Alkene Epoxidations • A huge topic which we will only skim the surface of • References will be include for those who want more detail Peracids: The Prilezhaev (Prileschajew) Reaction Reagent: O • for the Caddick group with O their love of named reactions R O H Transformation: O General Mechanism R' R' O R' O R O O O H O H R R" O H R R" O O R" Use in Synthesis • Peracids much weaker acids than carboxylic acids (pKa 8.2 vs 4.8) • But carboxylic acid is a by-product so buffer with NaHCO3 • Peracids are electrophilic so electron withdrawing groups on R good (mCPBA) • Electron-rich alkenes more reactive • Hydrogen-bonding can direct epoxidations Ar O OH OH O H ArCO3H H O O O H Hydroperoxides • H2O2 & alkyl hydroperoxides require the presence of a transition metal to initiate epoxidation • tBuO2H (TBHP) favoured as safe, soluble and stable in anhydrous solvents and cheap R O M O R O O + + M OR M O R R O O O M O M Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 16 Directed Epoxidations Utilising Hydroperoxides 93CR1307 (directed reactions) • The use of transition metals can allow directed epoxidations • Use to control chemoselectivity OH OH OH O O mCPBA: 1 : 2 TBHP / VO(acac)2 49 : 1 • chemo- and • Used to control stereoselectivity stereoselective Cl O OH Cl O OH H H O MeO N MeO N TBHP O O VO(acac)2 N O N O H H OMe OMe Mechanism O tBuOOH O V O tBuOH O O HO HO O • internal delivery VO(acac)2 • TBHP rapid ligand exchange O tBu O O V O V O O tBu O O O O OO • activation of peroxide tBu O O V O O OO Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 17 Acyclic systems also show good selectivity TBHP 19 : 1 erythro VO(acac)2 O OH OH TBHP 2.5 : 1 O OH VO(acac)2 OH erythro tBu O • biggest effect is R"' L L V O R"' R' iv R O R Rv • therefore use temporary blocking group SiMe3 SiMe3 TBHP TBAF 25 : 1 VO(acac) O erythro 2 O OH OH OH 85CC1636 • this all leads on to probably the most famous epoxidation system… Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 18 Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 19 Use in Synthesis • DCM is an uniquely efficient solvent • Complex can not be stored • Catalyst must be aged Substrates R2 OH Yield = good R2 OH R3 e.e. = 90 % R1 R1 few examples OH R2 OH but generally good R3 R3 R2 OH Poor R3 substrate TsOH Ti(OiPr)4, (+)-DET, TBHP HO O H HO HO HO Kinetic resolution • must stop reaction before R1 R 100% completion or you will just recover a different racemate R2 OH • both enantiomers react just at different rates R3 • R group hinders attack and slows epoxidation down slow fast "O" (–)-DET R2 R2 R1 R1 R H 3 3 R OH R OH H R • produced faster R1 R R1 R O R2 OH R2 OH R3 R3 • If allylic alcohol is the desired product use 0.6 equiv. TBHP • If epoxy alcohol is the desired product use 0.45 equiv. TBHP Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 20 • Although very useful, kinetic resolution only allows a maximum of 50 % yield • Desymmetrisations allow a theoretical 100 % yield • desymmetrisation preferentially forms one isomer OH Slow Fast O OH OH O O OH Slow Fast • kinetic resolution O removes unwanted isomer • Attractive strategy due to combining initial desymmetrisation with a subsequent kinetic resolution to result in very impressive enantiomeric excesses • e.e. of desired product increases with time (84 % 3hrs ® >97 % 140 hrs) NHPh OH OH (–)-DIPT, PhNCO, O O Ti(OiPr)4, O pyr OBn OBn TBHP OBn OBn O OBn OBn BF3.OEt2 O O OH HO OH O HO2C O OH OBn OBn OH HO KDO What have we learnt? • Peracids and hydroperoxides are good epoxidising reagents • Use of transition metals allows directed epoxidations • SAE is the cornerstone of many total synthesis • It works well for the majority of trans allylic alcohols • It can be used in kinetic resolution or desymmetrisation reactions References: directed: 93CR1307 Sharpless: 87JACS5765(good), Comp.Org.Syn. Vol.7, Ch.3.2, 91CR437 Resolution: 81JACS464 Desymmetrisation: 87JACS1525, 94ACR9 KDO: 90T4793 Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 21 • Two building blocks from KC Nicolaou's synthesis of amphotericin B show the power of SAE OH BnO BnO (+)-DET, Ti(OiPr)4, O TBHP OH OH OTBS HO OBn (-)-DET, Ti(OiPr)4, TBHP OBn HO 1. Swern OBn O 2. Wittig MeO2C O 1. DIBAL 2. tBuCOCl 3. TPSCl 4. DIBAL OBn