Weinreb-type amides

Pyranopyrrolizines can be prepared from prolinylcoumarin derivatives. Treatment of the Weinreb-type amide 174 with methyllithium in THF gives a ketone intermediate, which when treated with silica gel in chloroform undergoes a cyclodehydration to give the triheterocyclic system 175 <1999T13211> (Scheme 52). 

The indolizinoquinoline 106 can be prepared by intramolecular acylation of the precursor 105. The organolithium derivative of 105 reacts intramolecularly with the amide this Parham-type reaction gives the triheterocyclic product in reasonable yield, and higher yields are obtained when the Weinreb-type methoxyamide (Rz = OMe) is used (Equation 21) <20030L1115>. 

A synthesis of the prostaglandin analogue TEI-9826 is presented in Scheme 9.40 as an example of the use of an Ir-catalyzed aUyUc alkylation [44]. The allylic alkylation with a malonic amide of the Weinreb type as pronucleophile gave the substi-... 

In the case of 489, the product 490 cyclizes to the isoquinolone 491, and the amide substituent is a required part of the target molecule" . However, it frequently occurs that the amide substituent is not required in the final product, and the acid-sensitive alkenyl substituent of 492 has been used as a solution to the problem of cleaving a C—N bond in the product (Scheme 193) ° °. Weinreb-type amides 493 can also be laterally lithiated, and the methoxy group removed from 494 by TiCU" . Hydrazones similarly can be laterally lithiated and oxidatively deprotected. ... 

A number of selective transformations (Fig. 10) have been described which include the selective allylation on alcohols in the presence of amides [47], the Lewis acid catalyzed cleavage of benzyl alcohol esters with secondary amines to afford tertiary amides [48], the synthesis of ketones from Weinreb-type amides [49], and the synthesis of tertiary amines by a Michael addition/alkylation/Hoffman elimination sequence [50],... 

Weinreb type amide followed by hydrolysis as shown in Scheme 1.9.4.1. 

More recently, several papers reporting the solid phase synthesis of peptide aldehydes have been published. Dinh and Amstrong (61) outline the use of Weinreb-type amides on solid support for the synthesis of ketones and aldehydes Ede and Bray (62) report a new linker based on the oxazolidine moiety and use this method with Multipin technology Galeotti et oL (63) apply their thiazolidinyl linker to a solid support. The great interest in these aldehydic compounds has also been demonstrated by the fact that the Weinreb amide resin is now commercially available from Bachem and Novabiochem. 

Carretero s group further developed a highly exo-diastereoselective and enantioselective catalytic asymmetric protocol for the [3-h2] cycloaddition of a-iminoamides by using Cu(l)/DTBM-SEGPHOS complexes as catalyst system, providing a variety of 2-amido pyrrolidines, including Weinreb-type amides, with excellent levels of enantiocontrol (Scheme 10) [22]. Other activated alkenes, such... 

The cycloaddition of Weinreb amide functionalized nitrile oxide with a range of dipolarophiles has been studied. N-Methoxy-N-methylcarbonocyanidic amide, nitrile oxide 207 (i.e., a nitrile oxide of Weinreb amide type derivative) was generated from 2-chloro-2-(hydroxyimino)-N-methoxy-N-methylacetamide as intermediate and used in situ. Thus, addition of 3-bromo-l-propyne as dipolarophile to this precursor of 207, followed by quenching with triethylamine, gave 5-(bromo-methyl)-N-(methoxy)-N-methyl-3-isoxazolecarboxamide 208 in 55% to 60% yield (367). 

With respect to the substrate scope, ketones are the most efficient nucleophiles although the intermolecular reaction works also well for esters, amides and Weinreb amides (Fig. 2.7). Regarding the Michael acceptor, enones are the best electrophiles with a wide range of substituents tolerated (alkyl, aryl and heteroaryl ketones). a,p-Unsaturated esters, in the case of the intermolecular cyclopropanation, and a,p-unsaturated diimides for the intramolecular reaction, extends the substrate scope of the process (Fig. 2.7). A transition state model for the intramolecular cyclopropanation reaction has been proposed as depicted in Scheme 2.38 for catalyst 65 [106d]. In this model the ammonium salt adopts a conformation that gives the Z-enolate of the nucleophile on deprotonation with the base. The intramolecular conjugate addition of the enolate then takes place through a boat-type transition state. 

Moving to a related type of [2 + 2] cycloaddition, not involving aldehydes or imines as partners, Calter and coworkers reported Cinchona alkaloid (TMSO-QN) catalysed asymmetric dimerisation of ketenes, generated in situ from the corresponding acid chlorides, yielding (3-lactones via a formal Claisen condensation (Scheme 14.29). The unstable ketene dimers were trapped with an alko>yamine to afford p-keto amides i.e. Weinreb amides) with variable yields and excellent enantioselectivities. 

Weinreb amides are another type of electrophiles that can be used with lithiated pyridazine to access long-chain a-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolase (eq 8). An excess of pjnidazine (4—6 equiv) is needed for optimal results (78-86% yields based on the amide). 

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