Academic literature on the topic 'Stereoselective synthesis'

Secondary alkyllithium reagents were prepared stereoselectively via an iodo–lithium exchange by using tert-butyllithium. The resulting secondary alkyllithiums were converted directly into the corresponding alkylcopper reagents by transmetalation with copper(I) bromide–triethyl phosphite [CuBr·P(OEt)3] with retention of configuration and without significant loss of stereoselectivity. The resulting alkylcopper reagents were used for carbocupration or acylation reactions. In addition, a new intramolecular carbolithiation of secondary alkyllithium reagents possessing a remote alkyne moiety was also investigated, allowing the stereoselective production of alkylidenecylobutane derivatives with very high stereocontrol.

Stereoselective synthesis has been emerging as a resourceful tool because it enables the obtaining of compounds with biological interest and high enantiomeric purity. Flavonoids are natural products with several biological activities. Owing to their biological potential and aiming to achieve enantiomerically pure forms, several methodologies of stereoselective synthesis have been implemented. Those approaches encompass stereoselective chalcone epoxidation, Sharpless asymmetric dihydroxylation, Mitsunobu reaction, and the cycloaddition of 1,4-benzoquinone. Chiral auxiliaries, organo-, organometallic, and biocatalysis, as well as the chiral pool approach were also employed with the goal of obtaining chiral bioactive flavonoids with a high enantiomeric ratio. Additionally, the employment of the Diels–Alder reaction based on the stereodivergent reaction on a racemic mixture strategy or using catalyst complexes to synthesise pure enantiomers of flavonoids was reported. Furthermore, biomimetic pathways displayed another approach as illustrated by the asymmetric coupling of 2-hydroxychalcones driven by visible light. Recently, an asymmetric transfer hydrogen-dynamic kinetic resolution was also applied to synthesise (R,R)-cis-alcohols which, in turn, would be used as building blocks for the stereoselective synthesis of flavonoids.

This short review aims to summarize the reports on stereoselective synthesis of naturally occurring tetrahydrofuran lignans published during the period of 2006 to 2018. The stereoselective construction of non-natural tetrahydrofuran frameworks is not included in this review.1 Introduction2 Stereoselective Synthesis of 2,5-Diaryltetrahydrofuran (CL5-a)2.1 Synthesis of CL5-a via Friedel–Crafts Arylation or Nucleophilic Addition/Reduction of γ-Butyrolactones2.2 Synthesis of CL5-a via Intramolecular Cyclization of 1,4-Diaryl­butanediols2.3 Synthesis of CL5-a via Diastereoselective Hydrogenation of Furan Derivatives2.4 Synthesis of CL5-a via Cycloaddition Reaction of Substituted Cyclopropane­ Derivatives3 Stereoselective Synthesis of 2-Aryl-4-benzyltetrahydrofuran (CL5-b)4 Stereoselective Synthesis of 3,4-Dibenzyltetrahydrofuran (CL5-c)5 Conclusions

The total synthesis of clusianone was accomplished through the stereoselective construction of a bicyclo[3.3.1]nonane derivative via a three-step sequence which has been utilized for the total syntheses of nemorosone garsubellin A and hyperforin: intramolecular cyclopropanation formation of a geminal dimethyl group and regioselective ring opening of cyclopropane. Further elaboration including chemo- and stereoselective hydrogenation to generate the C7 stereogenic center and cross-metathesis to construct prenyl groups in the side-chains was employed to complete the total synthesis of clusianone.

The stereoselective synthesis of 3-substituted and 3,4-disubstituted piperidine and piperidin-2-one derivatives was achieved starting from 2-pyridone. After N-galactosylation and subsequent O-silylation, nucleophilic addition of organometallic reagents proceeded with high regio- and stereoselectivity at 4-position. Substituents at position 3 were stereoselectively introduced by reaction of electrophiles with amide enolates of the N-galactosyl-2-piperidones.

An intermediate (20) containing four of the five rings and seven of the ten chiral centers of bruceantin (1) was prepared. In a key reaction, 3-iodo-1-trimethylsilyl-5-hexen-1-yne (9) was found to add chemoselectively and stereoselectively to a dianion. The sequence also includes a selective attack by a sulfinate (17) on the terminal acetylene C-atom of the dianion of a keto acetylene, a concomitant cyclization in which the acetylene acts as an electrophile, and the use of the resulting allyl sulfoxide for the introduction of oxygen functionality by a reductive rearrangement. Keywords: bruceantin, sigmatropic rearrangement, stereoselective alkylation.

