Mukaiyama Research Articles

Total Synthesis of Aflastatin A.

The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.

On the role of β-silyloxy- and β-alkoxyaldehyde protecting groups in Mukaiyama aldol 1,3-diastereocontrol

Longstanding paradigmatic studies have noted anti-1,3-diastereocontrol in Mukaiyama aldol reactions with β-silyloxy- and β-alkoxyaldehydes. In our efforts to exploit this stereocontrol, we found that an aldehyde of this type that lacks branching at the γ-carbon led to eroded diastereoselectivity that was restored upon changing the β-protecting group. This suggested the hypothesis that 1,3-anti selectivity in these cases is inversely dependent on the size of the β-protecting group. In testing this hypothesis, Mukaiyama aldol reactions of several analogs of unbranched β-silyloxy- and β-alkoxyaldehydes, varying only the protecting group, showed improved selectivity with smaller silyl and alkyl groups. These results will aid synthetic design as well as provide experimental benchmarks for computational studies.

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine.

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating α-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-β inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.

Synthetic Approaches Towards the Total synthesis of tubulysin and its fragments: A review.

Tubulysins, linear tetrapeptides show extraordinary cytotoxicity against various cancer cells, with IC50 values in nano or picomolar range. Due to their extremely vigorous anti-proliferative and antiangiogenic characteristics, tubulysins exhibit captivating prospects in the development of anticancer drugs. This review focuses on diverse routes for the total synthesis of natural and synthetic tubulysins as well as their fragments. The purpose of this review is to present the synthetic strategies for the development of antitumor agents, tubulysins. A range of synthetic pathways adopted for the total synthesis of tubulysins and their fragments have been described in this review. Synthesis of fragments, Tuv, Tup, and Tut can be accomplished by adopting appropriate strategies such as Manganese-mediated synthesis, Ireland-Claisen rearrangement, Mukaiyama aldol reaction, and Mannich process etc. Tubulysin B, D, U, V, and N14-desacetoxytubulysin H have been prepared through Mitsunobu reaction, tert-butanesulfinamide method, Tandem reaction, aza-Barbier reaction, Evans aldol reaction, and C-H activation strategies etc. The remarkable anticancer potential of tubulysins toward a substantiate target make them prominent leads for developing novel drugs against multidrug-resistant cancers.

Copper complex featuring Cation-Excess alternation counterion catalyzing Mukaiyama-Aldol reaction of ketene silyl acetals and ketones

The [(P+B-P+)CuCl3-]2 complex (P+B-P+ = phosphonium-borate-phosphonium) featuring the dication-monoanion-type counterion was synthesized. The resulting cationic copper catalyst enhanced the Mukaiyama-Aldol reaction of ketene silyl acetals and ketones for the formation of protected tertiary alcohols.

Synthesis of 3-epi-Hypatulin B Featuring a Late-Stage Photo-Oxidation in Flow.

A synthesis of 3-epi-hypatulin B, a highly oxygenated and densely functionalized bicyclic scaffold, is reported. The carbon skeleton was prepared by functionalization of a cyclopentanone and an intramolecular Mukaiyama aldol reaction. Highlights include a late-stage photo-oxidation of a methoxyallene to provide an ester group. The problems encountered in the batch process were solved by translation into a flow protocol. Our synthesis highlights the value of flow chemistry to enable challenging late-stage transformations in natural product synthesis.

Fluoride Anion Catalyzed Mukaiyama–Aldol Reaction: Rapid Access to α-Fluoro-β-hydroxy Esters

The Mukaiyama-aldol reaction is probably one of the most efficient strategies to prepare synthetically useful β-hydroxy carbonyl compounds. However, only several reported methods were concerned with the accesses to α-fluoro-β-hydroxy esters. Herein, we report a protocol for a fluoride anion-mediated Mukaiyama aldol reaction with low catalytic loading in a short reaction time to incorporate fluorine at the α position into β-hydroxy esters. The method shows good functional-group tolerance and scale-up potential, moreover, is applicable to the late-stage modification of natural products and small molecular drugs.

Synthesis of Functionalized δ-Hydroxy-β-keto Esters and Evaluation of Their Anti-inflammatory Properties.

δ‐Hydroxy‐β‐keto esters and δ,β‐dihydroxy esters are characteristic structural motifs of statin‐type natural products and drug candidates. Here, we describe the synthesis of functionalized δ‐hydroxy‐β‐keto esters in good yields and excellent enantioselectivities using Chan's diene and modified Mukaiyama‐aldol reaction conditions. Diastereoselective reduction of δ,β‐dihydroxy esters afforded the respective syn‐ and anti‐diols, and saponification yielded the corresponding acids. All products were evaluated for their anti‐inflammatory properties, which uncovered a surprising structure‐activity relationship.

