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Highly enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. Mechanism and synthetic implications [22]
... This screening strategy provided some candidates with high binding affinity, including MKN-1 (1) and MKN-3 (2) with London dG values of −9.134 and −9.555, respectively. 67,69) MKN-1 (1) and MKN-3 (2) derivatives, (4), showed significant anti-HIV activity at the level of micromolar, 67,69) although itself failed to show anti-HIV activity below 50 µM because of relatively high hydrophilicity of the compound. 69) In the present study, several derivatives of MKN-1 (1) were synthesized, and their anti-HIV activity and cytotoxicity were evaluated. ...
... 67,69) MKN-1 (1) and MKN-3 (2) derivatives, (4), showed significant anti-HIV activity at the level of micromolar, 67,69) although itself failed to show anti-HIV activity below 50 µM because of relatively high hydrophilicity of the compound. 69) In the present study, several derivatives of MKN-1 (1) were synthesized, and their anti-HIV activity and cytotoxicity were evaluated. ...
... In our previous study, although , with a London dG value of −9.555, has high binding affinity for a CA molecule, it failed to show significant anti-HIV activity, possibly due to the poor cell membrane permeability of MKN-3 (2), which therefore could not penetrate the cells. 69) In general, the hydrophobicity of compounds is correlated to their cell membrane permeability. 73) The Log P value of MKN-3 (2) is 0.27, which is markedly lower than that of MKN-1 (1) (LogP: 2.97), which show significant anti-HIV activity. ...
The capsid of human immunodeficiency virus type 1 (HIV-1) forms a conical structure by assembling oligomers of capsid (CA) proteins and is a virion shell that encapsulates viral RNA. The inhibition of the CA function could be an appropriate target for suppression of HIV-1 replication because the CA proteins are highly conserved among many strains of HIV-1, and the drug targeting CA, lenacapavir, has been clinically developed by Gilead Sciences, Inc. Interface hydrophobic interactions between two CA molecules via the Trp184 and Met185 residues in the CA sequence are indispensable for conformational stabilization of the CA multimer. Our continuous studies found two types of small molecules with different scaffolds, MKN-1 and MKN-3, designed by in silico screening as a dipeptide mimic of Trp184 and Met185 have significant anti-HIV-1 activity. In the present study, MKN-1 derivatives have been designed and synthesized. Their structure–activity relationship studies found some compounds having potent anti-HIV activity. The present results should be useful in the design of novel CA-targeting molecules with anti-HIV activity.
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... This method was applicable to our case, providing 3-dihydropyridones 30 and 31 as an inseparable mixture. The resulting ketones underwent the CBS reduction [15] to provide a separable mixture of secondary alcohols 32 and 33 in 78 and 7.2% yields, respectively ...
Development of a unified total synthesis of madangamine alkaloids is described. The synthesis consists of three parts: (1) construction of the central ABC-ring, (2) installation of the skipped diene bearing a trisubstituted olefin, and (3) the synthesis of various D-rings from a tetracyclic ABCE-common intermediate. The ABC-tricyclic framework is successfully assembled by intramolecular allenylation. The most significant issue in this synthesis is the stereoselective installation of the skipped diene. This challenge is ultimately overcome by development of a stereodivergent approach using hydroboration of allenes and Migita-Kosugi-Stille coupling. The hydroboration is especially useful because the reaction of 1,1-disubstituted allenes with either 9-BBN or (Sia) 2 BH gives ( E )- or ( Z )-allylic alcohols, respectively. The key to the success of our unified total synthesis is macrocyclic alkylation to form a wide variety of D-rings from the tetracyclic ABCE-common intermediate. Our collective synthesis of madangamine alkaloids revealed structure–activity relationship of D-rings in their cytotoxicity against human cancer cell lines.
... 13,16 Oxazaborolidine catalysts, particularly CBS−oxazaborolidine complexes, are vital in asymmetric reduction, playing a crucial role in obtaining chiral alcohols and diols with high enantioselectivity. 42,43 Building on our prior work utilizing CBS−oxazaborolidine complexes for the synthesis of chiral alcohols and diols, we demonstrate their efficiency in achieving a single enantiomer of chiral diols by reducing chiral keto alcohols. 14,44 The rationale behind employing asymmetric reduction at this stage is to ensure the highly selective formation of the secondary stereogenic center, increasing the probability of obtaining a single enantiomer. ...
