Enantioselective Polyene Cyclization Catalyzed by a Chiral Brønsted Acid

The first enantioselective polyene cyclization initiated by a BINOL‐derived chiral N‐phosphoramide (NPA) catalyzed protonation of an imine is described. The ion‐pair formed between the iminium ion and chiral counter anion of the NPA plays an important role for controlling the stereochemistry of the overall transformation. This strategy offers a highly efficient approach to fused tricyclic frameworks containing three contiguous stereocenters, which are widely found in natural products. In addition, the first catalytic asymmetric total synthesis of (?)‐ferruginol was accomplished with an NPA catalyzed enantioselective polyene cyclization, as the key step for the construction of the tricyclic core, with excellent yield and enantioselectivity.     

Stereospecific ring expansion of chiral vinyl aziridines

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.     

Concurrent induction of two chiral centers from symmetrical 3, 4-disubstituted and 3,3,4-trisubstituted 4-pentenals using Rh-catalyzed asymmetric cyclizations

Asymmetric cyclization of symmetrical 3,4-disubstituted and 3,3, 4-trisubstituted 4-pentenals was studied using Rh-complexes with chiral ligands. The cyclization of symmetrical 4-pentenals 4a,b by a neutral Rh[(R)-BINAP]Cl afforded cis-3,4-disubstituted (4R)-cyclopentanones 9a,b of >95% ee in 25-31% yields; on the other hand, the cyclization of 4a-c by a cationic Rh[(R)-BINAP]ClO(4) afforded trans-3,4-disubstituted (4S)-cyclopentanones 10a-c of >95% ee in 70-81% yields. All stereoisomers could be stereoselectively made by the selection of a neutral or cationic Rh-complex, and (R)- or (S)-BINAP ligand. The Rh-catalyzed cyclization could be applied to the construction of cyclopentanones 17 and 18 bearing a chiral quaternary carbon. The cyclization by the cationic Rh[(R)-BINAP]ClO(4) afforded the optically active trans-3,3, 4-trisubstituted cyclopentanones 18a-c of 92-95% ee in 75-83% yields. The catalytic cycle was also studied by using deuterium aldehyde, and the tentative mechanisms of the enantio- and diastereoselection were proposed.     

Biomimetic Cyclization of Enamide-Containing Polyenes as a New Route to Azapolycycles

Enamide 4 was studied for its effectiveness as a polyene precursor in biomimetic cyclizations. While most conventional Lewis acids were poor cyclization promoters, FeCl(3).6H(2)O initiated the conversion of 4 into tricycles 6 and 7 in excellent yield. The two isomeric products result from the cyclization of intermediate aldehyde 5 by either a chair or boat B-ring transition state. These results suggest that enamides may be incorporated into polyene precursors for the construction of larger azapolycycles such as azasteroids.     

Super acid-induced Pummerer-type cyclization reaction: improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.     

Gold(I)-catalyzed asymmetric synthesis of planar chiral arene chromium complexes

Gold(I)-catalyzed asymmetric cyclization of 1,3-dihydroxymethyl-2-alkynylbenzene chromium complexes gave planar chiral isochromene chromium complexes with high enantioselectivity. Enantiomeric excess of the cyclization products was largely affected by a combination of axially chiral diphosphine(AuCl)(2) precatalysts and silver salts. A system of segphos(AuCl)(2) with AgBF(4) resulted in the formation of the corresponding antipode.     

Copper catalyzed asymmetric conjugate addition-bromination of α,β-unsaturated ketones: a highly efficient one-pot reaction for the synthesis of chiral α-bromo-β-alkylketones

An efficient one-pot reaction for the synthesis of chiral α-bromo-β-alkyl ketones was developed. The final products were obtained with excellent enantiomeric excess and good isolated yields. The synthetic potential was illustrated by the radical cyclization of the α-brominated ketone.     

O-(α-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’: synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids

An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(α-phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.     

Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles using squaramide as the catalyst

The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem Michael addition–cyclization reaction of cyclohexane-1,3-diones and benzylidenemalononitriles gave the corresponding products in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 83% ee). This investigation provides an efficient and useful process for the synthesis of chiral 2-amino-4H-chromenes.     

Application of Rh-catalyzed cyclization to the formation of a chiral quaternary carbon

Rh-Catalyzed cyclization was applied to the formation of a chiral quaternary carbon. It has become clear that the Rh-complex can discriminate between isopropenyl and 2-isopentenyl (or isopentyl) substituents, and the cyclization afforded 3,3,4-trisubstituted cyclopentanones with a chiral quaternary carbon in a stereoselective manner. The cyclization of 4-pentenals 6a, b by an achiral neutral Rh(PPh3)3Cl afforded 3,3,4-cis-trisubstituted cyclopentanones (+/-)-7a,b in 86-96%, and the cyclization by a cationic Rh[(R)-BINAP]CIO4 afforded 3,3,4-trans-trisubstituted cyclopentanones (-)-8a, b of 82-86% ee in 88-98% yields. The mechanism of stereoselection by Rh-complexes is also discussed.     

