Synthesis of chiral 4-hydroxy-2,3-unsaturated carbonyl compounds from 3,4-epoxy alcohols by oxidation: application in the formal synthesis of macrosphelide A

An interesting transformation during the oxidation of 3,4-epoxy alcohols 1a-d, derived from the corresponding homoallylic alcohols, led to the formation of 4-hydroxy-2,3-unsaturated carbonyls 2a-d in very good yields. One of these products 2c was transformed into the functionalised carboxylic acid 5, an advanced stage intermediate from which the total synthesis of macrosphelide A has been reported.     

Enhancing the solubility for hypervalent ortho-sulfonyl iodine compounds

The synthesis and characterization of new hypervalent iodine reagents ArINTs (2a), ArIO (3a), and ArIO₂ (4a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are described. These reagents are compared to previously reported analogous set of reagents Ar=2-tert-butylsulfonylphenyl and found to have significantly enhanced solubility and similar chemical reactivity. The X-ray crystal structures of 4a and of ArI (1a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are discussed and compared. These reagents find use in atom and group transfer reactions.     

A new approach to 2,2-disubstituted chromenes and tetrahydroquinolines through intramolecular cyclization of chiral 3,4-epoxy alcohols

An efficient route to chiral chromene and tetrahydroquinoline ring models 3 and 4 was developed by means of the vanadium epoxidation of chiral homoallylic alcohols 12 and 19 followed by an intramolecular epoxide opening of 3,4-epoxy alcohols 14 and 20. The configuration of all compounds was confirmed using NMR analysis.     

An efficient method for the preparation of 3-hydroxyl-5-substituted 2-pyrrolidones and application in the divergent synthesis of (−)-preussin and its analogues

An asymmetric method to (S,R)-α-hydroxyl-γ-amino alcohols 12 through a diastereoselective addition of Grignard reagents to β-chiral aldimines 11 is described. Subsequent oxidation/cyclization with Sarett reagent provided a novel approach to lactams 14, a flexible building block whose utility was demonstrated in the divergent synthesis of antifungal agent (−)-preussin 5 and its three analogues 23, 24, 25.     

Facile conversion of pyridine propargylic alcohols to enones: stereochemistry of protonation of allenol

The conversion of 4-pyridyl propargylic alcohols 1 to the (E)-propenones 3 and propynones 2 occurs under mild reaction conditions, pyridinium chloride in methanol at room temperature. (Z)-4-Pyridyl propenones 11 are detected as initial products when large substituents such as trimethylsilyl, tert-butyl and phenyl are attached at C-3 of the propynols and these (Z)-enones 11 are isomerised to the (E)-isomers 3 under the reaction conditions. In the presence of deuterated solvent, both hydrogens at the double bond of enone 3d are deuterated. An allenol is proposed as intermediate whose preferential protonation occurs at the less hindered side giving the (Z)-enone. The propargylic alcohols, pyridin-2-yl 12 and quinolin-4-yl 5, are converted to (E)-enones 13 and 7, respectively.     

Gas-phase pyrolytic reaction of 3-anilino-1-propanol derivatives: kinetic and mechanistic study

3-Anilino-1-propanol derivatives 4a-c, 5a-c, 6a-c containing primary, secondary, and tertiary alcohols and PhNH, PhNMe, and (Ph)₂N were prepared and subjected to gas-phase pyrolysis in a static reaction system. The pyrolytic reactions were homogeneous and followed a first-order rate equation. Reactions took place by retro-ene process, with the exception of compounds 5a and 5b. Analysis of the pyrolysate showed the products to be N-substituted aniline and carbonyl compounds. The kinetic results and product analysis of each of the nine investigated 3-amino alcohols are rationalized in terms of a plausible transition state for the elimination pathway.     

