Transalpinecine and Analogues: First Total Synthesis, Stereochemical Revision and Biological Evaluation

Abstract

The first total synthesis of transalpinecine, a pyrrolizidine alkaloid extracted from Heliotropium transalpinum is reported. The concise synthetic route developed towards these unusual iminosugar‐like natural compounds relies on an intramolecular Morita–Baylis–Hillman reaction. The four diastereoisomers of transalpinecine, as well as the two diastereoisomers of the parent epoxide subulacine, were prepared. 1H NMR‐based stereochemical assignment of these different diastereoisomers was substantiated by quantum calculations of NMR shifts and coupling constants, allowing revision of the initially reported transalpinecine structure. One of these synthetic compounds significantly potentiates the activity of the F508del‐CFTR corrector VX‐809.

C‐Branched Imino Sugars: Synthesis and Biological Relevance

“…Authors reported as well the first isolation of a compound claimed to be a naturally occurring α‐isomer of subulacine ( 8 ). Total synthesis and in‐depth NMR study of the four diastereoisomers of transalpinecine proved that the isolated compound was the 1β,2α‐dihydroxy‐1α‐hydroxymethyl‐8α‐pyrrolizidine 17b and not the initially reported 1β,2β‐dihydroxy‐1α‐hydroxymethyl‐8α‐pyrrolizidine 17a . In addition, synthesis and thorough NMR analysis of the α‐isomer of subulacine ( 8 ) also allowed refuting its structural assignment to the second reported natural product…”

“…We recently developed a concise stereodivergent synthesis of racemic transalpinecine ( 17b ) which allowed the stereochemical revision of the claimed structure 17a (Figure ) . The enal 28 was prepared by an olefin cross‐metathesis of the N ‐allyl pyrrolidine 27 with acrolein.…”

“…l ‐isoDMDP ( 117 ) showed also an important rescue of F508del‐CFTR function but nevertheless weaker than isoLAB ( 5 ) and NB‐DNJ. Recently transalpinecine ( 17b ) and analogues were evaluated for their ability to rescue the defective F508del‐CFTR function cells . Despite of their structural resemblance with IsoLAB ( 5 ), neither 17b nor its analogues were efficient to rescue F508del‐CFTR alone.…”

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

“…The synthesis of all compounds involved an intramolecular acid-mediated Morita-Baylis-Hillman reaction as the key step (TfOH/Me2S) [142], enabling the formation of the bicyclic compound ±59 from a pyrrolidine scaffold and thereby the access to racemic supinidine (±60) after reduction of the aldehyde function (Scheme 8). Then, double bond epoxidation accomplished via bromohydrin formation led to subulacine ±62 and its diastereoisomer ±63, while the four diastereoisomers ±64 were obtained by epoxide-ring opening of ±62 and ±63 under acidic conditions (TFA/H2O) or double bond OsO4-catalysed cis-dihydroxylation of ±59 or ±60 [143]. Differing from previous examples, branched pyrrolidines 4-C-Me-DAB and 4-C-Me-LAB, in which a methyl group is introduced at C4 position of DAB and LAB ( Figure 10), exhibited no correction effect on the functional properties of the defective CFTR [131].…”

Recent Advances in Total Synthesis of Alkaloids from α,β‐Unsaturated Aldehydes

“…A similar strategy to synthesis of α,β-unsaturated aldehyde 156 was employed by Dehoux and co-workers in the total construction of (�)-supinidine (158) and transalpinecine (160) from the pyrrolizidine alkaloids family (Scheme 22). [61] Starting from the cross-metathesis reaction of the N-allyl pyrrolidine (155) and acrolein (15) using a Hoveyda-Grubbs catalyst, the synthesis of a enal 156 was achieved in 72 % yield. Then key intramolecular Morita-Baylis-Hillman reaction of aldehyde 156 afforded the bicyclic aldehyde 157 which was reduced to bioactive (�)-supinidine (158) and transalpinecine (160).…”