WEINREB Ketone synthesis

OCOR Z = O-alkyl, O-aryl, oxazolidine R = alkyl, alkenyl, alkynyl, aryl base pyridine, EtsN 

Reaction of the organometallic species with Weinreb s amide  

The first total synthesis of the Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf and co-workers. The installation of the butyrolactone moiety commenced with the preparation of a Weinreb s amide from a methyl ester. The tricyclic methyl ester substrate was exposed to A/,0-dimethylhydroxylamine hydrochloride and Me2AICI and the tertiary amide was isolated in excellent yield. Next, the bromo ortho ester was treated with LDBB in THF to generate the corresponding primary alkyllithium species, which cleanly and efficiently added to the Weinreb s amide to afford the desired ketone. 

The preparation of the C1-C21 subunit of the protein phosphatase inhibitor tautomycin was completed by J.A. Marshall et al., and it constituted a formal total synthesis of the natural product. The spiroketal carbon of the target was introduced by the Weinreb ketone synthesis between a lithioalkyne and A/-methoxy-A/-methylurea (a carbon monoxide equivalent). The triple bond of the resulting Weinreb s amide was first reduced under catalytic hydrogenation conditions to yield the corresponding saturated amide, which was reacted with another lithium acetylide to afford an ynone. 

In the laboratory of E.J. Corey, the first synthesis of nicandrenones (NIC), a structurally complex steroid-derived family of natural products, was accomplished. The side chain of NIC-1 was constructed from the known six-membered lactone which was converted to the Weinreb s amide by treating it with excess MeNH(OMe) HCI and trimethyl-aluminum. The resulting primary alcohol was protected as the TBS ether. The ethynylation of this amide was carried out by reaction with two equivalents of lithium trimethylsilylacetylide to afford an ynone, which was reduced enantioselectively to the corresponding propargylic alcohol using CBS reduction. 

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WEERMAN Degradation 405 WEIDENHAGEN Imidazole synthesis 406 WEINREB Ketone synthesis 407 WEISS Annulation 408 WENCKER AZsidsie synthesis 409 WENZL-IMAMOTO Reduction 4t0... 

W-methoxy-W-methyl amide Weinreb ketone synthesis... 

Reaction with amides. Benzamides and thiobenzamides are converted to a,a-disubstituted benzylamines. Tertiary amides form ketones on reaction with RCeCl even when the reagent is present in large excess, therefore Weinreb amides are not necessary for the ketone synthesis. Enaminones are also attacked at the carbonyl group, and in the cases of a -silylated derivatives the reaction products are 3,y-unsaturated ketones. ... 

Ketone synthesis. It is not necessary to prepare individual Weinreb reagents for the preparation of ketones. Sequential exposure of the title pyridyl carbamate to two different organometallic compounds is the most expedient procedure. 

Danishefsky used a variety of silyloxybutadienes in Diels-Alder reactionsin place of alkoxy and acetoxy derivatives. Treatment of these cycloadduct siloxy derivatives with fluoride (sec. 7.3.A.i) will unmask an enol moiety, which tautomerizes to the carbonyl under very mild conditions. Silyloxy dienes have become very popular for this type of reaction. In Weinreb s synthesis of phyllanthine,150 imine 144 reacted with diene I43151 in the presence of Yb(OTf)3 to give 145. Hydrolysis converted this functionality to the conjugated ketone 146 in 84% overall yield. The previous development of 143 as a reagent was due to several unsuccess-... 

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>. 

Scheme 54 shows the synthesis reported by Cox et al. of the pyrazoline compound 198 [98]. The Weinreb amide (e.g., 199) was reacted with a terminal alkyne followed by a reaction of the resulting alkyl ketone (200) with an aryl cuprate to produce the pyrazoline 198. Cox et al. employed the use of microwave technology in this reaction. Kidwai and Misra also employed microwave technology to produce pyrazoline compounds [99]. 

In 1999, Salvino and coworkers developed a novel supported Weinreb amide resin tli3,t facilitates p3T3.11cl synthesis of aldehydes nd ketones on 3. sc3le useful for chemical library synthesis (Scheme 107). 

The stereochemistry at C7 was introduced by the hydrogenation of the ketone. Although this hydrogenation was very selective for the desired stereoisomer, the process provided no information to confirm or refute the tentative stereochemical assignment at this center, which remained incorrectly assigned until Weinreb completed a stereocontrolled synthesis of 7-epicylindrospermopsin in 2001.7a... 

Weinreb s synthesis4 has two OMe groups where the ortho-quinone will be and puts in the pyrrole last. The idea was to use a Reissert indole synthesis where reduction of the nitro group in 42 would lead to condensation with the ketone. 

The second phase of the synthesis by Auerbach and Weinreb was concerned with the construction of ring D. This proved to be rather difficult and initial attempts failed. Thus, alkylation of 225 with propargyl bromide gave 226, which upon hydration with aqueous mercuric sulfate yielded the expected ketone 227. However, all attempts to cyclize 227 failed. In a modified... 

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],... 

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