石川 勇人

A concise synthesis of WIN 64821 (1), eurocristatine (2), 15,15′-bis-epi-eurocristatine (3), ditryptophenaline (4), ditryptoleucine A (6), WIN 64745 (7), cristatumin C (8), asperdimin (9), naseseazine A (10) ,and naseseazine B (11) is detailed based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and one-pot procedure for construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10% up to 27%. In addition, 1′-(2 - phenylethylene) -ditryptophenaline (5) was synthesized using three one -pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin-specific protease 7 (USP7) and foam cell formation in macrophages.

A concise two one-pot synthesis of WIN 64821, eurocristatine, 15,15'-bis-epi-eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazineB is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one-pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27%. In addition, 1'-(2-phenylethylene)-ditryptophenaline was synthesized by using three one-pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin-specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan-based dimeric diketopiperazine alkaloids discovered 15,15'-bis-epi-eurocristatine, 1'-(2-phenylethylene)-ditryptophenaline, and WIN 64745 as new drug candidates.

Over the last decade, several excellent enantioselective total syntheses of important alkaloids using asymmetric reactions mediated by chiral secondary amine organocatalysts as a key step have been accomplished. This perspective article examines the full strategies of these alkaloid syntheses, especially the application of the organocatalytic reaction to construct the alkaloid scaffolds.

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Unique redox switching of orthoquinone-containing pentacyclic aromatic compounds with molecular hydrogen and oxygen in the presence of a palladium nanoparticle catalyst (SAPd) is disclosed. These molecules were predicted by in silico screening before synthesis. Efficient protocols for the synthesis of orthoquinone-containing aromatic compounds by palladium-mediated homocoupling and the benzoin condensation reaction were developed. Clear switching between orthoquinone and aromatic hydroquinone compounds was observed on the basis of their photoluminescence properties. Furthermore, the twist strain of the orthoquinone moiety could induce dramatic changes in color and emission.

Oxygen functional groups (OFGs) in graphene oxide (GO) are responsible for the unique optical, electrical, magnetic as well as ionic, liquid and gaseous transport properties. In the present study, we have discovered reversible epoxide opening/closing reactions in GO upon alkaline and acid treatments, respectively, under ambient conditions. We suggest that unique properties of GO including stability of the carbocation and fast proton migration on the surfaces enable the unusual pH-driven epoxide ring opening/closing reactions. Our experimental results indicate that an irreversible epoxy formation observed in base-treated GO under flux conditions is due to the decomposition of the vic-diol groups formed by epoxy ring opening in alkaline solutions. A high concentration of basal plane epoxides is a remarkable feature of GO. Thus, the reversible epoxy formation should be an important part of our understanding of reactivity and properties of GO. For example, the epoxy ring opening can be a mechanism for anomalous photoluminescent (PL) quenching of GO dispersions in alkaline conditions. (C) 2014 Elsevier Ltd. All rights reserved.

Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi. These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished <i>via</i> bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide <i>C</i><sub>2</sub>-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)<sub>3</sub>, VOF<sub>3</sub>, and V<sub>2</sub>O<sub>5</sub> as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (−)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based <i>C</i><sub>2</sub>-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.<br>

Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished via bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide C-2-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)(3), VOF3, and V2O5 as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (-)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based C-2-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.

Tryptophan-based dimeric diketopiperazine alkaloids such as ditryptophenaline, WIN 64821, naseseazine A, and naseseazine B, exhibit a unique architecture and interesting biological activity. These alkaloids have been the subject of intense study by the synthetic organic chemistry community, and several elegant total syntheses have been discovered, especially using bioinspired strategies. Described herein is a brief overview of these alkaloid syntheses via bioinspired transformations as key steps.

Tryptophan-based dimeric diketopiperazine alkaloids such as ditryptophenaline, WIN 64821, naseseazine A, and naseseazine B, exhibit a unique architecture and interesting biological activity. These alkaloids have been the subject of intense study by the synthetic organic chemistry community, and several elegant total syntheses have been discovered, especially using bioinspired strategies. Described herein is a brief overview of these alkaloid syntheses via bioinspired transformations as key steps.

