2812-46-6Relevant articles and documents
Synthesis of the marine sponge cycloheptapeptide phakellistatin 51
Pettit, George R.,Toki, Brian E.,Xu, Jun-Ping,Brune, Daniel C.
, p. 22 - 28 (2000)
Phakellistatin 5 (1), a constituent of The Federated States of Micronesia (Chuuk) marine sponge Phakellia costada, was synthesized by solution-phase and solid-phase techniques. Because the linear peptide bearing (R)-Asn resisted cyclization, the synthesis of this peptide was repeated using the PAL resin attachment proceeding from N-Fmoc-D-Asp-α-OCH2CH=CH2. After addition of the final unit (Ala), the allyl ester was removed under neutral conditions with Pd°[P(C6H5)3l4. Removal of the final Fmoc- protecting group and cyclization with PyAOP provided (R)-Asn-phakellistatin 5 (2) in 28% overall yield. The same synthetic route from (S)-Asp led to natural phakellistatin 5 (1) in 15% overall recovery. The solution-phase and solid-phase synthetic products derived from (S)-Asp were found to be chemically but not biologically identical with natural phakellistatin 5 (1). This important fact suggested that a trace, albeit highly cancer-cell growth inhibitory, constituent accompanied the natural product or that there is a subtle conformational difference between the synthetic and natural cyclic peptides.
Structure, Total Synthesis, and Biosynthesis of Chloromyxamides: Myxobacterial Tetrapeptides Featuring an Uncommon 6-Chloromethyl-5-methoxypipecolic Acid Building Block
Gorges, Jan,Panter, Fabian,Kjaerulff, Louise,Hoffmann, Thomas,Kazmaier, Uli,Müller, Rolf
, p. 14270 - 14275 (2018)
Soil-living microbes are an important resource for the discovery of new natural products featuring great structural diversity that are reflective of the underlying biosynthetic pathways as well as incorporating a wide range of intriguing small-molecule building blocks. We report here the full structural elucidation, total synthesis, and biosynthesis of chloromyxamides, a new class of tetrapeptides that display an unprecedented 6-chloromethyl-5-methoxypipecolic acid (CMPA) substructure. Chemical synthesis—including an approach to access the CMPA unit—was pursued to confirm the structure of the chloromyxamides and enabled determination of the absolute configuration in the CMPA ring. A model for the nonribosomal assembly of chloromyxamides was devised on the basis of the combined evaluation of the biosynthetic gene cluster sequence and the feeding of stable isotope-labeled precursors. This provided insight into the formation of the various chloromyxamide derivatives and the biogenesis of the CMPA unit.
Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives
Breen, Christopher P.,Jamison, Timothy F.
supporting information, p. 14527 - 14531 (2019/11/03)
A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h?1, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h?1.
