Copper‐Catalyzed 1,5‐Addition of Grignard reagents to Enantioenriched Donor–Acceptor Cyclopropanes with Inversion

Abstract

Ah ighly regioselective and stereoselective 1,5addition of alkyl groupst oe nantioenriched donor-acceptor cyclopropanes 1 and bicyclic cyclopropanes such as 6aryl-1-methoxycarbonyl-3-oxabicyclo[3.1.0]hexan-2-ones 4 using aG rignard reagentw ith ac atalytic amounto f Cu(OTf) 2 (0.1 equivalent) afforded optically active diesters 2 or trans-a,b-disubstituted g-butyrolactones 5 with an excellent level of stereoinduction. An excesso ft he Grignard reagent is necessary to perform the 1,5-alkylation with high yields.I nt he reactiono ft he enantioenrichedb icyclic lactone 4,ahighly stereoselective 1,5-addition and subsequent highly trans-selective protonation of the magnesium enolate via keto-enol isomerization furnished the trans-a,b-disubstituted-g-lactones with three contiguous chiral centers with excellent enantioselectivity. Based on the results, we also proposed the mechanism through cluster ion pairs or as imple ion pairt or ationalize the high stereoselectivity of the reaction.Supportinginformation for this article can be found under http:// dx.

A Widely Applicable and Versatile Method for the Ring‐Opening 1,3‐Carbocarbonation of Donor‐Acceptor Cyclopropanes

“…We began our optimizations with methylmagnesium chloride as nucleophile and p ‐methoxybenzyl bromide (PMBBr) as electrophile. For the ring‐opening step, the improved conditions from Nishi [16] were applied (see Supporting Information) and PMBBr was added after full conversion of the starting material. However, without additional base only poor yields were obtained (Table 1, entry 1).…”

“…Since it has already been shown by Nishi that nucleophilic ring-opening of DACs with Grignard reagents is Chemistry-A European Journal stereoselective, [16] further mechanistic experiments were not performed.…”

Stereoselective Synthesis of Contiguous Cyclopropylaziridines: Enabling the Construction of Versatile Chiral Molecules Including γ‐Lactams via Ring‐Opening Reactions

“…The ROR of donor‐acceptor (D−A) cyclopropane [14] such as enantioenriched bicyclic lactone 3 b with Gilman reagent [(R 2 Cu)MgX], which is derived from CuI and RMgX, was also examined. Mechanistically, in‐situ prepared Gilman reagent chelates with dicarbonyl groups in 3 b and promotes a nucleophilic attack by the alkyl group from an organocuprate on the less hindered donor‐substituted site of a cyclopropane via a 1,5‐addition manner, resulting in the formation of target molecule 5 b with inversion of configuration (Scheme 4, entry 2) [15] . We turned our focus to the ROR of vinylcyclopropane by boronic acid, which was performed in water with Pd(OAc) 2 as the catalyst [16] .…”

“…Mechanistically, in-situ prepared Gilman reagent chelates with dicarbonyl groups in 3 b and promotes a nucleophilic attack by the alkyl group from an organocuprate on the less hindered donorsubstituted site of a cyclopropane via a 1,5-addition manner, resulting in the formation of target molecule 5 b with inversion of configuration (Scheme 4, entry 2). [15] We turned our focus to the ROR of vinylcyclopropane by boronic acid, which was performed in water with Pd(OAc) 2 as the catalyst. [16] Under these conditions, the reaction between vinylcyclopropane in 3 d and phenylboronic acid proceeded smoothly, yielding the linear trans ring-opened product 5 c in 53% yield (Scheme 4, entry 3).…”

Creating Stereocenters within Acyclic Systems by C–C Bond Cleavage of Cyclopropanes

“…Regio- and diastereoselective direct nucleophilic attack on activated cyclopropanes produced diastereomerically enriched open-chain products (Scheme ). Many different Lewis acids as well as nucleophiles could be used on variously activated cyclopropane derivatives (Scheme a–e). − Strikingly, weak nucleophiles such as ketones can open the cyclopropyl core in an intramolecular manner, and aromatization of a quinone-type spiro system may serve as a strong enough driving force for ring opening, sparing the use of any Lewis acid (Scheme e–g). , This strategy was used for the diastereoselective copper-catalyzed addition of benzyl alcohol to activated cyclopropane 96 , resulting in the formation of the key intermediate 97 en route to the total synthesis of tupichilignan A (Scheme ). …”