Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp³)H Alkylation

Abstract

β-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd(0)-catalyzed C-H functionalization for aryl-aryl couplings, related reactions involving the formation of saturated C(sp(3))-C(sp(3)) bonds are elusive. Reported here is an asymmetric C-H functionalization approach to β-lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp(3))-C(sp(3)) and strain-building reductive eliminations to for the four-membered ring. In general, the β-lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.

Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

“…Although levels of enantioselectivity higher than 92:8 could not be reached, this result constitutes a proof-of-concept enantioselective synthesis of blactams by desymmetrization of unactivated methyl groups, which is to date unprecedented. [10] The cleavage of the TMB group was best performed employing potassium persulfate [21] to give the known free lactam (R)-4a, which was previously synthesized through the separation of diastereoisomeric precursors. [22] Scheme 4.…”

“…In this context, Cramer and co-workers employed a-chloroamides as precursors to construct the Ca-Cb bond of b-lactams (Scheme 1c). [10] Using a chiral phosphoramidite ligand, high enantioselectivities were achieved for the desymmetrization of enantiotopic 2 ary C-H bonds. However, the reaction occurred only on activated methylenes adjacent to a (hetero)aryl or ester group.…”

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)−H Bond Activation

“…[7] The initial key achievements in C(sp 3 )ÀHa ctivation concerned mainly intramolecular reactions in which ac hiral catalyst,p reinstalled on am olecule, was prompted to differentiate two stereotopic aliphatic motifs. [8] Intermolecular catalytic systemsi nw hich ac hiral induction is attained by differentiation of stereotopic protons of am ethylene bridge are even more challenging. To achieve this goal, severalr esearch groups focusedo nt he functionalizationo fc hiral amino acid derivatives,i mposing the chiral induction by the presence of ap roximal stereogenic center.…”

Gold(I)‐Catalyzed Desymmetrization of 1,4‐Dienes by an Enantioselective Tandem Alkoxylation/Claisen Rearrangement

“…[5] Thus we endeavored to develop al igand-controlled enantioselective alkoxylation/Claisen rearrangement. [6] [*] H. Wu, [+] We envisioned that an enantioselective variant might be available through ad esymmetrization reaction [7,8] of 1,4dienes.R ecently,g old-catalyzed enantioselective desymmetrization by nucleophilic addition to alkynes has been reported either through differentiation of enantiotopic alkynes [9] or nucleophiles. [10] In contrast, successful implementation of ad esymmetrization strategy to the tandem alkoxylation/3,3sigmatropic rearrangement reaction does not rely on enantiocontrol of the nucleophilic addition because this step forms achiral intermediate A.Rather,the proposed mechanism and the chirality transfer experiment suggest that the catalysts must exert influence over the sigmatropic rearrangement [11,12] event and thus differentiate between enantiotopic transition states B and B' ' (Figure 2b)O nt he basis of this intriguing possibility,herein we describe our efforts to develop agold(I)catalyzed asymmetric tandem alkoxylation/Claisen rearrangement reaction enabled by as trategic desymmetrization of 1,4-dienes ( Figure 2b).…”

“…Thus,D TBM-Segphos (L4)w as chosen as the ligand for further optimization. Va rious solvents were screened (entries [6][7][8][9], revealing that nonpolar solvents such as benzene gave the best results (1,3/3,3 = 17:1, > 95 % conversion, 85 % ee). [14] Interestingly,w hen the reaction was conducted in DCM, the opposite sense of enantioinduction was obtained (entry 6).…”