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A method for the synthesis of natural product-inspired decalin systems on solid support is reported. It employs the Robinson annulation as key step and immobilised Nazarov reagents as key intermediates. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The superposition analysis of (–)-patchoulol (1), the odorous principle of patchouli oil, with the recently discoveredhigh-impact spirocyclic patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (2) resulted in the question as to whether a patchoulolderivative in which the gem-dimethyl group is replacedby a carbonyl function would be a powerful patchouliodorant. The total synthesis of the racemic superstructure (1R*,3S*,6S*,7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undecan-2-one (3) was accomplished in 13 steps from the inexpensive commercial odorant Cyclal C (7) with a total yield of 7 %. Conversion of 7 to the corresponding enamine 8 and subsequent copper-catalyzed oxidative degradation afforded 2,4-dimethylcyclohex-3-enone (6), which was subjected to a Robinson annulation with 1,4-dimethoxybutan-2-one (9). The carbonyl function of the resulting annulation product 10 was removed by LAH reduction, acylation with Ac2O, and dissolving metal reduction. The deoxygenated methyl enol ether 12 thus obtained was then cleaved by mild hydrolysis with oxalic acid, and the resulting 2,9-dimethyl-Δ1-octalin-5-one (5) was hydroxymethylenated by Claisen ester condensation with ethyl formate to provide thecis-configured (2Z)-2,3,4,4a,8,8a-hexahydro-2-(hydroxymethylene)-4a,6-dimethylnaphthalen-1(7H)-one (4). In a novel intramolecular Prins reaction with an equimolar amount of p-toluenesulfonic acid monohydrate, the ideally preformed precursor 4 cyclized to (1R*,2R*,3S*,7R*,8S*)-2-hydroxy-4,8-dimethyltricyclo[5.3.1.03,8]undec-4-en-11-one (13), comprising the complete carbon framework of the target compound 3. A Barton–McCombie deoxygenation of the corresponding O-phenoxythiocarbonyl derivative, followed by oxidation of the lithium enolate of the resulting ketone 14 with the molybdenum peroxide reagent MoO5–pyridine–DMPU, and the face-selective hydrogenation of the obtained(1R*,3S*,7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undec-5-en-2-one (15) concluded the synthesis of the target molecule 3, which was accompanied by its odorless C-6 epimer epi-3 in the ratio 84:16. Both the target structure 3 and its unsaturated precursor 15 possessed pronounced patchouli odors, albeit slightly weaker in threshold than (–)-patchoulol (1). This proved the superposition analysis of the templates 1 and 2 to be correct and provided novel insight into the structural requirements of patchouli odorants. As 3 was an intermediate in a total synthesis of rac-1, the synthesis also constitutes a new formal total synthesis of racemic patchoulol (rac-1). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The synthesis of the spirocyclic sesquiterpenes (−)-gleenol and (−)-axenol in enantiomerically pure form has been achieved starting from R-(−)-carvone. The key step is the silicon guided acid-promoted rearrangement of a 9-trimethylsilyl-5,6-epoxy-noreudesmane prepared from 3-trimethylsilyldihydrocarvone in several steps involving Robinson annulation, enone deconjugation and epoxidation. Acid treatment of the epoxy-noreudesmane gave a norspiroaxane as the main product, which was used as intermediate for the synthesis of two naturally occurring sesquiterpenes gleenol and axenol.

Facile Michael addition of active methylene compounds to α,Β-unsaturated carbonyl compounds takes place on the surface of potassium carbonate under microwave irradiation. Further studies on microwave-mediated Robinson annulations reveal a convenient and facile method for condensation of chalcone with methylene compounds to furnish cyclohexenones.

A sequence which accomplishes the preparation of cycloheptadienones by ring-expansion of fused cyclohexenones has been developed and applied to the improved synthesis of a key intermediate in the total synthesis of guanacastepene A.

