Optimization in organic synthesis

Abstract

Art is always a bonus to synthesis . . . . the artistic aspect of synthesis, beautiful and marvelous as it is, should not be a justification for carrying out a total synthesis. If your problem is truly essential then you don't care about the elegance. The more essential your first E is, the less important your last E becomes." 1 "Will we be able to recapture the many millions of presumed 'transient'natural products that were evolutionarily de-selected along the paths that eventually led to the natural products synthesized on Earth today? . . . I cannot imagine that in a young synthetic chemist's lifetime, it will not be accomplished." 2 Organic Synthesis, quo vadis? 3 has been a phrase, perhaps in a more modern language, on the lips of the practitioners of this demanding science-art, undoubtedly from the earliest times 4 but more vigorously in the last two decades. 5 Comparison of achievements of yesterday 6 and today 7 suggests progress in our abilities to construct molecules of complexity, with higher stereocontrol, faster analysis, and greater prediction of eventual success. However, the practical aspects, on any scale, of brevity, efficiency, safety, eco-consciousness, and energy-and resource-frugality remain, as noted by a major synthetic craftsman, 8 crudely addressed. The Y2K symbolism is perhaps also appropriate for urgently dedicating our efforts to making headway in the solution of these interrelated goals.Our central science 5a progresses on fronts of method development and total synthesis with a great deal of cross-talk and interdependency (see Fig. 1). The burgeoning literature of new methods suggests that 70% are not repeated, perhaps even in the original laboratories, a situation with dire consequences for ascertaining true yield ranges and reproducibility a la the Org. Syn. religion. Furthermore, as judged from a cursory glance of tables in recent journals, much is left to be desired in giving confidence to the user that a method has generality (substrate diversity, FG and steric tolerance, catalyst or reagent minimization, and temperature and solvent optimization). Although the beauty of judiciously modeled use of PGs is to be applauded, 9 FG protection is a continuing embarrassment and annoyance. Synthetic chemists are challenging the dogma by daring the multi-FG molecules to behave in the manner desired. Ugi multicomponent reactions 10 and combinatorial synthesis 11 will undoubtedly soon influence the PG-expediency problem. In industry, statistical programs 12 at times drive optimization of reactions thus meeting the normal intense time constraints to produce mulit-kg of commercial substances.Atom-economy, a term coined by another influential synthetic chemist, 13 has brought awareness of an issue to academic scientists which their industrial process and development colleagues un-

Synthesis of 2-amino-4-(methoxycarbonyl)Phenylboronic Acid Hydrochloride, a key Intermediate for the Synthesis of Quinolines Derivatives

“…178-180 °C, which matched that observed for the corresponding product purchased from Combi-Blocks Company. 1 …”

“…In the search for biologically active compounds as potential drug candidates, the efficient synthesis of both libraries and individual heterocyclic small molecules is of major importance to the pharmaceutical industry. 1 Approaches involving a sequence of regiocontrolled halogenation followed by palladiumcatalysed coupling reaction based upon a heterocyclic scaffold have been successfully developed. 2 In particular, functionalised arylboronic acids and arylboronates are highly valuable because consecutive cross-coupling is possible from these compounds, which can rapidly lead to the complex structure of target molecules.…”

Polyhalogenated heterocyclic compounds. Part 47.1 Syntheses of multi-substituted pyridine derivatives from pentafluoropyridine

“…Application of, for example, sequential electrophilic substitution and palladium catalysed coupling reactions to the synthesis of many heterocyclic analogues (rapid analogue synthesis, RAS) has been reviewed recently in this journal 3 and the requirement for short, high yielding, regioselective and flexible routes to multiply functionalised heteroaromatic derivatives has been emphasised. 4 A sequence of substitution processes involving the functionalisation of a heteroaromatic "core scaffold" is a strategy frequently employed. This idea is illustrated in Scheme 1 in which pyridine is the parent of heterocyclic systems bearing up to five different substituents R 1 -R 5 .…”

Ethyl 2-Chlorooxazole-4-carboxylate: A Versatile Intermediate for the Synthesis of Substituted Oxazoles

“…As part of a medicinal chemistry program, we required a flexible route that would give high-yielding and rapid access to a series of substituted oxazoles. A method involving a sequence of regiocontrolled halogenation followed by palladium-catalyzed coupling, based upon a readily available oxazole scaffold, was identified as an attractive possibility . There was limited literature precedent for the elaboration of the oxazole nucleus with palladium-catalyzed coupling reactions 12 and the previously unreported ethyl 2-chlorooxazole-4-carboxylate ( 2 ) and the 2-bromo analogue 3 were identified as potential precursors.…”