Cassaic acid

S-hydroxyMovaleric acid, Mcj. C(OH). CHj. COOH, cassaic acid, Cj,H57(CHOH)(CO)(COOH), and dimethylaminoethanol,... 

The authors point out that erythrophleie acid may be a methoxy-derivative of cassaic acid,... 

On oxidation by chromic acid cassaic acid yields dehydrocassaic acid (diketocassenic acid), C20H2JO4, m.p. 238-9°, — 164 5° (EtOH), a... 

On alkaline hydrolysis coumingic acid and coumingine yield cassaic acid, C2QH39O4, for which and its derivatives somewhat different [cf. p. 728) constants are now recorded, viz., acid, m.p. 223-4°, [a] ° — 123° (EtOH) methyl ester, m.p. 188-9°, [a] ° — 124° (EtOH) acetyl derivative of... 

Kai-ho-chien 775 Ketodihydromethylmorphimethine, 235 l-Keto-6 7-dimethoxy-2-methyI-tetrahydroisoquinoline, 354 Ketohydroxycassanic acid, 728, 729, 730 Ketohydroxycassenic acid. See Cassaic acid, 728... 

Cassane and Miscellaneous Tricyclic Diterpenoids.—A group of furanoid diterpenoids, related to the caesalpins, has been isolated from Pterodon emargina-and P. pubescens. They include compounds (39—42). Some further diterpene alkaloids of the cassaic acid class have been isolated from Erythro-phleum ivorense. 

The absorption spectra of cassaic acid and of cassaine show that the double bond which is shown to be present by the ready reduction of the alkaloid to dihydrocassaine (m.p. 115-116°) [a]n 0° in ethanol, —6.5° in A /10 hydrochloric acid) is a,fi- to the carboxyl rather than to the carbonyl. Dihydrocassaic acid melts at 253-255° and has [a] 0° (ethanol), — 5° (A /IO sodium hydroxide). 

The hydroxyl in cassaic acid is secondary because oxidation of the acid with chromic acid generates a diketo acid (m.p. 238-239°, [a] —164.5° in ethanol) which did not give positive reactions for aldehydes and which formed a methyl ester (m.p. 129-130°), a dioxime (m.p. 130-132°), and a disemicarbazone (m.p. 290°). Ruzicka and Dalma (19) have suggested that the saturated acid, free of oxygen-containing substituents, from which cassaic acid is derived, be named cassanic acid. The diketo acid obtainable... 

Cassane is the basic skeleton of cassaic acid, the parent diterpenoid of alkaloids from the bark of Erythrophleum guinese and other Erythrophleum species (Fa-baceae). These act as local anaesthetics, cardiotonics, antihypertonics, and also induce cardiac arrest. Erythrophleum alkaloids such as cassaidine, cassain and cassamine are 2-(iV,iV-dimethylamino)ethyl esters of cassaic acid derivatives. 

Cassaine, the alkaloid available in greatest quantity, has been the one most studied chemically. Cassaine, C24H39O4N, on mild acid hydrolysis yields -dimethylaminoethanol and cassaic acid, C20H30O4 (/). This acid has been shown to possess a double bond, which is in a position a,j3 to the carboxyl group (A ,ax 215 mfx, e 20,000), a hydroxyl, and a ketonic function (1, 2). The recent chemical interest in this Erythrophleum alkaloid has been focused on the structural elucidation and synthesis of cassaic acid. Compounds related to this acid have been named (d) as derivatives of cassanic acid, C20H34O2, which can be obtained from cassaic acid by reduction of the double bond, oxidation to a diketone, followed by Wolff-Kishner reduction. 

Cassaidine, C24H41O4N 4), on acid hydrolysis also provides j8-di-methylaminoethanol and the acid, cassaidic acid, C20H32O4. Adihydroxy-cassanic acid and a diketocassanic acid can be obtained from cassaidic acid which are identical with samples prepared from cassaic acid. Thus the relationship between cassaic acid and cassaidic acid (consequently cassaine and cassaidine) is that the keto group in the former is found as a hydroxy function in the latter. 