A straightforward synthesis of optically active decahydro-6-isoquinolone derivative 3, containing a quaternary stereocenter, is reported. The starting (R)-configured enantiopure enone 2, which is readily accessible through a copper-catalyzed, L-valine amide mediated Michael reaction and a subsequent Robinson annulation, was hydrogenated with Pd/C in iPrOH to give the decahydroisoquinolone 4. Treatment of 4 with ethyleneglycol in the presence of PPTS yielded the dioxolane-protected derivative 7. A sequence of ester reduction with LiAlH4 and subsequent Ley oxidation of the resulting primary alcohol 10 accomplished the synthesis. Enantiomerically pure aldehyde 3, with three groups for further functionalization, was thus obtained in 63% overall yield. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

2,2,3,4-Tetrachloro-8-oxabicyclo[3.2.1]octa-2,6-diene, derived in a single step from the cyclocondensation of furan and tetrachlorocylopropene, serves as a key intermediate for the construction of bicyclo[5.4.0]undecane synthons. Conversion to a meso-1,3 diketone is followed by a high yielding Robinson annulation reaction. Studies on the reduction of the enone product reveals a powerful preference for formation of the cis-ring fusion.

Several novel hydroxylated cis-decalin derivatives, potential intermediates for the synthesis of the AB ring system of the important cardiotonic steroid ouabain, have been synthesized from commercially available starting materials. The first step in the preparation of these highly functionalized intermediates is a Robinson annulation of the β-keto ester 6 and the 4-silyl-3-buten-2-one 5 to furnish the octalone 4 with good diastereoselectivity in fair yield (due to competition with a novel silicon-to-carbon phenyl migration). Reduction of the epoxy alcohol 3 (derived from 4 in two high-yielding steps) with LiAlH4 gave a mixture of the desired triol 11 along with the product of an unusual reductive opening at the tertiary carbon, namely the triol 12. A plausible mechanism for this unusual reduction is presented as are possible methods for avoiding it. In particular, reduction of the corrresponding epoxy ketone 15 with aluminum amalgam proceeded in good yield to give the hydroxy ketone 16. Also reduction of ...

4-Cyano-2-cyclohexenones were found to be susceptible to reductive alkylation reactions, giving the corresponding 2,2-disubstituted-3-cyclohexenone derivatives in a completely regioselective manner. This newly developed methodology has been successfully applied towards the total synthesis, in racemic form, of the marine natural product nanaimoal.

A total synthesis is presented for himachalene-related norsesquiterpene ketone 1 (racemic), based on the Robinson annulation and other standard reactions. The route involved five steps from cycloheptanone. A favorable result was that the desired diastereomer of 1 was obtained preferentially (97:3) over the unwanted one. Molecular modeling (ab initio calculations) aided in confirming the assignment of relative stereochemistry of 1 and in rationalizing the observed ratio of diastereomers. Three related sesquiterpene hydrocarbons and two alcohols were subsequently produced from 1. The six compounds occur naturally in several flea beetle species and likely serve a pheromonal function.

An effective total synthesis of the trinorditerpenoid moluccanic acid methyl ester has been achieved. The synthesis features a Robinson annulation, followed by aromatization to construct the aromatic ring and Baeyer–Villiger oxidation of the A ring to finish the target molecule.

[reaction: see text] The synthesis of the fully fuctionalized A/B ring of ouabain has been accomplished efficiently from commercially available starting materials. A key Robinson annulation allows for the building of the desired carbon framework in one high-yielding step. Directed epoxidation followed by selective epoxide opening furnished the final tetraol with the desired all-cis stereochemistry.

α-Branched ketones remain a challenging type of substrates in aminocatalysis due to their congested structures as well as the associated difficulties in controlling chemo- and stereoselectivity. In this work, we have explored asymmetric aminocatalysis with α-substituted β-ketoesters. A simple chiral primary amine catalyst was identified to enable unprecedentedly effective catalysis of β-ketoesters in α-hydrazination and Robinson annulation reaction with good yields and high enantioselectivities. Stoichiometric experiments with preformed enamine ester intermediates revealed their enamine-catalytic nature as well as the critical roles of acidic additives in facilitating catalytic turnovers and in tuning the chemo- and stereoselectivity. With the identical catalytic system, the two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved.

A Robinson annulation, van Leusen homologation, and a desymmetrizing CH oxidation enabled an enantiospecific synthesis of the neurotrophic natural product jiadifenolide. From a pulegone-derived building block, a key propellane intermediate was constructed through the use of simple reagents in a highly diastereoselective fashion. A short series of oxidations of this tricylic framework allowed progression to the natural product.