This thesis begins in Chapter One with a discussion of the role of electrophilic cyclisation in the synthesis of tetrahydrofurans. Chapter Two begins with a discussion of the synthesis of iodo-olactones, by the iodolactonisation of β-silyloxy-δ-alkenoic acids (Scheme A). It will show how the potential of this chemistry has been expanded by proving the absolute stereochemistry at the iodine centre. Chapter Two goes on to consider the stereospecific synthesis of 2,3,5-trisubstituted iodo-tetrahydrofurans by the related iodo-etherification of homoallylic alcohols (Scheme B). This is facilitated by the use of anhydrous conditions. The synthesis of 2,3,5-trisubstituted iodo-tetrahydrofuranacetic acid esters and 2,3,5-trisubstituted hydroxy-tetrahydrofuranacetic acid esters by the iodocyclisation of geometrically pure (E)- and (Z)-β-hydroxy-δ-alkenoates was then developed and the stereochemical outcome of the reactions was proven (Scheme C). Targets were chosen which illustrated the utility of the key cyclisations of β-hydroxy-δ-alkenoates. Chapter Three discusses the synthesis of muscarine 93. It was chosen to synthesise muscarine from the cyclisation of the (Z)-β-hydroxy-δ-alkenoate 146. This synthesis is particularly versatile as it not only allows the preparation of muscarine itself, but also of various potentially highly biologically active analogues 146a. The second target selected was Goniofufurone 170. Approaches to this molecule will be discussed in Chapter Four. Model work in the synthesis of goniofufurone began with the cyclisation of the (E)-β-hydroxy-δ-alkenoate 53b, which indeed, led to the facile synthesis of the iodolactone 204. However, early attempts to incorporate the natural side chain met with limited success. Chapter Five discusses an approach to the 2-oxabicyclo-2.2.11-heptane ring system, which has been synthesised by the radical cyclisation of various β,y-unsaturated tetrahydrofurans of the general form shown in Scheme D.

The 2,6-diaryl-3,7-dioxabicyclo[3,3,0]octanes (or furofurans) belong to the lignan family of natural products. Lignans represent very attractive synthetic targets owing to their large range of biological properties including anticancer, antiviral and immunosuppressant activities. There is considerable structural variation in this series in both the nature and the stereochemistry of the aryl substituents. Since activity is dependent on stereochemistry, synthetic routes, which can provide controlled but tuneable access to one particular class, are very attractive. In this respect, we have been interested in developing efficient ways to synthesise the furofuran skeleton. Based on previous work in our group, the first synthesis of a natural endo-endo furofuran, Epiasarinin, has been achieved via a five step strategy. It included a Darzens condensation followed by a thermal rearrangement of vinyl epoxide to cis dihydrofuran, a Lewis acid promoted cyclisation of a dihydrofuryl alcohol and a reduction of a glycosidic bond. Variations of this methodology afforded the selective the thermal rearrangement has been explored and improvement of this step via different activation methods considered. Another aim of this thesis was to extend this existing method to generate aza analogues. Two strategies have been explored. Generation of furopyrroles can be achieved via the thermal rearrangement of vinyl aziridines or via the acid catalysed cyclisation of dihydrofuryl amines. In conclusion, this short and selective synthetic route leads to a large range of natural or unnatural furofurans and the extension to their aza analogues was also explored.

La Tesis que se presenta trata sobre el desarrollo de nuevos métodos selectivos de síntesis de carbohidratos. En la primera parte de la tesis se estudió la epoxidación de glicales utilizando catalizadores de Mo y ácido meta-cloroperbenzoico (MCPBA), en relación con la obtención de mano-oligosacáridos. En todos los casos estudiados, el epóxido formado se abría in situ para dar lugar al correspondiente diol o glicósido. Se observó un efecto director por parte de los hidroxilos libres, lo que permitía obtener derivados de manosa a partir de glucosa. En el caso del Mo, los resultados figuran entre los mejores descritos para epoxidación de glicales con catalizadores. Los resultados con MCPBA fueron excelentes, aplicándose este último procedimiento a la síntesis ortogonal de dadores de glicosilo. En la segunda parte, relacionado con la síntesis del cardiotónico digitoxina, se estudiaron dos metodologías sintéticas para obtener 2-desoxi-glicósidos mediante reacción de olefinación-ciclación-glicosilación y a través de síntesis asimétrica.
This thesis deals with two topics connected with carbohydrate chemistry. The first part presents epoxidation and dihydroxylation reactions of glycals using Mo-catalysts and m-chloroperbenzoic acid (MCPBA) towards the synthesis of manno oligosaccharides. The oxidation of glycals afforded in all cases the corresponding diols or glycosides, as a consequence of the in situ opening of the epoxides initially formed. Free hydroxyl groups were observed to direct the stereoselectivity of the epoxidation, and then manno derivatives were obtained from unprotected or partially protected glucals. The results using Mo-catalysts are among the best described for the catalytic epoxidation of glycals. The results using MCPBA were excellent, and this methodology was applied to the synthesis of orthogonally protected glycosyl donors. The second part is related to the synthesis of the cardiotonic digitoxin. Two different strategies were studied in order to obtain 2-deoxy-glycosides through olefination-cyclization-glycosylation reaction and using asymmetric synthesis.

