Multi-step syntheses

In processes involving whole cells the required product can often be formed in a single step, although the cells essentially carry out a multi-step synthesis. This means that only a single product purification is necessary. Conversely, in chemical synthesis of compounds, each step in the synthesis is usually carried out separately. Thus the product of one reaction must often be purified before it can be used in the next step in the synthetic sequence. This multi-step approach is expensive, time consuming and can require a complex process plant to handle the individual steps on an industrial scale. 

Process A Genetic instability Substrate repression Multi-step synthesis Product (volatile) inhibition Mode of operation Batch Fed-batch Continuous... 

Nowadays, a strategic area of research is the development of polymers based on carbohydrates due to the worldwide focus on sustainable materials. Since the necessary multi-step synthesis of carbohydrate-based polymers is not economical for the production of commodity plastics, functionalization of synthetic polymers by carbohydrates has become a current subject of research. This aims to prepare new bioactive and biocompatible polymers capable of exerting a temporary therapeutic function. The large variety of methods of anchoring carbohydrates onto polymers as well as the current and potential applications of the functionalized polymers has been discussed recently in a critical review [171]. Of importance is that such modification renders not only functionality but also biodegradability to the synthetic polymers. 

Diazo coupling was used to demonstrate the feasibility of organic multi-step synthesis on a chip [4]. This involved showing the safe quenching of hazardous intermediates such as the diazonium salts needed as precursor for that synthesis. Especially, this involves the in situ generation and consumption of such species. 

Aminodehalt enation - Alkylaminodefluorination in the Ciproflaxin Multi-step Synthesis... 

The synthesis of Ciproflaxin was one among several syntheses being performed in contract research by a micro reactor developer for the pharmaceutical industry [83]. In this multi-step synthesis, alkylaminodefluorinations were an essential part of the chemistry. 

OS 42] ]R 25] [P 31] The multi-step synthesis of the pharmaceutical agent Cipro-fiaxin was carried out in a CPC micro reactor [83,118]. 

Broadwater, S.J., Roth, S.L., Price, K.E., Kobaslija, M., McQuade, D.T. (2005) One-Pot Multi-Step Synthesis A Challenge Spawning Innovation. Organic and Biomolecular Chemistry, 3, 2899-2906. 

Baxendale, I.R., Deeley, J., Griffiths-Jones, C.M., Ley, S.V., Saaby, S., Tranmer, G.K. (2006) A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine A New Paradigm for Molecular Assembly. Chemical Communications, 2566-2568. 

The relative contribution of any flow in this life cycle to the total global-warming score of the production of a unit mass of product 6 is shown. The highest shares in the impact score are exhibited by the two substrates, because their production is taken into account, comprising multi-step synthesis routes starting from crude oil. All other input mass flows show relatively small contributions (maximum of 4% for solvent 2). This is due to relatively high... 

Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine a new paradigm for molecular assembly. Chem Commun, p 2566-2568... 

Scheme 6. Multi-step synthesis of pyrroles employing support-bound reagents and scavengers.

PA FT-IR has been successfully used by Gossehn et al. [182] for monitoring a solid-phase multi-step synthesis. However the use of PA FT-IR is not yet widespread, even though it is nondestructive and allows surface analysis. This could be caused by the high cost of the instrumentation coupled with larger sample requirements and sHghtly longer acquisition times. 

Schwesingefs phosphazene base 2-tert-butylamino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (PS-BEMP has a pKb = 27.5 in MeCN) has been immobilized and shown to have immense utility in the N- and O-alkylation of many weakly acidic heterocycles. Kim et al. has made extensive use of this reagent in the multi-step synthesis of a small collection of guanines possessing potential antiviral activity [90]. The generic procedure involved the direct alkylation of the purine moiety (20) (Scheme 2.64), promoted by PS-BEMP, resulting in a mixture... 

The preparation of soHd-phase bound homogeneous catalysts is often accompanied with multi-step synthesis on the chosen support. This implies that the linkers have to be weU chosen, as is known from solid-phase synthesis [3, 4]. To give a demonstration of this extra work" some examples of attachment of important chiral catalysts are given in this section. 

These macromolecule-based purification methods isolate polymer-bound products from soluble impurities, but do not generally purify the product from other polymer-bound byproducts. Such byproducts arise from incomplete reactions or side reactions and in classical solution chemistry, similar byproducts are removed during product purification at each step of a multi-step synthesis. Support-based methodologies, while removing the multiple, laborious purification steps of a classical synthesis, generally do not provide a method for the purification of intermediates. Instead, these methodologies demand that reaction conditions be optimized such that reactions are driven to completion to avoid a complicated final mixture of products. However, some developed liquid-phase methods achieve high purity of products without quantitative reaction yields [21-26]. 

In the search to develop new materials for immobilization of homogeneous transition metal catalyst to facilitate catalyst-product separation and catalyst recychng, the study of dendrimers and hyperbranched polymers for application in catalysis has become a subject of intense research in the last five years [68], because they have excellent solubility and a high number of easily accessible active sites. Moreover, the pseudo-spherical structure with nanometer dimensions opens the possibility of separation and recycling by nanofiltration methods. Although dendrimers allow for controlled incorporation of transition metal catalysts in the core [69] as well as at the surface [70], a serious drawback of this approach is the tedious preparation of functionalized dendrimers by multi-step synthesis. 

Example 14 an efficient strategy has been described by Koganty and his associates for the synthesis of compound which is a novel lipid A mimetic [42] The multi-step synthesis is exemplified from the introduction of the phosphate moiety onwards. 

Kim and Park [71] reported multi-step synthesis of various unsymmetrical chiral salen Co(lll)(OAc) complexes co-valently bonded onto MCM-41 type mesoporous Al-Si material (39-44) (Figure 14). Authors developed a new approach of anchoring method where the reaction of a functionalized ligand, diformylphenol, was carried out with 3-aminopropyltrimethoxysilane modified Al-MCM-41. These supported catalysts were used in the HKR of racemic epichlorohydine, 1,2-epoxyhexane, epoxystyrene and epoxycyclohexane under mild conditions to produce respective epoxides and diols in high yield and ee (Table 2). 

The use of this enzyme in multi-step synthesis is relatively recent. Clapes et al. have reported the first example of FSA-mediated synthesis of iminocyclitols [53]. The synthetic strategy is similar to the one previously described for DHAP-dependent aldolases without the need for the dephosphorylation step. AldoUc reaction of DHA with N-Cbz-3-aminopropanal catalyzed by FSA followed by selective catalytic reductive aminahon furnishes the naturally occurring imino-sugar D-fagomine (Scheme 4.22). 

An ingenious multi-step synthesis of oxo[l,3]thiazolo[5,4-/]azocine 214 is based on the transformations of ethyl tetrahydro[l,3]benzothiazolyl acetate 209 (81CPB1780 Scheme 59). Under the action of methylamine, 209 cyclizes to thiazolo[4,5-e]indolone 210 which, through compounds 211 and 212, converts into quaternary salt 213. The key stage of the process is the efficient rearrangement of this salt into thiazoloazocine under the action of alcoholic base. 

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