The first total synthesis of nardoaristolone B, a nor-sesquiterpenoid with an unusual fused ring system and having protective effects on the injury of neonatal rat cardiomyocytes, has been accomplished. Stereoselective synthesis of its novel analogues inlcuding exo-cyclopropyl ring fusion is also part of this disclosure. In addition, an alternate and more efficient one-step method to make a 3/5/6 tricyclic ring system using the Robinson annulation method has been developed toward the generation of a library of compounds around this skeleton.

A diastereoselective synthesis of cis-5-oxodecahydroquinolines is described in which three stereocenters are generated in a one-pot reaction. The reaction involves a lithium hydroxide-promoted Robinson annulation/intramolecular aza-Michael domino process from an achiral acyclic tosylamine-tethered β-keto ester. The development and scope of this reaction was facilitated through the use of DFT-based mechanistic studies, which enabled the observed diastereodivergent course of the azacyclization to be rationalized. The varying stereochemistry and stability of the resulting decahydroquinolines was found to depend on whether a β-keto ester or ketone were embedded in the substrates undergoing aminocyclization. This synthetic approach gave access not only to both diastereomeric cis-decahydroquinolines from the same precursor, but also to the corresponding trans isomers, through an epimerization processes of the corresponding N-unsubstituted cis-5-oxodecahydroquinolines. The described methodology provides advanced building-blocks with the three relative stereochemistries required for the total synthesis of phlegmarine alkaloids.

As an important building block, developing efficient and green synthesis strategy of cyclohex-2-enones is of great importance. In this present work, a general approach to the mild synthesis of substituted cyclohex-2-enones derivatives starting fro m simple aldehydes and acetone have been achieved via d-aminoacylase-initiated Aldol condensation/Robinson annulation cascade reaction using imidazole as an additive in organic media. The influences of reaction conditions including solvents, enzyme concentration, additives type, molar ratio of enzyme to additive, and substrate scopes were systematically investigated. Furthermore, some experiments were designed to explore the catalytic roles of d-aminoacylase and imidazole in the multistep cascade process, and one possible mechanism was proposed.

Acid-catalyzed Robinson annulation of ketone (I) obtained in three steps from 2-iodocyclohexenone gives the bicyclic enone (III).

Treatment of epoxyisophorone (1) with ethyl acetoacetate under basic conditions resulted in the stereoselective formation of dihydroxybenzofuran 2 in moderate yield. This result is in contradiction to previous work where similar conditions were reported to afford a bicyclo [4.3.0]nonadienone via a putative Robinson annulation reaction.

The first, stereospecific, and elegant synthesis of the natural product (+)-Carainterol A was developed by using the Robinson annulation reaction as a key step to build the eudesmane sketeton.

A single-step enantioselective synthesis of the Wieland–Miescher ketone ( 5 ) is presented. We show that l -proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identified as catalysts of Michael and aldol addition reactions.

Bridged 1,6-diphenyl-1,3,5-hexatrienes were prepared from 1-indanone by successive Robinson annulation and McMurry coupling reaction. Rigidification produces a decrease in oxidation potential and HOMO-LUMO gap, and a considerable enhancement of fluorescence quantum yield compared to the open-chain analog.

The synthesis of 4-hydroxy-3-[(1 S )-1,2,2-trimethylcyclopentyl]benzaldehyde [(−)-α-formylherbertenol 1 ], a herbertane-type sesquiterpene isolated from the leafy liverwort Herberta adunca , from β-cyclogeraniol is described. The synthesis is based on the previously described preparation of an enantiopure 1,2,2-trimethylcyclopentane synthon from which the characteristic aromatic moiety of 1 is elaborated, using a Robinson annulation and a palladium-catalysed methoxycarbonylation of an aryl triflate as key synthetic steps. The synthesis of the natural sesquiterpene (−)-α-herbertenol, also a natural sequiterpene, using the same methodology is also described.

(-)-(4aS,8aR)-5,5-8a-trimethyl-trans-decaline 1 was prepared in a stereoespecific synthesis of 4 steps and 38% yield. The key-step involves an asymmetric Robinson annulation via Michael addition of chiral imine.