A one-pot transformation of aldehydes into α,β-unsaturated aldehydes was developed using both N-benzyl-N-methylamine and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as catalysts and MnO2 as a terminal oxidant. An oxidative and enantioselective reaction of aldehydes and nitromethane was established using both diphenylprolinol silyl ether and DDQ as a catalyst with MnO2 as a terminal oxidant, in which synthetically important β-substituted γ-nitro aldehydes were obtained with excellent enantioselectivity. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2- nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone. (-)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E-Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Doubling up: The direct bio-inspired dimerization of commercially available amine-free tryptophan derivatives in aqueous acidic media provides C 2-symmetrical and nonsymmetrical dimeric compounds. Further processing completes the concise syntheses of naturally occurring dimeric diketopiperazine alkaloids such as (+)-WIN 64821 (see picture) in overall yields of up to 20 %. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a delta-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6 pi) and the enamine double bond (2 pi) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

3-Hydroperoxypyrrolidine-2,4-diones substituted with an alkyl group at the 3-position were spontaneously transformed into 5-hydroxyoxazolidin-4-one derivatives at room temperature in air accompanied by the evolution of carbon monoxide.

A microflow reaction of the Curtius rearrangement by using trimethylsilyl azide as an azide source, followed by trapping of the generated isocyanate with a nucleophile was established, which is safe, inexpensive, and suitable for large-scale synthesis. By this flow reaction in the Curtius rearrangement and recrystallization of the late-stage acetamide intermediate the third-generation synthesis of (-)-Oseltamivir has been established, which is efficient, practical, and safe. A safe and efficient total synthesis of (-)-Oseltamivir has been developed by using the Curtius rearrangement with a microflow system, which avoids the isolation of a hazardous and potentially explosive intermediate. In addition, the product, possessing an acetamide group, was easily purified by recrystallization. Thus, this procedure can be scaled up as an industrial process. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In a "one-pot" reaction, several transformations are carried out to form several bonds. Such reactions eliminate several purification steps, minimize the generation of chemical waste, and save time; thus, they can be viewed as "green" processes. However, there are several limitations in a one-pot reaction, and it cannot be considered as a simple connection of each optimized reaction. Dipeptidyl peptidase IV (DPP4, also known as CD26), a 110kDa serine protease that is ubiquitously distributed in the body, deactivates glucose-regulating hormones, such as GLP-1 and GIP. Thus, DPP4 inhibition has become a potential therapy for type 2 diabetes. ABT-341 (1) is a highly potent, selective, and orally bioavailable DPP4 inhibitor developed by Abbott Laboratories. An efficient, enantioselective total synthesis of ABT-341 (1) via single flask operation has been accomplished, demonstrating the power of asymmetric reactions catalyzed by organocatalysts, in particular diphenylprolinol silyl ether. The present synthesis has several noteworthy features: 1) the total yield is excellent (63 % from nitroalkene 4); 2) the synthesis consists of six reactions, which were conducted in a single flask; 3) four components were combined, to afford ABT-341 (1) in nearly equimolar amounts, except for inexpensive acetaldehyde (2 equiv.); 4) a disubstituted chiral cyclohexene carboxylate with the correct configuration was synthesized from three starting materials by successive reactions, including an asymmetric Michael reaction mediated by a diphenylprolinol silyl ether, as developed by our research group, a domino Michael reaction/Homer-Wadsworth-Emmons reaction combined with a retro-aldol reaction, and a base-catalyzed isomerization; 5) amide-bond formation and functional-group manipulations can also be performed chemoselectively in the same single flask by the appropriate choice of reaction conditions.

Anti Mannich, try this! A direct asymmetric Mannich reaction catalyzed by a diarylprolinol silyl ether was developed to afford the anti-Mannich product with excellent enantioselectivity. Imines derived from both aliphatic and aromatic aldehydes were successfully used to obtain the synthetically important β-amino aldehydes (see scheme; Ts=tosyl). The reaction can also be performed in the presence of water. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The amine-catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid-catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4-NO(2)-C(6)H(4)OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol-% (Tables 2 - 5). Fast formation of an amino-nitro-cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all-trans-isomers of cyclobutanes (Fig. 3) in a [2 + 2] cycloaddition. This reaction was shown, in one case, to be acid-catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino-nitro-cyclobutanes with H(2)O led to mixtures of 4-nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6 - 9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C, C-bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6, which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13. While the enantioselectivity of the reaction is generally very high (> 97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1 - 5). Various acid-catalyzed steps have been identified. The cyclobutanes 12 may be considered an off-cycle 'reservoir' of catalyst, and the zwitterions 5 the 'key players' of the process (bottom part of Scheme 2 and Scheme 3).