Enantioselective Total Syntheses of Grayanane Diterpenoids: (-)-Grayanotoxin III, (+)-Principinol E, and (-)-Rhodomollein XX.

Enantioselective total syntheses of (-)-grayanotoxin III, (+)-principinol E, and (-)-rhodomollein XX were accomplished based on a convergent strategy. The left- and right-wing fragments were assembled via the diastereoselective Mukaiyama aldol reaction catalyzed by a chiral hydrogen bond donor. The unique 7-endo-trig cyclization based on a bridgehead carbocation forged the 5/7/6/5 tetracyclic skeleton that underwent redox manipulations and 1,2-migration to access different grayanane diterpenoids.

Poly(β-trimethylsilyloxy ester): A Degradable Polymer Based on Retro Mukaiyama Aldol Reaction.

Herein, a new type of degradable poly(β-trimethylsilyloxy ester) prepared by the organocatalyzed Mukaiyama aldol polyaddition between bis(silyl ketene acetal)s and dialdehydes is reported. Specifically, the t-Bu-P4 -catalyzed polyaddition between 1,2-bis[2-methyl-1-(trimethylsiloxy)prop-1-enyloxy]ethane (MTS2 ) and 4,4'-biphenyldicarboxaldehyde (BPDA) or butane-1,4-diyl bis(4-formylbenzoate) (BDA) can produce poly(β-trimethylsilyloxy ester)s with number-average molar mass greater than 10kg mol-1 . For the first time, it is found that these poly(β-trimethylsilyloxy ester)s are degradable in solution in the presence of nucleophiles such as fluoride and cyanide anions. It is also found that the degradation behavior of poly(β-trimethylsilyloxy ester)s is highly dependent on the nature of the used catalyst and the bond scission in polymer is fundamentally rooted in the retro Mukaiyama aldol reaction mechanism.

Modern Synthesis and Chemistry of Stabilized Ketene N,O-Acetals

AbstractKetene N,O-acetals are robust and versatile synthons. Herein, we outline the synthesis of stable ketene N,O-acetals in the twenty-first century. In addition, we review recent developments in the chemistry of ketene N,O-acetals, as it applies to the vinylogous Mukaiyama aldol reaction, electrolysis, and pericyclic transformations. While dated reports rely on in situ use, modern methods of ketene N,O-acetal synthesis are heavily oriented towards producing products with high ‘bench’ stability; moreover, in the present century, chemists typically enhance the stability of ketene N,O-acetals by positioning an electron-withdrawing group at the β-terminus or at the N-position. As propitious substrates in the vinylogous Mukaiyama aldol reaction, ketene N,O-acetals readily provide polyketide adducts with high regioselectivity. When exposed to electrolysis conditions, the title functional group forms a reactive radical cation and cleanly couples with a variety of activated olefins. Given their electron-rich nature, ketene N,O-acetals act as facile substrates in several rearrangement reactions; further, ketene N,O-acetals reserve the ability to act as either dienophiles or dienes in Diels–Alder reactions. Lastly, ketene N,O-acetals are seemingly more stable than their O,O-counterparts and more reactive than analogous N,N- or S,S-acetals; these factors, in combination, make ketene N,O-acetals advantageous substitutes for other ketene acetal homologues.1 Introduction2 Select Methods of Stabilization-Oriented Ketene N,O-Acetal Synthesis3 Ketene N,O-Acetals in the Vinylogous Mukaiyama Aldol Reaction4 Ketene N,O-Acetals in Anodic Coupling and Electrochemical Oxidation Reactions5 Rearrangement and Diels–Alder Reactions of Ketene N,O-Acetals6 Conclusions, Perspectives, and Directions

C2-Symmetric 2,2'-Bipyridine-α,α'-1-adamantyl-diol Ligand: Bulky Iron Complexes in Asymmetric Catalysis.

The synthesis of a chiral 2,2'-bipyridine-α,α'-1-adamantyl-diol ligand was achieved starting from commercially available materials. The bulky ligand was synthesized in three steps in 40% overall yield with stereoselectivities of 98% de and >99.5% ee for the S,S enantiomer. The absolute configuration of and structural insights into a heptacoordinated 2,2'-bipyridine-α,α'-1-Ad-diol/FeII chiral complex were obtained from single-crystal diffraction analyses. The newly synthesized ligand was used in iron-catalyzed asymmetric Mukaiyama aldol, thia-Michael, and Diels-Alder reactions.

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.

Synthesis of 2,2-Difluoro-3-hydroxy-1,4-diketones via an HFIP-Catalyzed Mukaiyama Aldol Reaction of Glyoxal Monohydrates with Difluoroenoxysilanes.

A novel efficient HFIP-catalyzed synthesis of structurally diverse 2,2-difluoro-3-hydroxy-1,4-diketone derivatives from readily available glyoxal monohydrates and difluoroenoxysilanes is described. This convenient protocol is induced by the distinctive fluorine effect of the reactants and the fluoroalcohol catalyst, which represents the first application of fluoroalcohol catalysis in a Mukaiyama aldol reaction.

