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Synthesis of the DE synthon of racemic camptothecin

| Abstract A concise formal synthesis of camptothecin is described

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ChemInform Abstract: Synthesis of the DE Synthon …

We believe that future developments along these lines–in combination with the modern possibilities of enzyme discovery and engineering, and recent efforts aimed at a better integration of biocatalytic and chemical transformations–will continue to establish a more central role of biocatalysis in the asymmetric synthesis of alkaloids.

Total Synthesis of (+)-Camptothecin - Ciufolini - …

(3) Total Synthesis of (±)-Camptothecin and (±)-10-Methoxy-camptothecin: Condensation of 3,4-dihydro-1-methyl-β-carbolines (29 and 30) with a mixture of the tetra-esters (33), followed by reduction and concurrent cyclization (enamine annelation), produced indolo[a]-quinolizin-4-ones (36 and 37).

Total Synthesis of (+)-Camptothecin ..

A Practical Six-Step Synthesis of (S)-Camptothecin

The chiral lactone(54) obtained has been then converted into (+)-quebrachamine(48) in highly enantioselective manner under the same conditions as the racemate.

Since the chiral halolactone(52) in both enantiomeric forms has been also obtained using (S)-proline as a chiral template, the present synthesis would imply a chiral synthesis.

A Novel, Expeditious Synthesis of Racemic Camptothecin


Figure 17. (a) Photoinduced proton transfer in the enantiomers of chiral salicylidenephenylethylamines upon keto–enol tautomerism. (b) Superimposed photographs of a chiral enol-()-1 crystal before and after irradiating the top of the crystal actuator with UV light. The crystalline cantilever achieved 26 nJ of work by lifting a 4.00 mg metal ring a height, δ, of 0.65 mm. Various photomechanical lifting work was achieved with different enantiomeric compositions within the crystal: the racemic crystal, enol-()-1, achieved 59 nJ of work by lifting a weight with mass 300 times larger than the crystal (not shown). Reproduced from ref . Copyright 2013 American Chemical Society.

The regiochemistry of the cyclisation was investigated in more detail in a follow-up study, which showed that the ratio of products 197 and 198 is influenced by the substitution pattern of the substrate, the pH of the reaction medium and the type and amount of co-solvents used. A complete switch in regioselectivity could be achieved by using substrates like compound 199, in which the usual site of C–C coupling, position 2′, is blocked by a fluorine atom. Preparative-scale biotransformations of 199 and two related derivatives gave good to excellent yields (32–50%) of the (S)-11-hydroxyberbines and the remaining (R)-benzylisoquinolines, and even though the regioselectivity of the reaction had been changed, the enantioselectivity was fully conserved (ee > 97% for all compounds).

3 the present work constitutes a formal total synthesis of the racemic ..
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    Synthesis of (S)-Camptothecin ..

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    Synthesis of camptothecin and ..

  • 02/09/2010 · The Logic of Chemical Synthesis ..

    wherein the analog is a racemic mixture of 20-R ..

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A Practical Six-Step Synthesis of (S) ..

Amongst the largest alkaloids that have been kinetically resolved are mappicine (177a) and 9-methoxymappicine (177b, ), two minor constituents of Nothapodytes foetida, which can be obtained in racemic form from the more abundant camptothecin. Kinetic resolution of the side-chain alcohol in 177a and 177b has been achieved by enantioselective hydrolysis of the corresponding acetates with baker's yeast or lipase PS35 (with enantioselectivities E ranging from 31 to >200), and by enantioselective acetylation with Candida cylindracea lipase (177a: E > 200, 177b: E = 146). Similarly, a side-chain secondary alcohol has been resolved in the chemo-enzymatic preparation of the quinoid indole alkaloid (R)-(–)-desprenylcarquinostatin A (178, ): In this case, a late synthetic intermediate of 178 was subjected to kinetic resolution by commercial lipase QLM, which proceeded with excellent enantioselectivity (E > 200) to afford the (R)-acetate and the (S)-alcohol in 98% and 97% ee, respectively. The synthesis was completed via oxidation to the quinone and, for the natural (R)-enantiomer, hydrolysis of the acetate. Lipase catalysis has also been employed in the kinetic resolution of vasicinone (179; lipase PS35, E > 200), sedamine (69, ; porcine pancreatic lipase, E = 35), as well as lupinine (180; lipase AK,E = 24), and in the desymmetrisation of lobelanidine (181) with CAL-B, which afforded the (S)-monoacetate 182 in 70% yield and >98% ee (). The latter compound was transformed into (–)-lobeline (183), a natural product with anti-addictive properties, by oxidation and ester hydrolysis.

Monatshefte für Chemie - Chemical Monthly (v.141, …

The enormous flexibility of the ‘chiral building block’ approach has enabled the chemo-enzymatic synthesis of alkaloids of remarkable structural complexity and diversity, often even in both enantiomeric forms. However, as chirality is introduced early in the synthetic sequence, an enantiodivergent synthesis requires several identical steps to be carried out independently for each enantiomer. In some cases it would clearly be more efficient to prepare the racemic alkaloid (or a late synthetic intermediate) and subject it to kinetic resolution. On the other hand, even if only one enantiomer of an alkaloid is to be synthesised, preparation of the racemate followed by deracemisation might be an attractive option. Biocatalysis offers possibilities for both these approaches; however, the sheer size and functional complexity of alkaloids make them challenging substrates even for enzymes, and hence examples are limited in number.

Camptothecin analogs in malignant gliomas: …

Monoamine oxidases (MAOs) are flavin-dependent enzymes catalysing the aerobic oxidation of amines to the corresponding imines or iminium ions. The one-pot combination of this reaction with chemical reduction of the imine leads–over several cycles of enantioselective oxidation and non-stereoselective reduction–to accumulation of the slower reacting amine enantiomer (). Over the last ten years, Nicholas Turner's research group has developed several highly enantioselective variants of MAO from Aspergillus niger (MAO-N), which have been engineered for the deracemisation of primary, secondary, and tertiary amines. Recent variants featuring a comparably broad substrate scope are interesting biocatalysts in the context of alkaloid synthesis, as has first been demonstrated by stereoinversion of (S)-nicotine (188) to the non-natural (R)-enantiomer by MAO-N-5 (). The same enzyme variant has also been found capable of deracemising crispine A (185, ), although in this case the reaction proceeded rather slowly. Further optimisation of the biocatalyst through directed evolution has led to the identification of a variant termed MAO-N-9, which displays exceptionally high activity (>5.5 kU/mg) towards crispine A. Very recent studies have demonstrated the broad applicability of MAO-N in the asymmetric synthesis of alkaloids: Variant MAO-N-9 was applied in the chemo-enzymatic preparation of the indole alkaloids (R)-eleagnine (189) and (R)-harmicine (190), while MAO-N-5 was used in the deracemisation of the hemlock neurotoxin coniine (72). In addition, a variant with opposite enantioselectivity (MAO-N-11) has been developed and applied in the synthesis of (S)-1-phenyltetrahydroisoquinoline (191), a building block for the urinary antispasmodic drug solifenacin.

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