Diastereoselective synthesis of 10b-substituted hexahydropyrroloisoquinolines from l-tartaric acid. Creation of a quaternary carbon stereocentre via N-acyliminium ion cyclization

A simple, three-step synthesis of 10b-substituted-hexahydropyrroloisoquinolines 12-17 starting from an L-tartaric acid derived imide is described. The methodology presented employs the addition of a Grignard reagent to the imide carbonyl group, followed by a one-pot acetylation-cyclization sequence. The crucial step, an acid-catalyzed carbon-carbon bond forming reaction via an N-acyliminium ion offers moderate to high stereoselectivity, which has been shown to be strongly dependent on the size of the R-substituent. The mixtures of pyrroloisoquinolines obtained can be separated as enantiomerically pure 2-silyloxy-derivatives.     

Architecturally diverse heterocycle formation by N-acyliminium ion initiated cyclization

Enaminoesters containing a tethered indole or aryl moiety on the amine react with substituted maleic anhydrides or acryloyl chlorides to provide pyrrolinone or dihydropyridone products, respectively. The indole-tethered dihydropyridones can be induced to undergo a one-pot cyclization whereas, the indole-tethered pyrrolinone intermediates are readily cyclized with HCl. The aryl-tethered pyrrolinones or dihydropyridones can be isolated and subsequently induced to cyclize with triflic acid. This methodology culminates in the synthesis of erythrane-like and other natural products that are readily amenable to combinatorial library production.     

Iodine-mediated electrophilic cyclization of 2-alkynylbenzaldoximes leading to the formation of iodoisoquinoline N-oxides

Reaction of 2-alkynylbenzaldoximes 1 with 5 equiv of iodine in EtOH at room temperature gives the corresponding iodoisoquinoline N-oxides 2 in good to excellent yields. The cyclization proceeds very smoothly and quickly without any additives such as bases under very mild reaction conditions.     

A diastereoselective construction of pyrazinoisoquinoline skeletons via tandem cyclization of phenylalanine derivatives: a facile synthesis of optically active pyrazinoisoquinolines

A facile and stereocontrolled construction of optically active pyrazinoisoquinoline skeletons based on tandem cyclization of enantiopure phenylalanine derivatives was examined. The reaction provided optically active 6,11b-trans pyrazinoisoquinoline ring systems in excellent diastereoselectivity, and this method was applicable to the cyclization of phenylalanine derivatives with diverse substituents.     

An enantiospecific synthesis of (+)-demethoxyerythratidinone from (S)-malic acid: key observations concerning the diastereocontrol in malic acid-derived N-acyliminium ion cyclisations

The stereochemical outcome of N-acyliminium ion mediated cyclisations of malic acid derived lactams depend upon the nature of the protecting group on the lactam secondary alcohol, and also on the nature of the substituent at the reacting electrophilic centre. The origins of an unusual syn-selective cyclisation of a TIPS protected lactam are discussed, and the cyclisation is employed as the key step in an asymmetric synthesis of 3-demethoxyerythratidinone (4).     

A new route to optically pure highly functionalized tetrahydro-isoquinolines with a quaternary carbon stereocenter

A facile synthesis of highly substituted, optically pure tetrahydro-isoquinolines with a quaternary carbon stereocenter is described. Glycolic cleavage of 1,2-dihydroxy-hexahydro-pyrrolo-isoquinolines 1 affords a mixture of cyclic hemiacetals, which can be converted via intramolecular chemoselective Cannizzaro reaction into respective β-amino alcohols, whereas the IBX oxidation gives N-formyl aldehydes. We have demonstrated the utility of such synthons by the synthesis of (+)-6,7-dimethoxy-salsoline-1-carboxylic acid and its new 1-phenyl analogue.     

Camphoric acid derived sulfur containing bicyclic carboxylic acids as chiral auxiliaries in N-acyliminium ion chemistry

Three novel sulfur containing chiral bicyclic carboxylic acids were synthesized from d-camphoric acid. Two of these compounds were briefly evaluated for their potency as chiral auxiliaries in Asymmetric Electrophilic α-Amidoalkylation (AEαA) reactions.     

Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 1: N-Acyliminium ion cyclisations with an internal arene nucleophile

A series of chiral non-racemic 5,5- and 5,6-bicyclic lactams is prepared from (R)-phenylglycinol. These are isomerised on treatment with aluminium trichloride in 1,2-dichloroethane to give spiro lactams in high yield and >3:1 diastereoselectivity. From four structures determined by X-ray crystallography, it follows that spiro indenes are formed preferentially with retention of configuration at the spiro carbon atom and spiro naphthalenes with inversion.     

Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium ion cyclisations with an internal alkene nucleophile

Chiral non-racemic bicyclic and tricyclic oxylactams obtained in two steps from N-(2-hydroxy-1(R)-phenylethyl)-succinimide and phthalimide are cyclised diastereoselectively in formic acid to give spiro[cyclohexane-1,2′-pyrrolidin]-5-ones and spiro[cyclohexane-1,1′-isoindolin]-3-ones, respectively.     

endo-Mode cyclizations of vinylogous N-acyliminium ions as a route to the synthesis of condensed thiazolidines

endo-Mode cyclizations of vinylogous N-acyliminium ions incorporating heteroatom-based nucleophiles have been examined as a route to the synthesis of condensed thiazolidines. The scope of these reactions and stereochemical outcome are discussed and explained using quantum chemical calculations.     

