Hydroxyethylene Dipeptide Isosteres Research Articles

L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.

Progressive cerebral amyloid beta-protein (A beta) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels of A beta(42) peptide formation have been linked to early-onset familial AD-causing gene mutations in the amyloid beta-protein precursor (A beta PP) and the presenilins. Sequential cleavage of A beta PP by the beta- and gamma-secretases generates the N- and C-termini of the A beta peptide, making both the beta- and gamma-secretase enzymes potential therapeutic targets for AD. The identity of the A beta PP gamma-secretase and the mechanism by which the C-termini of A beta are formed remain uncertain, although it has been suggested that the presenilins themselves are novel intramembrane-cleaving gamma-secretases of the aspartyl protease class [Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Nature 398, 513-517]. In this study we report the identification of L-685,458 as a structurally novel inhibitor of A beta PP gamma-secretase activity, with a similar potency for inhibition of A beta(42) and A beta(40) peptides. This compound contains an hydroxyethylene dipeptide isostere which suggests that it could function as a transition state analogue mimic of an aspartyl protease. The preferred stereochemistry of the hydroxyethylene dipeptide isostere was found to be the opposite to that required for inhibition of the HIV-1 aspartyl protease, a factor which may contribute to the observed specificity of this compound. Specific and potent inhibitors of A beta PP gamma-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease.

Transition-State Mimetics for HIV Protease Inhibitors: Stereocontrolled Synthesis of Hydroxyethylene and Hydroxyethylamine Isosteres by Ester-Derived Titanium Enolate Syn and Anti-Aldol Reactions.

Stereocontrolled syntheses of hydroxyethylene dipeptide isostere and aminoalkyl epoxides for hydroxyethylamine isosteres are described. The stereochemistry of both stereogenic centers of the aminoalkyl epoxides 10 and 15 as well as the gamma-lactone 17 was assembled by our recently developed highly selective ester-derived titanium enolate aldol reactions. The Ti-enolate of 6 reacted with (benzyloxy)acetaldehyde and cinnamaldehyde to provide the syn-aldol product 7 and anti-aldol product 12, respectively. Removal of the chiral template followed by Curtius rearrangement of the resulting acid provided the desired amine functionality. The present syntheses represent practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited to amino acid derived substituents.

A General, Catalytic, and Enantioselective Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones

A catalytic asymmetric synthesis of N-phthaloyl (S)-γ-[(S)-1-aminoalkyl]-γ-lactones, widely used intermediates in the preparation of hydroxyethylene dipeptide isosteres, is described. The highly enantiopure epoxy alcohols arising from the Sharpless epoxidation of (E)-allyl alcohols are first converted to (S)-N-phthaloyl-[(S)-1-aminoalkyl]oxiranes by means of an efficient four-step sequence involving the regio- and stereoselective ring opening of the starting epoxide by azide, reduction, phthaloylation, and intramolecular Mitsunobu cyclization of the intermediate phthalimido diol. Treatment of the resulting oxirane with lithium (1R)-menthyloxyacetylide in the presence of boron trifluoride etherate, followed by in situ hydrolysis of the ynol ether, leads to a (4R,5S)-5-phthalimido-4-hydroxy ester. A Mitsunobu reaction with p-nitrobenzoic acid (which establishes the correct (S)-configuration at C-4) and subsequent selective saponification of the benzoate and cyclization of the inverted hydroxy ester afford the target N-protected (S)-γ-[(S)-1-aminoalkyl]-γ-lactones. Using this methodology, lactones 19 and 26 were obtained in seven steps from the readily available epoxy alcohols 5 and 20, respectively, in high enantiomeric purity.

Enantioselective synthesis of N-Boc-2,2-dimethyloxazolidine-5-carbaldehydes, versatile precursors of dipeptide isosteres

Highly enantioenriched cis and trans N-Boc-2,2-dimethyl-oxazolidine-5-carbaldehydes have been efficiently prepared from N-Boc-3-amino-1,2-alkanediols, readily available in enantiopure or enantioenriched form by Sharpless epoxidation methodology. These compounds have been converted into N-Boc-( S)- γ-[( S)-1-aminoalkyl]-γ-lactones which are key intermediates of hydroxyethylene dipeptide isosteres.

