From Serendipity to Rational Design: Heteroleptic Dirhodium Amidate Complexes for Diastereodivergent Asymmetric Cyclopropanation

Abstract

A heteroleptic dirhodium paddlewheel complex comprising three chiral carboxylate ligands and one achiral acetamidate ligand has recently been found to be uniquely effective in catalyzing the asymmetric cyclopropanation of olefins with α-stannylated (silylated and germylated) α-diazoacetate derivatives. A number of control experiments in combination with detailed computational studies provide compelling evidence that an interligand hydrogen bond between the −NH group of the amidate and the ester carbonyl group of the reactive rhodium carbene intermediate plays a quintessential role in the stereodetermining transition state. The penalty for distorting this array outweighs steric arguments and renders two of the four conceivable transitions states unviable. Based on this mechanistic insight, the design of the parent catalyst is revisited herein: placement of appropriate peripheral substituents allows high levels of diastereocontrol to be imposed upon cyclopropanation, which the original catalyst lacks. Because the new complexes allow either trans- or cis-configured stannylated cyclopropanes to be made selectively and in excellent optical purity, this transformation also marks a rare case of diastereodivergent asymmetric catalysis. The products are amenable to stereospecific cross coupling with aryl halides or alkenyl triflates; these transformations appear to be the first examples of the formation of stereogenic quaternary carbon centers by the Stille reaction; carbonylative coupling is also achieved. Moreover, tin/lithium exchange affords chiral lithium enolates, which can be intercepted with a variety of electrophilic partners. The virtues and inherent flexibility of this new methodology are illustrated by an efficient synthesis of two salinilactones, extremely scarce bacterial metabolites with signaling function involved in the self-regulatory growth inhibition of the producing strain.

Photosensitized Dioxygen Enables Intermolecular Cyclopropanation of Alkenes Directly with Active Methylene Compounds

“…Next, we examined different organic and organometallic PC's with a range of redox ability for their efficacy. Among several common PC's examined (C3), Eosin Y sodium salt (11) Independent reactions conducted with dodecyl and hexadecyl iodides under the standard catalytic conditions confirmed the formation alkyl formates (22, 65%; 23, 72%) generated from the reaction of alkyl radicals with O2 in DMF along with the cyclopropyl product 1 and unreacted alkyl iodides in 78-85% and 23-32%, respectively (Scheme 4C). Since reaction solutions usually turned reddish brown during reaction, we further analyzed reaction mixtures by UV-Vis spectrometer and confirmed the generation of I2 (Scheme 4D).…”

“…Marketed drugs containing a cyclopropyl ring Among limited methods available for intermolecular cyclopropanation, 8 , the most preferred and reliable method is the carbene insertion into alkenes. 9,10 This method is profoundly dependent on reactive carbene and metal-carbenoid intermediates [[M]=CR2], in particular the donoracceptor Rh-carbenoids, [9][10][11] derived from highly energetic and explosive diazoalkanes, which require stringent precautions for handling. 12,13 The metal-carbenoids are generally generated from diazomethane (CH2N2), TMSCHN2, PhCHN2, and -diazocarbonyl compounds by decomposition upon transition-metal [M] catalysts, 8,14,15 and more recently under photoredox 16,17 and engineered enzymatic [18][19][20][21] conditions.…”

YfeX – A New Platform for Carbene Transferase Development with High Intrinsic Reactivity

“…Carbene transfer reactions are an important route in organic synthesis since they generate hard to synthesize carbon‐carbon and carbon‐heteroatom bonds, and, importantly, these methods can be used in late‐stage functionalization of larger molecules, especially drug precursors [1–8] . Different methods for carbene transfer reactions have previously been developed utilizing transition‐metal complexes of Rh(II), Ir(III), Au(I) and Pd(II) that catalyze the decomposition of diazo reagents to form an electrophilic metal‐carbene unit, which is subsequently attacked by a nucleophilic reagent such as an olefin (for cyclopropanation) or an amine (for N−H insertion), etc [8–11] . These methods have a negative impact on the environment once they are scaled up in industry due to the need for expensive rare metals, and the usage of organic solvents during catalysis, which generates large amounts of waste [1,12–16] .…”

“…[ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ] Different methods for carbene transfer reactions have previously been developed utilizing transition‐metal complexes of Rh(II), Ir(III), Au(I) and Pd(II) that catalyze the decomposition of diazo reagents to form an electrophilic metal‐carbene unit, which is subsequently attacked by a nucleophilic reagent such as an olefin (for cyclopropanation) or an amine (for N−H insertion), etc. [ 8 , 9 , 10 , 11 ] These methods have a negative impact on the environment once they are scaled up in industry due to the need for expensive rare metals, and the usage of organic solvents during catalysis, which generates large amounts of waste. [ 1 , 12 , 13 , 14 , 15 , 16 ] The implementation of biocatalysis for C−H functionalization is an attractive avenue due to the ability of metalloenzymes to operate under environmentally friendly conditions, at high rates and with high stereo‐ and enantioselectivity.…”

Photosensitized O 2 enables intermolecular alkene cyclopropanation by active methylene compounds

“…Among the limited methods available for intermolecular cyclopropanation (8), the most preferred and reliable is carbene insertion into alkenes (9)(10)(11). This method is profoundly dependent on reactive carbene and metal-carbenoid intermediates [[M]=CR 2 ], in particular the donor-acceptor Rh-carbenoids (9,10,12) derived from highly energetic diazoalkanes, which require stringent precautions for handling (13,14). The metal-carbenoids are typically generated from diazomethane (CH 2 N 2 ), TMSCHN 2 , PhCHN 2 , and a-diazocarbonyl compounds by decomposition in reaction with transition-metal [M] catalysts (8,15,16), and more recently under photoredox (17,18) and engineered enzymatic (19)(20)(21)(22) conditions.…”