Efficient synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F

The synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F was achieved by using a vinyloguous Mukaiyama aldol reaction on a chiral aldehyde with a silyloxyfuran and by using a C-glycosylation of a lactol derivative with an acetyl oxazolidinethione. From the available chiral acetonide-glyceraldehyde, all the stereogenic centers were perfectly induced along the synthesis. The C(1)-C(9) fragment was synthesized as a vinyl stannane at C(9) in 10 steps, with 16% yield.     

The enantiospecific,stereospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-majvinine, (+)-10-methoxyaffinisine,and (+)-N(a)-methylsarpagine,as well as the total synthesis of the alstonia bisindole alkaloid macralstonidine

The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-N(a)-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been accomplished. This approach employed the Sch?llkopf chiral auxiliary for the stereospecific construction of the desired d-(+)-tryptophan unit required for the asymmetric Pictet-Spengler reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd(0) coupling process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline (2) and N(a)-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other alkaloids for it is stereospecific and either enantiomer can be prepared with ease.     

Total synthesis of a new cytotoxic acetogenin, jimenezin, and the revised structure

The first total synthesis of jimenezin was achieved by using carbohydrates as chiral building blocks, thus revising the proposed structure 1 to 2. The key steps in this synthesis include an efficient construction of the THP-THF fragments 3 and 16 through a stereoselective condensation between the pyranyl aldehyde 5 and the acetylene derivative 6, and a palladium-catalyzed coupling reaction of 3 or 16 with a terminal butenolide 4.     

Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation

In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.     

Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost

We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.     

Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction.

A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Sch?llkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Sch?llkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.     

A new strategy for the enantioselective synthesis of carba-prostacyclin analogues based on organocopper conjugate addition to a bicyclic azoene and its application to the synthesis of 13,14-dinor-inter-p-phenylene carbacyclin

An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.     

A general strategy for the synthesis of vincamajine-related indole alkaloids: stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol, and vincarinol

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Sch?llkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).     

Stable hydrazone-linked chiral covalent organic frameworks: Synthesis,modification, and chiral signal inversion from monomers

The designed synthesis of chiral covalent organic frameworks(COFs) featuring intriguing properties is fairly scant and remains a daunting synthetic challenge.Here we develop a de novo synthesis of an enantiomeric pair of 2 D hydroxyl-functionalized hydrazone-linked chiral COFs,(S)-and(R)-HthBta-OH COFs,using enantiopure 2,5-bis(2-hydroxypropoxy)terephthalohydrazide(Hth) as monomers.The fo rmation process of hydroxyl-functionalized chiral COFs was monitored using rigorous time-dependent PXRD,vibrational circular dichroism(VCD),and electronic circular dichroism(ECD) studies.Remarkably,VCD spectra indicated a unique chiral signal inversion from the positive Cotton effect of(S)-Hth monomer to the negative Cotton effect of(S)-HthBta-OH COF,which has never been reported in chiral COFs.Moreover,two unprecedented carboxyl-functionalized chiral COFs,(S)-and(R)-HthBta-COOH,were constructed by a post-synthetic modification of the corresponding hydroxyl chiral COFs with succinic anhydride.Notably,carboxyl-functionalized COFs retained homochirality and crystallinity without linker racemization and structural collapse after the chemical modification due to the chemically robust nature of pristine hydrazone-linked chiral COFs.     

Design and synthesis of a conformationally restricted trans peptide isostere based on the bioactive conformations of saquinavir and nelfinavir

The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.     

Solution-, solid-phase, and fluorous synthesis of beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives: a comparative study

The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.     

Microwave-Assisted Preparation of a β-Cyclodextrin-Based Stationary Phase for Open Tubular Capillary Electrochromatography

Fluorescein isothiocyanate was used as a label to show that a 3-aminopropylmethyldimethoxysilane (KH 550)-modified capillary column was prepared by microwave irradiation. A bromoacetate-substituted β-cyclodextrin (Br-β-CD) was successfully bound to the KH 550-modified column as a chiral stationary phase for open tubular capillary electrochromatography. Compared with conventional synthesis, the microwave-assisted process significantly decreased the preparation time of the stationary phase from 16 h to 40 min. Baseline chiral separation of 1-phenyl-1,2-ethanediol was achieved using the Br-β-CD modified column.     

