Epoxidation, Dihydroxylation, and the Utility of Epoxides and Diols Ready Outline: Epoxidation Condensation approaches Dihydroxylation Darzens condensation General considerations Sulfur ylides Sharpless AD With organic peroxides Conditions and scope Peroxy acids Mechanism Peroxy iminic acids Applications Dioxiranes DMDO Enantioselective versions Metal-catalyzed Approaches V(O)(acac)2 Sharpless AE Metal Oxo’s MTO Fe, Pt and Mn-based (Salen)Mn Jacobsen AE Epoxide Ring Opening Opening under acid or basic conditions Organocopper additions Reactions of epoxy alcohols Ready Darzens Condensation Condensations: general scheme O OM M LG + R O R R R R R LG (carbene equiv) LG = leaving group Darzens condensation O CO2R Base O + CO2Et Cl O O CO2Et O O KOtBu KOtBu CO2Et Ph Ph + + OEt OEt 90% PhCHO 75% O Ph Cl Cl OHC O O + LDA Ar O CO2Et KOtBu O Br CO2Me CO2Me 70% dr = 3:4 + OEt O Ph 62% Ph O Cl 1:1 dr O Cl SiMe3 sBuLi Cl SiMe3 R SiMe3 R O Li High yields Magnus, JACS, 1977, 4536 Si stabilizes anions (and cations) Ready Sulfur Ylide Condensations Ready Sulfur Ylide Condensations: Enantioselective Variants Ready Epoxidation with Peroxides: general considerations Most common peroxides: AcOOH, mCPBA, MMPP, Oxone (KHSO5), DMDO Ready Epoxidation with Peroxides Payne Oxidation: mechanistically similar to peracids, but under basic conditions. H O H2O2 2 2 H OH CH3CN OH PhCN, MeOH N H -CH CONH OEt O KHCO3 3 2 KHCO3 OEt O 70% H3C O OEt OEt 'peroxy imidic acid' epoxidation driven by cleavage of O OO bond and by formation of amide Dimethyl Dioxirane: Very strong oxidant; very easy to use Organic Reactions, 2002, vol 61, p219 - ref includes prep for DMDO and experimental conditions for use. prep: O sold as oxone: 2KHSO5 KHSO4 K2SO4 KO S O OH O O O O Can be prepared in situ or as ~0.1M soln in acetone Like peracids, reacts via spiro transition state Most useful for prep of sensitive epoxides b/c byproduct is acetone OBz DMDO BnO O N O quant. O CO2Me N BnO TBSO N 99% O H Cbz OBn 20:1 dr 82% BF3;DMDO N O 85% O O H For even more horsepower: 72% H note: e- poor; no B.V. oxidation O O 1000x as reactive as DMDO Prepared in situ (JOC, 1988, 3890; 1995, 3887) CF3 Ready Enantioselective Epoxidation with Dioxiranes Several groups have developed chiral ketones as catalysts for asymmetric epoxidation. The most successful has been the Shi epoxidation. The catalyst is easily prepared from fructose and displays broad generality. Shi, Accts, 2004, 488 Principle drawbacks: requires slow addition of two reagent solutions Enantiomeric catalyst more difficult to access But: one of the most effective catalysts for AE. Ready Sulfur Ylide Condensations: Application S-trans configuration favored for dienes Ready Metal-Catalyzed Epoxidation: VO(acac); brief review Key point: V and Mo show increased reactivity and high selectivity Key points: VO(acac)2 reliable, chemoselective and stereoselective Ready Metal-Catalyzed Epoxidation: VO(acac); origin of selectivity R R R gem [O] R Rtrans R R : R R O O Preferred conformation OH Rcis OH R OH R erythro threo For table: R1 = Me Æ threo; R2 = Me Æ erythro Can use conformational analysis to understand and predict A1,3 strain between R2 and Rcis favors threo A1,2 strain between Rgem and R1 favors erythro Interaction b/w L and R1 favors erythro σC-R2Æπ* favors erythro Ready Metal-Catalyzed Epoxidation: Ti(OiPr)4 See lecture notes from Synthesis and Catalysis See handout from Andrew Myers From Sharpless, Masamune, Science, 1983, vol 220, 949; see also Tet, 1990, 254. Ready Metal-Catalyzed Epoxidation: inspiration Much research has gone into mimicking cytochrome P450, natures oxidant. The objectives are generally three-fold: 1) Identify highly reactive catalysts. 2) use H2O2 as the terminal oxidant and 3) induce asymmetry. Ready Metal-Catalyzed Epoxidation: MTO Rev on epox with H2O2: Chem Rev 2003, 2457. Ready Metal-Catalyzed Epoxidation: Epox with H2O2 TMTACN: Trimethyl-triazacyclononane (TACN) N Discovered by group from Unilever (oxidative stain removal) De Vos, TO, 1998, 3221 N N TMTACN (0.15%), MnSO4 (0.1%), Oxalic acid (0.3%) TMTACN H O (1.3 equiv) 2 2 O Expensive ligand (difficult to make) Mostly GC yields Minimal Functionality demonstrated Fe-based system White, Doyle, Jacobsen, JACS, 2001, 7194 N N N N Fe[SbF6]2 Assembles into di-iron core (2 AcO bridges) Mimic of MMO AcOH, H O Good yields for terminal olefins 2 2 O Little functionality allowed CH3CN Pt-based system Strukul, JACS, 2007, 7680 Asymmetric version: JACS, 2006, 