Multistep transformation

Biotransformations are carried out by either whole cells (microbial, plant, or animal) or by isolated enzymes. Both methods have advantages and disadvantages. In general, multistep transformations, such as hydroxylations of steroids, or the synthesis of amino acids, riboflavin, vitamins, and alkaloids that require the presence of several enzymes and cofactors are carried out by whole cells. Simple one- or two-step transformations, on the other hand, are usually carried out by isolated enzymes. Compared to fermentations, enzymatic reactions have a number of advantages including simple instmmentation reduced side reactions, easy control, and product isolation. 

Djakovitch and coworkers [114] have finally shown that Pd on activated carbon can also be used for these multistep transformations. Reaction of 2-iodoaniline 6/1-225 and phenylacetylene 6/1-226 in the presence of 1 mol% Pd/C and 1 mol% Cul at 120 °C led to the indole 6/1-228, probably via 6/1-227, though the latter compound was not detected in the reaction mixture (Scheme 6/1.58). 

Metal oxides possess multiple functional properties, such as acid-base, redox, electron transfer and transport, chemisorption by a and 71-bonding of hydrocarbons, O-insertion and H-abstract, etc. which make them very suitable in heterogeneous catalysis, particularly in allowing multistep transformations of hydrocarbons1-8 and other catalytic applications (NO, conversion, for example9,10). They are also widely used as supports for other active components (metal particles or other metal oxides), but it is known that they do not act often as a simple supports. Rather, they participate as co-catalysts in the reaction mechanism (in bifunctional catalysts, for example).11,12... 

There are two examples in which the carboxylic group is first reduced to an alcohol. In this manner a multistep transformation yielded kainic acid 7 with the correct configuration at all three chiral centers (82JA4978). A similar reaction afforded (-)- or (+ )-lram-2,5-dimethylpyrrolidine from L- or D-Ala (87TL2083). 

L-Asparagine was used for the synthesis of chiral pipecolates, building blocks for the alkaloid apovincamine. The iodo compound, formed in a multistep transformation from L-asparagine, was cyclized with LDA and ethyl iodide to give the pyridine derivative with a defined configuration (Scheme 36) (85JOC1239). 

Derivatives of the 2,5-diazabicyclo[2.2.1]heptaine ring system (bridged piperazines) have been prepared from 4-hydroxyprolines. In a multistep transformation from tra j-4-hydroxy-L-proline (the last step was cyclization with benzylamine) a mixture of diastereoisomers 71 was obtained and separated [92H(34)241]. In a similar manner, the methyl and oxo analogs were obtained [67AJC1493 92H(34)679]. The commercially available N-... 

Two syntheses of the pyrrole derivative detoxinine and a part of the natural depsipeptide detoxin are described. In each, the formation of detoxinine takes place from bicyclic system 74, obtained in a multistep transformation from A-protected 3-hydroxy- or 4-iodoproline (83LA982 90CC1240). 

In a multistep transformation between Gly and piperonal, the tetracyclic system ISO was prepared [92H(33)537]. During the studies of Securinenga alkaloids, ethyl 2-thienylacetoacetate was subjected to reductive amination with L-Pro-OMe after cyclization, two tetracyclic diastereoisomers 151 and 152 were formed (83JOC3428). 

Elaboration of the nitro group in 264 (R = NO2) has been reported and it leads, after multistep transformation, to alcohol 265 (Scheme 56, Section 3.2.1.1 (2005BMCL2515)). 

A key aspect of metal oxides is that they possess multiple functional properties acid-base, electron transfer and transport, chemisorption by a and 7i-bonding of hydrocarbons, O-insertion and H-abstraction, etc. This multi-functionality allows them to catalyze complex selective multistep transformations of hydrocarbons, as well as other catalytic reactions (NO,c conversion, for example). The control of the catalyst multi-functionality requires the ability to control not only the nanostructure, e.g. the nano-scale environment around the active site, " but also the nano-architecture, e.g. the 3D spatial organization of nano-entities. The active site is not the only relevant aspect for catalysis. The local area around the active site orients or assists the coordination of the reactants, and may induce sterical constrains on the transition state, and influences short-range transport (nano-scale level). Therefore, it plays a critical role in determining the reactivity and selectivity in multiple pathways of transformation. In addition, there are indications pointing out that the dynamics of adsorbed species, e.g. their mobility during the catalytic processes which is also an important factor determining the catalytic performances in complex surface reaction, " is influenced by the nanoarchitecture. 