Diastereoselective schenck ene reaction of singlet oxygen with chiral allylic alcohols; access to enantiomerically enriched 1,2,4-trioxanes

A series of antimalarial chiral 1,2,4-trioxanes (1-8) were synthesised in high enantiomeric purities. Enantioselective addition of R₂Zn reagent to 3-methyl-2-butenal catalysed by (+)-MIB or (−)-MIB yielded both the enantiomers of the chiral allylic alcohols 9-11 (90-98% ee), which were subjected to diastereoselective photooxygenation in the presence of tetraphenylporphine (TPP) to obtain (R,R)-threo- or (S,S)-threo-β-hydroperoxy alcohols (12-14). Reaction of β-hydroperoxy alcohols (12-14) with different cyclic ketones produced optically active trioxanes 1-8.     

Stereoselective construction of the 1,1,1-trifluoroisopropyl moiety by asymmetric hydrogenation of 2-(trifluoromethyl)allylic alcohols and its application to the synthesis of a trifluoromethylated amino diol

The asymmetric hydrogenation of a series of 2-(trifluoromethyl)allylic alcohols 1a-g catalyzed by a BINAP-Ru(II) diacetate complex gave the corresponding products 2a-g in high yield (>90% yield) and high diastereoselectivity (>95% de). The asymmetric hydrogenation of 2-(trifluoromethyl)allylic alcohols provided an efficient stereoselective method to construct the 1,1,1-trifluoroisopropyl moiety. Based on the asymmetric hydrogenation of the 2-(trifluoromethyl)allylic alcohol 5a prepared by the reaction of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde with 3,3,3-trifluoroisopropenyllithium, (2R,3S,4R)-4-trifluoromethyl-1-aminopentane-2,3-diol 9 was synthesized in 36% overall yield over five steps.     

Epoxide as an aldehyde equivalent in allyl-transfer reaction with γ-adduct of homoallylic alcohol (allyl donor) giving α-adduct of homoallylic alcohol

Acid-catalyzed reactions of epoxides 2 with homoallylic alcohol γ-adducts, 1 [Me₂C(OH)CHRCHCH₂], afford homoallylic alcohol α-adducts 3-5 via allyl-transfer reaction, sometimes being more effective than those using the corresponding aldehydes.     

A facile stereoselective synthesis of 1,3-dienyl sulfones via Stille coupling reactions of (E)-α-stannylvinyl sulfones with alkenyl iodides

Palladium-catalyzed hydrostannylation of acetylenic sulfones 1 in benzene at room temperature gives stereoselectively (E)-α-stannylvinyl sulfones 2 in good yields. (E)-α-Stannylvinyl sulfones 2 are new difunctional group reagents which undergo Stille coupling reactions with alkenyl iodides 3 to afford stereoselectively 1,3-dienyl sulfones 4 in high yields.     

Microwave-assisted epoxidation of hindered homoallylic alcohols using VO(acac)2: application to polypropionate synthesis

The VO(acac)₂ catalyzed epoxidation of hindered homoallylic alcohols was conducted under microwave irradiation in an open vessel using toluene as solvent. The reaction time for the epoxidation of a series of cis- and trans-2-methyl-3-alkenols was dramatically reduced from 6 to 10 days to less than 3 h when compared to conventional heating. The cis alkenols exhibited very high diastereoselectivity. The more elaborated polypropionate precursors 12, 14 and 16 were epoxidized in good yield and excellent diastereoselectivities using the microwave-assisted epoxidation technique described here, which is safe and suitable for multi-gram scales.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

Catalytic enantioselective borane reduction of arylketones with pinene-derived amino alcohols

Both cis- and trans-1,2-amino alcohols 5 and their N-alkylated derivatives 6 were prepared from (−)-α-pinene 7 as chirality source and utilized in asymmetric borane reduction of arylketones 12 employing a one-pot multi-substrate screening. The oxazaborolidine catalysts were generated in situ from amino alcohols 5 and 6 and trimethyl borate.     

Oxazine formation by MsCl/Et3N as a convenient tool for the stereochemical interconversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines

Use of MsCl/Et₃N was proven to provide a convenient synthetic tool for the stereochemical intercoversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Thus, under these conditions, the alcohols 4 and 6 smoothly converted to the oxazines 5 and 7, respectively, which were hydrolyzed to generate the corresponding inverted alcohols 6 and 4 in one pot. Further elaboration of 4 and 6 led to the efficient asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines (11 and 15), respectively, via olefin cross metathesis reactions.     