Chiral 1,3-diols are highly valuable molecules used in industries such as pharmaceuticals, cosmetics, and agriculture. Therefore, in this study, a new strategy was developed to synthesize enantiomerically pure (>99% ee) 1,3-diols. New chiral 1,3-diols (5a–5q) with high enantiomeric purity were synthesized from aldol products chiral 1,3-keto alcohols (4a–4q), which are aldol products with different structures. Chiral 1,3-keto alcohols (4a–4q) were synthesized by a new asymmetric aldol method in the first step. This method was developed using a new proline-derived organocatalyst (3g) and Cu(OTf)2 as an additive in DMSO–H2O for the first time. Almost >99% ee was obtained using our developed aldol procedure. In the second step, original chiral diols (5a–5q) of high enantiomeric purity were obtained by asymmetric reduction of chiral keto alcohols with chiral oxazaborolidine reagents. In this way, a two-step asymmetric reaction was developed for chiral 1,3-diol enantiomers with high enantiomeric purity. The structures of all the original chiral compounds obtained were elucidated by infrared and nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis methods. Their enantiomeric excesses were determined by the chiral high-performance liquid chromatography method. Both keto alcohols and their corresponding chiral diols synthesized can be used as chiral starting materials and chiral source materials or intermediates in the synthesis of many biologically active molecules, or they can be used as chiral ligands in asymmetric synthesis, serving as organocatalysts.
... Table 1, entry 3 summarises the use of a [2.2]paracyclophane substrate rac-7, 18 and Table 1, entry 4 the use of 1-tetralone-Cr(CO)3 rac-8 as substrate. 19 With prochiral aryl/alkyl ketones the CBS catalyst results in high reduction enantioselectivity (ypred = 56 from the 96.5% ee observed with acetophenone), 38 and a high level of catalyst control is maintained in the two planar chiral examples (yest = 37 and 46, entries 3 and 4). In contrast, the reaction of rac-7 is much more diastereoselective than the reaction of rac-8 (xest = 45 vs. 8 and xpred = 42 vs. 4) accounting for the inefficient kinetic resolution of the latter. ...
The catalysed reaction of an enantiopure substrate with formation of a new chirality element may result in higher
diastereoselectivity with one enantiomer of a catalyst (matched pair) than with the other (mismatched pair). The hypothesis
that the matched reaction is faster was investigated using literature examples of kinetic resolution procedures that result in
the formation of a new stereogenic centre. With one exception from fifteen examples, the selectivity factor (s = kfast/kslow) =
kmatched/kmismatched. A model to estimate the relative rate of a fast-matched reaction vs. the corresponding slow-mismatched
reaction is proposed. This model also provides insight into the basis of the selectivity displayed in the kinetic resolution
procedures studied.
Herein, we describe the first total synthesis of (±)-cochlearol B and the enantioselective total syntheses of (−)-cochlearol and (+)-ganocin A. The key steps include Corey-Bakshi-Shibata reduction, oxidative phenolic cyclization, intramolecular [2+2] photocycloaddition, and intramolecular radical cyclization-benzylic oxidative cyclization, enabling efficient access to 4/5/6/6/6 and 5/5/6/6/6-fused pentacyclic frameworks of these natural products.
Natural product chemistry has entered a mature phase, where the total synthesis of a variety of natural products has been achieved and can then promote structure-activity relationship studies and chemical biology research. However, bioorganic and chemical biological researches on natural products that are challenging to synthesize because of the large sizes and the structural complexities, are currently at a standstill. We have been working on the mystery of aplyronine A for almost 30 years from its isolation in 1993 to the present day and have clarified the mechanism of actions to a certain extent. In this article, we introduce our research to create ‘useful molecules’ based on aplyronine A as medicinal chemistry and chemical biology tools, which evolve further aplyronine A. Thus, we designed and synthesized aplyronine A-swinholide A hybrid 5, which consists of the macrolactone part of aplyronine A (1) and the side chain part of swinholide A (4). Hybrid 5 retained not only a strong actin-depolymerizing activity but also a potent cytotoxicity, which is much stronger than that of aplyronine A-mycalolide B hybrid (3) reported previously. In addition, hybrid 5 induces protein-protein interactions between actin and tubulin in the same manner as aplyronine A. These results showed that the substitution patterns and configurations at C24-C26 positions in the side chain are essential for the strong cytotoxicity of aplyronine A-type compound. Furthermore, we conducted the structure-activity relationship studies about the amino acid moiety at C7 using hybrid 5 and found that the methoxy group of the trimethylserine ester group is important for potent cytotoxicity. In addition, comparing the side chain analogs of aplyronine A and swinholide A, we clarified that the side chain analog of swinholide A had a weaker actin-depolymerizing activity than that of aplyronine A. These studies have provided important findings into the mechanism of cytotoxicity of the “molecular glue” between two major cytoskeletons, actin and tubulin.
