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The Overman rearrangement difficulties are tentatively explained using stereo-electronic considerations, helping chemists to understand their troubles in this process.

Napoleon Bonaparte once said, “A good sketch is better than a long speech”. Though an ardent promoter of beet sugar production, Napoleon could never have imagined that he was describing the thorny problem of the stereochemical representation of sugars. Drawing the structure of a sugar molecule (also called “carbohydrate”) means addressing the challenge of unambiguously transcribing a three-dimensional reality into a bi-dimensional representation as accurately as possible. Since Emil Fischer's initial proposals, several methods have been suggested, with their advantages and drawbacks. Consequently, selecting a particular approach is far from inconsequential and involves numerous pitfalls. The objective of this document is to raise awareness of the subtleties of sugar molecules representations.

International audience; p‐Hydroxycinnamic acids (i. e., p‐coumaric, ferulic, sinapic, and caffeic acids) are phenolic compounds involved in the biosynthesis pathway of lignin. These naturally occurring molecules not only exhibit numerous attractive properties, such as antioxidant, anti‐UV, and anticancer activities, but they also have been used as building blocks for the synthesis of tailored monomers and functional additives for the food/feed, cosmetic, and plastics sectors. Despite their numerous high value‐added applications, the sourcing of p‐hydroxycinnamic acids is not ensured at the industrial scale except for ferulic acid, and their production cost remains too high for commodity applications. These compounds can be either chemically synthesized or extracted from lignocellulosic biomass, and recently their production through bioconversion emerged. Herein the different strategies described in the literature to produce these valuable molecules are discussed.

International audience; Plant innate immunity is activated upon perception of invasion pattern molecules by plant cell-surface immune receptors. Several bacteria of the genera Pseudomonas and Burkholderia produce rhamnolipids (RLs) from l -rhamnose and ( R )-3-hydroxyalkanoate precursors (HAAs). RL and HAA secretion is required to modulate bacterial surface motility, biofilm development, and thus successful colonization of hosts. Here, we show that the lipidic secretome from the opportunistic pathogen Pseudomonas aeruginosa , mainly comprising RLs and HAAs, stimulates Arabidopsis immunity. We demonstrate that HAAs are sensed by the bulb-type lectin receptor kinase LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION/S-DOMAIN-1-29 (LORE/SD1-29), which also mediates medium-chain 3-hydroxy fatty acid (mc-3-OH-FA) perception, in the plant Arabidopsis thaliana . HAA sensing induces canonical immune signaling and local resistance to plant pathogenic Pseudomonas infection. By contrast, RLs trigger an atypical immune response and resistance to Pseudomonas infection independent of LORE. Thus, the glycosyl moieties of RLs, although abolishing sensing by LORE, do not impair their ability to trigger plant defense. Moreover, our results show that the immune response triggered by RLs is affected by the sphingolipid composition of the plasma membrane. In conclusion, RLs and their precursors released by bacteria can both be perceived by plants but through distinct mechanisms.

Plant innate immunity is activated upon perception of invasion pattern molecules by plant cell-surface immune receptors. Several bacteria of the genera Pseudomonas and Burkholderia produce rhamnolipids (RLs) from l-rhamnose and (R)-3-hydroxyalkanoate precursors (HAAs). RL and HAA secretion is required to modulate bacterial surface motility, biofilm development, and thus successful colonization of hosts. Here, we show that the lipidic secretome from the opportunistic pathogen Pseudomonas aeruginosa, mainly comprising RLs and HAAs, stimulates Arabidopsis immunity. We demonstrate that HAAs are sensed by the bulb-type lectin receptor kinase LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION/S-DOMAIN-1-29 (LORE/SD1-29), which also mediates medium-chain 3-hydroxy fatty acid (mc-3-OH-FA) perception, in the plant Arabidopsis thaliana. HAA sensing induces canonical immune signaling and local resistance to plant pathogenic Pseudomonas infection. By contrast, RLs trigger an atypical immune response and resistance to Pseudomonas infection independent of LORE. Thus, the glycosyl moieties of RLs, although abolishing sensing by LORE, do not impair their ability to trigger plant defense. Moreover, our results show that the immune response triggered by RLs is affected by the sphingolipid composition of the plasma membrane. In conclusion, RLs and their precursors released by bacteria can both be perceived by plants but through distinct mechanisms.

