Amides Weinreb amide synthesis

Although A-methoxy-A-methyl amides (Weinreb amides), very useful intermediates in organic synthesis, can be prepared from esters by use of McsAl-MeONH-Me HCl [57], Nakata and co-workers found that Me2AlCl-MeONHMe HCl reacted smoothly with a variety of esters and lactones to afford the desired A-methoxy-A-methyl amides in excellent yield [58]. This new method is especially effective for the aminolysis of the sterically hindered lactones as illustrated in Sch. 34. On the basis of NMR data [d 3.02 (3H, s, NMe), 3.83 (3H, s, OMe) in CD2CI2] the real species in the aminolysis was proved to be Cl2AlNMe(OMe). 

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

Mentzei, M., Hoffmann, H. M. R. N-Methoxy N-methyi amides (Weinreb amides) in modern organic synthesis. J. Prakt. Chem. 1997, 339, 517-524. 

Scheme 40 Weinreb amide synthesis from backbone amide linker (BAL)...

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

Mori later developed a shorter synthesis of these pheromones by employing a Weinreb amide A (Scheme 31) as the common intermediate [54]. The products 18-20, however, were less enantiomerically pure than those previously synthesized from the epoxy alcohol A of Schemes 29 and 30. 

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 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. 

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]. 

A concise stereoselective synthesis of a myoinositol derivative has been achieved by ring-closing metathesis of diene 21 prepared from a readily available bis-Weinreb amide 20 of D-tartrate [Eq. (6.19)]. ... 

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. 

In 2001, De Luca and GiacomeUi " reported a new simple and high-yielding one-flask synthesis of Weinreb amides from carboxylic acids and A-protected amino acids that uses different 1,3,5-triazine derivatives (such as 236) as the coupling agents (Scheme 104). The method allows the preparation of Weinreb amides 237 and hydroxamates as O-benzyl and 0-silyl hydroxamates that can be easily transformed into hydroxamic acids. 

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 other stereoselective synthesis/281 shown in Scheme 8, foresees conversion of Boc-L-Asp-OtBu 20 into the related (3-aldehyde 22 via the Weinreb amide 21 and its reduction with diisobutylaluminum hydride (DIBAL-H). Wittig condensation of 22 with the ylide derived from (3-carboxypropyl)triphenylphosphonium bromide using lithium hexamethyldisilaza-nide at —78 to 0°C, produces the unsaturated compound 23 which is catalytically hydrogenated to the protected L-a-aminosuberic acid derivative 24. Conversion of the co-carboxy group into the 9-fluorenylmethyl ester, followed by TFA treatment and reprotection of the M -amino group affords Boc-L-Asu(OFm)-OH (25). 

The reduction of Weinreb amide derivatives by LiAIH4 is not suitable for the synthesis of aspartyl or glutamyl aldehydes. Recently, Paris et a I.129 described the synthesis of various bland side-chain protected aspartyl or glutamyl aldehydes from the corresponding Weinreb amides by using bulky hydrides such as lithium tri-/ert-butoxyaluminum hydride. 

Scheme 9 Solid-Phase Synthesis of an a-Amino or Peptide Aldehyde by Reduction of the Corresponding Weinreb Amide LinkerN...

Enantiomerically pure a-amino aldehydes containing nonpolar side chains such as Boc-Ala-H, Boc-Leu-H, and Boc-Phe-H are synthesized by lithium aluminum hydride reduction of the corresponding Weinreb amides, Boc-Ala-N(Me)OMe, Boc-Leu-N(Me)OMe, and Boc-Phe-N(Me)OMe, respectively (Table 4). The lithium aluminum hydride does not affect the Boc group due to the low temperature and short 15-minute reaction time. Successful synthesis of side-chain Bzl-protected Boc-Thr(Bzl)-H gives a 95% yield of crude product, however, reduction of N-protected aspartyl and glutamyl aldehydes from their corresponding A-methoxy-A-methylamides leads to overreduction and unreacted hydroxamateJ1920 ... 

Table 4 Synthesis of a-Amino Aldehydes by Lithium Aluminum Hydride Reduction of Weinreb Amides 20-32 ...

Table 6 Synthesis of Peptide Aldehydes R -Xaa Xaa -H by Reduction of Weinreb Amides R1-Xaa2-Xaa1-N(Me)OMe with Lithium Aluminum Hydride135 ...

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

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