Diastereoselective Synthesis of Bicyclic γ-Lactams via Ring Expansion of Monocyclic β-Lactams

Abstract

cis-4-(1-Chloro-1-methylethyl)-1-(omega-hydroxyalkyl)azetidin-2-ones were diastereoselectively transformed into novel trans-1-aza-4-oxabicyclo[3.3.0]octan-8-ones and trans-1-aza-5-oxabicyclo[4.3.0]nonan-9-ones upon treatment with 1 equiv of AgBF4 and pyridine in toluene via intramolecular nucleophilic trapping of N-acyliminium intermediates by the hydroxyl moiety. Additionally, the corresponding aza-analogues of the aforementioned bicyclic gamma-lactams (i.e., trans-1,4-diazabicyclo[3.3.0]octan-8-ones and trans-1,5-diazabicyclo[4.3.0]nonan-9-ones) were prepared in a convenient way starting from cis-4-(1-chloro-1-methylethyl)-1-{omega-[(tert-butoxycarbonyl)amino]alkyl}azetidin-2-ones applying the same reaction conditions. The intermediate N-acyliminium ions were formed by ring expansion of the starting beta-lactams through generation of a transient silver(I)-induced carbenium ion.

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

“…Recent strategies toward the construction of the γ-lactam motif comprise β-lactam to γ-lactam ring expansions [29–30], aziridine ring openings followed by cyclization with enolates [31], palladium-catalyzed cyclizations [32], cycloadditions [33], multicomponent reactions [34], and even NHC catalysis [35–36]. Nevertheless, the methodology developed by Rovis indisputably represents an important breakthrough, providing an elegant alternative access to trans -γ-lactams in a highly enantio- and diastereoselective way.…”

Stereospecific Preparation of γ‐Lactam Derivatives via Ring Expansion of cis and trans β‐Lactam Derivatives: α‐Substituent Effect of β‐Lactam Derivatives

“…The stereochemistry in γ‐lactam has been a great importance in medicinal and synthetic chemistry due to a wide variety of biological activities . The various substituted γ‐lactam derivatives have been prepared stereospecifically via ring expansion from their corresponding β‐lactam derivatives . However, few examples have been reported about the effects of substituents on the α‐position in β‐lactam derivatives via ring expansion to lead γ‐lactam derivatives stereospecifically.…”

Ring Expansions of β-Lactams and β-(thio)lactones

“…The diastereoselectivity has been explained by the steric hindrance of the substituents of the 4-(1-bromoalkyl)-2-azetidinones directing the attack of the nucleophile even more into a trans-stereochemistry. A similar methodology has been also applied to the diastereoselective synthesis of bicyclic γ-lactams via ring expansion of monocyclic β-lactams [21]. Starting from 3,4-cis-4-isopropenylazetidin-2-ones, a new synthesis of pyrrolidin-2-ones was achieved (Scheme 11) [22].…”