Stereoselective Synthesis of 2-Deoxyoliogosaccharides
Autor: Omar Boutureira Martín


La tesi s'emmarca dins el camp de la síntesis de carbohidrats i glicoconjugats i mes concretament sobre la síntesi de 2-desoxi-glicòsids i oligosacàrids, que son unitats estructurals presents en substàncies biològicament actives i/o productes naturals com antitumorals, antibiòtics, agents antiparasitaris, cardiotònics...i a més a més són difícils d'obtenir a partir de carbohidrats naturals.
D'aquesta forma en aquesta tesi s'aborda la síntesis de 2-desoxi-2-iodo-1-tiopiranósids com a nous dadors de glicosil i la seva aplicació en la síntesis estereoselectiva d'oligosacàrids i glicòsids. Aquest dadors de glicosil es caracteritzen per la presència d'un grup fenilsulfanil com a grup sortint en la posició anomèrica (C1) i un grup iode en el C2 que actua com element de control en la reacció de glicosilació.
La memòria s'ha organitzat en una introducció general un capítol d'objectius, i quatre capítols on s'exposen i discuteixen els resultats obtinguts amb les seves corresponents conclusions.
La introducció (Capítol 1) tracta sobre els mètodes de síntesi de 2-desoxiglicòsids de configuracions  i ,. D'aquesta forma es fa una revisió dels mètodes desenvolupats fins avui per la síntesis d'aquest glicòsids. Lligat amb aquests mètodes anteriors, en els objectius (Capítol 2) es posa de manifest la necessitat d'arribar a un nou mètode de síntesis de 2-desoxicarbohidrats que permeti assolir totes les configuracions de piranòsids possibles.
En el Tercer capítol es desenvolupa el nou mètode d'obtenció de 2-desoxi-2 iodo-1-tioglicòsids que després es faran servir com a dadors de glicosil. A partir de pentoses de totes les configuracions i diferentment protegides es van estudiar diferent mètodes d'olefinació per tal d'obtenir polihidroxihexenilsulfurs. El mètode més eficaç en termes de rendiment i estereoselectivitat fou la olefinació amb òxid de fosfina (reacció de Wittig-Horner-WH). Aquests alquenols es van ciclar amb electròfils de iode, conduint de forma regioselectiva als 2-desoxi-2-iodo-1 tiopiranòsids. Aquest compostos es van utilitzar com dadors de glicosil i es van fer reaccionar amb colesterol com a model d'aglicona de diferents compostos bioactius i amb un glucòsid com a model de síntesi d'oligosacàrid.
Donat que la reacció de ciclació i la de glicolació eren activades per el mateix tipus de reactiu, es va pensar en realitzar la síntesi dels 2-desoxi-2-iode-glicòsids de forma consecutiva sense aïllar el tioglicòsid intermedi. Aquest procediment va resultar un èxit conduint al producte final con rendiments mol millors amb estereoselectivitats similars.
En el Quart capítol se estudia las mateixes reaccions que abans però emprant seleni en lloc de sofre i/o iode. Així, en primer lloc s'estudia la reacció de ciclació dels alquenols obtinguts en Capítol 3, però induïda per reactius electròfils de seleni. Se estudia com l'estructura del substrat afecta a la reacció. S'observa que en funció del substrat es formen principalment glicals o inclús selenoglicals. Solament s'obtenen els corresponents 2-desoxi-2-fenilselenenil-tioglicòsids quan existeixen grups protegits amb grups isopropilidé. En aquestos casos però els productes de ciclació amb seleni à la posició 2 son també excel.lents glicosil dadors, i el control de l'estereoselectivitat de la reacció es similar a quan s'utilitza iode.

