Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Stereocontrolled total synthesis of (-)-ephedradine A (orantine)

The stereocontrolled total synthesis of (-)-ephedradine A has been accomplished. The synthesis features an asymmetric C-H insertion reaction, an intramolecular ester-amide exchange reaction, and a Sharpless asymmetric aminohydroxylation reaction. Construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction.     

Asymmetric intramolecular Cannizzaro reaction of anhydrous phenylglyoxal

The use of anhydrous phenylglyoxal provides a solution to the problem of low reactivity in the asymmetric intramolecular Cannizzaro reaction with alcohols. Double asymmetric induction was achieved in the reaction of anhydrous phenylglyoxal with d-(+)-menthol promoted by a (S,S)-t-BuBox·copper(II) hexafluoroantimonate complex.     

Enantioselective intramolecular cyclopropanation of α-diazo-β-keto sulfones: asymmetric synthesis of bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes

Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a-d is found to proceed with high enantioselectivity (93-98% ee). The yield is moderate due to the competing intramolecular C-H insertion reaction. As intramolecular C-H insertion reaction is not observed in the reaction of the substrates possessing a quaternary carbon at the allylic position, the reactions of 19a and 19b proceed with high enantioselectivity (95% ee) and yield. It was also found that the substrates possessing an ether group, such as 19a and 19b, could be used in this enantioselective IMCP reaction.     

Synthetic studies of GKK1032s: the asymmetric synthesis of the decahydrofluorene skeleton via a novel cyclization of silyl enol ether and sequential retro Diels-Alder and intramolecular Diels-Alder reactions

GKK1032s, which were isolated from the culture broth of Penicillium sp. GKK1032, exhibit antitumor activity. We constructed the fully elaborated decahydrofluorene skeleton of GKK1032s. The C-ring was constructed by intramolecular cyclization reaction between a chiral epoxide and silyl enol ether, and the dienophile moiety was introduced concurrently. In addition, the AB-rings were stereoselectively constructed using novel sequential retro Diels-Alder (DA) and intramolecular Diels-Alder (IMDA) reactions. Several further modifications of the IMDA adduct were carried out, leading to the asymmetric synthesis of the desired hydroxyester including nine stereo centers.     

Terminating catalytic asymmetric Heck cyclizations by stereoselective intramolecular capture of η-allylpalladium intermediates: total synthesis of (−)-spirotryprostatin B and three stereoisomers

A catalytic intramolecular Heck reaction, followed by capture of the resulting η³-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (−)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η³-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.     

Asymmetric Total Synthesis of (−)‐Kravanhin B

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)‐(?)‐carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis‐fused decalin skeleton and an acid‐catalyzed dehydration and olefin isomerization to install the γ‐butenolide ring.     

Asymmetric Total Synthesis of (−)‐Maoecrystal V

The asymmetric total synthesis of (?)‐maoecrystal V, a novel cytotoxic pentacyclic ent‐kaurane diterpene, has been accomplished. Key steps of the current strategy involve an early‐stage semipinacol rearrangement reaction for the construction of the C10 quaternary stereocenter, a rhodium‐catalyzed intramolecular O?H insertion reaction, and a sequential Wessely oxidative dearomatization/intramolecular Diels–Alder reaction to forge the pentacyclic framework of maoecrystal V.     

Total synthesis of (±)-antofine

An efficient preparation of (±)-antofine is described. The main steps involved in this synthesis are the Horner–Wadsworth–Emmons reaction, the intramolecular Schmidt reaction of an azido aldehyde, and the one-pot deprotection of the N-formyl group, followed by Pictet–Spengler cyclization. The asymmetric hydrogenation of the trisubstituted α,β-unsaturated ester is also explored, however only moderate enantio-control (55% ee) is obtained. Finally, (±)-antofine is prepared in six steps from the phenanthryl aldehyde 5 with an overall yield of 35%.     