The copper catalysed conjugate addition of methyl magnesium iodide to cyclohexenones and trapping of the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloroantimonate (TrSbCl6) catalysed Mukaiyama-reaction, was applied to R-(−)-carvone. This proved to be an efficient method for the preparation of C-2, C-3 functionalised chiral cyclohexanones. These compounds were converted into their α-cyano ketones, which were submitted to Robinson annulation reactions with methyl vinyl ketone. The scope and limitations of these annulations were investigated. A series of highly functionalised chiral decalones were obtained that can be used as starting compounds in the total syntheses of enantiomerically pure clerodanes.

Both enantiomers of Wieland-Miescher ketone [3,4,8, 8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione], in a highly enantiomerically enriched form, became readily available by a newly developed kinetic resolution with yeast-mediated reduction. From a screening of yeast strains, Torulaspora delbrueckii IFO 10921 was selected. The collected cells of this strain, obtained by an incubation in a glucose medium, smoothly reduced only the isolated carbonyl group of the (S)-enantiomer, while the (R)-enantiomer remained intact. Starting from both enantiomers ( approximately 70% ee) prepared by an established proline-mediated asymmetric Robinson annulation, the reduction with T. delbrueckii gave the (R)-enantiomer (98% ee) and the corresponding alcohol (4aS,5S)-4,4a, 5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)-naphthalenone (94% ee, 94% de) in preparative scale in nearly quantitative yields. An approach for the asymmetric synthesis of the Wieland-Miescher ketone was also successful. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione, the prochiral precursor, was reduced with this strain to give a cyclic acetal form of (2S, 3S)-3-hydroxy-2-methyl-2-(3-oxobutyl)cyclohexanone, in a stereomerically pure form.

A strategy was devised for the synthesis of codeine that employed intramolecular insertion of a carbenoid into a benzylic methine CH bond for creation of the C13 quaternary center and construction of the pentacyclic skeleton of the alkaloid. The synthesis began from isovanillin, and asymmetry was introduced through catalytic hydrogenation of its Stobbe condensation product 7 over a chiral catalyst (8). The product (S)-9 was advanced to tetralone 12, which underwent Robinson annulation to give the phenanthrenone 33. The latter was brominated and treated with base to afford the fused benzofuran 35. Reduction with hydride followed by catalytic hydrogenation produced the tetracycle 44, which was converted to diazoketone 48. The latter was reacted in the presence of catalytic Rh2(OAc)4 to furnish the pentacyclic product 49. Beckmann rearrangement of the derived oxime brosylate 59 gave lactam 57, and the synthesis of (+)-1 (the nonnatural enantiomer of codeine) was completed after oxidation to 63, introduction ...

An alternative synthetic approach to diaryl ethers has been developed. In the key transformation, Robinson annulation of nonracemic aldehydes 16a , b , derived from l -glutamic acid 5-methyl ester and phenoxymethylvinyl ketone, provided α-phenoxyenones 17a , b . The Cbz-protected oxazolidine 17b was further converted into the diaryl ether 18b utilizing an oxidative selenation protocol.

The title racemate, C13H19NO2, is a pre-dehydration inter­mediate isolated from the base-catalysed Robinson annulation of (+/−)-2-(2-cyano­ethyl)cyclo­hexa­none. Centrosymmetric dimers are formed by reciprocal hydroxyl-to-ketone hydrogen bonding [O⋯O = 2.7902 (13) A and O—H⋯O = 176°]. One inter­molecular C—H⋯O close contact is found to the hydroxyl group.

The enolates of cyclic β-ketoesters react with electrophilic acetylenes to give the corresponding Michael adducts in good yields when the reaction is performed in acetone in the presence of catalytic amounts of K2CO3. The Michael adducts resulting from ethynylmethylketone, when refluxed in toluene in the presence of catalytic amounts of pTsOH, undergo an intramolecular aldol reaction leading mainly to bicyclo [n. 3. 1]alkadienones besides Robinson annulation products.

A key clerodane intermediate was prepared during the investigation of the total synthesis of clerocidin. The diterpene backbone was synthesized by an enantioselective Robinson annulation followed by trapping of the enolate using allyl bromide. Selective hydrogenation conditions were developed to introduce the axial methyl group at the C8 position. A palladium-mediated carbonylation reaction was employed to generate the key α,β-unsaturated dialdehyde.

