Total Syntheses of (+)-Himbacine and (+)-Himbeline

Abstract

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:

Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels–Alder Reactions of Double Diene Precursors

“…13 Synthesis of the corresponding precursor for the himandravine series ( B ) combines elements of our synthesis of the GB17 analogue (i.e, 28 ) with the previously reported syntheses of himbacine ( 1 ). 11,13 Ultimately, the requisite linear precursor 29 could be obtained in good overall yield after 11 steps from cycloheptene ( 22 ).…”

“…9,10 Early work focused on the synthesis of himbacine ( 1 ), the simplest member of the family, with the first synthesis of 1 reported by Hart and Kozikowski in 1995. 11 Subsequent completed efforts were reported by the groups of both Chackalamannil 12 and Baldwin, 13,14 while the Terashima, 15 De Clercq, 16 and Sherburn 17 laboratories reported formal syntheses. Much of the excitement surrounding himbacine ( 1 ) was due to its reported activity as a potent and selective muscarinic receptor agonist (M2 receptor subtype K i = 5–10 nM vs M3 subtype K i = 150 nM).…”

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

“…Since then, 1 has motivated many synthetic efforts [9], among which Baldwin et al proposed the first biomimetic total synthesis [6a] and later extended their approach to other alkaloids of Class I such as himbeline (2) and himandravine (3) Their strategy relied on their own biosynthetic hypothesis (summarized in Scheme 8.1), according to which polyketide derivative 4 would first undergo reductive lactonization followed by reductive amination and N-methylation or protonation to give rise to intermediate 5. The tetrahydropyridinium ring of the latter would serve as activator for a biological Diels-Alder reaction via an endo transition state that would lead, after hydride reduction of the iminium ion to form a cis-or trans-piperidine ring, to the general scaffold of Class I alkaloids.…”

Molecularly Imprinted Materials: Towards the Next Generation

“…Furthermore, the recent development of more potent functional monomers, e.g. use of metal coordinating interactions for specific amino acid sequences [4], should generate more homogeneous binding sites. In addition to the above-mentioned covalent and non-covalent approaches, attempts have been made to combine the advantages of both the covalent and non-covalent methods, whereby imprinting is carried out using polymerization of functional monomer being covalently coupled to a template, and selective rebinding by carefully designed non-covalent interactions [5].…”