Synthesis of (−)-(S,S)-clemastine by Invertive N → C Aryl Migration in a Lithiated Carbamate

Abstract

The first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer, has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of alpha-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement.

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li+ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

“…Finally, we note that, although we have located two alternative pathways leading to a 1,4-aryl shift in the ureas studied herein, we believe that we cannot infer from these results the reasons for the stereochemical outcomes observed in the carbamates [17,18] or thiocarbamates; [22] each system requires individual investigation.…”

“…LDA has been used experimentally as an alternative to alkyllithiums in rearrangements of more sensitive ureas, [16,19] and is essential for stereospecific rearrangements of the corresponding 1,4-aryl shift in carbamates. [17,18] We note that a crystal structure of an LDA-THF complex [35] shows a dimer with each Li + ion coordinated to a single THF molecule and sharing two amide ligands with the second lithium ion. In the system studied herein, the carbonyl oxygen replaces one of the THF molecules of this dimer.…”

“…In complementary experimental work, we have shown that, when carbamates carry an NЈ-aryl substituent, the lithio derivatives (formed with either alkyllithiums or N-lithioamines) of benzylic ureas [15,16] 5 and carbamates [17,18] 6 undergo a remarkable NǞC aryl migration (Scheme 2). Furthermore, related reactions occur with allylic ureas, [19] cyclic ureas, [20] lithiated ureas generated by carbolithiation, [21] and benzylic thiocarbamates.…”

“…However, the rearrangements of ureas and carbamates differ from one another in one very important respect: the aryl migration within the urea proceeds with retention of stereochemistry at the migration terminus, [15] whereas the aryl migration within the carbamate proceeds with inversion of stereochemistry at the migration terminus. [18] Chiral benzyllithium derivatives are known to react with electrophiles with erratic stereospecificity (retentive S E 2ret or invertive S E 2inv), [10][11][12] and while the detailed stereochemical pathways by which such stereospecific electrophilic substitution reactions proceed are yet to be fully clarified, it is generally clear that Lewis base electrophiles capable of coordination to lithium favour retentive over invertive substitution. [12] Scheme 1.…”

Asymmetric synthesis of tertiary thiols and thioethers

“…Treatment of an N -aryl S -benzyl thiocarbamate 92 leads to formation of a lithio derivative 93 comparable with those reported by Hoppe (Scheme 32). As in the case of lithiated N -aryl ureas [76–80] and N -aryl carbamates [81–82], the N -aryl ring is susceptible to attack by the anionic centre, and migration of the ring to the position α to sulfur occurs, presumably via an intermediate related to 94 . After work up the product is a tertiary thiocarbamate 95 , and simple mildly basic hydrolysis leads to the tertiary thiol 96 .…”