14006 Ph2 OTf P OH2 Propose addition to Pt-coordinated olefin, but details Pt (2 mol%) have evolved P C6H5 Ph2 Good yields for terminal, unhindered olefins Very sensitive to sterics and electronics O H2O2 (1 equiv) H2O/DCE Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation Background: Collman (review: Science, 1993, 261, 1404) showed metal porphyrin complexes could catalyse epoxidation Kochi (JACS 1986, 2309) showed that (salen)Mn and (Salen)Cr complexes could catalyze epoxidation Burrows (JACS, 1988, 4087) showed that (salen)Ni complexes could catalyze epoxidation Katsuki (TL, 1990, 7345) showed moderate enantioselectivity with (salen)Mn complexes Ligand synthesis: O N N R R R 2 + OH OH HO SALicylaldehyde Ethylene diamine (EN) salen ligand deriviative derivative Catalytic epoxidation: N N Mn t-Bu O O t-Bu O Cl 0.1-4mol% t-Bu t-Bu + NaOCl Csp2 R (pH 10-13) Csp2 R R R R R R Ar R R R Ar Ar Ar R n 87-98% ee 92-98%ee up to 97%ee >90%ee >80%ee 80's trans epoxide! JACS, 1991, 7063 JOC, 1994, 4378 JACS, 1994, 9333 TL, 1995, 5123 TL, 1991, 6533 TL, 1995, 5457 JOC, 1993, 6939 Csp3 Csp3 Warning: and poor substrates (slow, poor ee) Review: Chem Rev. 2005, 1563 Ar Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation: application (salen)MnCl Cat. H2SO4 +NaOCl + NaCl CH3CN OH R N+-O- 3 O amine oxides in Jacobsen AE: TL, 1996, 3271 OH H2O OH + AcOH O no byproducts N NH2 N CH3 Known as Ritter reaction OH Ph OH H N N N N O CONH(iPr) Indinavir - HIV protease inhibitor (Merck) Senanayake, Reider, Jacobsen, Org. Syn, 1999, 76. Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation: Mechanism in general, three different mechanisms possible for metal oxo epoxidation: [2+2] concerted O O O + n-2 O O O n M + Mn-2 + M M Mn Mn electron transfer O O O Mn-2 + Mn Mn-1 Experimental data: secondary KIE's k /k =0.82 H D kH/kD =0.91 Sp2 -> Sp3 H H H H O Sp2 H H H kH/kD =1.00 Mn kH/kD =0.90 Recall enynes and dienes R R R R R (salen)MnO R O O O n-1 R cis R M trans Mniv Ph Radical traps Ph R1 R1 R2 (salen)MnCl various ring-opened Ph products NaOCl R2 O Ph R2 O Ph R1 Ph epox: ring-opened Mn Mn R1 R2 Norby, Akermark, ACIEE, 1997, 1723 HMe 100:0 Note: these authors interpret the data in terms of a [2+2] mechanism Me H 56:44 Ready Epoxide Ring-Opening: Overview Three common classes of epoxide ring-opening reactions Nucleophilic addition Nu Nu- generally stereospecific O OH Isomerization Lewis acid O generally stereospecific O Elimination H Base O Stereoretentive OH General considerations: M Nu Nu H+/M+ - Addition to more stable partial cation O Common for solvolysis + Common with strong Lewis or protic acids O OH Total SN1 = loss of stereochemistry HO Addition to less hindered C Nu- Often good reaction for H-, RO-, RS-, CN-, N3-, R2N Nu Common with weak Lewis acids (esp R2N, CN- Stereospecific Generally, bond-breaking more advanced than bond- making with epoxides. Ready Epoxide Ring-Opening: Overview Ready Epoxide Ring-Opening: Diaxial opening Furst-Plattner Rule: experimentally observed that cyclohexene oxides react such that the nucleophile approaches along an axial trajectory. Nu path a Nu Nu O OH a b twist-boat-like TS disfavored +~5Kcal/mol O = Nu Nu O path b Furst, Helv Chem Acta, 1949, 275 O OH Barton, " 1954, 4284 Chair-like TS favored Notes: Faster-forming product may be less stable product Same analysis applies to conjugate additions, additions to halonium ions, additions to cyclic imines. H H Also known as 'trans-diaxial rule' for obvious reasons H O, cat. H SO HO O 2 2 4 H HO H HO LiAlH4 LiAlH4 HO H H O O MeO HO MeOH MeOH H H + H+ H HO MeO H H Ready Epoxide Ring-Opening: Carbon nucleophiles Addition of carbon-centered nucleophiles usually involves organocopper chemistry low temp, Review: Lipshutz, Tet, 1984, 5005. OH THF or Et2O Generally high yielding, stereospecific O + R2Cu(CN)Li2 R Addition to less substituted C Often waste 1 equiv R Problems: Tetrasubstituted Hindered trisubstituted Vinyl epoxides (good Sn2’) Ready Epoxide Ring-Opening: Additions to epoxy alcohols OH base OH Nu OH Nu O O Payne rearrangement OH (Major from SAE) (Major from SAE - KR) O Ph O OH 0.5N KOH, Et2NH Ph slow OH OH Sharpless Ph O 0.5N KOH, Et2NH Ph O Aldrichimica Acta, 16, 1983,67 NEt O Fast 2 Ph Ph OH Lewis-Acid promoted addition: Sharpless, JOC, 1985, 1557, 1560 R Nu O 1.5 equiv Ti(OiPr)4 +NuH O OH OH LnTi O OH generally >5:1 regioselectivity Nu = R NH,ROH,RSH,TMSN , OH O Nu O 2 3 O KCN, NH4X, NH4OBz O + Ti increases rate and selectivity X X X e.g.