General approach for the synthesis of 12-methoxy-substituted sarpagine indole alkaloids including (-)-12-methoxy-N(b)-methylvoachalotine, (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline

[structures: see text] The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Sch?llkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-N(b)-methylvoachalotine in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross-coupling processes served as key steps. The quaternary center at C16 of 12-methoxy-N(b)-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-N(a)-methylvellosimine and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion at [C6] to form a cyclic ether [C6-O17]. After oxidative formation of the alpha-ester at C16, the ether bond was reductively cleaved with TFA/Et3SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids.     

Primary amine/CSA ion pair: a powerful catalytic system for the asymmetric enamine catalysis

A novel ion pair catalyst containing a chiral counteranion can be readily derived by simply mixing cinchona alkaloid-derived diamine with chiral camphorsulfonic acid (CSA). A mixture of 9-amino(9-deoxy)epi-quinine 8 and (-)-CSA was found to be the best catalyst with matching chirality, enabling the direct amination of α-branched aldehydes to proceed in quantitative yields and with nearly perfect enantioselectivities. A 0.5 mol % catalyst loading was sufficient to catalyze the reaction, and a gram scale enantioselective synthesis of biologically important α-methyl phenylglycine has been successfully demonstrated.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate, a versatile intermediate for the synthesis of 3,3-dimethylproline derivatives

The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (+/-)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-)-9, from which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-dimethylprolinamides (+)-2 and (-)-2 could be accessed in nearly quantitative yield, without loss of optical purity. The absolute configurations of the resolved prolines and prolinamides were determined by correlation with an intermediate of known absolute stereochemistry.     

Near-Enantiopure Trimerization of 9-Ethynylphenanthrene on a Chiral Metal Surface

Enantioselectivity in heterogeneous catalysis strongly depends on the chirality transfer between catalyst surface and all reactants, intermediates, and the product along the reaction pathway. Herein we report the first enantioselective on-surface synthesis of molecular structures from an initial racemic mixture and without the need of enantiopure modifier molecules. The reaction consists of a trimerization via an unidentified bonding motif of prochiral 9-ethynylphenanthrene (9-EP) upon annealing to 500 K on the chiral Pd₃-terminated PdGa{111} surfaces into essentially enantiopure, homochiral 9-EP propellers. The observed behavior strongly contrasts the reaction of 9-EP on the chiral Pd₁-terminated PdGa{111} surfaces, where 9-EP monomers that are in nearly enantiopure configuration, dimerize without enantiomeric excess. Our findings demonstrate strong chiral recognition and a significant ensemble effect in the PdGa system, hence highlighting the huge potential of chiral intermetallic compounds for enantioselective synthesis and underlining the importance to control the catalytically active sites at the atomic level.     

Total synthesis of amphidinolide X

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13-C14 bond was achieved by the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.     

Platinum/Copper Dual-Catalyzed Asymmetric Vinylogous Addition Reactions for the Synthesis of Functionalized Indoles

The development of multicomponent ligands to improve catalytic reactivity and selectivity remains a significant challenge for the synthesis of chiral building blocks. Here, a modular synthesis of structurally diverse multiligated platinum complexes, characterized by X-ray crystallography, was revealed to open up a previously inaccessible reaction space. A library of more than 16 binary component-ligated platinum complexes was identified as a practical toolkit to enable faster screening. The isolated bench-stable Pt^II(oxazoline)(phosphine) complex paired with a chiral copper complex exhibits fundamentally new cooperative reactivity. The newly designed Pt/Cu dual catalytic system contributed to the development of highly enantioselective vinylogous addition reactions between a Pt-activated electrophilic α,β-unsaturated carbene and a Cu-activated nucleophile, resulting in a reliable process for the asymmetric synthesis of valuable functionalized indoles in good yields and excellent enantioselectivities.     

A new entry to asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones, using a carbohydrate derived amide as both a chiral auxiliary and a proton source

A new entry for the asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones was developed by using a carbohydrate-derived amide as both a chiral auxiliary and a proton source. Unlike the previously reported examples, the chiral auxiliary employed in this reaction also successfully functioned as a protonating agent. Excellent asymmetric induction could be achieved by this dual stereoselective control in the reaction process.