Weinreb amides Synthesis from esters

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). 

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 ... 

The intramolecular allylboration of an aldehyde function leads selectively to cir-disubstituted cyclic ethers. It has been shown that both the reactive aldehyde and the allylboronate moiety can be initially generated in situ in a masked form and then liberated simultaneously by hydrolysis of the precursor functions <1997JA7499>. This methodology was successfully applied to the one-pot synthesis of the oxocene 82, a precursor of (-l-)-laurencin (Scheme 13). A DIBAL reduction of the Weinreb amide 80, metalation with r f-butyllithium, borylation with the pinacol borate ester, and, finally, liberation of both the aldehyde and the allylboronate function by aqueous pH 7 buffer solution generated the reactive 81, which cyclized in 38% overall yield to the oxocene 82. Only the all-cis-diastereomer is formed, which means that the cyclization proceeds under high asymmetric induction from the resident stereogenic center present in 80. 

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). 

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. 

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. 

The same methodology has been extensively developed for the synthesis of optically active p-ketophosphonates from (3/ ,l 7 )-methyl T-phcnylethyl 3-hydroxypentanedioate. Low-temperature condensation of this unprotected hydroxy diester with dimethyl 1-lithiomethylphosphonate in excess in THF gives the desired optically active functionalized P-ketophosphonate in fair yield (43%). It has been observed that the methyl ester reacts faster than the I -phenethyl ester, and it is necessary to operate without the silyl protecting group to avoid a P-elimination reac-tion. - 2< By an analogous route, the reaction of dimethyl 1-lithiomethylphosphonate (1.3 eq) with the corresponding protected hydroxy ester-amide (Nahm-Weinreb amide) provides the... 

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... 

The synthesis of trisubstituted alkenes has scarcely been disclosed some exanples may be found in the work of Najera and coworkers using electron-deficient aryl sulfones 47 combined with phosphazene tScheme 19.21T The scope is even more limited for tetrasubstituted olefins as the yields are quite low. Acylsilanes afford trisubstituted vinylsilanes such as 48 mainly as the E isomers, but the stereoselectivity can be controlled by modulating the nature of the silyl group tScheme 19.22T E-configured conjugated esters and Weinreb amides have been synthesized successfully as well by Najera and coworkers starting from conveniently substituted arylsulfone 49 (Scheme 19.23). 

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. 

A number of selective transformations (Fig. 10) have been described which include the selective allylation on alcohols in the presence of amides [47], the Lewis acid catalyzed cleavage of benzyl alcohol esters with secondary amines to afford tertiary amides [48], the synthesis of ketones from Weinreb-type amides [49], and the synthesis of tertiary amines by a Michael addition/alkylation/Hoffman elimination sequence [50],... 

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]. 

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