Rhodium-catalyzed enantioselective cyclopropanation of electron-deficient alkenes

Abstract

The rhodium-catalyzed reaction of electron-deficient alkenes with substituted aryldiazoacetates and vinyldiazoacetates results in highly stereoselective cyclopropanations. With adamantylglycine derived catalyst Rh2(S-TCPTAD)4, high asymmetric induction (up to 98% ee) can be obtained with a range of substrates. Computational studies suggest that the reaction is facilitated by weak interaction between the carbenoid and the substrate carbonyl but subsequently proceeds via different pathways depending on the nature of the carbonyl.. Acrylates and acrylamides result in the formation of cyclopropanation products while the use of unsaturated aldehydes and ketones results in the formation of epoxides.

On the Structure of Chiral Dirhodium(II) Carboxylate Catalysts: Stereoselectivity Relevance and Insights

“…Fox model was very well supported by the results obtained earlier for Rh 2 (S-PTAD) 4 by being more enantioselective than Rh 2 (S-PTTL) 4 [37,[91][92][93]95,96]. The results were very relevant as the much bulkier adamantyl groups would more efficiently block the carbene ligands from coordinating to the achiral rhodium face (shrouded by the adamantly groups) compared to the tert-butyl groups of Rh 2 (S-PTTL) 4 leading to the observed more enantioselective outcome.…”

Improved Cyclopropanation Activity of Histidine‐Ligated Cytochrome P450 Enables the Enantioselective Formal Synthesis of Levomilnacipran

“…15 In particular, we hypothesized that an enantioselectiveBM3 catalyst could be used for the cyclopropanation of 1 with EDA in an expedient synthesis of the levomilnacipran core (Scheme 1). Levomilnacipran (Fetzima™) is a selective serotonin and norepinephrine reuptake inhibitor that was recently approved by the Food and Drug Administration for treatment of clinical depression.…”

Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion

“…3a). Treatment of 12 with methyl-p-bromophenyl diazoacetate (2) and Rh 2 (TPA) 4 in trifluorotoluene at 83°C selectively gave C-H insertion product 13 (44% yield, 2.2:1 dr), with no competing cyclopropanation at either olefin 43 . Furthermore, although securinine contains four C-H bonds adjacent to the amine (two methine and two diastereotopic methylene in nature), only a single methylene C-H bond undergoes carbene insertion.…”

“…Sercloremine (21) and apovincamine (14a) were obtained from the Novartis compound archive. Methyl-p-bromophenyl diazoacetate (2) as well as its analogues 8a and 8b were synthesized according to a previously reported procedure 43 . All reactions were conducted under an inert atmosphere of dry nitrogen.…”