Stereoselective Synthesis of Secondary Alkyllithiums and Their Application to Stereoselective Cuprations or Intramolecular Carbolithiations for the Stereoselective Synthesis of Alkylidene­cyclobutanes

Abstract

Secondary alkyllithium reagents were prepared stereoselectively via an iodo–lithium exchange by using tert-butyllithium. The resulting secondary alkyllithiums were converted directly into the corresponding alkylcopper reagents by transmetalation with copper(I) bromide–triethyl phosphite [CuBr·P(OEt)3] with retention of configuration and without significant loss of stereoselectivity. The resulting alkylcopper reagents were used for carbocupration or acylation reactions. In addition, a new intramolecular carbolithiation of secondary alkyllithium reagents possessing a remote alkyne moiety was also investigated, allowing the stereoselective production of alkylidenecylobutane derivatives with very high stereocontrol.

IntramolecularAnti‐Carbolithiation of Alkynes: Stereo‐Directing Effect of Lithium‐Coordinating Substituents

“…In addition, the presence of a TMS or a phenyl group at the terminus of alkynes lowers the syn activation barrier by several kcal/mol in comparison to a methyl group (Table 6, compare entries 1/3 and 1/5). This result is consistent with our (and others‘) experimental observations that silylated and arylated triple bonds efficiently take part in 5‐ exo ‐ dig cyclizations of aryllithiums, while alkylated alkynes struggle to cyclize [9,10,27] . For substrates 2 , the binding of the OMe substituent to the lithium results in the stabilization of the anti TSs while the presence of the chelating substituent does not change significantly the energy barriers for the syn ‐pathway (Table 6, compare entries 1/4, 2/5 and 3/6).…”

“…The debrominated open‐chain alkyne accounts for 69 % of the crude reaction mixture, which also contains 15 % of its allene isomer, formed after deprotolithiation at the propargylic methylene. It is well‐established that an aryl‐ or silyl‐substituent on an alkyne facilitates the carbolithiation by stabilizing the resulting alkenyllithium [9,10,27] . Accordingly, phenyl‐ or silyl‐substituted alkynes 1 b,c underwent regiospecific 5‐ exo ‐ dig cyclization to give products 3 b,c in excellent isolated yields (entries 2–4).…”

“…It is well-established that an aryl-or silyl-substituent on an alkyne facilitates the carbolithiation by stabilizing the resulting alkenyllithium. [9,10,27] Accordingly, phenyl-or silyl-substituted alkynes 1 b,c underwent regiospecific 5-exo-dig cyclization to give products 3 b,c in excellent isolated yields (entries 2-4). For all of these reactions, the cyclized product 3 was formed as the sole cyclized isomer, whose structure was unambiguously identified by NOESY analysis (see Supporting Information).…”

“…This result is consistent with our (and others') experimental observations that silylated and arylated triple bonds efficiently take part in 5-exo-dig cyclizations of aryllithiums, while alkylated alkynes struggle to cyclize. [9,10,27] For substrates 2, the binding of the OMe substituent to the lithium results in the stabilization of the anti TSs while the presence of the chelating substituent does not change significantly the energy barriers for the synpathway (Table 6, compare entries 1/4, 2/5 and 3/6). As a consequence, the anti TSs are calculated to be lower in free energy than those of the competing syn-pathway.…”

Stereoselective Preparation and Reactions of Chiral Secondary Alkyllithiums

“…After quenching with a proton source, the exoalkylidenecyclobutane syn-69 was obtained in 65% yield, E/Z 6:94 and dr 99:1 (Scheme 13). 20 Remarkably, organocopper reagents were observed to undergo highly chemo-and stereoselective allylic substitution reactions in THF. 21 Copper organometallics of type 70 react with unsymmetrical allylic bromides such as 71 with…”