Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Aram) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Aram enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Aram and aliphatic aldehydes are provided.

Divergolide A and its four congeners, divergolide E–H, possess an amido-substituted hydroquinone core, which is biosynthetically transformed from an aromatic starter unit, 3-amino-5-hydroxybenzoic acid (AHBA). The macrocyclic ring of divergolide A and F is assembled by linking the amido hydroquinone unit with the polyketide backbone through (Z)-γ-methylglutaconic acid as the tether while (E)-γ-methylglutaconic acid is found in divergolide E, G, and H. A model study has been conducted for installation of (Z)-γ-methylglutaconic acid onto the 3-aminophenol core of divergolide A via two methods: (a) the CuI–MeNHCH2CH2NHMe-catalyzed amidation of methyl (Z)-4-carbamoyl-2-methylbut-2-enoate with an aryl bromide; and (b) regioselective aminolysis of (Z)-γ-methylglutaconic anhydride with an aniline derivative. Isomerization of the (Z)-configuration under the CuI catalysis conditions was observed to give mainly the (E)-product while (Z)-product was obtained exclusively under the aminolysis conditions. These results might be useful for total synthesis of divergolide A and E–H.

A number of enediyne prodrugs 1–5 possessing an (E)-3-hydroxy-4-(2′-hydroxy-1′-phenylethylidene)cyclodeca-1,5-diyne scaffold have been synthesized via the Sonogashira coupling and an intramolecular Nozaki–Hiyama–Kishi reaction as the key steps. Upon incubation with enediyne prodrugs 4 and 5 possessing a free hydroxymethyl group on the exocyclic double bond, circular supercoiled DNA (Form I) underwent single strand cleavage into circular relaxed DNA (Form II) in buffer solution at pH 8.5, while the silylated analogs 1–3 showed very weak DNA cleavage activity. Alternatively, the silylated analogs 1–3 could be activated by UV irradiation via a photochemical alkene isomerization followed by an allylic rearrangement to form the putative epoxy enediyne, resulting in efficient DNA cleavage similar to the level observed with the prodrugs 4 and 5.

P-Stereogenic secondary phosphine oxides are configurationally stable in the presence of metal ions both in solution and in the solid state. They have the potential to serve as chiral monodentate phosphorus ligands for asymmetric catalysis. In the asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate, ca. 80% ee was achieved using (Rp)-tert-butylphenylphosphine oxide.Graphic

A novel C2-symmetric chiral arsine was synthesized from (S)-(−)-1,1′-bi-2-naphthol in three steps. It was employed in the enantioselective olefination of 4-substituted cyclohexanones via a stabilized ylide formed in situ from the corresponding arsonium salt. Enantioselectivity up to 40% was obtained. Moreover, a reversal in the stereochemistry of the product was observed simply by changing the counter cation of the base from lithium to potassium.Graphic4,5-Dihydro-4-phenyl-3H-dinaphtho[2,1-c:1′,2′-e]arsepinC28H21AsMp=150–155°C (CH2Cl2–hexane)[α]D20=−213.2 (c 1.43, CHCl3)Source of chirality: (S)-(−)-1,1′-bi-2-naphtholAbsolute configuration: S4-Carbomethoxymethyl-4,5-dihydro-4-phenyl-3H-dinaphtho[2,1-c:1′,2′-e]arsepinium bromideC31H26AsBrO2Mp=189–190°C (MeOH)[α]D20=−79.5 (c 0.40, MeOH)Source of chirality: (S)-(−)-1,1′-bi-2-naphtholAbsolute configuration: SMethyl (4-phenylcyclohexylidene)acetateC15H18O2Ee=25.4%[α]D20=−32.5 (c 0.71, CHCl3)Source of chirality: asymmetric synthesis (Wittig)Absolute configuration: RMethyl (4-methylcyclohexylidene)acetateC10H16O2Ee=33.5%[α]D20=−21.1 (c 0.64, CHCl3)Source of chirality: asymmetric synthesis (Wittig)Absolute configuration: RMethyl (4-tert-butylcyclohexylidene)acetateC13H22O2Ee=40.0%[α]D20=−26.5 (c 0.51, CHCl3)Source of chirality: asymmetric synthesis (Wittig)Absolute configuration: RMethyl [4-(1′,1′-dimethylpropyl)cyclohexylidene]acetateC14H24O2Ee=39.2%[α]D20=−24.7 (c 1.21, CHCl3)Source of chirality: asymmetric synthesis (Wittig)Absolute configuration: R

