Degradative synthesis approach

In the early years after the discovery of silybin (1), the structure determination of this compound class was mainly achieved through extensive chemical conversions and degradative reactions (15, 95), which often led to structures that later needed revision. Analysis of comprehensive spectroscopic data along with classical chemical reactions and synthesis approaches has led to the unequivocal determination of the absolute stmctures of flavonolignans (102,135). The complete structure elucidation of flavonolignans is summarized below. 

Pharmaceutically useful steroids may be either obtained by total synthesis or by degradation and functional group conversions from inexpensive natural steroids. Both approaches will be discussed in this section (H. Langecker, 1977 R.T. Blickenstaff, 1974). 

A bacterial isolate APN has been shown to convert a-aminopropionitril enantioselectively to L-alanine (94% yield, 75% e e). However, the major disadvantage of this approach, is the low stability of most aminonitriles in water (for example a-aminophenylacetonitrile in water of pH 7, degrades completely within 48 hours). The aminonitriles are always in equilibrium with the aldehyde or ketone and ammonia/HCN. Polymerisation of hydrogen cyanide gives an equilibrium shift resulting in the loss of the aminonitrile. Therefore, a low yield in amino adds is to be expected, which makes this method less attractive for the industrial synthesis of optically active amino adds. 

Several syntheses of secoquettamines have been performed. Seco compounds 234 and 235 were semisynthesized from quettamine (236) by Hofmann and Emde degradations, respectively (179). Chattopadhyay and Shamma (184) conducted a total synthesis of these bases with the intermediacy of quettamine (236) (Scheme 36). In this approach Reissert compound 237 served as substrate. On reaction with 4-benzyloxybenzaldehyde 237 supplied the addition product 238, which after N-methylation and sodium borohydride reduction afforded amino carbinol 239. Compound 239 was cyclized to... 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

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