Organic synthesis
Kamil Paruch
Masaryk University, Brno
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
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• 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
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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:
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Kamil Paruch Organic Synthesis C4450Oxidation
vanadium-based reagents
• frequently used for directed epoxidations
J. Am. Chem. Soc. 2007, 129, 429.
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typically: VO(acac)2 + t-BuOOH
Nature Chemistry 2018, 10, 938.
Kamil Paruch Organic Synthesis C4450Oxidation
dimethyldioxirane (DDO)
J. Chem. Soc.,Chem. Commun. 1993, 1220.
asymmetric variant (Shi epoxidation)
J. Am. Chem. Soc. 1996, 118, 9806.
J. Am. Chem. Soc. 1997, 119, 11224.
usually 20-30 mol% used
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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
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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
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Kamil Paruch Organic Synthesis C4450Oxidation
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.
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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.
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Kamil Paruch Organic Synthesis C4450Oxidation
selenation-oxidation-elimination
PhSeCl
J. Am. Chem. Soc. 1982, 104, 4502.
• proceeds as intramolecular syn- elimination
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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.
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Kamil Paruch Organic Synthesis C4450Oxidation
duBois amination
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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“)
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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
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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 non-trivial transformations…
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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
Baran‘s synthesis of taxol: tour de force in oxidation chemistry
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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).