Nicholas DeVito CEM 852 14 March 2020...PowerPoint Presentation Author: Devito, Nicholas Created Date: 3/23/2020 4:37:21 PM ...

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