General Methods of Synthesis of Indole Alkaloids. V. Syntheses of d,E-Corynantheidol and d,Z-Epialloyohimbane’*’ Ernest Wenkert, K. G. Dave, and F. Haglida
Contribution from the Department of Chemistry, Indiana University, Bloomington, Indiana, and the Department of Organic Chemistry, Weizmann Institute of Science, Rehovoth, Israel, Received July 21,1965 A variety of N-alkylnicotinic ester salts is shown to be transformed into tetrahydropyridines on hydrogenation. The development of simple procedures of alkaloid synthesis based on the hydrogenation and subsequent acidcatalyzed, intramoledar cyclization of the reduction products is portrayed. Three methods for removal of the P-carbalkoxy “handle” of the tetrahydropyridines are discussed and their use in the syntheses of d,l-corynantheidol and d,l-epialloyohimbane is illustrated.
A recent synthesis of the alkaloid eburnamonine featured an unusual hydrogenation (the conversion of the pyridinium salt Ia into the tetrahydropyridine IIa) as well as an acid-induced cyclization (IIa to IIIa) as a crucial, two-step reaction sequence in the construction of the alkaloidal indoloquinolizidine skeleton. The novelty of the reduction process and the ease of synthesis of the fairly complex ring system demanded an investigation of the general applicability of the procedure to other indole alkaloid syntheses. As a consequence a study of the hydrogenation of l-alkyl-3carbalkoxypyridinium salts and the utilization of the reduction products for alkaloid synthesis was initiated.
change on methyl nicotinate (IVa) with sodium tbutoxide yielded t-butyl nicotinate (IVb). Dihydrogentianine (V), initially obtained by hydrogenation of g e n t i a ~ h ewas , ~ synthesized by a variation of the Govindachari proced~re.~Hydrolysis of nitrile VIa and subsequent esterification yielded VIb. Condensation of the latter with dimethyl oxalate afforded ester lactone VI16 whose alkaline hydrolysis, alkaline hydrogen peroxide treatment, and esterification led to diester VIc. Lithium aluminun hydride reduction of the diester gave diol VId whose manganese dioxide oxidation produced dihydrogentianine (V). Finally, Ccarbo-t-butoxy-5,6,7,8-tetrahydroisoquinoline(IXd), yet one more pyridine needed for the present investigation, was prepared in the following manner. Phosphorus oxychloride treatment of glutaconimide VIII’ yielded IXa whose hydrogenation gave IXb.8 Acid hydrolysis of the latter and subsequent esterification afforded ester IXc, and ester interchange with sodium t-butoxide produced the desired ester IXd.
IVa,R=Me b,R=t-Bu
v COzMe
II
I a, R
b, R C, R d, R e, R
Me; R’ = P-(3-indolyl)ethyl OMe; R‘ = P-(3-indolyl)ethyl O-t-Bu; R’ = /3-(3-indolyl)ethyl O-t-Bu;R‘ = Me = O-t-Bu; R’ = H = = = =
IC\
IIIa, R c= Ac b, R = COzMe c,R = H
While much of the work was based on methyl nicotinate as starting compound, several pyridines had to be prepared for the present investigation. Ester inter(1) Part of this work was supported by the U. S . Department of Health, Education, and Welfare (Grant MY-5815) and presented for the first time in the course of a series of lectures by E. W. at the Institut de Chimie des Substances Naturelles (C.N.R.S.), Gif-sur-Yvette, France, in April-May 1963. (2) Part IV: E. Wenkert and B. Wickberg, J. Am. Chem. SOC.,87, 1580 (1965). (3) Van Leer Visiting Fellow, Weizmann Institute of Science, AprilJuly 1965.
