Wittig reactions in water media employing stabilized ylides with aldehydes. Synthesis of alpha,beta-unsaturated esters from mixing aldehydes, alpha-bromoesters, and Ph3P in aqueous NaHCO3.

Water is demonstrated to be an effective medium for the Wittig reaction over a wide range of stabilized ylides and aldehydes. Despite sometimes poor solubility of the reactants, good chemical yields normally ranging from 80 to 98% and high E-selectivities (up to 99%) are achieved, and the rate of the reactions in water is unexpectedly accelerated. The efficiency of water as a medium in the Wittig reaction is compared to conventional organic solvents ranging from carbon tetrachloride to methanol. The aqueous Wittig reaction works best when large hydrophobic entities are present, such as aromatic, heterocyclic aromatic carboxaldehydes, and long-chain aliphatic aldehydes with triphenylphosphoranes. The E/Z-isomeric ratio of the Wittig products appears dependent on the electron-accepting/donating capacity and the location of the substituents present in the aromatic ring. The effect of additives, such as benzoic acid, LiCl, and sodium dodecyl sulfate (SDS), on the Wittig reaction has been explored. The Wittig reaction can also be conducted in the presence of acidic entities, such as phenols and carboxylic acids. In addition, large alpha-substituents in the aliphatic aldehydes do not jeopardize the reaction. It is also demonstrated that hydrates of aldehydes can be used directly in the aqueous Wittig reaction as substrates. The scope of the aqueous Wittig reaction is extended to 24 examples of one-pot mixtures of Ph3P, alpha-bromoesters, and aldehydes in sodium bicarbonate solution (at 20 degrees C for 40 min to 3 h) to provide Wittig products of up to 99% yield and up to 98% E-selectivity. Since water is inexpensive, extremely easy to handle, and represents no environmental concerns, it should be considered a possible medium for new organic reactions.

The conformation of acetylated virginiamycin M1 and virginiamycin M1 in explicit solvents.

The three-dimensional structure of acetylated virginiamycin M(1) (acetylated VM1) in chloroform and in a water/acetonitrile mixture (83:17 v/v) have been established through 2D high resolution NMR experiments and molecular dynamics modeling and the results compared with the conformation of the antibiotic VM1 in the same and other solvents. The results indicated that acetylation of the C-14 OH group of VM1 caused it to rotate about 90 degrees from the position it assumed in non-acetylated VM1. The conformation of both VM1 and acetylated VM1 appear to flatten in moving from a nonpolar to polar solvent. However, the acetylated form has a more hydrophobic nature. The acetylated VM1 in chloroform and in water/acetonitrile solution had a similar configuration to that of VM1 bound to 50S ribosomes and to the Vat(D) active sites as previously determined by X-ray crystallography. Docking studies of VM1 to the 50S ribosomal binding site and the Vat(D) gave conformations very similar to those derived from X-ray crystallographic studies. The docking studies with acetylated VM1 suggested the possibility of a hydrogen bond from the acetyl carbonyl group oxygen of acetylated VM1 to the 2' hydroxyl group of ribose of adenosine 2538 at the ribosomal VM1 binding site. No hydrogen bonds between acetylated VM1 and the Vat(D) active sites were found; the loss of this binding interaction partly accounts for the release of the product from the active site.

The conformational flexibility of the antibiotic virginiamycin M(1).

The antibiotic virginiamycin is a combination of two molecules, virginiamycin M(1) (VM1) and virginiamycin S(1) (VS1) or analogues, which function synergistically by binding to bacterial ribosomes and inhibiting bacterial protein synthesis. Both VM1 and VS1 dissolve poorly in water and are soluble in more hydrophobic solvents. We have recently reported that the 3D conformation of VM1 in CDCl(3) solution differs markedly from the conformation bound to a VM1 binding enzyme and to 50S ribosomes as found by X-ray crystallographic studies. We now report the results of further NMR studies and subsequent molecular modeling of VM1 dissolved in CD(3)CN/H(2)O and compare the structure with that in CD(3)OD and CDCl(3). The conformations of VM1 in CD(3)CN/H(2)O, CD(3)OD and CDCl(3) differ substantially from one another and from the bound form, with the aqueous form most like the bound structure. We propose that the flexibility of the VM1 molecule in response to environmental conditions contributes to its effectiveness as an antibiotic.

