吲哚生物碱Desbromoarborescidine A 的全合成及烯胺C-亚磺酰化反应研究

从新几内亚核桃木的树皮中分离得到的吲哚类喹诺里西定生物碱10-Desbromoarborescidine A，因发现其具有阻滞钙离子通道的活性而倍受关注。10-Desbromoarborescidine A由A、B、C、D四个环组成，只有一个手性中心，是吲哚生物碱中结构较简单的一种，常作为此类生物碱全合成方法的模型化合物。但迄今为止，能高效而简便的实现手性10-Desbromoarborescidine A不对称全合成方法线路不多，大多数以不对称诱导的方式建立其手性中心，手性催化的方式仅有一例金属催化。从逆合成分析可知，Desbromoarborescidine A的全合成可以通过亚胺不对称催化还原进行关键的手性中心构建，而本课题组在之前的研究中通过手性有机小分子催化剂的发展，已将三氯硅烷氢转移还原亚胺发展成了一类简便实用、高效、高对映选择性并具有优良底物适应范围的不对称催化反应，我们希望以这一反应作为关键手段，发展一条Desbromoarborescidine A及其类似物不对称合成新路线。 根据我们设计的新路线，首先成功合成了其关键中间体，然后我们进行了关键的不对称催化尝试。用本实验室已有的高性能有机小分子催化剂虽得到了较好的对应选择性，但是产率很低。同时，为了验证整条线路的可行性，我们也用消旋的中间体进行拉通线路的尝试。但不幸的是，在脱除保护基时遇到了很大困难。尝试换不同的保护基，或改变脱保护基的顺序，都未能成功合成目标产物。究其原因可能是由于吲哚的特殊性造成的，吲哚类亚胺与常规的芳香亚胺有较大的差异，其NH基团无论保护还是不保护，对与其2位相联接的C=N双键均有很大的影响，导致其不对称催化还原难以进行。另外，由于所设计的还原产物含有处在吲哚苄位的胺基，稳定性较差，造成保护基脱除困难。 烯胺C-亚磺酰化反应是本课题组最近发现的一个新反应，之前未见文献报道。本研究对该反应进行了反应条件优化和底物扩展，发现带Cbz，Ac，COt-Bu，CO2Et，Bz等保护基的一系列环状和非环状烯胺在亚磺酸钠、DMAc和MeSiCl3的共同作用下能高效高产率生成β-胺基烯基亚砜类新化合物，为合成多官能团化的烯基亚砜新化合物提供了一条简便实用的途径。 The main constituent of Dracontomelum mangiferum B1, indoloquinolizidine alkaloid 10-Desbromoarborescidine A, has drawn great attention due to its calcium channel blocking activity. Its molecular structure is relatively simple compared with the other alkaloids of the same type, which has only one chiral center, albeit with four cycles A, B, C, and D. This compound is often used as a model target for exploring different strategies for the total synthesis of indole alkaloids. Nevertheless, so far there still lack practical and highly efficient methods for the asymmetric total synthesis of 10-Desbromoarborescidine A. Most of the current available methods rely on stoichiometric asymmetric synthesis for the construction of the chiral center. There is only one example reporting utilization of asymmetric catalysis, but with transition metal complex as the catalyst. Our retrosynthetic analysis shows that catalytic asymmetric reduction of imine could be used as the key step for the construction of the chiral center of Desbromoarborescidine A. Since in the previous studies our group has developed the asymmetric reduction of imines by trichlorosilane into a practical and highly efficient and enantioselective method using newly designed chiral organocatalysts, we hope to apply this method to develop a novel synthetic route for the total synthesis of Desbromoarborescidine A and its analogues in this study. According to the newly designed synthetic route, we first accomplished the synthesis of the key intermediates which was then examined for the critical asymmetric catalysis. The asymmetric reduction using the highly efficient organocatalysts, developed in our lab afforded high ee but poor yield. We tried different reaction conditions to improve the yield, but failed to get any good results. Simultaneously, to vertify the feasibility of the synthetic route we designed, we also tired to go through the route toward the racemic synthesis of Desbromoarborescidine A. But unfortunately, protection and deprotection proved to be big hurdles. All the different protection groups and different sequences of protection and deprotection we tried failed to get us through the designed synthetic sequence and furnish the final product. Most likely, the indole part is the culprit behind the failures.The NH group of the indole, no matter protected or not, may impact the catalytic asymmetric reduction of C-N double bond connected with 2-C. Additionally, the reduction product we designed contains an amino group in the β-position of the indole, which may cause problems due to its instability. C-sulfenylation of enamines is a novel reaction discovered recently by our group, which has not been seen before in the literature. In this study, optimization of the reaction conditions and exploration of the substrate scope were further undertaken for this reaction, which reveal that a series of enamines with N-Cbz, Ac, COt-Bu, CO2Et protection groups could all undergo smooth C-sulfinylations with the comined use of sodium benzene sulphinate, DAMc and MeSiCl3, efficiently furnishing the β-amino vinylsulfoxide products in high yield, affording a practical and highly efficient methods for synthesis of functional vinylsulfoxides.