A diastereoselective chemoenzymatic synthetic pathway to D‐(+)‐ribono‐1,4‐lactone, a versatile chiral sugar derivative widely used for the synthesis of various natural products, has been designed from cellulose‐based levoglucosenone (LGO). This route involves a sustainable Baeyer‐Villiger oxidation of LGO to produce enantiopure (S)‐γ‐hydroxymethyl‐α,β‐butenolide (HBO) that is further functionalized with various protecting groups to provide 5‐O‐protected γ‐hydroxymethyl‐α,β‐butenolides. The latter then undergo a diastereoselective and high‐yielding syn‐dihydroxylation of the α,β‐unsaturated lactone moiety followed by a deprotection step to give D‐(+)‐ribono‐1,4‐lactone. Through this 4‐step synthetic route from LGO, D‐(+)‐ribono‐1,4‐lactone is obtained with d.r. varying from 82:18 to 97:3 and in overall yields between 32 and 41 % depending on the protecting group used. Moreover, valuable synthetic intermediates 5‐O‐tert‐butyldimethylsilyl‐, 5‐O‐tert‐butyldiphenylsilyl‐ as well as 5‐O‐benzyl‐ribono‐1,4‐lactones are obtained in 3 steps from LGO in 58, 61 and 40 %, respectively.

Napoleon Bonaparte once said, “A good sketch is better than a long speech”. Though an ardent promoter of beet sugar production, Napoleon could never have imagined that he was describing the thorny problem of the stereo- chemical representation of sugars. Drawing the structure of a sugar molecule (also called “carbohydrate”) means addressing the challenge of unambiguously transcribing a three-dimensional reality into a bi-dimensional representation as accurately as possible. Since Emil Fischer's initial proposals, several methods have been suggested, with their advantages and drawbacks. Consequently, selecting a particular approach is far from inconsequential and involves numerous pitfalls. The objective of this document is to raise awareness of the subtleties of sugar molecules representations., En disant « Un bon croquis vaut mieux qu'un long discours », Napoléon Bonaparte, pourtant promoteur de la production de sucre de betterave, n'imaginait sans doute pas contribuer au débat sur la représentation stéréochimique des sucres. Dessiner la structure d'une molécule de sucre (en anglais, la terminologie anachronique « hydrate de carbone » subsiste parfois) impose de transcrire, le plus fidèlement possible et sans ambiguïté, une correspondance entre une réalité tridimensionnelle et une représentation bidimensionnelle. Depuis les propositions initiales d'Emil Fischer, plusieurs méthodes ont été présentées. Cet article vise à faire prendre conscience de la subtilité des représentations isomériques des molécules de sucres.

Plant innate immunity is activated upon perception of invasion pattern molecules by plant cell-surface immune receptors. Several bacteria of the genera Pseudomonas and Burkholderia produce rhamnolipids (RLs) from L- rhamnose and (R)-3-hydroxyalkanoate precursors (HAAs). RL and HAA secretion is required to modulate bacterial surface motility, biofilm development, and thus successful colonization of hosts. Here, we show that the lipidic secretome from the opportunistic pathogen Pseudomonas aeruginosa mostly comprising RLs and HAAs stimulates Arabidopsis immunity. We demonstrate that HAAs are sensed by the bulb-type lectin receptor kinase LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION/S-DOMAIN-1-29 (LORE/SD1-29) that also mediates medium-chain 3-hydroxy fatty acid (mc-3-OH-FA) perception in the plant Arabidopsis thaliana. HAA sensing induces canonical immune signaling and local resistance to plant pathogenic Pseudomonas infection. By contrast, RLs trigger an atypical immune response and resistance to Pseudomonas infection independent of LORE. Thus, the glycosyl moieties of RLs, albeit abolishing sensing by LORE, do not impair their ability to trigger plant defense. In addition, our results show that RL-triggered immune response is affected by the sphingolipid composition of the plasma membrane. In conclusion, RLs and their precursors released by bacteria can both be perceived by plants but through distinct mechanisms.SignificanceActivation of plant innate immunity relies on the perception of microorganisms through self and nonself elicitors. Rhamnolipids and their precursor HAAs are exoproducts produced by beneficial and pathogenic bacteria. They are involved in bacterial surface dissemination and biofilm development. As these compounds are released in the extracellular milieu, they have the potential to be perceived by the plant immune system. Our work shows that both compounds independently activate plant immunity. We demonstrate that HAAs are perceived by the receptor protein kinase LORE. By contrast, rhamnolipids are not senses by LORE but activate a non-canonical immune response affected by the sphingolipid composition of the plant plasma membrane. Thus, plants are able to sense bacterial molecules as well as their direct precursors to trigger a distinct immune response.

