Reduction of Weinreb amides

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. 

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

The amino aldehydes Boc-Ala-H, Boc-Leu-H, Boc-Phe-H, and Boc-Thr(Bzl)-H had a much higher enantiomeric purity when prepared by reduction of Weinreb amides compared to the identical aldehydes prepared by the Collins oxidation of the alcohols (Table 5). 1314-20 ... 

Peptide aldehydes have also been prepared successfully by direct reduction of Weinreb amides. Peptide linkages were stable during the reduction of dipeptide /V-methoxy-/V-methylamides. For example, the dipeptides Boc-Phe-Leu-H and Z-Tyr-Val-H were prepared in 96-98% yield (Table 6)J351... 

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 ...

Fig. 6.42. Preparation of Weinreb amides through SN reactions at the carboxyl carbon. Chemoselective reduction of Weinreb amides to aldehydes.

The Swem oxidation of A-Fmoc-protected -amino alcohols 8 (Scheme 4) and the reduction of Weinreb amides prepared from Fmoc-a-amino acids with LiAlH4 at — 78°C were compared [83]. Both approaches afforded comparable synthetic yields, typically between 70 and 90% of the... 

Conversion of solid-supported hydroxamates to aldehydes is a useful tool for the generation of C-terminal peptide-aldehydes. Martinez et aL firstly used LiAlH4-reduction for the cleavage of hydroxamates from solid supports and succeeded in synthesizing tripeptide aldehydes that could be obtained in about 40% yield after purification [83]. Reduction of Weinreb amides on... 

Aldol 307 became the central starting material for three advanced intermediates. Thus, tret-butyldimethyl-silyl (TBS) protection followed by Red-Al reduction of "Weinreb amide produced aldehyde 308, which underwent "Wittig reaction. The latter gave mediocre 30% yield and was one of the most difficult reactions to scale up (Scheme 10.59). 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Cyclization of the Weinreb amide 356 under reductive conditions using lithium aluminium hydride (LAH) led to formation of the carbinolamine 357 which underwent elimination on treatment with methanesulfonic acid to give 358 in 72% yield as shown in Scheme 27 <2005TL249>. 

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). 

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

Polystyrene-bound Weinreb and related amides react with organolithium or Grignard reagents to yield ketones (Table 12.2). Amides have also been used for this purpose, without significant formation of tertiary alcohols. Aldehydes can be prepared on solid phase by reduction of A/,0-dialkylhydroxamates with LiAlH4 (Entry 1, Table... 

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 ... 

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 ... 

Horner-Emmons reaction of N-terminal blocked aldehyde 1 with sulfonylphosphonates in the presence of sodium hydride gives the amino acid vinyl sulfone 2, which is deprotected with acid and converted into its chloride or tosylate salt 3 and coupled by the mixed anhydride method with an N-terminal protected peptide or amino acid to give the desired peptide vinyl sulfones 4 (Scheme 2). 4 5 N-Terminal protected aldehydes 1 are obtained from reduction of Boc amino acid V-methoxy-A-methylamides (Weinreb amides, see Section 15.1.1) by lithium aluminum hydride. 9 The V-methoxy-V-methylamide derivatives are prepared by reaction of Boc amino acids with N,O-dimethylhydroxylamine hydrochloride in... 

The TEMPO moiety (2,2,6,6-tetramethylpiperidine-l-oxyl) has been incorporated into acetoacetic derivatives to achieve E-selective Knoevenagel condensations, exploiting the steric hindrance that it causes.269 In contrast, acylacetoamides (including Weinreb amides) produce Z-adducts. Downstream reductions of carbonyl groups in the products allow access to a variety of useful materials. 

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