Asymmetric Michael addition of aldehydes to nitroolefins catalyzed by L-prolinamide derivatives using phenols as co-catalysts

The asymmetric Michael addition of aldehydes to nitroolefins was investigated using L-prolinamide derivatives of 2-(2'-piperidinyl)pyridine as catalyst and a variety of phenols as co-catalyst. Extensive screening toward the effect of prolinamides, phenols, and solvents on this transformation revealed that a combination of (S)-2-(2'-piperidinyl)pyridine-derived trans-4-hydroxy-L-prolinamide 2c, (S)-1,1'-bi-2-naphthol, and dichloromethane was a promising system. This system was shown to be amenable to a rich variety of aldehydes and nitroolefins and afforded the nitroaldehyde products with excellent yield, enantiomeric excess (up to 99%) and diastereoselectivity ratio (up to 99/1), even in the case of 1 mol % catalyst loading and 1.5 equiv of aldehydes.

Chemoenzymatic synthesis of chiral 2,2 '-bipyridine ligands and their N-oxide derivatives: applications in the asymmetric aminolysis of epoxides and asymmetric allylation of aldehydes

A series of enantiopure 2,2'-bipyridines have been synthesised from the corresponding cis-dihydrodiol metabolites of 2-chloroquinolines. Several of the resulting hydroxylated 2,2'-bipyridines were found to be useful chiral ligands for the asymmetric aminolysis of meso-epoxides leading to the formation of enantioenriched amino alcohols (-> 84%ee). N-oxide and N,N'-dioxide derivatives of these 2,2'-bipyridines, including separable atropisomers, have been synthesised and used as enantioselective organocatalysts in the asymmetric allylation of aldehydes to give allylic alcohols (-> 86%ee).

Transformações organocatalíticas e mediadas por metais de transição na síntese de novos heterociclos nitrogenados e ciclo-hexanos