Front Cover: Highly Efficient and Stereoselective Mukaiyama Aldol Reaction with Chiral Aziridine‐2‐carboxaldehyde and Its Synthetic Applications (Asian J. Org. Chem. 1/2022)

The straight forward and highly diastereoselective synthesis of β-(aziridin-2-yl)-β-hydroxy ketones was achieved by the Mukaiyama aldol reaction of optically pure 1-(α-methylbenzyl)-aziridine-2-carboxaldehyde and various enol-silanes in the presence of ZnCl2 via a chelation-controlled transition state (98:2 dr, and >82% yields). These β-(aziridin-2-yl)-β-hydroxy ketones were applied for the synthesis of various alkaloids including epiallo-isomuscarine, epi-enigmol, and epi-galantinic acid. More information can be found in the Full Paper by Nikhil Srivastava and Hyun-Joon Ha.

BF3 -Catalyzed Mukaiyama aldol reaction of acetaldehyde with 2-siloxy-1-propene.

The Mukaiyama aldol reaction is a powerful tool for the construction of the carbon-carbon bond and the formation of β-hydroxycarbonyl compounds. In this work, the mechanism of acetaldehyde and 2-siloxy-1-propene both in the absence and presence of the catalyst BF3 was investigated based on density functional theory. The mechanism includes two major steps: the formation of the carbon-carbon bond and the removal of SiH3 /BF2 by water. The energy barrier of the carbon-carbon bond formation process in the presence of BF3 is obviously lower, indicating that BF3 is a good catalyst for this reaction. In terms of molecular configuration, the different tensions between the five-membered-ring and six-membered-ring can be considered as the possible reason for the catalytic effect of BF3 . In terms of charge transfer, the charges of natural population analysis in the carbon atom of the carbonyl group in acetaldehyde becomes more positive, which is easier to attack by nucleophiles and promote the nucleophilic process.

A Chiral, Dendralenic C–H Acid

AbstractWe report the synthesis of a chiral dendralenic C–H acid, which contains three unsubstituted binaphthyl moieties. This motif and an achiral variant can be made from their corresponding bis(sulfone) precursors in one step. Despite the presence of the enantiopure binaphthyl backbone, the newly designed chiral C–H acid showed only poor enantioselectivity in a Mukaiyama aldol reaction. First attempts toward the synthesis of 3,3′-hexasubstituted binaphthyl-based dendralenic acids are also reported.

Silyldienolates in Organocatalytic Enantioselective Vinylogous Mukaiyama-Type Reactions: A Review.

Mukaiyama aldol, Mannich, and Michael reactions are arguably amongst the most important C–C bond formation processes and enable access to highly relevant building blocks of various natural products. Their vinylogous extensions display equally high potential in the formation of important key intermediates featuring even higher functionalization possibilities through an additional conjugated C–C double bond. Hence, it is much desired to develop highly selective vinylogous methods in order to enable unconventional, more efficient asymmetric syntheses of biologically active compounds. In this regard, silyl-dienolates were discovered to display high regioselectivities due to their tendency toward γ-additions. The control of the enantio- and diastereoinduction of these processes have been for a long time dominated by transition metal catalysis, but it received serious competition by the application of organocatalytic approaches since the beginning of this century. In this review, the organocatalytic applications of silyl-dienolates in asymmetric vinylogous C–C bond formations are summarized, focusing on their scope, characteristics, and limitations.

Oxazaborolidinone-Mediated Asymmetric Bisvinylogous Mukaiyama Aldol Reaction.

A bisvinylogous Mukaiyama aldol reaction using oxazaborolidinones as a source of chirality was developed. This methodology allows the fast assembly of conjugated dienols by expanding the vinylogy principle by two additional carbons, and can be conducted using a readily available Lewis acid at reasonable reaction times. A broad range of aromatic and aliphatic aldehydes can be used providing access to complex building blocks for polyketide synthesis.

Highly Efficient and Stereoselective Mukaiyama Aldol Reaction with Chiral Aziridine‐2‐carboxaldehyde and Its Synthetic Applications

AbstractA straightforward and highly diastereoselective synthesis of β‐(aziridin‐2‐yl)‐β‐hydroxy ketones was achieved by the Mukaiyama aldol reaction of optically pure 1‐(α‐methylbenzyl)‐aziridine‐2‐carboxaldehyde and various enol‐silanes in ZnCl2 via a chelation‐controlled transition state (98 : 2 dr and >82% yields). These β‐(aziridin‐2‐yl)‐β‐hydroxy ketones were applied for the synthesis of various alkaloids including epiallo‐isomuscarine, epi‐enigmol, and epi‐galantinic acid.