diastereoselective intramolecular Alder-Ene reaction on chiral perhydro-1,3-benzoxazines. a rapid entry to enantiopure cis-3,4-disubstituted pyrrolidines

Chiral 3-acryloyl-2-vinyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol participate in an ene reaction leading to 3,4-disubstituted pyrrolidinone derivates with excellent diastereoselectivity. The cycloadducts were transformed into enantiopure 3,4-disubstituted pyrrolidines after elimination of the chiral adjuvant.     

Regio- and stereoselective 6-exo-trig radical cyclisations onto chiral perhydro-1,3-benzoxazines: synthesis of enantiopure 3-alkylpiperidines

Enantiopure 3-alkyl substituted piperidines are prepared by diastereoselective 6-exo-trig cyclisation of perhydro-1,3-benzoxazines derived from (−)-(8)-amino menthol. The diastereoselective cyclisation is promoted by tributyltin hydride, and the competitive 1,5-hydrogen migration depends on the position of the acceptor double bond and the radical site.     

Enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN3 catalyzed by chiral Lewis acids

A catalytic enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN₃ using chiral Lewis acids afforded products with high enantioselectivity. As proof of the utility of this procedure, the precursor of selective κ-opioid agonist (1S,2S)-(−)-U-50,488 was synthesized.     

Enantioselective synthesis of (L)-Fmoc-α-Me-Lys(Boc)-OH via diastereoselective alkylation of oxazinone as a chiral auxiliary

Benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (4) was successively alkylated with methyl iodide and 1,4-diiodobutane using a base. In each alkylation step anti-alkylated product formed exclusively. The iodo group was displaced with azide, which served as a precursor for the side-chain amino function. Catalytic hydrogenation with concomitant cleavage of the chiral auxiliary afforded (L)-α-Me-Lys-OH (9) in a total of four steps in good yield. (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained from 9 via regioselective benzyloxycarbonylation. Alternately, (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained via Staudinger reduction of azide (8) in a total of six steps in good yield.     

A novel synthesis of enantiopure octahydropyrrolo[3,4-b]pyrroles by intramolecular [3 + 2] dipolar cycloaddition on chiral perhydro-1,3-benzoxazines

[reaction: see text] Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespecific leading to a single diastereoisomer. The chemical yields are dependent on the reaction temperature and the presence or absence of a base.     

A new class of nitrogen based chiral ligands: 2H-1,3-benzoxazines. Ligand synthesis, X-ray structural studies and asymmetric catalysis

A new class of chiral ligands, e.g., (−)-9, based on the benzoxazine nucleus, has been designed and synthesized in three steps from the commercially available starting materials salicylamide and (−)-menthone. Application of (−)-9 in the palladium catalyzed-allylic substitution of 1,3-diphenyl-2-propenylacetate with dimethyl malonate gave enantioselectivities of up to 62%ee. Ees of 42% and 20% in asymmetric hydrosilylations and diethylzinc additions, respectively, were also obtained.     

Highly diastereoselective cycloaddition reactions of variously substituted 1-thia- and 1-thia-3-aza-buta-1,3-dienes. Synthesis of enantiomerically pure 5,6-dihydro-4H-[1,3]thiazines and 3,4-dihydro-2H-thiopyrans

The cycloaddition of 2- or 2,3-substituted 1-thia- and 1-thia-3-aza-4-dimethylamino-buta-1,3-dienes with various dienophiles in the presence of a Lewis acid provides a rapid and diastereoselective access to the 3,4-dihydro-2H-thiopyran and 5,6-dihydro-4H-[1,3]thiazine backbones. The generally observed trans relationship between the two newly created strereogenic centres was demonstrated to be the expression of a thermodynamic control of the reaction. The use of chiral dienophile derived from chiral oxazolidin-2-ones allowed us to prepare enantiopure 5,6-dihydro-4H-[1,3]thiazines and 3,4-dihydro-2H-thiopyrans. In the asymmetric synthetic process the chiral auxiliary removal step was best accomplished in the presence of samarium triflate in methanol.     

Synthesis of enantiopure 3-azabicyclo[3.2.0]heptanes by diastereoselective intramolecular [2+2] photocycloaddition reactions on chiral perhydro-1,3-benzoxazines

[2+2] photocycloadditions involving chiral 3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from (-)-8-aminomenthol are highly diastereoselective reactions. The facial selectivity depends on the type of substitution at the vinyl double bond, and always leads to cis-fused bicyclic derivatives. The de is good for compounds with one substituent at the outer carbon of the double bond at C-2, but only one diastereomer is formed in cyclizations of compounds with two substituents at that position. The elimination of the menthol appendage gives enantiopure 3-azabicyclo[3.2.0]heptanes.     

Cationic cyclization of keto-epoxides mediated by zirconium(IV) tetrachloride: diastereoselective synthesis of cis-decalinols

10-Methyl-cis-9-decalinols are important motifs in several natural products and key intermediates in total synthesis. Herein, we wish to describe a highly chemo- and diastereoselective cyclization of keto-epoxides leading to 10-methyl-cis-9-decalinols. This method based on the use of zirconium(IV) tetrachloride permits the access to a wide variety of cis-decalinols in good to excellent yields. The cationic cyclization could also be performed with chiral keto-epoxide with complete control of the diastereoselectivity affording cis-bicyclic tertiary alcohol with good enantiomeric excess. The chemo- and the diastereoselectivity are assumed to result from the ability of Zr(IV) to generate highly stable bidentic complexes with α-hydroxy-ketone intermediates.     