Conjugate additions of a simple monosilylcopper reagent with use of the CuI.DMS complex: stereoselectivities and a dramatic impact by DMS.

Conjugate additions utilizing the simple monosilylcuprate reagent Li[PhMe2SiCuI] to alpha,beta-unsaturated carbonyl compounds are described. The presence of dimethyl sulfide (DMS), either as a component originating from the (CuI)4(DMS)3 complex or as a solvent added, has an amazing influence on both chemical yield and the level of diastereomeric ratio (dr) of the products. Gilman-type silylcyanocuprates {Li(Ph2MeSi)2Cu/LiCN} have previously been used to guarantee good results in conjugate addition reactions. External additives such as HMPA, tributylphosphine, or dialkylzinc are not necessary in conjunction with the simple Li[PhMe2SiCuI] reagent. It is demonstrated that the monosilylcuprate reagent with DMS as the solvent is very useful with sterically hindered (beta,beta-disubstituted) enones, and provides very high yields of the beta-silylated 1,4-addition products. Since there is no oligomerization problem associated with the simple monosilylcuprate reagent, this reagent should be considered as a very useful 1,4-silyl donor to enals, enones, and enoates in conjugate addition reactions.

Solvent affects the conformation of virginiamycin M1 (pristinamycin IIA, streptogramin A).

The streptogramins are antibiotics which act by binding two different components at separate nearby sites on the bacterial 50S ribosome, inhibiting protein synthesis. The first component, a macrolactone, is common to many of the streptogramin antibiotics and, thus, is referred to by many names including virginiamycin M1(VM1), pristinamycin IIA, ostreogrycin A and streptogramin A. X-Ray crystallographic studies of VM1 bound to ribosomes and to a deactivating enzyme show a different conformation to that of VM1 in chloroform solution. We now report the results of high resolution 2D NMR experiments that show that the conformation of VM1 in dimethyl sulfoxide and methanol differs from both that in chloroform solution and in the bound form. The 3D structure and the 1H NMR and 13C NMR chemical shifts of VM1 in dimethyl sulfoxide and methanol are described.

Direct copper(I) iodide dimethyl sulfide catalyzed conjugate addition of alkenyl groups from vinylzirconocene reagents.

[reaction: see text] CuI.0.75DMS complex is an excellent catalyst for the direct conjugate addition of alkenyl groups from vinylzirconocene reagents to alpha,beta-unsaturated aldehydes and ketones. The presence of the catalyst with an alkenylzirconocene, at +40 degrees C in THF, circumvents the need for making discrete alkenylcopper reagents. The catalyst is superior in terms of product yields and alkene flexibility in comparison to other copper(I) sources as well as the nickel(II)-catalyzed conjugate addition. This simple one-pot procedure shows that only 1 equiv of the vinylzirconocene is needed.

The remarkable ability of lithium ion to reverse the stereoselectivity in the conjugate addition of Li[BuCuI] to a chiral N-crotonyl-2-oxazolidinone.

[reaction: see text] The influence of lithium ions on the conjugate addition of the monoorganocuprate reagent, Li[BuCuI], to a chiral crotonate has been investigated. The results show that iodotrimethylsilane (TMSI) is crucial for the asymmetric conjugate addition of the copper reagent, but only in THF or when 12-crown-4 is used. The reaction is thought not to involve any halosilane in any critical steps in the organocopper mechanisms conducted in Et(2)O.

Employing the simple monosilylcopper reagent, Li[PhMe2SiCuI], in 1,4-addition reactions.

Conjugate addition reactions using the simple Li[PhMe2SiCuI] reagent to a variety of alpha,beta-unsaturated carbonyl compounds is described; dimethyl sulfide from the purification of CuI plays a key role for very high yields as well as high stereoselectivities in the formation of beta-silyl carbonyl compounds.