OBn OBn 1. Red-Al (-)-DET, 2. tBuCOCl Ti(OiPr) , O 4 tBuOCO OH OH OH OTPS TBHP OH OTPS Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 22 Dioxirane Epoxidations Reagent: O O R R1 Transformation: • cis-spiro O transition state •syn-addition General Mechanism O O O R R H • concerted H R mechanism R H H Preparation • Most common dioxirane is dimethyldioxirane (DMDO) • Prepared as a pale yellow solution in acetone by the action of oxone or caroate KHSO5 H 2– "SO4" O O O SO3 O H O O O O SO3 • ~0.08–0.10 M acetone solution "distilled" off with carrier gas to prevent further reaction of oxone and DMDO Use in Synthesis • cis-alkenes react more efficiently for steric reasons (~7-9 times more reactive) R R O O O O R R • Stereocentrol is a result of steric interactions • Addition of DCM or H2O decreases stability therefore increases reactivity • Used at low temperature and neutral conditions (as generates acetone as a by-product) • Mild so can generate very sensitive epoxides O tBu O O tBu • • H 84 % O H • Disadvantages: VERY reactive, heteroatoms and hydroxyl groups can be oxidised • Disadvantages: Even unactivated C–H can be oxidised Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 23 O S O S O HO HO N N O 97 % O O OH O O OH O Catalytic Variant • As the dioxirane precursor, the ketone, is regenerated during the reaction only a catalytic quantity is required if dioxirane generated in situ • Possible if pH is kept between 7.0 – 7.5 with phosphate or bicarbonate buffer • if pH too low then dioxirane formation can not proceed (deprotonation impossible viva supra) • if pH too high dioxirane destroyed by oxone O O O O SO O O SO4 2– O 3 Catalytic Asymmetric Variant • Shi has developed an asymmetric variant using a chiral sugar derivative 97JOC2328 Ph 0.2 – 0.3 eq. cat. O yield 75 % Ph oxone ph 7-8 e.e. 97 % Ph Ph H2O / MeCN O O O O O O • High catalyst loadings are required as the ketone decomposes via Baeyer-Villiger reaction R R O O O O 1 O SO3 O R 1 SO R R1 O 3 R O • Armstrong has developed a more robust catalyst (00TA2057) • Operates < 10 mol% and up to 76 % e.e. CO2Et N F H O What have we learnt? • Dioxiranes are extremely powerful oxidants that function under very mild conditions • Readily generated from ketones • Ketones can be used catalytically • Asymmetric variant now possible Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 24 Jacobsen–Katsuki Epoxidation • Aim to develop an asymmetric epoxidation catalyst which would operate on substrates with no functionality for preco-ordination • A number of reasonably efficient porphyrin based oxo–transfer reagents were developed but the real success story has been the us of SALEN–based reagents Reagent: 2 2 R R 1 R1 R N N Mn O O R3 R3 NaOCl (bleach) Transformation: O General Mechanism • Still contraversial 97Ang2060 •Possibilities R R1 R R1 R O O O M M M R1 concerted stepwise oxametallocycle (radical or polar) • oxidations proceed with a degree of scrambling of geometry tBu Et > 99 : 1 cis : trans epoxide Ph CO Et 2 78 : 22 cis : trans epoxide TMS 29 : 71 cis : trans epoxide • Suggests that concerted mechanism is not occurring • Present believe is probably radical - stepwise mechanism (00Ang589) Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 25 Stereoselectivity • My interpretation would again suggest that Katsuki and Jacobsen disagree on this • Both agree that alkene approaches metal oxo complexes side-on 1 R R1 R R R 1 O O O R M M M • approach so that p-HOMO of alkene overlaps with • cis alkenes work well *-LUMO of oxo p • small substituent • trans alkenes generally bad passes axial proton RS RL tBu RSMALL O H tBu O RLARGE MnN O N H H tBu H N N Mn tBu tBu O O tBu • bulky tBu groups block attack from front or sides tBu tBu • Jacobsen implies attack on oxo-species occurs from the back face over the diamine bidge • Katsuki implies that skewed shape of salen complex results in attack from the side • skewed shape of salen complex shields one side • back face blocked by H of nucleophile of cyclohexane group RL RS RL S H R O N N Mn • large substituent far O H O from bulky front face • bulky tBu groups block approach from front Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 26 Use in Synthesis R R1 R O R1 0.1-4.0 mol % cat.