Stereoselective synthesis of 2-azetidinones as cholesterol-absorption inhibitors

The synthesis of two 2-azetidinones possessing powerful cholesterol-absorption inhibition properties has been accomplished by a short and highly stereoselective reaction sequence. The key step is the condensation of the titanium enolate of the easily prepared 2-pyridylthioester (R)-11 with imine 6 which affords the desired β-lactam intermediate in the correct relative and absolute configuration. Conversion to the pharmacologically active compounds is readily accomplished by simple functional group manipulation.     

New approaches to the industrial synthesis of HIV protease inhibitors

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from l-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to l-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.     

Stereoselective synthesis of 3,3-diarylacrylonitriles as tubulin polymerization inhibitors

A series of 3,3-diarylacrylonitriles were synthesized stereoselectively as tubulin polymerization inhibitors for potential use in cancer chemotherapy. This synthetic route features stannylcupration and palladium-catalyzed Stille cross-coupling chemistry, allowing both E and Z isomers of 3,3-diarylacrylonitriles to be prepared in a very short sequence of reactions.     

Synthesis of novel lysophosphatidylcholine analogues using serine as chiral template

Four novel lysophosphatidylcholine (lysoPC) analogues, (S)-N-stearoyl-O-phosphocholineserine methyl ester [(S)-1a], (R)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3-phosphatidylcholine [(R)-2a], (R)-N-stearoyl-O-phosphocholineserine methyl ester [(R)-1b], and (S)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3-phosphatidylcholine [(S)-2b], were synthesized starting from serine as a chiral template. These synthetic compounds exhibited greatly enhanced hyphal transition inhibitory activity in Candida as compared to the natural lysoPC.     

Stereoselective synthesis of cytoxazone and its analogues

A variety of synthetic routes to (−)-cytoxazone 1, a cytokine modulator isolated from Streptomyces cultures, and its stereomers 2 and regioisomers 3 have been reviewed.     

Design and synthesis of novel [60]fullerene derivatives as potential HIV aspartic protease inhibitors

[structure] Two water-soluble fullerene derivatives have been computer-designed and synthesized. They may exhibit interesting anti-HIV activity owing to the presence of two ammonium groups strategically located on the spheroid surface.     

Stereoselective synthesis of 3-aminoindan-1-ones and subsequent incorporation into HIV-1 protease inhibitors

A new method for the stereoselective synthesis of 3-aminoindan-1-ones from triflates of salicylic sulfinyl imines and ethylene glycol vinyl ether has been developed. The reaction sequence starts with a regioselective Heck reaction followed by stereoselective Lewis acid mediated annulation. Acidic cleavage of the sulfinamides produced pure (R)- and (S)-3-aminoindan-1-ones, which were successfully isolated and incorporated into active HIV-1 protease inhibitors.     

Stereoselective synthesis of enantiopure analogues of (−)-cephalotaxine

The asymmetric total synthesis of three analogues of (?)-cephalotaxine with structural modification of the aromatic ring was achieved in 16 steps and acceptable overall yields. The procedure used was quite similar to that reported by our group for the total synthesis of (?)-cephalotaxine in 2004. The enantiopure spiranic compound 4 is a common intermediate on which various aromatic groups can be introduced. Unexpected and interesting different chemical behaviors were observed during these syntheses.     

Stereoselective aldol reactions using ticl4 as stereochemical template

TiCl₄ mediated aldol condensations establish multiple contiguous chiral centers in an almost complete enantio- and diastereoselective way.     

Stereoselective synthesis and anticancer activity of broussonetine analogues

The stereoselective synthesis of two broussonetine analogues 14·HCl and ent-14·HCl with differing stereochemistry of the polyhydroxylated pyrrolidine core and a simple C₁₃ alkyl fragment has been achieved. For their construction, the known oxazolidinones 15 and 16 were chosen as appropriate advanced scaffolds. The common hydrophobic side chain was incorporated at an early stage of the synthesis through Grubbs’ cross metathesis chemistry. The required pyrrolidine skeleton was then formed by the cyclization of open chain intermediates 17 and 18. Four synthesized compounds were screened in vitro for antiproliferative/cytotoxic activity against six cancer cell lines by MTT assay. Compounds 14·HCl (HeLa and A-549) and ent-14·HCl (Caco-2 and Jurkat) showed comparable or higher potency than conventional anticancer agent cisplatin on at least two evaluated cancer cells, respectively.     

