Syntheses of Enantiomerically Pure 2‐Substituted Pyrrolidin‐3‐ones via Lithiated Alkoxyallenes – An Auxiliary‐Based Synthesis of both Enantiomers of the Antibiotic Anisomycin

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the ‘diacetone‐fructose’‐substituted allene 1 and the N ‐Boc‐protected imine precursor 2a . Addition of an excess of lithiated 1 to 2a provided a 2 : 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion ( Scheme 2 ). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin‐3‐ones (2 R )‐ 5a and (2 S )‐ 5a . A similar sequence yielded the N ‐Tos‐protected compounds (2 R )‐ 5b and (2 S )‐ 5b . Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio‐ and stereoselective hydroboration into pyrrolidine derivatives 7 ( Scheme 3 ). Straightforward functional‐group transformations led to the hydrochlorides 9 of anisomycin ( Scheme 3 ). The (2 R ) series provided the hydrochloride (2 R )‐ 9 of the natural occurring enantiomer, whereas the (2 S ) series furnished the antipode (2 S )‐ 9 . The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.