Hydroxyethylene isostere

Stereoselective routes to the lactone precursors of the 1-hydroxyethylene isosteres using a titanium-mediated condensation has been reported by both Shibuya and co-workers1 and DeCamp et al. 19 The former method (Scheme 9) features the reaction between (2S)-2-dibenzylamino aldehydes and optically active dichloroisopropoxytitanium ester homo-enolates to provide the desired lactone with high erythro selectivity. Then, the lactone is opened by treatment with an amine and trimethylaluminum to give the 1-hydroxyethylene isostere. The experimental details of DeCamp et al. s high yielding and stereoselective synthesis 19 of lactone 8 (Scheme 10) is discussed in Section 10.6.2.2. 

In several of the previously described methods the anion of the three-carbon fragments was added to an a-amino aldehyde to construct a C—C bond between the C3 and C4 atoms of the 1-hydroxyethylene isostere. However, Sakurai et al.[27l used an add chloride instead of an a-amino aldehyde. They synthesized 6-phthalimido-y-oxo esters by a palladium-catalyzed reaction between acid chlorides and organozinc reagents derived from p-iodo esters. Then, the oxo esters were converted into the y-lactone precursors. 

The remaining three steps are accomplished without purification of the intermediate products. The secondary hydroxy group is protected by acetylation and the benzyl ether is removed by hydrogenolysis to provide a primary alcohol. The alcohol is oxidized to a carboxylic acid by ruthenium(III) chloride or pyridinium dichromate. This method has been applied to the synthesis of various enzyme inhibitors containing the 1-hydroxyethylene isostere. 

DeCamp et al.t19l synthesized the lactone intermediate of the 1-hydroxyethylene isostere with high yields and stereoselectivity. As summarized in Scheme 10 (Section 10.6.2), the titanium homoenolate is prepared from ethyl 3-iodopropionate. The iodide is metalated with zinc/copper couple to give the iodozinc homoenolate species. The alkyltitanium homoenolate is then generated by transmetalation of the iodozinc precursor with one of the several chlorotitanium isopropoxide species. The resulting titanium homoenolate reacts with a N-protected a-amino aldehyde, leading to a mixture of 45-diastereomers. In the last step, the product is lactonized. 

The 2-hydroxyethylene isostere is different from the 1-hydroxyethylene isostere only in the position of the hydroxy goup. In the 2-hydroxyethylene isostere the hydroxy group is attached to the C2 of ethylene, while it is on Cl in the 1-hydroxyethylene isostere. The 2-hydroxyethylene isostere has been applied to the design HIV-1 protease inhibitors.[51] However, the activity of the resulting compounds is lower than that of inhibitors in which the isostere is replaced with the 1-hydroxyethylene group. 

Chen et al.[57] reported the synthesis of the 2-hydroxyethylene isostere using two methods. The first method is initiated with readily available a-amino acids and utilizes the Evans chiral aldol condensation to control the stereochemistry (Scheme 25). The second method does not start with a-amino acids, and thus allows for the synthesis of isosteres having side chains other than those obtained from the available a-amino acids (Scheme 26). Thus, this synthesis relies on an anti-aldol product for the 2-hydroxyethylene isosteres via an E-selective ethyl hydrocinnamate enolization. 

Other interesting hybrids between hydroxyethylene and hydroxyethylamine dipeptide isosteres have been reported. Getman et al (1993) developed a series of hydroxyethylureas that potently inhibited HIV-1 protease. The concept of these urea isosteres, first introduced as renin inhibitors, may be envisioned as a modification of the hydroxyethylene isostere (e.g., compound 22), in which the PV chiral a-car-bon is replaced with a trigonal nitrogen. One example of this class of inhibitors, SC-52151 (26) (Table III), inhibited HIV-1 protease with an IC50 value of 6 nMand blocked the cytopathic effect of HIV-1 in cell cul-... 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

Konieczny, M.T., Toma, PH., and Cushman, M., Synthesis of hydroxyethylene isosteres of the transition state of the HIV protease-catalyzed Phe-Pro hydrolysis. Reaction of 2-[(Boc)amino]-l-(2 -oxocyclopentyl)-3-phenylpropanols with diethyl phosphorocyanidate and lithium cyanide followed by samarium iodide, J. Org. Chem., 58, 4619, 1993. 

Plata, D.J., Leanna, M.R., and Morton, H.E., The stereospecific preparation of an hydroxyethylene isostere precursor via a novel piperidine-2,5-dione template. Tetrahedron Lett.. 32, 3623, 1991. 

QSAR 48 was derived [ 14] for the antiviral data of hydroxyethylene isostere derivatives (40) for inhibition of HIV protease in H9 human T-lymphocytes cells, reported by De Solms et al. [160]. One of the prototype pentapeptides (L-682,679) was modified at the carboxy terminus and mostly variations of the P2 amino acid and the elimination/replacement of the P3 amino acid were studied [160]. This model showed that overall bulky molecules would favor the activity. However, the X-substituents would have a negative steric effect. 

QSAR 50 was reported [14] for a series of compoimds containing R-hydroxyethyl urea isostere (42) studied by Getman et al. [162]. Replacement of the PI chiral or-carbon center of the hydroxyethylene isostere with trigonal nitrogen gives a urea isostere (Fig. 11b) [158]. 

---