Asymmetric direct aldol reaction of trifluoromethylacetaldehyde with aldehyde using diarylprolinol as a catalyst, to afford a synthetically useful beta-trifluoromethyl-beta-hydroxy aldehyde with excellent enantioselectivity, was developed. Commercially available trifluoromethylacetaldehyde ethyl hemiacetal was used directly as a precursor of trifluoromethylacetaldehyde without acid pyrolysis or distillation prior to use.

Asymmetric epoxidation of α-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether to afford α-substituted-β,β-unsubstituted-α,β-epoxy aldehyde with excellent enantioselectivity and the generation of a chiral quaternary carbon center. The method was applied to a short synthesis of (R)-methyl palmoxirate. © 2010 American Chemical Society.

An efficient, asymmetric, four-component, one-pot synthesis of highly substituted piperidines with excellent diastereo- and enantioselectivity was established through the diphenylprolinol silyl ether mediated Michael reaction of aldehyde and nitroalkene, followed by the domino aza-Henry reaction/hemiaminalization reaction and a Lewis acid mediated allylation or cyanation reaction. All carbons of the piperidine ring are substituted with different groups, and its five contiguous stereocenters are completely controlled in both relative and absolute senses. © 2010 American Chemical Society.

A great deal of attention has been paid both in the scientific literature and the general media to the high potential risk of a worldwide spread of avian H5N1 influenza virus, the death rate of which is over 50%. (-)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza, is one of the most promising therapeutics. An efficient, enantioselective, total synthesis of (-)-oseltamivir via two "one-pot" sequences has been accomplished. The present synthesis has several noteworthy features: 1) Only two pots are needed for the synthesis of rather complex (-)-oseltamivir. 2) A higyly functionlalized chiral cyclohexane framework of the correct relative and absolute configuration can be synthesized in the first one-pot sequence, which consists of a sequence of reactions made up of a diphenylprolinol silyl ether-mediated, asymmetric Michael reaction as developed in our group, a domino Michael reaction/Horner-Wardsworth-Emmons reaction, retro-Michael reactions, a thiol-Michael reaction and base-catalyzed isomerization. 3) Six transformations can be succssfully conducted in the second one-pot sequence, including deprotection of a tert-butyl ester and its conversion to an acid chloride then acyl azide, Curtius rearrangement, amide formation, reduction of a nitro froup to an amine, and a retro-Michael reaction of a thol. 4) ONly 1mol% loading of the diphenylprolinol silyl ether, which was deeloped in our group as an efficient organocatalyst, can promote the asymmetric direct Michael reaction, which is suitable for a large-scale synthesis. 5) No halogeneated solvents are used. 6) Isolation and concentraton of the potential haardous acyl azide can be avoided, which makes the synthesis safer. 7) The intermediate can be purified by an acid-base extraction process. Efficient purification of (-)-oseltamivir was achieved by a simple acid-base extraction at the fial stage. Thus, the synthesis is free from column chromatography. This synthesis requires nine transformations in a total of two separate reacton pass. The total yield of (-)-oseltamivir (1) is 60%.

Diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of commercially available polymeric ethyl glyoxylate, affording gamma-ethoxycarbonyl-beta-hydroxy aldehydes, versatile synthetic intermediates, in good yield with excellent enantioselectivity.

Chiral bicyclo[3.3.0]octatrienes with excellent enantioselectivity were synthesized from the simple starting materials of alpha,beta-unsaturated aldehyde and cyclopentadiene via one-pot operation, which consisted of a diphenylprolinol silyl ether-mediated ene-type reaction, intramolecular addition reaction of cyclopentadiene moiety with aldehyde and dehydration reaction. (C) 2010 Elsevier Ltd. All rights reserved.