International audience; Chirality is greatly sought for pharmaceutical compounds or fragrance and flavors. (S) -γ-hydroxymethyl-α,β-butenolide, aka HBO, is a chiral (5H)-furanone providing a polarized double bond, a lactone ring and a primary alcohol as playground for synthetic chemists. This molecule has been used for forty years in a wide range of synthetic pathways to natural and/or bioactive molecules. Its own synthesis, always from biosourced product, has also significantly evolved and could be now achieved both at large scale and by applying Green Chemistryprinciples. This review will explore the syntheses, the reactivity and the uses of HBO.

International audience; To investigate lignin degradation, scientists commonly use model compounds. Unfortunately, these models are most of the time simple β-O-4 dimers and do not sufficiently mimic the wide complexity of lignin structure (i.e., aliphatic side chains and robust CC bonds). Herein, we present a methodology to access advanced lignin models through the first synthesis of two trimers of monolignol G-possessing side-chains and both robust β-5 bond and labile β-O-4 bond-via a chemo-enzymatic pathway. Key steps were (1) the CC coupling via laccase-mediated oxidation, (2) the CO coupling via a simple S N2 between a phenolate and a bromoketoester, and (3) a modified Upjohn dihydroxylation or a palladium-catalyzed hydrogenation. (β-5)-(β-O-4) dihydroxytrimer and dihydrotrimer of coniferyl alcohol (G) were obtained in good global yield, 9 and 20%, respectively, over nine steps starting from ferulic acid.

A “map” is presented to describe the different stereochemical relationships among carbohydrates, in both the hexose and pentose series. When implemented, it allows chemistry students, teachers, and researchers to readily identify different sugars’ stereochemical interconnections. It may also help orient chemists toward retrosyntheses, in which carbohydrates are used as starting material goals.

International audience; Glycolipids constitute a class of molecules with various biological activities. Among them, sugar-based bolaamphiphiles characterized by their biocompatibility, biodegradability and lower toxicity, became interesting for the development of efficient and low cost lipid-based drug delivery systems. Their activity seems to be closely related to their interactions with the lipid components of the plasma membrane of target cells. Despite many works devoted to the chemical synthesis and characterization of sugar-based bolaamphiphiles, their interactions with plasma membrane have not been completely elucidated. In this work, two sugar-based bolaamphiphiles differing only at the level of their sugar residues were chemically synthetized. Their interactions with membranes have been investigated using model membranes containing or not sterol and with in silico approaches. Our findings indicate that the nature of sugar residues has no significant influence for their membrane interacting properties, while the presence of sterol attenuates the interactions of both bolaamphiphiles with the membrane systems. The understanding of this distinct behavior of bolaamphiphiles towards sterol-containing membrane systems could be useful for their applications as drug delivery systems.

This chapter reviews the synthesis of altro - C -furanosides. Approaches include nucleophilic and radical substitutions at the anomeric carbon, reduction of anomeric hemiketals, hydrogenation of exo -glycals, stereospecific and stereoselective cyclization reactions, and dihydroxylation of 1,4-dihydrofurans. The major stereocontrol elements are bicyclic induction, Woerpel 1,2- and 1,3- cis induction, thermodynamic control, and stereospecific substitution.

