Multistep sequence

Bromo or chloro-2,6-difluoropyridines can be prepared in 50% yield by diasotization of the corresponding 3-halo-2,6-diarninopyridine in ammonium fluoride—hydrogen fluoride solvent (371). 5-Chloro-2,3-difluoropyridine [89402-43-7], a precursor to the herbicide pyroxofop [105512-06-9], was synthesized by a multistep sequence based on aHyl chlorodifluoroacetate [118337-48-7], C1CF2C02-CH2CH=CH2 (415). 

The synthesis of 1-ethoxy-1-butjme has been reported previously, but the preparations have required multistep sequences. Two of the procedures use 1,2-dibromo-l-ethoxy butane which is dehydrohalogenated in two successive steps, first by an amine base and then by either powdered potassium hydroxide or sodium amide no yields are given. The... 

This Part of the book could as well have been titled "Synthesis in Action" for it consists of specific multistep sequences of reactions which have been demonstrated by experiment to allow the synthesis of a variety of interesting target molecules. Graphical flowcharts for each synthesis define precisely the pathway of molecular construction in terms of individual reactions and reagents. Each synthetic sequence is accompanied by references to the original literature. 

A-Dinor-5a-cholestan-l-one has been prepared by Cava and Vogt by a multistep sequence involving, as the final ring contraction reaction, photolysis of 2-diazo-A-nor-5a-cholestan-1 -one. 

Metarhodopsin 11 is then recycled back into rhodopsin by a multistep sequence involving cleavage to all-traws-retinal and cis-trans isomerization back to 11-ris-retinal. 

The conversion occurs through a multistep sequence of reactions catalyzed by a complex of enzymes and cofactors called the pyruvate dehydrogenase complex. The process occurs in three stages, each catalyzed by one of the enzymes in the complex, as outlined in Figure 29.11 on page 1152. Acetyl CoA, the ultimate product, then acts as fuel for the final stage of catabolism, the citric acid cycle. All the steps have laboratory analogies. 

Figure 29.11 MECHANISM Mechanism of the conversion of pyruvate to acetyl CoA through a multistep sequence of reactions that requires three different enzymes and four different coenzymes. The individual steps are explained in the text.

Jacobsen demonstrated that the (salen)Cr system used to effect intermolecular, cooperative asymmetric azidolysis of meso-epoxides (Schemes 7.3 and 7.5) could be applied to sulfur-centered nucleophiles (Scheme 7.13). In order to overcome moderate enantioselectivity (<60% ee), a dithiol nucleophile was employed as part of a double resolution strategy in which the minor enantiomer of the monoaddition product reacts preferentially to form the meso- bis-addition product, thereby increasing the ee of the C2-symmetric bis-addition product. Enantiopure 1,2-mer-capto alcohols (>99% ee) were obtained from the meso-epoxide in ca. 50% overall yield by a burdensome (though effective) multistep sequence, [23]. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

The 3,4-dihydrodiol of BcP was synthesized from 4-oxo-l,2,3,4-tetrahydro-BcP (15) by Method I (66). The ketone L was itself prepared from 4-oxo-l,2,3,4-tetrahydrophenanthrene via a multistep sequence entailing Reformatsky reaction with methyl bromocrotonate, dehydration of the resulting alcohol, isomerization to the aryl-butyric acid, and cyclization of its acid chloride with SnCl - Full... 

Solid-supported technologies are already well established methods in medicinal chemistry and automated synthesis. Over the last couple of years new trends have evolved in this field which are of utmost importance as they have the potential to revolutionize the way chemical synthesis especially for library production is performed. Microchip-based synthesis technologies and multistep sequences with solid-supported catalysts or reagents in flow-through systems are only two spectacular examples. A new approach is the use of solid-supported systems for the scale-up of chemical reactions thereby enabling the rapid and smooth transition from discovery to development units. 

The carbacephem was converted into the carbapenam-2-one system ( )-143 by a multistep sequence (equation 78)68. 

The route is, however, important as it shows the possibility of passing from multistep sequences in batch that usually require intermediate isolation and purification in between steps to a continuous sequence using flow chemistry that produces the desired molecules requiring a minimum purification at the end and providing important savings in time and resources. 

Reductive ring closure of l-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,l-c][l,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R = H) or ester (R = Et) 205 followed by CDI or thermal cyclization (1992JHC1005). 

The homochiral dione 205 undergoes magnesium sulfate-mediated acetalization to give the bisacetal 206 as a single enantiomer in reasonable yield from a multistep sequence (Equation 136) <1998TL5717>. 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

As outlined in Sect. 2, various classes of concave acids and bases may be synthesized in gram quantities. But the syntheses are multistep sequences and the yields are often limited by the macrocyclization steps. Therefore, for a practical use, these reagents are quite expensive and recovery and recycling is necessary. 

The Claisen rearrangement of lactonic enolates provides a new route to cycloalkenes. Cyclocitral was converted to the lactone (642) through a multistep sequence, the lactone deprotonated with LDA in THF at -78 °C, and the enolate quenched with f-butyldimethyl-chlorosilane (80JA6889, 6891). The crude ketene acetal (643) was heated at 110 °C for 10 h, and the product treated with fluoride ion to afford a single acid. Replacement of the quaternary carboxyl group by hydroxyl was accomplished through use of the carboxy inversion reaction (Scheme 147). The product (645) of this last reaction was identical with an authentic sample of widdrol in all respects excluding its optical rotation. 

Many of the reactions with hydrazines are complicated multistep sequences which sometimes require the presence of an oxidizing agent. Oxidizing capability can come from adventitious 02, sacrificial reduction of the metal or the hydrazine itself (equations 134-136). 

Baxendale, I.R., Ley, S.V. and Piutti, C., Total Synthesis of the Amaryllidaceae Alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions, Angew. Chem., Int. Ed. Engl., 2002, 41, 2194. 

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