Phosphine peptide-based

Simple acyclic a,/ -unsaturated esters are not reactive in the conjugate addition of dialkylzincs. In contrast, nitro-substituted unsaturated esters68 and malonates69 are applicable for this reaction. Using peptide-based chiral phosphine 66, Hird and Hoveyda realized the Cu-catalyzed conjugate addition of Et2Zn to iV-acyloxazolidinones with excellent enantioselectivity (Scheme 21).70... 

Hoveyda and co-workers presented the asymmetric addition of alkylzincs to small-, medium-, and large-ring nitroolefins with chiral peptide-based phosphines 57 as catalyst.87 The enantioselectivities were typically >90%. Ligand 57 also worked well in the asymmetric addition of dialkylzinc to acyclic disubstituted nitroalkenes (up to 95% ee Scheme 26).88... 

Gilbertson. S.R. and Wang. X. (1999) The parallel synthesis of peptide based phosphine ligands. Tetrahedron, 55. 11609-11618 Gilbertson. S.R. and Wang. X. (1995) The combinatorial synthesis of chiral phosphine ligands. Tetrahedron Lett.. 37. 6475-6478. 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

As shown in Eq. (4), parallel screening of ligand libraries has allowed us to establish that a closely related peptide-based phosphine ligand promotes the catalytic asymmetric conjugate addition of alkylzincs to nitroalkenes [14]. Not only are the corresponding alkyl nitrones obtained efficiently and in high diaster-eo- and enantioselectivity, appropriate acid workup can deliver the derived ketone directly. 

An interesting approach to develop an asymmetric allylic alkylation catalyst by using a peptide-based phosphine hgand was examined by Gilbertson (Scheme 3.70) [135]. Phosphine-sulfide amino acid 211 was incorporated into a peptide sequence on a polymer support After reduchon of the phosphine sulfide to phosphine, the polymer-supported pephde sequence having phosphine-(support-Gly-Pps-D-Ala-Pro-Pps-D-Ala-Ac) was prepared. The complex of the peptide with Pd was uhhzed for the asymmetric addition of dimethyl malonate 202 to 3-acetoxycy-clopentene 212 to give 213 in 59% yield and 66% ee. 

The peptide-based phosphine ligand 105 was identified from a polymer-supported phosphine library of 75 members [154]. Enantioposition-selective desymmetrization of the meso-cyclopentenediol derivative 100 was promoted by a palladium complex of 105 to afford the cyclic carbamate 101 with 76% ee. This result demonstrated that the combinatorial approach is effective in the lead-generation stage of stereoselective catalyst development [155, 156]. The resin-supported palladium complex of Ac-D-Phg-Pro-D-Val-Pps-D-Leu-NH resin 106, which has also been developed through the combinatorial approach. 

Successful representative catalysts for asymmetric acylations include phosphine catalysts, chiral pyridine derivatives, other N-heterocycles " and peptide-based catalysts. Miller and coworkers designed peptide catalysts with -turns, a common feature within proteins and enzymes, in order to obtain secondary structure in which the catalytically active residues can be incorporated. During their initial work on asymmetric acylation reactions peptides were employed containing the catalytic histidine moiety to serve as nucleophile in a series of j0-tum type small peptides for the kinetic resolution of trans-1,2 acetamidocyclohexanol (- -/-)146 (Figure 53a). 

Jiracek, J., Yiotakis, A. Vincent, B., Checler, F. and Dive, V., Development of the first potent and selective inhibitor of the zinc endopeptidase neurolysin using a systematic approach based on combinatorial chemistry of phosphinic peptides, J. Biol. Chem., 271 (1996) 19606-19611. 

Calcium-binding proteins, 6, 564, 572, 596 intestinal, 6, 576 structure, 6, 573 Calcium carbonate calcium deposition as, 6, 597 Calcium complexes acetylacetone, 2, 372 amides, 2,164 amino acids, 3, 33 arsine oxides, 3, 9 biology, 6, 549 bipyridyl, 3, 13 crown ethers, 3, 39 dimethylphthalate, 3, 16 enzyme stabilization, 6, 549 hydrates, 3, 7 ionophores, 3, 66 malonic acid, 2, 444 peptides, 3, 33 phosphines, 3, 9 phthalocyanines, 2,863 porphyrins, 2, 820 proteins, 2, 770 pyridine oxide, 3,9 Schiff bases, 3, 29 urea, 3, 9... 

Reactions of the hydroxy peptides with selected phosphine chlorides in the presence of a base and catalytic amounts of DMAP resulted the corresponding phosphinites, which readily form Pd and Pt complexes (Scheme 2). 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

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