Multistep route

The amino acid leucine is biosynthesized from n-ketoisocaproate, which is itself prepared from -ketoisovalerate by a multistep route that involves (1) reaction with acetyl CoA, (2) hydrolysis, (3) dehydration, (4) hydration. (5) oxidation, and (6) decarboxylation. Show lhe steps in the transformation, and propose a mechanism for each. 

The preparation of fluorinated alcohols was carried out in multistep routes according to the reported procedures.1012 The synthesis of acrylic and methacrylic esters as shown in Table 11.1 was carried out in a fluorocarbon solvent such as Freon 113 by the reaction of the respective fluorinated alcohol with acryloyl chloride or methacryloyl chloride and an amine acid acceptor such as triethyla-mine with examples shown in Scheme 1. Other attempts to esterify the fluoroalcohols directly with acrylic acid or acrylic anhydride were not successful.11 Product purification by distillation was not feasible because of the temperature required, but purification by percolation of fluorocarbon solutions through neutral alumina resulted in products of good purity identified by TLC, FTIR, and H-, 13C-, and 19F- FTNMRs. 

The Brellochs reaction represents a significant breakthrough in monocarbaborane chemistry, the exploration of which was previously limited by multistep routes. For example, the important carborane anion CBnFI12 can now be made in two steps with an overall yield of 66%.88 Its synthesis previously required three steps involving undesirable compounds such as hydrogen cyanide, dimethylsulfate, and trialkylamine. (COMC (1982) 5.4.2.6.2) The arachno-cztbotznc... 

Removal of Side Products Using solid-phase protocols, unreacted reagents, consumed reagents, and the products of protecting group manipulations are washed away. Solution-phase strategies will be limited to a single transformation per step with subsequent purification of the product (a multistep route) unless the byproducts either (1) are not produced or (2) do not interfere with subsequent transformations. 

TSAs that could be found in a chemical catalogue, the most synthetically demanding cases have perforce employed multistep routes of considerable sophistication (e.g. Appendix entry 13.2). And, lastly, the TSA has to survive in vivo for at least 2 days to elicit the necessary antigenic response. 

We have recently discovered that phosphoramidite 18 is also an excellent ligand for copper-catalyzed kinetic resolution of chiral 2-cyclohexenones (Scheme 7.15). Chiral 2-cyclohexenones are attractive building blocks for a variety of natural products, but their synthesis usually requires multistep routes from chiral starting materials [65]. The development of the new kinetic resolution was the product of two impor-... 

Rappoport and co-workers work has continued in a study of the substitution of ( )-and (Z)-/3-bromo- or chloro-styrenes, (1) and (2), by MeS in DMSO-d 6 (sometimes in admixture with CD3OD) as solvent. Product studies indicated retention stereochemistry rate measurements found only a small Br/Cl element effect, slower reactions of the p-OMe bromo compounds, and retardation by CD3OD. These results are consistent with Tiecco s suggestion in 1983 that even this system, activated by only a single phenyl group, reacts through the nucleophilic addition-elimination multistep route. 

Epoxide rings may also be opened by intramolecular nucleophiles derived from allylsilane groups (see Scheme 9) to permit aldol-like closure onto aldehyde functions. Compound 63 (Scheme 15), derived by a multistep route from L-arabinose, when activated... 

The essential stages of the multistep route used by nature to synthesize aromatic amino acids were elucidated in the 1950s by studies on mutant bacteria (e.g. Aerobacter and Escheridiia coi) the cyclization of D-glucose (17) to 5-dehy-droquinic acid (18) and the formation of shikimic acid (19) [28], The first aromatic compound in the reaction chain is anthranilic acid (20) ... 

The presence of NH3 enables step f and, by reversing step e, prevents the accumulation of the undesired C-substituted imine, so the dehydro dimer is obtained in good yield. The dimerization of i-PrNH2 gives the useful diamine H2NCMe2NH2, previously only available in quantity by a tedious multistep route. 

Serotonin (8) mimics have been used effectively as treatments for a variety of psychiatric illnesses [199-201]. Homotryptamines could be constructed by multistep routes. One-pot synthesis of homotryptamines 277a-k was achieved by the conjugate addition of indoles with acrolein in the presence of the MacMillan organocatalysts (118a, 274) followed by reductive amination (Scheme 60) [201]. 

The amino acid methionine is biosynthesized by a multistep route that includes reaction of an imine of pyridoxal phosphate (PLP) to give an unsaturated imine. which then reacts with cysteine. What kinds of reactions are occurring in the two steps ... 

These examples illustrate the synthesis of organic compounds by multistep routes. In Chapter 12 we will learn other useful reactions that expand our capability to do synthesis. 

Fatty acids are synthesized by a multistep route that starts with acetate. The first step is a reaction between protein-bound acetyl and malonyl units to give a 3-keto-butyryl unit. Show the mechanism, and tell what kind of reaction is occurring. (See Section 29.7). 

Yields are important, but minimizing the number of steps can have greater impact than increasing yields on a multistep route. This is particularly true for multistep routes on scale, where the cumulative risk and impact of processing problems increase. 

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