Asymmetric synthesis of cyclopropanes and dihydrofurans based on phosphine oxide chemistry

The asymmetric synthesis of gamma-azido trans-cyclopropyl ketones is accomplished via a short, simple and efficient sequence. The cyclopropanation step is achieved by an intramolecular nucleophilic ring closure, with a diphenylphosphinate leaving group, to give trans-cyclopropane exclusively. beta-Keto-diphenylphosphine oxides cyclise to form optically active dihydrofurans. All possible diastereoisomers of dihydrofurans can be prepared selectively starting from the same olefin.     

Asymmetric synthesis of trifluoromethyl substituted dihydropyrans via organocatalytic cascade Michael-hemiketalization reaction

Asymmetric conjugate addition of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl substituted nucleophiles to β,γ-unsaturated α-keto esters has been developed. The reaction efficiently provided dihydropyrans via cascade Michael-hemiketalization pathways. Quinine-derived thiourea was identified to be the best catalyst. A number of trifluoromethyl substituted dihydropyrans with three consecutive chiral centers were obtained in excellent yields, diastereoselectivities, and enantioselectivities. The product was readily transformed to the corresponding tetrahydropyridine without the loss of the optical purity.     

Stereoselective synthesis of tetracyclic indolines via gold-catalyzed cascade cyclization reactions

A reliable synthetic route to fused polycyclic indolines is documented by the development of a stereoselective gold catalyzed cascade cyclization of indole propargylic alcohols.     

A 1,5-Diene synthesis via titanium and aluminum mediated reactions

(1) 1,5-Dienes are readily prepared by titanium mediated methylenation of allyl esters, Claisen rearragement followed by a second methylene transfer reaction. (2) The same 1,5-diene may be approached in “one pot” combining an allyl acetate and 3 equivalents biscyclopentadienyl-titanium-μ-methylidene-bismethyl aluminum.     

Regioselective synthesis of spiro isoxazole-oxindole-tetrahydrothiophene hybrids via cascade reactions under catalyst-free conditions

Catalyst-free synthesis of the isoxazole-spirooxindole-tetrahydrothiophene hybrids is reported. Formation of 1,4-thia-Michael and intramolecular aldol reactions were observed (instead of 1,6-thia-Michael followed by vinylogous Henry reactions) in a regioselective fashion to give new isoxazole-spirooxindole-tetrahydrothiophene hybrids with excellent yields.     

Asymmetric polymerization via cycloaddition reactions

The reaction of N‐phthaloyl‐L ‐leucine acid chloride (1) with isoeugenol (2) was carried out in chloroform, and novel optically active isoeugenol ester derivative 3 as a chiral monomer was obtained in high yield. Compound 3 was characterized by ¹H‐NMR, IR, and mass and elemental analysis and then was used for the preparation of model compound 5 and polymerization reactions. 4‐Phenyl‐1,2,4‐triazoline‐3,5‐dione, PhTD (4), was allowed to react with compound 3. The reaction is very fast and gives only one diastereomer of 5 via Diels–Alder and ene pathways in quantitative yield. In order to explain this diastereoselectivity, a nonconcerted two‐step mechanism involving benzylic cation (BC) and aziridinium (AI) have been proposed for the Diels–Alder and ene reactions, respectively. The polymerization reactions of novel monomer 3 with bis(triazolinedione)s [bis(p‐3,5‐dioxo‐1,2,4‐triazolin‐4‐ylphenyl)methane (8) and 1,6‐bis(3,5‐dioxo‐1,2,4‐triazolin‐4‐yl)hexane] (9)] were performed in N,N‐dimethylacetamide (DMAc) at room temperature. The reactions are exothermic, fast, and gave novel optically active polymers 10 and 11 via repetitive Diels–Alder–ene polyaddition reactions. These polymers have inherent viscosities in a range about 0.18–0.22 dL/g. Some physical properties and structural characterizations of these new polymers have been studied and are reported. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1211–1219, 1999     

Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.     

Asymmetric cascade reaction sequences via chiral lithiated intermediates

The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a collection of products each containing a common stereogenic center. The stereogenic center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The methodology is demonstrated by the synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 (+/-1). The heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole or indolone rings.     

Copper-catalyzed synthesis of benzimidazoles via cascade reactions of o-haloacetanilide derivatives with amidine hydrochlorides

We have developed an efficient method for the synthesis of benzimidazoles via cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides. The protocol uses 10 mol % CuBr as the catalyst, Cs2CO3 as the base, and DMSO as the solvent, and no ligand is required. The procedure proceeds via the sequential coupling of o-haloacetoanilide derivatives with amidines, hydrolysis of the intermediates (amides), and intramolecular cyclization with the loss of NH3 to give 2-substituted 1H-benzimidazoles.     

Stereoselective synthesis of dibenzoxapine containing tetrasubstituted exocyclic alkenes via cascade methylboronic acid coupling reactions

A stereoselective method for the preparation of dibenzoxapine containing tetrasubstituted exocyclic E-alkenes has been developed. The key reaction involves an intramolecular cyclocarbopalladation of alkynes to form a vinylpalladium species and subsequently coupling the vinylpalladium with methylboronic acid. The approach provides a straightforward method for the synthesis of tetrasubstituted exocyclic E-alkenes.     

