Enantioselective Desymmetrization of 3-Substituted Oxetanes: An Efficient Access to Chiral 3,4-Dihydro-2H-1,4-benzoxazines

Abstract

Herein, we describe a versatile transition metal/ oxidant free synthesis of the chiral 2H-1,4-benzoxazines through chiral phosphoric acid (CPA) catalyzed enantioselective desymmetrization of prochiral oxetanes (30 examples) in up to 99% yield and 99% enantioselectivity under mild reaction conditions. The reported strategy not only complements the conventional 2H-1,4benzoxazine synthetic strategies but also provides access to key intermediates of therapeutic candidates, i.e., prostaglandin D2 receptor antagonist and M1 positive allosteric modulator (PAM) compound VU0486846.Letter pubs.acs.org/OrgLett

Dynamic kinetic resolution of transient hemiketals: a strategy for the desymmetrisation of prochiral oxetanols

“…According to literature precedent, a number of catalysts qualify to activate oxetanes towards desymmetrisation. 8 Among them, Co III ·salen 9 as well as chiral phosphoric acids 10 are worth mentioning because they proved viable for the synthesis of various oxygen-heterocycles in the past. However, no synthetic strategy towards the formation of 1,3-dioxolanes was reported so far, which we now wish to report on along with our efforts identifying a suitable catalyst system for a highly selective desymmetrisation process.…”

Asymmetric Synthesis of Pyrrolidines via Oxetane Desymmetrization

“…In 2009, Loy and Jacobsen reported a single example catalyzed by Co­(salen) complexes, resulting in only 10–50% ee for the construction of a tertiary stereocenter of this type . During the preparation of this manuscript, Veselý and co-workers reported the synthesis of 3,4-dihydro-2 H -benzoxazines with chiral phosphoric acid catalysis . In this case, the use of a heteroatom and a benzene ring in the tether renders the transition state conformation more rigid, which facilitates stereocontrol.…”

“…11e During the preparation of this manuscript, Veselýand co-workers reported the synthesis of 3,4-dihydro-2H-benzoxazines with chiral phosphoric acid catalysis. 13 In this case, the use of a heteroatom and a benzene ring in the tether renders the transition state conformation more rigid, which facilitates stereocontrol. Notably, while tertiary stereocenters could be established with excellent enantioselectivity, quarternary ones were generated with compromised selectivity.…”

“…Finally, we compared the performance of different protective groups (entries 12−15). The use of p-tosyl (Ts) and mesyl (Ms) groups resulted in lower enantioselec-tivity (entries 12,13). Drastically, no conversion was observed with acetyl (Ac) and benzoyl (Bz) groups (entries 14,15).…”

Reductive Opening of Oxetanes Catalyzed by Frustrated Lewis Pairs: Unexpected Aryl Migration via Neighboring Group Participation

“…This is partly attributed to its relatively low reactivity as well as the limited reaction modes . The reactivity of oxetane (mostly ring opening and expansion) essentially relies on LUMO-lowering activation of the ether oxygen owing to its relatively strong Lewis basicity. , Currently, various Brønsted acids and metal-based Lewis acids have been demonstrated as effective activators for this purpose. ,− However, activation by nonmetal-based Lewis acids has been much less established, with BF 3 being the most used one. , Recently, frustrated Lewis pair (FLP) has emerged as a type of powerful metal-free Lewis acidic catalyst . However, its application in oxetane activation has remained essentially unknown …”