Stereoselective Outcome Research Articles

Synthetic routes toward pentasaccharide repeating unit corresponding to the O-antigen of Escherichia coli O181

An efficient synthetic strategy has been developed for the synthesis of the pentasaccharide repeating unit corresponding to the O-antigen of Escherichia coli O181. A one-pot, two step iterative glycosylation and [2 + 3] block glycosylation strategy have been adopted for the construction of the pentasaccharide derivative 2, which was then transformed into target compound 1 after a series of functional group transformations. Here H2SO4-silica has been used successfully as a promoter for all glycosylation reaction. The stereoselective outcomes of all glycosylation reactions were very good. The 2-acetamido-2,6-dideoxy-l-glucose (l-QuipNAc) building block was obtained from known carbohydrate l-rhamnose precursors.

Origin of Stereocontrol in Photoredox Organocatalysis of Asymmetric α-Functionalizations of Aldehydes.

The merger of the common photoredox catalyst Ru(bpy)3Cl2 with an imidazolidinone organocatalyst by MacMillan et al. has enabled a series of highly enantioselective α-functionalizations of aldehydes, a landmark discovery in photoredox organocatalysis. Herein, we present the theoretical investigation into the origin of enantioselectivity in asymmetric radical additions to the MacMillan imidazolidinone enamines, the key stereocontrolling step in photoredox organocatalysis of asymmetric α-functionalizations of aldehydes. The calculations reveal a hidden but crucial role of E-cis enamine in enantiocontrol. The enantioselectivity in the radical additions is mainly determined by steric effects. A model based on the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst is proposed. This rationalizes the stereoselective outcome of these reactions and provides a good model to understand MacMillan's imidazolidinone/photoredox dual catalysis. The insights obtained from this study should be valuable in future efforts toward the design and development of new enantioselective catalytic radical reactions.

Catalytic enantioselective one-pot approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines.

The first enantioselective catalytic approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been conveniently developed in a one-pot fashion, starting from α,β-unsaturated acyl pyrazoles and 2-aminothiophenol. The organocatalytic two-step sulfa-Michael/lactamization sequence is promoted by a readily available bifunctional thiourea and p-toluenesulfonic acid, respectively. The protocol enables access to both N-unprotected cis- and trans-diastereoisomers in moderate to satisfactory overall yields (up to 84%) and good to excellent ee values (up to 99%). Mechanistic investigations helped to shed light on the regio- and stereoselective outcome of the process.

α-Alkylidene-γ-butyrolactone Formation via Bi(OTf)3-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity.

A Bi(OTf)3-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-alkylidene-γ-butyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf)3 serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for E/Z selectivity was developed using DFT calculations.

Highly Efficient Atom‐Economic Synthesis of Chiral Bis(indolyl)methanes Bearing Quaternary Stereogenic Carbon Centers

AbstractA highly efficient atom‐economic method for the preparation of chiral 3,3′‐bis(indolyl)methanes (3,3′‐BIMs) was developed. A chiral phosphoric acid (1 mol %) was found to promote the formation of structurally divers BIMs with quaternary stereogenic carbon centers in excellent yields with excellent enantioselectivities. Control experiments indicated that the simultaneous formation of two hydrogen bonds between the catalyst and the substrate was the key factor to obtain a good stereoselective outcome.

Stereospecific Hydrogenolysis of Lactones: Application to the Total Syntheses of (R)-ar-Himachalene and (R)-Curcumene

A straightforward strategy for the syntheses of curcumene and ar-himachalene is reported. Synthetic highlights include a catalytic and asymmetric vinylogous Mukaiyama reaction and a stereospecific hydrogenolysis of a tertiary benzylic center using Pd/C or Ni/Raney catalysts. Notably, using Ni/Raney, the stereoselectivity outcome (inversion vs retention) of the hydrogenolysis depends on the tertiary benzylic alcohol substitution.

