Silatranes

Silatranes are a special kind of organotrialkoxysilanes, namely -organyl-2,8,9-trioxa-5-aza-l-silabicyclo[3.3.3] undecanes. The phenomenon of their specific biological activity has been studied in detail, and will be discussed in Chapter 4. Silatranes were first prepared in 1960 by azeotropic distillation of triethanolamine and organyl trialkoxysilanes with benzene [307]. Organotrihalosilanes can also be used (Eq. 3.139)  

The water-soluble silatranes (CH2) CH2N(CH2) Si(OCH2CH2)3N, where m = 3,4, 5 = 1, 3, were obtained in 66-70% yield [311]. Heterocyclic cage silatranes have been prepared by condensation of trifunctional disilanes with tris(2-hydroxymethyl)amine [312] (Eq. 3.142)  

A series of more than 70 papers on silatranes have been published since 1964 by Voronkov and co-authors. He has recently also published an extensive review [313]. 

Most investigations in this field have been carried out by Voronkov and coworkers. Comprehensive surveys36 38 concerning the chemistry and biological properties of silatranes are given by Voronkov himself. Only the most remarkable and most important results are represented in this chapter in a condensed form. 

The most prominent biological feature of silatranes is the remarkable mammalian toxicity exhibited by their 1-aryl derivatives (Table 4). Some of them are several times more toxic than widely known poisons such as hydrocyanic acid and strychnine. At the same time 1-arylsilatranes are almost harmless for cold-blooded animals, plants, and microorganisms. For example, frogs are very resistant to 1-phenylsilatrane (9) doses of 30-40 mg/kg have no effect. 

Remarkable is the fact, that toxicity of silatranes varies within extremely wide limits, being determined mainly by the nature of the substituents R in structure 8 (Table 4). While 1-arylsilatranes are very toxic, 1-alkyl-, 1-vinyl-, and 1-ethinylsila-tranes are practically non-toxic. 1-Alkoxysilatranes have low toxicity and many of them can also be regarded as practically non-toxic. 

Comparison of the LDS0 values of 1-phenylsilatrane (LDS0 = 0.33 mg/kg), 1-cyclohexylsilatrane(LDS0= 150mg/kg),and l-benzylsilatrane(LD5o=ll 15 mg/kg) illustrates the strong dependence of toxicity on the substituent R. 

The high toxicity of 1-arylsilatranes is already used commercially in the USA. Marketing of l-(p-chlorophenyl)silatrane (II) as a rodenticide began in 197143  

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The physical properties of commercial alkoxysilanes are provided in Table 1. Two classes of silane esters have very distinct properties and are generally considered apart from alkoxysilanes. Sdatranes are compounds derived from trialkanolamines and have siHcon—nitrogen coordination. These are generally hydrolytically stable and have unique physiological properties (3). A second special class of monomeric esters are cycHc diesters of polyethyleneoxide glycols designated sila-crowns, which have appHcation as catalysts (4). Neither silatranes nor sila-crowns are considered herein. 

Mowery and DeShong reported on the use of siloxanes 72 (Figure 16) as versatile transmetallation agents for Pd(dba)3-catalyzed couplings with aryl halides and allylic alcohol derivates, in the presence of TBAF and at high temperature (95 They later used aryl silatrane 73 (Figure 16) as a suitable partner for the fluoride-promoted... 

Several tests with silicon containing compounds as therapeutics in human medicine have already been crowned with success. In France certain organosilicon preparations, DNR and RDN (compare Chap. 5.5), are used in the treatment of cardiovascular diseases, cancer and virus infections. In the Soviet Union extensive clinical tests with ointments of l-(chloromethyl)- and 1-ethoxysilatrane as possible drugs for treatment of different typs of alopecia were successful (compare Chap. 5.1). Further clinical studies showed that l-(chloromethyl)silatrane is also very promising in treatment of wounds and bums. In a Swedish hospital patients with poorly differentiated prostatic carcinoma were treated with 2,6-c/s-diphenyl-hexamethyl-cyclo-tetrasiloxane (Cisobitan ) the clinical study also yielded promising results (compare Chap. 5.3). 

The first synthesis of silatranes has been described by C. L. Frye et al.40J and Finestone41-42). In the meantime, further simple and convenient methods for the preparation of silatranes have been found. Some examples [syntheses of 1-phenyl-silatrane (9), 1-ethoxysilatrane (18), and l-(chloromethyl)silatrane (25)] are given in Scheme 2 ... 

Table 4. LD5q values3 of some 1-substituted silatranes (i.p., white mice)...

Table 5. Oral toxicity of l-(p-ch orophenyI)silatrane for warmblooded animals...

Numerous other metallatranes have also been tested biologically, but they show much lower effects than the silicon species. The mechanism of the toxic effects of silatranes is not clear in all cases so far. 

Voronkov, M. G. Biological activity of silatranes. In Biochemistry of silicon and related problems, pp. 395—433. New York Plenum Press, 1978... 

During the following years investigations in the field of organosilicon compounds were concentrated on the development of new methods of synthesis of silatranes and on the study of their steric and electronic structure, various physical properties and, especially, their biological activity2-15 ... 

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