This chapter reviews the synthesis of C -furanosides of the galacto - configuration series. Approaches include nucleophilic and radical additions, reductions at the anomeric carbon, hydrogenation of exo -glycals, stereospecific and stereoselective cyclization reactions, stereochemical inversions at C-2 or C-3, and cycloaddition reactions. The principal stereocontrol elements are bicyclic induction, internal delivery, and thermodynamic control.

International audience; Ces vingt-cinq dernières années ont vu émerger la possibilité d’une société reposant sur un apport carboné biosourcé en remplacement du carbone fossile, transition souvent appelée à tort « société décarbonée ». Le territoire champardennais, terre agricole, s’est engagé dès les années 1990 dans une démarche de bioraffinerie durable en associant recherche académique et acteurs économiques et politiques.C’est dans ce contexte que s’est développée une recherche en chimie du végétal tournée vers les secteurs à moyenne ou haute valeur ajoutée en visant des produits de spécialité ou des actifs originaux et performants dans des domaines aussi variés que les matériaux, la chimie fine, l’environnement, l’agrochimie, la santé ou la cosmétique.

This chapter reviews the synthesis of allo - C -furanosides. Approaches include nucleophilic, radical, and transition metal–catalyzed substitutions at the anomeric carbon, reduction of anomeric hemiketals, hydrogenation of exo -glycals, stereospecific and stereoselective cyclization reactions, and dihydroxylation of 1,4-dihydrofurans. The major stereocontrol elements are bicyclic induction, Woerpel 1,3- cis induction, kinetic cyclization, thermodynamic control, and stereospecific substitution.

This chapter reviews the synthesis of manno - C -furanosides. Approaches include nucleophilic and radical substitutions at the anomeric carbon, reduction of anomeric hemiketals and glycals, stereospecific and stereoselective cyclization of 1,4-diol derivatives, and stereoselective oxa -Michael cyclizations. The major stereocontrol elements are stereospecific substitution, thermodynamic control, and Woerpel 1,3- and 1,2-inductions.

This chapter reviews the synthesis of gluco- and gulo-C-furanosides. Approaches include nucleophilic, radical, and carbene-mediated substitutions at the anomeric carbon, reduction of anomeric hemiketals, hydrogenation and hydroboration of glycals, stereospecific and stereoselective cyclization reactions, and inversions at C-3 or C-4 of allo- and galacto-C-furanosides. The major stereocontrol elements are internal delivery, Woerpel 1,3- and 1,2-inductions, thermodynamic control, and stereospecific substitution.

This chapter reviews the synthesis of ido - C -furanosides. Approaches include nucleophilic, radical, and transition metal–catalyzed substitutions at the anomeric carbon, reduction of anomeric hemiketals and glycals, stereospecific cyclization of 1,4-diol derivatives, stereoselective oxa -Michael cyclizations, and inversions at C-2 of altro - C -furanosides. The major stereocontrol elements are internal delivery, stereospecific substitution, and Woerpel 1,3- and 1,2-inductions.

This chapter discusses in more depth the stereochemical issues in the synthesis of galacto-, altro-, talo-, and allo-C-furanosides, as well as the remaining experimental results, where the selectivity was below 3:1, or the stereochemistry of the product was unassigned or unspecified. Further insight is provided into stereospecific subsitution, tight ion pairs, thermodynamic control, anchimeric participation, bicyclic induction, Woerpel 1,2- and 1,3-cis induction, radical additions, kinetic oxa-Michael, and electrophilic cyclization. Synthetic approaches include nucleophilic, radical, and transition metal–catalyzed substitutions at the anomeric carbon, reduction of anomeric hemiketals, hydrogenation of exo-glycals, stereospecific and stereoselective cyclization reactions, and dihydroxylation of 1,4-dihydrofurans.

The three previous chapters discussed methods where the selectivities were greater than 3:1 in favor of the gluco -, ido -, or manno - C -furanoside stereoisomer. In this chapter, we will discuss methods that give lower selectivities, or those in which the stereochemistry of the product was unspecified or unassigned. In addition, we will discuss in more depth certain aspects of stereocontrol in C -furanoside synthesis: Competing stereochemical elements and mechanisms exist, and the less selective results may give insight into the complex interplay between factors that determine the experimental outcome. The sections thus have a double heading, one synthetic and one stereochemical. It is our hope that this discussion will shed useful light on the scope and limitations of the different models.

