Dihydrocorynantheine

Masumiya H, Saitoh T, Tanaka Y, et al. Effects of hirsutine and dihydrocorynantheine on the action potentials of sino-atrial node, atrium and ventricle. Life Sci 1999 65 2333-2341. 

The synthesis of (-)-hirsutine (2-795) was concluded by removal of the Boc-group, condensation with methyl formate, and methylation of the formed enol moiety. In a similar manner as was described for 2-795, (+)-dihydrocorynantheine (2-797) [399] with the (3S)- and (15 k)-configuration was synthesized from ent-2-800. 

Normal Series. After 1967, only one new alkaloid was isolated in the normal series the N-oxide of dihydrocorynantheine (54) (55). 

The first total synthesis of ( )-dihydrocorynantheine (54) (163) and ( )-corynantheine (52) (164) with normal stereo arrangement of the C-3, C-15, and C-20 hydrogens (a, 3, a, respectively) was published in full detail by van Tamelen and co-workers in 1969. [In preliminary form it has been published earlier (165, 166).]... 

Lactam 299 was prepared from tryptamine and cyano diester 298 by reductive alkylation in about 12% yield. Phosphorus oxychloride cyclization of 299, followed by catalytic reduction, resulted in the corresponding trans disubstituted indolo[2,3-a]quinolizine 300. After transesterification, formylation and methyla-tion were carried out in two subsequent steps with ethyl formate in the presence of triphenylmethylsodium and with an excess of diazomethane to supply ( )-dihydrocorynantheine (163). 

Lactam 299 has later been synthesized by another route from ethyl trans-5-ethyl-2-oxo-4-piperidineacetate and 3-chloroacetylindole, which represents a new formal total synthesis of ( )-dihydrocorynantheine and related alkaloids (104). 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Similarly to the above results, from dihydrocorynantheine (54) also two isomeric IV-oxides (559 and 560) could be prepared at the same time, from hirsutine (58) only one (561) could be obtained. On the basis of spectral evidence, the authors concluded that the major IV-oxide derived from yohimbine and dihydrocorynantheine maintained the original stereo arrangement and they have the C/D-trans ring junction (276). 

A similar result was obtained for hirsutine (58), which gave the corresponding (3R)- and (3S)-ethoxy-3,4-secocyanamide (564 and 565) upon treatment with cyanogen bromide. Both products could be cyclized 564 gave dihydrocorynantheine (54), while 565 afforded hirsutine (58) stereospecifically (278). 

Hirsutine (85) is a corynantheine-type indole alkaloid with a C/D cis ring juncture (pseudo stereochemistry). This compound has recently been found to exhibit highly potent inhibition of the replication of the strains of influenza A (subtype H3N2) [63]. The EC50 of hirsutine was 11- to 20-fold more potent than that of the clinically used ribavirin. Exploration of the important structural features of this molecule revealed that the stereochemistry at C-3 (.R) and C-20 (R) as well as the presence of the Nb lone pair were essential for the anti-influenza A activity. Thus, the C-3 epimer, dihydrocorynantheine (86) (normal stereochemistry), was much less active than hirsutine (85). 

Dihydrocorynantheine (86), in turn, along with other structurally related alkaloids, has been found to decrease specific [3H]-5-hydroxytryptamine (5-HT) binding to membrane preparations from rat... 

Recently, both hirsutine (85) and dihydrocorynantheine (86) were found to be active when the effects of these compounds on the action potentials of sino-atrial node, atrium and ventricle tissues were studied with standard microelectrode techniques [65]. In sino-atrial node preparations, both compounds concentration-dependently increased cycle length, decreased the slope of the pacemaker depolarization, decreased the maximum rate of rise and prolonged action potential duration. Thus, it was for the first time shown that hirsutine and dihydrocorynantheine have direct inhibitory effects on the cardiac pacemaker. In atrial and ventricular preparations, both compounds concentration-dependently decreased the maximum rate of rise and prolonged action potential duration. Although stereochemically different, these two alkaloids exhibited no difference in their effects on various myocardial action potential parameters. Dihydrocorynantheine also displays potent a-adrenoceptor blocking activity, while hirsutine is inactive [66]. Experiments with ion channels indicate that the mechanisms for these two phenomena probably differ. The direct effects of hirsutine and dihydrocorynantheine on the action potential of cardiac muscle through inhibition of multiple ion channels may explain the negative chronotropic and antiarrhythmic activities of these two alkaloids. 

Biotransformation studies of hirsutine (85) and dihydrocorynantheine (86) reveal an interesting difference between these two isomers [67]. Dihydrocorynantheine and some of its derivatives in the normal, alio and epiallo series are metabolized principally by O-demethylation, whereas hirsutine or other pseudo isomers are metabolized by a different process yielding unidentified products. 

The three-component domino-Knoevenagel-hetero-Diels-Alder reaction is especially fruitful if one uses aldehydes containing a protected amino function. In such cases the formed dihydropyranyl ether moiety can be used as a source of an aldehyde moiety that can undergo a condensation with the amino group after deprotection. Thus, several alkaloids such as hirsutine 108, dihydrocorynantheine... 

Scheme 12.25. Syntheses of hirsutine and dihydrocorynantheine using a three-component Knoevenagel/hetero[4+2] cycloaddition/ retro[4+2] fragmentation, by Tietze and Zhou...

The alkaloids hirsutine (1) and its 3or-epimer dihydrocorynantheine (2a) belong to the corynanthe group of indole alkaloids. They have been isolated from the plant Uncaria rhynchophylla MIQ, which was used for the preparation of the old Chinese folk medicine kampo . Nowadays, 1 and related compounds attract great attention in medicine because of their growth inhibition of the influenza A subtype H3N2 virus. With an EC50 value of 0.40-0.57 ig/mL 1 has shown itself to be 10-20 times more active than the clinically used drug ribavirine (3).1,2 Furthermore, 1 is known for its antihypertensive and antiarrhythmic activity.3... 

The route used earlier338 in the partial synthesis of dihydro-epipleiocarpamine from dihydrocorynantheine has now been adapted to the synthesis of 16-epipleio-carpamine (134) from geissoschizine.80 The major modification required was the protection of the enolic hydroxy-group at C-17 in geissoschizine (92) by the formation of a carbonate ester with ethyl chloroformate following fission of the... 

The formal synthesis56c of dihydrocorynantheine (Scheme 17), also by Takano s group, relies on the stereospecific addition of malonate to the unsaturated lactam (100) for the generation of the correct stereochemistry at positions 15 and 20. The... 

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