Enantioselective Formal Total Synthesis Research Articles

Enantioselective formal total synthesis of dihydrospirotryprostatin B

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

Enantioselective Formal Total Synthesis of Damsin

AbstractEnantioselective formal total synthesis of damsin, which was isolated from Compositae Ambrosia maritima L., is described. The highly enantio- and diastereoselective catalytic Mukaiyama–Michael reaction and subsequent highly stereoselective epimerization shorten the synthetic steps. It is also reported that the enolate, which was formed by the reaction of β-keto sulfone with lithium naphthalenide, reacted with methyl cyanoformate to form a quaternary stereogenic center in high yield with high stereoselectivity. This finding extends the synthetic chemistry starting from β-keto sulfones.

The analysis of two distinct strategies toward the enantioselective formal total synthesis of (+)-Gelsenicine

A full account of a formal enantioselective total synthesis of (+)-gelsenicine is described. Separate strategies based on catalytic cycloisomerization as the central step are considered. One plan involves chirality transfer from enantioenriched substrates, while the other employs asymmetric catalysis. The chirality transfer strategy is less effective, while in the latter, phosphoramidite- and bisphosphine-gold complexes are tested and ultimately provide a key intermediate in high enantiopurity in our Gelsemium alkaloid syntheses.

Synthesis of Axially Chiral Biaryls via Enantioselective Ullmann Coupling ofortho‐Chlorinated Aryl Aldehydes Enabled by a Chiral 2,2′‐Bipyridine Ligand

AbstractThe first nickel‐catalyzed highly enantioselective reductive Ullmann coupling ofortho‐chlorinated aryl aldehyde was achieved under mild reaction conditions with a chiral 2,2′‐bipyridine ligand (+)‐DTB‐SBpy, thus providing axially chiral biphenyl or binaphthyl dials with up to 99 % yield and 99.5:0.5 er. The versatility of the products as common synthetic intermediates for diverse axially chiral ligands, catalysts, and functional molecules was demonstrated by short‐step transformations. This protocol also allowed the concise and highly enantioselective formal total synthesis of biologically active natural products (+)‐kotanin, (−)‐isoschizandrin and (+)‐gossypol.

Synthesis of Axially Chiral Biaryls via Enantioselective Ullmann Coupling of ortho-Chlorinated Aryl Aldehydes Enabled by a Chiral 2,2'-Bipyridine Ligand.

The first nickel-catalyzed highly enantioselective reductive Ullmann coupling of ortho-chlorinated aryl aldehyde was achieved under mild reaction conditions with a chiral 2,2'-bipyridine ligand (+)-DTB-SBpy, thus providing axially chiral biphenyl or binaphthyl dials with up to 99 % yield and 99.5:0.5 er. The versatility of the products as common synthetic intermediates for diverse axially chiral ligands, catalysts, and functional molecules was demonstrated by short-step transformations. This protocol also allowed the concise and highly enantioselective formal total synthesis of biologically active natural products (+)-kotanin, (-)-isoschizandrin and (+)-gossypol.

Chirality Transfer and Asymmetric Catalysis: Two Strategies toward the Enantioselective Formal Total Synthesis of (+)-Gelsenicine.

Two strategies are described en route to an enantioselective total synthesis of gelsenicine. One approach centers on a chirality transfer cycloisomerization that ultimately fell short. Separately, an asymmetric catalysis route utilizing bisphosphine-gold-catalyzed cycloisomerization was pursued. A catalytic system was identified that provided a synthetic intermediate in our Gelsemium alkaloid syntheses in high enantiopurity and with absolute configuration determined by electronic circular dichroism, thus representing an enantioselective formal total synthesis of (+)-gelsenicine.

