Weinreb amides preparation

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... 

A New General Method for the Preparation of Weinreb Amides from Esters... 

The reaction of an ester with Weinreb amine and i-PrMgCl provides a general method for the preparation of Weinreb amides that has been widely used in the... 

Table 3.3 Preparation of Weinreb amides from esters.

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 preparation of 3-vinylpyrroles was investigated utilizing the Horner-Wads worth-Emmons reaction with 3-formyl-lV-tosylpyrrole <06S1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S1975>. 

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>. 

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. 

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... 

The enantiomerically-pure intermediate 1 was prepared from the dioxolanone 4, available in three steps from L-malic acid. Lewis acid-mediated homologation converted 4, a 4 1 mixture of diastereomers, into 5 as a single diastereomer. After establishment of the alkenyl iodide, it necessary to maintain the lactone in its open form. A solution was found in the formation of the Weinreb amide. The final stereogenic center was established by Brown allylation of the derived aldehyde. The alkene metathesis to form 1 was carried out with the commercially-available Schrock Mo catalyst. The authors did not comment on the relative efficacy of alternative alkene metathesis catalysts. 

Preparation of a N -Protected a-Amino (and Peptide) Aldehyde on Solid Support via the Weinreb Amide Linker General Procedure 461... 

Aldehydes and ketones have also been prepared by nucleophilic cleavage of resin-bound O-alkyl hydroxamic acids (Weinreb amides [744]) with lithium aluminum hydride [745] or Grignard reagents (Entries 1 and 2, Table 3.41). Similarly, support-bound thiol esters can be cleaved with Grignard reagents to yield ketones [272], or with reducing agents to yield aldehydes (Entry 3, Table 3.41). Polystyrene-bound sele-nol esters (RCO-Se-Pol) react with alkynyl cuprates to yield alkynyl ketones [746]. 

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... 

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... 

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

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. 

In an example illustrating a modification of the Knorr synthesis, the Weinreb amide derivative 171 is converted to the -enaminoketone 172 and annulated to the target pyrrole 173 (Scheme 97). Numerous pyrrole derivatives can be prepared using variations of this approach <1999T6555>. 

An intramolecular cyclization approach has also been used for the synthesis of the fused pyrroles 67, which were obtained by treatment of the Weinreb amides 68 with r-BuLi. The requisite precursors 68 were prepared by A-benzylation of the pyrrole 69 with the benzyl bromides 70 <03OLl 115>. 

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). 

---