Naturally occurring sesquiterpenes having humulane framework are structurally intriguing and possess significant biological profiles. Asymmetric synthesis of alashanoids B-C, E-F and 2,9-humuladien-6-ol-8-one is achieved for the first time through a...
For long years, meroterpenoids derived from Ganoderma family have received a great deal of attention due to their unique biological activities. Applanatumol compounds or lucidumone were isolated from G. applanatum or G. lucidum, featuring dihydroquinone motif fused to terpenoid structure. This article describes collective synthesis of applanatumol compounds and asymmetric synthesis of lucidumone. Applanatumol A, having a spiro [benzofranbicyclo[3.2.2]nonane] framework with four stereogenic centers, was synthesized via a tandem cascade cyclization using TBD to form tetracyclic skeleton. Applanatumol B was synthesized in 14 steps by employing an intramolecular cyclization and lactonization for quick construction of the tricyclic skeleton with desired stereochemistry. The key step includes efficient epimerization of α-position of the ketone under acidic condition. Lucidumone is a unique 6/5/6/6/5 polycyclic molecule with six contiguous stereogenic centers on a bicyclo[2.2.2]octane skeleton. The racemic total synthesis was accomplished in 10 steps through one-pot preparation of the tetracyclic core framework by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo[2.2.2]octane skeleton fused to an indanone structure. The enantioselective total synthesis of lucidumone was also described via a chiral transfer strategy in the Claisen rearrangement. Our work communicated here provides novel strategy for convenient and short-step synthesis of meroterpenoids using tandem reaction or one-pot reaction.
We describe the use of acyl imidazoles derived from aliphatic carboxylic acids for the N-heterocyclic carbene/organic photoredox co-catalyzed meta-selective functionalization of electron-rich arenes. Compared to our previous work, a change of the wavelength of the applied LED light from 440 nm to 390 nm promotes this reaction efficiently.
Aspidosperma and uleine alkaloids belong to the large family of monoterpene indole alkaloids with diverse biological activities and thus have attracted extensive synthetic interest. Reported is the development of a new synthetic strategy that allows direct C3–C2′ linkage of indoles with functionalized 2-hydroxypiperidines to construct the core common to all aspidoserma and uleine alkaloids. Such indole-piperidine linkage is enabled by coupling aza-Achmatowicz rearrangement (AAR) with indoles via an intermolecular aza-Friedel–Crafts (iAFC) reaction. This AAR-iAFC reaction proceeds under mild acidic conditions with wide tolerance of functional groups (33 examples). The synthetic application of the AAR-iAFC method was demonstrated with collective total syntheses of 3 uleine-type and 6 aspidosperma alkaloids: (+)-3-epi-N-nor-dasycarpidone, (+)-3-epi-dasycarpidone, (+)-3-epi-uleine, 1,2-didehydropseudoaspidospermidine, 1,2-dehydroaspidospermidine, vincadifformine, winchinine B, aspidospermidine, and N-acetylaspidospermidine. We expect that this AAR-iAFC strategy is applicable to other monoterpene indole alkaloids with the C3–C2′ linkage of indoles and piperidines.
Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.
Meroterpenoids isolated from fungi of the Ganoderma family have received much attention owing to their unique structures and diverse biological activities. A number of Ganoderma meroterpenoids have been isolated since 2000 and many total syntheses and synthetic studies have since been reported. In this review, we highlight fifteen total syntheses conducted from 2014 to 2023 of polycyclic Ganoderma meroterpenoids classified according to the connection pattern of the dihydroquinone with the terpenoid structure. The selected studies illustrate how the molecular complexity was constructed by unique tactics.
