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PubMed2005

[Nalpha-benzylTyr1,cyclo(D-Asp5,Dap8)]- dynorphin A-(1-11)NH2 cyclized in the "address" domain is a novel kappa-opioid receptor antagonist.

The cyclic dynorphin A analogue [N(alpha)-benzylTyr(1),cyclo(D-Asp(5),Dap(8))]dynorphin A-(1-11)NH(2) (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (K(i) ratio (kappa/mu/delta) = 1/194/330) for kappa-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH(2) at kappa-opioid receptors in the adenylyl cyclase assay (K(B) = 84 nM). This is the first dynorphin A-based antagonist with modifications in the C-terminal "address" domain that alter efficacy and thus represents a novel selective kappa-opioid receptor antagonist.

Adenylyl Cyclases↗
PubMed2000

A convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with beta and gamma-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A.

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyr role, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic gamma-chloroalkyl-benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-delta5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R, 8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-delta5,6-indo lizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfo nyl)-delta5,6-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.

Acylation↗
PubMed2000

Laser flash photolysis evidence for styryl radical cation cyclization in the SET-induced photorearrangement of a p-methoxy-substituted 2-phenylallyl phosphite.

The SET-induced photorearrangement of dimethyl 2-(4-methoxyphenyl)allyl phosphite, 9 (UV light, uranium glass filter, 9,10-dicyanoanthracene (DCA), biphenyl), gives phosphonate 12 in 83% isolated yield. Laser flash irradiation at 355 nm of oxygen saturated solutions of phosphite 9 containing DCA and biphenyl generates the transient UV spectrum of the biphenyl radical cation that is quenched by electron transfer from phosphite 9 (k(q) = 8.9 x 10(9) M(-1) s(-1) at 20 degrees C) to form the 4-methoxystyryl cation 10. The UV spectrum of 10 decays by a measured first-order rate constant of 8.0 x 10(6) s(-1), presumably to generate the cyclic distonic radical cation 11. Intermediate 10 was further characterized by measurement of the second-order rate constants for its reaction with azide, chloride, and bromide ions and with the neutral nucleophile trimethyl phosphite. This study provides the first spectroscopic evidence regarding the proposed mechanism (Schemes 1 and 2) for the SET-induced photorearrangements of dimethyl 2-arylallyl phosphites to the corresponding 2-arylallylphosphonates. Moreover, absolute rate constants for the intramolecular trapping of alkene radical cations have seldom been measured. The removal of the electron from the styryl moiety of phosphite 9, rather than from phosphorus, and the detectability of 10 arise from the stabilizing effect of the 4-methoxy substituent. These results, however, do not allow conclusions to be made concerning the site of removal of an electron in the SET-induced photorearrangement of dimethyl 2-phenylallyl phosphite 1 to phosphonate 6.

Allyl Compounds↗
PubMed2000

Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine.

Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded beta-epoxide 28 from 26 and alpha-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.

Catalysis↗
PubMed2001

Free-radical cyclizations onto differently substituted 1,2,3-triazoles installed in sugar templates.

The synthesis and manipulation of differently substituted 1,2,3-triazoles (7-11 and 12-16) installed in sugar templates gave compounds 29-34 and 44-50, after reaction with tributyltin hydride or tris(trimethylsilyl)silane. Following standard procedures compound 44 was transformed into piperidinose derivative 54. These compounds are chiral, useful building blocks for the synthesis of glycosidase inhibitors of the fused-azole piperidinose type.

Acetylation↗