Hormaomycin Analogues by Precursor‐Directed Biosynthesis – Synthesis of and Feeding Experiments with Amino Acids Related to the Unique 3‐( trans ‐2‐Nitrocyclopropyl)alanine Constituent

The deuterium‐labeled racemic 3‐( trans ‐2‐nitrocyclopropyl)‐alanine ( rac ‐[D 2 ]‐ 3 ) and 3‐( trans ‐2‐aminocyclopropyl)alanine ( rac ‐[D 2 ]‐ 4 ) as well as non‐labeled rac ‐3‐[ trans ‐2‐(hydroxycarbonyl)cyclopropyl]alanine ( rac ‐ 5a ) and rac ‐3‐[ trans ‐2‐(methoxycarbonyl)cyclopropyl]alanine ( rac ‐ 5b ) were prepared in 43, 18, 88 and 49 % overall yield, respectively, along a general synthetic route applying alkylations of the lithium enolate of tert ‐butyl (diphenylmethylene)‐aminoacetate (O’Donnel’s glycine equivalent 11 ) as a key step. Feeding experiments with these amino acids and Streptomyces griseoflavus (strain W 384) revealed that rac ‐[D 2 ]‐ 3 , rac ‐ 5a and rac ‐ 5b are incorporated to give hormaomycin 1b and its analogue 23 , respectively, while rac ‐[D 2 ]‐ 4 is not. Feeding of rac ‐2‐( trans ‐2‐nitrocyclopropyl)glycine ( rac ‐ 6 ) unexpectedly gave the 5‐nitronorvaline‐containing hormaomycin analogues 25a – c . This is rationalized as arising from a cyclopropyl to homoallyl anion rearrangement followed by enzymatic hydrogenation of the double bond. These experiments provided new insights into the substrate specificity of the enzyme which assembles hormaomycin. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)