Enantioselective construction of cis-hydroindole scaffolds via an asymmetric inverse-electron-demand Diels-Alder reaction: application to the formal total synthesis of (+)-minovincine.

cis-Hydroindole scaffolds widely exist in a large number of natural products, pharmaceuticals, and organocatalysts. Therefore, the development of efficient and enantioselective methods for the construction of cis-hydroindoles is of great interest and importance. Herein, a novel approach for the enantioselective synthesis of cis-hydroindole scaffolds has been realized through a chiral N,N′-dioxide/Mg(OTf)2 complex catalyzed asymmetric inverse-electron-demand Diels–Alder (IEDDA) reaction of 2-pyrones and cyclic enamines. A series of substituted cis-hydroindole derivatives bearing multiple contiguous stereocenters and functional groups were obtained in good to excellent yields and enantioselectivities (up to 99% yield, and 95% ee) under mild reaction conditions. Moreover, the enantioselective formal total synthesis of (+)-minovincine was concisely furnished with high efficiency and stereoselectivity to demonstrate the synthetic potential of this method.

Asymmetric total synthesis of (+)-dihydroitomanallene B and formal synthesis of (-)-kumausallene.

The first asymmetric total synthesis of (+)-dihydroitomanallene B and its two diastereomers, and the formal synthesis of (-)-kumausallene are reported. The synthesis of the former was completed in 18 steps from 1,4-butanediol (3.4% overall yield), with diastereoselective Tsuji-Trost cyclization to access cis-2,5-disubstituted-3-oxygenated THF scaffold and a Corey-White-Posner reaction to install the bromoallene moiety as the key steps. In addition, the enantioselective formal total synthesis of (-)-kumausallene involving the key Tsuji-Trost cyclization is also realized.

Cross-Metathesis of Methallyl Halides: Concise Enantioselective Formal Total Synthesis of (-)-Presphaerene.

The cross-metathesis (CM) of methallyl halides catalyzed using four different ruthenium-based complexes—Grubbs catalyst, Grubbs second-generation catalyst, Hoveyda-Grubbs second-generation catalyst, and Stewart–Grubbs catalyst—was investigated. When methallyl chloride or bromide was reacted with a model substrate containing a benzyl ether group, the Grubbs catalyst, and Grubbs second-generation catalyst did not promote the reaction well. However, the Hoveyda–Grubbs second-generation catalyst and Stewart–Grubbs catalyst afforded the corresponding products in moderate to good yield with moderate E/Z selectivity. Accordingly, several functionalized methallyl halides were prepared by CM. Various functional groups were well-tolerated in this system when the Stewart–Grubbs catalyst was used. To demonstrate the practical utility of our method, methallyl halide CM was successfully employed for the formal total synthesis of a natural product (–)-presphaerene, in which the precursor of the key cyclopentanecarboxylate intermediate was efficiently prepared in three steps.

Enantioselective Formal Total Synthesis of (-)-Quinagolide.

The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c) Lewis acid (TiCl4) catalyzed intramolecular Friedel-Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective ketone reduction-intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the course of the synthesis, an interesting reductive cleavage of the C-N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of (-)-quinagolide.

Rhodium-Catalyzed Asymmetric N-H Functionalization of Quinazolinones with Allenes and Allylic Carbonates: The First Enantioselective Formal Total Synthesis of (-)-Chaetominine.

An unprecedented asymmetric N-H functionalization of quinazolinones with allenes and allylic carbonates was successfully achieved by rhodium catalysis with the assistance of chiral bidentate diphosphine ligands. The high efficiency and practicality of this method was demonstrated by a low catalyst loading of 1 mol % as well as excellent chemo-, regio-, and enantioselectivities with broad functional group compatibility. Furthermore, this newly developed strategy was applied as key step in the first enantioselective formal total synthesis of (-)-chaetominine.

Formal Total Synthesis of Manzacidin C Based on Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines.

An enantioselective formal total synthesis of (+)-manzacidin C is described. A key feature of the synthesis is the construction of two chiral centers via the asymmetric 1,3-dipolar cycloaddition of an azomethine imine to methallyl alcohol by the use of (S,S)-DIPT as a chiral auxiliary.

A carbohydrate approach for the formal total synthesis of (-)-aspergillide C.