En la segona part d'aquest Capítol s'estudien mètodes de síntesi de selenoalquens, concluint que la reacció es particularment difícil en el cas dels sucres i que també la reacció de W-H es la més apropiada.
En Capítol 5, aborda el estudi d'un nou mètode de síntesi de sulfanilalquens derivats de carbohidrats mitjançant la reacció de metatesi creuada amb catalitzadors de ruteni amb lligands carbè. La reacció es conegut que presenta elevada dificultat quan s'utilitzen alquens rics en densitat de càrrega com es el cas dels vinilèters o vinilsulfurs, però s'han aconseguit rendiments moderats dels compostos objectiu utilitzant microonas com font de calor i el ús de catalitzadors comercials.
En el Capítol 6 s'exposa la síntesi de glicals a partir del 1-tio-2-desoxi-2 iodo-piranosids. El glicals són compostos molt versàtils i útils en la síntesis de carbohidrats i amb el procediment desenvolupat en aquest capítol s'arribà a obtenir glicals de configuracions difícils d'obtenir per altres mètodes, com el D-allal i el D-gulal. A més, en una segona part del capítol tercer, aplicant un procediment de glicosilació estàndard per a com el de Gin ("dehydrative glycosylation") s'obtenen a partir de 2 iodolactols diversos compostos com a 2 iodoglicals, glicals o 1,1'-disacàrids.
En conjunt i com resultat del treball de recerca desenvolupat s'han posat a punt un nou mètode de síntesi de 2-desoxiglicòsids i 2-desoxi-oligosacàrids, compatible amb totes les configuracions dels sucres i que consta de tres reaccions olefinació de pentoses, ciclació intramolecular induïda per electròfils i glicosilació. Les dues ultimes etapes poden ser realitzades en un sol matràs de forma consecutiva.
El estudi d'aquest mètode ha suposat el posar a punt reaccions d'obtenció de sulfanil i selenenil alquens, els primer per dos procediments diferents (W-H i metatesi creuada), ciclació intramolecular regio i estereoselectiva induïda per electròfils de iode i seleni, y la glicosilació a partir de nous dadors de glicosil (2-deoxi-2-iodo-tioglicòsids i 2-desoxi-2-fenilselenenil-tioglicòsids).

Finalment, El sulfanil alquens preparats han estat utilitzats per posar a punt un nou mètode de síntesi de glicals que permet acce3dir a glicals de totes les configuracions. Els glicals per altra banda son intermedis de síntesi estratègics in síntesi orgànica. Així doncs es pot considerar que els objectius científics plantejats per aquesta Tesi ha sigut àmpliament assolits.
Stereoselective Synthesis of 2-Deoxyoliogosaccharides
Autor: Omar Boutureira Martín

