Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents

Abstract

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step and time economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalyzed [5+2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalyzed or thermal [4+2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions - the homologous Diels-Alder and Diels-Alder cycloadditions - through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization

“…Ynamide formation ( 6 → 1 ) was achieved using copper-catalysed coupling of the sulfonamide with a bromoalkyne 32 , or via formation of an intermediate dichloroenamide 33 . Initial screening of ruthenium 14 and rhodium 20 34 catalyst systems ( Table 1 ) revealed that only the latter afforded high yields of azabicycle 7a from ynamide 1a ; using [Rh(cod)naphthalene]SbF 6 (5 mol%) as the catalyst 35 36 , the cycloisomerization could be effected within 3 h at room temperature, giving 7a in 91% yield (Entry 6).…”

Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors

“…The flexibility of these syntheses has enabled current studies aimed at achieving selective inhibition through scaffold modulation. More generally, this study illustrates how the confluence of bio-inspired and computer-aided design, informed by new reactions ([5 + 2]) or novel synthetic strategies (serialized [5 + 2]/[4 + 2] cycloadditions), 31 can be used to achieve practical kinase inhibitory function. Further studies on these novel kinase inhibitors are underway as are more general studies directed at achieving step-economically accessed function through synthesis-informed design.…”

Function through Synthesis-Informed Design

“…Our first strategy to step-economically access these analogs involved a three-component serial cycloaddition based on an initial [5 + 2] cycloaddition that we introduced in 1995. 30 The diene product of that step would then be captured in a second (Diels–Alder) cycloaddition, producing most of the target analog structure in one operation. In fact, while the process proved less direct, this approach did provide analogs in only seven steps with the lead analog sufficiently potent (IC 50 = 2.9 μM) to encourage further study.…”

“…For example, in studies directed at new kinase inhibitors, we developed an interest in 1,2,3-butatriene as a reagent for one-flask back-to-back cycloadditions. 30 Enophilic cycloaddition to its 2,3-double bond would generate a diene for a subsequent dienophilic cycloaddition. However, butatriene is difficult to make, is unsafe to handle, and reacts uncontrollably with most reactants.…”