Stephen G. Davies

4-Substituted-5,5-dimethyl oxazolidin-2-ones as effective chiral auxiliaries for enolate alkylations and Michael additions

Abstract 4-(Methyl, phenyl, benzyl, and i -propyl)-5,5-dimethyl-oxazolidin-2-ones, readily available from α-amino acids, are shown to be effective chiral auxiliaries for stereoselective enolate alkylations and conjugate additions of attached N-acyl moieties.

Chiral relay auxiliaries

Chiral auxiliaries and templates are effective tools for the asymmetric synthesis of homochiral molecules.1 Most chiral auxiliaries are small heterocyclic compounds which rely on sterically demanding functional groups to control the conformation of their ring systems. Under ideal circumstances, the conformation of an auxiliary should be constrained to ensure that its prochiral centre reacts with a reagent via diastereoisomeric transition states which are sufficiently different in energy to ensure that only a single diastereoisomer is formed as product. In order to maximise the diastereoselectivity observed for an auxiliary, it would appear reasonable that the Stereocontrolling functional group adopts a position in space as close as possible to the newly forming stereogenic centre. Structural considerations dictate that realisation of this ideal is not always attainable and numerous examples of chiral auxiliaries that rely on relatively remote stereogenic centres to control diastereoselectivity are known. Alkylation of the enolates of Seebach’s imidazolidinone (1),2 or Schollkopf’s bis-lactim ether auxiliary (2),3 for example, are controlled via 1,3- and 1,4- asymmetric induction respectively (scheme 1).

Asymmetric synthesis of (+)-negamycin

Abstract (+)-Negamycin was synthesised employing the highly diastereoselective conjugate addition of lithium (α-methylbenzyl)benzylamide in the key step. The synthesis was completed in 13 steps starting from ethyl 4-chloroacetoacetate with an overall yield of 24 %.

The use of lithium (α-methylbenzyl)allylamide for the asymmetric synthesis of unsaturated β-amino acid derivatives

Abstract The unsaturated β-amino acid derivatives (3 R )-( E )-3-( N - tert -butoxy-carbonyl)aminohex-4-enoate and methyl (2 S ,3 S )-3-( N - tert -butoxycarbonyl)-amino-2-hydroxyhex-4-enoate have been synthesised from lithium ( S )-( α -methylbenzyl)allylamide and ( E , E )- tert -butyl hex-2,4-dienoate. After a highly stereoselective conjugate addition of the lithium amide to the α,β-unsaturated ester, or a highly stereoselective conjugate addition-electrophilic hydroxylation, the adducts are deallylated and the resulting secondary amines converted to either a benzoyl amide or oxazolidinone. The N - α -methylbenzyl group is then removed with either formic acid or using a dissolving metal reduction. These deprotection procedures leave unsaturation in the molecules intact.

Lithium (α-methylbenzyl)allylamide: a differentially protected chiral ammonia equivalent for the asymmetric synthesis of β-amino acids and β-lactams

The addition products from the highly stereoselective conjugate additions of lithium (αS)-(α-methylbenzyl)allylamide to α, β-unsaturated tert-butyl esters are efficiently deallylated with tris(triphenylphosphine)rhodium(I) chloride and converted, after transesterification to the methyl esters and cyclisation with methylmagnesium bromide, to the corresponding homochiral N-(α-methylbenzyl)-4-substituted-azetidm-2-ones.

A HIGHLY ACID LABILE SILICON LINKER FOR SOLID PHASE SYNTHESIS

Abstract A novel arylsilane based linker has been prepared for the solid phase synthesis of small molecule combinatorial libraries. Efficient cleavage is achieved using TFA via anchimerically assisted protiodesilylation to yield aromatic products possessing no residual linker functionality.

Asymmetric synthesis of a highly functionalized β-amino acid: the key amino acid of sperabillins B and D

The asymmetric synthesis of the highly functionalized (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoic acid, the key amino acid fragment of sperabillins B and D, was achieved by an asymmetric Michael addition of lithium (R)-(α-methylbenzyl)allylamide 10 to (E,E)-2,5-heptadienoate establishing the C-3 stereogenic centre, the information from which was propagated to the C-5 and C-6 centres by a highly stereoselective iodocyclocarbamation reaction.

A FORMAL SYNTHESIS OF (-)-PUMILIOTOXIN C

Abstract An asymmetric synthesis of an advanced intermediate in the synthesis of natural (−)-pumiliotoxin C has been achieved in six steps and in 61 % overall yield employing as the key step a highly diasteroeselective lithium amide 1,4-conjugate addition to a dienoic ester derived from ( R )-(+)-pulegone.

A stereocontrolled approach to 1β-methylcarbapenem

Abstract Conjugate addition of lithium N -allyl- N - α -methylbenzylamide to chiral α,β-unsaturated esters is subject to double stereodifferentiation, the mismatched pair reaction allowing access to an intermediate for 1β-methylcarbapenem synthesis.

Voltammetry under high mass transport conditions. The application of the high speed channel electrode to the reduction of pentafluoronitrobenzene

Abstract The electroreduction of pentafluoronitrobenzene in dimethylformamide solution resulting in the formation of the dimer, octafluoro- 4, 4′-dinitro-biphenyl, is studied. The dimeric species is reduced further at the potentials applied to the corresponding di-anion. Microband electrodes are used in conjunction with a high speed channel flow cell to explore the mechanism of this process and to quantify the associated very fast homogeneous kinetics. In particular, the formation of the dimer is seen to proceed via the rate determining loss of fluoride anion from the initially formed radical anion of pentafluoronitrobenzene with a first order rate constant of 4.2 × 10 5 s −1 . The reduction of the dimer to its di-anion is seen to occur via a DISP2 mechanism in which the rate determining step is the disproportionation of the mono-anions of octafluoro,4,4′-dinitro-biphenyl with a rate constant of 2 × 10 8 M −1 s −1 . The merits of high speed channel electrodes for the measurement of fast homogeneous kinetics are examined and compared with those of microdisc voltammetry in stationary solution.