An enantioselective formal total synthesis of aspergillide C is accomplished using commercially available tri-O-acetyl-D-galactal employing a Ferrier-type C-glycosylation, utilizing a Trost hydrosilylation and protodesilylation as key reactions.

Improved Synthesis of Cyclic Tertiary Allylic Alcohols by Asymmetric 1,2‐Addition of AlMe3 to Enones

The development of an improved protocol for the enantioselective Rh(I) /binap-catalysed 1,2-addition of AlMe3 to cyclic enones is reported. (31)P NMR analysis of the reaction revealed that the catalyst in its resting state is a chloride-bridged dimer. This insight led to the use of AgBF4 as an additive for in situ activation of the dimeric precatalyst. Thus, the catalyst loading can now be reduced to only 1 mol% with respect to rhodium. Various 5-7-membered cyclic enones can be transformed into tertiary allylic alcohols with excellent levels of enantioselectivity and high yields. The obtained products are versatile synthetic building blocks, shown by a highly enantioselective formal total synthesis of the pheromone (-)-frontalin as well as formation of a bicyclic lactone that has the core structure of the natural flavour component "wine lactone".

The Enantioselective Formal Synthesis of Rhynchophylline and Isorhynchophylline

Formal attire: An enantioselective formal total synthesis of the alkaloids isorhynchophylline and rhynchophylline is described. The key steps include an organocatalyzed asymmetric Michael addition reaction and an efficient diastereoselective intramolecular iminium ion spirocyclization/lactamization cascade sequence.

Transition-metal-catalyzed synthesis of aspergillide B: an alkyne addition strategy.

A catalytic enantioselective formal total synthesis of aspergillide B is reported. This linchpin synthesis was enabled by the development of new conditions for Zn-ProPhenol catalyzed asymmetric alkyne addition. This reaction was used in conjunction with ruthenium-catalyzed trans-hydrosilylation to affect the rapid construction of a late-stage synthetic intermediate of aspergillide B to complete a formal synthesis of aspergillide B in a highly efficient manner.

ChemInform Abstract: Bicyclic Cyclopentenones via the Combination of an Iridium‐Catalyzed Allylic Substitution with a Diastereoselective Intramolecular Pauson—Khand Reaction.

Enantioselective syntheses of bicyclic cyclopentenones are described. Key steps are an iridium-catalyzed allylic substitution and an intramolecular diastereoselective Pauson–Khand reaction. The diastereoselectivity of the Pauson–Khand reaction was found to be crucially dependent on the unit connecting the propargylic and the olefinic parts of the precursor. Very high degrees of diastereoselection were obtained with an NBoc unit as connector. This methodology has been illustrated by application within an enantioselective formal total synthesis of (−)--kainic acid.

Bicyclic Cyclopentenones via the Combination of an Iridium‐ Catalyzed Allylic Substitution with a Diastereoselective Intramolecular Pauson–Khand Reaction

AbstractEnantioselective syntheses of bicyclic cyclopentenones are described. Key steps are an iridium‐catalyzed allylic substitution and an intramolecular diastereoselective Pauson–Khand reaction. The diastereoselectivity of the Pauson–Khand reaction was found to be crucially dependent on the unit connecting the propargylic and the olefinic parts of the precursor. Very high degrees of diastereoselection were obtained with an NBoc unit as connector. This methodology has been illustrated by application within an enantioselective formal total synthesis of (−)‐α‐kainic acid.

Enantioselective formal total synthesis of the Dendrobatidae frog toxin, (+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation

Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkylacetylenes (with Ph 3SnH and Et 3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman’s pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

Formal Total Synthesis of (–)‐Raphidecursinol B

AbstractAn efficient enantioselective formal total synthesis of antimalarial natural product (–)‐raphidecursinol B along with its all stereoisomers is described from commercially available 3,4,5‐trimethoxybenzaldehyde using the Sharpless asymmetric dihydroxylation, regioselective α‐tosylation, epoxide opening and Mitsunobu reaction as the key reaction steps.