Cyclopropene Derivatives as Precursors to Enantioenriched Cyclopropanols and n‐Butenals Possessing Quaternary Carbon Stereocenters

Abstract

The diastereoselective carbocupration reaction of cyclopropenylmethyl ethers followed by addition of oxenoid leads to the formation of diastereo- and enantiomerically enriched 2,2,3,3-tetrasubstituted cyclopropanol derivatives. Ring fragmentation of the copper cyclopropanolate leads to acyclic butenal derivatives possessing enantiomerically enriched α-quaternary carbon stereocenters in a single-pot operation.

Efficient Access to All‐Carbon Quaternary and Tertiary α‐Functionalized Homoallyl‐type Aldehydes from Ketones

“…[2] Fine-tuning of the reaction conditions enabled the development of highly enantioselective variants by the groups of List [3] and Yoshida, [4] which complement asymmetric organocatalytic (Jacobsen) [5] and stereodivergent dual-catalytic (Carreira) [6] approaches.T he process also benefits from switching to nickel catalysis,a sr ecently disclosed by Sauthier and coworkers. [10] However,t he high efficiency of these methods in terms of their enantioselectivity or general applicability is counterbalanced by the limited availability of a,b-unsaturated and a-quaternary b,g-unsaturated aldehydes,a nd there are hardly any methods for the synthesis of differently substituted aldehydes with all-carbon a-quaternary centers.P rior to Evans work, [9] the a-derivatization of aldehydes by enolate-type chemistryalbeit limited to the synthesis of a-tertiary species-has been achieved by Hodgson and co-workers [11] by epoxide-aldehyde isomerization (Scheme 1B1). [8] Amajor advancement in the field was reported in 2016 by Evans and Wright, who developed an enantioselective rhodium-catalyzed allylation of prochiral a,a-disubstituted aldehyde enolates with allyl benzoate (Scheme 1A2).…”

“…[7] Interestingly,f or simple linear aldehydes,t his reaction could be incorporated into at andem aldol condensation/allylation process.The development of these strategies also allowed overcoming the reluctance of the conceptually simplest strategy based on the use of aldehyde enolates as nucleophiles in alkylation chemistry. [10] However,t he high efficiency of these methods in terms of their enantioselectivity or general applicability is counterbalanced by the limited availability of a,b-unsaturated and a-quaternary b,g-unsaturated aldehydes,a nd there are hardly any methods for the synthesis of differently substituted aldehydes with all-carbon a-quaternary centers.P rior to Evans work, [9] the a-derivatization of aldehydes by enolate-type chemistryalbeit limited to the synthesis of a-tertiary species-has been achieved by Hodgson and co-workers [11] by epoxide-aldehyde isomerization (Scheme 1B1). [9] Furthermore,t he selective ring fragmentation of diastereomerically pure and enantioen-riched cyclopropanols represents av ersatile process for synthesizing acyclic n-butenals with all-carbon quaternary centers,a ss hown in elegant work by Marek and co-workers (Scheme 1A3).…”

“…The reactions proceeded cleanly and gave the corresponding products in high chemical yields regardless of the nature [cyclic (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)oracyclic (3,16)] of the substrates and the substitution pattern across the starting ketones.W ea nticipated that our method would provide access to important a-methyl aldehydes (e.g., [8][9][10], which are used as substrates for ap lethora of chemical transformations, [25] in just one chemical operation, without the need for the multistep (four) and complex procedures routinely employed. The reactions proceeded cleanly and gave the corresponding products in high chemical yields regardless of the nature [cyclic (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)oracyclic (3,16)] of the substrates and the substitution pattern across the starting ketones.W ea nticipated that our method would provide access to important a-methyl aldehydes (e.g., [8][9][10], which are used as substrates for ap lethora of chemical transformations, [25] in just one chemical operation, without the need for the multistep (four) and complex procedures routinely employed.…”

Copper mediated carbometalation reactions

“…64 Acetate was found to be the best leaving group. As previously discussed for Scheme 17, substituent R 2 is necessary to block one face of the cyclopropene allowing the high observed diastereoselectivity.…”

Efficient Access to All‐Carbon Quaternary and Tertiary α‐Functionalized Homoallyl‐type Aldehydes from Ketones

“…[9] Furthermore,t he selective ring fragmentation of diastereomerically pure and enantioen-riched cyclopropanols represents av ersatile process for synthesizing acyclic n-butenals with all-carbon quaternary centers,a ss hown in elegant work by Marek and co-workers (Scheme 1A3). [10] However,t he high efficiency of these methods in terms of their enantioselectivity or general applicability is counterbalanced by the limited availability of a,b-unsaturated and a-quaternary b,g-unsaturated aldehydes,a nd there are hardly any methods for the synthesis of differently substituted aldehydes with all-carbon a-quaternary centers.P rior to Evans work, [9] the a-derivatization of aldehydes by enolate-type chemistryalbeit limited to the synthesis of a-tertiary species-has been achieved by Hodgson and co-workers [11] by epoxide-aldehyde isomerization (Scheme 1B1). [12] Accordingly,the treatment of am onosubstituted epoxide with ah indered lithium amide base provided an ucleophilic enamine susceptible to alkylation to finally afford a-substituted aliphatic aldehydes.…”