Roderick John Dorgan

A conformational study of bafilomycin A1 by x-ray crystallography and nmr techniques

Abstract We report the structure determination of bafilomycin A1 by X-ray crystallography and a reassignment of the 1H and 13C NMR spectra. By the measurement of 13C NT1 and n.O.e. values the solution conformation was shown to be indistinguishable from that in the crystal.

Spiroacetal synthesis from a key lactone intermediate leading to novel C24 and C25-substituted milbemycins

Abstract The lactone intermediates (3), (4) and (5) are converted via lithium acetylide chemistry to a range of novel C24 and C25-substituted milbemycins. The methdology has been extended to afford milbemycins containing 6,5-spiroacetal units.

The conformational analysis of bafilomycin A1

The 1H and 13C n.m.r. spectra of bafilomycin A1, (1a), have been unambiguously solved by two-dimensional (2D) n.m.r. methods. Comparison of this spectral data with that reported for two other hygrolide antibiotics L-681, 110A1(1b) and L-155, 175 (1c), shows that the (Z)-C(4)–C(5) double bonds assigned to the latter two compounds are in fact E. The solution-state conformations of bafilomycin A1 have been determined by the use of proton–proton coupling constants, 1H nuclear Overhauser enhancements (n.O.e.s), and 13C spin–lattice relaxation times (T1s). The solution-state conformations have been compared with the known crystalline-state conformation of bafilomycin A1(with the aid of molecular modelling techniques) and are found to be very similar. In particular, it can be concluded that the hydrogen-bonding network involving 19-OH, 17-OH, and C(1)O is intact in CDCl3 solution.

Semi-synthetic C23-substituted milbemycins via spiroacetal cleavage and resynthesis

Abstract The lactone intermediates (2) and (3) are converted by lithium acetylide chemistry followed by mercury catalysed hydration to novel semi-synthetic 23-oxo C24 and C25 substituted milbemycins (7).

An investigation of the stereochemistry of a 22,23-dioxygenated milbemycin

Abstract We report NMR studies on a known 22,23-dioxygenated milbemycin which show that the 22 and 23 oxygen atoms are trans diequatorial (I) and not trans diaxial (II) as previously reported1. The stereochemistry of milbemycins α5 to α8 is also discussed in the light of this observation.

A practical synthesis of the milbemycin SB-201561

Abstract A 6-step synthesis of the potent anthelmintic SB-201561 is described. The key stage of the synthesis is a novel Beckmann type oxime fragmentation to give a lactone, followed by a 2-step reassembly of the spirolcetal moiety.

Fragmentations and rearrangements of 22-hydroxyl substituted milbemycins - synthesis of a key lactone intermediate

Abstract Beckmann fragmentation of 22-oximino milbemycins resulted in the cleavage of the C21–C22 bond to produce a key lactone intermediate which can be used to synthesise new spiroacetals. Cleavage of the C21–O25 bond and recyclisation to produce a furyl derivative is also described.

Novel long-range isotope effects in a macrolide antibiotic: bafilomycin A1

The 1H and 13C NMR spectra of bafilomycin A1(1), 21-O-trimethylsilylbafilomycin A1(2) and 7-O-acetyl-21-O-t-butyldimethylsilylbafilomycin A1(3) have been unambiguously solved in a variety of solvents by 1D and 2D NMR techniques. Partial deuteriation of the hydroxy groups of (1), (2), and (3) led to the observation of many novel and long-range isotope effects in the 1H and 13C spectra of (1), (2), and (3). These experiments also confirmed the existence in solution of the hydrogen-bonding network involving 19-OH, 17-OH, and C(1)O for (1), (2), and (3), as was found in the crystalline state for (1). The possible mechanisms of the isotope effects are discussed.

A convenient and concise synthesis of a key lactone intermediate in milbemycin chemistry

Abstract A short, convenient and inexpensive synthesis of lactone (3) from milbemycin (1) is described. This lactone is a key intermediate in the synthesis of milbemycins.