α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters

Abstract

The 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.

Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

“…6 We therefore considered using a sulfoxide as a latent organolithium, since the sulfoxide can be isolated and purified, and the corresponding organolithium regenerated by treatment with tert-butyl lithium, free from halide salts, cleanly and quantitatively in just a few minutes. 36 Sulfoxide 5 was prepared by trapping 1-lithio bicyclo[1.1.0]butane 3 with sulfinate ester 4, which, being crystalline, was easily purified and was isolated in 52 % yield on gram-scale (see supplementary section 2.2 for details). The sulfoxide-lithium exchange reaction of 5 was carried out in the presence of cyclohexyl pinacol boronic ester in 2-methyl tetrahydrofuran at −78 °C, to give the bicyclo[1.1.0]butyl boronate complex (Table 1).…”

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts

“…A slew of papers detailing the use of α-halo sulfoxides have been released from the group of Blakemore over the past 10 years. 209−215 A number of deleterious side reactions were sometimes observed when these precursors are employed and, as a result, investigations by O’Brien 216 and Aggarwal 217 focused on the use of α-sulfinyl carbonates and benzoates, respectively. O’Brien’s synthesis relied on a double induction strategy involving a chiral base and Andersen’s sulfinate to generate the key sulfoxides.…”

Urea Insertion Reaction of Rhodium-Carbenoid

“…Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, and br=broad), integration and coupling constants in Hz. For 13 IR spectrophotometer, equipped with attenuated total reflectance (ATR) (Smiths Detection, DuraSample IR II). Melting points were measured with a SIBATA NEL-270 melting point apparatus.…”

“…[5][6][7][8][9][10][11] The development of novel metal carbenoid reactions, therefore, is an attractive topic in the synthetic community. [12][13][14][15][16] Ylide chemistry of metal carbenoids, which is initiated by nucleophilic attack of a certain heteroatom on the carbenoid carbon center, enables synthetically valuable transformations in addition to the usual reactivity of the metal carbenoid, such as insertion reactions into a C−H bond [17][18][19] and multiple bonds. 20) Ylide intermediates and their equivalents have been utilized for heteroatom−hydrogen bond (X−H) insertions, [21][22][23] Stevens rearrangements, 24,25) and sigmatropic rearrangements.…”