Protecting-group-free synthesis as an opportunity for invention

Abstract

The constant pressure to prepare compounds in a more efficient manner has placed the process by which traditional synthetic chemistry is conducted under scrutiny. Areas that have the potential to be improved must be highlighted and modified, so that we can approach the criterion of the 'ideal synthesis'. One area that offers this prospect is the minimization of the use of protecting groups in synthesis. A protection/deprotection event introduces at least two steps into a sequence, incurring costs from additional reagents and waste disposal, and generally leads to a reduced overall yield. Here we present relevant historical context and highlight recent (post-2004) total syntheses that have developed new chemistry in an effort to exclude protecting groups. The invention of chemoselective methodologies is crucial to the execution of 'protecting-group-free' synthesis, and recent advances in this area are also highlighted.

A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds

“…Recently, the construction of complicated organic molecules without using protecting groups (protecting-group-free synthesis) 52,53 , especially from the viewpoints of atom economy 54 , step economy 55 and redox economy 56 , has received significant research interest in the context of ideal synthesis 57 and green sustainable chemistry 58 . Generally, skeleton-building steps are the most difficult with respect to avoiding usage of protecting groups because such steps often use strongly basic nucleophilic reagents.…”

A reação de Diels-Alder no início do século vinte um

“…O produto cicloaduto é um cicloexeno altamente funcionalizado, com até quatro centros estereogênicos novos, sendo criadas simultaneamente duas ligações σ novas. É digno de nota que as reações pericíclicas em geral, e certamente as cicloadições [4+2], as reações de Diels-Alder, não precisam de grupos protetores para a sua perfeita execução (conceito de Baran), 9 ocorrem com total economia de átomos (conceito de Trost), 10 apresentam um aumento considerável de complexidade estrutural (conceito de Wender) 11 e com a criação de duas ligações σ novas são altamente construtivas (conceito de Hendrickson). 12 Atualmente, a reação de Diels-Alder compete com as reações de metátese 13,14 e acoplamento cruzado 15 como as reações chaves em síntese total, frequentemente em parceria ou até em combinação dominó.…”

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

“…13 In addition, a distinct biosynthetic [4+2] cyclization is postulated for andranginine (7) (path C), involving an intermediate bearing a cross-conjugated triene with a higher oxidation level than 4. 14 The architectural complexity as well as the skeletal variation of the cognate alkaloids could be pre-encoded into the polyunsaturated structure of the achiral intermediate (4), settled at a branching point of the biogenesis. In the biosynthetic assembly line, the protection of the labile intermediates in an enzyme catalytic site provides kinetic stabilization and regulation of multimodal reactivity, allowing cascade synthesis with control of chemo-, regio-, stereo-, and even enantioselectivity.…”

“…Cleavage of two C-C bonds in the central core of 3 generates the hypothetical key intermediate dehydrosecodine (4), composed of a pair of diene units, a dihydropyridine (DHP), and a vinylindole. The intermediate (4) may undergo divergent Diels-Alder-type reactions in either of two ways, with the DHP group serving as a dienophile or diene to form the aspidosperma-type alkaloid tabersonine (5) (path A) or the iboga-type catharanthine (6) (path B). 13 In addition, a distinct biosynthetic [4+2] cyclization is postulated for andranginine (7) (path C), involving an intermediate bearing a cross-conjugated triene with a higher oxidation level than 4.…”

“…12 Multistep enzymatic transformations commence with the assembly of tryptamine (1) and secologanin (2) to produce preakuammicine (3). Cleavage of two C-C bonds in the central core of 3 generates the hypothetical key intermediate dehydrosecodine (4), composed of a pair of diene units, a dihydropyridine (DHP), and a vinylindole. The intermediate (4) may undergo divergent Diels-Alder-type reactions in either of two ways, with the DHP group serving as a dienophile or diene to form the aspidosperma-type alkaloid tabersonine (5) (path A) or the iboga-type catharanthine (6) (path B).…”