Showing papers on "Enone published in 2009"

Gold(I)-catalyzed tandem reactions initiated by hydroamination of alkynyl carbamates: application to the synthesis of nitidine.

Abstract: As a convenient and direct synthesis of 1,2-dihydroisoquinolines, the gold(I)-catalyzed intramolecular hydroamination of (2-alkynyl)benzyl carbamates has been developed. The reaction with cationic gold(I) complex [AuCl(PPh3)/AgNTf2] proceeded at room temperature, giving the desired 6-endo adducts. The addition of alcohol efficiently promoted the reaction, and the amount of the catalyst could be reduced to 1 mol %. However, the alkynes bearing either an electron-deficient aryl group or an alkyl group resulted in predominant production of 5-exo adducts. In such cases, use of a bulky gold catalyst, AuCl[(o-biPh)(tBu)2P]Cl/AgNTf2, improved the regioselectivity, giving the 6-endo adducts in better yields. Furthermore, the hydroamination of alkynyl carbamates bearing an acetal or enone was successfully applied to the concise synthesis of tetracyclic heterocycles such as nitidine via the single catalyst-mediated tandem cyclization which consists of a condensation or a Michael addition of the resulting enecarbamates.

Enantioselective Synthesis of Functionalized Nitrocyclopropanes by Organocatalytic Conjugate Addition of Bromonitroalkanes to α,β‐Unsaturated Enones

Abstract: A general enantioselective synthesis of functionalized nitrocyclopropanes by organocatalytic conjugate addition of a variety of bromonitroalkanes to alpha,beta-unsaturated enone systems is presented. The process, efficiently catalyzed by the salts of 9-amino-9-deoxyepiquinine 1 d serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes with high levels of enantio- and diastereoselectivities. Since only 0.6 equivalents of bromonitromethane are used as a reagent, (S)-2 e is obtained enantiomerically pure by employing chiral 1 d as a highly efficient catalyst for its kinetic resolution (97 % ee at 51 % conversion, selectivity s=120).

Synthesis and reactivity of six-membered oxa-nickelacycles: a ring-opening reaction of cyclopropyl ketones.

Abstract: Cyclopropanecarboxaldehyde (1 a), cyclopropyl methyl ketone (1 b), and cyclopropyl phenyl ketone (1 c) were reacted with [Ni(cod)(2)] (cod = 1,5-cyclooctadiene) and PBu(3) at 100 degrees C to give eta(2)-enonenickel complexes (2 a-c). In the presence of PCy(3) (Cy = cyclohexyl), 1 a and 1 b reacted with [Ni(cod)(2)] to give the corresponding mu-eta(2):eta(1)-enonenickel complexes (3 a, 3 b). However, the reaction of 1 c under the same reaction conditions gave a mixture of 3 c and cyclopentane derivatives (4 c, 4 c'), that is, a [3+2] cycloaddition product of 1 c with (E)-1-phenylbut-2-en-1-one, an isomer of 1 c. In the presence of a catalytic amount of [Ni(cod)(2)] and PCy(3), [3+2] homo-cycloaddition proceeded to give a mixture of 4 c (76%) and 4 c' (17%). At room temperature, a possible intermediate, 6 c, was observed and isolated by reprecipitation at -20 degrees C. In the presence of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr), both 1 a and 1 c rapidly underwent oxidative addition to nickel(0) to give the corresponding six-membered oxa-nickelacycles (6 ai, 6 ci). On the other hand, 1 b reacted with nickel(0) to give the corresponding mu-eta(2):eta(1)-enonenickel complex (3 bi). The molecular structures of 6 ai and 6 ci were confirmed by X-ray crystallography. The molecular structure of 6 ai shows a dimeric eta(1)-nickelenolate structure. However, the molecular structure of 6 ci shows a monomeric eta(1)-nickelenolate structure, and the nickel(II) 14-electron center is regarded as having "an unusual T-shaped planar" coordination geometry. The insertion of enones into monomeric eta(1)-nickelenolate complexes 6 c and 6 ci occurred at room temperature to generate eta(3)-oxa-allylnickel complexes (8, 9), whereas insertion into dimeric eta(1)-nickelenolate complex 6 ai did not take place. The diastereoselectivity of the insertion of an enone into 6 c having PCy(3) as a ligand differs from that into 6 ci having IPr as a ligand. In addition, the stereochemistry of eta(3)-oxa-allylnickel complexes having IPr as a ligand is retained during reductive elimination to yield the corresponding [3+2] cycloaddition product, which is consistent with the diastereoselectivity observed in Ni(0)/IPr-catalyzed [3+2] cycloaddition reactions of cyclopropyl ketones with enones. In contrast, reductive elimination from the eta(3)-oxa-allylnickel having PCy(3) as a ligand proceeds with inversion of stereochemistry. This is probably due to rapid isomerization between syn and anti isomers prior to reductive elimination.

