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Home , Epoxide

Epoxidation, Dihydroxylation, and the Utility of Epoxides and Ready

Outline:

Epoxidation Condensation approaches Dihydroxylation Darzens condensation General considerations Sulfur Sharpless AD With organic peroxides Conditions and scope Peroxy acids Mechanism Peroxy iminic acids Applications 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 Ready Darzens Condensation

Condensations: general scheme

O OM M LG + R O R R R R R LG ( 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 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

Dimethyl : 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 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 , 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 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

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 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 . 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

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 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. w/Et NH: +Ti 20:1 (90%y) Nu OH 2 -Ti 3.7:1 (4%y) X = OH, NHBn Nu = Et2NH +Ti 1:20 origin of selectivity: -Ti 6:1 orbital overlap? Least motion? Charge distribution?

OH R R 1:2 R [CH3OCH2CH2O]AlH2Na OH OH R hex 1:1 O OH OH 1 CH2OBn 5:1 2 OBn 40:1 Sharpless, JOC, 1982, 1378; Kishi, TL, 1982, 2719 Ready Lewis-acid catalyzed rearrangement of epoxides

M O O O Rearrangement to more stable Often high degree of stereospecificity H

Ph Ph H O CHO 10% MeAl(OAr)2 O BF 'Yamamoto's catalyst' 3 O tBu

OAr = O Br

tBu OTBS O CHO cat. MeAl(OAr)2 Br Br 88% OTBS CHO OTBS O cat. MeAl(OR)2 OTBS Yamamoto, JACS, 1989, 6431 Chen, JACS, 2009, ASAP

Ph Ph Ph

O O O O O O O O OM O OBz OH OBz Yb(OTf)3 TsOH

88% ee 90% ee Shi, JACS, 1999, 4080 Ready Conversion of epoxides to allylic alcohols Ready Conversion of epoxides to allylic alcohols Ready Dihydroxylation – general considerations

Stark, OL, 2006, 3433 Ready Dihydroxylation – OsO4 O -NR O Best conditions for dihydroxylating olfefin: Upjohn conditions 3 Os O O NR3 1mol%OsO4, 1.05 equiv NMO HO H2O/Acetone Os(VIII) OH O N O O O O NMO: Os O Os O O Catalytic Os NR3 Easy workup ([H-], H+) O NR3 Os(VI) R3N may accelerate rxn Os(VI)

Upjohn Co TL, 1976, p1973 OH H2O O Os OH O O NR N 3 HO Os(VI) O HO O O N-methyl-morpholine-N-Oxide OH (NMO) OH Ph OH OH 25% (from cis olefin) >95% OAc

OH OH OH OH OH OH

OH OH OH 91% 79% 78% O 65% Ready Sharpless Asymmetric Dihydroxylation: overview

Sharpless asymmetric dihydroxylation Shapless, Chem Rev 1994, 2483.

General considerations: Strategy based on observation that tertiary accelerate reaction. R3N*/OsO4 (cat) Monodentate ligand required for turnover oxidant HO OH Ligands based on cinchona alkaloids Simple experimental protocol One of the most general enantioselective reactions

R N* = Linkers: 3 NN Lig O O Lig Lig O O Lig [linker]O O[linker]

N N O O

N N Pseudo-enantiomers Phthalazine (PHAL) used in AD-Mix; OMe MeO Anthraquinone therefore most used (AQN) Dihydroquinidine (OH) Dihydroquinine (OH) (DHQD) (DHQ) Ph NN Lig O O Lig Lig O O Lig NN Lig O O Lig NN XX

Ph Pyridazine Ph Ph (PYDZ) Pyrimidine (PYR) X = N: DPP X=CH:DP-PHAL Ready Sharpless Asymmetric Dihydroxylation: details

AD-Mix- K3Fe(CN)6 0.94g(3equiv) AD-Mix (Lig = DHQ) K2CO3 0.41g(3equiv) HO OH AD-Mix (Lig = DHQD) Lig-PHAL 7.8mg(1mol%) AD-Mix- R R K2OsO2(OH)4 0.74 mg (0.2 mol%) s M R 1.36 g L H Rs RM RL H tBuOH:H2O (1:1) 1mmol H RL Rs RM R3N-OsO4 AD-Mix- HO OH AD-Mix- OsO4 O HO OH O Os O Proposals to rationalize stereochemistry: + O Corey, JACS, 1995, 10805; 1996, 319 NR3 L osmate Sharpless, JACS, 1994, 8470 org. aq.

2K CO O 2K2CO3 2 3 HO OH OK 2H O HO OH 4H4O 4 Os Os HO O HO OK OH OH Os(VIII) Os(VI)

2K4Fe(CN)6 2K3Fe(CN)6 2KHCO3 2K2CO3 Fe(II) Fe(III) net reaction +2H2O+2K2CO3 +2K3Fe(CN)6

HO OH +2KHCO3 +2K4Fe(CN)6 Ready Sharpless Asymmetric Dihydroxylation: scope

Shapless, JOC, 1995, 3940 Ready Sharpless Asymmetric Dihydroxylation: mechanism

A non-linear Eyring plot is taken as evidence for a stepwise mechanism. Sharpless interpreted these data to support a mechanism involving [2+2] cycloaddition (to yield an osmaoxetane) followed by ring expansion.

OH OsO4 (1 equiv) R' R' R ODHQD R 4: R = R' = n-Butyl OH 5: R = Ph, R' = H N 6: R = n-Octyl, R' = H (2-20 equiv)

P = e.r. Sharpless, ACIEE, 1993, 1329 Ready Sharpless Asymmetric Dihydroxylation: mechanism

Corey observed enzyme-like kinetics which he interpreted in terms of reversible binding followed by rate-limited [3+2] cycloaddition (aka Criegee mechanism).

olefin 2Fe(II)

L*OsO4 fast k1 2Fe(III) k-1

L*OsO3 L*OsO4(olefin)

fast kcat O O Os O *L O

JACS, 1996, 319 Ready Sharpless Asymmetric Dihydroxylation: mechanism

Houk, Singleton and Sharpless performed natural abundance KIE studies of the dihydroxylation of tBu ethylene. The data are more consistent with a concerted [3+2] addition. JACS, 1997, 9907

0.05

0

-0.05 [3+2] H2 Hcis Htrans C2 C1 [2+2] -0.1 expansion expt. - calc. - expt. -0.15

-0.2 Ready Sharpless Asymmetric Dihydroxylation: applications

‘no other known comes close to achieving such enormous scope coupled with such great selectivity.’ – Sharpless in Chem Rev.

OL, 2009, 293. Often AD-Mix is best way to do OL, 2008, 5007 (95% ee) dihydroxylation regardless of stereochemistry

d.r. 4:1 (15 major); [O]/[H-]: 9:1 (14 major); ACIEE, 2008, 3426 Ready Sharpless Asymmetric Dihydroxylation: applications

Diol-to-epoxide is common application of AD. ‘d’ in scheme is

1. TsCl. 2. K2CO3 Furstner, ACIEE, 2006, 5510, From the conclusion:

Synthesis of amphidinolide A: Trost, JACS, 13589. In scheme 2: d: 11:1 24/25, 90%ee.