Recent Advances in Amino Acid-Based Phosphine Catalysts and Their Applications in Asymmetric Reactions

Amino acid-based catalysts have been intensively researched in recent years. Amino acid-derived phosphines possess high nucleophilicity and exhibit unique catalytic activities in asymmetric synthesis. L-Threonine and valine are most utilized natural amino acids in the preparation of chiral phosphines. The efficient and versatile chiral phosphine catalysts are applied in a wide range of reactions such as MBH reaction, Rauhut–Currier reaction, Michael addition, [4 + 2]-annulation, [3 + 2]-annulation, 1,4-dipolar cycloaddition. They are also widely used in the construction of core structures of natural products. Amino acid-based phosphine catalysts and their applications in asymmetric synthesis are summarized.     

3 + 2]-annulation reactions of chiral allylsilanes and chiral aldehydes. studies on the synthesis of bis-tetrahydrofuran substructures of annonaceous acetogenins

[Structure: See text] Double asymmetric [3 + 2]-annulation reactions of chiral beta-silyloxyallylsilanes with chiral 2-tetrahydrofuranyl carboxaldehydes have been studied, leading to the stereocontrolled synthesis of six diastereomeric bis-tetrahydrofuran structures corresponding to the core subunits of members of the Annonaceous acetogenin family of natural products. Transition-state models are proposed to account for the stereoselectivity of the double-stereodifferentiating [3 + 2]-annulation reactions.     

Synthesis of the C11-C29 fragment of amphidinolide F

[reaction: see text] An efficient synthesis of the C(11)-C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 and a highly stereoselective methyl ketone aldol reaction to generate the C(11)-C(16) segment.     

Enantioselective [4 + 2]-annulation of chiral crotylsilanes: application to the synthesis of a C1-C22 fragment of leucascandrolide A

[reaction: see text] The asymmetric synthesis of a C1-C22 fragment (2) of leucascandrolide A is described. Synthetic highlights include the construction of the C9-C22 pyran fragment using a formal [4 + 2]-annulation of a chiral organosilane. A diastereoselctive Mukaiyama aldol was used to introduce the C9 stereocenter and complete the assembly of the macrocycle's carbon skeleton.     

Copper-catalyzed aerobic [3+2]-annulation of N-alkenyl amidines

A method for the synthesis of bi- and tricyclic amidines has been developed through copper-catalyzed aerobic [3+2]-annulation reaction of N-alkenyl amidines. These cyclic amidines could be converted into mono-benzyl-protected vicinal diamines by the reduction with aluminum hydride.     

Stereoselective synthesis of functionalized pyrrolidines via a [3 + 2]-annulation of N-Ts-alpha-amino aldehydes and 1,3-Bis(silyl)propenes

An efficient protocol for stereoselective synthesis of densely functionalized pyrrolidines by a [3 + 2]-annulation of N-Ts-alpha-amino aldehydes and 1,3-bis(silyl)propenes is described.     

Sc(OTf)3-catalyzed tandem (3+3)-annulation/lactonization of cyclopropanes with salicylaldehyde nitrones to access polycyclic 1,2-oxazines

A Sc(OTf)₃-catalyzed tandem (3 + 3)-annulation/lactonization of donor-acceptor cyclopropane 1,1-dieters with salicylaldehyde nitrones has been reported, affording a wide range of tetrahydrochromeno[4,3-c][1,2]oxazin-5(1H)-ones in moderate yields with excellent diastereoselectivities. Besides, the gram-scale reaction has also been explored to demonstrate the utility of this protocol. Moreover, the mechanism was investigated through control experiments, which show the reaction proceeds via a tandem (3 + 3)-annulation/lactonization reaction.     

Total synthesis of (-)-kendomycin

An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction) is employed to afford the protected macrocycle.     

Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C

Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first-generation sequence involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second-generation synthesis involves an intramolecular hetero-Michael cyclization of 8.     

