The reductive amination of KAPA to DAPA in the biosynthetic pathway involves PLP and SAM

May 27, 2024

• Title:       

  The reductive amination of KAPA to DAPA in the biosynthetic pathway involves PLP and SAM

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  The synthesis of the vitamers of biotin

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  SCHEME 1

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  Biotin (CAS 58-85-5) is a water-soluble vitamin that functions as a coenzyme in certain carboxyla-  tion and transcarboxylation reactions (1). Perhaps the most important of these, the  carboxylation of acetyl-CoA to form malonyl-CoA, is catalyzed by acetyl-CoA  carboxylase and is an initial step in fatty acid and polyketide biosynthesis. Since  the proper function of at least one of the reactions in which biotin participates is  a prerequisite for the growth and development of almost all organisms, biotin is  an essential nutrient. Many organisms, including the majority of plants and microbes,  synthesize their own biotin; others, including animals and certain microbes such as  yeast and Lactobacillus, must obtain the vitamin from external sources. The later  intermediates in the biosynthetic path, the so-called vitamers 7-keto-8-amino pelar gonic acid (KAPA), 7,8-diamino pelargonic acid (DAPA), and desthiobiotin (DTB)  (Scheme 1), have been identified.  
  Synthesis of DAPA. 
  The reductive amination of KAPA to DAPA in the biosynthetic pathway involves PLP and SAM (Scheme 1). Our initial approaches were to  carry out this reaction by nonenzymatic methods taking into consideration the  stereospecificity of the reductive step. Ketones have been converted to chiral amines  by reduction of their corresponding chiral imines, such as those obtained by conden-  sation with optically pure Ͱ-methylbenzyl amine, where the imine formation takes  place under basic conditions (8). In our case, since KAPA is an Ͱ-amino ketone  unstable in basic media, an initial N-protection step was required. N-protection  reactions are commonly conducted in basic media; however, in this case the protec-  tive step required nonbasic conditions in order to prevent the formation of Ͱ-amino  ketone intermolecular condensation products. Such an N-protection was carried  out by N-formylation in the presence of formic acid/acetic anhydride (9) (Scheme  5).