12b-Substituted indolo[2,3-a]quinolizidin-2-ones 5 are synthesized by treatment of Grignard reagents with O-acetyl iminium salt 4 generated by treating cyclic enaminoketone 3 with acetyl chloride. Subsequent Robinson annulation employing the Stork enamine protocol provided rac-3-phenyl-15,16-dehydroreserpone.

Michael addition of lithium enolates derived from ketones to a variety of α,β-unsaturated ketones was realized in the presence of aluminum tris(2,6-diphenylphenoxide) (ATPH). In this reaction, ATPH can be used as a carbonyl protector of α,β-unsaturated carbonyl substrates upon complexation, which facilitates the regioselective 1,4-addition of lithium enolates to Michael acceptors. Similarly, dianions of β-dicarbonyl compounds undergo Michael addition smoothly using ATPH as an effective promoter of the reaction. Subsequent regioselective, intramolecular aldol condensation was also demonstrated, leading to bicyclic carbon ring systems. Such systems are difficult to obtain by the Robinson annulation usually performed in protic media.

Organocatalyzed enantioselective allylation of 2-iodocyclohexenone followed by methylation and oxy-Cope rearrangement delivered enantiomerically enriched 2-methyl 3-allyl cyclohexanone, which engaged in acid-catalyzed Robinson annulation to give the bicyclic enone. Subsequent elaboration of the pendant allyl group into an α-diazo β-keto ester set the stage for Rh-mediated cyclization to deliver the tricyclic A-B-C core of the Veratrum alkaloids.

A concise synthesis of the Lycopodium alkaloid lycoposerramine Z is reported. Key to the strategy is a one-pot organocatalyzed Michael reaction followed by a domino Robinson annulation/intramolecular aza-Michael reaction promoted by LiOH, leading to enantiopure cis-decahydroquinolines.

Octalones (V) are obtained by a Diels—Alder reaction of cyclohexenone (I) with dienes (II) followed by a silica-mediated isomerization of octalones (III) and a subsequent Saegusa oxidation of silylenol (IV).

The fluorination of ketoesters (I) followed by Michael addition with chalcones (II) leads to desired fluorides (III) in high yields.

A diastereoselective synthesis of cis-5-oxodecahydroquinolines is described in which three stereocenters are generated in a one-pot reaction. The reaction involves a lithium hydroxide-promoted Robinson annulation/intramolecular aza-Michael domino process from an achiral acyclic tosylamine-tethered β-keto ester. The development and scope of this reaction was facilitated through the use of DFT-based mechanistic studies, which enabled the observed diastereodivergent course of the azacyclization to be rationalized. The varying stereochemistry and stability of the resulting decahydroquinolines was found to depend on whether a β-keto ester or ketone were embedded in the substrates undergoing aminocyclization. This synthetic approach gave access not only to both diastereomeric cis-decahydroquinolines from the same precursor, but also to the corresponding trans isomers, through an epimerization processes of the corresponding N-unsubstituted cis-5-oxodecahydroquinolines. The described methodology provides advanced building-blocks with the three relative stereochemistries required for the total synthesis of phlegmarine alkaloids., Financial support for this research was provided by the Spanish Ministry of Economy and Competitiveness (MINECO; projects CTQ2010–14846/BQU, CTQ2010–17436, and CTQ2011–29054-C02–02). Support from the Dirección General de Recerca (DGR, Catalunya, grant 2009SGR-00462), Gobierno de Aragón-FSE (E40), and from ICIQ Foundation is acknowledged. R.D. thanks CaixaBank for a fellowship.

The monoterpene thujone (1) is ring expanded regioselectively to provide homothujone (4) in order to explore its potential as a chiral starting material. Stereoselective Robinson annulation of homothujone provides an enone intermediate (5), further derivatization of which was undertaken to furnish functionalized naphthalenones useful for synthesis of the antifeedant (−)-polygodial and the ambergris fragrance (−)-Ambrox®. Key words: thujone, homothujone, synthesis, naphthalenones, polygodial, Ambrox.

