ABSTRACT
Introduction In the preceding article [1], we have reported the synthesis of the chiral lactam building blocks (1, 2, Schemes 1, 2) for the exible synthesis of poison-frog alkaloids of the 5,8-disubstituted indolizidine class. e utility of these chiral building blocks was demonstrated by the synthesis of alkaloids (-)-203A, (-)-205A from 1, and of (-)-219F from 2. Although the biological activity of most of the 5,8disubstituted indolizidines has not been investigated, certain 5,8-disubstituted
indolizidines have been shown to act as noncompetitive blockers of nicotinic acetylcholine receptors. [2,3]
Nicotinic receptors are ligand-gated ion channels composed of ve subunits. [4] To date, 12 nicotinic receptor subunits (α2-α10, β2-β4) have been identied. Subtypes of neuronal nicotinic receptors are constructed from numerous subunit combinations, which confer varied functional and pharmacological characteristics. [5] Nicotinic receptors have been implicated in a wide range of neuronal dysfunctions and mental illness, such as epilepsy, Tourette’s syndrome, Alzheimer’s disease, Parkinson’s disease, and schizophrenia. [5,6] Since dierent subtypes of nicotinic receptors are involved in dierent neurological disorders, subtypeselective nicotinic ligands would be valuable for investigation and potentially for treatment of cholinergic disorders of the central nervous system. However, there
are only a limited number of compounds that elicit subtype-selective blockade of nicotinic receptors because of the similarity of receptor-channel structure among the subtypes. Recently, we have investigated the eect of synthetic (-)-235B’, one of the 5,8-disubstituted indolizidine class of poison-frog alkaloids, on several subtypes of nicotinic receptors, and found that this alkaloid exhibits selective and potent blocking eects at the α4β2 nicotinic receptor. [3] e potency of (-)-235B’ for this receptor is comparable to that of the classical α4β2 competitive antagonist, dihydro-β-erythroidine. In this study, we have synthesized 5,8-disubstituted indolizidines (-)-209B, (-)-231C, (-)-233D, (-)-235B”, (-)-221I, and an alkaloid that proved to be an epimer of natural indolizidine 193E. e alkaloids (-)-209B and (-)-235B” are known to be noncompetitive nicotinic blockers [2], but eects of the other compounds have not yet been tested. To explore possible subtype selectivity, we examined the eects of (-)-231C, (-)-221I and (-)-epi-193E on α4β2 and α7 nicotinic receptors, the most abundant subtypes in the mammalian brain. [4]
Results and Discussion Reduction of the lactam 1 [1] with LiAlH4 followed by Swern oxidation of the resulting alcohol and Wittig reaction gave the olen 3 in 78% overall yield (Scheme 1). Hydrogenation of the double bond in 3 with 10% Pd/C provided (-)-209B, whose spectral data were identical with reported values. [7] e lactam 1 was also converted to the alcohol 4, [1] which was transformed into (-)-235B” by Swern oxidation followed by Wittig reaction under high dilution and ‘salt free’ conditions (Scheme 1). e spectral data of synthetic (-)-235B” were identical with reported values. [8,9] Indolizidines (-)-231C [10] and (-)-233D [10] were synthesized from common intermediate 5 prepared from the alcohol 4. us, the Swern oxidation of 4 and then the Wittig reaction of the resulting aldehyde under Stork’s conditions [11] provided the Z-iodoolen 5 in a highly stereoselective manner. e Sonogashira coupling reaction [12] of 5 with TMS-acetylene followed by cleavage of the trimethylsilyl group with K2CO3 aorded (-)-231C. Although the rotation of the natural alkaloid is unknown, the relative stereochemistry was determined to be 5,8-E and 5,9-Z by GC-MS and GC-FTIR comparison with natural 231C in extracts from a Panamanian dendrobatid frog, Dendrolbates pumilio. A similar, Ni-catalyzed cross coupling [13] reaction of 5 with vinylmagnesium bromide provided the (-)-233D, whose spectral data were identical with values
reported for the natural alkaloid isolated from the Panamanian dendrobatid frog. [10] Although diering in magnitude, the HCl salts of both synthetic (-) 233D and the natural alkaloid had negative optical rotations.
