Stereoselective Synthesis and Reactions of Secondary Alkyllithium Reagents Functionalized at the 3‐Position

Abstract

Secondary alkyllithium reagents bearing an OTBS group (TBS=tert-butyldimethylsilyl) at the 3-position can be prepared stereoconvergently through an I/Li exchange from a diastereomeric mixture of the corresponding secondary alkyl iodides. These lithium reagents react with a range of electrophiles, including carbon electrophiles, with retention of configuration to yield various 1,3-difunctionalized derivatives with good diastereoselectivities. Kinetic studies show that the 3-siloxy group strongly accelerates the epimerization at the lithium-substituted carbon atom. This method offers a new way to construct chiral open-chain molecules with excellent stereoselectivity.

Stereoselective Csp3−Csp2 Cross‐Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

“…To our delight, these conditions allow for the first time a highly stereoselective cross‐coupling of chiral non‐stabilized open‐chain secondary alkylzinc reagents with various alkenyl and aryl halides. Hence, we treated the diastereomerically enriched secondary alkyl iodide syn ‐ 2 a with t BuLi (2.2 equiv) in a 3:2 mixture of pentane/diethyl ether at −100 °C for 10 s leading to an intermediate alkyllithium species (see Table ). Addition of Me 3 SiCH 2 ZnBr⋅LiBr ( 3 a ; 0.95 m in diethyl ether, 1.05 equiv) at −100 °C provided the mixed dialkylzinc species syn ‐ 4 a .…”

“…Hence, we performed such a cross‐coupling reaction with other secondary alkylzinc reagents 4 b , c (see entries 8 and 9). The 1,3‐functionalized secondary alkyl iodide rac ‐ 2 b was prepared according to a reported procedure, followed by an I/Li‐exchange reaction, which after epimerization (−50 °C, 30 min) led to the chelate‐stabilized lithium species . Subsequent transmetalation to the corresponding dialkylzinc reagent syn ‐ 4 b followed by cross‐coupling with 5 a afforded the silyl‐protected alkene syn ‐ 6 g in 43 % yield (dr=93:7).…”

Stereoselektive C(sp3)‐C(sp2)‐Kreuzkupplungen von chiralen sekundären Alkylzinkreagenzien mit Alkenyl‐ und Arylhalogeniden

“…Glücklicherweise erlaubten diese Bedingungen die erste hoch‐stereoselektive Kreuzkupplung von chiralen nicht‐stabilisierten offenkettigen sekundären Alkylzinkreagenzien mit verschiedenen Alkenyl‐ und Arylhalogeniden. Infolgedessen behandelten wir das sekundäre Alkyliodid syn ‐ 2 a mit t BuLi (2.2 Äquiv.) in einer 3:2 Mischung aus Pentan:Diethylether bei −100 °C für 10 s, was zu einer intermediären Alkyllithiumspezies führte (siehe Tabelle ).…”

“…8 und 9) durch. Das 1,3‐funktionalisierte sekundäre Alkyliodid rac ‐ 2 b wurde nach einer Literaturvorschrift hergestellt, gefolgt von einem I/Li‐Austausch, was nach Epimerisierung (−50 °C, 30 min) zu der Chelat‐stabilisierten Lithiumspezies führte . Anschließende Transmetallierung zum entsprechenden Dialkylzinkreagenz syn ‐ 4 b gefolgt von einer Kreuzkupplung mit 5 a führte zu dem Silyl‐geschützten Alken syn ‐ 6 g in 43 % Ausbeute (dr=93:7).…”

Stereoselective Synthesis and Retentive Trapping of α‐Chiral Secondary Alkyllithiums Leading to Stereodefined α,β‐Dimethyl Carboxylic Esters

“…This reaction sequence was extended to other electrophiles such as MeOBpin, (MeOBpin=2‐methoxy‐4,4,5,5‐tetra‐methyl‐1,3,2‐dioxaborolane) leading to the boronic esters ( anti‐ 4 b and syn‐ 4 b , entries 1 and 2 of Table ) in 60 and 83 % yield, as well as 98 and 99 % retention of configuration, respectively . Reactions of the lithium reagents anti‐ 2 a and syn‐ 2 a with DMF, produced the anti‐ and syn‐ aldehydes ( anti‐ 4 c and syn‐ 4 c , entries 3 and 4) in 60 and 70 % yield with 93 and 95 % retention of configuration, respectively. The preparation of tertiary alcohols anti‐ 4 d (d.r.=97:3, 71 % yield) and syn‐ 4 d (d.r.=8:92, 50 % yield) was achieved by the addition of alkyllithiums anti ‐ 2 a and syn ‐ 2 a to Et 2 CO, respectively ,.…”