Stereoselective synthesis of (+/-)-rocaglaol analogues

An intramolecular hydroxy epoxide opening was used to access the cyclopenta[b]benzofuran ring system of the natural product rocaglaol (2). Our route allowed the stereocontrolled preparation of the rocaglaol derivative (+/-)-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the (+/-)-(3R*)-epimer of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring. [reaction: see text]     

The synthesis of azapeptidomimetic beta-lactam molecules as potential protease inhibitors

Synthetic methods for the construction of a novel peptidomimetic structure are reported. The structure incorporates a beta-lactam and an azapeptide in a peptide backbone with the intention of generating rationally designed substrate-based protease inhibitors. The beta-lactam is formed by subjecting serine or threonine-azapeptides to Mitsunobu reaction conditions. Importantly, the azapeptidomimetic beta-lactam structure permits extended binding inhibition and the synthetic methods to create tetrapeptidomimetic structures are described.     

Practical synthesis of novel purine analogues as Hsp90 inhibitors

The development of a straightforward synthesis of 4-amino-6-benzyl-6H-pyrrolo[3,4-d]pyrimidine and 7-amino-2-benzyl-2H-pyrazolo[4,3-d]pyrimidine derivatives allowed for the preparation of a small family of potential Hsp90 inhibitors. Some of the newly synthesized compounds showed Hsp90 inhibitory activity in preliminary biological assays.     

Stereoselective synthesis of photoreactive peptidomimetic gamma-secretase inhibitors

The first asymmetric synthesis of novel, potent photoreactive gamma-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO(2)-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells.     

Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids

The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common alpha-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from alpha,beta-unsaturated gamma-hydroxy-delta-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.     

Stereoselective synthesis of novel uracil polyoxin C conjugates as substrate analogues of chitin synthase

Stereoselective syntheses of both the natural (C5'- S) and unnatural (C5'- R) diastereoisomers of uracil polyoxin C methyl ester have been developed. The key stereocontrolled step involves nucleophilic addition of trimethylsilyl cyanide to the appropriate chiral sulfinimine derived from 2',3'-protected 5'-formyluridine and (S)-(-)-tert-butanesulfinamide or (R)-(+)-tert-butanesulfinamide, respectively. A variety of substrate mimics designed to function as inhibitors of chitin synthase have been synthesized by conjugation of the methyl ester of uracil polyoxin C (UPOC) with activated isoxazole carboxylic acids. Amide bond formation was accomplished via coupling of the amino functionality of UPOC methyl ester with a free isoxazole acid using HBTU or alternatively an isoxazole pentafluorophenyl ester. The substrate mimics incorporate features of the nucleoside-peptide antibiotics, the polyoxins and the nikkomycins, as well as features of the transition state structure expected during polymerization of the natural chitin synthase substrate uridine diphosphoryl-N-acetylglucosamine (UDP-GlcNAc), namely, a metal-binding site and glycosyl oxocarbenium ion mimic.     

Stereoselective total synthesis of protected sulfamisterin and its analogues

The stereoselective synthesis of sulfamisterin I and its unnatural analogues II and V in their protected form was achieved through a common strategy. The Wittig reaction of aldehydes VIII and IX with the C₁₄ hydrophobic side-chain X served as the key C-C connecting transformation. Subsequent functional group inter-conversions in the coupling products XI and XX completed the total synthesis.     

Stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres

A stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres 10 and 14 is described. The synthetic approach was designed to allow the introduction of functionality at the central core of the inhibitors, which should enable the identification of small molecule inhibitors of diverse aspartyl protease targets.     

Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartyl protease inhibitors. Nitroaldol methodology toward 2,3-substituted tetrahydrofurans

The Shibasaki heterobimetallic Binol lanthanide, and Trost dinuclear zinc catalysts were studied in a nitroaldol reaction of 3-methyl-1-nitrobutane with a chiral non-racemic tetrahydrofuran aldehyde. Other methods utilized KF, Amberlyst A-21, and t-BuOK as bases for the same nitroaldol reaction. The major isomer in the Binol lanthanide and dinuclear zinc catalyzed reactions was the syn/syn-nitroaldol product. Structures were confirmed by single-crystal X-ray crystallography. The major nitroaldol isomer was converted to a 2,3-substituted tetrahydrofuran 2-carboxylic acid containing a γ,δ-amino alcohol branch, corresponding to a constrained oxacyclic analogue of a hydroxyethylene isostere of aspartyl protease inhibitors.     

Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme

Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu-[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]-Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu-[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC(50) values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC(50) values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.