SEQUENCE synthesis/optimization

Keywords. Poly(3-hydroxybutyrate), Metabolic sequences, Fine regulation, Poly(3HB) cycle, Strategic survival polymer, Growth-associated synthesis, Energy-generating and -consuming synthesis, Optimization... 

Since its first synthesis, optimizations of the detailed reaction sequence have been carried out during the past decades finally leading to a bundle of patents covering diflerent possibilities to execute this reaction cascade." " Out of these patents a rather straightforward sucralose synthesis could be assembled (Scheme 9.3.6), the first step of which is a dibutyltin-oxide-supported selective... 

A description of the microstmcture by NMR spectroscopy of these copolymers, as well as a detailed understanding of the processes and mechanisms involved in these copolymerizations, proved difficult to achieve. A number of groups took on this challenge using various methodologies, which included synthesis of model compounds, NMR pulse sequences, synthesis of series of copolymers with different norbomene content and using catalysts of different symmetries, synthesis of copolymers selectively C-enriched, chemical shift prediction, and ab initio chemical shift computations. Such assignments enabled detailed information to be obtained on copolymerization mechanisms by Tritto et al. [24]. They employed a computer optimization routine, which allows a best fit to be obtained for the microstmctural analysis by NMR spectra in order to derive the reactivity ratios for both first- and second-order Markov models (Ml and M2, respectively). 

For a viable commercial process, the selection of materials and the choice of synthetic route is governed primarily by cost, not by overall yield. The selection of starting material is dictated usually by the desked C-3 substituent. For cephalosporins containing 3-acetoxymethyl or 3-(substituted)methyl such as 3-thiomethyl and 3-aminomethyl derived moieties, the most dkect synthetic route is from cephalosporin C, whereas pencillin V or G is the preferred starting material for the synthesis of the C-3 methyl cephalosporins. The three chemical transformations (2), (5), and 6) can potentially be carried out in a variety of ways, the precise sequence being determined by a balance of competing factors such as cost and optimization of yield (87). 

It is a common experience in synthetic chemistry that a truly optimal ordering of a synthetic route may not be possible in the planning stage, but may have to determined experimentally. The precise information necessary for the complete and unambiguous evaluation of each step in a possible synthesis is hardly ever available. Nonetheless it is clearly wise to try to optimize a synthetic plan on the basis of available information before the experimental approach begins. Such an effort may suggest certain preliminary or "model" experiments that can be helpful in the choice or refinement of a synthetic plan. It is also obviously desirable to devise and consider alternate or bypass paths for each problematic step of a synthetic sequence. 

The efficient synthesis of dithicno[2,3-A 32 -r/ thiophenes 12 has been achieved from 3-bromothiophene 298 <2006JOC3264>. The sequence of a-connection and [l-annelation afford annulated [1-trithiophene 12 (Scheme 54). Optimization of reaction conditions (solvent and temperature) for the a-connection step provides significantly improved yields compared to earlier report. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

The bottleneck of conventional parallel/combinatorial synthesis is typically optimization of reaction conditions to afford the desired products in suitable yields and purities. Since many reaction sequences require at least one or more heating steps for extended time periods, these optimizations are often difficult and time-consum-... 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

This chain of transformations was repeatedly documented in the literature (see, e.g., Refs (153, 264)). However, this sequence was not optimized as a method for the synthesis of conjugated enoximes. It can be concluded that the absence of an alkyl substituent at the C-3 atom (R1=H) and the use of steri-cally unhindered bases (e.g., of pyridine) is favorable for realizing the desired pathway. 

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