VI1 VIa, R b, R c, R d, R
= = =
Me; R’ = CN Me; R’ = COzMe CH2CO2Me;R’ = C02Me (CH&OH; R’ = CHzOH
N-Alkylnicotinic ester salts Ib, c, and d were prepared by standard means (see the Experimental Section) and their palladium-induced hydrogenation in methanol in the presence of triethylamine catalyst led to tetrahydropyridines IIb, c, and d, respectively. Thus the change from a p-acetylpyridine in the eburna(4) Cf C. T. Kyte, G. H. Jeffery, and A. I. Vogel, J. Chem. SOC., 4454 (1960). ( 5 ) The authors are indebted to Dr. Govindachari (cf. T. R. Govindachari, K. Nagarajan, and S . Rajappa, ibid., 551 (1957‘)) and to Drs. D. Lavie and R. Taylor-Smith (cf. Chem. Ind. (London), 781 (1963)), for samples of gentianine (cf. also M. Plat, M. Koch, A. Bouquet, J. Le Men, and M.-M. Janot, Bull. soc. chim. France, 1302 (1963)). (9 Cf.E. Wenkert, D. B. R. Johnston, and K. G. Dave, J. Org. Chem., 29, 2534 (1964). (7) U. Basu, J. Indian Chem. SOC.,8 , 319 (1931). (8) A. Zeitlin, Ph.D. Dissertation, University of New South Wales, Sydney, Australia, 1964.
Wenkert, Dave, Haglid
d,l-Corynantheidol arrd d,l-Epiailoyohimbane
5461
CN
R
0
s
WI
Scheme I
6 6-
IXa,X = C1; R = CN b,X = H; R = CN
,HOH
c , X = H; R = COlMe d, X H; R = COrt-BU
monine synthesis2 to /3-carbalkoxypyridines in the present cases had no ill effect on the hydrogenation.9 In view of the recent, successful, partial hydrogenation of P-acetylpyridine10 and methyl nicotinate (IVa)" a similar reduction was attempted on i-butyl nicotinate (IVb). It led to the tetrahydro product (1Ie) in high yield. While representing the pivotal reaction in the construction of the indole alkaloid ring system, the conversion of the tetrahydropyridine IIa into the tetrahydrscarboline derivative IIIa in the eburnamonine synthesis2 served also the purpose of introducing a necessary two-carbon side chain in the form of an acetyl group. Unfortunately such a substituent is out of place (side chains existing only at the starred positions in formula 111) in the majority of alkaloids of structure type 111. Consequently methods of removal of the acyl "handle" had to be devised. Compounds IIb and, thereafter, IIc served as models for this study. Acid treatment of IIb yielded the tetracyclic ester IIIb. Hydrolysis of the latter, followed by dehydrogenation with palladium in maleic acid solution, l 2 yielded a decarboxylated tetradehydro product which could be isolated as a perchlorate salt (Xa)13 and reduced by sodium borohydride to the unsubstituted tetracycle IIIc. Decarboxylation during the dehydrogenation was anticipated because of the instability of the a-pyridylacetic acid salt moiety in the intermediate Xb.15 Thus a three-step, high-yielding method of extrusion of the frequently undesirable acyl side chain was on hand. A procedure accomplishing the same task but by the use of three less reactions was encountered in a study of the alkaline hydrolysis of IIb. The reaction product proved to be IIIc. This surprising result can be interpreted best on the mechanistic basis shown in Scheme I. While the second scheme of deacylation was distinctly more attractive than the three-step procedure, it suffered from low reaction yields. Hence an efficient method of ester hydrolysis (the alkaline hydrolysis of IIb having been slow) and decarboxylation, prior to cyclization, had to be designed. Acid hydrolysis of tbutyl esters seems to fit this requirement and was tested (9) (a) Hydrogenation of N-alkylnicotinaldehyde, N-alkylnicotinamide, and N-alkylnicotinonitrile salts also have yielded tetrahydro products: E. Wenkert, K. G . Dave, and T. Oishi, unpublished observations. (b) A n attempted Raney nickel induced hydrogenation of methyl nicotinate methiodide to its piperidine reduction product has been reported to yield also appreciable quantities of the tetrahydro compound I1 (R == OMe, R ' = Me): C. A. Grob and F. Ostermayer, Helv. Chim. Acta, 45, 1119 (1962). (10) M. Freifelder, J . Org. Chem., 29, 2895 (1964). (11) E. Wenkert and M. Terashima, unpublished observation. (12) E. Wenkert and D. I
