Himbacine (1) is a piperidine alkaloid isolated from the Australian pine Galbulimima baccata.1•2 It is a potent muscarinic antagonist that displays selectivity for M2 or M4 receptors and, as such, has become a leading compound for identifying possible new drug candidates for the treatment of Alzheimer's dementia.3•4 For example, blockage of presynaptic inhibitory muscarinic receptors leads to an elevation of synaptic levels of acetylcholine, thus possibly offsetting some of the losses in the cholinergic system that occurs in Alzheimer's disease. Limited SAR studies suggest that the iraws-decalin substructure of himbacine may play an important role in conferring its selective binding properties4 Thus, it was desired to develop a synthesis of himbacine that would couple a decalin substructure to an appropriately substituted piperidine. This paper describes the first total synthesis of (+)-himbacine (1) via the related alkaloid (+)-himbeline (2).The initial target for synthesis was aldehyde 14. It was hoped that this would be available via an intramolecular Diels-Alder reaction of a substrate such as 9. Indeed, the presence of himgravine (3) as a congener with himbacine has led to the suggestion that an intramolecular cycloaddition might be involved in the biosynthesis of these alkaloids.5 The synthesis of 9 is shown in Scheme 1. Ozonolysis of cycloheptene according to the procedure of Schreiber provided aldehyde 5, and subsequent Wittig olefination gave 6 as a 2:1 mixture of geometrical isomers in 72% overall yield.6•7 Addition of the dienolate derived from 6 to the tetrahydropyranyl ether of (5)-2-hydroxypropanal,8 followed by acetal hydrolysis and lactonization using p-toluenesulfonic acid in methanol and dehydration (MsCl, Et3N, CH2CI2), provided diene 8 as an 8:1 mixture of (1) For the isolation of himbacine, see:
Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
Total syntheses of (+)-himbacine (1) and
(+)-himbeline (2) are described. The synthesis
involves
the preparation of sulfone 38 and aldehyde 42 as
single enantiomers followed by coupling of these
compounds using a Julia−Lythgoe olefination. The preparation of
sulfone 38 features an acid-promoted intramolecular Diels−Alder reaction of an α,β-unsaturated
thioester while the synthesis
of 42 features a Beak alkylation of piperidine
39.
In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.
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