Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Stereoselective synthesis of (R)-10-methyltridecan-2-one,the sex pheromone of the southern corn rootworm,using (4S)-benzylthiazolidinethione as a chiral auxiliary

The stereoselective synthesis of (R)-10-methyltridecan-2-one, the sex pheromone of the southern corn rootworm, was carried out in 20.7% overall yield based on (4S)-benzylthiazolidinethione (five steps). In the crucial step, the stereogenic center was generated by an asymmetric Michael addition using enantiomerically pure (4S)-benzylthiazolidinethione as a chiral auxiliary.     

Addition of tert-butylcuprate to (2S)-N-acyl-Δ-dehydroprolinates as a diastereoselective synthetic procedure for obtaining (2S,5S)-5-tert-butylproline

The synthesis of (2S,5S)-Boc-5-tert-butylproline ethyl ester via the addition of tert-butylcuprate to (2S)-N-Boc-Δ⁵-dehydroproline ethyl ester, formed from (2S)-N-Boc-5-methoxyproline ethyl ester, gives an excellent yield of 94% and a high diastereoselectivity (2S,5S):(2S,5R) 78:22. This synthesis opens up a new synthetic route to (2S,5S)-5-tert-butylproline, which is a useful, conformationally rigid, analogue of l-proline.     

Stereoselective total synthesis of almorexant

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral α-phenyl amide was introduced by means of S_N2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with chiral tetrahydroisoquinoline.     

New efficient synthesis of (3R,4S)-3-methyl-3-hydroxy-4-phenyl-β-lactam

A method is described for the chiral synthesis of (3R,4S)-3-methyl-3-hydroxy-4-phenyl-β-lactam, a useful precursor for the semi-synthesis of 2′-methyl-taxoids. This protocol follows Seebach's synthetic principle of `self-regeneration of stereocenters' (SRS) and has been applied to addition reactions of the (2S)-chiral enolates of dioxolan-4-ones, derived from the acetalization of (S)-α-lactic acid and tert-butylaldehyde or pinacolone, to N-trimethylsilylphenyl aldimine.     

Asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic acid using a 1,2-addition of PhMgBr to an N-sulfinimine derived from (R)-glyceraldehyde acetonide and (S)-t-BSA

We report an asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic acid via stereoselective addition of phenylmagnesium bromide (PhMgBr) to an N-sulfinimine derived from (R)-glyceraldehyde acetonide. (S)- and (R)-Glyceraldehyde acetonides, important chiral synthons in synthetic organic chemistry, are prepared from the corresponding epichlorohydrin using an identical synthetic methodology.     

Asymmetric synthesis of 1,4-disubstituted 3-methylidenedihydroquinolin-2(1H)-ones

A series of enantiomerically pure or highly enriched (R)- or (S)-3-methylidenetetrahydroquinolin-2-ones was readily prepared by highly diastereoselective Michael additions of various Grignard reagents to quinolin-2(1H)-ones, containing an (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl group as chiral auxiliary, followed by Horner-Wadsworth-Emmons olefination of formaldehyde. An efficient synthesis of the starting (R,R)- and (S,S)-3-({di[(1-phenylethyl)amino]}phosphoryl)-1-alkyl-quinolin-2(1H)-ones is also described. The relative and absolute configurations of the intermediate adducts and final methylidenequinolinones were established by NMR and X-ray analysis.     

Synthesis,Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

Herein is reported the synthesis of two Au(III) complexes bearing the (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (R,R-QuinoxP*) or (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (S,S-QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl₄.3H₂O to one equivalent of the corresponding QuinoxP* ligand, (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (1) and (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) were formed, respectively, in moderate yields. The structure of (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC₅₀ values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers (1 and 2) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes.     

Diastereoselective Pomeranz–Fritsch–Bobbitt synthesis of (S)-(−)-salsolidine using (R)-N-tert-butanesulfinylimine as a substrate

The highly diastereoselective addition of methyl Grignard reagent to chiral (R)-N-tert-butanesulfinylimine 8 was the key step in the synthesis of (S)-(−)-salsolidine 1 of high enantiomeric purity. The resulting addition product, tert-butanesulfinylamide 9, was then subjected to cyclization via amine 10 and Pomeranz–Fritsch aminoacetal 11.     

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids, has been developed starting from readily accessible optically active secondary propargyl phosphate (R)-2, where the asymmetric Michael addition of a chiral allenyltitanium to alkylidenemalonate 3 is a key reaction.     

