Abstract:We report a novel approach to some chiral tetrahydropyran and delta-lactone targets that utilizes the asymmetric amino-Cope rearrangement as a key synthetic step. Products of amino-Cope rearrangement chemistry have also been applied to access piperidine targets, further demonstrating the potential of the methodology.
“…Allin reported that a chiral auxiliary could be used for the anion-accelerated amino-Cope rearrangement (Scheme ). Unfortunately, elevated temperatures were required and significant stereochemical erosion was observed when chiral N -benzyl substituents were employed. Optimizations revealed that amino-alcohol chiral auxiliaries could somewhat improve this erosion challenge, but this was accomplished at a cost of using excess n -butyl lithium and much higher (reflux) temperatures.…”
We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C-C or C-X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation-recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot.
“…Allin reported that a chiral auxiliary could be used for the anion-accelerated amino-Cope rearrangement (Scheme ). Unfortunately, elevated temperatures were required and significant stereochemical erosion was observed when chiral N -benzyl substituents were employed. Optimizations revealed that amino-alcohol chiral auxiliaries could somewhat improve this erosion challenge, but this was accomplished at a cost of using excess n -butyl lithium and much higher (reflux) temperatures.…”
We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C-C or C-X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation-recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot.
“…Schemes B and C demonstrate the efficacy of allylic α‐amino nitriles 1 for the enantioselective construction of a variety of β‐stereogenic carbonyl derivatives. In this regard, the allylation of 1 a followed by in situ hydrolysis of the resulting cyanoenamine furnished the carboxylic acid 5 a in good yield and with excellent enantioselectivity (Scheme B). The carboxylic acid can be readily converted to a variety of other β‐substituted carbonyl derivatives.…”
An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.
“…As mentioned above, these salts in aprotic media and in the presence of base afford the dimer called bis(1,3-thiazolin-ylidene) or DTDAF (Scheme ). It is worth noting that in some conditions the ring opening of thiazole core is also observed instead of the coupling. , This synthetic strategy is one of the most employed pathways towards DTDAF and gives rise to various substituted donor derivatives (Tables −3). ,,,,,,− 5 …”
Section: 1 Coupling Of 13-thiazolium Salts In Basic
Medium (Route A)mentioning
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