Polyquinanes by [4 + 4] cycloaddition-transannular cyclization.

[reaction: see text] Photocycloaddition of 2-pyridones yields a rigid polycyclic product containing a 1,5-cyclooctadiene. The cis isomer, with the alkenes in close proximity, undergoes a transannular reaction when treated with chlorine to give a polyquinane product. The chlorination reaction involves migration of an amide nitrogen and forms a single isomer, generating eight stereogenic centers in two steps.

Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease.

BACKGROUND: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. RESULTS: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. CONCLUSIONS: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.

A [4 + 4] 2-pyridone approach to taxol. 3. Stereocontrol during elaboration of the cyclooctane.

Intramolecular photocycloaddition of 2-pyridones connected through a four-carbon tether (6-[4-(1,2-dihydro-1-methyl-2-oxo-3-pyridinyl)-4-[[(1,1-dimethylethyl)++ +dimethylsilyl]oxy]butyl]-4-methoxy-1,3-dimethyl-2(1H)-pyridinone) yields a single tetracyclic product with four new stereogenic centers. The diastereoselectivity of this [4 + 4] reaction is fully controlled by a stereogenic carbon of the tether. Treatment of the photoproduct with osmium tetraoxide transforms the alkene to a diol and the enol ether to an alpha-hydroxy ketone, with stereocontrol dictated by nearby lactams that block one face of each alkene. Allylmagnesium bromide addition to the ketone also yields a single diastereomer, but unexpectedly this product results from approach of the nucleophile to the most-hindered face of the ketone. Study of this reaction in a model system has found the allylic nucleophile to be unique, with nonallylic reagents approaching along the expected, least-hindered path. This contrasteric addition likely results from coordination of the allylic nucleophile to the nearby amide. The amide can therefore act either as a steric shield or as a directing group. The three steps of photocycloaddition, cis-hydroxylation, and nucleophilic addition constructs both quaternary carbons of the cyclooctane and four of the five stereogenic centers found in the eight-membered ring of Taxol.

Photoreactivity of 2-pyridones with furan, benzene, and naphthalene. Inter- and intramolecular photocycloadditions.

Pyridones, well-known for their ability to photodimerize, have been found to undergo [4 + 4] photocycloaddition with furan and naphthalene but not with benzene. In some cases these reactions can be highly regio- and stereospecific. Intramolecular reaction with furan produces both cis and trans [4 + 4] products. The cycloaddition with naphthalene can occur both inter- and intramolecularly. The intermolecular reaction yields primarily the cis isomer, whereas the trans isomer is the major product from the intramolecular reaction. A mixture of 4-methoxy-2-pyridone and 2-methoxynaphthalene that could form up to eight regio- and stereoisomers forms largely one [4 + 4] product.

Evidence for helicity in insect diuretic peptide hormones: computational analysis, spectroscopic studies, and biological assays.

The conformation of four insect diuretic hormones has been analyzed computationally using secondary structure prediction routines and comparison with structures in the Brookhaven Protein Databank. Based on this analysis, a common seven-residue peptide fragment (DVLRQRL) had a high probability of forming an alpha-helix. Circular dichroism (CD) studies found that addition of trifluoroethanol (TFE) to an aqueous solution of the seven-residue fragment induces a change from random coil to helix. Subsequent NMR studies in water-TFE (1:1) produced nOe values and 3JalphaNH coupling constants confirming a helical conformation: 3JalphaNH coupling constants for the first five residues (D1 to Q5) were all < or = 6.0 Hz and two medium-range nOe values (dalphaN (i,i+3)) were observed between V2 and Q5, and R4 and L7. The longer fragments PLDVLRQRL in water-TFE and Lom-DH 1-26 in water alone, both containing the DVLRQRL sequence of the locust (Locusta migratoria) diuretic hormone, maintained the helicity as determined by CD analysis. However, the remaining 20 residues of the locust diuretic hormone did not maintain the same amount of helicity in water and all of the truncated fragments were not biologically active.

Solvent-dependent stereoselectivity of bis-2-pyridone [4 + 4] photocycloaddition is due to H-bonded dimers.

[formula: see text] A solvent-dependent stereoselectivity found for intramolecular [4 + 4] photocycloaddition of tethered 2-pyridones is concentration dependent, indicating that a dimeric structure with four hydrogen bonds plays a critical role in the observed cis selectivity found for nonpolar solvents.