Synthesis and substrate-controlled reactions of 2,2′-unsaturated biquinazolinones

A series of BiQuinazolinones bearing either double or triple bonds in their lateral chains have been synthesized. These compounds were then subjected to substrate-controlled reactions such as Diels-Alder, epoxidation and Pauson-Khand reactions. The stereoselective outcome observed in these transformations is very promising for the future application of BiQuinazolinones as chiral auxiliaries.

Epoxide Ring-Opening Reactions of Two Diastereomeric 1,2- Epoxy-3-(N-benzyl-N-methylamino)cycloheptanes

Background: Cyclic amino alcohols comprise one of the most important functional motifs of aminoglycoside-type antibiotics. Development of the strategies towards new cyclic amino alcohols allows a broader investigation of these compounds in biology and medicine. Much attention is paid to the preparation of aminoglycoside mimetics that have simpler structures, but retain the biological activity of parent structures. Oxirane ring opening is a synthetically significant reaction for the creation of new pharmaceutically important scaffolds. A distinguishing feature of this approach is the synthesis of amino alcohols with the assigned stereochemistry. Regio- and stereochemical diversity within a sugar-like moiety in those mimetics may subtly influence their biological activity. We propose a regio- and stereospecific route towards trisubstituted cycloheptanes. Methods: Initially, two diastereomeric 1,2-epoxy-3-(N-benzyl-N-methylamino)cycloheptanes with opposite orientation of the oxirane ring to the amino moiety were synthesized. Then, epoxide ring-opening reactions with different nucleophiles under acid- or base-catalyzed conditions were performed. The structure of the products was confirmed by two dimentional NMR methods. Results: Three types of regioisomers, according to the direction of the nucleophilic attack, were obtained. The regio- and stereoselective outcome of these reactions depends on the relative orientation of the oxirane ring and the nature of the catalyst. Conclusion: In summary, the regio- and stereospecific outcome of the epoxide ring cleavage of 1,2-epoxy-3- substituted cycloheptanes was highlighted. The route allows to synthesize new regio- and stereochemically diverse aminocycloheptanol derivatives on multi-gram scale, which could serve as prospective building blocks for the aminoglycoside antibiotic research. The benzyl removal and the further functionalization of nitrogen atom could provide the creation of novel scaffolds for the pharmaceutical and biotech research communities. Keywords: Aminoglycoside mimetic, aminocycloheptanol, epoxide, ring cleavage, stereoselectivity, regioselectivity.

Highly Efficient Catalytic Formation of (Z)-1,4-But-2-ene Diols Using Water as a Nucleophile.

The first general catalytic and highly stereoselective formation of (Z)-1,4-but-2-ene diols is described from readily available and modular vinyl-substituted cyclic carbonate precursors using water as a nucleophilic reagent. These 1,4-diol scaffolds can be generally prepared in high yields and with ample scope in reaction partners using a simple synthetic method that does not require the presence of any additive or any special precaution unlike the stoichiometric approaches reported to date. Control experiments support the mechanistic view that hyperconjugation within the catalytic intermediate after decarboxylation plays an imperative role to control the stereoselective outcome of these reactions.

Highly Efficient Catalytic Formation of (Z)‐1,4‐But‐2‐ene Diols Using Water as a Nucleophile

AbstractThe first general catalytic and highly stereoselective formation of (Z)‐1,4‐but‐2‐ene diols is described from readily available and modular vinyl‐substituted cyclic carbonate precursors using water as a nucleophilic reagent. These 1,4‐diol scaffolds can be generally prepared in high yields and with ample scope in reaction partners using a simple synthetic method that does not require the presence of any additive or any special precaution unlike the stoichiometric approaches reported to date. Control experiments support the mechanistic view that hyperconjugation within the catalytic intermediate after decarboxylation plays an imperative role to control the stereoselective outcome of these reactions.