The axially chiral 2-substituted N,N-diisopropyl-1-naphthamides 1 and 2 were resolved by HPLC over a chiral stationary phase to provide enantiomerically pure atropisomers. The absolute stereochemistry of (−)-syn-1 was determined by X-ray crystallographic analysis of the corresponding (1S)-camphanic acid ester derivative. Desymmetrization of cyclic meso anhydrides 5a and 5b using (−)-syn-1 gave a single diastereomer in good yield.The axially chiral 1-naphthamide (−)-1 was obtained by HPLC resolution over a chiral stationary phase. The absolute stereochemistry of (−)-1 was determined by X-ray structural analysis of the (1S)-camphanic acid ester derivative. The desymmetrization of cis-1,2-cyclohexanedicarboxylic anhydride 2 using (−)-1 gave a single product, (−)-3.(−)-(aS,1′S,1″R,2″S)-N,N-Diisopropyl-2-[1′-(2″-methoxycarbonylcyclohexane-1″-carbonyloxy)ethyl]-1-naphthamideC28H37NO5[α]D20=−0.9 (c 0.54, CHCl3)Source of chirality: asymmetric reaction(−)-(aR,1′S,1″R,2″S)-N,N-Diisopropyl-2-[1′-(2″-methoxycarbonylcyclohex-4″-ene-1″-carbonyloxy)ethyl]-1-naphthamideC28H35NO5[α]D20=−51.0 (c 1.00, CHCl3)Source of chirality: asymmetric reaction(+)-(aS,1′R)-N,N-Diisopropyl-2-(1′-hydroxypropyl)-1-naphthamideC20H27NO2[α]D20=+100.9 (c 0.98, CHCl3)Source of chirality: HPLC resolution(+)-(aS,1′R)-N,N-Diisopropyl-2-(1′-hydroxyethyl)-1-naphthamideC19H25NO2[α]D20=+116.4 (c 1.09, CHCl3)Source of chirality: HPLC resolution(+)-(aS,1′S,1″S,4″R)-N,N-Diisopropyl-2-[1′-(4″,7″,7″-trimethyl-3″-oxo-2″-oxabicyclo[2.2.1]heptanecarbonyloxy)ethyl]-1-naphthamideC29H37NO5[α]D20=+49.4 (c 0.85, CHCl3)Source of chirality: (1S)-(−)-camphanic chloride(−)-(aR,1′S,1″R,2″S)-N,N-Diisopropyl-2-[1′-(2″-methoxycarbonylcyclohexane-1″-carbonyloxy)ethyl]-1-naphthamideC28H37NO5[α]D20=−47.4 (c 0.98, CHCl3)Source of chirality: asymmetric reaction(−)-(aR,1′S,1″S,4″R)-N,N-Diisopropyl-2-[1′-(4″,7″,7″-trimethyl-3″-oxo-2″-oxabicyclo[2.2.1]heptanecarbonyloxy)ethyl]-1-naphthamideC29H37NO5[α]D20=−9.9 (c 1.05, CHCl3)Source of chirality: (1S)-(−)-camphanic chloride(−)-(aS,1′S,1″S,2″R)-N,N-Diisopropyl-2-[1′-(2″-methoxycarbonylcyclohex-4″-ene-1″-carbonyloxy)ethyl]-1-naphthamideC28H35NO5[α]D20=−12.4 (c 0.48, CHCl3)Source of chirality: asymmetric reaction(−)-(aS,1′S,1″R,2″S)-N,N-Diisopropyl-2-[1′-(2″-methoxycarbonylcyclohex-4″-ene-1″-carbonyloxy)ethyl]-1-naphthamideC28H35NO5[α]D20=−5.1 (c 1.10, CHCl3)Source of chirality: asymmetric reaction

A number of chiral β-amino alcohols possessing a 3-indolylmethyl group have been synthesized from the alkaloid, (S)-abrine and elucidated for potency in the catalytic enantioselective ethylation of PhCHO with Et2Zn. In general, the secondary amines 15a–d bearing a dialkylhydroxymethyl group induced (R)-1-phenyl-1-propanol, whereas 15e–g and 18 bearing a diarylhydroxymethyl group favored the (S)-enantiomer. In contrast, the β-tertiary amino alcohols 20b–d and 21 produced (R)-1-phenyl-1-propanol, regardless of the substituents at the carbon bearing the hydroxy group. Enantiomeric excess of 87.5% was obtained for (R)-1-phenyl-1-propanol using ligand 21 as the promoter. Eleven substituted benzaldehydes and naphthaldehydes were examined for enantioselective ethylation by using 21 and the chiral alcohols were obtained in 93–97% ee, except for o-BrC6H4CHO and p-Me2NC6H4CHO. Excellent enantioselectivity was also observed in the ethylation of cyclohexanecarboxaldehyde (94.8% ee) and 2-thiophenecarboxaldehyde (94.9% ee) by using catalytic 21. The anti 5/4/4-fused tricyclic TS I was proposed to rationalize the asymmetric induction. The diethylhydroxymethyl and N-2-t-butylethyl groups are believed to enforce the preference for the anti-TS(R) I and it results in high enantioselectivity.

A number of novel 2-naphthyl propargylic sulfones were synthesized as nucleic base alkylating agents. Extremely high DNA cleavage activity was observed for the sulfones with a free ω-hydroxyl group in the carbon chain in contrast to the ester conjugates possessing an additional intercalating unit.2-Naphthyl propargylic sulfones 1 exhibit high DNA intercalating and alkylating activity (> 100-fold) compared to the phenyl sulfones. Diminished potency was observed for conjugates 2 possessing another intercalating moiety (Ar) compared to 1.