A connective Pummerer reaction was developed with a view to its use in the synthesis of analogues of ecteinascidin 597, a member of a family of potent anti-tumour natural products. A one-step synthesis of N-benzyl 2-hydroxyamides, involving the reaction of 2,2-dimethyl-1,3-dioxolan-4-one with amines, was investigated and the products were oxidised to give glyoxamides. Reaction conditions were optimised for the cyclisation of electron-rich N-benzyl glyoxamides in the presence of thiols and a Lewis acid (ZnCl2 or Sc(OTf)3) to give 4-sulfanyltetrahydroisoquinolinones, and mechanistic studies indicated the importance of hemithioacetal and thionium intermediates in these reactions. The scope of the reaction was found to encompass electron-rich N-benzyl pyruvamide substrates, which gave 4-methyl-4-sulfanyltetrahydroisoquinolinone products via what is believed to be a combination of thionium ion and cyclisation-substitution pathways. Under more forcing conditions, connective Pummerer cyclisation of N-benzyl 2,2-diethoxyacetamides was successful. Sharpless asymmetric aminohydroxylation and a Sharpless asymmetric dihydroxylation-Mitsunobu sequence were exploited in the synthesis of an enantioenriched 1,2-aminoalcohol. Subsequent conversion to branched, N-benzyl 2-hydroxyacetamides by PMB and silyl protection and N-acylation then oxidation and cyclisation furnished 1-silyloxymethyl-4-sulfanyl tetrahydroisoquinolinones. Modification of these tetrahydroisoquinolinones gave bridged macrolactones which map onto the A subunit of the ecteinascidins. A one-pot macrolactone synthesis using a connective Pummerer reaction was unsuccessfully attempted on a substrate bearing 2,2-diethoxyacetamide and thiol moiety in addition to an electron-rich benzene ring. A new protecting group strategy was necessary for continuation of the analogue synthesis and a variety of N,O-acetals were evaluated for the protection of the 1,2-aminoalcohol.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607024 |
| Date | January 2013 |
| Creators | Smith, Laura Hayley Susan |
| Contributors | Procter, David |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/development-of-a-pummerertype-cyclisation-for-the-synthesis-of-analogues-of-the-antitumour-natural-product-ecteinascidin-597(6efb1fa2-b021-471d-ad12-7953149f8e7d).html |
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