Oxomaritidines

Table 4.20 Summary of reaction metrics and synthesis tree parameters for oxomaritidine synthesis plans...

Baxendale, I.R., Deeley, J., Griffiths-Jones, C.M., Ley, S.V., Saaby, S., Tranmer, G.K. (2006) A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine A New Paradigm for Molecular Assembly. Chemical Communications, 2566-2568. 

Ley, S.V., Schucht, O., Thomas, A.W., Murray, P.J. (1999) Synthesis of the Alkaloids ( )-Oxomaritidine and ( )-Epimaritidine Using an Orchestrated Multi-Step Sequence of Polymer Supported Reagents. Journal of the Chemical Society Perkin Transactions I, 1251-1252. 

Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine a new paradigm for molecular assembly. Chem Commun, p 2566-2568... 

Scheme 7. Continuous flow synthesis of the natural product Oxomaritidine...

Ley SV, Baxendale IR (2002b) New tools and concepts for modern organic synthesis. Nat Rev Drug Disc 1 573-586 Ley S V, Massi A (2000) J Comb Chem Polymer supported reagents in synthesis preparation of bicyclo[2.2.2]octane derivatives via tandem michael addition reactions and subsequent combinatorial decoration. 2 104—107 Ley SV, Schucht O, Thomas AW, Murray PJ (1999) Synthesis of the alkaloids ( )-oxomaritidine and ( )-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents. J Chem Soc Perkin Trans 1 1251— 1252... 

Oxidative phenolic coupling. Biosynthesis of the alkaloid narwedine (3) is known to involve oxidative phenolic coupling of norbelladine derivatives (1), but the usual oxidants for such coupling in vitro convert 1(R = H) into the oxomaritidine skeleton (4) rather than 3. A new biomimetic synthesis of 3 involves the palladacycle 2, formed by reaction of 1(R = CH3) with Li2PdCl4, which is known to form complexes with allylic amines or sulfides (8,176-177). Oxidation of 2 with thallium(III) trifluoroacetate effects the desired coupling to give 3. 

The Ley research group [76] developed a flow process for the multistep synthesis of ( )-oxomaritidine, an alkaloid found in the Amaryllidaceae family, known to have antineoplastic activity (Scheme 34) [77, 78]. The route does not involve intermediate purification of the products, which is necessary in the previously reported... 

Ley SV, Schucht O, Thomas AW et al (1999) Synthesis of the alkaloids (t-/-)-oxomaritidine and (-l-/-)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents. J Chem Soc Perkin Trans 1(10) 1251-1252... 

L-phenylanine alkaloids alkaloids Crinine Eloramultine Galanthamine Galanthine Haemanthamine Lycorine Lycorenine Maritidine Oxomaritidine Vittatine... 

Ley and co-workers applied the polymer-supported hypervalent iodine reagents, poly(diacetoxyiodo)styrene (PDAIS) or polybis(trifluoroacetoxyio-do)styrene (PBTIS) to the above-mentioned spiroannulation reaction. They succeeded in the concise syntheses of ( )-oxomaritidine (40) and ( )-epimari-tidine (41) using this methodology as the key steps [116] (Scheme 26). 

Another approach for effecting the construction of the crinane ring system involved the photocyclization of bromophenolic compounds. For example, irradiation of 418 in 50% aqueous ethanol in the presence of sodium hydroxide followed by O-acetylation produced directly the tetracyclic intermediate 417, albeit in less than 4% yield 195). Saponification of the acetate function afforded an intermediate in a previous synthesis 176) of ( )-oxomaritidine (416). 

Photolytic cyclization of the phenolic bromo compounds 278 and 279 led to ( + )-oxocrinine (275) (methylenedioxy instead of methoxy-hydroxy) and ( )-oxomaritidine (275), known intermediates to crinine and maritidine (277) (59, 60). Oxocrinine was also obtained by photolysis of the isomeric bromophenol 280 (61). 

Scheme 75 Illustration of the reaction steps employed in the flow-assisted synthesis of ( )-oxomaritidine (266).

The systems described in Scheme 4.49 are for simple single-step transformations, typically with in-line purification however, the real opportunities presented by flow techniques will be multistep transformations occurring both in series and in parallel. Initial work in this field has already resulted in the total synthesis of natural products, such as grossamide [88] and ( )-oxomaritidine [89], and the drug candidate BMS-275291 [90], which are discussed later. 

The seven-step flow synthesis of ( )-oxomaritidine included the oxidation of benzylic alcohol 25 to aldehyde 26 (Scheme 4.67) using polymer-supported tetra-N-propylammonium perruthenate (TPAP) 27. Although this reaction is stoichiometric in ruthenium, the Ru(VII) species can be readily regenerated by flowing a solution of NMO through the spent reagent cartridge [89]. 

The most important paper to date on multistep synthesis in flow mode is the total synthesis of ( )-oxomaritidine, 81 [89]. This compound has been previously synthesized by our group in five steps and in 62% overall yield using only... 

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