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Nicholas DeVitoCEM 852
14 March 2020
Convergent Synthesis of (-)-Rubriflordilactone B
Retrosynthetic Strategy to (-)-Rubriflordilactone
1. Synthesis of fragments 1 and 22. Alkyne addition of fragment 1 to fragment 23. [2+2+2] cycloaddition
Mohammad, M.; Chintalapudi, V.; Carney, J. M.; Mansfield, S. J.; Sanderson, P.; Christensen, K. E.; Anderson, E. A. Convergent Total Syntheses of (−)-Rubriflordilactone B and (−)-Pseudo-Rubriflordilactone B. Angew. Chem. Int. Ed. 2019, 58, 18177–18181.
Fragment 1: Synthesis of Starting Material and Allylic Alcohol
Chaubet, G.; Goh, S. S.; Mohammad, M.; Gockel, B.; Cordonnier, M.-C. A.; Baars, H.; Phillips, A. W.; Anderson, E. A. Total Synthesis of the Schisandraceae Nortriterpenoid Rubriflordilactone A. Chemistry - A European Journal 2017, 23, 14080.propargyl alcohol: Sigma-Aldrich. https://www.sigmaaldrich.com/catalog/search?term=propargyl+alcohol&interface=All&N=0&mode=match partialmax&lang=en®ion&focus=product (accessed Mar 10, 2020).
Fragment 1: Sharpless Asymmetric Epoxidation
Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
*titanium catalyst is dimeric in structure, but simplified here for clarity of drawing
Fragment 1: Formation of Lactone Functionality
Fragment 1: Oxidative Cyclization
Synthesis of Starting Material for Fragment 2
Synthesis of Starting Material for Fragment 2
4-Methoxybenzyl Chloride. https://www.001chemical.com/chem/824-94-2 (accessed Feb 25, 2020).1,3-Propanediol. https://www.sigmaaldrich.com/catalog/substance/13propanediol760950463211?lang=en®ion (accessed Feb 25, 2020).Gao, D.; Li, B.; O’Doherty, G. A. Synthesis of Dehydro-Dephospho-Fostriecin and Formal Total Synthesis of Fostriecin. Organic Letters 2019, 21, 8334–8338.
Starting Material Price
$1.44/gram
$240.00/liter
Table 1. Cost of reagents
1. Chin. J. Org. Chem. 2018, 38, 2427−2434
Fragment 2: Ketene-Aldehyde Cycloaddition
Zhu, C.; Shen, X.; Nelson, S. G. Cinchona Alkaloid-Lewis Acid Catalyst Systems for Enantioselective Ketene−Aldehyde Cycloadditions. J. Am. Chem. Soc. 2004, 126, 5352–5353.
Fragment 2: Ring-Opening of Lactone
Kocienski, P.; Christopher, J.; Bell, R.; Otto, B. Nucleophilic Addition of α-Metallated Carbamates to Planar Chiral Cationic η3-Allylmolybdenum Complexes: A Stereochemical Study. Synthesis 2005, 2005, 75–84.
Fragment 2: Claisen Rearrangement and Methylation
Kühnel, E.; Laffan, D. D. P.; Lloyd-Jones, G. C.; Martínez Del Campo, T.; Shepperson, I. R.; Slaughter, J. L. Mechanism of Methyl Esterification of Carboxylic Acids by Trimethylsilyldiazomethane. Angew. Chem. Int. Ed. 2007, 46, 7075–7078.
Fragment 2: Oxidative Cleavage of Alkene
Vanrheenen, V.; Kelly, R.; Cha, D. An Improved Catalytic OsO4 Oxidation of Olefins to -1,2-Glycols Using Tertiary Amine Oxides as the Oxidant. Tetrahedron Letters 1976, 17, 1973–1976.
Fragment 2: Cyclization and Methylation
Fragment 2: Alcohol to Protected Alkyne
Nooy, A.; Besemer, A.; Bekkum, H. On the Use of Stable Organic Nitroxyl Radicals for the Oxidation of Primary and Secondary Alcohols. Synthesis 1996, 1996, (10), 1153–1176.
Fragment 2: Deprotection of p-Methoxybenzylether
E. A. Braude, L. M. Jackman and R. P. Linstead, J. Chem. Soc., 1954, 3548
Fragment 2: Corey-Fuchs Alkyne Synthesis
Corey, E. J., Fuchs, P. L. Synthetic method for conversion of formyl groups into ethynyl groups. Tetrahedron Lett. 1972, 3769–3772.
Ramirez, F., Desai, N. B., McKelvie, N. New synthesis of 1,1-dibromoolefins via phosphinedi-bromoethylenes. The reaction of triphenylphosphine with carbon tetrabromide. J. Am. Chem. Soc. 1962, 84, 1745–1747.
Fragment 2: Halogenation of Alkyne
J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, V. V. Fokin, Angew. Chem. Int. Ed. 2009, 48, 8018.
Completed Synthesis of Fragment 2
Matsuo, J.-I.; Murakami, M. The Mukaiyama Aldol Reaction: 40 Years of Continuous Development. Angewandte Chemie International Edition 2013, 52, 9109.
Convergent Synthesis to (-)-Rubriflordilactone B
Convergent Synthesis to (-)-Rubriflordilactone B
(-)-rubriflordilactone B
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