The research described in this thesis aims to investigate a new method for the stereoselective synthesis of 2-deoxyglycosides and oligosaccharides based on a new access to 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl glycosyl donors that would not be limited by the availability of pyranoid glycals and by the stereoselective addition of electrophiles.
Chapter 3 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 iodo-hexopyranosyl glycosides from furanoses. The procedure involves three reactions: Wittig-Horner olefination to give alkenyl sulfanyl derivatives, electrophilic iodine-induced cyclization to give phenyl 2-deoxy-2-iodo-1-thiopyranosides, a new type of glycosyl donor, and glycosylation. The olefination reaction afforded alkenyl sulfanyl derivatives in good to excellent yields, except in cases where the conformational freedom is constrained by cyclic protecting groups such as 3,4-O-isopropylidene. The cyclization reaction proceeds with complete regio- and stereoselectivity. The reaction proceeds exclusively as 6-endo cyclization to give phenyl 1-thiopyranoside derivatives. The stereochemistry of the iodine at C-2 is always cis to the neighboring alkoxy group, except for lyxo derivatives which lack cyclic protecting groups. This is a key point in the overall process because the iodine controls the stereoselectivity of the glycosylation reaction. The yield of the cyclization depends on the configuration of the starting material; it is very good for substrates with a ribo or xylo configuration, but more modest for those with an arabino or lyxo configuration. The glycosylation reaction proceeded with good yields and good to excellent stereoselectivities. The glycosidic bond created in the major isomers was always trans to the iodine at C-2. Although phenyl 2-deoxy-2-iodo-1-thioglycosyl donors of all configurations can be accessed using the proposed procedure, it is particularly effective in providing 2-deoxy-2 iodo-β-D-gulo- and -β-D-allo-glycosides. These glycosides are precursors of 2-deoxyglycosides of ribo and xylo configuration, which are difficult to obtain by the classical methodology starting from glycals.
Since 2-deoxy-2-iodo-1-thioglycosides are activated in conditions similar to those used to induce the cyclization, 2-deoxy-2-iodopyranosides were synthesized from sulfanyl alkenes using a "one pot" consecutive cyclization and glycosylation process. The "one pot" procedure has the advantage that it starts directly from the very stable acyclic alkenyl sulfide precursors and does not require isolation of the glycosyl donors. The overall strategy is fairly straightforward and operationally simple. Compared with the stepwise procedure, the "one pot" process gave significantly improved yields with similar or slightly lower selectivities. Furthermore, the "one pot" procedure was successfully applied to the synthesis of 2-deoxy- and 2,6-dideoxyglycosides.
Chapter 4 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 phenylselenenyl-hexopyranosyl glycosides from furanoses. We developed 2-deoxy-2-phenylselenenyl-1-thioglycosides as a new class of glycosyl donors that provide access to 2-deoxyglycosides. The cyclization reaction proceeds with complete regio- and stereoselectivity enhanced by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group. We have also demonstrated that the glycosylation of 2-deoxy-2-phenylselenenyl-1-thioglycosides is highly substrate dependent. Although glycosylation products of all configurations can be accessed by employing the present methodology, it is particularly effective in providing 2-deoxy-2-phenylselenenyl--D-gulo- and --D-allo-glycosides. In particular, regardless of the nature of the solvent employed, the high β-selectivity observed in gulo (α/β ratio 1:14) and more modest in allo (α/β ratio 1:4) series is comparable to that previously observed for analogous glycosylation reactions of 2-deoxy-2-iodo-1-thio-D-gulo- (α/β ratio 1:16) and -D-allo-glycosyl donors (α/β ratio 1:6). Furthermore, the use of phenylselenenyl group at C-2 gave us some insight into the likely pathway of glycosylation reactions by using 2-deoxy-2-phenylselenenyl-1-thioglycosyl donors. Since the stereoselectivity observed is similar to that obtained using 2-deoxy-2-iodo-1-thioglycosides it can be concluded that this explanation is general for the different glycosylations assisted by chalcogens and halogens at C-2.
Since 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl-1-thioglycosides have been evaluated as a new class of glycosyl donors, we became interested in the preparation of other useful glycosyl donors such as 2-deoxy-2-iodo-1-selenoglycosides, and exploit their higher reactivity in developing milder and orthogonal stereoselective glycosylation protocols by using this methodology. Thus, carbohydrate-based vinyl selenides of arabino, ribo, and 2-deoxy-ribo configurations were prepared by Wittig-type reactions of various protected furanoses. Moderate yields were always obtained due to nature and reactivity of both carbohydrate lactols and selenium-based olefinating reagents under the conditions tested. The reaction with electrophiles proved to be challenging and no cyclization products were obtained. The preparation of vinyl selenides proved to be much more difficult than the related vinyl sulfides, which can be prepared in good yields using Wittig-Horner reaction.
Chapter 5 reports olefin cross metathesis reaction between carbohydrate-derived hydroxy alkenes and electron-rich olefinic partners with commercially available ruthenium-based catalysts. Microwave irradiation effectively accelerates the cross metathesis reaction of electron-rich olefins although some of the conversions remained low. Cross metathesis can only be achieved with hydroxy alkenes derived from 2-deoxysugars. In contrast, the hydroxy alkenes bearing an allylic alkoxy group neither isomerizes nor couples under similar conditions.
Chapter 6 reports a new method for accessing pyranoid glycals of different configurations by a short route that uses readily available starting materials, and conventional transformations. Our method is particularly valuable for the synthesis of non-readily accessible glycals such as D-allal and D-gulal that are valuable products to prepare some oligosaccharide molecules with biologically interesting properties.
A series of 2-deoxy-2-iodopyranoses were evaluated as precursors that provide access to pyranoid glycals and 2-iodoglycals from sulfanyl alkenes. This synthetic route involves consecutive cyclization and hydrolysis reactions followed by treatment of the resulting lactol under Gins' dehydrative glycosylation conditions. Despite the fact that this procedure has proved to be an efficient and general glycosylation method, its application to 2-deoxy-2-iodopyranoses did not afford the expected products. Although the observed product distribution (glycals, 2-iodoglycals, and 1,1'-disaccharides) revealed that this reaction is very sensitive to the configuration of the 2-deoxy-2-iodopyranose, 2-iodo pyranoid glycals can be almost exclusively obtained in good yields by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group.