Overall Syntheses

Perfluoroisobutylene undergoes cycloadditions with azides only at elevated temperatures, the reaction can lead to subsequent loss of nitrogen [6] (equation 4) In another high-temperature reaction, chlorotrifluoroethylene undergoes cy cloaddition with the azomethineylide generated from the thermal electrocyclic nng opening of an azindine, a reaction that contributes to a good overall synthesis of 3,4-difluoropyrroles [7] (equation 5)... 

In most cases, the overall synthesis time was greatly reduced (from hours or days to minutes) by switching from conventional to microwave heating, facilitating the rapid preparation of novel chemical entities. The combination of soUd-phase synthesis with microwave irradiation also allowed access to a few classes of molecules that had proven elusive via other synthetic strategies (traditional solution-phase synthesis). 

However, we must be careful to control the regiochemistry properly in each of these two steps. In the elimination step, we need to form the less substituted double bond (i.e., the Hofmann product), and therefore, we must use a stericaUy hindered base. Then, in the addition step, we need to place the Br on the less substimted carbon (anh-Markovnikov addition), so we must use HBr with peroxides. This gives us the following overall synthesis ... 

In the first step above, we need a Markovnikov addition (Br needs to end up at the more substituted carbon), which we can easily accomphsh by using HBr. The second step requires an elimination to give the Zaitsev product, which we can accomphsh if we choose our base carefully (we will need to use a base that is NOT sterically hindered). Therefore, the overall synthesis is ... 

The equation for the overall synthesis of palmitate from acetyl-CoA and malonyl-CoA is ... 

A condensed schematic of the overall alternative synthesis of BMS-180291 (Ifetroban) is provided in Scheme 2. The synthesis of the key acid ester intermediate A has been reduced dramatically from 16 to four steps, and the yield has been increased ten-fold from 5 to 52%. The overall synthesis of Ifetroban has been cut virtually in half (from 23 to 12 steps) and the yield (via the longest linear sequence) improved from 3 to 28%. 

A Although it would be possible to convert 3-bromo-4-melhylani-line (7.2) into the corresponding hydrazine, by diazotization and reduction, react it with cyclohexanone, and then subject the product hydrazone to a Fischer indolization, the bromine substituent would still remain in the indole (note two isomers would form). Of course, this substituent could be displaced reductively using tributyltin hydride and a radical initiator [AIBN, azobis(isobuty-ronitrile)], but the overall synthesis is clumsy and non-selective and there should be a simpler route. 

The overall synthesis involves two consecutive steps. The first one is a CO-induced reductive carbonylation of RUCI3 3H2O, producing in sim an equilibrium mixture of two carbonylchlororuthenium(II) complexes, [Ru(CO)2Cl2] and [Ru(CO)3Cl2]2-... 

Overall, the chiral auxiliary approach to sitagliptin using (S)-PGA to install the amino group via diastereoselective hydrogenation resulted in a reduction of three chemical steps in the overall synthesis. This new synthetic approach essenhally followed the same convergent strategy (Route A on Scheme 5.8), but represented a big improvement over our previous route. The convergent approach made sense since the triazole heterocycle was a valuable intermediate that required an elaborate preparation with a modest yield of 26%. 

In some ways this classification is arbitrary since, for example, the formation of 30 could be catalogued as [3 + 2] according to the overall synthesis, or as [5 + 0] if cyclization of the intermediate 29 is considered. We have often tried to classify a synthesis according to the... 

The second category consists of starting from an appropriately mono- or di-substituted heterocycle and introducing the fifth atom, with the formation of two bonds (Scheme 49). An alternate method of construction of the second ring by forming two bonds is also shown in Scheme 49. It should be emphasized, however, that the classification involving the formation of two bonds is very arbitrary and is based on the overall synthesis. 

The conversion of the substituted 1,3-dicarbonyl compound into homophthalic acid is remarkably facile loss of the acetyl group by a retro-Claisen condensation and hydrolysis of the ester group are complete in a few minutes in aqueous sodium hydroxide. The overall synthesis of homophthalic acids from o-bromobenzoic acids occurs in high yield and provides an attractive route. 

Besson and co-workers have investigated the microwave-assisted multi-step (seven steps) synthesis of thiazoloquinazolinone derivatives, utilising commercially available nitroanthranilic acids as the initial precursors69. Comparison of the conventional thermal heating and microwave heating approaches demonstrated that the overall time for the multi-step synthesis could be considerably reduced (by a factor of 8) by adopting the microwave-heated reaction methods (Scheme 3.44). In addition, the reactions were cleaner and the products could be purified rapidly. For the microwave-heated multi-step synthesis, the overall yield of the final product was increased by a factor of 2, which enabled the scale of the overall synthesis to be increased from 0.2 to 1 g. 

Once the two TBS protecting groups have been removed with hydrofluoric acid as a source ot fluoride, the epoxide at C l 2 is constructed as the last step ot the overall synthesis. For this purpose di methyldioxirane (63> is utilized. It is conceivable that epoxidation could also have occurred at the exocyclic double bond at C 16, or that attack by the dimethyldioxirane could have taken place from the top face of the macrocycle. Schinzrr obtained the desired natural product (-)-epothilone A (la) in 48S yield 1. I IF, CH,CN/Et20. RT. 65f. ... 

Elucidate the overall synthesis and give a mechanism for the final step. 

Dibromoethane is prepared from ethylene. The overall synthesis from ethyl alcohol is therefore formulated as shown ... 

Because these steps are essentially chemical or biochemical reactions, they are often incomplete, meaning that there may be part of the material from the preceding step in each step of the overall synthesis. It... 

Ziegler149 has reported a highly efficient synthesis of the very similar M. avium serovar 21 trisaccharide hapten with attached linker-arm (89). The blockwise construction minimizes the manipulation of protecting groups and hence the number of steps in the overall synthesis. The synthesis featured two key operations (1) the kinetically controlled diastereoselective preparation from D-glucose of the... 

Although most of the dendrimers are synthesized by one of these two strategies, examples of metallodendrimer syntheses applying both methodologies have also been reported, which is done to improve their overall synthesis and/or purity (polydispersity) by minimizing the possible formation of defects in the dendritic framework. 

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