Synthesis of the Spiroiminal Moiety and Approaches to the Synthesis of Marineosins A and B

Abstract

A short and efficient synthesis of model spiroiminals that have the same stereochemistry but different conformations than marineosins A and B was carried out in 6-7 steps from 6-methyltetrahydropyran-2-one. These spiroiminals were also prepared biomimetically by reduction of an enol ether. A more highly substituted spiroiminal with the same stereochemistry and conformation as marineosin A was prepared in 11 steps from 6-methyl-4-propyl-3-phenyltetrahydropyran-2-one. A macrocyclic pyrrole lactone was prepared stereospecifically in 10 steps. A five step sequence converted the lactone to a late hemi-iminal intermediate that has resisted the methylation and spiroiminal formation that would lead to marineosin A.

Marine Pyrrole Alkaloids

“…Based on unsuccessful synthetic attempts (with the exception of individual key motifs) of several research groups [ 101 , 102 , 103 , 104 , 105 , 106 ], Shi and co-workers presented the first total synthesis of marineosin A ( 85a ) in 2016 [ 107 ]. The synthesis commenced with the commercially available (S)-pyrone 89 , which was converted into key fragment 90 in 10% yield over 14 steps.…”

“…This strategy yields several other prodiginine derivatives and premarineosin analogs that show promising cytotoxic and antimalarial activities [100]. Based on unsuccessful synthetic attempts (with the exception of individual key motifs) of several research groups [101][102][103][104][105][106], Shi and co-workers presented the first total synthesis of marineosin A (85a) in 2016 [107]. The synthesis commenced with the commercially available (S)-pyrone 89, which was converted into key fragment 90 in 10% yield over 14 steps.…”

“…The last two steps consisted of a Paal-Knorr reaction and a Vilsmeier-Haack reaction, not only allowing for the preparation of the sensitive pyrrole moieties in a late-stage procedure but also directly giving access to marineosin A′ (Scheme 8). It is also worth mentioning that Based on unsuccessful synthetic attempts (with the exception of individual key motifs) of several research groups [101][102][103][104][105][106], Shi and co-workers presented the first total synthesis of marineosin A (85a) in 2016 [107]. The synthesis commenced with the commercially available (S)-pyrone 89, which was converted into key fragment 90 in 10% yield over 14 steps.…”

Morita-Baylis-Hillman Reaction Inspired [3,3]-Rearrangement of Aryl Iodanes with α,β-Unsaturated Oxazolines

“…The LB addition then affords an iodine(III)-enolate species that could be an ideal rearrangement precursor. Subsequent [3,3]-rearrangement and β-elimination take place, nally producing valuable α-aryl α,β-unsaturated carbonyls that have signi cant utility in chemical synthesis [29][30][31][32][33] but may be di cult to make with E/Z selectivity through other known methods [34][35][36] . It should be noted that, while our study was underway, Wengryniuk reported an elegant iodonio-Claisen rearrangement of β-pyridinium silyl enol ethers that allows for α-arylation of α,β-unsaturated ketones.…”

Electrochemically Driven Desaturation of Carbonyl Compounds

“…They are often alternatively accessed through cross-coupling on the corresponding vinyl halide derivatives or through bromination/elimination sequences. 34,35 It worth noting that while comparing EDD with other precedented methods, the set of conditions reported by the Newhouse group was found to provide the desaturated -aryl lactones in moderate yields. Next, the particularly difficult class of aldehydes were investigated (32-34, silyl enol ethers employed).…”