Asymmetric synthesis of (−)-chicanine using a highly regioselective intramolecular Mitsunobu reaction and revision of its absolute configuration

First asymmetric synthesis of (−)-chicanine has been accomplished in 14 steps by employing the Evans asymmetric syn-selective aldol reaction, diastereoselective hydroboration and an regioselective, intramolecular Mitsunobu etherification. The absolute configuration of (+)- and (−)-chicanine has been revised to 2R,3S,4R,5R and 2S,3R,4S,5S, respectively, through CD analysis.     

Synthesis of both enantiomers of conosilane A

Conosilane A, an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 isolated from Conocybe siliginea, is a tremulane sesquiterpene with highly oxygenated tetracyclic ring system. In this study, we report the synthesis of both enantiomers of conosilane A. The key steps of this synthesis involve asymmetric aldol reaction, furan-ring oxidation followed by transacetalization and intramolecular reductive Heck-type cyclization.     

A Protecting-Group-Free Synthesis of (−)-Salvinorin A

A concise enantioselective total synthesis of the neoclerodane diterpene (−)-salvinorin A is reported. The stereogenic center at C-12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels-Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2-diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)-salvinorin A was synthesized in only 16 steps starting from 3-furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels-Alder strategy employing a 2-bromo-1,3-diene moiety was investigated.     

Total synthesis of (+)-UCS1025A based on a sequential Michael-retro Michael strategy featuring one-pot six-step cascade reaction

The asymmetric total synthesis of UCS1025A is accomplished by establishing a novel and efficient method for the construction of a tricyclic pyrrolizidinone skeleton based on a sequential Michael-retro Michael strategy. The key step is a one-pot six-step cascade reaction including oxidation of a primary alcohol to the corresponding carboxylic acid, a retro thio-Michael reaction, and an intramolecular oxy-Michael reaction. This newly-developed synthetic strategy inspired by “masked” electrophilic character of tricyclic pyrrolizidinone is efficient and high-yielding compared to that developed in previously-reported total syntheses.     

Mechanism of the Asymmetric Hydrogenation of Exocyclic α,β‐Unsaturated Carbonyl Compounds with an Iridium/BiphPhox Catalyst: NMR and DFT Studies

The mechanism of the asymmetric hydrogenation of exocyclic α,β‐unsaturated carbonyl compounds with the (aS)‐Ir/iPr‐BiphPhox catalyst was studied by NMR experiments and DFT computational analyses. Computed optical yields of the asymmetric hydrogenation proceeding by an iridium(I)/iridium(III) mechanism involving a transition state stabilized through two intramolecular hydrogen bonds are in good accordance with the experimental ee values.     

I-MCR-Ullmann cascade toward furo[2,3-b]indole scaffold

An efficient method for the construction of furo[2,3-b]indole derivatives 5 via an isocyanide-based multicomponent reaction (I-MCR) and a copper-catalyzed intramolecular Ullmann reaction sequence was described. This two-step sequence can be performed in a one-pot manner to produce the desired product 5 in moderate to good yield (up to 90%).     

Synthesis of (‐)‐herbertenediol and (aR,aS)‐mastigophorenes A via asymmetric intramolecular heck coupling reaction

Total enantioselective synthesis of the natural (‐)‐Herbertenediol (1) was accomplished in eleven steps with an overall yield of 15% starting from the 2‐methoxy‐4‐methyl‐phenol. The total synthesis features asymmetric intramolecular Heck reaction and Wolff‐Kishner‐Huang reduction. (aR, aS)‐Mastigophorenes A was also synthesized through the oxidative coupling reaction.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.     

Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2-Amido Benzyl Alcohols: Asymmetric Synthesis of 4H-3,1-Benzoxazines

An efficient method for the asymmetric synthesis of 4H-3,1-benzoxazines was developed by kinetic resolution of 2-amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram-scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Toward the synthesis of tetrodecamycin: asymmetric synthesis of a direct precursor of the C6C18 trans-decalin portion

We report the asymmetric synthesis of a direct precursor of the C6C18 trans-decalin portion of tetrodecamycin utilising an asymmetric intramolecular Diels-Alder (IMDA) reaction as the key step.