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The selective double hydroboration of CO2into bis(boryl)acetal (BBA) is a challenging yet appealing reduction process since BBA can be used as a versatile C1and Cnsources for the synthesis of value-added products. In the present study, we demonstrate that simple borohydride compounds are efficient and selective catalysts for the synthesis of BBA when using 9-borabicyclo(3.3.1)nonane (9-BBN) as a reductant. The experimental and theoretical investigations show that while the borohydride species catalyzes the first reduction step of CO2into formoxyborane (2e–reduction intermediate), the observed 4e–reduction selectivity is mostly due to the ability of 9-BBN to reduce the formoxyborane into BBA without a catalyst. Notably, 0.2 mol % of LiH2BBN catalyzed the hydroboration of CO2with 9-BBN as a reductant into the corresponding BBA in 77% yield with TON and TOF of 385 and 196 h–1, respectively. The simplicity of borohydride contrasts with the more elaborate catalytic systems used so far for the 4e–reduction of CO2.

GABAAreceptors (GABAARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([3H]azietomidate) and mephobarbital [[3H]1-methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid ([3H]R-mTFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the α1β3γ2 GABAAR transmembrane domain at β+–α−(β+sites) and α+–β−/γ+–β−(β−sites) subunit interfaces. We now use competition photolabeling with [3H]azietomidate and [3H]R-mTFD-MPAB to identify para-substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to β+, while derivatives with bulkier lipophilic substitutions [4-(tert-butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to β−sites. Similar to R-mTFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the α+–β−and γ+–β−sites. However, we discovered four compounds that bind with different affinities to the two β−interface sites. Two of these bind with higher affinity to one of the β−sites than to the β+sites. We deduce that 4-benzoyl-propofol binds with >100-fold higher affinity to the γ+–β−site than to the α+–β−or β+–α−sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the α+–β−site than to the β+and γ+–β−sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABAAR transmembrane domain, a property that may facilitate the development of subtype selective GABAAR PAMs.