Chemoselectivity and protecting groups

Mechanisms and catalysis chi 2 Removal of functional groups Retrosynthetic analysis ch28 

Most organic molecules contain more than one functional group, and most functional groups can react in more than one way, so organic chemists often have to predict which functional group will react, where it will react, and how it will react. These questions are what we call 

Selectivity comes in three sorts chemoselectivity, regioselectivity, and stereoselectivity. Chemoselectivity is which group reacts regioselectivity is where it reacts. Stereoselectivity is how the group reacts with regard to the stereochemistry of the product. 

We have talked a lot about regioselectivity, without calling it that, in the last two chapters. In Chapter 21 you learned how to predict and explain which productfs) you get from electrophilic aromatic substitution reactions. The functional group is the aromatic ring where it reacts is the reaction s regioselectivity. in Chapter 22 you saw that nucleophilic addition to an unsaturated ketone can take place in a 1,2- or 1,4-fashion—the question of which happens (where the unsaturated ketone reacts) is a question of regioselectivity. We wUl address regioselectivity in much more detail in the next chapter. 

But with just one equivalent of acetic anhydride in the presence of a base (pyridine) only the NH2 group is acylated, and paracetamol is the product. This is chemoselectivity, and it is to be expected that the NH2 group is more nucleophilic than the OH group. It is even possible to hydrolyse the doubly acetylated product to paracetamol with aqueous sodium hydroxide. The ester is more reactive than the amide and hydrolyses much more easily. This is another chemo-selective reaction. 

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Chemoselective methods for oxidation and reduction, and protecting groups to help control chemoselectivity, will appear throughout this book, and we shall return in detail to peptides and their biological functions in Chapter 42. Before then we will address in detail stereoselectivity (in Chapters 32,33, and 41) but the very next chapter will deal with the other aspect of selectivity—regioselectivity. 

Thioacetalization. A range of carbonyl compounds including aliphatic and aromatic aldehydes and ketones were converted into the corresponding thioacetals in high yields in the presence of a catalytic amount of Hf(OTf)4 (0.1 mol%) at room temperature. The mild conditions tolerated various sensitive functional and protecting groups and were racemization-free when applied to a-aminoaldehydes. Transacetalization and chemoselective thioacetalization of aromatic aldehydes in the presence of aliphatic aldehydes and ketones were also documented (eq 12). 

A synthetically useful virtue of enol triflates is that they are amenable to palladium-catalyzed carbon-carbon bond-forming reactions under mild conditions. When a solution of enol triflate 21 and tetrakis(triphenylphosphine)palladium(o) in benzene is treated with a mixture of terminal alkyne 17, n-propylamine, and cuprous iodide,17 intermediate 22 is formed in 76-84% yield. Although a partial hydrogenation of the alkyne in 22 could conceivably secure the formation of the cis C1-C2 olefin, a chemoselective hydrobora-tion/protonation sequence was found to be a much more reliable and suitable alternative. Thus, sequential hydroboration of the alkyne 22 with dicyclohexylborane, protonolysis, oxidative workup, and hydrolysis of the oxabicyclo[2.2.2]octyl ester protecting group gives dienic carboxylic acid 15 in a yield of 86% from 22. 

Clean removal of trityl ether groups from O-isopropylidenated furanoses by using NaHS04-Si02 was previously described by Das et al.116 and afforded the corresponding alcohols at room temperature. The chemoselective deprotection was accomplished in yields above 91% within 2-2.5 h, leaving other protective-groups intact (Scheme 27). 

The hydrazinium nicotinate group on these reagents commonly is protected against reaction with the active ester by the addition of acetone to form the acetone hydrazone derivative. This hydrazone protective group is readily reversible at neutral or mildly acidic pH and will immediately exchange with a benzaldehyde on the corresponding chemoselective partner to form a stable hydrazone linkage. 

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