Scalable synthesis of (−)-trans-3-hydroxypipecolic acid via a useful chiral building block

A scalable synthesis of (−)-trans-2-(hydroxymethyl)-1,2,3,6-tetrahydropyridin-3-ol, a versatile chiral building block is described along with its transformation to (−)-trans-3-hydroxypipecolic acid.     

Enantiodivergent synthesis of trans-3,4-disubstituted succinimides by SmI2-mediated Reformatsky-type reaction

An enantiodivergent strategy for the synthesis of trans-3,4-disubstituted succinimides is reported. The key step is a highly trans-stereoselective SmI₂-induced Reformatsky-type reaction of 4-substituted-O-benzoylated malimides with carbonyl compounds. Double chirality transmissions were performed with good to excellent diastereoselectivities.     

Concise synthesis of trans- and cis-3,4-disubstituted piperidines based on regio- and stereoselective allylation of cyclopentenyl esters

3,4-Disubstituted piperidines were synthesized through anti S_N2′ allylation of 4-substituted 2-cyclopentenyl esters with reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxetine intermediate was synthesized efficiently. During the investigation, the MeOCH₂CO₂ group was found to show high reactivity in the pivotal anti S_N2′ type reaction using the reagent derived from (i-PrO)Me₂SiCH₂MgCl and CuCN.     

Lewis acid-catalyzed cascade radical addition/cyclization for the synthesis of 3-substituted isoindolin-1-one derivatives

Radical addition reactions to 2-formylbenzoate-derived hydrazones in the presence of a Lewis acid were developed. Under the reaction conditions, the resulting products were readily converted into 3-substituted isoindolin-1-one derivatives. Diastereoselective synthesis of 3-substituted isoindolin-1-one derivatives was also established employing L-proline as a chiral auxiliary. The cascade radical addition–cyclization reaction allows direct access to 3-substituted isoindolin-1-one derivatives under tin-free conditions.     

10b-Substituted hexahydropyrrolo-isoquinolines: studies on diastereoselective formation of a quaternary carbon stereocenter via N-acyliminium ion cyclization

The stereoselective synthesis of hexahydro-pyrroloisoquinolines with a quaternary carbon stereocenter is described. The presented methodology employs the addition of a Grignard reagent to the carbonyl group of imide 1, derived from l-tartaric acid, followed by acetylation and BF₃·Et₂O induced cyclization. The acetylation-cyclization sequence can be run either as a one-pot process, or stepwise in a selected solvents. The crucial step, an acid-catalyzed carbon-carbon bond-forming reaction via an N-acyliminium ion offers high stereoselectivity, which has been shown to be strongly dependent on the size of the R¹ substituents and the reaction conditions, that is, choice of solvent, amount of a Lewis acid, temperature, and concentration of the substrate. Based on the results observed, participation of solvent in the cyclization, via an N-acyliminium cation is proposed.     

SnCl4-Catalyzed Aza-Acetalization of Aromatic Aldehydes: Synthesis of Aryl Substituted 3,4-Dihydro-2H-1,3-benzoxazines

Stannic tetrachloride was an efficient Lewis acid catalyst for the aza-acetalization of aromatic aldehydes with o-arylaminomethyl phenols, and a series of novel aryl substituted 3,4-dihydro-2H-1,3-benzoxazines were prepared in good yields under mild conditions. SnCl₄ was a more efficient catalyst for the reaction than p-toluenesulfonic acid, sulfuric acid, and aluminium chloride.     

Synthesis of cis-2-aryl-3-pyrrolidine carboxylic esters via diastereoselective cyclization of γ-imino esters using a TiCl4/Et3N reagent system

Facile synthesis of cis-2-aryl-3-pyrrolidine carboxylates from readily accessible γ-imino esters by intramolecular cyclization mediated by a TiCl₄/Et₃N reagent system is described.     

l-Proline-catalyzed diastereoselective synthesis of cis-isoquinolonic acids and evaluation of their neuroprotective effects

l-Proline efficiently catalyzes the one-pot, three-component reaction of homophthalic anhydride, amines, and aldehydes in CH₃CN at room temperature, to afford the corresponding cis-isoquinolonic acids in high yields and with excellent diastereoselectivities. The synthesized compounds are screened for neuroprotective activities.     

Scale-up synthesis of a deuterium-labeled cis-cyclobutane-1,3-Dicarboxylic acid derivative using continuous photo flow chemistry

Continuous photo flow synthesis of tert-butyl 3-oxo-2-oxabicyclo[2.2.0]hex-5-ene-6-carboxylate (2b) from tert-butyl 2-oxo-2H-pyran-5-carboxylate (1b) has been investigated for scale-up synthesis of cis-3-(tert-butoxycarbonyl)-2,3,4-d₃-cyclobutanecarboxylic acid (3c) as a useful building block for preparation of various biologically active compounds and those of material sciences containing cyclobutane ring system(s) labeled with deuterium atoms. Optimization of reaction conditions and modification of the photo flow reaction system have brought about the production of cis-3-(tert-butoxycarbonyl)-2,3,4-d₃-cyclobutanecarboxylic acid (3c) with excellent deuterium content in 3.6?g through the continuous photo flow synthesis for 22?h followed by hydrogenation with deuterium gas. Also, application of the product to synthesis of cis-3-((benzyloxycarbonyl)methyl-d₂)cyclobutane-1,2,4-d₃-carboxylic acid (11) is described for preparation of internal standards of drug candidate compounds in quantitative mass spectrometry analyses in nonclinical and clinical pharmacokinetic studies.