Total Synthesis of (±)‐Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen‐Oxygen Bonds

Abstract

The development of a concise total synthesis of (±)‐phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen‐oxygen (N−O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early‐stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N−O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.

Iron-catalyzed regioselective synthesis of (E)-vinyl sulfones mediated by unprotected hydroxylamines

“…Hydroxylamines widely exist in many natural products, pharmaceuticals and agrochemicals 1 and usually act as versatile synthetic intermediates, valuable ligands and catalysts in organic synthesis. 2 Among them, O -protected hydroxylamines are well known as effective electrophilic amination reagents 3 because of their oxidative properties (Scheme 1A).…”

Catalytic Reduction of Oximes to Hydroxylamines: Current Methods, Challenges and Opportunities

“…The hydroxylamine motif is present in many active ingredients of pharmaceuticals and agrochemicals, as well as in natural products. [ 1 , 2 , 3 , 4 , 5 ] Additionally, hydroxylamine derivatives are versatile intermediates in organic synthesis,[ 3 , 6 , 7 , 8 , 9 ] powerful ligands[ 10 , 11 ] and catalysts. [12] Therefore having efficient synthetic access to this scaffold is of significant importance.…”

Synthesis of Dimeric Securinega Alkaloid Flueggeacosine B: From Pd-Catalyzed Cross-Coupling to Cu-Catalyzed Cross-Dehydrogenative Coupling

“…Thioester 2 was designed to be derived from aldehyde 4 , which would be accessed by an oxidative cleavage , of enamine 6 previously reported by our group . Stannane 3 was planned to be accessed from phyllantidine ( 5 ) via a δ-stannylation of the α,β–γ,δ-unsaturated ester moiety. Phyllantidine would be prepared by anoxidation of allosecurinine .…”