We present a comprehensive account on our efforts behind the recently published synthesis of waixenicin A. Our approach for constructing the dihydropyran ring relied on an Achmatowicz rearrangement. For the assembly of the nine‐membered ring, four distinct strategies were investigated. Our initial attempts using radical‐based addition/fragmentation reactions targeting the C7−C11 bond proved unsuitable for accessing the 6/9‐bicycle. By employing anionic fragmentation conditions at the furfuryl alcohol stage, we successfully reached a 5/9‐bicycle. However, subsequent ring‐expansion was unsuccessful. Alternative approaches, such as Nozaki–Hiyama–Kishi or Heck reactions to connect the C6−C7 bond, also encountered difficulties, with no nine‐membered ring formation observed. Our first breakthrough came from our attempts to install the C5−C6 bond via an intramolecular alkylation. Surprisingly, subsequent functional group modifications proved unexpectedly challenging, necessitating a redesign of our synthetic route. Drawing from all our investigations, we concluded that construction of the C9−C10 bond would enable efficient nine‐membered ring alkylation and would facilitate the installation of the desired substitution pattern along the southern periphery. Exploration of this strategy yielded further surprises but ultimately led to the successful synthesis of waixenicin A and 9‐deacetoxy‐14,15‐deepoxyxeniculin. For the latter compound, a bioinspired one‐step rearrangement to xeniafauranol A was achieved.
The total synthesis of the proposed structure of anti‐glioblastoma natural product neaumycin B was achieved in 22 longest linear steps. The synthesis features an in situ‐generated HCl‐mediated [6,6]‐spiroketalization, a combination of novel Krische Ir‐catalyzed crotylation, Marshall Pd‐catalyzed propargylation, Fürstner Ni‐catalyzed regio‐ and enantio‐selective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide‐aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters.
The total synthesis of the proposed structure of anti‐glioblastoma natural product neaumycin B was achieved in 22 steps (longest linear sequence). The synthesis features HCl‐mediated [6,6]‐spiroketalization, a combination of Krische iridium‐catalyzed crotylation, Marshall palladium‐catalyzed propargylation, Fürstner nickel‐catalyzed regio‐ and enantioselective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide‐aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters.
The selectivity in a group of oxazaborolidinium ion-catalysed reactions between aldehyde and diazo compounds cannot be explained using transition state theory. VRAI-selectivity, developed to predict the outcome of dynamically controlled reactions, can account for both the chemo- and the stereo-selectivity in these reactions, which are controlled by reaction dynamics. Subtle modifications to the substrate or catalyst substituents alter the potential energy surface, leading to changes in predominant reaction pathways and altering the barriers to the major product when reaction dynamics are considered. In addition, this study suggests an explanation for the mysterious inversion of enantioselectivity resulting from the inclusion of an orthoⁱPrO group in the catalyst.
The classical proline-derived oxazaborolidines as powerful and versatile organocatalysts (CBS, Corey-Bakshi-Shibata) have significant applications on asymmetric catalysis, especially enantioselective reduction of prochiral ketones and various asymmetric cycloaddition reactions. Despite having...
The C–H borylation and hydroboration reactions have emerged as promising synthetic tools to construct organoboron compounds. Organoboron compounds of N-heterocycles, particularly indole derivatives, have found widespread application in a variety of fields. As a result, considerable advancement in the area of C–H borylation and hydroboration reactions of indoles was observed in the last few decades. Among the various synthetic methods applied, the metal-free approach has received special attention. This mini-review discusses the recent progress in the area of C–H borylation and hydroboration reactions of indoles under metal-free conditions, their scope, and brief mechanistic studies.
