Ligands conformationally constrained

Ghosh and co-workers have also demonstrated that the Cu(II)-bis(oxazoline) complexes of conformationally constrained inda-box ligands 9a and ent-9a are excellent catalysts for the enantioselective Diels-Alder reaction. Using copper(II) trrflate as the metal source, the reaction resulted in selectivities up to >99 1 endo/ exo ratio with endo ee up to 99% (2R isomer), as shown in Table 9.10 (Fig. 9.24). Of particular interest, Cu(II)-phe-box ligand 6-derived catalyst complex exhibited considerably lower enantioselectivity (30%)." Furthermore, they have shown that the use of Mg(II) as the chelating metal resulted in a reversal of stereochemistry [up to 98 2 endo/exo and 61% endo ee for the (25) isomer]. Davies also showed that the use of copper(II) triflate with his stmcturally related inda-box ligands 9b and 34a led to similar selectivities. 

The ligand-based approach of conformationally constrained peptides has been widely used. The process involves the incorporation of conformational constraints into known peptides, either agonist or antagonist, which enforce a... 

In addition to the deductions one might make about a receptor binding site on the basis of receptor binding data from conformationally constrained ligands as previously described, models of bradykinin and bradykinin antagonists bound to their respective sites on the receptor as complimentary aspects of the overall strategy are also valuable. Unfortunately, due to the nature of the bradykinin... 

The synthesis of a new enantiopure, conformationally constrained 1,4-amino alcohol (25) has been reported, starting from commercially available reagents from the chiral pool.107 This 1,4-amino alcohol has been used as a chiral ligand in the addition of Et2Zn to aldehydes (best ee 98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species. 

Enantiomerically pure d.v-1 -amino-2-indanol and its derivatives have been used as ligands in numerous catalytic asymmetric carbon-hydrogen, carbon-carbon, and carbon-heteroatom bond formation reactions. The conformationally constrained indanyl platform has emerged as a particularly valuable backbone in a variety of catalytic processes leading to high levels of asymmetric induction. The aminoindanol 1 has also been used as a resolution agent (Chapter 8) as well as a chiral auxiliary (Chapter 24). For the synthesis of 1 see Chapter 24. 

Another promising conformationally constrained amino alcohol is cis-1 -arnino-2-hydroxy-1,2,3,4-tetrahydronaphthalene. Early studies using the tetrahydronaphthol backbone as a ligand in catalysis often showed that the relative flexibility of the 6-membered ring was highly detrimental to the... 

The explosion of new aminoindanol-derived ligands disclosed in the past few years is the unmistakable mark of recognition and appreciation of the indanyl platform as a valuable backbone in the field of catalytic asymmetric synthesis. The emergence of related and novel structural designs and their success in achieving improved selectivities clearly reveal the continuing interest in the synthetic potential of conformationally constrained amino alcohols. 

BIOACTIVE CONFORMATION OF CONFORMATIONALLY CONSTRAINED DELTA PEPTIDE LIGANDS... 

A series of cyclic conformationally constrained peptides related to somatostatin were designed, synthesized and tested for opioid receptor interaction by Hruby and his collaborators. Compounds (17)-(22) were found to be pure opioid antagonists (GPI) with high affinity (IC50 = 1.2 to 4.3 nM) and exceptional selectivity for p over S opioid receptors (Table 3.1) and with minimal or no somatostatin-like activity (ligand binding assays)[63-65]. 

The simple alkyl derivatives such homo-, propyl-, and /Ao-propylanatoxin-a (Fig. 7.4A) are all potent nicotinic ligands (Wonnacott et al. 1992). Most of the efforts to determine the precise stmc-tural requirements of the receptor have resulted in the synthesis of conformationally restricted derivatives (Hernandez and Rapoport 1994 Brough et al. 1992). The first bioisosteric and conformationally constrained variation of (+)-anatoxin-a found to retain mnch of the potency of the natn-ral compound was racemic ( )-pyrido[3,4-b]homotropane (PHT) (Fig. 7.4B), representing the... 

---