Nas últimas décadas a quiralidade tornou-se essencial na conceção, descoberta, desenvolvimento e comercialização de novos medicamentos. A importância da quiralidade na eficácia e segurança dos fármacos tem sido globalmente reconhecida tanto pelas indústrias farmacêuticas como pelas agências reguladoras de todo o mundo. De forma a produzir eficazmente medicamentos seguros e dar resposta à demanda da indústria de compostos enantiomericamente puros, a pesquisa de novos métodos de síntese assimétrica, assim como o desenvolvimento estratégico dos métodos já disponíveis tem sido um dos principais objetos de estudo de diversos grupos de investigação tanto na academia como na indústria farmacêutica No primeiro capítulo desta dissertação são introduzidos alguns dos conceitos fundamentais associados à síntese de moléculas quirais e descritas algumas das estratégias que podem ser utilizadas na sua síntese. Apresenta-se ainda uma breve revisão bibliográfica acerca dos antecedentes do grupo de investigação e sobre a ocorrência natural, atividade biológica e métodos de síntese e transformações de compostos do tipo (E,E)-cinamilidenoacetofenona. O segundo capítulo centra-se na adição de Michael enantiosseletiva de diversos nucleófilos a derivados de (E,E)-cinamilidenoacetofenona. Inicialmente descreve-se a síntese de derivados de (E,E)-cinamilidenoacetofenona através de uma condensação aldólica de acetofenonas e cinamaldeídos apropriadamente substituídos. Estes derivados são posteriormente utilizados como substratos na adição de Michael enantiosseletiva de três diferentes nucleófilos: nitrometano, malononitrilo e 2-[(difenilmetileno)amino]acetato de metilo. Nestas reações são utilizados diferentes organocatalisadores de forma a induzir enantiosseletividade nos aductos de Michael para serem utilizados na síntese de compostos com potencial interesse terapêutico. É descrita ainda uma nova metodologia de síntese de Δ1-pirrolinas através de um procedimento one-pot de redução/ciclização/desidratação mediada por ferro na presença de ácido acético de (R,E)-1,5-diaril-3-(nitrometil)pent-4-en-1-onas com bons rendimentos e excelentes excessos enantioméricos. O terceiro capítulo centra-se no estabelecimento de novas rotas de síntese e transformação de derivados do ciclo-hexano. Após uma breve revisão bibliográfica, são descritas três metodologias enantiosseletivas distintas, sendo que a primeira envolve a utilização de organocatalisadores e catalisadores de transferência de fase derivados de alcaloides cinchona. Os derivados do ciclo-hexano foram obtidos a partir da reação entre as (E,E)-cinamilidenoacetofenonas e o malononitrilo com bons rendimentos, mas baixas enantiosseletividades independentemente do catalisador utilizado. De forma a contornar este problema e uma vez que a formação do derivado do ciclo-hexano envolve inicialmente a formação in-situ do aducto de Michael, a segunda e terceira metodologias de síntese envolvem a utilização dos aductos de Michael enantiomericamente puros preparados no segundo capítulo. Assim, a reação do (S,E)-2-(1,5-diaril-1-oxopent-4-en-3-il)malononitrilo com os derivados de (E,E)-cinamilidenoacetofenona organocatalisada pela hidroquinina permitiu obter os compostos pretendidos com excelentes excessos enantioméricos. A utilização de um catalisador de transferência de fase não foi tão eficiente em termos de enantiosseletividades obtidas na reação entre as (R,E)-1,5-diaril-3-(nitrometil)pent-4-en-1-onas e os derivados de (E,E)-cinamilidenoacetofenona, apesar de estes terem sido obtidos em bons rendimentos. A preparação destes derivados levou ainda à idealização de uma nova metodologia de síntese de análogos do ácido γ-aminobutírico (GABA) devido à presença de um grupo nitro em posição gama relativamente a um grupo carboxílico. No entanto, apesar de terem sido testadas várias metodologias, não foi possível obter os compostos pretendidos. No quarto capítulo apresenta-se uma breve revisão bibliográfica acerca da ocorrência natural, atividade biológica e métodos de síntese de derivados de di-hidro- e tetra-hidropiridinas, assim como um enquadramento teórico acerca das reações pericíclicas utilizadas na síntese dos compostos pretendidos. Inicialmente é descrita a preparação de N-sulfonilazatrienos substituídos através da condensação direta de derivados de (E,E)-cinamilidenoacetofenona e sulfonamidas. Estes compostos são posteriormente utilizados na síntese de derivados de 1,2-di-hidropiridinas através de uma aza-eletrociclização-6π por duas metodologias distintas: utilização de organocatalisadores quirais e utilização de complexos metálicos de bisoxazolinas. Na síntese das tetra-hidropiridinas os N-sulfonilazatrienos são utilizados como dienos e o étoxi-eteno como dienófilo numa reação hetero-Diels-Alder inversa utilizando também os complexos metálicos de bisoxazolinas como catalisadores. Todos os novos compostos sintetizados foram caracterizados estruturalmente recorrendo a estudos de espetroscopia de ressonância magnética nuclear (RMN), incluindo espetros de 1H e 13C e estudos bidimensionais de correlação espetroscópica homonuclear e heteronuclear e de efeito nuclear de Overhauser (NOESY). Foram também efetuados, sempre que possível, espetros de massa (EM) e análises elementares ou espetros de massa de alta resolução (EMAR) para todos os novos compostos sintetizados.

