Strategy for enantio- and diastereoselective syntheses of all possible stereoisomers of 1,3-polyol arrays based on a highly catalyst-controlled epoxidation of alpha,beta-unsaturated morpholinyl amides: application to natural product synthesis

We describe a new strategy for enantio- and diastereoselective syntheses of all possible stereoisomers of 1,3-polyol arrays. This strategy relies on a highly catalyst-controlled epoxidation of alpha,beta-unsaturated morpholinyl amides promoted by the Sm-BINOL-Ph(3)As[double bond]O (1:1:1) complex, followed by a conversion of morpholinyl amides into ketones and diastereoselective ketone reduction. Highly enantio- (up to >99 % ee) or diastereoselective (up to >99.5:0.5) epoxidation was achieved using 5-10 mol % of the Sm complex to afford synthetically very useful, nearly optically pure alpha,beta-epoxy morpholinyl amides. Stereoselectivity of the epoxidation was controlled by the chirality of BINOL with overwhelming inherent diastereofacial preference for the substrate. Combination with the syn- and anti-selective ketone reduction with the highly catalyst-controlled epoxidation allowed for an iterative strategy for the syntheses of all possible stereoisomers of 1,3-polyol arrays. Eight possible stereoisomers of 1,3,5,7-tetraol arrays were synthesized with high to excellent stereoselectivity. Moreover, the efficiency of the present strategy was successfully demonstrated by enantioselective syntheses of several 1,3-polyol/alpha-pyrone natural products, for example, cryptocaryolone diacetate.     

Catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters: application to 1,3-polyol/alpha-pyrone natural product synthesis

[reaction: see text] We describe a catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters. The method relies upon catalytic asymmetric epoxidation of alpha,beta-unsaturated imidazolides and amides, using lanthanide-BINOL complexes, and diastereoselective reduction of ketones. The method was applied to the enantioselective syntheses of 1,3-polyol/alpha-pyrone natural products 9a, 9b, and strictifolione (10). The absolute stereochemistry of 9a and 9b was also determined.     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated amides: efficient synthesis of beta-aryl alpha-hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process

The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm-BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including beta-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity.     

Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters using an yttrium-biphenyldiol complex

We succeeded in a catalytic asymmetric epoxidation reaction of alpha,beta-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with beta-aryl and beta-alkyl substituents were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy esters in up to 97% yield and 99% ee.     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

Enantioselective syntheses of aeruginosin 298-A and its analogues using a catalytic asymmetric phase-transfer reaction and epoxidation

We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogues, in which all stereocenters were controlled by a catalytic asymmetric phase-transfer reaction and epoxidation. Furthermore, drastic counteranion effects in phase-transfer catalysis were observed for the first time, making it possible to three-dimensionally fine-tune the catalyst (ketal part, aromatic part, and counteranion).     

Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.     

Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization

[chemical reaction: see text]. 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of alpha,beta-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.     

Catalytic asymmetric phase-transfer reactions using tartrate-derived asymmetric two-center organocatalysts

A new highly versatile asymmetric two-center catalyst, tartrate-derived diammonium salt (TaDiAS), was designed and a catalyst library containing more than 70 new two-center catalysts was constructed. A variety of (S,S)- and (R,R)-TaDiAS were easily synthesized from diethyl l- and d-tartrate, respectively, using common and inexpensive reagents under operationally simple reaction conditions. TaDiAS was used in phase-transfer alkylations and Michael additions to afford various optically active α-amino acid equivalents in up to 93% yield. Moreover, dramatic counter anion effects were observed in phase-transfer catalysis (PTC) for the first time, making it possible to further improve reactivity and selectivity. These findings validate the usefulness of three-dimensional fine-tuning of the catalyst (acetal, Ar, and counter anion) for optimization. Recovery and reuse of the catalyst was also possible using simple procedures. The present asymmetric PTC was successfully applied to enantioselective syntheses of serine protease inhibitor aeruginosin 298-A and its analogues.     

Catalytic enantioselective peroxidation of alpha,beta-unsaturated ketones

Despite the potential of chiral peroxides as biologically interesting or even clinically important compounds, no catalytic enantioselective peroxidation has been reported. With a chiral catalyst not only to induce enantioselectivity but also to convert a well established epoxidation pathway into a peroxidation pathway, the first efficient catalytic peroxidation has been successfully developed. Employing readily available alpha,beta-unsaturated ketones and hydroperoxides and an easily accessible cinchona alkaloid catalyst, this novel reaction will open new possibilities in the asymmetric synthesis of chiral peroxides. Under different conditions a highly enantioselective epoxidation with the same starting materials, reagents, and catalyst has was also established.     

Conjugate addition of 2- and 4-pyridylcuprates: an expeditious asymmetric synthesis of natural (-)-evoninic acid

[reaction: see text] The scope and limitations of the conjugate addition of 2- and the first 4-pyridyl Gilman homocuprates to various alpha,beta-unsaturated Michael acceptors are delineated. The conjugate addition of the cuprate of 2-bromo-3-methylpyridine to (E)-methyl crotonate then diastereoselective enolate alkylation and lipase-mediated enantioselective ester hydrolysis have enabled an efficient four-step first asymmetric synthesis of the Celastraceae sesquiterpenoid esterifying ligand (-)-(1'S,2'S)-evoninic acid.     

Asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes with hydrogen peroxide

The first asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes is presented. A chiral bisaryl-silyl-protected pyrrolidine acts as a very selective epoxidation organocatalyst using simple oxidation agents, such as hydrogen peroxide and tert-butyl hydroperoxide. The asymmetric epoxidation reactions proceed under environmental friendly reaction condition in, for example, water mixtures of alcohols, and the scope of the reaction is demonstrated by the formation of optically active alpha,beta-epoxy aldehydes in high yields and enantioselectivities >94% ee. Furthermore, the direct synthesis of the sex pheromone from an acaric mite by asymmetric epoxidation of citral is presented.     

Enantioselective formal hydration of alpha,beta-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.     

First total syntheses of aeruginosin 298-A and aeruginosin 298-B, based on a stereocontrolled route to the new amino acid 6-hydroxyoctahydroindole-2-carboxylic acid

The first total syntheses of aeruginosin 298-A (1) and aeruginosin 298-B (3) are described. The syntheses of the alternative putative structures 2 and 4 were also accomplished. The key common strategic element is the stereo-controlled synthesis of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid (L-Choi, 5) from L-tyrosine. The synthesis of this new bicyclic alpha-amino acid, which is the core of aeruginosins, involves Birch reduction of O-methyl-L-tyrosine (6) and aminocyclization of the resulting dihydroanisole 7 in acid medium, followed by N-benzylation to give the diastereoisomers 12 and 13. Upon acid treatment with HCl-MeOH, the last two produce an equilibrium mixture in which the endo isomer 13 significantly predominates. Hydrogenation of 13 in the presence of (Boc)2O gives 16, which on reduction with LS-Selectride furnishes the alcohol 22, a protected L-Choi. Successive couplings of 22 with D-leucine, protected (R)-(4-hydroxyphenyl)lactic acid, and L-arginine fragments, followed by reduction to the argininol level and a deprotection end step complete the synthetic sequence to produce aeruginosin 298-A (1). Spectral comparison showed that peptide 2, with the structure previously proposed for aeruginosin 298-A, was different from the natural product. However, synthetic 1 was found to be identical to the isolated natural sample of aeruginosin 298-A. These results unequivocally establish that the absolute stereochemistry of aeruginosin 298-A, formerly assigned incorrectly, is D-Hpla-D-Leu-L-Choi-L-Argol, as shown by structure 1. Aeruginosin 298-B was also synthesized and shown to be a mixture of rotamers of D-Hpla-D-Leu-L-ChoiNH2 (3), rather than an epimeric mixture of 3 and the L-Leu-incorporating 4.     

Enantioselective total synthesis of (-)-strychnine using the catalytic asymmetric Michael reaction and tandem cyclization

The enantioselective total synthesis of (-)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol % of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99% ee) as well as a tandem cyclization that simultaneously constructed B- and D-rings (>77% yield). Moreover, newly developed reaction conditions for thionium ion cyclization, NaBH3CN reduction of the imine moiety in the presence of Lewis acid to prevent ring opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

Catalytic enantioselective Strecker reaction of ketoimines

A new method for the catalytic enantioselective Strecker reaction (cyanation) of N-diphenylphosphinoyl ketoimines is described. The asymmetric catalyst is a chiral gadolinium complex prepared from Gd(OiPr)3 and the d-glucose-derived ligand 3 in a 1:2 ratio. The reaction has a broad substrate generality, giving high enantioselectivity from aromatic, ethyl, primary alkyl, and alpha,beta-unsaturated ketoimines. The products could be easily converted to disubstituted alpha-amino acids and their derivatives.     

Catalytic enantioselective pyrrole alkylations of alpha,beta-unsaturated 2-acyl imidazoles

[reaction: see text] Enantioselective additions of pyrroles to alpha,beta-unsaturated 2-acyl imidazoles catalyzed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex (1) have been accomplished. The alpha,beta-unsaturated 2-acyl imidazoles were synthesized in high yields through Wittig olefination. A short, enantioselective synthesis of the alkaloid (+)-heliotridane has been accomplished utilizing this methodology and a 2-acyl imidazole cleavage and cyclization. This methodology was then extended to the one-pot asymmetric synthesis of 2-substituted indoles.     

Enantioselective total synthesis of (−)-strychnine: development of a highly practical catalytic asymmetric carbon-carbon bond formation and domino cyclization

An enantioselective total synthesis of (−)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol% of (R)-ALB, greater than kilogram scale, without chromatography, 91% yield and >99% ee), and a domino cyclization that simultaneously constructed the B- and D- rings of strychnine (>77% yield). Newly-developed reaction conditions for thionium ion cyclization, NaBH₃CN reduction of the imine moiety in the presence of a Lewis acid to prevent the ring-opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.