Gold-catalyzed and N-iodosuccinimide-mediated cyclization of gamma-substituted allenamides.

Chiral gamma-substituted allenamides have been shown to undergo efficient gold-catalyzed and N-iodosuccinimide-mediated cyclization to highly functionalized dihydrofurans. These reactions proceed rapidly and without loss of stereochemistry.

Synthesis and properties of cobalt(III) complexes of 4-substituted pyridine-capped dioxocyclams.

Cobalt(III) acetate and cyanide complexes of a series of 5,12-dioxocyclams capped across the 1,8-position by 4-substituted pyridines or pyrazine were synthesized and fully characterized. Both the spectroscopic and structural parameters for these complexes were remarkably insensitive to the electronic nature of the capping group, which ranged from the pi-accepting pyrazine group to the sigma-donating 4-[(dimethylamino)phenyl]pyridyl group. All of the complexes underwent an irreversible, one-electron reduction [Co(III)-->Co(II)] at potentials ranging from -0.

Boron-mediated stereoselective syntheses of gamma,gamma-disubstituted allenamides.

Propargylic boranes generated by lithiation of optically active N-propargyloxazolidinones undergo reaction with a range of aldehydes to produce gamma,gamma-disubstituted allenamides with good diastereoselectivity.

Synthesis and complexation of "back-to-back" capped bis-dioxocyclams.

Pyridine-capped 5,12-dioxocyclams were coupled "back-to-back" directly, with one or two intervening phenyl groups, an ethynyl group, or a diazo group via Suzuki, Sonogashira, or reductive coupling of the 4-nitropyridine monocyclam. These bis-dioxocyclams linked through extended pi-conjugated systems were complexed to copper(II) and cobalt(III), producing bis-metal complexes which were characterized spectroscopically and electrochemically. These studies gave little evidence for electronic communication between metal centers across the pi-conjugated linkers.

Reaction of optically active alpha-aminoallenylstannanes with aldehydes formed in situ from the Lewis-acid-catalyzed rearrangement of epoxides.

Reaction of optically active alpha-oxazolidinonylallenylstannanes with oxiranes in the presence of BF3.OEt2 produced beta-hydroxypropargylamines with high syn diastereoselectivity and high enantioselectivity through an initial Lewis-acid-catalyzed rearrangement of the oxirane to the corresponding aldehyde via an alkyl, aryl, or hydride shift. This permits the use of readily available oxiranes as alternatives to aldehydes that are difficult to prepare and/or unstable.

Synthesis of 4'-methyl and 4'-cyano carbocyclic 2',3'-didehydro nucleoside analogues via 1,4-addition to substituted cyclopentenones.

Carbocyclic 4'-methyl and 4'-cyano nucleoside analogues were synthesized using the Michael reaction to introduce the 4'-substituent and Pd-catalyzed allylic substitution to introduce the nucleoside base. Use of both the desired beta- and undesired alpha-1'-carbonate diastereomers in the Pd-catalyzed substitution was demonstrated in principle by epimerization of the alpha-diastereomer and kinetic diastereodifferentiation of a 1:1 alpha/beta mixture of 1'-carbonates.

Synthesis of 1-deoxy-D-galactohomonojirimycin via enantiomerically pure allenylstannanes.

1-Deoxy-D-galactohomonojirimycin was synthesized in seven steps from optically pure allenylstannane 4 and L-lactate-derived aldehyde 5 in 48% overall yield. The key step was the Lewis acid catalyzed reaction of 4 and 5 to give the syn-amino alcohol in excellent yield and very high diastereoselectivity.

Syntheses and reactions of optically active alpha-aminoallenylstannanes.

Lithiation/stannylation of optically active N-propargyloxazolidinones produced optically active alpha-oxazolidinonylallenylstannanes. Reaction of these with aldehydes in the presence of BF(3).OEt(2) produced beta-hydroxypropargylamines with high syn diastereoselectivity and ee.

Synthesis and structural studies of 5,12-dioxocyclams capped by 4-substituted pyridines across the amine nitrogens.

A series of 4-substituted pyridine-capped 5,12-dioxocyclams was synthesized and fully characterized. The 4-substituent varied from electron-withdrawing groups (NO2, NO, CN) to electron-donating groups (NHCbz, NH2). The most versatile substituent was the 4-bromo group, which could be replaced by a variety of groups using Stille, Sonogashira, or Buchwald-Hartig palladium-catalyzed chemistry.

Direct synthesis of 1,1'-[1,4-phenylenebis(methylene)]-bis- 1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD 3100) without the use of protecting groups.

A four-step synthesis of the title compound starting from methyl acrylate, ethylenediamine, and dimethyl malonate is reported. The synthesis can be run on a multigram scale and is operationally simple. The use of protecting groups is avoided by utilizing the trioxocyclam as the key coupling intermediate.