Nickel‐Catalyzed Borylative Coupling of Alkynes, Enones, and Bis(pinacolato)diboron as a Route to Substituted Alkenyl Boronates

Abstract: Three-component coupling reactions of an alkyne, an enone, and a diboron reagent provide access to highly substituted alkenyl boronates in good to excellent yields (see scheme). The coupling is highly regio- and stereoselective, and the products are amenable to further functional-group transformations. R(1),R(2) = H, alkyl, aryl, CO(2)Me; R(3) = alkyl, Ph; R(4),R(5) = H, alkyl.

α-Fluorovinyl Weinreb Amides and α-Fluoroenones from a Common Fluorinated Building Block

Abstract: Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones to give α-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are ≥98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give α-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermedia...

Cyclocondensation of α-Aminonitriles and Enones: A Short Access to 3,4-Dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-Trisubstituted Pyrroles

Abstract: The reaction of α,β-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from α-substituted α-aminonitriles can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation.

Palladium-Catalyzed Preparation of Silyl Enolates from α,β-Unsaturated Ketones or Cyclopropyl Ketones with Hydrosilanes

Abstract: α,β-Unsaturated ketones and cyclopropyl ketones undergo palladium-catalyzed hydrosilylation with hydrosilanes to yield (Z)-silyl enolates.

Nickel-Catalyzed [4 + 2] Cycloaddition of Enones with Alkynes

Abstract: A nickel-catalyzed [4 + 2] cycloaddition reaction has been developed where enones react with alkynes to afford polysubstituted pyrans. A mechanistic rationale is proposed, implying oxa-nickela cycle formation by oxidative cyclization of nickel to enone, followed by alkyne insertion.

