Organic synthesis Kamil Paruch Masaryk University, Brno develop the ability to design viable syntheses of organic compounds of medium complexity • build database of synthetically useful transformations/reagents • be able to assess reactivity of organic compounds (i.e. precursors and intermediates) understand (greater part of) organic syntheses in current literature Kamil Paruch Organic Synthesis C4450Aims 2 lecture (C4450) + seminar (C4455) merged -> lecture with problems to solve/think about • three tests during the semester: >50% points in total to pass (= get the credits for) the seminar < 50% points in total : make-up test • exam: written test (>50% points) followed by oral part draw structures & mechanisms Kamil Paruch Organic Synthesis C4450Format 3 Petr Beňovský: Organická chemie - Organická syntéza László Kürti, Barbara Czakó: Strategic applications of named reactions in organic synthesis K. C. Nicolaou et al.: Classics in Total Synthesis Leo A. Paquette (Ed.): Encyclopedia of reagents for organic synthesis (14 vols) Organic Reactions Science of Synthesis + additional literature in the central library (organic chemistry section) Kamil Paruch Organic Synthesis C4450Literature 4 (more complex) • chemoselectivity • regioselectivity • stereoselectivity • cost of reagents • feasibilty (number of steps, scale up) 5 starting material product synthesis Kamil Paruch Organic Synthesis C4450 6 Kamil Paruch Organic Synthesis C4450Chemo- and regioselectivity enantioselectivity J. Am. Chem. Soc. 1987, 109, 5765. 7 Kamil Paruch Organic Synthesis C4450Diastereoselectivity more complex reagents less complex products • e.g. easily available natural products, often only one enantiomer 8 Kamil Paruch Organic Synthesis C4450 • functional groups interconversion • protecting groups • single bond formation C-C C-O C-N C-S • formation of several bonds • multicomponent reactions domino reactions • solid phase /combinatorial chemistry J. Chem. Soc. 1917, 762. 9 starting material product synthesis Kamil Paruch Organic Synthesis C4450 10 • many syntheses (of complex molecules) include oxidation/reduction steps • installation of reactive site – e.g. oxidation of alcohol to ketone for subsequent nucleophilic attack • removal of H or installation of O Kamil Paruch Organic Synthesis C4450Oxidation SeO2 • oxidation on allylic C 11 Kamil Paruch Organic Synthesis C4450Oxidation 12 Kamil Paruch Organic Synthesis C4450Oxidation Jones reagent CrO3 + aq. H2SO4 (H2CrO4) Tetrahedron Lett. 1961, 493. J. Org. Chem. 1981, 46, 1492. • acidic conditions; some functional groups not compatible 13 Kamil Paruch Organic Synthesis C4450Oxidation Collins reagent J. Org. Chem. 1976, 41, 3883. PCC J. Chem. Soc. Perkin Trans. I 1985, 1. Chem. Lett. 1979, 709. 14 Kamil Paruch Organic Synthesis C4450Oxidation activated DMSO Swern oxidation: base: amine (Et3N) J. Org. Chem. 1993, 58, 3912. J. Am. Chem. Soc. 1982, 104, 4708. 15 Kamil Paruch Organic Synthesis C4450Oxidation note: Pummerer rearrangement – mechanistically similar Dess-Martin reagent J. Am. Chem. Soc. 1988, 110, 6891. J. Am. Chem. Soc. 1990, 112, 9645. 16 J. Am. Chem. Soc. 2005, 127, 14146. Kamil Paruch Organic Synthesis C4450Oxidation TPAP: Pr4N+RuO4 • typically used in catalytic amounts • stoichiometric oxidant: typically NMO Tetrahedron 1992, 48, 1145. J. Chem. Soc. Perkin Trans. I 1992, 979. 17 Kamil Paruch Organic Synthesis C4450Oxidation Sodium chlorite: NaClO2 • selective oxidant, mild conditions (Pinnick oxidation) J. Org. Chem. 1980, 45, 4825. J. Am. Chem. Soc. 1994, 116, 1004. 18 Kamil Paruch Organic Synthesis C4450Oxidation Potassium permanganate): KMnO4 • strong oxidant; oxidation of alkenes and other functional groups J. Am. Chem. Soc. 1992, 114, 10181. Vogel’s Textbook of Practical Organic Chemistry, 5 ed. 1989, p. 668. 19 Kamil Paruch Organic Synthesis C4450Oxidation 20 Kamil Paruch Organic Synthesis C4450Oxidation 3-chloroperoxybenzoic acid, MCPBA, m-CPBA) • reactivity of alkenes: tetra, trisubst. > disubst. > monosubst. • stereospecific reaction: syn-addition : cis-alkene -> cis-epoxide • stereochemistry of epoxidation can be directed by neighboring functional groups J. Org. Chem. 1966, 31, 2509. R = Me: 1:3 R = t-Bu: 1:9 Synlett 1991, 529. Tetrahedron Lett. 1987, 28, 5129. but: 21 Kamil Paruch Organic Synthesis C4450Oxidation vanadium-based reagents • frequently used for directed epoxidations J. Am. Chem. Soc. 2007, 129, 429. 