Weinreb amide additions

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. 

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). 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

The addition of allenyl ether-derived anions to Weinreb [4] or to morpholino amides [5] follows a slightly different pathway (Eq. 13.2). For example, the addition of lithioallene 6 to Weinreb amide 7 at -78 °C, followed by quenching the reaction with aqueous NaH2P04 and allowing the mixture to warm to room temperature leads to cyclopentenone 9 in 80% yield [6]. The presumed intermediate of this reaction, allenyl vinyl ketone 8, was not isolated, as it underwent cyclization to 9 spontaneously [7]. These are exceptionally mild conditions for a Nazarov reaction and are probably a reflection of the strain that is present in the allene function, and also the low barrier for approach of the sp and sp2 carbon atoms. What is also noteworthy is the marked kinetic preference for the formation of the Z-isomer of the exocyclic double bond in 9. Had the Nazarov cyclization of 8 been conducted with catalysis by strong acid, it is unlikely that the kinetic product would have been observed. 

The so-called Weinreb amides (or Af-methoxy-A-methylamides) are versatile building blocks in organic synthesis . Their preparation can be accomplished by coupling carboxylic acids and Af,0-dimethylhydroxylamme. The majority of the methods reported use peptide coupling reagents such as chloroformates , BOP , DCC and others "" or phosphonic derivatives ". These reactive reagents are expensive in some cases, and the removal of their excess (and/or the removal of byproducts) from the reaction mixtures may be difficult. Additional purification of the reaction product is often required. 

The c 5-23-dimethylchionian-4-one 53 is obtained with fair enantioselectivity through an asymmetric Michael addition in the presence of (-)-quinine (Scheme 32) <99TL3777>. Directed metallation of protected phenols and subsequent reaction of the li derivative with enantiopure Weinreb amides of glycidic acids feature in a route to stereoisomers of 2-alkyl-3-hydroxychroman-4-ones (Scheme 33) <99JOC3489>. 

The TV-methoxy-jV-methylamide of tiglic acid (17) is used as an aeylating agent in a procedure developed by Weinreb.9 Lithiated aromatic species 18 attacks Weinreb amide 17 with formation of the chelate 19. which is hydrolyzed to ketone 5. Use of Weinreb amide 17 circumvents the primary threat here multiple addition and formation of a tertiary alcohol. Since complex 19 decomposes only in the course of workup, the ketone 5 itself is protected against further nucleophilic attack.10 "BuLi, LiCl. THF. 0 C->RT 17. 77%. 

As shown in Scheme 8, the synthesis of aldehyde 45 was achieved in eight steps utilizing the common precursor 31 [46-48], Remarkably, the Mukaiyama aldol addition of silyl enol ether 46 to aldehyde 47 proceeded with anti-Felkin selectivity, which was attributed to involvement of the Weinreb amide and aldehyde carbonyl... 

The second variant of this method uses a,/(-unsaturated Weinreb amides as electrophiles1066,1076 1077. The 1,2-addition of compound 740 to the amide 742 gave the ketone 743, which underwent spontaneous Nazarov cyclization upon work-up1077... 

The addition of dimethyl 1-lithiomethylphosphonate (5.5 eq) to the protected amide-acid (Nahm-Weinreb amide) gives a clean reaction, and treatment of the crude product with CH2N2 affords the P-ketophosphonate in high yield (77%, Scheme 8.73). To avoid the use of CH2N2, an alternative and safer route uses a reactive phosphonyl enol lactone, which is converted into the same P-ketophosphonate by treatment with MeONa in MeOH. - ... 

Both syntheses made the bond between the two alkenes by a Stille coupling. One put the tin on the amide part by a Cu(I) catalysed conjugate addition of Bu3SnLi to the acetylenic ester 212 and Weinreb amide formation. Coupling this vinyl stannane with a single enantiomer of the iodide derived from the rest of the molecule gave crocacin C in good yield. The synthesis of the iodide uses an asymmetric aldol reaction and is described in the workbook.30... 

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