Synthesis and stereochemistry of occidenol, a 4,5-dihydrooxipin-containing sesquiterpene: a pericyclic approach.

The first synthesis of occidenol (1), a 4,5-dihydrooxipin-containing sesquiterpene, is reported. The stereochemistry is corrected from that postulated by Tomita and Hirose, by a synthesis starting with natural occidentalol (4), the stereochemistry of which was also initially in error. The route (schemes 1 and 2) utilizes a retro-electrocyclic [2+2+2] fragmentation with N2 expulsion from 9 to produce, quantitatively, the acid sensitive dihydrooxipin system.

Addition of the phenoxathiin cation radical to alkenes and nonconjugated dienes. Formation of (E)- and (Z)-(10-phenoxathiiniumyl)alkenes and (E)- and (Z)-(10-phenoxathiiniumyl)dienes on basic alumina.

Addition of phenoxathiin cation radical (PO*+) to acyclic alkenes in acetonitrile (MeCN) solution occurred stereospecifically to form bis(10-phenoxathiiniumyl)alkane adducts. Stereospecific trans addition is ascribed to the intermediacy of an episulfonium cation radical. The alkenes used were cis- and trans-2-butene, cis- and trans-2-pentene, cis- and trans-4-methyl-2-pentene, cis- and trans-4-octene, trans-3-hexene, trans-3-octene, trans-5-decene, cis-2-hexene, and cis-2-heptene. The erythro bisadducts (compounds 6) were obtained with trans-alkenes, while threo bisadducts (compounds 7) were obtained with cis-alkenes. The assigned structures of 6 and 7 were consistent with their NMR spectra and, in one case, 6c (the adduct of trans-4-methyl-2-pentene) was confirmed with X-ray crystallography. Additions of PO*+ to 1,4-hexa-, 1,5-hexa-, 1,6-hepta-, and 1,7-octadiene gave bis(10-phenoxathiiniumyl)alkenes (compounds 8), the assigned structures of which were consistent with their NMR spectra. Each of these adducts lost a proton and phenoxathiin (PO) when treated with basic alumina in MeCN solution. Compounds 6 (from trans-alkenes) gave mixtures of (Z)- (9) and (E)-(10-phenoxathiiniumyl)alkenes (10) in which the (Z)-isomers (9) were dominant. On the other hand, compounds 7 (from cis-alkenes) gave mixtures of 9 and 10 in which, with one exception (the adduct 7c of cis-4-methyl-2-pentene), compounds 10 were dominant. The path to elimination is discussed. The alkenes 9 and 10 were characterized with NMR spectroscopy and, in one case (9a), with X-ray crystallography. Reactions of 8b-d with basic alumina gave mixtures of (E)- (13) and (Z)-(10-phenoxathiiniumyl)dienes (14), in which compounds 13 were dominant. The configuration of the product from 8a (the adduct of 1,4-hexadiene) could not be settled. Noteworthy features in the coupling patterns and chemical shifts in the NMR spectra of some of the adducts and their products are discussed and related to adduct conformations.

Adducts of thianthrene- and phenoxathiin cation radical tetrafluoroborates to 1-alkynes. Structures and formation of 1-(5-thianthreniumyl)- and 1-(10-phenoxathiiniumyl)alkynes on alumina leading to alpha-ketoylides and alpha-ketols.

[structure: see text] Thianthrene cation radical tetrafluoroborate (Th*+ BF4(-)) added to the terminal alkynes 1-pentyne, 1-hexyne, 1-heptyne, 1-octyne, 1-nonyne, and 1-decyne to form trans-1,2-bis(5-thianthreniumyl)alkene tetrafluoroborates (1-6). Similarly, addition of phenoxathiin cation radical tetrafluoroborate (PO*+ BF4(-)) to the same alkynes gave 1,2-bis(10-phenoxathiiniumyl)alkene tetrafluoroborates (7-12). The trans configuration of two of the adducts (1 and 4) was shown with X-ray crystallography. When solutions of 1-6 in chloroform were stirred with activated alumina, cis elimination of a proton and thianthrene (Th) occurred with the formation of 1-(5-thianthreniumyl)alkyne tetrafluoroborates (1a-6a). Similar treatment of 8-12 caused elimination of a proton and phenoxathiin (PO) with formation of 1-(10-phenoxathiiniumyl)alkene tetrafluoroborates (8a-12a). Stirring of 1a-6a with alumina for short periods of time caused their conversion into 5-[(alpha-keto)alkyl]thianthrenium ylides (1b-6b) and alpha-ketols, RC(O)CH2OH (1c-6c).

Adducts of thianthrene- and phenoxathiin cation radical salts with symmetrical alkynes. Structure and formation of cumulenes on alumina leading to alpha-diketones, alpha-hydroxyalkynes, and alpha-acetamidoalkynes.

[reaction: see text] Thianthrene cation radical tetrafluoroborate (Th*+ BF4-) added to 2-butyne, 3-hexyne, 4-octyne, and 5-decyne in MeCN to form trans bisadducts R(Th+)C=C(Th+)R, where R = Me, Et, Pr, Bu (7a-d). Phenoxathiin cation radical tetrafluoroborate (PO*+ BF4-) added similarly to the last three alkynes to form adducts R(PO+)C=C(PO+)R, 8b-d. Cyclic monoadducts were not found. The trans structures of 7 and 8 were deduced with X-ray crystallography (7c) and NMR spectroscopy. When solutions of adducts in CHCl3 and MeCN were deposited on activated alumina, elimination of thianthrene (Th) and phenoxathiin (PO) occurred almost quantitatively. Detailed studies with (7b-d) indicated that a cumulene (15) was formed by the elimination of Th and that 15 was subsequently converted into small amounts of other products. In CHCl3, these products were the respective alkyne, thianthrene 5-oxide, an alpha-diketone (11), an alpha-hydroxyalkyne (12), and hydrogen. The same products were formed in MeCN along with an alpha-acetamidoalkyne (13). The formation of 15 and products derived from it is explained and was confirmed by preparation and reactions of 2,3,4-hexatriene.

