Synthetic Approaches Towards the Total synthesis of tubulysin and its fragments: A review

Background: Tubulysins, linear tetrapeptides show extraordinary cytotoxicity against various cancer cells, with IC50 values in nano or picomolar range. Due to their extremely vigorous anti-proliferative and antiangiogenic characteristics, tubulysins exhibit captivating prospects in the development of anticancer drugs. This review focuses on diverse routes for the total synthesis of natural and synthetic tubulysins as well as their fragments. Objective: The purpose of this review is to present the synthetic strategies for the development of antitumor agents, tubulysins. Conclusion: A range of synthetic pathways adopted for the total synthesis of tubulysins and their fragments have been described in this review. Synthesis of fragments, Tuv, Tup, and Tut can be accomplished by adopting appropriate strategies such as Manganese-mediated synthesis, Ireland-Claisen rearrangement, Mukaiyama aldol reaction, and Mannich process etc. Tubulysin B, D, U, V, and N14-desacetoxytubulysin H have been prepared through Mitsunobu reaction, tert-butanesulfinamide method, Tandem reaction, aza-Barbier reaction, Evans aldol reaction, and C-H activation strategies etc. The remarkable anticancer potential of tubulysins toward a substantiate target make them prominent leads for developing novel drugs against multidrug-resistant cancers.

Modern Synthesis and Chemistry of Stabilized, Ketene N,O-Acetals

Ketene N,O-acetals are robust and versatile synthons. Herein, we outline the synthesis of stable ketene N,O-acetals in the twenty-first century. In addition, we review recent developments in the chemistry of ketene N,O-acetals, as it applies to the vinylogous Mukaiyama aldol reaction, electrolysis, and pericyclic transformations. While dated reports rely on in situ use, modern methods of ketene N,O-acetal synthesis are heavily oriented towards producing products with high “bench” stability; moreover, in the present century, chemists typically enhance the stability of ketene N,O-acetals by positioning an electron-withdrawing group at the β-terminus or at the N-position. As propitious substrates in the vinylogous Mukaiyama aldol reaction, ketene N,O-acetals readily provide polyketide adducts with high regioselectivity. When exposed to electrolysis conditions, the title functional group forms a reactive radical cation and cleanly couples with a variety of activated olefins. Given their electron-rich nature, ketene N,O-acetals act as facile substrates in several rearrangement reactions; further, ketene N,O-acetals reserve the ability to act as either dienophiles or dienes in Diels-Alder reactions. Lastly, ketene N,O-acetals are seemingly more stable than their O,O- counterparts and more reactive than analogous N,N- or S,S-acetals; these factors, in combination, make ketene N,O-acetals advantageous substitutes for other ketene acetal homologs.

A Chiral, Dendralenic C–H Acid

We report the synthesis of a chiral dendralenic C–H acid (2), which contains three unsubstituted binaphthyl moieties. This motif and an achiral variant (1) can be made from their corresponding bis(sulfone) precursors in one step. Despite the presence of the enantiopure binaphthyl backbone, the newly designed chiral C–H acid showed only poor enantioselectivity in a Mukaiyama aldol reaction. First attempts toward the synthesis of 3,3’-hexasubstituted binaphthyl-based dendralenic acids are also reported.

Silyldienolates in Organocatalytic Enantioselective Vinylogous Mukaiyama-Type Reactions: A Review

Mukaiyama aldol, Mannich, and Michael reactions are arguably amongst the most important C–C bond formation processes and enable access to highly relevant building blocks of various natural products. Their vinylogous extensions display equally high potential in the formation of important key intermediates featuring even higher functionalization possibilities through an additional conjugated C–C double bond. Hence, it is much desired to develop highly selective vinylogous methods in order to enable unconventional, more efficient asymmetric syntheses of biologically active compounds. In this regard, silyl-dienolates were discovered to display high regioselectivities due to their tendency toward γ-additions. The control of the enantio- and diastereoinduction of these processes have been for a long time dominated by transition metal catalysis, but it received serious competition by the application of organocatalytic approaches since the beginning of this century. In this review, the organocatalytic applications of silyl-dienolates in asymmetric vinylogous C–C bond formations are summarized, focusing on their scope, characteristics, and limitations.

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.