Expeditious Synthesis of a Tetrasaccharide Repeating Unit of the O-Antigen of Escherichia coli O163

The synthesis of the tetrasaccharide repeating unit of the O-antigen of <i>Escherichia coli</i> O163 as its <i>p</i>-methoxyphenyl (PMP) glycoside was achieved followed by sequential glycosylation strategy through thioglycoside activation using sulfuric acid immobilized on silica ­(H₂SO₄–silica) in conjunction with <i>N</i>-iodosuccinimide as a Brønsted acid catalyst. The application of one-pot reaction conditions for two glycosylations and in situ PMB-group removal reduced the number of reaction steps significantly. The <sc>l</sc>-QuipNAc building block was obtained from known carbohydrate <sc>l</sc>-rhamnose precursors. The stereoselective outcomes of all glycosylation reactions were found to be very good. A late-stage TEMPO-mediated oxidation was performed for the formation of required uronic acid moiety. An analogue of the target tetrasaccharide was also prepared by using one-pot glycosylation approach. Such synthetic oligosaccharides could later be effectively conjugated with an appropriate protein to furnish glycoconjugate derivatives for their use in immunochemical studies.

Cinchona Alkaloid-Catalyzed Asymmetric Conjugate Additions: The Bifunctional Brønsted Acid-Hydrogen Bonding Model.

Wynberg's report from 1977 that natural cinchona alkaloids catalyze the asymmetric conjugate addition of aromatic thiols to cycloalkenones is a landmark discovery in hydrogen bonding organocatalysis. Wynberg proposed that this reaction proceeded via the formation of a thiolate-alkylammonium tight ion pair and activation of the enone electrophile by a hydrogen bond from the catalyst's hydroxyl group. This reaction model provided the mechanistic basis for understanding Wynberg's reaction and many other asymmetric transformations since. Our quantum mechanical calculations reveal a different model should be used to explain the results: the alkylammonium ion activates the enone by Brønsted acid catalysis, and the catalyst's hydroxyl group orients the thiolate nucleophile. The new model rationalizes the stereoselective outcome of Wynberg's reaction and provides a new, general model for asymmetric cinchona organocatalysis.

Deviation from the anti-Markovnikov rule: a computational study of the regio- and stereoselectivity of diene hydroboration reactions

Hydroboration and subsequent use of boron compounds in novel organic synthesis have been flourishing in recent years largely due to its amiability in producing asymmetric stereo- and regioselective products. Direct products of diene hydroboration, however, have received little attention, with most substrates being assumed to produce the anti-Markovnikov product expected from textbook organic chemistry understanding. Previous experimental studies have observed the presence of a plethora of hydroboration products, and a significant progress has been made in assigning species to experimental data—though often with contradicting results. This study has used a computational approach employing quantum chemical calculations to determine atomic charges of cyclic and acyclic dienes and correlate these with calculated activation energy barriers in order to predict the regio- and stereoselective outcome of hydroboration reactions. Results indicated a strong correlation between the most polarized atomic charges of double-bonded carbons and the lowest energy transition states as expected. Intriguingly, we identified 1,3-cyclohexadiene as the main example that does not follow the anti-Markovnikov rule. We proceed to show that in addition to the polarity of the double bonds within a molecule, in this case, the conjugation with the allyl double bond and the specific geometric features of the cyclohexane ring were key stabilizing factors for the unexpected transition state preference, resulting in a regioselectivity that is in quantitative agreement with previous experimental data. Our results further indicated that Re-face attacks and steric factors due to substituents of the substrate influenced mainly the stereoselective outcome of the reaction, also affecting the pathways available to proceed through to complete the hydroboration process.

Expedient Synthesis of the Pentasaccharide Repeating Unit of the Polysaccharide O-Antigen of Escherichia coli O11.