In addition to the dehydrogenation data the presence of C=CH—COOH in cassaic acid is strongly supported by the isolation of oxalic acid and a triketone, C18H26O3, on ozonization of diketo-cassenic acid (9). 

Definitive evidence for the assignment of the keto group at C-7 was provided by formation of the conjugated enedione VII by bromination and dehydrobromination of the acetoxy diketone Vl-A obtained from the ozonization of cassaic acid acetate methyl ester. The 1,4 relationship of the keto groups in VII was demonstrated by the maximum in the... 

Since one of the keto groups arose from the double bond which is known to be at C-13, the position of the carbonyl group at C-7 cassaic acid was thus established 11, 12). 

The efforts which led to the formal total synthesis of cassaic acid and of the parent alkaloid cassaine confirmed the structure deduced from degradative reactions and provided evidence for the assignment of the stereochemistry of cassaic acid. Since part of the arguments for the stereochemical assignments deal with reactions in the synthetic sequence it is advantageous to discuss the synthetic work prior to the stereochemistry. 

On the basis of the evidence which will be discussed formula XX has been written to represent the complete structure of cassaic acid (12). The trans A-B ring fusion has been assigned on the basis of the catalytic reductions of the 4,5-double bond in the synthetic sequence with the formation of a trans ring fusion in close analogy with other systems. Conclusive evidence for this assignment was provided by the correlation... 

The remaining asymmetric center in cassaic acid to be assigned is C-14. Cassaic acid acetate methyl ester provides, on ozonization, the acetoxy diketone XXI-A which has been obtained synthetically as discussed earlier. It was observed that this diketone was unstable to... 

In an attempt to provide further information about this isomerization, compound XXIV, which has only one epimerizable center, was obtained from cassaic acid acetate methyl ester by sodium borohydride reduction to XXIII and subsequent ozonization. This substance was resistant to... 

Detailed analysis of the NMR- and UV-spectra of several cassaic acid derivatives and synthetic model compounds have confirmed the stereochemical conclusions deduced for C-14 in cassaic acid and in addition led to the assignment of the stereochemistry of the double bond (20, 21). The model compounds, cis- and [Pg.295]

For the completion of the total synthesis from XXI-A it was necessary to preferentially attach the unsaturated acetic acid side chain to C-13 by a Reformatsky-type reaction and to maintain the base-unstable configuration at C-14. Compound XXIV, which has been obtained from XXI-A and from XXII-A through the equilibration of the ketals, was a very important intermediate since it is a monoketone and the methyl group adjacent to the keto function is held in an axial position by the equatorial hydroxy group at C-7. A Reformatsky reaction, followed by oxidation, dehydration, and hydrolysis afforded cassaic acid (XXXIV) identical with an authentic sample (12). Since cassaic acid had been converted to cassaine (XXXV) in 1939 by Faltis and Holzinger (2), this constituted a total synthesis and a final confirmation of structure of the parent alkaloid. 

Chapman et al. (32) also studied the isomerization of the methyl group in the diketones analogous to XXI and XXII. These authors concluded in variance with the work of Turner that the methyl at C-14 is /3 in cassamic acid and consequently in cassaic acid. This assignment was ultimately based on the isolation of XLI from the ozonolysis of 7-desoxo-cassamic acid obtained from cassamic acid by a Clemmensen reduction. The configuration of rings B and C in XLI was shown by ORD-data. 

The bark of this tree yielded ivorine, C26H44O5N (mp 159° [aj — 43°), which on treatment with methanol-hydrogen chloride gave the methyl ester of cassaic acid and methylaminoethanol. The acid esterifying the secondary hydroxyl was shown to be j8-methylcrotonic (Me2C = CH-Cl2H) and hence ivorine is XXXVI (86). 

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