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
• 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. • other oxidants NaOCl can be used H H H
• Wide range of substrates tolerated • Cis better than trans
H H N N Yields = 63-87 % Mn e.e. = 86-98 % cis-alkenes tBu O Cl O tBu
tBu tBu
Yields = 41-91 % N N e.e. = 83-99 % Mn cis-alkenes O Cl O limited success with trans-alkenes (e.e. 50%) PhPh
Recent Development
O N O O2N O 2 2 % achiral salen, 40 % (–)-sparteine AcHN AcHN PhIO; e.e. 73 % O • use of an achiral salen complex in conjunction with a second ligand gives good (and cheaper, control
What have we learnt? • Unfunctionalised alkenes can be catalytically epoxidised with good selectivity
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 27