Michael John Crimmin

The chemistry of pseudomonic acid. Part 10. Preparation of heterocyclic derivatives

The preparation of a large variety of normonyl heterocycles is described. Methods involving cyclisation of monic acid derivatives gave access to only a limited number of types of heterocycles. Olefination methods proved to be of wider applicability with phosphonate stabilised anions providing the biologically active E-isomer in a 3–4 : 1 excess. The Peterson type olefination proved to be the most useful method with the largest range of heterocycles and stereoselectivity of E:Z 4 to >10 : 1.

The chemistry of pseudomonic acid, part II. Dehydrative cyclisation of α-acylamino ketones to oxazoles

A number of mild methods for the preparation of 2-substituted 5-normonyloxazoles (1) by dehydrative cyclisation of the corresponding monamides (2) have been developed and are described. The preferred conditions involve using trichloroacetyl chloride, pyridine, and 4-N,N-dimethylaminopyridine. The stabilities of the vinyloxazoles to both the reaction conditions and to light are also reported.

Application of the Suzuki biphenyl synthesis to the natural products biphenomycin and vancomycin

The synthesis of the unsymmetrical biphenyls 10 and 25 has been carried out by the palladium(0) catalysed coupling of the aryl boronic acid derivatives 5 and 20 with the aryl bromides 9 and 23 derived from (R)-4-hydroxyphenylglycine and (S)-tyrosine. In the former case unsuccessful attempts were made to bring about cyclization to compound 4 which is an analogue of the biphenyl ring system found in vancomycin. In the latter case, a variety of cyclization methods were used to give the cyclic products 34 and 35 which are analogues of the biphenomycin antibiotics.

The effect of added salts on enantioselective transformations of cyclic ketones by chiral lithium amide bases

The asymmetric transformation of certain cyclic ketones, using enantiomerically pure chiral lithium amide bases, has been carried out using several reaction protocols. In general, the enantioselectivity observed in the conversion of ketones into non-racemic enol silanes is optimal under in situ quench (ISQ) conditions, with products of lower enantiomeric excess being obtained using the external quench (EQ) protocol. However, substantial improvements in the enantiomeric excess of products obtained from EQ reactions can be achieved if either LiCl or ZnCl2 is included in the reaction mixture.

The chemistry of pseudomonic acid. Part 8. Electrophilic substitutions at C-2 and C-15 of the pseudomonic acid nucleus by means of lithium dienolates

The regiochemistry of substitution at C-2 (α) and C-15 (γ) of lithium dienolates (2) derived from esters of manic acid (1d) depends on the nature of the electrophile. Substitution at C-2 affords diastereoisomeric mixtures of the deconjugated esters (3). The stereochemistry of reconjugation can be controlled. The ester (3d) when heated with hindered bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) favours formation of methyl 2-methylisomonate (4f) whilst, in contrast, use of potassium t-butoxide favours the biologically active methyl 2-methylmonate (1 m).

The chemistry of pseudomonic acid. Part 7. Stereochemical control in the preparation of C-2-substituted monic acid esters via the Peterson olefination

The preparation of 2-substituted monic acid esters (1; R ≠ H) by means of olefination reactions with the ketone (3b) and anions of the appropriate reagent (6) are described. Anions derived from 2-substituted phosphonoacetates generally did not react except for (6d) which afforded good yields of ethyl 2-fluoromonate (1g) and its isomer (5c). However, anions of α-substituted-α-silylesters reacted efficiently with (3b) but stereoselectivity was highly in favour of the biologically inactive isomonate esters (5). Only 2-fluoro- and 2-methyl-monate esters possessed antimicrobial activity.

Formation of alcohols from the reactions of buta-1,3-diene and isoprene with aldehydes catalysed by nickel complexes

The reaction of buta-1,3-diene with acetaldehyde, benzaldehyde, and acrolein in the presence of bis(1,5-cyclooctadiene)nickel and an organophosphorus ligand has been demonstrated to yield 2 : 1 adducts. With triphenylphosphine as ligand high selectivity to 1-substituted-3,6,8-nonatrien-1-ols was found. A similar reaction between isoprene and acetaldehyde in the presence of (cyclododecatriene) nickel and triphenylphosphine gave mainly 2 : 1 adducts in which the isoprene was dimerised in a head-tail manner. The major products were 3,7-dimethyl-3-vinylocta-7-en-2-ol and its isomer 3,7-dimethyl-3-vinylocta-6-en-2-ol. The selectivity of this reaction is discussed in terms of the σ,η character of the bis(η-allyl)nickel intermediate.