Asymmetric Synthesis of Cis-Fused Bicyclic Pyrrolidines and Pyrrolidinones via Chiral Polycyclic Lactams

Abstract

Condensation of racemic keto-ester 2 and 1.1 equiv of (R)-(−)-phenylglycinol in toluene with azeotropic removal of water and methanol gave rise to a tetracyclic lactam in greater than 90% yield. Examination of the crude reaction product by 1H and 13C NMR, capillary GC, and HPLC revealed this product to be a single isomer, the absolute configuration of which was determined to be that illustrated by structure 3. The tetracyclic lactam 3 was stereospecifically reduced to either the cis-fused bicyclic pyrrolidine 4 or the cis-fused bicyclic pyrrolidinone 9. The chiral auxiliaries in both 4 and 9 were removed using different, novel methodologies. This highly stereoselective reaction establishes two contiguous chiral centers via the deracemization of an achiral keto-ester. This methodology has been applied to the synthesis of (1R,5R)-2-azabicyclo[3.3.0]octane 15. This important amine is now readily available from commercial materials in only three steps.

First and Highly Stereoselective Synthesis of Both Enantiomers of Octahydroindole‐2‐phosphonic Acid (OicP)

“…This underwent base‐induced elimination using t BuOK in t BuOH to give enamide (3a R ,7a R )‐ 14 in 95 % yield . Also, treatment of (1′ R ,3a R ,7a R )‐ 12 with lithium hydroxide monohydrate in DMSO at 140 °C gave enamide (3a R ,7a R )‐ 14 in 89 % yield in a single step . Finally, hydrolysis of the enamide group in (3a R ,7a R )‐ 14 with HCl (1 n aq.)…”

Recent Advances on the Total Syntheses of Communesin Alkaloids and Perophoramidine

“…The NÀH aminal was convertedt ot he tert-butyl carbamate 233 in 89 % yield, and the second quaternary stereocenter was introduced via allylationw ith allyl iodide in > 20:1 d.r.At hree-step sequencew as used to removet he (S)-OTBS-phenylglycinol auxiliary from carbamate 233 which included protiodesilylation of the OTBS group, elimination, and hydrolysis, affordingl actam 234 in 93 %y ield over two steps. [44] The olefin moiety was cleaved oxidatively under modified Johnson-Lemieux conditions to provide an aldehyde, which was reduced to primary alcohol 235 with NaBH 4 in 95 %y ield over two steps. At this stage,aHeck reactions imilar to the one employed by Qin was used to install the side chain for assembly of the benzazepine ring.…”

Type 1 Ring-Opening Reactions of Cyclopropanated 7-Azabenzonorbornadienes with Organocuprates

“…The same cis -framework 20 also serves as a precursor to triazolium salts, which can be used to generate chiral carbene catalysts for highly efficient conjugate nucleophilic acylation, transesterification, polymerization, and benzoin condensation reactions . This versatile intermediate may be readily accessible by alkene reduction of lactams 15 of the present work, which would be a likely improvement to the current syntheses of 20 , − which at best is obtained in 22% over six steps . In addition, further carbonyl reduction of 20 may allow for the preparation of carbocyclic analogues of martinelline receptor antagonists, whose total synthesis has been extensively studied over the years. − …”