Entry to Heterocycles Based on Indium‐Catalyzed Conia‐Ene Reactions: Asymmetric Synthesis of (−)‐Salinosporamide A

Abstract

Conica can: The In(OTf)3‐catalyzed cyclization of nitrogen‐ and oxygen‐tethered acetylenic malonic esters gives five‐ to seven‐membered heterocycles in moderate to excellent yields (see scheme; Tf=trifluoromethanesulfonyl). The asymmetric synthesis of (−)‐salinosporamide A illustrates the synthetic utility of the method.

Advances toward the Synthesis of Functionalized γ-Lactams

“…35 Indium trifluoromethanesulfonate [In (OTf) 3 ] was identified as the most effective Lewis acid, affording functionalized pyrrolidinones. The classical Conia-ene reaction requires harsh conditions that can lead to racemization and/or isomerization of the reaction substrates; however, this modified method used mild reaction conditions, tolerating a broad range of substrates.…”

“…35 The synthetic efforts commenced with the treatment of compound 106 with In (OTf) 3 in the absence of DBU (as the substrate was base-labile). The resultant product was treated with Lipase to selectively free the primary hydroxyl group, which was oxidized with Dess Martin periodinane (DMP) to afford compound 107.…”

Recent Developments in Indium Metal and Its Salts in Organic Synthesis

“…An efficient and versatile indium-catalyzed methodology for the synthesis of pyrrolidinones and its application to the synthesis of salinoporamide A has recently been reported. [96] The cyclization proceeded with E selectivity, without any racemization at high temperature and also with high atom efficiency. The reactivities of different substrates in indium catalyzed Conica-ene reactions are shown in Table 8.…”

Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies

“…79,80) The importance of nitrogen-containing heterocycles as drugs and other various chemical entities continues to inspire the development of tactical methods for their synthesis. In connection with a project [81][82][83][84] directed toward the synthesis of biologically intriguing natural products with highly functionalized pyrrolidinone cores such as lactacystin (72), salinosporamide A (73), neooxazolomycin (74), and oxazolomycin A (75), we became interested in developing a novel approach relying upon the Conia-ene reaction of amidomalonate 76 to give 78 via 77 (Chart 16). We envisaged that the suitably functionalized pyrrolidinone skeletons useful for the synthesis 4.1 Indium-Catalyzed Cyclization 83) Conia-ene reactions 85) usually require harsh conditions so that racemization of the product and isomerization of the exo olefin from the β,γ-to α,β-position are serious matters of concern in the reaction shown in Chart 16.…”

“…Intermediate 82 then undergoes protonation from another molecule of 76 to produce pyrrolidinone 83 with the E-configuration with regeneration of indium enolate 81. 83) Salinosporamide A (73), 90) a secondary metabolite of the marine actinomycete Salinospora tropica, displays very potent proteasome-inhibitory activity (IC 50 =1.3 nM) that is 35-fold more potent than that of omuralide, a representative proteasome inhibitor. In addition, this compound shows very potent in vivo cytotoxicity against many tumor cell lines and is therefore currently in clinical trails for the treatment of cancer.…”