Mukaiyama Research Articles

A Novel Enantioselective Synthesis of Cryptophycins Unit A from Rocher’s Ester

A novel synthesis of cryptophycin unit A in its enantiomerically pure form was achieved. In five steps, an enantiomeric mixture of unit A was initially prepared from trans-cinnamaldehyde. Subsequently, in its enantiomerically pure forms, unit A was prepared from Rocher’s ester in six steps, involving an essential aldehyde (2R,3E)-2-methyl-4-phenylbut-3-enal. The final step of this process involved two different approaches: a Reformatsky reaction of an essential aldehyde with tertbutyl 4-bromocrotonate and the vinylogous Mukaiyama aldol reaction with O,O-Silyl ketene acetal in the presence of isopropyl alcohol and L-tryptophane-based B-phenyloxazaborolidinone, thereby resulting in the desired products in good overall yields and high enantioselectivities.

Sparteine Metal Complexes as Chiral Catalyst for Asymmetric Synthesis – A Review

The commercial availability of (2)-sparteine reflects its easy isolation by extraction of papilionaceous plants such as Scotch broom (Cytisus scoparius). The aim of this review is to highlight recent advances in the field of asymmetric synthesis that use sparteine as chiral diamine ligand, emphasizing the use of sub-stoichiometric or catalytic amounts of this ligand. Lithium, palladium copper, cobalt, nickel, titanium and zinc chloride complexes with sparteine. It has found widespread use as a chiral ligand for asymmetric reactions. Asymmetric aldol reaction, Sonogashira-type reaction, Henry reaction, Oxidative kinetic resolutions of secondary alcohols, Michael addition reaction, asymmetric aerobic oxidative, Wacker cyclization of allylphenol, deprotonation, Mukaiyama aldol reaction are the various asymmetric reactions often lead to highly enantioselective transformations biologically active molecules and natural products.

“Water” accelerated B(C6F5)3-catalyzed Mukaiyama-aldol reaction: Outer-sphere activation model

“Water” accelerated B(C6F5)3-catalyzed Mukaiyama-aldol reaction: Outer-sphere activation model

New Polymeric Disulfonimide for Heterogeneous Silicon Lewis Acid Catalysis

AbstractA new heterogeneous polymeric disulfonimide was very easily synthesized from simple commercially available reagents. The new cost-effective catalytic material exhibited a tremendously enhanced reactivity in a benchmark Mukaiyama aldol reaction via silicon Lewis acid activation when compared with common acidic resins. Moreover, the reported polymeric disulfonimide exhibits outstanding robustness, as confirmed by its good thermal stability and excellent recyclability.

Optimizing the Synthesis Strategy of the Chlorinated Chain Characteristic to the Enacyloxin Series Using Models.

In this paper are presented the results of the preliminary studies conducted on two model substrates that allowed the testing of various strategies and set the proper conditions that thereafter culminated in the synthesis of the C1-C23 chain of enacyloxin-IIa and its congeners. Innovative strategic options were explored on each model allowing the stereochemical control of the following two elements: (a) the 2E, 4E, 6E, 8E, and 10Z chlorinated undecapentaenoic chain, thanks to Z-selective Kaneda's alkyne allylchlorination and an E-selective Pd/Cu allene-alkyne coupling and (b) the unusual syn-anti -OH/-Cl/-OCONH2 C17-C19 triad, thanks to a highly diastereoselective Mukaiyama aldol reaction.

Synthesis of 4'-Thionucleoside Analogues Bearing a C2' Stereogenic All-Carbon Quaternary Center.

The design of novel 4'-thionucleoside analogues bearing a C2' stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2' center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1',2'-anti thioaminal furnished the desired β-D-4'-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1',4'-trans isomers, causing a significant decrease in their reaction rate relative to 1',4'-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4'-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.

Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure-Activity Relationships.

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure-activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations.

Installation of superacidic carbon acid moieties into polymer materials via post-polymerization modification.

In the fields of polymer and material chemistries, strong acid units have mainly included sulfonic acids, which has limited the extension of related material chemistries. Here, a unique carbon acid functionality, namely the bis[(trifluoromethyl)sulfonyl]methyl group, was integrated with polymers via a simple postpolymerization modification with the outstandingly electrophilic 1,1-bis[(trifluoromethyl)sulfonyl]ethylene. The proposed synthesis protocol was verified as an efficient process even for solid-state reactions. The synthesis afforded an organic material with a surface decorated with bis[(trifluoromethyl)sulfonyl]methyl units. The fabricated membranes featuring surface bis[(trifluoromethyl)sulfonyl]methyl units functioned as efficient organocatalysts with high catalytic activity for the Mukaiyama aldol reaction. This study provides a simple method for installing superacidic carbon acid moieties onto the surfaces of materials without tedious chemical treatments.