Ultrasound-assisted addition of alcohols to N-acyliminium ions mediated by In(OTf)3 and synthesis of 1,2,3-triazoles

An easy and mild approach using ultrasound-assisted reaction addition of alcohols to N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the synthesis of ether pyrrolidinones; next, the products were converted to 1,2,3-triazoles using click chemistry reaction conditions. The products in both reactions were afforded in moderate to good yields.     

Spiro cyclisations of N-acyliminium ions involving an aromatic π-nucleophile

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.     

Efficient iodine catalyzed chemoselective synthesis of aminals—an access to N,N-acetals by the addition of lactams to N-acyl imines

A highly efficient protocol has been developed for the synthesis of aminals from γ-butyrolactam and benzaldehyde using iodine as Lewis acid catalyst. The attack of γ-butyrolactam nucleophile to intermediate N-acyliminium ion was more favorable, when aryl aldehyde bears the electron donating group (EDG). Iodine plays a key role in these reaction transformations. This current mild protocol is environmentally benign and cost-effective method for the synthesis of industrially and pharmaceutically useful scaffolds.     

Lanthanide triflate catalyzed generation of N-acyliminium ions from α-amido sulfones: the synthesis of (1-alkyl-1-aryl)methyl phenyl sulfones

The reaction of α-amido sulfones with various aromatic and heteroaromatic compounds in the presence of a catalytic amount of lanthanide triflate provides a facile route for the synthesis of (1-alkyl-1-aryl)methyl phenyl sulfones.     

Synthesis of cis-2,5-disubstituted pyrrolidines via diastereoselective reduction of N-acyl iminium ions

A new procedure for forming cis-2,5-disubstituted pyrrolidines having unsaturated side chains has been developed that features the diastereoselective reduction of N-acyl iminium ions, which were formed in situ by acid-catalyzed cyclizations of unsaturated γ-keto carbamates, with triphenylsilane. The sequence was applied to a very concise synthesis of 16, a subunit in the nonpeptide cholecystokinin antagonist (+)-RP-66803.     

Racemic N-sulfonyloxaziridines as highly diastereoselective enolate hydroxylating agents: enantioselective synthesis of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide

A new, highly enantioselective synthesis of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide, a synthetic fragment of the experimental hepatitis C drug Telaprevir, has been described. Conjugate addition of the enantiomerically pure Davies lithium amide followed by hydroxylation of the in situ generated β-amino enolate was employed for the formation of the required stereogenic centres. Importantly, very high diastereoselectivities can still be achieved in the key-step when the relatively expensive and enantiopure (camphorsulfonyl)oxaziridine hydroxylating agent is replaced by racemic trans-N-sulfonyloxaziridines. Among the tested N-sulfonyloxaziridines the iso-propyl substituted analogue proved to be the ideal choice from an economic viewpoint.     

Asymmetric radical cyclization reactions of axially chiral N-allyl-o-iodoanilides to form enantioenriched N-acyl dihydroindoles

Radical cyclizations of enantiomerically enriched N-allyl-o-iodoanilides provide N-acyl-3-alkyl-2,3-dihydroindoles in good yields and with good to excellent levels of chirality transfer from the N-Ar axis to the new stereocenter. In competitive cyclizations of N-acryloyl-N-allyl-o-iodoanilides, the addition of an o-methyl group reverses the regioselectivity of the radical cyclization from the acryloyl group to the allyl group. Approximate rate constants for representative radical cyclizations have been measured to provide insight into the origin of these observations.     

Synthesis of functionalized N-triazolyl maleimides

An easy and mild two-step one-pot reaction allowed the synthesis of functionalized N-triazolyl maleimide. Next, the addition of propargyl alcohol and propargyl amine to the N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the introduction of a second 1,2,3-triazol ring at position 5 of the amide. The products in both reactions were achieved in moderate to good yields.     

The stereoselective addition of titanium(IV) enolates of 1,3-oxazolidin-2-one and 1,3-thiazolidine-2-thione to cyclic N-acyliminium ion. The total synthesis of (+)-isoretronecanol

(+)-Isoretronecanol (1) has been prepared in four steps and 36% overall yield via the diastereoselective addition of the titanium(IV) enolate derived from N-4-chlorobutyryl-1,3-thiazolidine-2-thione (3) to N-Boc-2-methoxypyrrolidine (5), which afforded 2-substituted pyrrolidine 7 in 84% yield (8:1 diastereoisomeric ratio), followed by reductive recovery of the chiral auxiliary and cyclization.     

Stereoselective synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-propargylaminyl radicals

Tandem cyclization of N-propargylaminyl radicals, generated by N-chlorination of (E)-alk-4-enylamines 2a-d and 2f followed by treatment with tributyltin radical, afforded 2-methylenepyrrolizidines 3a-d and 3f in a highly stereoselective manner. A similar radical cyclization of (Z)-N-propargyl-1-methyl-5-phenylpent-4-enylamine (2e) gave pyrrolizidine 3b having the same stereochemistry as that obtained from the E isomer 2b.