Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary α‐Oxy‐ and α‐Thio‐Substituted Organolithium Species

Abstract

Nonstabilized a-O-substituted tertiary organolithium species are difficult to generate,and the a-S-substituted analogues are configurationally unstable.W en ow report that they can both be generated easily and trapped with arange of electrophiles with high enantioselectivity,p roviding ready access to ar ange of enantioenriched tertiary alcohols and thiols.T he configurational stability of the a-S-organolithium species was enhanced by using aless coordinating solvent and short reaction times.Chiral a-heteroatom (O,N ,a nd S)-substituted organolithium compounds are av ersatile class of nucleophiles that are useful in the asymmetric synthesis of chiral alcohols, amines,a nd thiols.[1] Although the use of secondary and mesomerically stabilized (e.g., benzylic and allylic) tertiary a-O-and a-S-substituted organolithium reagents in synthesis is well established, [1c-e] the use of non-mesomerically stabilized (i.e., dialkyl-substituted) tertiary reagents is not. This discontinuity is due to contrasting problematic features governing a-O-and a-S-substituted organolithium species. Nonstabilized tertiary a-O-organolithium compounds are configurationally stable but are difficult to generate owing to their reduced kinetic acidity (Scheme 1B); [1e, 2] tertiary a-Sorganolithium species are easily formed but are not configurationally stable (Scheme 1A). To apply a-O/S-substituted organolithium compounds in asymmetric synthesis,both ease of generation and configurational stability are essential requirements. [1a-d,3] Through variation of the directing group,b ase,s olvent, and additives we discovered reaction conditions enabling the stereospecific deprotonation of secondary dialkyl benzoates (TIB esters) [4] and demonstrated their configurational stability in lithiation-borylation reactions.[5] Herein, we report the broad applicability of these novel enantioenriched nucleophiles in reactions with ab road range of electrophiles.I n addition, we have discovered reaction conditions for the generation of enantioenriched, tertiary,n onstabilized a-Sorganolithium compounds and report their subsequent trapping with electrophiles in high enantioselectivity (Scheme 1C).Boronic esters represent an iche class of electrophiles, [6] and therefore,w ei nitially embarked on as tudy of the trapping of tertiary a-O-substituted organolithium species, which were generated by lithiation of the enantioenriched TIB esters 1a-1e,w ith ar ange of electrophile classes (Scheme 2). Upon exposure of av ariety of enantioenriched benzoates to sec-BuLi and TMEDAinCPME at À60 8 8C, the corresponding organolithium species Li-1a-1e were generated. Pleasingly,L i-1a-1e were successfully trapped with ar ange of electrophiles,i ncluding methyl chloroformate (2aa), benzoyl chloride (2ab), isocyanates (2ac and 2ad), aldehydes (2ae and 2af), and trialkyl tin chlorides (2ag, 2ah, 2ba-2ea). Reactions with aldehydes gave mixtures of diastereomers (see 2ae and 2af)b ut in the case of PhCHO,h igh Scheme 1. A, B) Previous studies regardingnonstabilized tert...

Highly Diastereoselective Preparation of Tertiary Alkyl Thiocyanates en Route to Thiols by Stereoinvertive Nucleophilic Substitution at Nonclassical Carbocations

“…This synthetic pathway is significant as it enables the synthesis of tertiary thiols, compounds pivotal in various applications, with notable efficiency. 38,39 In conclusion, we have developed an effective approach for the synthesis of tertiary alkyl thiocyanates via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinols, through the formation of the nonclassical cyclopropylcarbinyl cation (CPC). A range of tertiary alkyl thiocyanates were obtained in good yields with excellent diastereomeric ratios.…”