Total synthesis

About: Total synthesis is a research topic. Over the lifetime, 25578 publications have been published within this topic receiving 489319 citations.

Catalyst-controlled asymmetric synthesis of fostriecin and 8-epi-fostriecin.

Abstract: Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.

Human calcitonin. VI. Synthesis of calcitonin M

Abstract: A detailed account is given of the total synthesis of human calcitonin M, the hypocalcaemic hormone possessing the dotriacontapeptide sequence I. In the build up of I, the protected sequences 1–10 and 11–32 served as intermediates for the preparation of the protected precursor dotriacontapeptide 1–32 (II). While the synthesis of the fragment 1–10 has been reported previously [1], the present account includes a detailed description of the build up of the intermediate 11–32. Racemisation encountered in the synthesis of this fragment is discussed and conditions indicated in which it is minimized. From the final coupling step using dicyclohexylcarbodiimide-N-hydroxysuccinimide [3], the protected dotriacontapeptide II was obtained pure in a yield of 65% after counter-current distribution. In the removal by acidolysis of the protecting groups from II even under optimal conditions two side reactions occur: alkylation of the 8-methionine side chain and N to O acyl migration at the serine or threonine residues. By-products from these reactions were removed by counter-current distribution giving very pure I free of diastereoisomers and possessing the biological activity of highly purified natural calcitonin M. In the routine assay [4] after repeated testing its activity was evaluated at 100 ± 5 U/mg (calculated on content of free peptide).

One-pot native chemical ligation of peptide hydrazides enables total synthesis of modified histones

Abstract: One of the rising demands in the field of protein chemical synthesis is the development of facile strategies that yield the protein in workable quantities and homogeneity, with fewer handling steps. Although the native chemical ligation of peptide hydrazides has recently been shown to be useful for the chemical synthesis of proteins carrying acid-sensitive modification groups, previous hydrazide-based protein synthesis studies have used sequential ligation strategies. Here, we report a practical method for a “one-pot” native chemical ligation of peptide hydrazides that would circumvent the need for the isolation of the intermediate products. This method employed a fast and selective arylboronate oxidation reaction mediated by H2O2, which draws attention to the potential applications of the thus far under-exploited boron-based functionalities in protein chemical synthesis. To demonstrate the practicality and efficiency of the new one-pot method, we report its application to a scalable total synthesis of modified histones (with five analogues of H3 and H4 as examples) on a multi-milligram scale, with good homogeneity.

Access to the akuammiline family of alkaloids: total synthesis of (+)-scholarisine A.

Abstract: The planning and implementation of an enantioselective total synthesis of (+)-scholarisine A is presented. Key tactics employed include a novel cyclization, consisting of a nitrile reduction coupled with concomitant addition of the resultant amine to an epoxide; a modified Fischer indolization; an oxidative lactonization of a diol in the presence of an indole ring; and a late-stage cyclization to complete the caged ring scaffold. The development of a possible "retro-biosynthetic" approach to other members of the akuammiline alkaloid family is also described.