The intramolecular cycloaddition of 5 yields the unsaturated lactones 17a, 17b, and 17c as three major isomeric adducts. These were further reduced to the corresponding derivatives 21a, 21b, and 21c, which are intermediates for the synthesis
A convergent strategy towards himbacine (1) , involving a Julia coupling between aldehyde 5 and sulfone 6 was found to be ineffective. The aldehyde 5 was synthesized via the thermal intramolecular cycloaddition of 4 with preferred formation of the endo -adduct. The Diels-Alder precursor 4 was obtained from butenolide 7 , the result of a single-step condensation between the enoate derived from the ( Z )-conjugated olefin 12 and 2-acetoxypropanal. In the context of the synthesis of sulfone 6 Taber's method for the synthesis of 2,6-trans -disubstituted piperidine was adapted towards a large scale synthesis of 49 , a useful intermediate for the synthesis in this area.Himbacine (1) was first isolated in 1956 from the bark of Galbulimima baccata , a tree encountered in New Guinea and in parts of Australia. 1 A series of related alkaloids, including himbeline (2) and himgravine (3) , have also been isolated from the same source. 2 The relative and absolute configuration of 1 were determined via an X-ray diffraction study of the corresponding hydrobromic salt. 3 Interestingly, himbacine (1) is a potent muscarinic receptor antagonist that displays selectivity for the M 2 receptor. 4 As such it could become an important lead structure in the development of drugs for the treatment of Alzheimer's disease. 5For a synthetic chemist himbacine (1) possesses an attractive structure. Its skeleton consists of a trans -fused perhydronaphthalene with a cis -fused γ -lactone, the ABC-ring part of the molecule, to which is connected, via a ( E )-double bond, the N -methyl piperidine D-ring. A convergent strategy calls for a coupling of both parts via appropriate ( E )-olefination methodology. The two parts further possess an interesting stereochemical pattern: in the ABCring part six contiguous stereocentres are present, while the D-ring consists of a 2,6-trans -disubstituted piperidine ring.The first total syntheses of (+)-himbacine were described by the groups of Hart for the construction of the ABC-ring system, different intramolecular Diels-Alder strategies with formation of five stereogenic centres (Scheme 1). In the first strategy endo -cycloaddition involving approach of an ( E )-dienophile to the least hindered side of the diene leads to an adduct with the correct stereogenicity at centres C-3, 8, 9, 10 and 11. 6 In the second strategy the exo -cycloaddition involving reaction of the diene to the least hindered side of the ( Z )-dienophile gives an adduct possessing the correct stereochemistry at C-8, 9, 10 and 11 with the further possibility of facile epimerisation at C-1. 7 It is interesting to note that in the same period (1995) independent studies were also reported from this laboratory and by Baldwin and co-workers that follow the first Diels-Alder approach. 8,9 Since the reduction of himgravine (3) to himbacine (1) is a known process, 10 the choice of this particular strategy is a very logical one. In the present paper we would like to describe in detail the work we performed along this line.The convergent route that we...
Synthesis and Affinity Studies of Himbacine Derived Muscarinic Receptor Antagonists. -Himbacine related analogues, e.g. (I)-(III), are prepared by recently reported procedures and their binding affinities towards M 1 -M 4 muscarine receptor subtypes are investigated. (I) and (III) show a promising 10-fold selectivity for the M 2 relative to the M 1 receptor. (II) on the other hand has a 10-fold M 4 /M 3 selectivity. -(GAO, LING-JIE; WAEL-BROECK, MAGALI; HOFMAN, SVEN; VAN HAVER, DIRK; MILANESIO, MARCO; VITERBO, DAVIDE; DE CLERCQ, PIERRE J.; Bioorg. Med.
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