Total Synthesis of Thiostrepton, Part 2: Construction of the Quinaldic Acid Macrocycle and Final Stages of the Synthesis

Abstract

In the preceding Communication in this issue [1] we described the construction of the thiazoline-containing macrocycle 2 as an advanced intermediate toward the total synthesis of thiostrepton (1). Herein we report the construction of suitable dipeptide (8, Scheme 1) and quinaldic acid (22, Scheme 2) fragments, their union with 2, and the final stages of the total synthesis of 1.Scheme 1 outlines the synthesis of the required dipeptide derivative 8 from 3, a known phenylseleno-substituted derivative of alanine. [2] Thus, 3 was converted into allyl ester 4, which was treated with TFA to effect its conversion into the amino derivative 5. Coupling of amine 5 with Boc-l-alanine

Thiopeptide Antibiotics: Retrospective and Recent Advances

“…Pioneering work by the groups of Kelly [121,122,123,124], Shin [35], Moody [125,126], Nicolaou [127,128], Ciufolini [36,37], and Bach [127,129,130] developed different methodologies that led to the total synthesis of various thiopeptides. However, most efforts have been devoted to the construction of the central polyheterocyclic core [121,122,123,124,131,132,133,134,135,136,137,138], which have been synthesized by two well-distinguished main strategies: modification of an existing pyridine and construction of the central ring.…”

From Amino Acids to Heteroaromatics—Thiopeptide Antibiotics, Nature's Heterocyclic Peptides

“…[87,[107][108][109] The strategy is convergent, and whilst relying on standard peptide technology to form amide bonds, it also deviates from convention, for example, in its use of the azido group as a masked amine to obviate potentially difficult deprotection steps. [110][111][112][113] The synthesis starts with the tetrahydropyridine core 109.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…It consists in transformations of diimines (77) and (78) readily available from dialdehydes (75) and (76), respectively, using the double Staudinger reaction accompanied by the formation of two additional four-membered rings. It is noteworthy that diimine (77) with closely located functional groups reacted low-selectively yielding a mixture (1:1) of cys-syn-cys (72) and cys-anti-cys (73) diastereomers, and diimine (78) almost exclusively turned into cys-anti-cys diastereomer (74) (Scheme 19).…”

“…[68] The formation of cys-bridged cycles (109-113) though with low yields during the interaction of unsubstituted cyclen (31) and cyclam (32) with bis-electrophiles (114-118) (Scheme 27) seems to be surprising. [3] Locking two macro rings [69][70][71][72][73] is required in synthesis of some bicyclic compounds, including and biologically active.…”