The First Asymmetric Halogen/Metal‐Exchange Reaction: Desymmetrization of Alcohols with Enantiotopic Bromoarene Substituents

Abstract

Desymmetrizations of the prochiral bis(bromoaryl)alcohols 1 and 4 were effected by treatment with iPr2Mg and enantiomerically pure lithium alkoxides. The resulting arylmagnesium compounds were quenched with various electrophiles. The absolute and (if relevant) relative configurations of the resulting products were determined. The best ee/yield combination was obtained for the protonolysis furnishing monobromoalcohol (R)-2 (53 % ee, 51 % yield). The latter was converted into (R)-orphenadrine, an antihistaminic and anticholinergic drug.

Desymmetrization of Prochiral Diaryl Sulfoxides by an Asymmetric Sulfoxide–Magnesium Exchange

“…Although we expected the intended bromine-magnesium exchange to proceed relatively fast, [21] exposing 8 a in THF solution to essentially the same conditions as 5, [22] that is to slight excesses both of MgHal 2 -free iPr 2 Mg [23] and the lithium salt (Li-11) of the monomethyl ether (11) [24] of (S)-BINOL (À40 8C, 20 min) we obtained none of the expected diaryl sulfoxide 7 a but 25 % isopropyl phenyl sulfoxide (+)-(R)-9 b and 57 % bromoisopropyl phenyl sulfoxide (+)-(R)-9 a (Scheme 1, middle). This suggested that a selective sulfoxide-magnesium exchange [25] had occurred first (!…”

“…6 + iPrBr). [22] Theorizing about the underlying mechanism we wondered whether a similar reaction de- Representative substrates for enzymatic desymmetrizations by acetylation of 1, [16] nitrile hydrolysis of 2, [17] and ester hydrolyses of 3 [18] and 4. [19,20] Scheme 1.…”

“…Desymmetrization of dibromo alcohol 5 by an asymmetric bromine-magnesium exchange (top). [22] Our attempt to transfer this concept to the dibromo sulfoxide 8 a (middle). Extrapolation of the asymmetric sulfoxide-magnesium exchange to a novel concept for the desymmetrization of prochiral diaryl sulfoxides 8 (bottom).…”

Symmetric Diarylsulfoxides as Asymmetric Sulfinylating Reagents for Dialkylmagnesium Compounds

“…Preparation of Alkyl 2 Mg solutions in Et 2 O (Alkyl = Et, Bu, n-Hex, (CH 2 ) 2 Ph, Bn, i-Bu and c-C 6 H 11 ) 41 At room temperature the appropriate alkyl bromide (128 mmol) was added dropwise to a suspension of Mg turnings (3.14 g, 129 mmol, 10 was extracted with Et 2 O (3 × 10 mL) from precipitated LiCl. The concentration of the resulting clear and colorless solution was determined by titration with salicylic aldehyde phenylhydrazone.…”

Catalytic Asymmetric Bromine‐Lithium Exchange: A New Tool to Build Axial Chirality

“…[6] Then, using Mg instead Li, the group of Brückner described the kinetic resolution of symmetrical alcohols in the presence of stoichiomeric amounts of enantiomerically pure lithium alkoxides. [7] To the best of our knowledge, high levels of enantiomeric excess and the use of a catalytic amount of catalyst have never been reported so far.…”