Of securinine alkaloids

The potential pharmacological properties of securinine alkaloids (Section V) no doubt are responsible for the development of teehniques suitable for both rapid and exact analysis of these alkaloids (Table V) (84-94). A number of other papers have dealt with determination of the most effective methods for alkaloid extraction (86, 95, 96). 

Securinine.—Further details of one group s study of the biosynthesis of securinine (13) have been published.21 The origins of this alkaloid are well defined,22 and information which adds to this definition is that tyrosine is incorporated without loss of tritium from the carbon atoms flanking the phenolic hydroxy-group.21... 

DL-[2- C]Lysine [as (1)] and [2- C]-A -piperideine [as (2)] afforded securinine (3) in which the label was confined essentially to the asterisked carbon atom. Further, [i 5-6- H 6- C]-DL-lysine [as (1)] gave securinine without loss of tritium. Consequently C-6 of lysine does not undergo oxidation in the course of securinine biosynthesis and so the e-amino-group of (1) must be retained whilst the a-amino-group and carboxy-function are lost. The combined results are consistent with the hypothetical route to securinine shown in Scheme 1. This pathway will now gain more validity if alkaloids with structures similar to those of the proposed intermediates can be found in Securinega or related plants. 

Although reference to individual securinine alkaloids have been made in previous volumes of this treatise (Vol. VII, XIII) and the literature dealing with work since 1969 has been summarized (9), no comprehensive review on this subject has appeared. It is the purpose of this contribution to fill this gap in the alkaloid literature. Coverage is complete through March 6, 1972 Chemical Abstracts. 

Securinine, the major alkaloid in the leaves of Securinega suffruticosa (Pall.) Rehd. was first described by Murav eva and Bankovskii (10, 11). These Russian workers determined the empirical formula (CisH gNOg) and some other physical properties of securinine and prepared a series of derivatives. They also established the absence of A-methyl, 0-methyl, hydroxyl, methylenedioxy, and ketone groups by functional group analysis and the presence of a lactone moiety and extended conjugation by IR and UV spectroscopy (12). The skeletal structure was first established independently and almost simultaneously by two Japanese teams on securinine isolated from domestic S. suffruticosa plants (13, 14). Subsequently, securinine was also isolated from... 

Thus allosecurinine (96) is a C-2 epimer of securinine (27). Further stereochemical interrelationships of allosecurinine with other Securinega alkaloids which establish its absolute configuration as represented by formulation 96 are described in Section II, G. 

In their structural elucidation work on securinine and allosecurinine, Parello et al. carried out detailed NMR analysis by which they were able to assign precisely most of the protons in the alkaloids 16). Subsequently, Parello elaborated on certain aspects of these assignments 41a) and also investigated the NMR spectra of dihydro and tetrahydro derivatives of these alkaloids with the aid of deuterated... 

Trimethylsilylation of the mother liquor from the securinine crystallization obtained from Securinega suffruticosa followed by gas-liquid chromotography (GLC) revealed, aside from peaks due to allosecurinine and dihydrosecurinine, a new peak which was not observed in the GLC of the original mother liquor and which thus suggested the presence of hydroxylated alkaloids (57). Further separation led to the isolation of three alkaloids, securinol A, B, and C, whose structures were elucidated by combination spectral and degradative methods (57, 58). These alkaloids turn out to be ring C hydroxylated derivatives of the seourin-... 

Undoubtedly owing to the potentially beneficial biological activity of the securinine alkaloids (Section V) most of the synthetic work has been covered by patents (71, 72). 

An alternative partial synthesis of securinine was also developed by Horii and co-workers (65, 69). The unconjugated lactone 12 available from a key degradation of the alkaloid (Scheme 1) gave upon bromina-tion a 71% yield of the dibromide 195 which upon basic treatment yielded natural securinine (27) in 15% yield. It may be envisaged that this short route could provide a new relay stage for the total synthesis of the alkaloid. 

The synthetic work above on the securinine-t5rpe alkaloids carried out to date has been directed mainly along one particular avenue of approach. In view of the intrinsically interesting structure and potentially useful biological activity of these alkaloids other synthetic attacks are to be expected particularly since new and intriguing methods for construction of the 6-azabicyclo[3,2,l]octane skeleton are being rapidly developed (73, 74). 

The first biological screening of securinine and its derivatives was carried out in Russia soon after the discovery of the alkaloid. Turova and Aleshkina reported that securinine nitrate is a central nervous system (CNS) stimulant similar to strychnine but possessing lower toxicity (75). They found that this derivative when administered in... 

Securinine.—A unique tetracyclic structure is a feature of the alkaloids of the Securinega genus (family Euphorbiaceae). Study of the biosynthesis of the most commonly occurring base, securinine (47), has revealed an appropriately unusual genesis for rings c and d. 

The yellow colour of allosecurinine in solution [u.v. (max) 342 nm in hexane] as well as in the crystal suggests the presence of the transannular interaction between the nitrogen lone pair and the conjugated diene in both states. Interestingly, available chemical and physical (including A-ray) evidence supports the conformational representation (33) for securinine (diastereomeric with allosecurinine), and this alkaloid also exhibits the transannular interaction [u.v. (max) 328 nm in hexane]. On the basis of the results on securinine and allosecurinine, it may be conjectured that this interaction is independent of conformation. Further work is required in particular, an A-ray structure determination of securinine as the free base would be welcome. 

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