An efficient one-pot asymmetric synthesis of biaryl compounds via Diels-Alder/retro-Diels-Alder cascade reactions

[reaction: see text] A single-step chirality transfer method for the synthesis of axially chiral biaryl compounds by construction of the second aromatic ring via a Diels-Alder/retro-Diels-Alder cascade reaction is reported. This methodology should find broad application in the synthesis of natural products and asymmetric catalysts.     

Copper-catalyzed synthesis of primary arylamines via cascade reactions of aryl halides with amidine hydrochlorides

We have developed an efficient method for the synthesis of primary arylamines from aryl halides using amidine hydrochlorides as the ammonia surrogates. The protocol uses 10 mol % CuI as the catalyst, 20 mol % L-proline as the ligand, Cs2CO3 as the base, and DMF as the solvent and proceeds the sequential coupling of aryl halides with amidine hydrochlorides and hydrolysis of intermediates to give the target products. This is a convenient, inexpensive, and practical approach to primary arylamines.     

Asymmetric synthesis of beta-hydroxy amino acids via aldol reactions catalyzed by chiral ammonium salts

The Cinchona alkaloid derived chiral ammonium salt developed by Park and Jew functions as an effective catalyst for the synthesis of beta-hydroxy alpha-amino acids via asymmetric aldol reactions under homogeneous conditions. The syn diastereomers are obtained in good ee, and aryl-substituted aliphatic aldehydes are the best substrates for the reaction. These results represent the highest ee's obtained to date in direct aldol reactions of glycine equivalents catalyzed by inexpensive, readily prepared chiral ammonium salts.     

HOTf mediated cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes

The cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes proceed smoothly in freshly distilled HOTf to give the corresponding tetrahydro-5H-benzo[c]fluorene derivatives in good yields along with high stereoselectivities under mild conditions.     

Synthesis and cross-coupling reactions of 7-azaindoles via a new donor-acceptor cyclopropane

[reaction: see text] A new type of donor-acceptor cyclopropane has been prepared from commercially available cyclopropane-1,1-diesters. This cyclopropane reacts with triflic anhydride to produce an isolable tristrifloxy intermediate which when treated with primary amines gives 6-trifloxy-7-azaindolines which in turn can be dehydrogenated to the azaindoles. The 6-trifloxy substituent can be used to introduce diversity at this position via a variety of cross-coupling reactions thus preparing potentially interesting compounds based on the important 7-azaindole pharmacophore.     

Asymmetric induction of conduritols via AAA reactions: synthesis of the aminocyclohexitol of hygromycin A

Two synthetic routes towards the construction of the aminocyclohexitol moiety of hygromycin A have been developed based on palladium-catalyzed asymmetric alkylation of conduritol derivatives. A protocol has been established whereby this biologically relevant molecule is formed from benzoquinone. A conduritol A derivative is synthesized in eight steps from benzoquinone and is then subjected to the palladium reaction. From this flexible intermediate, four epimers of the aminocyclitol, including the natural one, can be obtained with complete stereoselectivity. Racemic conduritol B derivatives are available in four steps from benzoquinone, and these are then made enantiomerically pure by a palladium-catalyzed dynamic kinetic resolution. From the chiral conduritol B, the aminocyclitol is available in six steps. Excellent levels of enantio- and diastereoselectivity highlight these strategies.     

A facile synthesis of highly functionalized 4-arylcoumarins via Kostanecki reactions mediated by DBU

An efficient synthesis of 4-arylcoumarins has been accomplished via Kostanecki reactions of 2-hydroxybenzophenones with acetic anhydride employing DBU at ambient temperature. Using the same strategy, several 2-acyloxybenzophenone derivatives were readily converted to 3,4-difunctionalized coumarins. This protocol offers a notable improvement in reaction conditions for coumarin synthesis and takes advantage of its synthetic capability, especially for highly functionalized 4-arylcoumarins with structural diversity.     

Stereoselective synthesis of the cis-decalin subunit of vinigrol via three pericyclic reactions in cascade

Synthesis of the cis-decalin portion of vinigrol using a tandem oxy-Cope/Claisen/ene reaction is described. This three pericyclic reaction cascade proves to be a valuable synthetic tool in the construction of such systems.     

Preparation of fused polycyclic vinylcyclopropanes via radical cascade reactions

Radical cascades employing (dichloromethyl)dimethylsilyl ethers as both a point of radical initiation and termination, allow efficient entry to fused polycyclic cyclopropanes, and are also suitable for the design of other radical processes terminated by beta-elimination of chloride.     

Copper oxide nanoparticles catalyzed synthesis of aryl sulfides via cascade reaction of aryl halides with thiourea

Recyclable copper oxide nanoparticles catalyzed simple and highly efficient protocol for the synthesis of symmetrical aryl sulfides was developed by the cross-coupling of aromatic halides with inexpensive and commercially available thiourea which was used as an effective sulfur surrogate. The present cross-coupling protocol of thiourea, via cascade reaction with various substituted aryl halides, producing desired aryl sulfides, has an added advantage of avoiding foul-smelling thiols.