Catalytic Carbonylative Spirolactonization of Hydroxycyclopropanols

Abstract

A palladium-catalyzed cascade carbonylative spirolactonization of hydroxycyclopropanols has been developed to efficiently synthesize oxaspirolactones common to many complex natural products of important therapeutic value. The mild reaction conditions, high atom economy, broad substrate scope, and scalability of this new method were highlighted in expedient total syntheses of the Turkish tobacco natural products α-levantanolide and α-levantenolide in two and four steps respectively. The hydroxycyclopropanol substrates are readily available in one step via a Kulinkovich reaction of the corresponding lactones. Mechanistic studies utilizing high-resolution electrospray ionization mass spectrometry (ESI-MS) identified several key intermediates in the catalytic cycle as well as those related to catalyst decomposition and competitive pathways.

Modern Developments in the Chemistry of Homoenolates

“…An elegant example of homoenolate‐carbonyl capture was reported in 2016 by Waymouth and Dai in their palladium‐catalyzed spirolactonization of hydroxycyclopropanols (Scheme ) . A key feature of this reaction is the formation of palladium(II) homoenolate 182 , which can be trapped by the tethered alcohol via nucleophilic addition to the carbonyl, giving intermediate 183 .…”

“…The groups of Waymouth and Dai applied their palladium‐catalyzed spirolactonization protocol towards a concise four‐step synthesis of α‐levantenolide (Scheme ) . Subjecting commercially available lactone (+)‐sclareolide 207 to a zirconium‐mediated Kulinkovich reaction gave cyclopropanol 208 as a mixture of diastereomers in 57 % yield.…”

Total Syntheses of Bisdehydroneostemoninine and Bisdehydrostemoninine by Catalytic Carbonylative Spirolactonization

“…The Stemonaceae plants have been widely used in Chinese and Japanese traditional medicines for their antitussive effect and insecticidal activity.T hey are rich sources of complex bioactive natural products,e specially alkaloids.S of ar, over 150 stemona alkaloids have been isolated from these plants. [1] These alkaloids are categorized into eight different groups and most of them feature ac haracteristic pyrrolo[1,2-a]azepine nucleus.O ur recent interest in oxaspirolactone synthesis [2] and the stemofoline group [3] brought our attention to the stemoamide group because many of its members,such as bisdehydroneostemoninine (1a,F igure 1A), (iso)bisdehydrostemoninine (1b and 1c), [4] stemoninines Aa nd B( 1d and 1e), [5] tuberstemoamide (1f), [6] sessilifoliamide A(1g), [7] (dihydro)stemoninine (1hand 1i), [8] and stemoenonine (1j), [9] contain an oxaspirolactone moiety.Despite the recent efforts toward the total syntheses of stemona alkaloids, [10] only afew members of the stemoamide group have been synthesized. While there are over 20 total syntheses of the simplest member stemoamide (1l, Figure 1B), [11] total syntheses of the more complex ones are very rare.N otably,W illiams and coworkers reported the first total synthesis of stemonine (1m)in 2003 [12] and Chida, Sato and co-workers developed au nified approach to synthesize both 1mand saxorumamide (1n)from 1l in 2017.…”

Natural and Synthetic Spirobutenolides and Spirobutyrolactones

“…[41] The synthesis of α-Levantenolide was done by Dai and coworkers viacatalytic carbonylative spirolactonization as a key step (Scheme 11). [42] Rugulovasines A and B (11) are indole alkaloids from the Ergot family and have novel structural motifs. Both the isomers have been isolated as racemic form and are interconvertible on heating.…”