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Molecular assembly lines, where molecules undergo iterative processes involving chain elongation and functional group manipulation are hallmarks of many processes found in Nature. We have sought to emulate Nature in the development of our own molecular assembly line through iterative homologations of boronic esters. Here we report a reagent (α-lithioethyl triispopropylbenzoate) which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol. Through repeated iteration we have converted a simple boronic ester into a complex molecule (a carbon chain with ten contiguous methyl groups) with remarkably high precision over its length, its stereochemistry and therefore its shape. Different stereoisomers were targeted and it was found that they adopted different shapes (helical/linear) according to their stereochemistry. This work should now enable scientists to rationally design and create molecules with predictable shape, which could have an impact in all areas of molecular sciences where bespoke molecules are required.

Synthesis of Tetrasubstituted Pyridines by the Acid-CatalyzedBohlmann-Rahtz Reaction.-An improved methodology for the Bohlmann-Rahtz reaction is presented, which allows the synthesis of pyridine derivatives in one step and at lower temperatures. Thus, enamino esters (I) and (V) react with alkynones in the presence of acetic acid or catalytic amounts of ZnBr 2 or Yb(O-Tf) 3 to furnish directly the poly-substituted pyridines in moderate to good yields. The reaction can additionally be extended to acid-labile educts when Amberlyst 15 is used as the catalyst.

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A range of highly functionalised pyridines is prepared from enamino esters and alkynones in a single synthetic step by the use of acetic acid or amberlyst 15 ion exchange resin at 50°C.The synthesis of trisubstituted pyridines from β-aminocrotonates and ethynyl ketones was first reported by Bohlmann and Rahtz in 1957. 1 This reaction is a two step process, the initial conjugate addition of enamine 1 to alkynone 2 at 50°C in ethanol generates an aminopentadienone intermediate 3 that is isolated and subsequently cyclodehydrated to give pyridine 4. The conditions required to affect this cyclisation are quite harsh, typically requiring temperatures of 120-160°C under reduced pressure (Scheme 1). Since its discovery, only a few examples of this transformation have been reported including, most notably, a synthesis of the modified oxazole-thiazole-pyridine core of the promothiocin antibiotics. 2-4 Thus, in spite of great interest in the synthesis and biological properties of pyridine derivatives, the use and application of this transformation remains largely unexplored. Scheme 1In order to improve the utility of the Bohlmann-Rahtz pyridine synthesis, and to facilitate the transfer of this technology to the solid phase, we decided to investigate a new and simple method to affect the conjugate addition and cyclodehydration in a single preparative step. It was proposed that the presence of an acid would promote cyclodehydration of 3 at a lower temperature and obviating the need to isolate the conjugate addition product. In order to test this hypothesis, aminoheptadienone 3a was prepared, according to the standard Bohlmann-Rahtz protocol, 1 and stirred at 50°C in toluene-acetic acid (5:1) for 6 hours to generate pyridine 4a in excellent yield and without any need for further purification (Scheme 2). Scheme 2The successful cyclodehydration of dienone 3a under acidic conditions established the validity of this approach. The problem remained to affect the conversion of enamine 1 to pyridine 4 in a single synthetic step and facilitate the initial conjugate addition in the presence of an acid. To this end, a range of enamino esters was prepared by standard procedures 5 and reacted with a number of alkynones 6 at 50°C in toluene-acetic acid (5:1) 7 to provide highly functionalised pyridines 4b-g in good to excellent yield (Scheme 3, Table 1). 8 It was apparent that 4-substituted butynones were good substrates for this reaction, a finding that has not been reported previously for the BohlmannRahtz pyridine synthesis. Only reactions involving 4-phenylbut-3-yn-2-one (R 4 = Ph, R 6 = Me), β-aminocrotonitrile (R 2 = Me, R 3 = CN) or tert-butyl aminocrotonate (R 2 = Me, R 3 = CO 2 t Bu) failed to generate the desired products and these difficulties were attributed to the acid catalysed decomposition of the material. Thus the new modified reaction conditions for Bohlmann-Rahtz pyridine synthesis allow conjugate addition and subsequent cyclodehydration to be conducted in a single step without any need for isolation of intermediates and...