A series of manganese(I) carbonyl complexes bearing structurally related NN- and NNN-chelating ligands have been synthesized and assessed as catalysts for transfer hydrogenation (TH). Notably, the NN-systems based on N-R functionalized 5,6,7,8-tetrahydroquinoline-8-amines, proved the most effective in the manganese-promoted conversion of acetophenone to 1-phenylethanol. In particular, the N-isopropyl derivative, Mn1, when conducted in combination with t-BuONa, was the standout performer mediating not only the reduction of acetophenone but also a range of carbonyl substrates including (hetero)aromatic-, aliphatic- and cycloalkyl-containing ketones and aldehydes with especially high values of TON (up to 17 200; TOF of 3550 h-1). These findings, obtained through a systematic variation of the N-R group of the NN ligand, are consistent with an outer-sphere mechanism for the hydrogen transfer. As a more general point, this Mn-based catalytic TH protocol offers an attractive and sustainable alternative for producing alcoholic products from carbonyl substrates.
The construction of 2,2-disubstituted indolines has long presented a synthetic challenge without any general solutions. Herein, we report a robust protocol for the dearomative Meerwein-Eschenmoser-Claisen rearrangement of 3-indolyl alcohols that provides efficient access to 2-substituted and 2,2-disubstituted indolines. These versatile subunits are useful for natural product synthesis and medicinal chemistry. The title [3,3] sigmatropic rearrangement proceeds in generally excellent yield and transfers the C3-indolic alcohol chirality to the C2 position with high fidelity, thus providing a reliable method for the construction of enantioenriched 2,2-disubstituted indolines. The power of this methodology is demonstrated through the concise and strategically unique total synthesis of the marine natural product hinckdentine A, which features a dearomative Claisen rearrangement, a diastereocontrolled hydrogenation of the alkene product, a one-pot amide-to-oxime conversion using Vaska's complex, and a regioselective late-stage tribromination.
A recently developed photochemical cascade reaction provides access to diastereomeric pentacyclic products, which display the carbon skeleton of prezizane natural products. The minor diastereoisomer with a 2β-Me configuration was converted in 12 reaction steps into (+)-prezizaan-15-ol. The major diastereoisomer with a 2α-Me configuration gave in an analogous route (+)-jinkohol II, which was oxidized at C13 to (+)-jinkoholic acid. A previous ambiguity regarding the configuration of the natural products could be clarified by total synthesis.
This research Account describes the development of chiral organocatalysts, focusing on diphenyl-2-pyrrolidinemethanol and its derivatives as valuable tools in asymmetric transformations. The research also includes the discovery of a novel anionic Si→C alkyl migration method, which has been developed into a one-pot procedure for synthesizing (E)-chalcones from hydroxyamide and N,N-diethylcarbamates. The findings underscore the potential of sulfide and silicon as valuable reagents for organic synthesis and emphasize the importance of exploring new reaction pathways and mechanisms to discover novel synthetic methods.
1 Introduction
2 Synthesis of 2 and Sulfur Reagent as Chiral Lewis Acid
3 Sulfur/Selenium Reagent as Chiral Lewis Base
4 Anionic Si→C Alkyl Migration
5 Conclusion
We herein report an enantioselective bioreduction of ketones that bear the most frequently used nitrogen-heteroaromatics in FDA-approved drugs. Ten varieties of these nitrogen-containing heterocycles were systematically investigated. Eight categories were studied for the first time and seven types were tolerated, significantly expanding the substrate scope of plant-mediated reduction. By use of purple carrots in buffered aqueous media with a simplified reaction setup, this biocatalytic transformation was achieved within 48 h at ambient temperature, offering medicinal chemists a pragmatic and scalable tool to access a broad variety of nitrogen-heteroaryl-containing chiral alcohols. With multiple reactive sites, the structurally diverse set of chiral alcohols can be used for library compound preparation, early route-scouting activities, and synthesis of other pharmaceutical molecules, favorably accelerating medicinal chemistry campaigns.