Stereoselective synthesis of 5-substituted pyrrolo[1,2-c]imidazol-3-ones. Access to aldosterone synthase inhibitors and chiral precatalysts

Compounds containing the pyrrolidine moiety are key substructures of compounds with biological activity and organocatalysts. In particular, annulated chiral pyrrolidines with alpha stereogenic centers have aldostereone synthase inhibition activity. In addition, 5-substituted pyrroloimidazol(in)ium salts precursors to N-heterocyclic carbene (NHC) precatalysts are rare due to a lack of convenient synthetic routes to access them. In this thesis is described a rapid synthesis of NHC precursors and a possible route to 5-substituted pyrroloimidazole biologically active compounds. The method involves the preparation of chiral saturated and achiral unsaturated pyrrolo[I,2- c]imidazol-3-ones from N-Cbz-protected t-Butyl proline carboxamide. The resulting starting materials may be used to prepare the target chiral annulated imidazol(in)ium products by a two-step sequence involving first stereoselective lithiation-substitution, followed by POCh induced salt formation.

Mirroring Enzymes: The Role of H-Bonding In HQuin-BAM Catalyzed Asymmetric Aza-Henry Reactions: A DFT Study into the Reactivity, Mechanism, and Origins of Selectivity

The exact mechanistic understanding of various organocatalytic systems in asymmetric reactions such as Henry and aza-Henry transformations is important for developing and designing new synthetic organocatalysts. The focus of this dissertation will be on the use of density functional theory (DFT) for studying the asymmetric aza-Henry reaction. The first part of the thesis is a detailed mechanistic investigation of a poorly understood chiral bis(amidine) (BAM) Brønsted acid catalyzed aza-Henry reaction between nitromethane and N-Boc phenylaldimine. The catalyst, in addition to acting as a Brønsted base, serves to simultaneously activate both the electrophile and the nucleophile through dual H-bonding during C-C bond formation and is thus essential for both reaction rate and selectivity. Analysis of the H-bonding interactions revealed that there was a strong preference for the formation of a homonuclear positive charge-assisted H-bond, which in turn governed the relative orientation of substrate binding. Attracted by this well-defined mechanistic investigation, the other important aspect of my PhD research addressed a detailed theoretical analysis accounting for the observed selectivity in diastereoselective versions of this reaction. A detailed inspection of the stereodetermining C-C bond forming transition states for monoalkylated nitronate addition to a range of electronically different aldimines, revealed that the origins of stereoselectivity were controlled by a delicate balance of different factors such as steric, orbital interactions, and the extent of distortion in the catalyst and substrates. The structural analysis of different substituted transition states established an interesting dependency on matching the shape and size of the catalyst (host molecule) and substrates (guest molecules) upon binding, both being key factors governing selectivity, in essence, offering an analogy to positive cooperative binding effect of catalytic enzymes and substrates in Nature. In addition, both intra-molecular (intra-host) and inter-molecular (host-guest, guest-guest) stabilizing interactions play a key role to the high π-facial selectivity. The application of dispersion-corrected functionals (i.e., ωB97X-D and B3LYP-D3) was essential for accurately modeling these stabilizing interactions, indicating the importance of dispersion effects in enantioselectivity. As a brief prelude to more extensive future studies, the influence of a triflate counterion on both reactivity and selectivity in this reaction was also addressed.

