Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

[reaction: see text] The highly diastereoselective oxy-Michael addition of the "naked" anion of (6S)-methyl delta lactol to alkylidiene-, arylidene-, and heteroarylidenemalonate derivatives leading to the direct formation of THP-protected beta-hydroxy ester derivatives is described. Subsequent acid-mediated deprotection affords the enantioenriched aldol products in quantitative yields.

The "naked" anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to alpha,beta-disubstituted nitro olefins to give the THP* protected Henry products with excellent (95-->98% de) stereocontrol at the beta-position and moderate (up to 3 : 1) stereocontrol at the alpha-position in favour of the syn-diastereoisomer. Nitro group reduction with in situN-Boc protection and THP* removal provides alpha,beta-disubstituted ethanolamine derivatives, while treatment with tetrapropylammonium perruthenate gives THP* protected alpha-hydroxy ketone derivatives in high diasteromeric excess.

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The conjugate addition of pyrrole as a nitrogen nucleophile can be catalyzed by potassium pyrrolate in coordinating solvents or by lithium pyrrolate in the presence of coordinating ligands offering an efficient route to protected b-amino carbonyl compounds.b-Amino carbonyl compounds are key components in many biologically active natural and unnatural products such as taxol, 1 streptothricin F 2 and the renin inhibitor KR1 1314. 3 They are also useful precursors to the b-lactam motif found in the antibiotics penicillin and cephalosporin. 4 In recent years there has been much development in stereoselective methods of synthesis of bamino acids. 5 One of the most attractive and powerful strategies is the conjugate addition of nitrogen-centered nucleophiles to a,b-unsaturated carbonyl compounds and other electron-deficient alkenes. 6,7 Scheme 1 Proposed catalytic cycle Towards our aim of developing a conjugate addition of nitrogen nucleophiles using substoichiometric base for use in b-amino carbonyl synthesis, we focused on the conjugate addition of pyrrole (1) to enoates 2. 8 The reaction (Scheme 1) appeared to offer considerable scope for employment of substoichiometric base since, from studying the pK a values (quoted here in DMSO as a model aprotic solvent), it was predicted that pyrrole (1, pK a = 23) 9 would be rapidly deprotonated by the intermediate enolate 3 (pK a = 30), 10 regenerating the catalytic metal pyrrolate 4 and releasing the adduct 5. The results (Table 1) show that this was indeed the case for a range of a,b-unsaturated tert-butyl esters when substoichiometric potassium pyrrolate was used in the presence of excess pyrrole in chilled THF, giving excellent yields of the adducts 5a-e for all but the most hindered of substrates. 11,12 The lower yields for 5e (R = t-Bu) can be explained by increased steric hindrance at the b-carbon giving rise to reduced reaction rates. For the reaction with tert-butyl crotonate (entry a), it was found necessary to maintain the reaction temperature below 0°C, and reduce the reaction time, in order to prevent formation of an unwanted bisadduct 6 ( Figure 1) believed to arise from a competing carbonyl substitution pathway. Interestingly, this was not seen with any of the other tert-butyl ester substrates. However, with less sterically demanding ester groups, such as ethyl crotonate, ester aminolysis was a major pathway.The potassium pyrrolate-catalyzed conjugate addition of pyrrole is general to a range of a,b-unsaturated substrates ( Table 2). Of interest are the nitrile 7 and Weinreb amide 9 since they allow access to both aldehyde 13 and ketone 14