Organoboron represents an organic compound bearing boron atom(s) in the molecule. The compounds play essential roles in organic synthesis because of their adequate reactivity derived from the electrophilicity of the boron center and the nucleophilicity of the carbon–boron bond. This chapter provides a brief introduction to the early development of organoboron compounds, their derivatization reactions, and their current applications. The latter part focuses on the preparation of organoboronates, the esters of organoboronic acids. In 2000, the Hosomi and Ito group and the Miyaura and Ishiyama group independently developed copper(I)-catalyzed borylation reactions using diboronic acid esters. The active species in the reaction, a boryl copper(I) intermediate, has a variety of reaction modes including a conjugate addition, 1,2-insertion, and radical generation. Therefore, this catalytic system has been used for various borylation reactions.KeywordsOrganoboron compoundBorylation reactionCopper(I) catalysisBoryl copper(I) species
This expansive and practical textbook contains organic chemistry experiments for teaching in the laboratory at the undergraduate level covering a range of functional group transformations and key organic reactions.The editorial team have collected contributions from around the world and standardized them for publication. Each experiment will explore a modern chemistry scenario, such as: sustainable chemistry; application in the pharmaceutical industry; catalysis and material sciences, to name a few. All the experiments will be complemented with a set of questions to challenge the students and a section for the instructors, concerning the results obtained and advice on getting the best outcome from the experiment. A section covering practical aspects with tips and advice for the instructors, together with the results obtained in the laboratory by students, has been compiled for each experiment.
Targeted at professors and lecturers in chemistry, this useful text will provide up to date experiments putting the science into context for the students.
This expansive and practical textbook contains organic chemistry experiments for teaching in the laboratory at the undergraduate level covering a range of functional group transformations and key organic reactions.The editorial team have collected contributions from around the world and standardized them for publication. Each experiment will explore a modern chemistry scenario, such as: sustainable chemistry; application in the pharmaceutical industry; catalysis and material sciences, to name a few. All the experiments will be complemented with a set of questions to challenge the students and a section for the instructors, concerning the results obtained and advice on getting the best outcome from the experiment. A section covering practical aspects with tips and advice for the instructors, together with the results obtained in the laboratory by students, has been compiled for each experiment.
Targeted at professors and lecturers in chemistry, this useful text will provide up to date experiments putting the science into context for the students.
Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.
The total synthesis of lucidumone (1), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one‐pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.
The total synthesis of lucidumone ( 1 ), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one‐pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.
There is a wide range of biological activities associated with C1 chiral carbon containing 1-substituted-1,2,3,4-tetrahydroisoquinolines (1-substituted-THIQs) which constitute the isoquinoline alkaloids, a large group of natural products. This work summarizes several novel catalytic stereoselective approaches to enantioselectively reduce the 1-substituted-3,4-dihydroisoquinolines (1-substituted-DHIQs) to produce the desired 1-substituted-THIQs. The 1-substituted-DHIQs were prepared by using the Bischler-Napieralski reaction. The enantioselective reduction of 1-substituted-DHIQs was accomplished by using chiral hydride reducing agents, by hydrogenation with a chiral catalyst, by enantioselective reduction of DHIQs possessing a chiral auxiliary at the imine nitrogen by achiral metallic hydride reducing agents, or by enzymatic catalysis. Among these methods, much more work was carried out on the hydrogenation of 1-substituted-DHIQs in the presence of a chiral catalyst. This review summarizes articles and advancements on this topic from 1972 to 2023.
A scalable total synthesis of leucascandrolide A macrolactone has been accomplished with a longest linear sequence of 17 steps from readily available feedstocks in 31.2% yield. The key steps in this synthesis are the enantioselective allylation reaction by chiral phosphoric acid (CPA)/CuBr cooperative catalysis and the diastereoselective catalytic crotylation in the presence of CPA with CuCl. These catalytic reactions can be performed on a gram scale to afford the desired products with excellent stereoselectivities.
Synthesis of the C19-truncated maltepolide E has been accomplished via a diene-ene ring-closing metathesis (RCM) strategy without damage to the C11-C14 alkenyl epoxy unit. Upon release of the C17-OH group, it attacked at the C14 position with double bond migration and epoxide ring opening to furnish the C19-truncated maltepolides A and B as proposed for the biosynthesis of maltepolides.
The total synthesis of a series of new carolacton derivatives that mainly lack selected methyl substituents along the polyketide backbone is reported. Their inhibitory activity towards bacterial biofilms reveals that selective removal of the methyl group at C10 does not have a major effect on biological activity, whereas additional removal of the methyl group at C14 in carolacton results in a large decrease in antibacterial activity. A key new feature of this work is the replacement of the Nozaki-Hiyama-Kishi (NHK) vinylation with a titanium-mediated protocol for the fusion of the two main fragments.