Synthesis of the bicyclic butenolide core of pallamolide A: a biomimetic approach.

Pallamolide A is a 7,8-seco-labdane terpenoid possessing a unique bicyclo[2.2.2]octane core and a spiro-butenolide moiety. A biomimetic synthesis of the bicyclic butenolide core over 10 steps is reported, featuring an unexpected autoxidation ring opening, and a vinylogous Mukaiyama aldol reaction which was spontaneously followed by an unusual intramolecular vinylogous aldol reaction to assemble the spiro-butenolide moiety and bicyclic core of pallamolide A.

Synthesis of chiral functional polyhydroxylated arenes via Mukaiyama aldol reaction from Perlin aldehydes

Functionalized aryl polyhydroxylated compounds could be of great synthetic value for natural product synthesis. However, the synthesis of such compounds usually requires multi-step synthesis or the usage of sensitive reagents. We present here a practically simple route for the synthesis of such functionalized arylpolyols from glycal derived α,β-unsaturated 2,3-dideoxy aldehyde as well as α,β-saturated 2,3-dideoxy aldehyde (Perlin aldehydes) via Mukaiyama cross aldol condensation in the presence of silyl enol ether and TiCl4. It was observed that the nature of the electronic substitution of the silyl enol ether does not play any role in the yield of the desired products. Further functionalization of the products has also been shown.

Catalyst-Free Reactions under Biocompatible Conditions

AbstractCatalyst-free biocompatible reactions are a class of green chemical processes that are also applicable to the field of chemical biology. In this account, we detail our journey in this exciting area of research since 2000. Various types of catalyst-free biocompatible reactions, such as the Mukaiyama aldol reactions and thiol-specific click reactions, and their applications to the functionalization of proteins are described. These reactions work well without destroying the three-dimensional structures of the proteins. Other reactions, including the C–SO2 and C–N bond-forming reactions, are also discussed. These reactions work in a truly green manner in which the use of organic solvents can be totally avoided. This toolbox of green chemical processes will certainly facilitate the work of researchers in the pharmaceutical industries.1 Introduction2 C–C Bond-Formation Reactions: The Mukaiyama Aldol Reaction3 C–S Bond-Formation Reactions: Allenic Amide as the Electrophiles4 C–SO2R Bond-Formation Reactions4.1 Allylic Alcohols as the Electrophiles4.2 Allenic Carbonyl Compounds as the Electrophiles5 C–N Bond-Formation Reactions6 Conclusions and Outlook

Synthesis of the 5/6 fused-spiro tricyclic framework of manginoid A

We developed a concise, ten-step route to the 5/6 fused-spiro tricyclic framework (A/B/C rings) of manginoid A from the starting materials cyclopentenone and 1,3-cyclohexanedione. Michael addition and subsequent Mukaiyama aldol reaction introduced two side chains at the α,β-positions of cyclopentenone. Tsuji–Trost allylation of this cyclopentenone moiety and 1,3-cyclohexanedione afforded a key intermediate. A late-stage Michael addition formed the spiro-fused tricyclic framework.

Mukaiyama aldol reaction: an effective asymmetric approach to access chiral natural products and their derivatives/analogues.

The Mukaiyama aldol reaction is generally a Lewis-acid catalyzed cross-aldol reaction between an aldehyde or ketone and silyl enol ether. It was first described by Mukaiyama in 1973, almost 5 decades ago, to achieve the enantioselective synthesis of β-hydroxy carbonyl compounds in high percentage yields. Mukaiyama aldol adducts play a pivotal role in the synthesis of various naturally occurring and medicinally important organic compounds such as polyketides, alkaloids, macrolides, etc. This review highlights the significance of the Mukaiyama aldol reaction towards the asymmetric synthesis of a wide range of biologically active natural products reported recently (since 2020).

Concise total synthesis and structure revision of metacridamides A and B.

Concise total synthesis of metacridamides A and B was accomplished through repetitive vinylogous Mukaiyama aldol reactions and ynamide-mediated macrolactonization. Spectral data of both synthetic products were identical to those of the natural products, resulting in the revision of the absolute configuration of the C-9 position to be S.

Organocatalytic synthesis of axially chiral tetrasubstituted allenes.