International audience; Natural and synthetic amphiphilic molecules including lipopeptides, lipopolysaccharides, and glycolipids are able to induce defense mechanisms in plants. In the present work, the perception of two synthetic C14 rhamnolipids, namely, AlkRL and Ac-RL, differing only at the level of the lipid tail terminal group have been investigated using biological and biophysical approaches. We showed that Alk-RL induces a stronger early signaling response in tobacco cell suspensions than does Ac-RL. The interactions of both synthetic RLs with simplified biomimetic membranes were further analyzed using experimental and in silico approaches. Our results indicate that the interactions of Alk-RL and Ac-RL with lipids were different in terms of insertion and molecular responses and were dependent on the lipid composition of model membranes. A more favorable insertion of Alk-RL than Ac-RL into lipid membranes is observed. Alk-RL forms more stable molecular assemblies than Ac-RL with phospholipids and sterols. At the molecular level, the presence of sterols tends to increase the RLs’ interaction with lipid bilayers, with a fluidizing effect on the alkyl chains. Taken together, our findings suggest that the perception of these synthetic RLs at the membrane level could be related to a lipid-driven process depending on the organization of the membrane and the orientation of the RLs within the membrane and is correlated with the induction of early signaling responses in tobacco cells.

International audience; An unusual recycling Mitsunobu reaction proved to be successful to couple two fragments in the courseof the synthesis of the hydrophobic moiety of rhamnolipid derivatives. Based on the obtained pivotalintermediate, a one pot ‘cross-metathesis/reduction’ approach gave access to structural variations of theside chains. Further study of these molecules will contribute to a better understanding of the role of thelipid moiety in immunostimulatory and plant defense eliciting properties.

Ilhem Zebiri was born in 1986 in Oran. She is currently in her second year of the Masters program “Chemistry, NaturalSubstances and Medicine” in Reims. She is deeply interested in organic and analytical chemistry (chromatography, NMRspectroscopy), especially directed to the field of natural substances and their extraction methods.Sebastien Balieu was born in 1979 in Rouen, France. He graduated with an M.Sci. degree in Chemistry from RouenUniversity in 2004 under the supervision of Prof. S. Piettre in the field of carbohydrates. He obtained his Ph.D. degreein 2007 from the University of Rennes 1 under the supervision of Dr. B. Boitrel in the field of porphyrins and alpha-therapy. In 2007, he joined the group of Prof. C. Courillon (Paris VII) as a postdoctoral fellow working on ynamidesand radical cyclizations. In 2009, he joined the group of Prof. S. Bouquillon (Reims) as a postdoctoral fellow workingon dendrimers and encapsulation. He is now in the group of Prof. A. Haudrechy (Reims) as a postdoctoral fellow workingon carbohydrates for the synthesis of biologically active molecules.After several jobs in the agri–food and pharmaceutical industries, Arnaud Guilleret has worked for Soliance since 2007as an R&D project manager. He holds an M.Sc. degree in chemistry of natural substances and an herbalist diploma. Hespecializes in phytochemistry and biotechnology.Romain Reynaud is the head of R&D of Soliance. For more than 10 years, he has directly contributed to the discovery,the development, and the launch of more than 30 cosmetic-active ingredients. He holds an M.Sc. degree in formulationchemistry. He worked at ARD (Agro-industrie Recherche et Developpement) for three years and joined Soliance in 2004.Arnaud Haudrechy was born in 1965 in Rouen, France. He obtained his Ph.D. degree in 1990 from the University ofParis VI under the supervision of Prof. P. Sinay in the field of carbohydrates and transition-metal chemistry (Tebbe’sreagent). In 1990, he joined the group of Professor Y. Kishi (Harvard University) as a postdoctoral fellow working onpreferred conformations of C-glycosides. In 1992, he joined the University Paris Sud as a lecturer in organic chemistry,working with Prof. Y. Langlois on low-temperature asymmetric Diels–Alder reactions and a sequential Claisen–Ireland/metathesis concept. He is now full Professor of Organic Chemistry at the University of Reims Champagne-Ardenne, andhis research program is focused on the use of carbohydrates for the synthesis of biologically active molecules.