A new type of (RC,SP)-1-(2-diphenylphosphino)ferrocenylethylamine N-substituted with a (RC)-5,6,7,8-tetrahydroquinolinyl group (LPNN-1) was successfully employed as a chiral chelating ligand in both Mn-catalyzed asymmetric transfer hydrogenation (ATH) and asymmetric hydrogenation (AH) of a broad range of ketonic substrates (39 examples), leading to high conversions and excellent enantioselectivities for their product alcohols. In particular, PNN-pincer complex Mn-1 and its NN-bidentate analogue Mn-2 have been isolated and their comparative performance as catalysts studied with Mn-1 proving more effective in both ATH and AH. Moreover, Mn-1 generally imparted higher degrees of enantiomeric excess (ee) in both hydrogenation processes which can reach up to 99% in ATH and 93% in AH for propiophenone-type substrates. DFT calculations highlight the importance of π-π interactions and steric hindrance between catalyst and substrate which manifests itself in enhancements in ee for propiophenone over acetophenone substrates. Furthermore, a possible mechanism for the Mn-catalyzed ATH has been proposed on the basis of a joint DFT and experimental investigation.
Detailed proton NMR analyses were made on the diboranes, B2H6, CH3B2H5, 1,1-(CH3)2B2H4, 1,2-(CH3)2B2H4, 1,1,2-(CH3)3B2H3, 1,1,2,2-(CH3)4B2H2 and ClB2H5. The bridge hydrogen chemical shift moves −0.40 ppm per methyl group on the diborane molecule and −1.1 ppm with a chlorine substituent. From 11B-decoupled proton spectra long-range homonuclear proton coupling could be observed in the methyl substituted diboranes: Both the terminal proton (on methyl and chloro diboranes) and the methyl proton chemical shifts are moved significantly upfield with substitution on the far boron atom.
In the presence of the optically active amino alcohol–borane complex, an oxime ether was reduced with various hydride reducing agents to give a chiral primary amine of high optical purity. Catalytic use of the chiral complex was also investigated.
The asymmetric reduction of aromatic and aliphatic ketones, halogeno ketones, hydroxy ketones, keto esters, and ketone oxime ethers with reagents prepared from borane and chiral amino alcohols has been investigated. When α,α-diphenyl β-amino alcohols, such as (2S,3R)-(–)-2-amino-3-methyl-1,1 -diphenylpentanol (2d), were used as a chiral auxiliary, very high enantioselectivities (ca. 90 % e.e.) were obtained in the reduction of various ketones and oxime ethers.
The polymer-supported chiral amino alcohol (3) has been prepared by the reaction of chloromethylated polystyrene resin and (S)-(–)-2-amino-3-(p-hydroxy)phenyl-1,1-diphenylpropan-1-ol (2); the chiral polymeric reagent has been prepared from (3) and borane. The asymmetric reductions of ketones and oxime ethers with the polymeric reagent have been shown to give optically active alcohols (up to 97% optical purity) and amines (up to 67% optical purity), respectively. The results are compared with those obtained with (S)-(–)-2-amino-1,1,3-triphenylpropan-1-ol (4) or (S)-(–)-2-amino-3-(p-benzyl-oxyphenyl)-1,1 -diphenylpropan-1-ol (5) which are soluble model reagents.
Asymmetric reduction of prochiral aromatic ketones with the reagent prepared from (S)-(–)-2-amino-3-methyl-1,1-diphenylbutan-1-ol [(S)-(1)] and borane afforded the corresponding aromatic secondary alcohols in high optical (94–100% enantiomeric excess) and chemical (100%) yields.
An empirically derived correlation of configuration and nmr chemical shifts for diastereomeric mandelate, O-methylmandelate and α-methoxy-α-trifluoromethylphenylacetate (MTPA) esters has been developed and rationalized in terms of useful models 4 and 5. These models have been successfully applied to well over 40 examples as given in Table I. The correlations involve the relative chemical shifts of the proton resonances from the groups attached to the carbinyl carbon of these diastereomeric esters. This nmr-configurational correlation should prove to be widely applicable in assigning the configuration of additional secondary carbinols, as well as other chiral α-substituted carboxylic acid derivatives.
Reagent menthyl chloroformate use in optical analysis of asymmetric amino and hydroxyl compounds by gas chromatography