Sels d’imidazolium avec des anions catalytiques : vers le développement de nouveaux catalyseurs bio-hybrides actifs en milieu liquide ionique

Les liquides ioniques connaissent depuis quelques décennies un essor particulier en raison de leurs nombreuses propriétés physico-chimiques intéressantes, telles qu’une faible pression de vapeur saturante, une viscosité limitée, une faible miscibilité avec la plupart des solvants communs, ou encore des propriétés d’agencement supramoléculaire, qui en font des outils puissants dans de nombreux domaines de la chimie. Les sels d’imidazolium représentent la plus grande famille de liquides ioniques à ce jour. Leur modulabilité leur permet d’être dérivés pour de nombreuses applications spécifiques, notamment en synthèse organique, où ils sont utilisés majoritairement comme solvants, et plus récemment comme catalyseurs. Les travaux présentés dans cette thèse se concentrent sur leur utilisation en synthèse organique, à la fois comme solvants et principalement comme catalyseurs chiraux, catalyseurs pour lesquels l’anion du sel est l’espèce catalytique, permettant d’ajouter de la flexibilité et de la mobilité au système. En tirant parti de la tolérance des liquides ioniques envers la majorité des macromolécules naturelles, l’objectif principal des travaux présentés dans cette thèse est le développement d’un nouveau type de catalyseur bio-hybride reposant sur l’encapsulation d’un sel d’imidazolium dans une protéine. Par le biais de la technologie biotine-avidine, l’inclusion supramoléculaire de sels d’imidazolium biotinylés portant des contre-anions catalytiques dans l’avidine a été réalisée et exploitée en catalyse. Dans un premier temps, le développement et l’étude de deux sels de 1-butyl-3-méthylimidazolium possédant des anions chiraux dérivés de la trans-4-hydroxy-L-proline sont rapportés, ainsi que leur comportement dans des réactions énantiosélectives d’aldol et d’addition de Michael. Ces types de composés se sont révélés actifs et performants en milieu liquide ionique. Dans un second temps, la préparation de sels d’imidazolium dont le cation est biotinylé et portant un contre-anion achiral, a été réalisée. Le comportement de l’avidine en milieu liquide ionique et son apport en termes de chiralité sur le système bio-hybride ont été étudiés. Les résultats montrent le rôle crucial des liquides ioniques sur la conformation de la protéine et l’efficacité du catalyseur pour des réactions d’aldol. Dans un dernier temps, l’influence de la structure du cation et de l’anion sur le système a été étudiée. Différents espaceurs ont été introduits successivement dans les squelettes cationiques et anioniques des sels d’imidazolium biotinylés. Dans le cas du cation, les résultats ne révèlent aucune influence majeure sur l’efficacité du catalyseur. La structure de l’anion se montre cependant beaucoup plus importante : la préparation de différents catalyseurs bio-hybrides possédant des anions aux propriétés physico-chimiques différentes a permis d’obtenir de plus amples informations sur le mode de fonctionnement du système bio-hybride et de la coopérativité entre l’avidine et l’anion du sel d’imidazolium.La nature ionique de la liaison cation-anion offrant une liberté de mouvement accrue à l’anion dans la protéine, la tolérance à différents substrats a également été abordée après optimisation du système.

First Example of Organocatalysis by Polystyrene-Supported PAMAM Dendrimers: Highly Efficient and Reusable Catalyst for Knoevenagel Condensations

This paper describes the first use of polystyrene-supported poly(amidoamine) (PAMAM) dendrimers as heterogeneous basic organocatalysts for carbon–carbon bond formation. Polystyrene-supported PAMAM dendrimers of first, second and third generations have been used as reusable base catalysts in Knoevenagel condensations of carbonyl compounds with active methylene compounds. The reactions proceed in short periods of time and with 100% selectivity. This novel catalyst eliminates the use of aromatic and halogenated solvents, as well as complex purification processes. The catalysts can be recycled ten times.

Functionalized Silicon Polymers: Novel Materials for Catalysis

Dept.of Applied Chemistry,Cochin University of Science and Technolgy

Organocatalysis with proline derivatives: improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions

Tetrazole and acylsulfonamide organocatalysts derived from proline have been synthesised and applied to the asymmetric Mannich, nitro-Michael and aldol reactions to give results that are superior to the proline-catalysed counterpart.