A convergent [3+2] block synthetic strategy was developed for the synthesis of the pentasaccharide repeating unit of the cell wall O‐antigen of Escherichia coli O11 strain in excellent yield in a minimum number of steps. Several suitably functionalized thioglycoside derivatives were used as glycosyl donors during the synthesis of the target compound. A thioglycoside was the glycosyl donor used to couple with another thioglycoside derivative in a highly stereoselective manner exploiting the difference of their reactivity profile. A combination of Niodosuccinimide (NIS) and perchloric acid supported over silica gel (HClO4−SiO2) was used as a thiophilic glycosylation activator system in all stereoselective glycosylation reactions. HClO4−SiO2 acted as a user‐friendly solid acid catalyst. Yields were very good in all glycosylation steps with a high stereoselective outcome. The synthetic pentasaccharide could be coupled to an appropriate protein to furnish a glycoconjugate derivative for its use in immunochemical studies.

Convergent Synthesis of Oligosaccharide Fragments Corresponding to the Cell Wall O-Polysaccharide of Salmonella enterica O53.

Conventional glycoconjugate vaccines are prepared with polysaccharides isolated from bacterial fermentation, an approach with some significant drawbacks such as handling of live bacterial strains, the presence of biological impurities, and inter‐batch variations in oligosaccharide epitope structure. However, it has been shown in many cases that a synthetic fragment of appropriate structure conjugated to a protein can be an effective vaccine that circumvents the shortcomings of using full‐length oligosaccharides. The development of synthetic strategies to prepare glycoconjugate derivatives against pathogenic bacterial strains is therefore of great interest. Oligosaccharide fragments corresponding to the repeat unit of the cell wall O‐antigen of Salmonella enterica strain O53 were synthesized in good yield. Sequential and block glycosylation strategies were used for the synthesis of the target compounds. A number of recently developed reaction conditions were used in the synthetic strategy. A one‐pot reaction scheme was also developed for the multiple glycosylation steps. The stereoselective outcomes of all glycosylation reactions were very good.

Total synthesis of tetraacylated phosphatidylinositol hexamannoside and evaluation of its immunomodulatory activity.

Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myo-inositol. A short synthesis of tuberculostearic acid in six steps from the Roche ester is also described. Mice exposed to the synthesized Ac2PIM6 exhibit increased production of interleukin-4 and interferon-γ, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies.

Stereoselective C-glycosidation of d-fucose derivatives directed by the protective groups

Stereoselectivity in the C-glycosidation of lactones derived from d-fucose by following Kishi’s method, which involves the addition of a nucleophile onto a carbohydrate-derived lactone and subsequent reduction of the lactol, was found to be reliant on the nature of the C2 and C3 protective groups. Lactones bearing TBDMS protecting groups selectively afford 1,3-trans products (α anomer), in which the stereoselective outcome is in apparent concordance with Woerpel’s model. On the other hand, their benzylated congeners produce the 1,3-cis products (β anomer) as the major diastereoisomers. The latter results suggest an abnormal behavior during the stereoselective nucleophilic substitution at the anomeric position of the benzylated lactones.

Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

ChemInform Abstract: Diastereoselective Additions of Titanium Enolates from N‐Glycolyl Thiazolidinethiones to Acetals.

AbstractThe stereoselective outcome of the title reaction is found to depend on the nature of the O‐protecting group of glycolate substrate.

Stereochemistry of C7-allyl yohimbine explored by X-ray crystallography

X-ray crystallographic analysis revealed that the palladium-catalyzed β-allylation of yohimbine proceeded in a (7S)-selective manner. The crystal structure had an indolenine unit that was generally unstable in air. A stereoselective outcome was obtained when the palladium π-allyl complex approached yohimbine from the less-hindered pro-S side. However, during reserpine allylation—because the structure of reserpine is that of a transoid-3, 15-ring junction—the palladium π-allyl complex approached from both sides: pro-S and pro-R. A computational method was developed to discuss this selectivity. Experimental details and considerations of the reaction are provided.