22 typically: VO(acac)2 + t-BuOOH Nature Chemistry 2018, 10, 938. Kamil Paruch Organic Synthesis C4450Oxidation dimethyldioxirane (DDO) asymmetric variant (Shi epoxidation) J. Am. Chem. Soc. 1996, 118, 9806. J. Am. Chem. Soc. 1997, 119, 11224. usually 20-30 mol% used 23 Kamil Paruch Organic Synthesis C4450Oxidation enantioselective Sharpless asymmetric epoxidation: Ti(Oi-Pr)4,+ t-BuOOH + optically pure ester of tartaric acid DET without chiral ligand, but on chiral substrate (substrate control): • allyl alcohol binds to chiral Ti complex J. Am. Chem. Soc. 1987, 109, 5765. of allylalcohols 24 Kamil Paruch Organic Synthesis C4450Oxidation enantioselective Jacobsen asymmetric epoxidation + NaOCl catalyst J. Org. Chem. 1992, 57, 4320. J. Am. Chem. Soc. 1991, 113, 7063. • substrate does not have to contain allylic alcohol 25 Kamil Paruch Organic Synthesis C4450Oxidation suggest the mechanism of Rubottom oxidation 26 Kamil Paruch Organic Synthesis C4450Oxidation • DMDO was particularly selective in the epoxidation of the bis enol ether derived from 31, leading to the diol 32 Org. Lett. 2022, 24, 202. OsO4; OsO4 + NMO; OsO4 + t-BuOOH J. Am. Chem. Soc. 1976, 98, 1986. asymmetric (Sharpless) dihydroxylation: AD-mixK3Fe(CN)6 + K2CO3 + K2OsO2(OH)4 + (DHQD)2-PHAL J. Org. Chem. 1992, 57, 2768. Angew. Chem. Int. Ed. Engl. 1995, 34, 2031. 27 stoichiometric oxidant catalytic amt. chiral ligand Kamil Paruch Organic Synthesis C4450Oxidation ozone: O3 OsO4 + NaIO4 RuO4: RuO2 + NaIO4 Tetrahedron Lett. 1974, 1387. • generated from O2 by el. discharge Org. Lett. 2004, 6, 3217. reaction with O3 : cleavage of the PMB group • strong oxidant • often oxidizes other reactive sites J. Chem. Soc.,Chem. Commun. 1986, 1319. Tetrahedron Lett. 1971, 2941. 28 Kamil Paruch Organic Synthesis C4450Oxidation 29 Kamil Paruch Organic Synthesis C4450Oxidation 30 Kamil Paruch Organic Synthesis C4450Oxidation Nat. Chem. 2023, 15, 1262. Capturing primary ozonides for a syn-dihydroxylation of olefins selenation-oxidation-elimination PhSeCl J. Am. Chem. Soc. 1982, 104, 4502. • proceeds as intramolecular syn- elimination J. Org. Chem. 1974, 39, 120. structure of products? 31 Kamil Paruch Organic Synthesis C4450Oxidation Barton reaction; remote oxidation J. Am. Chem. Soc. 1961, 83, 4083. similar rationale: J. Am. Chem. Soc. 1993, 115, 11648. 32 Kamil Paruch Organic Synthesis C4450Oxidation duBois amination 33 Kamil Paruch Organic Synthesis C4450Oxidation review: Org. Process Res. Dev. 2011, 15, 758. J. Am. Chem. Soc. 2003, 125, 11510. J. F. Hartwig et al. Nature 2012, 483, 70. direct oxidation of unactivated C-H bond („C-H activation“) 34 Fleming-Tamao oxidation similar concept: site-selective arylation of primary aliphatic amines (catalytic transient directing group) Nature Chemistry 2017, 9, 26. Kamil Paruch Organic Synthesis C4450Oxidation 35 Kamil Paruch Organic Synthesis C4450Oxidation A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation Nature Chemistry volume 13, pages1207–1213 (2021)Cite this article Abstract Achieving the transition metal-catalysed pyridine C3−H alkenylation, with pyridine as the limiting reagent, has remained a long-standing challenge. Previously, we disclosed that the use of strong coordinating bidentate ligands can overcome catalyst deactivation and provide Pd-catalysed C3 alkenylation of pyridines. However, this strategy proved ineffective when using pyridine as the limiting reagent, as it required large excesses and high concentrations to achieve reasonable yields, which rendered it inapplicable to complex pyridines prevalent in bioactive molecules. Here we report that a bifunctional N-heterocyclic carbene-ligated Ni–Al catalyst can smoothly furnish C3–H alkenylation of pyridines. This method overrides the intrinsic C2 and/or C4 selectivity, and provides a series of C3-alkenylated pyridines in 43–99% yields and up to 98:2 C3 selectivity. This method not only allows a variety of pyridine and heteroarene substrates to be used as the limiting reagent, but is also effective for the late-stage C3 alkenylation of diverse complex pyridine motifs in bioactive molecules. • analogous strategy can be used in other transformations… 36 site-selective functionalization of tertiary C-H bond H. M. L. Davies et al. Nature 2017, 551, 609. • (stereoselective) manipulation of most accessible tert. C-H bond e.g. Kamil Paruch Organic Synthesis C4450Oxidation 37 Kamil Paruch Organic Synthesis C4450Oxidation Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters Y.-A. Zhang et al. Science 2022, 378, 383. Baran‘s synthesis of taxol: tour de force in oxidation chemistry 38 Kamil Paruch Organic Synthesis C4450Oxidation Paclitaxel (Taxol®) (2) has become a mainstay of cancer chemotherapy. Phil S. Baran of Scripps/La Jolla developed a two-stage route to 2, based on the preparation and oxidation of 1 (J. Am. Chem. Soc. 2020, 142, 10526, DOI: 10.1021/jacs.0c03592; J. Org. Chem. 2020, 85, 10293, DOI: 10.1021/acs.joc.0c01287).