The control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy’s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised.; La régulation de l’apoptose fait partie des nouvelles cibles thérapeutiques dans la lutte contre le cancer. L’apoptose est l’autodestruction programmée des cellules qui, suite à un besoin physiologique, permet de réguler le développement des cellules. Dans de nombreux cancers, ce mécanisme est inhibé par une surexpression des protéines anti-apoptotiques de la famille Bcl-2 comme Bcl-xL et Mcl-1. Ce phénomène entraîne le développement des cellules tumorales et des résistances aux chimiothérapies. Dans cette optique, notre équipe à l’Institut de Chimie des Substances Naturelles a développé un criblage de plantes tropicales sur ces cibles. Des écorces d’une annonacée de Malaisie, Meiogyne Cylindrocarpa, a été isolé un sesquiterpène dimère, la meiogynine A, présentant une bonne affinité vis-à-vis de Bcl-xL (Ki = 10.7 M). Sa synthèse totale a été réalisée au laboratoire afin de déterminer sa configuration absolue et d’étudier les premières relations structure activité. Un de ses diastéréoisomères a également présenté une bonne affinité vis-à-vis de la protéine Bcl-xL.Afin d’étudier et d’approfondir les premières relations structure activité, la modulation de la meiogynine A a été réalisée. La synthèse des diénophiles acides a été optimisée afin de conduire majoritairement aux diénophiles précurseurs des composés actifs. Différents triènes ont également été synthétisés au laboratoire en vue de modifier la partie Sud de la meiogynine A. Plusieurs analogues ont ainsi pu être obtenus et ont été évalués biologiquement sur des tests in vitro et ex vivo. Des études de modélisation moléculaire et de RMN structurale ont également été réalisées.

Computational study of the mechanisms and stereoselectivities of a dual amino-catalyzed synthesis of cyclohexenones containing all-carbon γ-quaternary and ∂-tertiary stereocenters is reported. Extensive conformational search with density functional theory optimizations, the high-accuracy SCS-MP2/cc-pV∞Z energies, and PCM solvation corrections were used to characterize all intermediates and transition states. Six mechanisms were considered, all consistent with available experiments. The reaction proceeds via sequential Michael and Mannich conjugate additions whereby the primary amine activates the aldehyde and the catalyst activates the pentenone. We have discovered a rare duumvirate stereocontrol: the Michael reaction sets the enantioselectivity, but both the Michael and the Mannich reactions control the diastereoselectivity.

The aldol reaction, which was discovered by Kane in 1838, is one of the most fundamental reactions in synthetic organic chemistry. In addition, it is also an essential biological process involved in glycolysis, gluconeogenesis, and the Calvin cycle. Near the end of the twentieth century, small metal-free organic molecules renewed attention as aldolase-type organocatalysts. Organocatalytic asymmetric direct aldol reactions of carbonyl compounds have become highly advantageous in modern synthetic organic chemistry, especially in generating chiral building blocks that previously have not been easily available by traditional methods. Research in this area has advanced rapidly over the past decade. This chapter addresses significant achievements in asymmetric synthesis focusing on organocatalytic direct aldol reactions over two chapters. Aldol reactions catalyzed by proline and related amino acid derivatives are reviewed in this chapter, and reactions catalyzed by nonproline derivatives are reviewed in Chapter 6.5.

The control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy’s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised., La régulation de l’apoptose fait partie des nouvelles cibles thérapeutiques dans la lutte contre le cancer. L’apoptose est l’autodestruction programmée des cellules qui, suite à un besoin physiologique, permet de réguler le développement des cellules. Dans de nombreux cancers, ce mécanisme est inhibé par une surexpression des protéines anti-apoptotiques de la famille Bcl-2 comme Bcl-xL et Mcl-1. Ce phénomène entraîne le développement des cellules tumorales et des résistances aux chimiothérapies. Dans cette optique, notre équipe à l’Institut de Chimie des Substances Naturelles a développé un criblage de plantes tropicales sur ces cibles. Des écorces d’une annonacée de Malaisie, Meiogyne Cylindrocarpa, a été isolé un sesquiterpène dimère, la meiogynine A, présentant une bonne affinité vis-à-vis de Bcl-xL (Ki = 10.7 M). Sa synthèse totale a été réalisée au laboratoire afin de déterminer sa configuration absolue et d’étudier les premières relations structure activité. Un de ses diastéréoisomères a également présenté une bonne affinité vis-à-vis de la protéine Bcl-xL.Afin d’étudier et d’approfondir les premières relations structure activité, la modulation de la meiogynine A a été réalisée. La synthèse des diénophiles acides a été optimisée afin de conduire majoritairement aux diénophiles précurseurs des composés actifs. Différents triènes ont également été synthétisés au laboratoire en vue de modifier la partie Sud de la meiogynine A. Plusieurs analogues ont ainsi pu être obtenus et ont été évalués biologiquement sur des tests in vitro et ex vivo. Des études de modélisation moléculaire et de RMN structurale ont également été réalisées.

