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α‑Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters
journal contribution
posted on 2017-08-16, 13:27 authored by Giorgia Casoni, Murat Kucukdisli, James M. Fordham, Matthew Burns, Eddie L. Myers, Varinder K. AggarwalThe stereoselective
reagent-controlled homologation of boronic
esters is one of a small number of iteratable synthetic transformations
that if automated could form the basis of a veritable molecule-making
machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl
chlorides have emerged as useful building blocks for the iterative
homologation of boronic esters. However, α-stannyl benzoates
need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer
of the scarcely available and expensive diamine sparteine; also, these
building blocks, together with the byproducts that are generated during
homologation, are perceived as being toxic. On the other hand, α-sulfinyl
chlorides are difficult to prepare with high levels of enantiopurity
and are prone to undergo deleterious acid–base side-reactions
under the reaction conditions for homologation, leading to low stereospecificity.
Here, we show that the use of a hybrid of these two building blocks,
namely, α-sulfinyl triisopropylbenzoates, largely overcomes
the above drawbacks. Through either the sulfinylation of α-magnesiated
benzoates with either enantiomer of Andersen’s readily available
menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a
range of highly enantiopure mono- and disubstituted α-sulfinyl
benzoates, some bearing sensitive functional groups. Barbier-type
reaction conditions have been developed that allow these building
blocks to be converted into lithium (t-BuLi) and
magnesium (i-PrMgCl·LiCl) carbenoids in the
presence of boronic esters, thus allowing efficient and highly stereospecific
homologation. The use of magnesium carbenoids allows carbon chains
to be grown with the incorporation of sensitive functional groups,
such as alkyl/aryl halides, azides, and esters. The use of lithium
carbenoids, which are less sensitive to steric hindrance, allows sterically
encumbered carbon–carbon bonds to be forged. We have also shown
that these building blocks can be used consecutively in three- and
four-step iterative homologation processes, without intervening column
chromatography, to give contiguously substituted carbon chains with
very high levels of enantio- and diastereoselectivity.
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α- sulfinyl triisopropylbenzoatesdisubstituted α- sulfinyl benzoatesα- stannyl benzoates needBarbier-type reaction conditionschiral α- sulfinyl benzoatescarbon chainsfour-step iterative homologation processesbuilding blocksboronic estersStereoselective Iterative Homologationα- magnesiated benzoatesα- stannyl triisopropylbenzoatesstereoselective reagent-controlled homologationα- sulfinyl chlorides
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