs; R,
cleavage of them to the isoquinuclidines 4a,b.4
=

For
=
5
ch3
stereoselective synthesis of 2a, the known compound e, Ri =
CN; R2 =
CH3
5a,6 after conversion into the tetrahydropyranyl ether
5b7 8(83 %), bp 123-129° (0.8-0.9 mm), was reduced with
L1A1H4 to 6a (91 %), bp 130-134° (0.5 mm), which on
vinylation [6b (80% based upon the consumed 6a), bp
110-115 (0.1 mm)] followed by pyrolysis8 gave the alde-

(1) S. I. Sallay, J. Am. Chem. Soc., 89, 6762 (1967).

(2) The work was presented at the 11th National Symposium on the
Chemistry of Natural Products, Oct 9, 1967, Kyoto, Japan. See the
Abstracts, p 41.
(3) For previously reported total syntheses, see (a) G. Blichi, D. L.
Coffen, K. Kocsis, P. E. Sonnet, and F. E. Ziegler, J. Am. Chem. Soc.,
87, 2073 (1965); 88, 3099 (1966); (b) J. P. Kutney, W. J. Cretney, P. Le 10 11a, R =
CH2OH
Quesne, B. McKague, and E. Piers, ibid., 88,4756 (1966). The formulas b, R =
CH2OTs
are shown in their absolute configuration. Cf. J. P. Kutney, R. T. c, R =
CN
Brown, and E. Piers, Can. J, Chem., 44, 637 (1966), and ref 3a.
(4) W. Nagata, S. Hirai, K. Kawata, and T. Okumura, J. Am. Chem.
Soc., 89, 5046 (1967). (9) K. E. Pfitzner and J. G. Moffat, ibid., 85, 3027 (1963); 87, 5661,
(5) W. Nagata, S. Hirai, K. Kawata, and T. Aoki, ibid., 89, 5045 5670(1965).
(1967). (10) Separation of the cis and trans isomers by glpc was effective only
(6) E. E. Van Tamelen and G. T. Hildahl, ibid., 78, 4405 (1956). for the olefinic nitriles 7e and 11c. This is the reason for this transfor-
(7) Satisfactory elemental analyses were obtained for all the com- mation.
pounds for which melting point or boiling point values are given. All (11) Preparation of the authentic sample will be described in a full
the compounds cited showed reasonable spectral data. paper.
(8) A. W. Burgstahler and I. C. Nordin, J. Am. Chem. Soc., 83, 198 (12) A. J. Birch, P. Hextall, and S. Sternkell, Australian J. Chem., 7,
(1961). 256 (1954).

Journal of the American Chemical Society / 90:6 j March 75, 7965

 1651

a)Rl C2H5;R2 H
= =

b, Ri H; R2 C2H5
= =

nitrobenzoate mp 101-103°), which on hydrolysis (9a) and 15b with LiAlH4 gave carbinolamines which without
followed by methylation gave 9b (41 % from 8b), mp purification were dehydrated with alumina to the enam-
71-72.5°. Treatment of 9b with ethylmagnesium ines 16a (40%) and 16b (32%) (16a: mp 185-187°,
bromide gave 10 (68%), which underwent the Wolff- =£ 235 (e 25,200), 285 µ (e 14,100); 16b: mp 178-
Kishner reduction giving crude 11a (65%), bp 85-90° 182°, 234.5 (e 21,100), 244 (shoulder), 285 µ (e
(5 mm). This crude material was found to be con- 12,500). Catalytic hydrogenation of 16a,b gave me-
taminated with ca. 25 % of the cis isomer 7c from glpc10 thoxyibogamine (17a; 55%) and methoxyepiibogamine
of the corresponding olefinic nitrile 11c. Basic treat- (17b; 67%) (17a: mp 152-154°; 17b: mp 144-147°),
ment of a pure sample of 11c, bp 118-121° (32 mm), which were reduced14 smoothly to dZ-ibogamine (la) and
obtained by preparative glpc, gave a 6:5 equilibrium dZ-epiibogamine (lb) (la: mp 127-128°; lb: mp
mixture of 7e and 11c, and this fact proves the trans 196.5-197.5°). The samples of la and lb were proven
configuration of the latter. Reduction (L1AIH4) of to be identical with authentic samples of dZ-ibogamine
pure 11c gave the trans amine 2b, bp 101-104° (30 and dZ-epiibogamine (mixture melting point, infrared
mm); picrate mp 158-159.5°. From the preparative spectra, and tic).16 The present synthesis is parallel to
viewpoint, the crude material of 11a was used for trans- our previous skeleton synthesis,4 confirming the cor-
formation into crude 2b {ca. 75% purity, 58% over-all rectness of the latter synthesis and of the synthesis re-
yield), bp 95-98° (24 mm), by tosylation (11b) and sub- ported by Huffman and his coworkers.16 dZ-Ibogamine
sequent Gabriel amination. (la) was directly obtained together with the unstable
Compounds 2a and b were oxidized with lead tetra- enamine 16a (R H instead of OCH3) by diisobutyl-
=

acetate6 giving the bridged aziridines 3a,b (3a: picrate aluminum hydride reduction of the lactam tosylate 14a.
mp 152-154°, flavianate mp 173-176°; 3b: picrate mp Conversion of this enamine into la is currently being
142-144°, flavianate mp 167-169°), which without studied.
purification were cleaved with /3-indolylacetic anhydride (14) Cf. G. Büchi and R. E. Manning, ibid., 88, 2532 (1966).
to give 4a,b. On alkaline hydrolysis, the last com- (15) The authors wish to express their sincere thanks to Professor G.
pounds were led to the crystalline 12a,b (33 and 20% Büchi for his courtesy in providing an authentic sample of dZ-ibogamine
and performing the identification of dZ-epiibogamine.
over-all yield from 2a,b, respectively) (12a: mp 206-
(16) J. W. Huffman, C. B. S. Rao, and T. Kamiya, J. Am. Chem. Soc.,
208°; 12b: mp 193-196°), which on oxidation by the 87, 2288 (1965); J. Org. Chem., 32, 697 (1967).
Oppenauer method or, better, with dimethyl sulfoxide Wataru Nagata, Shoichi Hirai
and acetic anhydride13 were converted into the keto Tamotsu Okumura, Kyozo Kawata
lactams 13a,b. Cyclization of 13a and 13b without re-
Shionogi Research Laboratory, Shionogi and Company Ltd.
arrangement was effected by refluxing (5-10 min) the Fukushima-ku, Osaka, Japan
benzene solution in the presence of 1.3-1.5 molar equiv Received January 3, 1968
of p-toluenesulfonic acid to give the lactam tosylates
14a,b (14a: amorphous; 14b: mp 175-178°) which
were converted4 into the methoxy lactams 15a,b (30
A New Convenient Reagent for Peptide Syntheses
and 34% over-all yield from 12a,b, respectively) (15a:
mp 283-285°; 15b: mp 275-278°) Reduction of 15a Sir:
The preparation and biological activity of the pseudo-
(13) J. D. Albright and L. Goldman, J. Am. Chem. Soc., 89, 2416
(1967). base N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

Communications to the Editor