Toward Palau′amine: Hg(OTf)2-Catalyzed Synthesis of the Cyclopentane Core

Abstract: The pyrrole-imidazole alkaloids, which comprise a large family of natural products,1 have received a great deal of attention due to their potent biological activities and tremendous structural diversity. Palau’amine (1a) was originally isolated from a sponge, Stylotella agminata, in 1993 by Scheuer as a novel class of the pyrrole-imidazole alkaloid.2 Since the initial disclosure of its proposed structure (1a), palau’amine (1) has been an attractive synthetic target because of its intriguing molecular architecture and significant biological properties such as antifungal, antitumor, and immunosuppressive activities. However, according to several groups, the originally proposed structure 1a was recently revised as 1b, which possesses the indicated the trans-D/E ring junction and the β-chlorine substituent.3, 5e, 5g The noteworthy structural features of palau’amine include: two guanidine moieties, fused polycyclic system with a spiro cycle, complex all carbon substituted cyclopentane ring, nitrogen-substituted quaternary carbon center, and eight contiguous stereogenic centers. Not surprisingly, many attempts to synthesize palau’amine and related natural products have been reported so far, 4, 5 and the first total synthesis of the related natural products axinellamines A and B (2) was recently accomplished.6 However, a total synthesis of palau’amine itself has not yet been reported. Efficient construction of the complex cyclopentane core with the correct stereochemistry at each carbon center, including a quaternary carbon center, is definitely one of the most difficult synthetic challenges for the synthesis of palau’ amine. Herein, we describe an efficient synthesis of the cyclopentane core of palau’amine by the application of a highly efficient novel Hg(OTf)2-catalyzed reaction developed in our laboratory.7 In 2008, the Hg(OTf)2-catalyzed alkyne cyclization reactions were expanded to the alkene cyclization reactions by using allylic alcohol or vinyl methyl ether substrates that, after cyclization, undergo a smooth proto-demercuration to give the cyclized products and the regenerated Hg(OTf)2 catalyst.8 For instance, Hg(OTf)2-catalyzed cyclization of N-tosylanilino allylic alcohol 3 provided 2-vinylindolines 4 in high yield (Scheme 1).8b Thus, the cyclization of cyclopentylidene alcohol 5 is expected to give 6 by constructing a quaternary carbon center that corresponds to the C16 of palau’amine. However, the catalytic cyclization of amide 5 is also possible to give the O-cyclized product 7 in preference to the N-cyclized product 6. Indeed, we confirmed this was the case. The conventional methods for N-selective cyclization are limited by the cumbersome substrate modifications, the addition of strong Lewis acids and/or strong base, or the formation of N-radical. 9 Moreover, the catalytic conditions for generating such a quaternary carbon center have not yet to be determined. Therefore, we designed an acylhydrazide 8 as a simple modification of primary amides for Hg(OTf)2-cataylized cyclization. The vinyl lactum 9, prepared by the Hg(OTf)2-catalyzed cyclization of 8, could be an excellent precursor to construct cyclopentane core 10 by introducing two CH2-N groups (Scheme 1). Scheme 1 Hg(OTf)2-Catalyzed Cyclization of Allylic Alcohol and Synthetic Design of Palau’amine Cyclopentane Core 10. Commercially available 2-cyclopentene-1-one 10 was employed as the starting material. A Morita-Baylis-Hillman reaction of 10 with a commercial preparation of (tert-butyldimethylsilyloxy)-acetaldehyde afforded 11 in 70% yield. 11 was subsequently converted to 13 by a sequential operation of acetylation, a Luche reduction, 10 and a TBS protection. The acetate 13 were then obtained as a 2: 1 diastereomeric mixture, setting the stage for an Ireland-Claisen rearrangement.11, 12 After the treatment of 13 with LHMDS/TBSCl/HMPA in THF at −78 °C, refluxing in toluene induced the desired Ireland-Claisen rearrangement to afford the cyclopentylidene carboxylic acid 15 via 14 in good yield. Next, we attempted to prepare an acylhydrazide by the coupling of 15 with N-tosylhydrazide by the combined action of EDCI and DMAP in dichloromethane. Surprisingly, the nitrogen masked with a tosyl group participated in the condensation to give a 2: 1 diastereomeric mixture of 16 in 68% overall yield after four steps from 13. Presumably, the nucleophilicity of the more basic primary amine was attenuated by protonation with the HCl derived from the used EDCI-HCl salt.13 The double bond geometry of 15 was determined to be Z by the NOE experiment of its amide derivative (Scheme 2). The TBS groups were cleaved under mild acidic conditions to give diol 17. Scheme 2 Synthesis of Hydrazide 17 Reaction of 17 with 2 mol % of Hg(OTf)2 took place smoothly in nitromethane at room temperature to afford 18α and 18β in 84% yield as a separable 1:2 diastereomeric mixture. The lactone 19 was not detected (Sheme 3). Stereochemical outcome at the ring junction was completely controlled to cis regardless of the stereocenter of the secondary alcohol at C17. The structures of 18α and 18β were unambiguously confirmed by an X-ray diffraction study and NOE studies (see supporting information). 14 We thus established that the Hg(OTf)2-catalyzed protocol efficiently mediates N-selective cyclizations of amide carbony moieties, which is very difficult to achieve using conventional methodologies.15 Having prepared a sufficient amount of N-cyclized product 18, we attempted to construct the cyclopentane core of palau’amine. The SO3·pyridine oxidation of the mixture of 18α and 18β gave a single ketone 20 in quantitative yield.16 Direct oxidation of 20 to enone 22, using IBX,17 and selenium dioxide, or enolate oxidation using selenium halide, sulfinimidoyl chloride,18 and NBS, were unsuccessful. Although the preparation of the silyl enol ether was not straightforward, a combination of TMSI and hexamethyldisilazane in dichloromethane was found to give trimethylsilylenolether 21 in quantitative yield.19, 20 Saegusa-Ito oxidation of 21 provided enone 22 in good yield.21 Morita-Baylis-Hillman reaction of 22 with formaldehyde gave alcohol 23 in excellent yield. Subsequent 1, 4-addition of nitromethane in the presence of a catalytic amount of a 1, 1, 3, 3-tetramethylguanidine (TMG) afforded the desired 1, 4-adduct 24.22 We found that 24 was readily converted to the exomethylene product by dehydration during a column chromatography purification on silica gel. Therefore, the crude 24 was directly subjected to reduction with NaBH4 to give 25. The stereochemistry of 25 was confirmed to be as we planned for our palau’amine synthesis by an NOE experiment. Finally, the primary alcohol of 25 was converted to azide 26 that is the targeted cyclopentene core of palau’amine. The structure of 26 was unequivocally established by an X-ray diffraction study (Scheme 6 and supporting information). 23 In summary, we have established an efficient route to the cyclopentane 26, which corresponds to our E ring synthetic intermediate of palau’ amine by the application of novel Hg(OTf)2-catalyzed cyclization. Furthermore, a selective N-cyclization protocol of acylhydrazide for catalytic construction of a quaternary carbon center was also developed. Throughout this investigation, Hg(OTf)2 was shown to be a powerful catalyst for the construction of complex carbon frameworks of the type found in natural products. Total synthesis of palau’amine, one of the most challenging synthetic targets in the last decade, is currently underway in our laboratory.

