Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D

Abstract

An improved second-generation synthesis of the unnatural amino acid components of the anticancer peptaibol culicinin D has been developed. With a protected glutamic acid derivate as the starting material, the process readily delivered the Fmoc-protected free acid derivatives of AHMOD ((2S)-amino-(6R)-hydroxy-(4S)-methyl-8-oxodecanoic acid) and AMD ((2S)-amino-(4S)-methyldecanoic acid) required to support solid phase peptide synthesis (SPPS) for structure-activity studies of the natural product. The same approach also provides improved access to pipecolic acid derivatives. A novel Wittig reagent for one-carbon homologation of aldehydes, developed during this work, is also reported.

Catalytic Asymmetric Total Synthesis of Leucinostatin A

“…In 2015, an improved synthesis was published (Scheme 7), [29] in which a glutamic acid diester ( 37 ) was employed as a chiral starting compound. The methyl side chain unit was introduced by deprotonation by LHMDS and subsequent methylation ( 38 , 90 %).…”

“…Regarding development of a synthetic route to AHMOD, which contains more complex structural feature compared to that of HyLeu, the great contribution of the pioneering works in the stereo-controlled total synthesis of peptaibol antibiotics, culicinin D, [28,29,30,31] and trichoderin A, [32] by Brimble and coworkers should be highlighted. Only one research group had previously disclosed synthetic routes to AHMOD (Scheme 5) before the synthesis; Lavergne and co-workers preinstalled the absolute configuration of the methyl group at the 4-position into the structure of one of the starting materials (21).…”

“…It would be reasonable to synthesize a nonapeptide framework of leucinostatin A by SPPS; indeed, Brimble [28,29,30] used this protocol to connect amide linkages of culicinin D and trichodermin A. In our synthesis, however, solution phase synthesis was also used from the elongation step with the HyLeu residue to reduce the amount of precious building blocks used.…”

Facile synthesis of α-alkoxymethyltriphenylphosphonium iodides: new application of PPh3/I2

“…Functionalized phosphonium salts are gaining much attention for their diverse applications in organic synthesis [ 1 – 5 ]. α -Alkoxymethyl phosphonium salts are largely used for carbon homologation to carbonyl compounds [ 6 – 10 ] and also as significant synthetic intermediates [ 11 – 17 ]. Recently, unique reactivity of this class has been explored in nucleophilic substitution [ 18 – 20 ] and in novel phenyl transfer reactions [ 21 , 22 ].…”

“…Recently, unique reactivity of this class has been explored in nucleophilic substitution [ 18 – 20 ] and in novel phenyl transfer reactions [ 21 , 22 ]. Methoxymethyltriphenylphosphonium chloride is commercially available salt from this class, but problem associated with its preparation involve toxic intermediate, higher temperature and long reaction time [ 9 , 11 , 23 ]. In perspective of alternative derivatives; α-methoxymethyl triphenylphosphonium iodide was reported by reaction of bis -methoxymethane ( 1a ) with TMSI, followed by phosphination of methoxymethyl iodide in benzene (Scheme 1 a) [ 24 ].…”