Weinreb preparation from esters

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

Table 3.3 Preparation of Weinreb amides from esters.

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). 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Acyl oxazolidinones 50-52 are easily prepared from commercially available chiral starting materials. As shown in Scheme 4.6, treatment of the amino-acid-derived amino alcohols with diethyl carbonate, followed by N-acylation, affords 54 [6, 46], The removal of the auxiliary following the aldol addition reactions proceeds smoothly under a variety of mild conditions to afford carboxylic acids 56 (UO2H) [47, 50], primary alcohols 57 (LiBH,) [51], esters 58 (Ti(OBn)4) [52], or Weinreb amides 59 [51]. 

Aside from the pyrimidine preparations which follow well-established strategies, several new pathways have been developed. In model studies for the synthesis of cylindrospermopsin, Weinreb and Keen reported a novel route to N-hydroxydihydrouracil 33 from a,P-unsaturated ester 30 followed by aromatization to give pyrimidone 34 <00TL4307>. 

The best way to prepare peptide aldehydes from the corresponding N -protected amino acids is by using a handle based on the Weinreb amide.f This commercial handle allows classical solid-phase elongation of peptides using protected Boc or Fmoc amino adds and, at the end of the synthesis, the peptide aldehyde is formed by reduction and concomitant cleavage from the resin with lithium aluminum hydride. Although the 4-hydro-xybenzoic acid handle also allows the preparation of peptide aldehydes by reduction of the resin-bound phenyl ester with lithium tri-tert-butoxyaluminum hydride, a noixture of the aldehyde and the alcohol is always formed. 

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. 

Using chemistry developed by Tanikaga and coworkers [134], Trost [135] prepared the methyl ester of 4-hydroxy-2 -eicosenoic acid from octadecanal. The acetate of the former compound, in the presence of 0,N-bis(trimethylsilyl) acetamide and molybdenum hexacarbonyl underwent elimination, furnishing methyl 2,4-eicosadienoate as a 4 1 E,E E,Z mixture. Group transfer, by Weinreb s procedure afforded, after crystallization of the product, the corresponding pyrrolidyl amide, trichonine, 9(n=14), contaminated by some 8% of the E, Z diene isomer. The overall yield, from octadecanal, for the Trost synthesis was 28% (Scheme 6) [135]. 

The preparation of the other essential building block needed to carry out the critical aspects of the synthetic plan, acetylenic ketone 28, was achieved in two steps in 74 % overall yield from the known methyl lO-hydroxy-5-decynoate (49) through initial conversion of the ester into the corresponding Weinreb amide (50), followed by the controlled addition of a single equivalent of ethynylmagnesium bromide as shown in Scheme 6. 

Preparation of the A-ring unit (Scheme 11) started with ethyl L-malate, which was converted into the enone 37 through the Weinreb amide derived from the ester 36. Stereoselective reduction [41] of 37 produced the syn... 

We have focused our attention on the solid phase synthesis of such compounds and described our results here. Alternative routes for the preparation of peptide aldehydes and side-chain protected peptide aldehydes in solid phase synthesis are described. Three new linkers that are stable tmder classical Fmoc or Boc strategies have been developed to obtain the peptide aldehyde from the solid support. One of these linkers was conceptualized on the basis of the Weinreb amide (49) and the other on the basis of phenolic esters (50). Both strategies required the reduction with hydrides of the peptide-linker-resin to release the peptidic aldehydic function. The use of these two different approaches was demonstrated by the synthesis of N-protected a-amino-aldehydes and peptide aldehydes, llie third approach used the ozonolysis reaction for the generation of the desired aldehyde. This concept requires a linker incorporating a double bond in the a-position of the asymmetric carbon of the C-terminal residue that will be cleaved by ozone to produce the carbonyl function. 

Apart from the common heteroatom-derived nucleophiles described, cleavage with other nucleophiles is also possible. For example, reductive cleavage with hydride sources is possible. For ester-linked substrates, Kurth et al. reported an example in which substituted propane-1,3-diols were prepared (Table 1.2, Entry 11). In related work, Chandrasekhar et al. prepared tertiary alcohols by treating an ester-linked substrate with excess Grignard reagent (Table 1.2, Entry 12). If, however, it is desirable to prepare the carbonyl derivative (and not reduce all the way to the corresponding alcohol), then Weinreb-type linker units can be used (Table 1.2, Entries 13 and 14). Treatment of substrates attached via such linkers... 

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