Synthesis of (−)-pericosine B, the antipode of the cytotoxic marine natural product

Abstract: The stereoselective synthesis of (−)-pericosine B, which is the antipode of the cytotoxic metabolite of the fungus Periconia byssoides OUPS-N133 separated from the sea hare, was accomplished in 9 steps in 12% total yield from (−)-quinic acid, together with the synthesis of its epimer. Every crucial step of this total synthesis, including ring opening of a β-epoxide and NaBH4reduction of an unstable β,γ-unsaturated enone, proceeded with excellent stereoselectivity.

Synthesis of (+)-Coronafacic Acid

Abstract: An enantioselective synthesis of (+)-coronafacic acid has been achieved. Rhodium-catalyzed cyclization of an α-diazoester provided the intermediate cyclopentanone in high enantiomeric purity. Subsequent Fe-mediated cyclocarbonylation of a derived alkenyl cyclopropane gave a bicyclic enone that then was hydrogenated and carried on to the natural product.

A Benzannulation Protocol To Prepare Substituted Aryl Amines Using a Michael-Aldol Reaction of β-Keto Sulfones

Abstract: A practical benzannulation method to prepare variously substituted aryl amines and sulfides was developed. The approach involves a Michael-aldol reaction of β-keto sulfones with enones followed by a subsequent condensation of the initial adduct with various amines. The base-induced Michael-aldol cascade proceeds smoothly with a number of different β-keto sulfones, affording the adducts as single diastereomers. Heating the resulting Michael-aldol product with an amine in toluene at 120 °C results in the formation of a transient enamine, which then undergoes loss of phenyl sulfenic acid to furnish the aromatized amine in good yield. A related reaction also occurred when the Michael-aldol product was heated with thiols or alcohols, giving rise to aryl-substituted sulfides or ethers.