“…In the synthesis of cis -proline dipeptide mimics, we have used the Still−Wittig [2,3]-sigmatropic rearrangement to form trisubstituted ( Z )-alkenes selectively. Others have similarly synthesized disubstituted ( E )-alkene dipeptide mimics . The general [2,3]-sigmatropic rearrangement has been studied extensively, , providing detailed accounts of how substitution of the allylic ether precursor determines the stereochemical outcome of the rearrangement in a predictable fashion; the tabular survey compiled by Nakai gives an excellent overview of these effects 4b.…”
[see reaction]. The Still-Wittig rearrangement gave opposite selectivities for (Z:E)-alkenes in THF (3:1) vs toluene (1:3) in the synthesis of serine-proline dipeptide amide isosteres. Four transition states leading to (Z)-and (E)-alkenes with THF and without (representing toluene) were identified by ab initio calculations at the 3-21G* level. The calculated (Z:E)-ratios with THF (4.7:1) and without THF (1:3.2) suggested that the transition state geometries and energies were well-represented by the calculations.
“…In the synthesis of cis -proline dipeptide mimics, we have used the Still−Wittig [2,3]-sigmatropic rearrangement to form trisubstituted ( Z )-alkenes selectively. Others have similarly synthesized disubstituted ( E )-alkene dipeptide mimics . The general [2,3]-sigmatropic rearrangement has been studied extensively, , providing detailed accounts of how substitution of the allylic ether precursor determines the stereochemical outcome of the rearrangement in a predictable fashion; the tabular survey compiled by Nakai gives an excellent overview of these effects 4b.…”
[see reaction]. The Still-Wittig rearrangement gave opposite selectivities for (Z:E)-alkenes in THF (3:1) vs toluene (1:3) in the synthesis of serine-proline dipeptide amide isosteres. Four transition states leading to (Z)-and (E)-alkenes with THF and without (representing toluene) were identified by ab initio calculations at the 3-21G* level. The calculated (Z:E)-ratios with THF (4.7:1) and without THF (1:3.2) suggested that the transition state geometries and energies were well-represented by the calculations.
“…In addition, it has been reported that the stereochemis try at the α-carbon center in dipeptide isosteres is one of the essential factors for enzyme inhibition 4a , recently we and Wipf have described convenient and highly stereoselective synthesis of ( E )-alkene dipeptide isosteres 5 and 6 via an organocopper-mediated S N 2‘ reaction of N -activated 4,5-epimino 2-enoates ( 1 and 2 ) and ( 3 and 4 ), respectively (Scheme 1). …”
Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl) or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-N-(arylsulfonyl) 2-enoates is also presented.
“…Surprisingly, this simple dipeptide mimic has not yet been synthesized. Other cis -proline mimics have been reviewed. , Nonproline cis -amide alkene isosteres have been made, some as E / Z mixtures. , The fluoroalkene trans isosteres have been made . Stereoselective routes to trans -alkene dipeptide isosteres ,, and trans -Pro mimics are known …”
mentioning
confidence: 99%
“…Other cis-proline mimics have been reviewed. 5,15 Nonproline cis-amide alkene isosteres have been made, 16 some as E/Z mixtures. 17,18 The fluoro-alkene trans isosteres have been made.…”
mentioning
confidence: 99%
“…17,18 The fluoro-alkene trans isosteres have been made. 19 Stereoselective routes to trans-alkene dipeptide isosteres 16,20,21 and trans-Pro mimics are known. 22 The synthetic challenges associated with the cis-Pro mimic were as follows: (1) versatility for introducing a variety of amino acid side chains to mimic the residue N-terminal to Pro, (2) enantiospecific synthesis of the key S,R enantiomer of the mimic, and (3) formation of the (Z)-alkene exocyclic to a cyclopentyl ring to mimic the cis-amide.…”
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