Stereoselective Preparation and Reactions of Chiral Secondary Alkyllithiums

Abstract

The preparation of chiral non-stabilized open-chain alkyl­lithium reagents prepared from the corresponding chiral secondary alkyl iodides and their subsequent transmetalation to the corresponding secondary alkylcopper or alkylzinc derivatives is reviewed. These new organometallic reagents allow the stereoselective preparation of a broad range of chiral molecules.1 Introduction2 Stereoselective Preparation of Secondary Alkyllithiums3 Preparation of Stereodefined Secondary Alkylcopper Reagents4 Preparation of Stereodefined Secondary Alkylzinc Derivatives and Their Stereoselective Cross-Coupling with Alkenyl and Aryl Halides­5 Conclusion

General stereoretentive preparation of chiral secondary mixed alkylmagnesium reagents and their use for enantioselective electrophilic aminations

“…The enantioselective preparation of carbon-sulfur bonds was briefly examined since it proceeded also directly with chiral secondary alkyllithiums. 6 We observed that the coupling of ( R )- or ( S )-5h and syn -5d with MeSO 2 SMe (6k) led to the thioethers ( R )- or ( S )-4o and syn -4p in up to 85% yield, but moderate stereoselectivity (up to 78% ee or dr = 93 : 7). However, phosphorus electrophiles such as Ph 2 PCl (6l) reacted with high stereoretention with chiral Grignard reagents.…”

“…−50 °C for ca. 1 h and in comparison with the corresponding alkyllithium reagents (configurationally stable only below −100 °C for some minutes) 6 were better suited for synthetic applications.…”

“…Although enolizable ketones did not give satisfactory results, addition of Grignard reagents ( R )-5a, ( R )- and ( S )-5g and ( R )-5h to aldehydes such as c -hexylcarboxaldehyde (6c), ( S )-(−)-citronellal (6d) and (1 R )-(−)-myrtenal (6e) afforded after Dess–Martin oxidation the corresponding ketones ( R )-4g (68%, 89% ee), (2 R ,5 S )-4h (74%, dr = 95 : 5), (2 S ,5 S )-4h (75%, dr = 5 : 95) as well as (2 R ,1′ R ,5′S)-4i (46%, dr = 95 : 5) and (2 S ,1′ R ,5′S)-4i (49%, dr = 3 : 97). Performance of acylations did not require Weinreb amides as used for the acylation of chiral alkyllithiums, 6 c but commercially available acid chlorides were employed. Thus, ( R )-5a reacted with ( S )-tetrahydrofuran-2-carbonyl chloride (6f) affording (2 S ,2′ R )-4j in 89% yield and dr = 11 : 89.…”

“…Recently, we have shown that various enantiomerically enriched secondary alkyl iodides of type 1 underwent an I/Li-exchange 5 at −100 °C in pentane:ether mixtures furnishing the corresponding chiral alkyllithiums of type 2 with retention of configuration ( Scheme 1a ). 6 After transmetalations with appropriate ether soluble Cu and Zn salts at −100 °C, chiral organometallics of type 3 were obtained, which reacted with various electrophiles providing products of type 4 with high retention of configuration. 7 Although chiral building blocks and natural products were available by these procedures, 7 d , g , h such reaction sequences required very low temperatures (−100 °C) due to the occurrence of configurationally labile alkyllithium reagents (2), which epimerized readily at temperatures above −100 °C (ref.…”

Recent Advances in Cross-Couplings of Functionalized Organozinc Reagents

“…Thus, secondary and tertiary amines of types 4 and 5 can be prepared via these electrophilic amination reactions using various functionalized organozinc reagents of type 6 (Scheme 2). Besides, we will also cover in this short review novel stereoselective cross-couplings of organozinc reagents involving stereoselective I/Li-exchange reactions 5 as well as regioselective magnesiations of N-aryl azoles and related aromatic and heterocyclic substrates 6 followed by Negishi crosscouplings after transmetalation with ZnCl2 or Cu-catalyzed cross-couplings.…”