This article reviews the different methods and highlights the general trends that have been developed to selectively obtain α- or β- d - C -mannopyranosides.

A key intermediate corresponding to a rare sugar framework has been synthesized, starting from d -xylose, an inexpensive carbohydrate. This approach gave access to new elaborated sugar moieties for structure–activity relationships in the KRN research.

An effective method for the preparation of enantiomerically pure 1-aminocycloalkene-1-carboxylic acids is reported using a chelate Claisen rearrangement–metathesis sequence. Enantioselectivity is achieved through substrate control and a highly ordered transition state, without the use of a chiral auxiliary. A synthesis of 1-aminocyclopent-3-ene-1-carboxylic acid 1 in five steps and 47% overall yield is also described.

Many analogues of KRN 7000, a synthetic glycolipid (α-galactosylceramide) exhibiting immuno-stimulatory activity and antitumor properties, were previously synthesized and tested in order to understand the reasons for the resulting biological activity and Th1/Th2 cytokine profile. Principles have been established for the interaction of such glycolipids with the human CD1d molecule but the exact mechanism by which different ligands with the same polar head elicit distinct biological responses remains unclear. Based on these experiments and on the available crystal structures, protein–ligand interactions are explored using molecular dynamics simulations. Hydrogen bond interactions are examined with regard to the polar group orientation. The influence of modulations on the dynamic behavior of the CD1d–glycolipid complex is addressed. Overall, our data support the mechanism by which the shortening of the α-GalCer sphingosine chain causes a significant twist of the CD1d α1 helix structure from residue Phe84 that affects the position of CD1d residues involved in the TCR recognition.

International audience; A new approach toward the synthesis of the hydrophobic moiety of rhamnolipid derivatives has been developed, involving two key cross-metatheses and an unusual Mitsunobu reaction. Small structural variations of the side chains should enable a better understanding of the role of the lipid moiety in immunostimulatory and plant defense eliciting properties.

Depending on the metal, solvent and protective groups, functionalized aldehydes may react through either Felkin or chelated transition states leading to the Felkin–Anh product or the 1,2-anti Felkin–Anh product, respectively. Zinc chloride addition proved to be a key aspect in order to favor 1,2-syn nucleophilic attack.

A sequence of two reactions, consisting of a highly stereoselective silylated ketene acetal Claisen–Ireland rearrangement followed by a ring closing metathesis, gave a stereocontrolled access to various carbocycles.

The agalacto-spirotetronate B subunit of quartromicins was synthesized in a predictible manner, following the Claisen-Ireland/metathesis approach (CIM strategy). Ene-yne ring-closure and selective mismatch Sharpless dihydroxylation are discussed as key steps, allowing an efficient approach to these structures.

After a brief account of the syntheses previously described in literature, several approaches of the antiangiogenic sesquiterpene fumagillin are described. Particularly, a Claisen-Ireland ring-closing metathesis strategy allowed the stereoselective preparation of several advanced intermediates in the fumagillin synthesis. Fumagillin 1, isolated in 1951 by Elbe and Hanson (1) from the microbial organism Aspergillus fumi- gatus, is representative of a class of sesquiterpenes such as ovalicin 2 (2) and FR 65814 3 (3), which display interesting biological activities. Fumagillin itself was first described as an antimicrobial agent, but more recently, Folkman and coworkers (4) discovered that this compound is a potent and selective inhibitor of angiogenesis. The same activity has been reported later for ovalicin 2 (5) which, as FR 65814 3, is also a potent immunosuppressor (3). More recently, semisynthetic compound TNP-470 4 (6,7) showed a better therapeutic index than fumagillin 1. The recent discovery that methionine aminopeptidase II (MetAp-II) is selectively inhibited by fumagillin 1 (8) and the X-ray structure of the covalent complex between fumagillin 1 and MetAp-II (9) increases the interest of the synthesis of fumagillin 1 and of new fumagillin analogs (10,11). After the pioneering synthesis of racemic fumagillin 1 by Corey in 1972 (12), this area of research remained dormant for 25 years. But in the past 5 years, 3 syntheses of (-)-fumagillin 1 or (-)-fumag- illol 5, the direct precursor of fumagillin 1, (13-15) as well as two syntheses of racemic fumagillin 1/fumagillol 5 (16,17) have been published. From a biogenetic point of view, it has been demonstrated that fumagillin 1 and ovalicin 2 have as a common precursor cis-farnesyl pyrophosphate (18,19). This biogenetic pathway has been recently reinforced by the discovery of a new metabolite 6 in the fermentation broth producing fumagillin 1 (20). The structure of fumagillin 1 is characterized by the presence of six stereogenic centers, of a func- tionalized cis diol and of two epoxides. The spiro epoxide is easily the subject of nucleophilic attack and is essential (21) for the anti angiogenesis activity. Thus, the nucleophilic attack of histidine 231 of MetAp II gave rise to the formation of a covalent bond shown in the X-ray structure of the complex between 1 and MetAp II (9). From a synthetic point of view, a possible precursor of fumagillin could be the terpene-like derivative 7 characterized by the presence of four double bonds. The selective func- tionalization of three of these double bonds can be considered as the main challenge in the synthesis of 1. Owing to the relative reactivity of these double bonds, the sequence of functionalization of each alkene is also fundamental.