Catalytic asymmetric reactions in alkaloid and terpenoid syntheses

Catalytic asymmetric induction is one of the most important methods in current synthetic organic chemistry for designing efficient and attractive synthetic routes. The efficient total synthesis of a natural product can be achieved through the identification of appropriate method and strategy. This Letter introduces the catalytic asymmetric syntheses of alkaloids and terpenoids based on an overview of four recently reported types of asymmetric reaction: (1) asymmetric decarboxylative allylation, (2) organocatalytic cascade reaction, (3) polyene cyclization, and (4) asymmetric [2+2]-photocycloaddition catalyzed by a chiral Lewis acid.     

Fusion of photochromic reaction and synthetic reaction: photoassisted cyclization to highly strained chiral azobenzenophanes

A method for synthesizing highly strained cyclic structures by combining photochromic and synthetic reactions is described. Tightly linked azobenzene-binaphthyl dyads (R)-4 and (R)-6 could not be obtained by conventional cyclization, but continuous application of photoirradiation, which induced (E)→(Z) isomerization of the azobenzene moiety, allowed the cyclization reaction to proceed, affording the desired chiral azobenzenophanes.     

Synthesis of enantiomerically pure inherently chiral calix[4]arenes using the meta-substitution strategy

A meta-substituted aminocalix[4]arene 4 immobilized in the cone conformation was prepared via mercuration of the starting tetra-propoxy derivative, followed by nitrosation and reduction reactions. Acylation of the amino group by chiral amino acid residues ((S)-N-trifluoroacetyl-Ala or (S)-N-trifluoroacetyl-Phe) allowed for the preparation of diastereomeric amides that were separated by preparative TLC on silica gel. Subsequent cyclization under Bischler-Napieralski reaction conditions yielded calixarenes 7b and 7c bearing an oxazole moiety in the meta position instead of the expected upper rim-bridged compounds. The reaction sequence represents a straightforward approach towards enantiomerically pure inherently chiral calix[4]arene derivatives (without HPLC separation steps). The absolute configuration of the enantiomers were confirmed by single crystal structure determination (X-ray).     

On the mechanism and stereochemistry of chiral lithium-carbenoid-promoted cyclopropanation reactions

An investigation into the mechanism and stereochemistry of chiral lithium-carbenoid-promoted cyclopropanation reactions by using density functional theory (DFT) methods is reported. Previous work suggested that this type of cyclopropanation reaction may proceed by competition between a methylene-transfer mechanism and a carbometalation mechanism. In this paper, it is demonstrated that the intramolecular cyclopropanation reactions promoted by chiral carbenoids 1 and 2 proceed by the methylene-transfer mechanism. The carbometalation mechanism was found to have a much higher reaction barrier and does not appear to compete with the methylene-transfer mechanism. The Lewis base group does not enhance the carbometalation pathway enough to compete with the methylene-transfer pathway. The present computational results are consistent with experimental observations for these cyclopropanation reactions. The factors governing the stereochemistry of the intramolecular cyclopropanation reaction by the methylene-transfer mechanism were examined to help elucidate the origin of the stereoselectivity observed in experiments. Both the directing group and the configuration at the C(1) centre were found to play a key role in the stereochemistry. Carbenoid 1 has a chiral C(1) centre of R configuration. The Lewis base group directs the cyclization of carbenoid 1 to form a single product. In contrast, the Lewis base group cannot direct the cyclization of carbenoid 2 to furnish a stereoselective product due to the S configuration of the chiral C(1) centre in carbenoid 2. This relationship of the stereochemistry to the chiral character of the carbenoid has implications for the design of new efficient carbenoid reagents for stereoselective cyclopropanation.     

Enantioselective Michael reactions of chiral secondary enaminoesters with 2-substituted nitroethylenes. Syntheses of trans, trans-2,4-disubstituted pyrrolidine-3-carboxylates

The Michael reaction of chiral 3-substituted secondary enaminoesters with 2-substituted nitroethylenes leads to (Z)-adducts, with good to excellent diastereoselectivity. The nitro group of these adducts was catalytically reduced to give, after cyclization and chiral amine elimination, pyrrolines or pyrrolidines after further reduction. In particular, the syntheses of ethyl (2R,3S,4S)-2,4-dimethylpyrrolidine-3-carboxylate and ethyl (2R,3R,4S)-2-(4-methoxyphenyl)-4-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-carboxylate are described.     

