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A mild resin-immobilization strategy employing a readily prepared trityl bromide resin for anchoring building blocks via a phenol group has been developed. With N^α-Fmoc-Tyr-OPfp as a starter building block, it was possible to prepare asymmetrically substituted hybrids of spider- and wasp-type polyamine toxins using solid-phase peptide synthesis conditions.

Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus, tyrosine was replaced by either apolar, conformationally constrained, or bulky amino acids, whereas the acyl unit and the polyamine moiety were kept unchanged. Analogues with tertiary amide groups were prepared for the first time. Pentafluorophenyl esters were employed for amide bond formation, establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39−90% and 42−54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)propanoic acid receptors (AMPAR) expressed in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the α-NHCO group as a donor in hydrogen bonding.

An expedient solid-phase synthetic approach to secondary and tertiary amines was developed. The protocol employs conversion of resin-bound amino alcohols to the corresponding iodides, followed by iodide displacement with primary or secondary amines or with unprotected amino alcohols. This two-step procedure, affording products in good to excellent yields, is suitable for solid-phase synthesis of polyamines.

The iridoid glucoside antirrhinoside (1) was transformed into polysubstituted 3-azabicyclo[3.3.0]octanes 3, 12, and 13 in 4 to 5 steps. Ozonolysis of the diacetonide of 1 and of its 7-deoxy-derivative 8 afforded cyclopentanoids 2 and 10, respectively. Conditions for the selective conversion of 2 and 10 into the corresponding ditosylates 4 and 11 were investigated. Cyclization of 4 and 11 was achieved with benzylamine and 2-methoxybenzylamine to yield bicyclic pyrrolidines 3, 12, and 13. Additional building blocks 14 and 15 were obtained by selective deprotection of the N-benzyl and isopropylidene moieties in 12 and 13, respectively.

Stereoselective hydrogenation of the iridoids geniposide (9) and aucubin (19) was achieved by using the 1-methyl-1-methoxyethyl ether as a protecting group for the allylic alcohol, as it enhanced the stereoselectivity and prevented undesired hydrogenolysis. Ozonolysis of the hydrogenation product from 9, adoxoside (11), with reductive workup, afforded either a chiral lactone (25) or a chiral polyol (26), depending on the reduction conditions. Polyol 26 was subjected to protecting-group manipulation and subsequent oxidation and reductions to yield cyclopentane building blocks (29−34), which, by Mitsunobu couplings with purines, afforded carbocyclic nucleoside analogues (7, 8, and 35).

Treatment of the iridoid glucoside antirrhinoside (1) with pyridinium chloride in dimethylformamide gave rise to the two possible trans-halohydrins, linarioside (4) and isolinarioside (5). Pyridinium bromide gave the two analogous bromohydrins. It is shown that the iridoid glucosides 8-epi-muralioside from Linaria arcusangeli and 7,8-epi-antirrhinoside from Linaria dalmatica are both identical with isolinarioside, and therefore, these names are redundant. The structure of muralioside isolated from Cymbalaria muralis is revised to that of its 8-epimer (8), while the structure of an isomeric, new iridoid glucoside from Paulownia tomentosa has been elucidated to be 7β-hydroxyharpagide (3), the structure originally assigned to 8. In addition, 7α-hydroxyharpagide (2), the known product from the base-catalyzed hydrolytic opening of 1, has been isolated from Antirrhinum majus and thus shown to be a natural product.

Synthesis of five novel piperidine monoterpene alkaloids (17−21) using the iridoid glucoside antirrhinoside (4) as a synthon is described. Two strategies for their preparation were investigated:  the first possible pathway involved an intermediate diol, 13, from which the piperidine ring was expected to be constructed via reaction of its ditosylate with an amine; the second strategy involved a double reductive amination as the key step to the piperidine ring, which proved successful. The stereochemistry of C-5 and C-9 in the obtained piperidine monoterpenes was the same as that reported for α-skytanthine (3), a known isolate from Skytanthus acutus (Apocynaceae).

Two unique 2-(3,4-dihydroxyphenyl)ethyl glycosides, namely, dopaol β-d-2-ketoglucopyranoside and dopaol β-d-2,3-diketoglucopyranoside, were isolated from Chelone obliqua together with the iridoid glucoside catalpol, dopaol β-d-glucopyranoside, descaffeoylverbascoside, and verbascoside. Glycosides with a diketosugar have not so far been isolated from natural sources.

Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was employed for the total synthesis of novel analogues of wasp polyamine toxins (philanthotoxins).

Two novel quinazolines, verrucines A (1) and B (2), have been isolated as a major and a minor metabolite, respectively, of Penicillium verrucosum. Both are condensates of one mole each of anthranilic acid, phenylalanine, and glutamine. The structures were elucidated by spectroscopic methods, and the two compounds were found to be epimers. The spectroscopic data for the ostensible benzodiazepine anacine reported from Penicillium aurantiogriseum, composed of one mole each of anthranilic acid, leucine, and glutamine, appeared very similar to those of 1. Therefore, a revised quinazoline structure for anacine is proposed.

An unusual iridoid glucoside, namely 9-hydroxy-8-epihastatoside (1), was isolated from Junellia seriphioides (Verbenaceae), together with the known compounds auroside (2), pulchelloside I (3), and 8-epihastatoside (4) as well as verbascoside.