Silyl-Modified Analogues of 2-Tritylpyrrolidine: Synthesis and Applications in Asymmetric Organocatalysis

Silicon-based organocatalysts: In an effort to study the effects of substituting carbon by silicon within the catalyst backbone, we developed an efficient synthesis of (S)-2-triphenylsilylpyrrolidine [(S)-2]. The evaluation of (S)-2 against its carbon analogue (S)-1 in two organocatalytic reactions is complemented by computational studies.

General aspects of organocatalytic cyclizations

Ring-forming reactions are an essential part of synthetic chemistry and allow access to a range of useful natural products and biologically important molecules. The applications of organocatalysis to the synthesis of functionalized, enantiopure structures really begins where organocatalysis itself begins; with the Hajos-Parrish reaction in the 1970s for the synthesis of steroids using proline. This chapter then will review the uses of organocatalysts in cyclization methodology – from the initial Hajos-Parrish discovery to current advances in the field.

Anion recognition and transport properties of sulfamide-, phosphoric triamide- and thiophosphoric triamide-based receptors

Studies of sulfamide, phosphoric triamide and thiophosphoric triamidebased organocatalysts show that the phosphorus containing systems are effective new hydrogen bonding motifs for the recognition and transport of anions.

Neue Katalysatoren für die asymmetrische Strecker-Reaktion auf Kohlenhydratbasis

Die asymmetrische Strecker-Reaktion ist von großer Bedeutung zur Darstellung optisch aktiver natürlicher und artifizieller -Aminocarbonsäuren beider Enantiomerenreihen. In der vorliegenden Arbeit wurden Synthesen einer Reihe von metallfreien, löslichen und immobilisierten Organokatalysatoren auf Kohlenhydratbasis für die enantioselektive Hydrocyanierung von Iminen ausgearbeitet. Durch gezielte Variation sowohl der Substituenten als auch des monosaccharidischen chiralen Rückgrates, konnten durch Aktivitäts- und Selektivitätsvergleich mit bereits bekannten Glucokatalysatoren und mit Hilfe einfacher, durch MM2-Kraftfeldmethoden gewonnener, Molekülmodelle Struktur-Wirkungs-Beziehungen aufgestellt und Rückschlüsse auf den mechanistischen Ablauf der enantioselektiven pseudo-Strecker-Reaktion gezogen werden.

Enantioselective Reactions Promoted by Organocatalytic Species From The Natural Chiral Pool

During the course of my Ph.D. in the laboratories directed by Prof. Alfredo Ricci at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, I was involved in the study and the application of a number of organocatalytic systems, all coming from the natural chiral pool. The first part of this thesis will be devoted to new homogeneous organocatalytic reactions promoted by Cinchona alkaloid-based organocatalysts. Quinine based catalysts were found to be a very effective catalyst for Diels-Alder reactions involving 3-vinylindoles. Excellent results in terms of yields and enantioselectivities were achieved, outlining also a remarkable organocatalytic operational mode mimicking enzymatic catalysis. The same reaction with 2-vinylindoles showed a completely different behaviour resulting in an unusual resolution-type process. The asymmetric formal [3+2] cycloaddition with in situ generated N-carbamoyl nitrones using Cinchona-derived quaternary ammonium salts as versatile catalysts under phase transfer conditions, outlines another application in organocatalysis of this class of alkaloids. During the seven months stage in the Prof. Helma Wennemers’ group at the Department of Chemistry of the University of Basel (Switzerland) I have been involved in organocatalysis promoted by oligopeptides. My contribution regarded the 1,4-addition reaction of aldehydes to nitroolefins. In the work performed at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, in collaboration with the ‘Institut Charles Gerhardt-Montpellier, of Montpellier (France) the possibility of performing for the first time heterogeneous organocatalysis by using a natural polysaccharide biopolymer as the source of chirality was disclosed. With chitosan, derived from deacetylation of chitin, a highly enantioselective heterogeneous organocatalytic aldol reaction could be performed. The use of an eco-friendly medium such as water, the recyclability of the catalytic specie and the renewable nature of the polysaccharide are assets of this new approach in organocatalysis and open interesting perspectives for the use of biopolymers.