Topics in organic stereochemistry : studies in optical resolutions

Abstract

The thesis entitled “Topics in Organic Stereochemistry: Studies in Optical Resolutions” describes, in four chapters, investigations aimed at: (i) developing methodologies for the resolution of racemic alcohols both kinetically and thermodynamically; (ii) the dynamic kinetic resolution of an atropisomeric molecule in a chiral crystalline matrix; and (iii) kinetically resolving secondary carbanions via their reaction with a chiral 1,1 bi 2,2 naphthol carbonate. The latter part of the work is supported by X ray crystallographic results of considerable novelty and interest.

Chapter 1 This chapter briefly surveys current activity in organic stereochemistry, especially in the areas of racemate resolution and supramolecular chiral assemblies. Recent reports on desymmetrisation strategies and the resolution of secondary alcohols are covered.

Chapter 2 This chapter describes, in two sections, (i) the design of a chiral Mitsunobu reaction and (ii) the kinetic resolution of 1,1 bi 2,2 naphthol (BINOL), both accomplished using the camphor derived chiral auxiliary 15 (+)-ketopinic acid. Section 1 – Chiral Mitsunobu Reaction The chiral Mitsunobu reaction overcomes the inherent 50% yield limitation of standard kinetic resolutions by performing both resolution and inversion in one step. A kinetic resolution experiment using 1 equiv. of racemic alcohol (±)-2 and 0.5 equiv. each of ketopinic acid (1), TPP and DEAD (Scheme 1) resulted in complete diastereoselective esterification, as shown by ^1H NMR, which detected only one diastereomeric ester (3). Purified esters (3) and the enriched unreacted alcohol (2) were obtained by chromatography (with some epimerisation, 15–20%). Saponification with KOH/EtOH at 0 °C gave the alcohols, which retained the same configuration as the unreacted enantiomer. Overall yields: 75–82%; enantiomeric excess: 78–86% (polarimetry). These results are consistent with a rigid transition state involving a carboxylate anion tightly bound to a pentavalent phosphorane coordinated to the ketone oxygen of (1). When the Mitsunobu reaction was carried out with 1 equiv. each of (1), (2), TPP and DEAD, two alcohols (4) and (5) exhibited dynamic kinetic resolution (DKR) (Scheme 2). Total diastereoselection was observed by ^1H NMR. The esters were obtained in 63% and 75% yields. The DKR likely arises through reversible dissociation of the activated alcohol into TPPO and the benzylic cation derived from (4) or (5).

Section 2 – Kinetic Resolution of BINOL Racemic BINOL (7) was kinetically resolved using ketopinic acid (1) either as:

its acid chloride (6) with Et N, or the acid (1) with DCC as condensing agent (Scheme 3).

The unreacted BINOL showed ee values of 72% (acid chloride) and 56% (DCC), determined polarimetrically.

Chapter 3 This chapter describes, in two sections, studies on the dynamic resolution of triphenylphosphine oxide (TPPO) (8), an atropisomeric molecule. Section 1 – Dynamic Kinetic Resolution of TPPO TPPO is chiral but undergoes rapid enantiomer interconversion and is therefore normally unresolvable. However, it forms crystalline complexes with hydrogen bond donors, raising two possibilities:

Pasteur-type manual resolution (triage) if conglomerates form. Dynamic kinetic resolution if TPPO becomes homochiral within a chiral host lattice.

A crystalline complex of TPPO with (±)-BINOL was obtained by co crystallisation but was shown by single crystal X ray diffraction to be a racemic compound, not a conglomerate-thus ruling out triage. With (S)-BINOL, however, a noncentrosymmetric crystalline complex was formed, and X ray diffraction showed TPPO to be homochiral in the lattice. Solid state ^31P NMR supported this finding. Section 2 – Optical Activity from Dust Contamination A remarkable observation was that several TPPO samples in solution showed faint optical rotations. Filtration removed both the dust and the optical activity, suggesting that trace biological chiral contaminants (e.g., pollen) form chiral complexes with TPPO. This may have implications for theories of the origin of optical activity in nature.

Chapter 4 This chapter, in two sections, involves studies on BINOL carbonate derivatives (9–12). Section 1 – Attempts at Chiral Carbanion Resolution Attempts were made to resolve secondary carbanions kinetically using in situ generated BINOL carbonate (12). However, only poor yields were obtained due to side reactions between the product anion and carbonate (12). Section 2 – Conglomerate Behaviour of BINOL Ethyl Bis carbonate BINOL ethyl bis carbonate (10) was found to be a conglomerate, as demonstrated by polarimetry and DSC on single crystals. X ray crystallography showed a noncentrosymmetric unit cell with a chiral space group. A striking structural feature was a very short C–C bond (1.29 Å) in one O ethyl group, aligned nearly parallel to the carbonate system. This likely indicates the onset of an eliminative process.