Decomposition of alkene adducts of thianthrene cation radical in nitrile solvents. Formation of alkyl-2-oxazolines and a new class of four-component products: 5-[(1-alkoxyalkylidene)ammonio]alkylthianthrenium diperchlorates.

The monoadducts (4a-d) of thianthrene cation radical perchlorate (1a) and isobutene, 2-methylbutene, 2-methyl-2-butene, and 2-methylpentene decompose spontaneously in acetonitrile (MeCN) solution, with the formation of thianthrene (Th). Decomposition of 4a (1,2-(5,10-thianthreniumdiyl)-2-methylpropane diperchlorate) and 4a', the corresponding dihexafluorophosphate, was studied in depth and extensively with (1)H and (13)C NMR spectroscopy. Decomposition of 4a was found to involve the solvent itself as well as water in the solvent, remaining from incomplete drying, and gave, apart from Th, successively, the perchlorate salts of 2,4,4-trimethyl-2-oxazoline (6) and 2-amino-2-methylpropyl acetate (7). These salts, 6-HClO(4) and 7-HClO(4), respectively, were prepared and used in understanding the reactions of 4a as well as the relationships among 6, 7, and 2-(acetylamino)-2-methyl propanol (8) in acidified MeCN solution. Decompositions of 4a-d in MeCN and other nitriles (RCN) containing an added alcohol (R'OH) led to new products, 5-[(1-alkoxyalkylidene)ammonio]alkylthianthrenium diperchlorates (5a-u). These compounds were identified with (1)H and (13)C NMR spectroscopy and, in part, with X-ray crystallography and elemental analysis. The mechanisms of formation of 5-7 are discussed.

Adducts of phenoxathiin and thianthrene cation radicals with alkenes and cycloalkenes.

Phenoxathiin cation radical perchlorate (PO.+ClO4(-)) added stereospecifically to cyclopentene, cyclohexene, cycloheptene, and 1,5-cyclooctadiene to give 1,2-bis(5-phenoxathiiniumyl)cycloalkane diperchlorates (4-7) in good yield. The diaxial configuration of the PO+ groups was confirmed with X-ray crystallography. Unlike additions of thianthrene cation radical perchlorate (Th.+ClO4(-)) to these cycloalkenes, no evidence for formation of monoadducts was found in the reactions of PO.+ClO4(-). This difference is discussed. Addition of Th.+ClO4(-) to five trans alkenes (2-butene, 2-pentene, 4-methyl-2-pentene, 3-octene, 5-decene) and four cis alkenes (2-pentene, 2-hexene, 2-heptene, 5-decene) gave in each case a mixture of mono- and bisadducts in which the configuration of the alkene was retained. Thus, cis alkenes gave erythro monoadducts and threo bisadducts, whereas trans alkenes gave threo monoadducts and erythro bisadducts. In these additions to alkenes, cis alkenes gave predominantly bisadducts, while trans alkenes (except for trans-2-butene) gave predominantly monoadducts. This difference is explained. 1,2-Bis(5-phenoxathiiniumyl)cycloalkanes (4-7) and 1,2-bis(5-thianthreniumyl)cycloalkanes underwent fast elimination reactions on activated alumina forming, respectively, 1-(5-phenoxathiiniumyl)cycloalkenes (8-11) and 1-(5-thianthreniumyl)cycloalkenes (12-16). Among adducts of Th.+ClO4(-) and alkenes, monoadducts underwent fast ring opening on alumina to give (5-thianthreniumyl)alkenes, while bisadducts underwent fast eliminations of H+ and thianthrene (Th) to give (5-thianthreniumyl)alkenes also. Ring opening of monoadducts was a stereospecific reaction in which the configuration of the original alkene was retained. Thus, erythro monoadducts (from cis alkenes) gave (E)-(5-thianthreniumyl)alkenes and threo monoadducts (from trans alkenes) gave (Z)-(5-thianthreniumyl)alkenes. Among bisadducts, elimination of a proton and Th occurred and was more complex, giving both (E)- and (Z)-(5-thianthreniumyl)alkenes. These results are explained. Configurations of adducts and (5-thianthreniumyl)alkenes were deduced with the aid of X-ray crystallography and (1)H and (13)C NMR spectroscopy. In the NMR spectra of (E)- and (Z)-(5-thianthreniumyl)alkenes, the alkenyl proton of Z isomers always appeared at a lower field (0.8-1.0 ppm) than that of E isomers.

Facile, efficient conjugation of a trifunctional lanthanide chelate to a peripheral benzodiazepine receptor ligand.

[reaction: see text] Receptor-mediated imaging and therapy of diseased tissue is rapidly gaining favor in the medical community. The synthesis and facile aqueous/organic coupling of a peripheral-type benzodiazepine receptor ligand to a cyclen-based fluorophore is described herein. The contrast agent QM-CTMC-PK11195, when chelated with lanthanides, produces bright luminescence and good MRI contrast and can potentially serve as an imaging and demarcation agent for certain types of cancers.