Retro-Synthetic approach

These processes have flourished, mainly due to their selectivity and versatility, to the point where cross-coupling chemistry is often the initial thinking of organic chemists in synthetic and retro-synthetic approaches [2]. In fact, nowadays it is difficult to find a contribution in fine chemical or natural product synthesis where these molecular assembly tools are not employed. This is often due to the simple preparation and handling of the reaction partners as well as their relative compatibility with several functional groups. 

Nicolaou s Synthesis. Nicolaou s synthesis also involves a B-ring closure to connect the A and C rings.33 The retro synthetic approach is depicted in Scheme 7-59. 

In fact, the overall perspective and conception of a synthesis commences with a careful logical dissection of the tai et-drug-molecular skeleton into S3mthons. However, the disconnection of a bond within a monocyclic system shall be a retro-synthetic ring-opening phenomenon, otherwise termed as the retro-synthetic approach. Likewise, the disconnection of a bond caused in a bridged-structure would ultimately produce either a mono- or a di- substituted monocyclic structure. Sometimes, it may also be possible to accomplish two-bond disconnections taking place almost simultaneously. 

When planning the synthesis of a compound using an organometallic reagent or indeed any synthesis the best approach is to reason backward from the product This method is called retrosynthetic analysis Retro synthetic analysis of 1 methylcyclohexanol suggests it can be prepared by the reaction of methylmagnesmm bromide and cyclohexanone... 

For some of the reactions described in this book, rather precise and detailed ideas about the reaction mechanism exist. However, for many catalytic reactions, the mechanistic understanding is very poor and further experimental studies are certainly needed. Calculations proved to be a highly valuable tool to gain a more precise picture of the reaction pathways. However, mostly only model systems can be studied due to the complexity of the problem. Anyway, it is the firm believe of the authors that for any reaction with an activation barrier a suitable catalyst can be found. This book shall give an insight into what has been achieved in this area concerning the synthesis of heterofunctionalized organic molecules. It is the hope of all contributors that future retro-synthetic schemes will include the catalytic approaches outlined in this book. 

Retro synthetic analysis provides two main approaches to the disulfonium-dication functionality. The first approach involves double alkylation of disulfides so far has been unsuccessful (Scheme 5).36 All currently known methods... 

The most frequent synthetic approaches, summarized in Scheme 4, are towards the primary photophores. The preparation of aryl azide derivatives follows the typical retro-synthetic pathway in the majority of the reported cases (Scheme 4 A), and, practically, diazotation is the most commonly used procedure [24 - 29]. In the case of diazirines only one major synthetic sequence is repeated ammonolysis of oximes followed by dehydrogenation (Scheme 4B) [30-32]. There are various ways of preparing diazo- or diazocarbonyl-compounds most frequently the Forster and Bamford-Stevens reactions (Scheme 4C) are employed [33-37]. 

Schemes 2.3a-c outline the retro-synthetic production of BTX B (1). The final approach to PbTx-2 involved separate assembly of the ABCDEFG and UK ring systems 4 and 5, their coupling, and final elaboration to the end. The didehydrooxocane ring in BTX B (ring H) was thus designated as the final ring to be constructed. Retro-synthetic cleavage of the indicated C-0 bond in 1 and removal of the terminal electrophilic groupings reveal hydroxy dithioketal 3 as a plausible precursor. Tricyclic aldehyde 4 and heptacyclic phosphonium salt 5 can thus be defined as potential precursors to 3. The reliable and usually stereoselective Wittig reaction would be employed to accomplish the union of compounds 4 and 5 (Scheme 2.3a). Tricyclic aldehyde 4 was traced retro-synthetically to D-mannose 10.

A chemo- and diastereoselective carboityl addition reaction and standard manipulations could be used to fashion compound 26 from ketone 27, a substance that can ultimately be traced retro-synthetically to enantiomerically pure 2-deoxy-D-ribose (29) (Scheme 2.3c). This doubly convergent approach reduces the synthetic problem to three readily available and enantiomerically pure building blocks, D-mannose (10), D-mannitol (18), and 2-deoxy-D-ribose (29). 

Unlike carbon-heteroatom bonds, carbon-carbon bonds do not show obvious retro-synthetic scissions hence, formation of the latter significantly enhances the (structural) complexity of a molecular scaffold. The methods presented in the following sections combine the formation of carbon-carbon bonds -with the cyclative cleavage approach. 

In 2001, Funk reported a synthesis of ( )-FR901483 using an approach very different from those described previously, taking advantage of his amidoacrolein cycloaddition methodology to prepare 1 -alkyl-1 -aminocyclohexane derivatives, starting the synthesis from acyclic compounds. Moreover, Funk neither uses tyrosine derivatives nor needs an inversion at C(9) to install the phosphate unit. In Funk s retro synthetic analysis, shown in Scheme 23, he envisaged that lactam 60 possessed the necessary functionality for the introduction of the C(6) p-methoxy benzyl and C(3) methylamino substituents via enolate alkylation and amination reactions, respectively. 

The final example illustrates yet another use of the biomimetic approach. Figure 10.9shows a retro-synthetic analysis for Masamune s synthesis of deoxyerythronolide B (213). The biosynthetic building blocks of this and other macrolide antibiotics are known to be acetate and/or propionate units combined head-to-tail, as seen in 213. 7 xhe stereocenters in 213 are clearly shown in the acyclic (seco acid) form of the macrolide 215. The specific biopathway is not utilized but rather modified to include the basic building blocks, seven propionate units (bold lines in 213).Seco acid 215 was constructed by sequential aldol condensation reactions (sec. 9.4.A) of propionaldehyde units, as shown by the disconnections in Figure 10.9. Asymmetric... 

It will be useful to use a few terms coined by Corey and Wipke pS) in the discussion of this work. Since the logic-centred approach of generating a synthetic tree involves analytic processes which depend heavily upon the structural features of reaction products and the consideration of molecular changes in the retro-synthetic sense, the direction of computer analysis is termed antithetic as opposed to the direction of laboratory execution which is termed synthetic . A process in the antithetic direction is called a transform while a process in the synthetic direction is called a reaction . A reac-... 

C(37) oxazole-containing fragment 1322a-c as a key intermediate in their retro-synthetic strategies (Scheme 1.339). However, the different approaches to the... 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

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