Studies on the synthesis of pectenotoxin II: synthesis of a C(11)-C(26) fragment precursor via [3 + 2]-annulation reactions of chiral allylsilanes

[see reaction]. A synthesis of tetracycle 2 corresponding to the C(11)-C(26) fragment of pectenotoxin II is described. The synthesis features two highly stereoselective [3 + 2]-annulation reactions of chiral allylsilanes, generated via allylboration of aldehydes with the chiral gamma-silylallylborane 4 or the gamma-silylallylboronate 19, for construction of the highly substituted C and E rings.     

Formal [4 + 1]- and [5 + 1]-annulation by an S(N)2-conjugate addition sequence: stereoselective synthesis of highly substituted carbocycles

K(2)CO(3)-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S(N)2-conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner.     

Organocatalytic strategies for the construction of optically active imidazoles, oxazoles, and thiazoles

This study demonstrates the first enantioselective synthesis of hydroxyalkyl- and aminoalkyl-substituted imidazoles, oxazoles, and thiazoles. The approach developed utilizes a highly effective one-pot reaction cascade that consists of either an organocatalytic epoxidation or aziridination of α,β-unsaturated aldehydes coupled with a [3+2]-annulation, in which amidines, ureas, or thioureas act as effective 1,3-dinucleophilic species. The methodology described benefits from low catalyst loadings, commercially and readily available starting materials, and mild reaction conditions.     

Cyclohexenol annulation via the alkoxy-accelerated rearrangement of vinylcyclobutanes

The lithium and potassium salts of 2-vinylcyclobutanols undergo vinylcyclobutane rearrangement at 25–70°, providing an efficient method for the synthesis of 3-cyclohexenol derivatives. 2-Vinylcyclobutanones are prepared from α,β-unsaturated carbonyl compounds by the method of Trost and via [2 + 2]-cycloadditions of olefins and vinylketenes. Addition of hydride or alkyllithium reagents then generates 2-vinylcyclobutanol salts which directly rearrange to afford 3-cyclohexenols. The two methods constitute new [3 + 3]- and [4 + 2]-annulation approaches to 6-membered carbocycles.     

Total synthesis of (+)-isatisine A

Total synthesis of (+)-isatisine A is described based on the application of a silyl-directed Mukaiyama-type [3 + 2]-annulation for the preparation of a fully substituted furan core. The indole branch forming the quaternary carbon center at C2 was constructed by addition to an intermediate N-acyliminium ion derived from aminal 4. In addition, the fused tetracyclic framework including furan core was built up using modified Buchwald amidation conditions.     

Mn(III)-mediated formal [3+3]-annulation of vinyl azides and cyclopropanols: a divergent synthesis of azaheterocycles

Mn(III)-mediated formal [3+3]-annulation has been developed using readily available vinyl azides and cyclopropanols with a wide range of substituents. Vinyl azides were successfully applied as a three-atom unit including one nitrogen to prepare pyridines and δ-lactams by the reactions with monocyclic cyclopropanols as well as to construct 2-azabicyclo[3.3.1] and 2-azabicyclo[4.3.1] frameworks with bicyclic cyclopropanols, bicyclo[3.1.0]hexan-1-ols, and bicyclo[4.1.0]heptan-1-ols. These reactions were initiated by a radical addition of β-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give iminyl radicals, which cyclized with the intramolecular carbonyl groups. In addition, application of the present methodology to a synthesis of the quaternary indole alkaloid, melinonine-E, was accomplished.     

Formal [4+2]-annulation of chiral crotylsilanes: synthesis of the C19-C28 fragment of phorboxazoles

A stereoselective synthesis of the C19-C28 fragment of phoborxazole A and B is described. The key step is an enantioselective [4 + 2]-annulation of a crotylsilane 10 with a propargylic aldehyde 11 affording a functionalized dihydropyran 12. A solvent-dependent stereoselective epoxidation of dihydropyrans is also documented.     

