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The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported., Enantiomerically enriched azabicyclic compounds found in several important families of alkaloids can be prepared by a remarkably stereospecific and stereoselective intramolecular Schmidt reaction. The initial asymmetric alcohol center controls the whole process, leading to the formation of one out of up to four possible diastereoisomers with inversion of the configuration at the original asymmetric center.

The stereoselectivity and stereospecificity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (–)-(cis)-3-propylindolizidine and (–)-(cis)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

The stereoselectivity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity of is rationalized based on theoretical calculations.

Science 363(6425), 391 - 396 (2019). doi:10.1126/science.aav1610, Published by Moses King, Cambridge, Mass.

A ‘direct’ alkynylation of isatins, which uses potassium tert-butoxide to provide the desired 3-hydroxy-3-ethynyl-2-oxindoles in good to high yields, is reported. This protocol proceeds smoothly for both electron-rich and electron-deficient alkynes in comparable reaction rates and does not require any specially design ligand or expensive transition-metal catalysts.

The Cu-catalyzed oxidation of ketones with O2 has recently been extensively utilized to cleave the α-C-C bond. This report examines the selective aerobic hydroxylation of tertiary α-C-H bonds in ketones without C-C cleavage. We set out to understand the underlying mechanisms of these two possible reactivity modes. Using experimental, in situ IR spectroscopic, and computational studies, we investigated several mechanisms. Our data suggest that both C-C cleavage and C-H hydroxylation pathways proceed via a common key intermediate, i.e., an α-peroxo ketone. The fate of this peroxide dictates the ultimate product selectivity. Specifically, we uncovered the role of hppH [=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine] to act not only as a base in the transformation but also as a reductant of the peroxide to the corresponding α-hydroxy ketone. This reduction may also be accomplished through exogenous phosphine additives, therefore allowing the tuning of reduction efficiency toward higher driving forces, if required (e.g., for more-activated substrates). The likely competitive pathway is the cleavage of peroxide to the α-oxy radical (likely catalyzed by Cu), which is computationally predicted to spontaneously trigger C-C bond cleavage. Increasing the susceptibility of this deperoxidation step via (i) the removal of reductant (use of different base, e.g., DBU) or the modulation of (ii) the substitution pattern toward greater activation (substrate control) and (iii) the nature of Cu catalyst (counterion and solvent dependence) will favor the C-C cleavage product.

Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process.

The Cu-catalyzed oxidation of ketones with O2 has recently been extensively utilized to cleave the α-C–C bond. This report examines the selective aerobic hydroxylation of tertiary α-C–H bonds in ketones without C–C cleavage. We set out to understand the underlying mechanisms of these two possible reactivity modes. Using experimental, in situ IR spectroscopic, and computational studies, we investigated several mechanisms. Our data suggest that both C–C cleavage and C–H hydroxylation pathways proceed via a common key intermediate, i.e., an α-peroxo ketone. The fate of this peroxide dictates the ultimate product selectivity. Specifically, we uncovered the role of hppH [= 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine] to act not only as a base in the transformation but also as a reductant of the peroxide to the corresponding α-hydroxy ketone. This reduction may also be accomplished through exogenous phosphine additives, therefore allowing the tuning of reduction efficiency toward higher driving forces, i...

A one-pot procedure for the efficient hydroazidation of alkenes involving hydroboration with catecholborane followed by reaction with benzenesulfonyl azide in the presence of a radical initiator is described. The regioselectivity is controlled by the hydroboration step and corresponds in most cases to an anti-Markovnikov regioselectivity. This procedure is applicable to a wide range of alkenes and gives excellent results with 1,2-disubstituted and trisubstituted alkenes.

Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process.

Recent advances in radical azidation using sulfonyl azides are presented. For instance, radical carboazidation using α-iodoketones, desulfitative carboazidation, and anti- Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a large number of functional groups and allow the synthesis of organic azides that would be difficult to synthesize otherwise. The transformation of the azides using reductive processes as well as a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids includ- ing indolizidine 167B, monomorine I, cylindricine C, and lepadiformine C.

A powerful intramolecular Schmidt reaction starting from primary azidoalcohols is reported. This approach involves a nonacidic activation of the alcohol via triflation. The synthetic potential offered by the mild reaction conditions is demonstrated by a highly selective synthesis of (−)-indolizidine 167B.

A powerful intramolecular Schmidt reaction starting from primary azidoalcohols is reported. This approach involves a nonacidic activation of the alcohol via triflation. The synthetic potential offered by the mild reaction conditions is demonstrated by a highly selective synthesis of (−)-indolizidine 167B.