Controlled isomerization of the double bond of certain Diels–Alder reaction products provides substrates that, upon oxidation, give rise to products whose gross structure corresponds to that of a Robinson annulation. In these cases, the stereochemistry of the Robinson annulation product reflects the fact that the initial combination occurred in a Diels–Alder mode. Using these principles, we have synthesized carissone and cosmosoic acid. In the latter case, our total synthesis raised serious questions as to the accuracy of the assigned structure of the natural product.

A strategy to utilize the thujone-derived enone 1 for the development of a synthetic route to ambergris fragrances is presented. Thujone (8) is transformed to the tricyclic enone 9, via the Robinson annulation reaction, and the latter is then elaborated to the cis-fused tricyclic intermediates 10, 11, and 12. Extrusion of the isopropyl side chain in 12 is achieved through an initial ozonation reaction and the resulting ketone 14 is then treated with m-CPBA to afford 16. Cyclopropyl ring opening in 16 is performed via initial saponification to the alcohol 17 and the latter is then reacted with FeCl3 and sodium acetate to enone 1. The necessary elaboration of a tetrahydrofuran ring attached to ring B of 1 is achieved through reaction of 1 with vinylmagnesium bromide, alkylation, hydroboration, and final acid-catalyzed ring closure of the 1,5-diol 4. The route affords the opportunity of synthesizing a variety of analogues within the Ambrox series.

Two conjugate addition/annulation methodologies for S-(+)-carvone are reported. The conjugate addition of Grignard reagents, followed by the Lewis acid catalyzed Michael reaction of the intermediate silyl enol ethers with MVK and cyclization of the diketones, gave decalones 2a-d stereoselectively and in good yield. The conjugate addition of cyanide anion followed by base catalyzed Robinson annulation with MVK and dehydration gave decalone 2e stereoselectively in very high yield.

α- and γ-substituted vinylthionium ions from SnCl 4 ionisation of a range of substituted 1,3- and 3,3-bis (alkyl/phenylthio) propenes allylate enol allyl ethers in good yield. Levels of regioselectivity are sterically dependent and in the case of methyl as γ-substituent may be controlled by the steric bulk of the sulfur substituent. As with the Pummerer methodology, γ-addition generally gave (E)-vinyl sulfides exclusively implying the intermediacy of a ‘free’ vinylthionium ion. In appropriate cases, the allylated products may be hydrolysed and cyclised to the Robinson annulation products, desulfurised to the olefin or eliminated to the diene. Allyltrimethylsilane and indole are also allylated in good yield. Vinylthionium ions with a γ-phenylthio or methoxy group also undergo the reaction. In the methoxy case the reaction is highly sensitive to the number of equivalents of Lewis acid used and found to be truly catalytic in TiCl 4 . A mechanistic rationale for this is presented. The study concludes with a pentannulation sequence involving intramolecular capture of a vinylthionium ion generated by the methodology.

Two effective synthetic approaches to (±)-euryfuran 1 are described. One synthetic route makes use of sequential furan ring transfer reaction type I and type III as key steps followed by Eschenmoser-type [3,3]sigmatropic rearrangement, and another route proceeded through furan ring transfer reaction type I and annulation with ethyl vinyl ketone subsequently.

The first total synthesis of jiadifenolide (1), a potent neurotrophic modulator, has been reported. Highlights of the synthesis include: construction of the B ring via an asymmetric Robinson annulation; assembly of the E ring lactone via a novel acid-induced cascade reaction; and Pd(0)-mediated carbomethoxylation and methylation reactions for the construction of the C and A rings respectively.