Ketones from Weinreb amides

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],... 

An important innovation in the Parham cyclization leading to cyclic ketones is the use of Weinreb amides as the electrophile, rather than carboxylic acids or esters. For example, compoimd 23 is converted to 24 in excellent yield,and benzocyclobutenones 26 are readily available from Weinreb amides 25. Lower yields of 26 are obtained using n-butyllithium. 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

The diketoindoles 777 were prepared in three steps starting from indol-3-ylacetic acid (680) and 5-chloro indol-3-ylacetic acid (774) in 75% and 66% overall yield, respectively. The indole acids 680 and 774 were converted into Weinreb amides 775, followed by reaction with ethyl Grignard reagent to afford the corresponding indol-3-yl ketones 776. In order to introduce the second carbonyl moiety, the 3-substituted... 

This is a Wittig reaction. The stable ylide is prepared from 29 prior to the reaction. Only the ketone reacts to form the corresponding olefin via the oxaphosphetane intermediate, as the Weinreb amide is not reactive enough. Owing to the use of a stable phosphonium ylide, only the product with the -configured double bond is obtained in 90 % yield ( /Z 99 1). 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

More recently an alternative synthesis has been proposed (91) in which the fragments C1-C5 and C6-C10 were joint together under Stille conditions (92). Starting from the suitably protected P-methyl-aspartic acid (1) its reduction to the aldehyde and conversion to the trans vinyl iodide followed by staimylation with hexamethyldistannane in the presence of freshly prepared Pd(PPh3)4 led to the trans vinylstannane 2 (Fig. 6). The commercially available (S)-phenyllactic acid (3) was converted to the Weinreb amide which was methylated at the secondary alcohol function and then converted to the propargylic ketone (4). Syn-stereoselective... 

The preparation of the other essential building block needed to carry out the critical aspects of the synthetic plan, acetylenic ketone 28, was achieved in two steps in 74 % overall yield from the known methyl lO-hydroxy-5-decynoate (49) through initial conversion of the ester into the corresponding Weinreb amide (50), followed by the controlled addition of a single equivalent of ethynylmagnesium bromide as shown in Scheme 6. 

For the final part (Scheme 5.3), the 20-carbon chain of fumonisin Bj was coupled from the Uthium acetylide derived from 273 and the Weinreb amide 279 (233). After enantioselective reduction of the alkynyl ketone 281 (234, 235), the C-10 stereochemistiy was set, followed by benzyl ether formation and acid-catalyzed acetonide removal, to provide diol 282 (236). Using tricarballylic acid dibenzyl ester, the two hydroxy groups were esterified (237) and the hydrogenation of the azide, the alkyne, and the benzylic ethers led to the target product, fumonisin Bj (249). The spectroscopic analysis matched with those of commercial fumonisin Bj and further experiments on the synthetic material showed inhibitoiy activity on sphingoUpid biosynthesis. 

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. 

Although this methodology is not successful with acyclic carboxylic acid derivatives (e.g. Weinreb amides, A-acyloxazolidinones, carboxylic esters or thioesters), it is possible to reach this kind of valuable enantiomerically enriched products by a simple oxidation with commercial bleach from the corresponding ketone (Scheme 29, top). If the ketone possesses a substituent prone to oxidation, an alternative procedure, involving the formation of a silyl enol ether (which does not need isolation/purification), can be followed instead (Scheme 29, bottom). 

The reaction of Weinreb amides to ketones can be performed cleanly using Grignard reagents in large excess. Yields of that transformation range from 16% up to 78% and no overaddition was observed as described by Armstrong et al. on Rink resin [213]. 

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