Introduction to Nucleophilic Acyl Substitution

Cephalosporins represent a second group of P-lactam antibiotics that contain a four-membered ring fused to a six-membered ring. Cephalosporins are generally active against a broader range of bacteria than penicillins. 

ProbiGm 22.9 For both amoxicillin and cephalexin (a) How many stereogenic centers does each compound 

The characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. This is a general reaction that occurs with hoth negatively charged nucleophiles (Nu ) and neutral nucleophiles (HNu ). 

The mechanism for nucleophilic acyl substitution was first presented in Section 20.2. 

Carboxylic acid derivatives (RCOZ) react with nucleophiles because they contain an electrophilic, unhindered carbonyl carbon. 

The characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. 

The mechanism for nucleophilic attack followed by loss of the leaving group, as shown in Mechanism 22.1. acyl substitution was first presented in Section 20.2. 

In Step [2], elimination of the leaving group forms the substitution product. 

The overall result of addition of a nucleophile and elimination of a leaving group is substitution of the nucleophile for the leaving group. Recall from Chapter 20 that nucleophilic substitution occurs with carbanions (R ) and hydride (H ) as nucleophiles. A variety of oxygen and nitrogen nucleophiles also participate in this reaction. 

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Introduction to Nucleophilic Acyl Substitution Mechanism 22.1 General Mechanism—Nucleophilic Acyl Substitution... 

Chapter 18 discussed the acyl addition reactions of several nucleophiles with the carbonyl unit of aldehydes and ketones. As pointed out in Chapter 16, carboxylic acids and their derivatives also contain a carbonyl unit. Although these acid derivatives react with nucleophiles via attack at the acyl carbon, the presence of a leaving group attached to the acyl carbon leads to a subsequent reaction that is not possible with aldehydes and ketones. Acid derivatives react with nucleophiles via acyl substitution. This reaction pathway proceeds by an intermediate called a tetrahedral intermediate. The introduction to this reaction, presented in Chapter 16 (Section 16.8), will be explained and expanded here. 

The introduction of substituents into position 7 of a 2,4-disubstituted pteridine can be effected very cleanly by the use of acyl radicals typically and has been known for many years. Treatment of aldehydes with /-butyl hydroperoxide and iron(ll) generates acyl radicals which add selectively to the 7-position. A recent exploitation of this chemistry has provided a large number of new examples including both aryl and alkyl acyl radicals as reagents <2004PTR129> pA , data have been compiled (Section 10.18.4) and many nucleophilic substitution reactions of the 7-acylated pteridines and functional group modifications have been described (Section 10.18.7.2). 

Figure 3.4 The synthesis of ibuprofen is initiated by a Friedel-Crafts acylation of an aUcyl-substituted benzene ring. The resulting ketone is then reduced to an alcohol with sodium boro-hydride. The alcohol functionality then undergoes a functional group interchange by conversion to a bromide. In turn, this permits the introduction of an additional carbon atom in the form of a nitrile introduced via an 8, 2 nucleophilic displacement. This is then hydrolyzed to give the target molecule.

The reaction presented in this problem is known as a Friedel-Crafts acylation. Technically, this example belongs to a class of reactions referred to as electrophilic aromatic substitutions. Furthermore, the actual mechanism associated with this reaction, utilizing Lewis acid reagents as catalysts, proceeds through initial formation of an electrophilic acyl cation followed by reaction with an aromatic ring acting as a nucleophile. This mechanism, shown below, reflects distinct parallels to standard addition-elimination reaction mechanisms warranting introduction at this time. 

Figure 3 Different approaches for the introduction of lipid functionalities, here exemplified via the farnesyl group, into peptides. (A) Lipidated amino acid building blocks. (B) Substitution of bromoalanine with a nucleophile. (C) Alkylation or acylation of a free thiol functionality of a cysteine. (D) Conjugate addition of a nucleophile (e.g., farnesylthiolate) to a dehydroalanine. (E) Conjugate addition of a nucleophile to aziridine-2-carboxylic acid containing...

Similarly, Shono studied the diastereoselective introduction of the allyl group into the 5-position of A/ -acylated L-proline derivatives by reaction of the N,0-aceia with allyltrimethylsilane in the presence of titanium tetrachloride [214]. Substitution of the anodically introduced methoxy group by cyanide using trimethylsilyl cyanide [215,216] or an isocyanide [217] as the nucleophile can be used to generate a-amino acids via hydrolysis of the cyano function. Equation (41) shows an example [216]. 

Scheme 25). The introduction of greater diversity at C-2 and C-4 can be achieved by intercepting the tetrahydropyridinone intermediate in a multi-step sequence involving C-2 ammonolysis, microwave-assisted W-acylation, acid-catalyzed cyclization (to introduce diversity at C-2), treatment with POCI3, and either microwave-assisted nucleophilic substitution or Suzuki coupUng (to introduce diversity at C-4) [89]. 

A more modern approach for the direct introduction of a carbon side-chain into the pteridine nucleus has been developed by homolytic nucleophilic substitution reactions , especially using acyl radicals -i as well as alkyl radicals as reactive species. These reactions, however, take place regioselectively with 6,7-unsubstituted pteridine derivatives at the most electron-deficient 7-position leading to the unnatural isomers. Direction of the incoming nucleophile towards the C-6 atom can only be achieved in the presence of a 7-substituent " . A reasonable "protecting" group for C-7 has been the alkylmercapto and thione function, since it was found that the difficulties encountered with the Raney-nickel desulfurization reaction " in the pteridine series could be overcome using Raney-cobalt and copper-aluminum alloy, respectively . 

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