Figure 5.4 Energy profile of a multistep transformation showing the rate determining step. Intermediate /1 is the reactant in the rate determining step and intermediate I2 is the product.

Scheme 5.19 Four-membered ring systems are also generated in less systematic ways by various multistep transformations.

The systems described in Scheme 4.49 are for simple single-step transformations, typically with in-line purification however, the real opportunities presented by flow techniques will be multistep transformations occurring both in series and in parallel. Initial work in this field has already resulted in the total synthesis of natural products, such as grossamide [88] and ( )-oxomaritidine [89], and the drug candidate BMS-275291 [90], which are discussed later. 

A nice stereoselective synthesis of validamine 202 was accomplished by Yoshikawa s group [51], capitalizing on the longstanding familiarity with cyclization of nitrofuranose derivatives [52]. The focal intermediate of the synthesis was nitrofuranose adduct 206 (Scheme 34), which was obtained via a high-yielding multistep transformation of D-glucuronolactone 205. 

Mondon et al. (65) reported a multistep transformation of the erythrinandione 85 to the dibenzazonine 81 (Scheme 22). Other routes to ring expansion in the policyclic system of Erythrina derivatives have been reported. Thus cocculine (86) rearranges by treatment with acetic anhydride to give the N, O-diacetyl derivative 87 (66). 

Aryl-5-hydroxypyrones. Treatment of 5-(a-hydroxybenzyl)furoic acids (1) with Brj in CH3OH containing Na2CO, results in the hydroxypyrones 2 in about 40% yield. Only two intermediates have been identified in this multistep transformation. 

Similar chemistry using chiral sultam auxiliaries demonstrates superior yields and selectivities for specific cases of cuprate conjugate additions, but have not yet been extended to the more complex multistep transformation series illustrated above. Moderate selectivities have been obtained in alkyl cuprate additions to y-aminocrotonate equivalents where the nitrogen is derived from the oxazolidinone. ... 

In an imaginative construction of the angular triquinane ( )-hirsutene (158), Oppolzer and Robyr reported the carbonylative closure of allylic carbonate 155 to yield bicyclooctanes 156 and 157 (Scheme 6-27) [57]. In this multistep transformation, a alJylpalladium intermediate arising from the allylic carbonate 155 undergoes intramolecular Heck insertion of the pendant alkyne. Carbonylation of the resulting vinylpalladium intermediate, another Heck cyclization, and a second carbonylation then provide a mixture of acids, which after esterification yield esters 156 and 157 in good yield. 

Various other sequential, clean, multistep transformations based solely on PSRs have been described. Starting from alcohols 152, which were oxidized to the corresponding carbonyl compounds (153), a,fi-unsaturated ketones 158 were prepared by a Mukaiyama aldol condensation using Nafion-TMS 159 as silylating agent and... 

In fact, the Eey group reported the first total synthesis of (-i-)-plicamine 188 and its enantiomer using only a combination of supported reagents and scavengers to effect all of the synthetic steps. No less than thirteen immobilized systems were used to produce the clean product. Given the relative complexity of the molecule, the synthesis is a powerful demonstration of the ability to achieve multistep transformation without conventional chromatographic methods. 

The characteristic feature of this group of natural compounds is existence of a macrocycle in which other characteristic subunits like spiro, a,j8-unsaturat-ed, polyene, heterocyclic moieties are built in. Due to this structural diversity, total syntheses of macrocycles are complex and difficult. Therefore, research works do not always present full syntheses but approaches to precursors, syn-thons, model compounds, analogues, etc. Such multistep transformations often include useful, new phosphonate reagents and new methodologies based on them. 

There is one more way for conversion of ort/to-nitroarylacetonitriles into indoles. Alkylation of such nitriles with allyl or benzyl halides followed by treatment of the compounds obtained with basic agents results in a multistep transformation, which is likely to proceed via intermediate nitrosoarenes, to produce 1-hydroxyindoles. For instance, alkylation of ort/io-nitroarylacetonitriles with 3-phenylallyl bromide gives the compounds that in the presence of chlorotri-methylsilane and triethylamine undergo cyclization into 3-cyano-l-hydroxy-2-vinylindoles (Scheme 70) [188]. Presumably, this reaction proceeds via 0-silylation of the nitronate anion and 1,5-elimination of trimethylsilanol from the intermediate trimethylsilyl nitronate, followed by cyclization and a hydrogen shift. 

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