René W. M. Aben

Novel 20-Carbonate Linked Prodrugs of Camptothecin and 9-Aminocamptothecin Designed for Activation by Tumour-Associated Plasmin

The first prodrugs of camptothecin and 9-aminocamptothecin that are activated by the tumour-associated protease plasmin are reported. The tripartate prodrugs consist of a tripeptide sequence recognised by plasmin, which is linked to the 20-hydroxyl group of the camptothecins via a 1,6-elimination spacer. After selective N-protection of 9-aminocamptothecin with an Aloc group, the promoiety (tripeptide-spacer conjugate) was linked to camptothecin or 9-Aloc-9-aminocamptothecin via a 20-carbonate linkage by reacting parent drugs with the p-nitrophenyl carbonate activated promoiety in the presence of DMAP. Both prodrugs showed to be stable in buffer solution and both parent drugs were released upon incubation in the presence of plasmin. Furthermore, the prodrugs showed an average 10-fold decreased cytotoxicity with respect to their parent drugs upon incubation in seven human tumour cell lines.

High pressure -Lewis acid catalyzed diels-alder reactions of 3-methylcyclohex-2-en-1-one. A straightforward route to cis and Tras angularly methylated octalones.

Abstract By the application of high pressure in combination with EtAlCl 2 as the Lewis acid, it is possible to achieve Diels-Alder reactions of 3-methylcyclohex-2-en-1-one with simple acyclic dienes. This cycloaddition offers the most straigthforward route to cis and trans angularly methylated octalones, precursors in the total synthesis of terpenes and steroids.

Synthesis of endo-2-phenyl-7-azabicyclo[2.2.1]heptane via high pressure Diels-Alder reactions of pyrroles

Abstract A straightforward route to racemic endo-2-phenyl-7-azabicyclo[2.2.1]heptane (an analogue of epibatidine) is described via the high pressure Diels-Alder reaction of 1-methoxycarbonyl-3-phenylthio-pyrrole with phenyl vinyl sulphone.

High pressure-promoted cycloadditions of ketene acetals and α,β-unsaturated aldehydes and ketones

Abstract Cycloadditions of ketene acetals with α,β-unsaturated carbonyl compounds are strongly promoted by high pressure. The influence of the solvent and the substitution pattern on the product distribution at 12 kBar has been investigated. In the polar solvent, acetonitrile, α,β-unsaturated aldehydes not having large β-substituents, yield mainly cyclobutane aldehydes, which are minor products at normal pressure. The products can be transformed under basic conditions without ring opening.

An Approach to Canthine Derivatives Using the Intramolecular Pictet-Spengler Condensation

Abstract The canthine derivative 1b was synthesized efficiently by treatment of N a -(4,4-diethoxybutyl)-N b -allyloxytryptamine 9b with TFA/H 2 O in chloroform. This result demonstrates that PS cyclization can indeed occur by direct attack of the indole 2-position at the intermediate iminium ion under mild conditions. With N a -propanal chains, only dimeric and oligomeric compounds were isolated. With the N a -pentanal chain (unidentified) oligomeric compounds were formed as well. The monomeric canthine-like products have not been detected in these cases, probably because formation has to proceed via conformationally disfavored intermediate cyclic iminium ions. Cyclization of N a -butanal functionalized N b -formyl- or N b -benzyltryptamines 9c and 9d , which are known rate enhancing substituents in the PS condensation, unexpectedly gave the 3,4-dihydro pyrimidino[1,2- a ]indoles 16c,d in high yields. The products 16c,d were formed by a direct electrophilic attack of the protonated aldehydes on the indole 2-position.

High pressure promoted (2+2) cycloadditions of ketene acetals with carbonyl compounds

Cycloadditions of ketene acetals (R1R2C=C(OR)2) with carbonyl compounds (R3COR4) are strongly promoted by increase or pressure. At 12 kbar oxetanes are even obtained from very polar ketene acetals (R1,R2=H,H or H,Cl) and - in the presence of a Lewis acid - with unactivated ketones (R3 and R4 = alkyl). The reaction proceeds via a cisoid dipolar transition state; when relevant mainly trans-substituted oxetanes are formed.

Solid-phase synthesis of piperidines by N-acyliminium ion chemistry.

Functionalised piperidines are frequently encountered structural motifs in bioactive compounds and in natural products.[1] The piperidine ring is often present as a substructure in drug-like molecules.[2] A well-known example is Ritalin (1, methyl α-phenyl-2-piperidinylacetate), used for the treatment of attention deficiency/hyperactivity disorder (ADHD) in children (Scheme 1).[3] Some other piperidinecontaining natural products that show interesting biological activity are febrifugine (2)[4] and ( )-lobeline (3).[5] Consequently, a plethora of synthetic routes affording functionalised piperidines has been developed.[6] In many groups, including ours, N-acyliminium ion pathways towards these scaffolds have been developed over the years.[7] In conjunction with this work, a solid-phase approach that

EXPLORATION OF HIGH-PRESSURE CYCLOADDUCTS OF FURANS AND CITRACONIC ANHYDRIDE AS PRECURSORS FOR CD-RING FRAGMENTS OF PACLITAXEL AND ITS ANALOGUES

The high-pressure promoted Diels–Alder reactions between several furans and citraconic anhydride have been studied and the cycloadducts obtained have been explored in new straightforward routes to the CD-ring fragment of paclitaxel. The reaction between furan and citraconic anhydride afforded the exo cycloadduct diastereoselectively, whereas a variety of 2-substituted furans afforded approximate 1:1 mixtures of exo regioisomers. Separation of both regioisomers was accomplished after either diastereoselective esterification or regioselective reduction of the anhydride function. Ether cleavage of the bicyclic compounds by either high-pressure promoted ether cleavage or Boord elimination afforded several potential CD-ring precursors which can be used in the total synthesis of paclitaxel analogues.

High-Pressure Promoted Cycloadditions of Enol Ethers and 3-Aryl-2-cyano-2-propenoates

The high-pressure promoted cycloadditions of enol ethers (1) and alkyl 3-aryl-2-cyano-2-propenoates (2) lead stereoselectively in high yields to 2,6-dialkoxy-4-aryl-3,4-dihydro-2H-pyran-5-carbonitriles (3). These cycloadducts have a high potential for further synthesis due to the presence of various functionalities. This is illustrated with some representative conversions. As reactive cyclic ketene acetals the cycloadducts 3 were easily hydrolyzed to aldehydes (6) or ketones or alcoholized to acetals having additional ester and cyano groups (5). Removal of the ester group by decarboxylation gave γ-cyano acetals (7), which were further reduced to δ-amino acetals (8). Selective reduction of the cyano group gave access to acetals of β-amino acid esters (9). The potential of such amino acid esters is demonstrated in a straightforward synthesis of a paroxetin precursor 17 from 13. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Chemistry of electron-rich conjugated polyenes. Part 4. A simple and general synthesis of 1-alkoxy-3-trimethylsilyloxybuta-1,3-dienes

Acid-catalysed addition of ketens to 1-alkoxyalkenes yields alkoxycyclobutanones, which on trimethylsilylation under basic conditions give trans-3-alkoxy-1-trimethylsilyloxycyclobutenes. These derivatives undergo electrocyclic ring opening below 100 °C to give the title compounds in which the 1-alkoxy-group and the 4-substituent are trans. Some reactions to illustrate the synthetic application of these highly functionalized electron-rich butadienes are given.