Asymmetric organocatalysis is a growing method for the synthesis of axially chiral tetrasubstituted allenes, the most challenging one among allene syntheses. In this method, chiral organocatalysts such as phase-transfer catalysts, peptides, disulfonimides, and binaphthyl/bispiro phosphoric acids have displayed remote control of regio- and stereoselectivity. Highly functionalized enantiopure allenes including those with an adjacent tertiary or quaternary stereocenter have been efficiently prepared with high levels of regio-, diastereo-, and enantioselectivity using this method. Several mechanistic pathways, including electrophilic addition to cumulenolate or zwitterionic enolate intermediates, alkynylogous Mukaiyama aldol reaction, nucleophilic addition to quinone methides, and dearomative addition to imino esters, were proposed. The method is necessary for providing access to axially chiral tetrasubstituted allenes, which can be utilized for the preparation of novel ligands, natural products, and organic materials, particularly those having complex structures. This review covers the enantioselective organocatalytic synthesis of these tetrasubstituted allenes and the mechanistic insights into the formation of the chiral axis up to July 2022.

A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

Total Synthesis of Puberuline C.

Puberuline C (1) is an architecturally complex C19-diterpenoid alkaloid with a unique ring fusion pattern. The 6/7/5/6/6/6-membered rings (ABCDEF-rings) contain one tertiary amine and six oxygen functionalities, and possess 12 contiguously aligned stereocenters, three of which are quaternary. These structural features of 1 make its chemical construction exceptionally challenging. Here, we disclose the first total synthesis of 1. The synthesis was accomplished from 2-cyclohexenone (9) by integrating radical cascade and Mukaiyama aldol reactions as the key transformations. A double Mannich reaction fused the A- and E-rings, and Sonogashira coupling attached the C-ring, efficiently leading to ACE-rings with the requisite 19 carbons of 1. The chemically stable tertiary chloride of the ACE-ring structure was then transformed to the corresponding bridgehead radical, which participated in the simultaneous cyclization of the B- and F-rings via a highly organized radical cascade process. This unusual step installed five contiguous stereocenters, including two quaternary carbons, without damaging the preexisting multiple polar functionalities. Subsequently, the intramolecular Mukaiyama aldol reaction between silyl enol ether and acetal was realized by applying a combination of SnCl4 and ZnCl2, forging the last remaining D-ring of the hexacycle. Finally, 3 was elaborated into 1 through regio- and stereoselective functionalizations of the BCD-rings. Our novel radical-based strategy achieved the total synthesis of 1 in 32 total steps from simple 9, demonstrating the power of the radical cascade reaction to streamline the assembly of highly complex molecules.

Studies Towards the Total Synthesis of Populusone: Stereoselective Construction of Functionalized 2-Oxa-bicyclo[2.2.2]octenes

AbstractA short and efficient synthetic access to functionalized compounds displaying major structural elements of the natural product populusone is elaborated by exploiting a diastereoselective Mukaiyama aldol addition followed by a triflic anhydride-induced oxa-Michael addition to construct the sensitive 2-oxa-bicyclo[2.2.2]octene unit as an enol triflate, which is directly used in a subsequent Suzuki cross-coupling. While attempts to close the strained 10-membered ring by means of Ru-catalyzed ring-closing metathesis were not successful, the developed synthetic scheme opens a rapid synthetic access to advanced intermediates, which may allow the completion of the total synthesis of populusone in the future.

Stereodivergent Total Syntheses of (+)-Mycaperoxides C, D, G Methyl Ester and (-)-Mycaperoxide B.

Mycaperoxides are natural endoperoxides isolated from different Mycale genus sponges, showing significant antiviral or antibacterial activities. We report herein the first total syntheses of representative congeners of this family from sclareol using a stereodivergent approach. Thus, an innovative oxidative ring expansion of cyclobutanol was used to bring the 1,2-dioxane subunit, and a Mukaiyama aldol reaction on peroxycarbenium species was utilized to install the propionic acid subunit. During the study toward (+)-mycaperoxide D methyl ester (2), the isolation of the eight possible diastereomers under their ethyl thioester form allowed to build a pertinent database for further NMR assignment studies. Thus, we completed the total syntheses of (+)-mycaperoxides D, C, G methyl ester, and (-)-mycaperoxide B in 11 to 15 steps, confirming their original assignment.

Ruthenium-Catalyzed Butadiene-Mediated Crotylation and Oxazaborolidine-Catalyzed Vinylogous Mukaiyama Aldol Reaction for The Synthesis of C1-C19 and C23-C35 of Neaumycin B.

Neaumycin B is a femtomolar inhibitor of U87 human glioblastoma. Using a newly developed anti-diastereoselective ruthenium-catalyzed butadiene-mediated crotylation of primary alcohol proelectrophiles via hydrogen auto-transfer, as well as a novel variant of the catalytic asymmetric vinylogous Mukaiyama aldol (VMA) reaction applicable to linear aliphatic aldehydes and terminally methylated dienyl ketene acetals, preparation of the key C1-C19 and C23-C35 substructures of neaumycin B is achieved in 12 and 7 steps (LLS), respectively.