Singlet oxygen addition to homoallylic substrates in solution and microemulsion: novel secondary reactions

The photooxygenation of three homoallylic substrates, the γ,δ-unsaturated ketone 1a, nitrile 2a, and the γ,δ-unsaturated ester 3a was investigated in homogeneous solution and in microemulsion (for 1a). Two secondary reaction pathways were detected for the allylic hydroperoxides of type b and c, respectively. The cyclization reactions of 1b and 2b to the 1,2-dioxanes 1d and 2d followed well-known reaction patterns, whereas the base-catalyzed epoxide (1e-3e) formation from the tertiary allylic hydroperoxides 1c-3c is a unprecedented reaction type.     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Synthesis and reactivity of Z and E functionalized allylic fluorides

The allylic fluorides 1 and 2 are used as models to study the effect of the allylic C-F bond on the diastereoselectivity of reactions occurring on the vicinal double bond, as well as the compatibility of this C-F bond with various reagents. The configurational stability of the Z double bonds in enals and enones 1 and 3 is noteworthy. This allowed us to perform various types of reactions (including thermal Diels-Alder cycloadditions) on derivatives 1 with full control of the Z geometry.     

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane with enol ethers of cyclic ketones

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane (1) with methyl and trimethylsilyl ethers of cyclopentanone and cyclohexanone enols (2a-d) in a MeCN/H₂O system were investigated. 2-(2,2,2-Trifluoroethylidene)cyclopentanone (4a) and 2-(2,2,2-trifluoroethylidene)-cyclohexanone (4b), respectively, were obtained as the main products and isolated in reasonable yields. The reaction with a 1:1 mixture of 5- and 3-methyl substituted 1-methoxycyclohexenes, 2e and 2f, revealed strong influence of steric hindrance on the reaction rate; a mixture of 2-(2,2,2-trifluoroethylidene)-5-methylcyclohexanone (6) and 2-(2,2,2-trifluoroethylidene)-3-methylcyclohexanone (7) in a 9:1 ratio was formed. Ketones 4a and 4b were reduced to the corresponding alcohols 8 and 9 and the reaction of 4b with hydrazine gave an indazole derivative 10.     

Two-step allylic carbon insertion between ketone carbonyl and α carbons giving α-quaternary α-vinyl ketones

Ketones 1 were converted to α-quaternary α-vinyl ketones 2 by a two-step formal allylic carbon insertion between ketone carbonyl and α carbons, which involves the reaction of 1 with propargyltitanium reagents, derived from propargyl carbonates 3 and a divalent titanium reagent Ti(O-i-Pr)₄/2i-PrMgCl, and the following rearrangement of the resulting α-allenyl alcohols 4 with NBS.     

First cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides

The halogenated 1H-1,2,4-triazole glycosides 6-10 were synthesized by BF₃-activated glycosylation of 3(5)-chloro-1,2,4-triazole (2), 3,5-dichloro-1,2,4-triazole (3), 3,5-dibromo-1,2,4-triazole (4), and 3(5)-bromo-5(3)-chloro-1,2,4-triazole (5) with 1,2,3,4-tetra-O-pivaloyl-β-d-xylopyranose (1). The β-anomeric major products 3-chloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (6β), 3,5-dichloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (7β), and 3,5-dibromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (8β) were used as starting materials for transition metal catalyzed C-C-coupling reactions. Arylations of the triazole ring of 7β, and 8β were successful in 5-position with phenylboronic acid, 4-vinylphenylboronic acid, and 4-methoxyphenylboronic acid, respectively, under Suzuki cross-coupling conditions (products 11-17). Moreover, a Cu-catalyzed perfluoroalkylation of 8β is reported with 1-iodo-perfluorohexane yielding 3-perfluorohexyl-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (18). Compound 18 was depivaloylated to the trihydroxy derivative 19. The copper-mediated reaction of 8β with Rupert's reagent gave the bis(3-bromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazol-5-yl) (20).