palmerolide A

.......................................................................................................................................... xi Chapter 1. Drugs, nature, and synthesis .................................................................................... 1 1.1 Natural products as a source of drugs ................................................................... 1 1.2 Drugs from the sea ................................................................................................ 1 1.3 Drugs from microorganisms ................................................................................... 4 1.4 Relevance of synthesis in natural products chemistry ........................................... 7 1.4.1 Structure verification via degradation studies ........................................... 8 1.4.2 Structure verification via total synthesis .................................................. 10 1.4.3 Drug supply by total synthesis and semisynthesis ................................. 14 1.4.4 Synthetic derivatives of natural products as drugs ................................. 18 1.5 Research objectives ............................................................................................. 20 1.6 References Cited ................................................................................................. 20 Chapter 2. Synthetic studies of palmerolide A ........................................................................ 24 2.1 Isolation, structure elucidation, and bioactivity of palmerolide A ......................... 24 2.2 Palmerolide A as a synthetic target ..................................................................... 26 2.2.1 Total syntheses ....................................................................................... 26 2.2.1.1 Total synthesis by De Brabander ............................................... 26 2.2.1.2 Total synthesis by Nicolaou ....................................................... 28 2.2.1.3 Total synthesis by Hall ............................................................... 31 2.2.2 Partial syntheses of palmerolide A ......................................................... 33 2.2.3 Formal total synthesis of palmerolide A .................................................. 35 2.3 Degradation of palmerolide A to confirm absolute configuration ......................... 35 2.3.1 Ozonolysis of palmerolide A ................................................................... 36 2.3.2 Synthesis of hexane-1,2,6-triol ............................................................... 36 2.3.3 Synthesis of hexane-1,2,3,6-tetraol ........................................................ 38 2.3.4 Re-evaluation of absolute configuration ................................................. 39 2.4 Synthesis of the C3-14 fragment of palmerolide A .............................................. 40 2.4.1 Julia Kocienski olefination ....................................................................... 40 2.4.2 Grubb’s olefin cross metathesis .............................................................. 42 2.5 References Cited ................................................................................................. 43 Chapter 3. Meridianin A and psammopemmin A: structure investigation ........................... 46 3.1 Indole and pyrimidine containing natural products .............................................. 46 ii 3.1.1 Indoles and pyrimidines from Southern cold water sponges .................. 48 3.1.2 Indoles and pyrimidines from Southern cold water tunicates ................. 49 3.2 Review of meridianin syntheses .......................................................................... 51 3.2.1 Synthesis of natural meridianins ............................................................. 51 3.2.2 Synthesis and biological activity of merdianin analogs ........................... 53 3.2.3 Synthesis and biological activity of meriolins .......................................... 59 3.3 Isolation of meridianins A, B, C, and E from Antarctic tunicate Synoicum sp. ..................................................................................................... 61 3.4 Synthesis and biological activity of 3-pyrimidylindoles ........................................ 63 3.4.1 Synthesis of meridianin A, 4-methoxymeridianin A, and 5bromomeridianin E ........................................................................... 63 bromomeridianin E 3.4.2 Synthesis of psammopemmin A and 2’-chloropsammopemmin A ......... 64 3.4.3 Structural reassessment of psammopemmin A ...................................... 66 3.4.4 Synthesis of meridoquin .......................................................................... 68 3.4.5 Biological activity of 3-pyrimidylindoles ................................................... 69 3.5 References Cited ................................................................................................. 74 Chapter 4. Antimalarial natural products ................................................................................. 77 4.1 The malaria dilemma ........................................................................................... 77 4.2 Current malaria treatment .................................................................................... 78 4.2.1 Quinolines, antifolates, and artemisinins ................................................ 78 4.2.2 Drug resistant parasites .......................................................................... 80 4.3 Natural products as antimalarial leads ................................................................. 81 4.4 Medicines for Malaria Venture project ................................................................. 83 4.4.1 MMV project overview ............................................................................. 83 4.4.2 MMV project methodology ...................................................................... 84 4.4.2.1 Antimalaria and cytotoxicity assays, prioritization of active extracts ................................................................................... 84 4.4.2.2 Antarctic microbe cultivation, extraction, and processing .......... 85 4.4.2.3 Fungi extraction and processing ................................................ 86 4.4.2.4 Scale up fermentation and fractionation .................................... 87 4.4.2.5 Active fractions to pure compounds ........................................... 87 4.4.2.6 Protocol validation ...................................................................... 88 4.4.3 Antimalarial compounds from endophytic mangrove fungi ..................... 88 4.4.3.1 Cytochalasins ............................................................................. 88 4.4.3.2 Trichothecenes .......................................................................... 90 4.4.4 MMV project outlook ............................................................................... 93 4.5 References Cited ................................................................................................. 94 Chapter 5. Experimental ............................................................................................................. 97 5.1 General ................................................................................................................ 97 5.2 Experimental supporting Chapter 2 ..................................................................... 98 5.2.1 Ozonolysis of palmerolide A forming 1,2,3-trihydroxyhexane (2.51) and 1,2,3,6-tetrahydroxyhexane (2.52) .................................. 98 5.2.2 (R)-hexane-1,2,6-triol (R-2.53) and (S)-hexane-1,2,6-triol (S2.53) ................................................................................................. 98 5.2.3 (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2.54)............................... 99 5.2.4 (R)-4-(3-(1,3-dioxolan-2-yl)prop-1-enyl)-2,2-dimethyl-1,3dioxolane (2.55) ................................................................................ 99 iii 5.2.5 (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (2.56) ............................ 100 5.2.6 ethyl 4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (2.57) ................. 101 5.2.6.1 Synthesis of R-2.57 .................................................................. 101 5.2.6.2 Synthesis of S-2.57 .................................................................. 102 5.2.6.3 Physical data common to R-2.57 and S-2.57 .......................... 102 5.2.7 4-(2,2-dimethyl-1,3-dioxolan-4-yl)butan-1-ol (2.58) .............................. 102 5.2.8 hexane-1,2,3,6-tetraol (2.59) ................................................................ 103 5.2.8.1 Synthesis of (2R,3R)-hexane-1,2,3,6-tetraol (S,S-2.59) .......... 103 5.2.8.2 Synthesis of (2S,3S)-hexane-1,2,3,6-tetraol (S,S-2.59) .......... 103 5.2.8.3 Physical data common to R,R-2.59 and S,S-2.59 ................... 104 5.2.9 ((4R,5R)-5-(2-(1,3-dioxolan-2-yl)vinyl)-2,2-dimethyl-1,3dioxolan-4-yl)methyl acetate (2.61) ................................................ 104 5.2.10 ethyl 3-((4S,5S)-5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan4-yl)acrylate (2.62) .......................................................................... 105 5.2.11 ethyl 3-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4yl)propanoate (2.63) ....................................................................... 106 5.2.12 (S)-5-(2-(tert-butyldimethylsilyloxy)hept-6-enylsulfonyl)-1-phenyl1H-tetrazole (2.65).......................................................................... 107 5.2.13 ethyl 3-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl) propanoate (2.66) ........................................................................... 108 5.2.14 (S)-hept-6-ene-1,2-diol (2.67) ............................................................... 109 5.2.15 (S)-2-(tert-butyldimethylsilyloxy)hept-6-enyl-4methylbenzenesulfonate (2.68) ..............