ChemInform Abstract: Zinc‐Mediated Allylation of N‐Protected α‐Amino Aldehydes in Aqueous Solution. Stereoselective Synthesis of Phe‐Phe Hydroxyethylene Dipeptide Isosteres.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Stereocontrolled, Convergent Synthesis of Hydroxyethylene Dipeptide Isosteres

A simple, convergent, and stereoselective synthesis of hydroxyethylene dipeptide isosteres 1 and 2 from scalemic α-hydroxy esters has been developed. The method is short (six steps), efficient (≈15−25% overall), and highly diastereoselective (86−94% de) and enantioselective (>95% ee).

Zinc-Mediated Allylation of N-Protected α-Amino Aldehydes in Aqueous Solution. Stereoselective Synthesis of Phe-Phe Hydroxyethylene Dipeptide Isosteres

An efficient route for the synthesis of a Phe-Phe hydroxyethylene dipeptide isostere utilized for the design of potential inhibitors of renin and HIV-protease was developed.

ChemInform Abstract: A New Chiral, Cationic β‐Amino Alcohol Equivalent: A Variable Approach to Enantiomerically Pure Building Blocks for Hydroxyethylene Dipeptide Isosteres.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Bioactive Hydroxyethylene Dipeptide Isosteres with Hydrophobic (P3‐P1)‐ Moieties. A Novel Strategy Towards Small Non‐Peptide Renin Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Stereoselective Synthesis of Hydroxyethylene Dipeptide Isostere from Sugar.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Bioactive hydroxyethylene dipeptide isosteres with hydrophobic (P 3-P 1)-moieties. A novel strategy towards small non-peptide renin inhibitors

The design and synthesis of new truncated δ-amino hydroxyethylene dipeptide isosteres lacking the P 4-P 2 peptide backbone is described. The most active compounds 15c and 30c inhibited human renin in the submicromolar range. This promising concept may offer the possibility to discover completely non-peptide, lowmolecular weight renin inhibitors with improved pharmacokinetic properties.

Stereoselective Synthesis of Hydroxyethylene Dipeptide Isostere from Sugar

Abstract Regioselective opening of the aziridine ring in the carbohydrate-based precursor led to the stereoselective synthesis of N-Boc-O-benzyl-(4S,5S)-5-amino-4-hydroxy-6-phenylhexanoic acid methyl ester, the hydroxyethylene dipeptide isostere moiety of potent HIV-1 protease inhibitor.

ChemInform Abstract: Thiazole‐Based Stereoselective Routes to Leucine and Phenylalanine Hydroxyethylene Dipeptide Isostere Inhibitors of Renin and HIV‐1 Aspartic Protease.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Thiazole-Based Stereoselective Routes to Leucine and Phenylalanine Hydroxyethylene Dipeptide Isostere Inhibitors of Renin and HIV-1 Aspartic Protease

Thiazole-Based Stereoselective Routes to Leucine and Phenylalanine Hydroxyethylene Dipeptide Isostere Inhibitors of Renin and HIV-1 Aspartic Protease

ChemInform Abstract: A Simple Strategy for the Synthesis of Hydroxyethylene Dipeptide Isostere from D‐Glucose.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A General Stereocontrolled Synthesis of Hydroxyethylene Dipeptide Isosteres.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A Formal Stereoselective Synthesis of a Hydroxyethylene Dipeptide Isostere.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A general stereocontrolled synthesis of hydroxyethylene dipeptide isosteres

Hydroxyethylene dipeptide isosteres were synthesized by stereocontrolled hydroboration of homoallylic alcohols derived from syn protected aminoepoxides followed by chemoselective oxidation of the resulting primary alcohols.

A formal stereoselective synthesis of a hydroxyethylene dipeptide isostere

4-Hydroxy-5-amino-6-phenyl-4-hexanolide has been synthesized under its cyclized form (lactone 5) from a very inexpensive chiral starting material, L-glutamic acid. The key steps were an original reduction of carbonyl of a ketone with n-Bu 3SnH in the presence of silica gel, followed by an SN 2 displacement of a mesylate group with sodium azide

A simple strategy for the synthesis of hydroxyethylene dipeptide isostere from D-glucose

A general approach is outlined here for the synthesis of hydroxyethylene dipeptide isostere ( 1) starting from D-glucose which can be employed to introduce any group at P 1 or P 1, positions of such isosteres. A highly stereoselective synthesis of ( 2R,4 S,5S)- N-Boc- O-benzyl-5-amino4-hydroxy-2-methyl-6-phenylhexanoic acid methyl ester ( 2) is accomplished based on this strategy.