The efficient asymmetric total synthesis of (-)-oseltamivir, an antiviral reagent, has been accomplished by using two "one-pot" reaction sequences, with excellent overall yield (60%) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wadsworth-Emmons reaction combined with retro-aldol/Horner-Wadsworth-Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (-)-oseltamivir has also been established. Fighting the flu: Two "one-pot" and column-free asymmetric sequences are used to accomplish the synthesis of (-)-oseltamivir, known as the anti-influenza drug Tamiflu (see scheme; TMS: trimethylsilyl). This high-yielding synthesis takes advantage of a diphenylprolinol silyl ether as an organocatalyst and single-pot domino operations. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A great deal of attention has been paid both in the scientific literature and teh general media to the high potential risk of a worldwide spread of avian H5N1 influenza virus, the death reate of which is over 50%. Indeed, shoud this virus acquire the ablility to become capable of spreading easily and directly from human to human it could very possibly cause a disastrous pandeic. (-)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza, is one of the most promising therapeutics, and many nations have plans to stock a significant amount of this compound in case of a possible influenza outbreak. An efficient, enantioselective total synthesis of (-)-oseltamivir (1 via separated three one pot operation has been accomplished, demonstrating the power of asymmetric reactions catalyzed by organocatalysts, in particular diphenylprolinol silyl ether. The present synthesis has several noteworthy features: 1) A highly functionalized chiral cyclohexane framework of the correct configuration is synthesized in the first one-pot operation, which consists of a succession of reactions, including a diphenylprolinol silyl ether-mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wardsworth-Emmons reaction combined with retro-aldol and retro-Michael reactions, a thiol-Michael reaction, and a base catalyzed isomerization. 2) Three reactions occur in the third one-pot operaton: a Curtius rearrangement, the reduction of a nitro group to an amine, and a retro-Michael reaction of the thiol. 3) The Curtius rearrangement proceeds at room temperature without heating, decreasing the potential hazards. 4) The domino reaction consisting of a Curtius rearrangement and amide formation is a direct method for the synthesis of 14. This synthesis requires nine reactions, a toal of three separate one-pot operations, and one purificaton by column chromatography. The total yield of (-)-oseltamivir from nitroalkene 4 is 57%. All the reagents are inexpensive. The metal-based reagents employed in the present total synthesis contain either alkali-metal ions (Na, K, and Cs) or nontoxic Zn. No special care is needed to exclude water or air. Thus, the present procedure is suitable for large-scale preparation.

The asymmetric aldol reaction of isatin derivatives and acetaldehyde has been developed using 4-hydroxydiarylprolinol as a catalyst, affording the aldol products with high enantioselectivity, these products being key intermediates in the synthesis of 3-hydroxyindole alkaloids. Short syntheses of ent-convolutamydine E and CPC-1 and a half fragment of madindoline A and B have been accomplished.

Diphenylprolinol silyl ether was found to be an effective organocatalyst in the enantioselective and direct Michael reaction of nitroethanol and alpha,beta-unsaturated aldehydes, affording the 1-hydroxy-trans-3,4-disubstituted tetrahydropyrans after isomerization. The generated Michael addition products are useful synthetic Intermediates, which can be converted Into chiral tetrahydropyran with a quaternary stereocenter, 3-substituted cis- and trans-prolines, and alpha-amino acid derivatives.

The first asymmetric total synthesis of FD-838, a naturally occurring azaspirobicyclic product, has been accomplished allowing determination of its absolute stereochemistry. (C) 2009 Elsevier Ltd. All rights reserved.

Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 21 cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As a key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were also prepared by total synthesis including both enantiomers of vindorosine, minovine, 4-desacetoxyvindoline, 4-desacetoxy-5-desethylvindoline and 4-deaacetoxyvindorosine as well as N-methylaspidospermidine.

Taking shortcuts: A remarkably short and high-yielding asymmetric total synthesis of (-)-oseltamivir takes advantage of organocatalysis and single-pot domino operations. The target, known as the drug Tamiflu, is prepared efficiently in a short time, and also its derivatives can be synthesized effectively. © 2009 Wiley-VCH Verleg GmbH & Co. KGaA.