The optimization of the synthesis of 6β-hydroxymethylsulbactam is described. The primary challenge in this synthesis is the installation of the 6β-hydroxymethyl group with the proper stereochemistry. Engineering challenges associated with the addition of gaseous formaldehyde to a Grignard reagent at low temperature and a number of approaches to achieving the appropriate β-stereochemistry are presented.
One- and two-dimensional 6Li and 15N NMR spectroscopic studies of lithium diisopropylamide (LDA) solvated by substoichiometric concentrations of oxetane, THF, Et2O, and diisopropylamine are described. Partially solvated dimers and trimers are identified. Possible benefits of carrying out organolithium chemistry at low ligand concentrations are discussed.
6Li and (13)C NMR spectroscopic studies were carried out on [(6)Li]n-BuLi and [(6)Li]PhLi (RLi) in toluene-d(8) containing the following diamines: N,N,N',N'-tetramethylethylenediamine (TMEDA), N,N,N',N'-tetraethylethylenediamine, 1,2-dipyrrolidinoethane, 1,2-dipiperidinoethane, N,N,N',N'-tetramethylpropanediamine, trans-(R,R)-N,N,N',N'-tetramethylcyclohexanediamine, and (-)-sparteine. Dimers of general structure (RLi)(2)S(2) (S = chelating diamine) are formed in each case. Treatment of RLi with two different diamines (S and S') affords homosolvates (RLi)(2)S(2) and (RLi)(2)S'(2) along with a heterosolvate (RLi)(2)SS'. Relative binding constants and associated free energies for the sequential solvent substitutions are obtained by competing pairs of diamines. The high relative stabilities of certain heterosolvates indicate that solvent binding to the RLi dimer can be highly correlated. Rate studies of both the 1,2-addition of RLi/TMEDA to the N-isopropylimine of cyclohexane carboxaldehyde and the RLi/TMEDA-mediated alpha-lithiation of the N-isopropylimine of cyclohexanone reveal monomer-based transition structures, [(RLi)(TMEDA)(imine)], in all cases. The complex relationships of solvent binding constants and relative reactivities toward 1,2-additions and alpha-lithiations are discussed.
[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)