Intramolecular carbolithiation reactions of chiral alpha-amino-organolithium species

Enantiomerically enriched alpha-amino-organolithium species, in which the lithium atom is attached to a stereogenic carbon centre, have been found to be chemically stable at room temperature in a solvent of very low polarity and undergo intramolecular carbolithiation onto an unactivated alkene. The configurational stability of the chiral organolithium species, bearing a variety of N-alkenyl substituents, was probed by studying the enantiomeric purity of the cyclization products. With N-but-3-enyl-2-lithiopyrrolidine, cyclization to the five-membered ring is more rapid than racemization and a high yield of the pyrrolizidine alkaloid (+)-pseudoheliotridane was obtained with no loss of optical purity. In contrast, with N-pent-4-enyl-2-lithiopyrrolidine, cyclization to the six-membered ring was found to occur with significant loss of optical purity. The cyclization to the six-membered ring was determined to occur with a half-life, t(1/2) approximately 90 min at 23 degrees C. The epimerization of this organolithium species in hexane/Et2O 4:1 was calculated to have a half-life, t(1/2) approximately 30 min at 23 degrees C. Enhanced levels of enantioselectivity for the formation of the indolizidine ring system were obtained using an alkene bearing a terminal phenylthio substituent. With N-[(3-phenylthio)-prop-2-enyl]-2-lithiopyrrolidine, cyclization to the four-membered ring occurs with poor enantioselectivity at low temperature in THF but is highly enantioselective at room temperature in a solvent of very low polarity.     

Enantiospecific synthesis of the (9S,18R)-diastereomer of the leukocyte adhesion inhibitor cyclamenol A

Cyclamenol A is one of the very few non-carbohydrate and non-peptide natural products that inhibit leukocyte adhesion to endothelial cells. We report on the first enantioselective total synthesis of the (9S, 18R)-diastereomer of this macrocyclic polyene lactam. Key elements of the synthesis are i) the synthesis of the required chiral building blocks by employing readily accessible building blocks from the chiral pool, that is, (S)-malic acid and (R)-hydroxyisobutyric acid, ii) assembly of a linear polyene precursor by means of Wittig and Horner olefination reactions as key C-C bond-forming transformations, iii) ring closure by means of a vanadium-mediated pinacolisation reaction and iv) conversion of the generated cis-diol into a (Z)-olefin to complete the entire polyene system of the natural product. Attempts to close the macrocyclic ring by a macrolactamisation, a double Stille coupling or direct olefination in a McMurry reaction failed. Crucial to the successful completion of the synthesis was the correct orchestration of the final steps. It was necessary to first deprotect the intermediate formed after macrocycle formation and to generate the sensitive heptaene system in the last step by means of a Corey-Hopkins sequence.     

Catalytic enantioselective synthesis of chiral phthalides by SmI2-mediated reductive cyclization of 2-acylarylcarboxylates

A significant new and efficient catalytic asymmetric approach for the highly enantioselective synthesis of chiral phthalides by SmI2-induced reductive cyclization of 2-acylarylcarbonylates was developed. The combination of (4S,5R)-4,5-diphenyloxazolidin-2-one and 2,2,6,6-tetramethylpiperidine was found to be a very effective catalyst system in the reaction. This method provides a ready access to a broad range of enantiomerically enriched phthalides (up to 99% ee).     

Synthesis of chiral 1,3-dihydroisobenzofurans (phthalans) containing functional substituents in the 1-position

Chiral 3-methyl-1,3-dihydroisobenzofurans (phthalans) having a carbonyl or α-hydroxybenzyl group in position 1 were synthesized by cyclization of the corresponding trimethyl[(S)-1-phenylethyl]ammonium iodides. The configuration of the chiral centers in the products was determined by X-ray analysis.     

Chiral proton donor reagents: tin tetrachloride--coordinated optically active binaphthol derivatives

The Lewis acid–assisted chiral Brønsted acids (chiral LBAs), which are prepared from tin tetrachloride and optically active binaphthol derivatives, are highly effective chiral proton donor reagents for enantioselective protonation and biomimetic polyene cyclization. These chiral LBAs can directly protonate various silyl enol ethers and ketene disilyl acetals to give the corresponding α‐aryl or α‐halo ketones and α‐arylcarboxylic acids, respectively, with high enantiomeric excess (up to 98% ee). A catalytic version of enantioselective protonation was also achieved using stoichiometric amounts of 2,6‐dimethylphenol and catalytic amounts of monomethyl ether of optically active binaphthol in the presence of tin tetrachloride. The biomimetic cyclization of simple isoprenoids to polycyclic isoprenoids using chiral LBA is also described. This is the first example of a chiral Brønsted acid–induced enantioselective ene cyclization in synthetic chemistry. Geranyl phenyl ethers, o‐geranylphenols, and homogeranylphenol derivatives were directly cyclized in the presence of (R)‐binaphthol derivatives and tin tetrachloride (up to 90% ee). Compounds bearing a farnesyl group could also be cyclized under the same conditions to give the natural products (?)‐ambrox^® and (?)‐chromazonarol, and (?)‐tetracyclic polyprenoids of sedimentary origin. These chiral LBAs recognize the prochiral face of a trisubstituted terminal olefin and site selectively generate carbocations on the substrates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 177–188,2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10020