The complete description of the conformational behaviour of sugars involves assessing exocyclic dihedral angles and ring conformations, both in terms of static conformations and dynamic behaviour within these limiting conformers. We have focused here on the conformation of the tetrahydrofuran ring and its deviation from planarity. Beyond the well-knownpseudo-rotational analysis based on two parameters, puckering angle and amplitude, we present a complementary and new approach to describe ring conformational dynamics which is better able to describe unsymmetrical conformations that are lost bypseudo-rotational analysis. Principal Component Analysis (PCA) of the endocyclic dihedral angles proved to be an efficient method to describe collective, global motions of the carbohydrate ring, with two or three principal components containing the largest mean-square fluctuation. Our ring dihedral principal component analysis model (RdPCA) describes ring conformational dynamics based on inherent ring motions rather than arbitrarily restrictive descriptors. RdPCA analysis of both classical and full quantum mechanical molecular dynamics indicates that furanosides have dominant minimum energy conformations but are rather flexible within these conformers, showing broad wells from a thermodynamic point of view. This RdPCA model also gave indications on the kinetic behaviour of such systems suggesting possible energy pathways for ring motions on the energy landscape. We believe that this useful tool can give a better understanding of the behaviour of the tetrahydrofuran ring, and hence of carbohydrate conformation.

A new formal stereoselective synthesis of (+)-Huperzine A (1) was achieved using as a key step a palladium mediated annulation between 2-methylene-1,3-propanediol diacetate and (1R,2S)-2-phenylcyclohexanol derived β-ketoester 2c.

A new formal stereoselective synthesis of (+)-huperzine A 1 was achieved using as a key step a palladium mediated annulation between 2-methylene-1,3-propanediol diacetate and (1R,2S)-2-phenylcyclohexanol derived β-ketoester 14.

A Claisen-Ireland rearrangement led to the formation of C-glycan derivatives. Azidonitration-reduction or dihydroxylation afforded gluco- and galacto-derived β-C-glycosides. Subsequent deprotonation of bicyclic lactones 16 allowed the control of the newly created asymmetric centre.

A strategy using a highly stereoselective Claisen-Ireland rearrangement followed by a Grubbs metathesis afforded in a good overall yield after further functionalisation a potentially synthetic precursor of fumagillin and ovalicin.

The presence of a small amount of water has proven to be necessary in order to obtain a reproducible amount of an epoxydithio compound. Conversely, under anhydrous conditions, an interesting thiosugar derivative results from a selective internal attack of sulfur, followed by an ‘ethyl’ transfer.

Chiral orthoesters 14–22 were prepared by an exchange reaction with orthoester 13 . These compounds, after treatment with trimethylsilytriflate or tin(IV) chloride, gave rise to vinyl dioxolanylium cations which proved to be very reactive dienophiles in various Diels-Alder reactions.

A five steps sequence of reactions afforded in high yield the tetrahydroquinoline derivative 3, a key intermediate in Huperzine A synthesis.