Synthesis, complexation, and coordination oligomerization of 1,8-pyrazine-capped 5,12-dioxocyclams.

(Methyl)(methoxy)-5,12-dioxocyclam 1 was alkylated on the secondary amines (capped) with 2,6-bis(bromomethyl)pyrazine. The resulting macrocycle was complexed to copper(II) to produce a five-coordinate complex 5a which was fully characterized by a range of spectroscopic methods (IR, UV-vis, ESR) as well as by X-ray crystallography. The structure of this complex is similar to the previously reported pyridine complex, with the five-coordinate copper having distorted square pyramidal geometry and a Cu-Pz bond length of 2.

Synthesis of 5,12-dioxocyclam nickel (II) complexes having quinoxaline substituents at the 6 and 13 positions as potential DNA bis-intercalating and cleaving agents.

Several dioxocyclams containing quinoxaline moieties, as well as their nickel(II) complexes were synthesized and studied for their ability to bind and oxidatively cleave DNA. Although no evidence for binding by intercalation was found, the ability of the Ni(II) complexes to cleave DNA in the presence of Oxone was strongly dependent on both the nature and the spatial orientation of the quinoxaline moieties, suggesting at least transient association of these complexes with DNA.

De novo synthesis of 4'-ethoxy nucleoside analogues.

Butenolides 5a and 13 were used as optically active templates in the de novo synthesis of 4'-disubstituted nucleoside analogues. The butenolides were reduced and acylated in situ to give acetates 10 and 14. Vorbrüggen coupling gave the protected nucleoside analogues 11 and 15.

Asymmetric synthesis of 4'-ethoxy-2',3'-didehydro-2',3'-dideoxynucleosides by palladium-catalyzed kinetic discrimination between the corresponding diastereoisomeric lactol acetates.

4'-Substituted nucleoside analogues have been synthesized using palladium-catalyzed asymmetric allylic amination conditions. A kinetic discrimination between the diastereomeric lactol acetates (3) produced the desired aminated products (6a-d) and recovered acetate (alpha-3) in high yields and <97:3 diastereoselectivity. Epimerization of the recovered lactol acetate (alpha-3) produced a 60:40 alpha/beta mixture of (3), which could be resubjected, in principle, to the palladium-catalyzed asymmetric allylic amination conditions.

Effect of adjacent chiral tertiary and quaternary centers on the metal-catalyzed allylic substitution reaction.

The metal-catalyzed allylic substitution reaction of 5a,b and 6a was examined. Reaction with stabilized nucleophiles led to exclusive attack at the less-hindered allylic terminus, and the stereoselectivity varied with the bidentate ligand used but favored retention. The yields and reaction times were improved with the use of microwaves.

Effect of beta-Substituents on the Regioselectivity of the Diazomethane Ring Expansion of alpha-Methyl-alpha-methoxycyclobutanones to Cyclopentanones.

The ring expansion of 22 differently beta-substituted alpha-methyl-alpha-methoxycyclobutanones by diazomethane was studied. Migration of the less-substituted alpha-carbon was favored with the single exception of a very sterically hindered beta-benzyloxy beta-substituent.

Synthesis and Reactivity of Optically Active Spiroketals by Ring-Expansion of Chromium Carbene Complex-Derived Cyclobutanones.

Photolysis of cyclic chromium alkoxycarbene complexes with an optically active ene-carbamate gave spirofused, optically active cyclobutanones. Baeyer-Villiger ring expansion followed by further functionalization gave optically active spiroketals. Photochemical ring expansion of these spirofused cyclobutanones in the presence of acetic acid or thiophenol gave 2-acetoxy- or 2-(thiophenoxy)-4-spirofused tetrahydrofurans.

Synthesis of 4-Alkyl-4-alkoxybutenolides Having Unsaturated Side Chains via Chromium Carbene Complex Photochemistry: (+)-Cerulenin.

The photochemical reaction between optically active ene carbamates and chromium alkoxycarbene complexes containing unsaturated aliphatic side chains was further developed. Although remote olefinic groups, including conjugated dienes, were tolerated, a homoallylic side chain underwent intramolecular reaction to give a strained cyclobutanone. (+)-Cerulenin was synthesized utilizing the photochemical reaction of an alkynylcarbene complex with an optically active ene carbamate and the bis(pi-crotyl)nickel halide alkylation of a vinyl bromide as key steps.

Photochemical Reaction between Tertiary Allylic Amines and Chromium Carbene Complexes: Synthesis of Lactams via a Zwitterion Aza Cope Rearrangement.

Photolysis of chromium carbene complexes in the presence of tertiary allylic amines resulted in a zwitterionic aza Cope rearrangement to produce unsaturated lactams in fair yield.