Synthesis of chiral unsaturated aminolactones using Pd-catalyzed allylic amination

Stereoselective synthesis of (5R,6R)- and (5S,6S)-5-benzylamino-6-(tert-butyldimethylsilanyloxymethyl)-5,6-dihydropyran-2-ones starting from d-glucal and furanaldehyde, respectively, is described. The synthesis relies on a Sharpless asymmetric dihydroxylation, an Achmatowicz reaction, and a stereoselective Pd-catalyzed allylic amination as the key steps.     

The first synthesis of N,O-protected β-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams

The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (S_R)-tert-butyl sulfinyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained β^2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers in the form of N-sulfinyl protected 1′-amino-dioxolan-4-ones. The selective acid-induced removal of the sulfinyl protecting group provided the corresponding 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding chiral tetra-substituted 3-hydroxy-β-lactams. The synthesis of a dipeptide by reaction coupling between the 1′-aminodioxolanone (2S,5R,1′R)-19 and N,N-dimethylglycine was successfully achieved.     

Synthesis of functionalized chiral ammonium,imidazolium, and pyridinium-based ionic liquids derived from (−)-ephedrine using solvent-free microwave activation. Applications for the asymmetric Michael addition

An efficient procedure for the synthesis of functionalized chiral ammonium, imidazolium, and pyridinium-based ionic liquids derived from (1R, 2S)-ephedrine using solvent-free microwave activation has been described. Good yields were obtained in very short reaction time. These chiral ionic liquids were used as chiral reaction media for the asymmetric Michael addition, giving good yields and moderate enantioselectivities.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. The corresponding Michael adducts bearing a new stereocenter were generally obtained in high or quantitative yields and with good enantioselectivities (up to 93% ee).     

Efforts towards the synthesis of microsporin B: ready access to both the enantiomers of the key amino acid fragment

Both the isomers methyl-(2S,8R)-2-((tert-butoxycarbonyl)amino)-8-hydroxydecanoate and methyl-(2S,8S)-2-((tert-butoxycarbonyl)amino)-8-hydroxydecanoate of an unusual amino acid residue and the key fragment of microsporin B are prepared. The key steps include cross metathesis and enzymatic kinetic resolution. In addition, a linear tetrapeptide with desired components towards total synthesis is also reported.     

Total synthesis of (+) methyl β-d-vicenisaminide

The total synthesis of methyl β-d-vicenisaminide 1 has been achieved. In this approach, the synthesis of enantiomerically pure methyl (4R,5S)- and (4S,5R)-4-azido-5-hydroxy-2(E)-hexenoates 2 was established by enzymatic resolution of (±)-anti-5-acetoxy -4-azido-2(E)-hexenoate 4. Another stereogenic center was introduced by base-catalyzed intramolecular conjugate addition of a hemiacetal-derived alkoxide nucleophile obtained by the reaction of methyl (4S,5R)-N-4-tert-butoxycarbonyl-N-methylamino-5-hydroxyl-2(E)-hexenoate 8 and benzaldehyde in the presence of a base.     

An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.     

Total synthesis of (+)-negamycin and its 5-epi-derivative

(+)-Negamycin was prepared in 13 steps in an overall yield of 31% from commercially available ethyl (R)-(+)-4-chloro-3-hydroxybutanoate. The key step in the reaction sequence was a highly stereoselective asymmetric Michael addition of chiral amine (−)-21 [(1S,2R)-(−)-2-methoxybornyl-10-benzylamine] into the α,β-unsaturated carbonyl moiety of key intermediate 8, thus establishing the second chiral center in (+)-negamycin. 5-epi-Negamycin was also prepared in a similar fashion.     

A new enantiodivergent synthesis of the Geissman-Waiss lactone

Intramolecular Michael reaction of methyl (R)-6-(tert-butoxycarbonylamino)oxy-4-hydroxy-2-hexenoate, in turn obtained from tert-butyl (R)-3-hydroxy-4-pentenoate, paved the way to the synthesis of both enantiomers of 2-oxa-6-azabicyclo[3.3.0]octan-3-one (the Geissman-Waiss lactone), a precursor for necine bases. Key intermediates in this approach were represented by enantiomeric bicyclic lactones incorporating a [1,2]-oxazinane nucleus, which has been conveniently used to install the pyrrolidine framework of the target compounds through a synthetic scheme featuring the reduction of the nitrogen-oxygen bond and an intramolecular S_N2 reaction.     

An improved process for chiron synthesis of the atorvastatin side chain

An improved and practical synthesis of tert-butyl ((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate 3 has been developed for supplying this key chiral side-chain of atorvastatin by using a Blaise reaction of (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile 7 and the Raney Ni catalyzed hydrogenation of tert-butyl 2-((4R,6R)-6-(-2-oximeethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 12 as the key steps. This nine-step route from (R)-epichlorohydrin afforded the target compound in 55% overall yield of high chemical and enantiomeric purity.