Sharpless Asymmetric Epoxidation: Mechanism, Catalyst, and Applications, Study notes of Chemistry

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Sharpless Asymmetric Epoxidation R4 OH R3R2 R1 O R4 OH R3 R1 R2"Magic" Karl Barry Sharpless • Born in Philadephia in 1941 • Ph.D from Stanford University in 1968 • Postdoc at Harvard and at Stanford • Research on chiral synthesis and catalysts at the Scripps Institute • Received Nobel Prize in 2001 for his work on stereoselective oxidation reactions The Catalyst • Via rapid ligand exchange of OiPr and diethyl tartrate O O O O Ti CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH CH3 O O O OH O CH3 CO2Et EtO2C EtO OiPr O O OiPr O iPrO OiPr O O O Ti Ti OEt Diethyl Tartrate (DET) Chirally controls reaction Ti(OiPr)4 catalyst The Mechanism CO2Et EtO2C EtO OiPr O O OiPr O iPrO OiPr O O O Ti Ti OEt + OH O CH3 CH3 CH3 + OH CH2 CH2 H OEt O EtOOC O O O O O Ti tBu + EtOOC EtOOC O O OiPr OiPr OiPr OiPr Ti Transition State CH2 H OEt O EtOOC O O O O O Ti tBu CH2 H OEt O EtOOC O O O O O Ti tBu CH Improvements • Many potential areas of improvement to the original reaction • Possible problems: – Stoichiometric amount of catalyst required – Water soluble substrates (Polymer Support) cannot be isolated after reaction – Requirement for low temperatures (high cost for SAE) – Some substrates react very slowly – Heterogeneous reaction? Molecular Sieves • Original reaction requires stoichiometric amount of Ti(iOPr)4 catalyst • Very reactive allyl alcohols need 50% catalysts – still significant • Major reasons for failure of SAE reactions: – Water destroys catalyst – Water ring-opens epoxide • 3Å molecular sieves absorb water improving yield • Requirement of Ti catalyst reduced to <10% and the tartrate ester to <13% • Allyl alcohol concentration can be kept high since side reactions are minimized (no ring opening) Molecular Sieves • Advantages: – Economy – less catalyst required – Somewhat milder conditions – Ease of isolation – Increased yields – Possible in-situ derivatization • Problem: the substrate may not be soluble in the solvent (low propoxide ion concentration) Higher Temperatures SAE • Problem: High cost due low temperatures • Solution: Titanocene-tartrate (TT) catalyst • Very good catalytic activity and decent enantioselectivity at higher temperatures • TT has bulky cyclopentadienyl rings which create steric hindrance, inducing chirality (compare with BINOL) • In classic SAE, the tartrate-titanium complex forms through ligand exchange Higher Temperatures SAE • But the titanocene-tartrate cannot form through ligand exchange (Ti-halide stable) • Titanocene tartrate is generated before the reaction: In Situ Modification • Ideal use for SAE is to make low molecular weight chiral products – synthetic utility • Low molecular weight substrates react slowly – product is lost during workup • The epoxide formed may also be ring-opened during workup • With molecular sieves, the catalyst concentration is reduced, so solubility of product also decreases • Better solution is in-situ derivatization Competing Methods • Many competing reactions for generating epoxides: • Jacobsen-Katsuki epoxidation • Prilezhaev reaction • Shi expoxidation R 1 R 2 aq. NaOCl Mn-salen catalyst CH2Cl2 R 1 R 2 O H H R 1 R 2 R 3 R3CO3H R 2 O H R 3 R 1 R 1 R 2 Oxone H2O,CH3CN pH 10.5 R 2 R 1 O O O O O O CH3 CH3 O CH3 CH3 Jacobsen-Katsuki Epoxidation • Uses cis alkene as a reactant • Allows broader scope of substrate (R: Ar, alkenyl, alkynyl; R': Me, alkyl) • Mn-salen catalyst and a stoichiometric oxidant H H N + N + O O Mn 3- Cl CH3 CH3 CH3 CH3 CH3CH3 CH3 CH3 CH3 CH3 CH3CH3 Jacobsen-Katsuki Epoxidation • Mechanism’s catalytic cycle shows the formation of an Mn(V)-oxo complex • Good yields with high enatomeric excess Uses of the Reaction • The Sharpless Asymmetric Epoxidation converts alkenes into chirally active epoxides • Innumerable syntheses published that use the SAE • Chiral epoxides easily converted into: – 1,2 Diols – Make carbon-carbon bonds (stereospecifically) – Aminoalcohols • Two examples considered: – A complex synthesis of Venustatriol by EJ Corey – Simpler synthesis of Untenone by Mizutani et al. Venustatriol • Marine-derived natural product discovered initially in 1986 • Found in red alga Laurencia venusta • Derived in vivo from squalene, made as a triterpene • Shown to have antiviral and anti-inflammatory properties • Structure contains repeated polyether moieties • Key problems: multiple stereocenters and polyether moieties. • Corey proposed a “simple and straightforward” disconnection Br’ A Zin - Reterosynthetic Analysis s % % Fragment A  tep - Venustatriol CHO 1. ‘BuLi (Li-Grig.) 2. (COCI), [ox] 3. MeMgBr (Grignard) Untenone • Isolated from a marine sponge in 1993 • Exhibits inhibitory activity against mammalian DNA polymerases • These enzymes are important for DNA replication, repair and cell divisions (cancer implications) • Biosynthetic pathway not investigated • The critical part of the synthesis is the introduction of a quaternary carbon center (done via SAE) • The total synthesis is 15 steps eterosynthetic Analysis COOMe ——> Ho OR CH, “ty CHg 15 15 Untenone | Ring Close COOMe yw0 HC 15 OH