Is the metal involved or not? A computational study of Cu(I)-catalyzed [4 + 1] annulation of vinyl indole and carbene precursor

The Cu(I)-catalyzed [4 + 1] annulation of vinyl indoles and a carbene precursor is a powerful method for constructing cyclopentaindole derivatives. Density functional theory (DFT) calculations were used to elucidate the mechanism and regioselectivity of this reaction. After Cu-assisted indole C3-alkylation, direct 1,5-annulation was favored over the Cu-assisted annulation pathway. Furthermore, the regioselectivity for 1,5-annulation was attributed to the generated five-membered-ring product being more stable than the three-membered-ring product from 1,3-annulation, which was the kinetically favored pathway.     

2,3-Bis(phenylsulfonyl)-1,3-butadiene: Substrate for Michael Donor/Acceptors in a Novel Synthesis of Fused Cyclopentenes

The reaction of 2,3-bis(phenylsulfonyl)-1,3-butadiene with the anion of various 1-substituted dimethyl 1-pentenedioates has been investigated with the purpose of devising a tandem conjugate addition-[3 + 2]-anionic cyclization route for the synthesis of bicyclo[3.3.0]octenes. The reaction proceeds with complete stereospecificity as was evidenced by treating (E)- and (Z)-dimethyl (3-cyano-2-propenyl)propanedioate with NaH in the presence of the bis(phenylsulfonyl)diene. In both cases only a single cycloadduct was obtained with no detectable signs of the other diastereomer. The overall process involves a series of three sequential conjugate additions followed by benzenesulfinate ion ejection. The success of the method is dependent on the electrophilicity of the proximal pi-bond. When 2-((5-oxo-2,5-dihydrofuranyl)methyl)malonic acid dimethyl ester was used, a mixture of the tricyclic adduct as well as an allene was obtained. In this case, elimination of the benzenesulfinate group from the initially formed sulfone-stabilized carbanion is competitive with the intramolecular [3 + 2]-annulation process. The base-induced reaction of dimethyl 2-(methoxycarbonyl)-2-pentenedioate with the bis(phenylsulfonyl)diene was also studied. Even though the position of the acceptor moiety on the pi-bond was altered, the tandem Michael reaction sequence still occurs. The course of the reaction is dependent upon the length of the tether as well as the relative placement of the electron-withdrawing group on the olefin. Reaction with gamma-substituted beta,gamma-alkenyl derivatives leads to bicyclo[3.3.0]octenes, whereas beta-substituted beta,gamma-alkenyl reagents provide bicyclo[3.3.0]octenes derived from a novel alpha-elimination reaction.     

Gallium(iii)-mediated dimerization routes for (5-phenyl-2-thienyl)cyclopropane-1,1-dicarboxylate

A selectivity-switched dimerization process for (5-phenyl-2-thienyl)cyclopropane-1,1-dicarboxylate under activation conditions with anhydrous Gaiii salts was developed. Using GaCl3 or Ga(NTf2)3 as catalysts, 3a,4,5a,6,7,8-hexahydro-5H-pentaleno[6a,1-b]thiophene and 5,6-dihydro-4H-cyclo-penta[b]thiophene derivatives can be selectively obtained as a result of ipso-type and [3+2]-annulation type dimerization. The crucial role of a phenyl substituent at position 5 of the thiophene ring and some regularities are discussed.     

3H-Pyrroles as a platform for the catalyst-free construction of dihydropyrrolo[2,1-b]oxazoles: [4 + 2]-cycloaddition vs [2 + 3]-annulation with 1-cyano-3-hydroxyalkynes

Non-aromatic pyrrole isomers, 3,3-dialkyl-2-aryl-3H-pyrroles, were reacted with 1-cyano-3-hydroxyalkynes under mild, catalyst-free conditions (20–60?°C) to regio- and stereoselectively afford (Z)-2-(dihydropyrrolo[2,1-b]oxazolylidene)acetonitriles in 62–82% yield, thus evidencing the preference for [2?+?3]-annulation over the [4?+?2]-Diels-Alder alternative. The reaction involves initial nucleophilic addition of the pyrrole moiety at the triple bond followed by tandem ring closure of an anionic intermediate.