Myers Chem 115 Transformations of 2,3-Epoxy Alcohols Opening of Terminal Epoxides: Payne Rearrangement-Opening Sequence: • Nucleophilic opening of terminal epoxides is often highly regioselective BnO OH O BnO aq CH3OCH2CH2OH 91% OH BnO N3 OH BnO St-Bu OH BnO Et2O, –40 ºC 74% O St-Bu NaOH H2O O fast-reacting isomer (CH3)3O+ BF4– CH2Cl2 OH OH (CH3)2CuLi BnO OH CH3 BnO BnO OH OH t-BuSNa • #-Hydroxy sulfides are readily converted into terminal epoxides OH Et2O, ºC 83% O H2O, t-BuOH reflux OH LiAlH4 OH BnO OH OH NaN3, NH4Cl, ! BnO NaOH O OH BnO O NaH 80-85% CH3 OH Behrens, C H.; Sharpless, K B.; Aldrichimica Acta, 1983, 16, 67–80 OH OH LiC CCH2OTHP BnO O BnO Et2O, –40 " 23°C 63% Proposed: 2,3-Epoxy alcohols: OTHP OH • Ti(O-i-Pr)4 can catalyze the addition of nucleophiles to C3 of 2,3-epoxy alcohols: O Ti(OR)3 O OH OH KCN BnO BnO CH3OH, 23 °C 50% O CN H3C OH O Nu Nu OH H3C Payne Rearrangement H3C CH3 [A] NaOH H2O 23 °C, 1h H3C O H CH3 [B] OH + H3C [B] Keq = [A] = 92 Et2NH Et2NH i-PrOH i-PrOH (allyl)2NH allyl alcohol NH4OBz NH4OAc KCN Ti(Oi-Pr)4 (equiv) 1.5 1.5 1.5 1.5 1.5 1.5 1.7 OH OH C2 C3 Nucleophile O OH OH Behrens, C H.; Sharpless, K B.; Aldrichimica Acta, 1983, 16, 67–80 HO Nu C3 : C2 3.7 : 20 : 100 : 100 : 100 : 100 : 65 : 2.4 : yield 90 88 96 90 74 73 76 • Steric factors permitting, equilibrium generally favors the more substituted epoxide Payne, G B J Org Chem 1962, 27, 3819–3822 Caron, M.; Sharpless, K B J Org Chem 1985, 50, 1557–1560 M Movassaghi Myers Chem 115 Transformations of 2,3-Epoxy Alcohols • C2 reduction of 2,3-epoxy alcohols using Red-Al is highly selective when C4 is oxygenated • Regioselectivity of uncatalyzed nucleophilic opening of 2,3-epoxy alcohols varies with the substrate and reaction conditions O R 2 R OH OH OH R Nu + OH substrate H3C Nu Nu nucleophile Red-Al = [(CH3OCH2CH2O)2AlH2]–Na+ regioselectivity C3 : C2 O R OH OH O NaN3 OH C3 reduction yield (%) 1:1 94 5:1 89 40 : 98 >100 : 78 100 : 95 OH O BnO O : >10 NaSPh OH OH O BnO 76 OH O O OH O H3C OH NaN3 O OH 1.4 : 71 : 1.4 • Phenyl substitution at C3 of 2,3-epoxy alcohols can lead to high C3-regioselectivity H OH Ph OH Ma, P.; Martin, V S.; Masamune, S.; Sharpless, K B.; Viti, S M J Org Chem 1982, 47, 1378– 1380 Finan, J.; Kishi Y Tetrahedron Lett 1982, 23, 2719–2722 • 1,3-Bis-epoxides: O BnO OH Nu H reagent CH3 O 72 Behrens, C H.; Sharpless, K B.; J Org Chem 1985, 50, 5696–5704 O O OBn NaSPh O Ph OH C2 : C3 O n-C6H13 90 CH3 O R OH epoxy alcohol O H3C + OH C2 reduction combined yield (%) : 10 R THF, °C CH3 O OH Red-Al O Red-Al OH OH THF, 22 °C 70% OH OH BnO OH Nu Nu allyl magnesium bromide allyl R2CuLi or R2(CN)CuLi2 R yield 96 76-88 NaN3/NH4Cl N3 R2NH/KOH R2N 84 ArONa ArO 83 PhSH/NaOH PhS 82 Ma, P.; Martin, V S.; Masamune, S.; Sharpless, K B.; Viti, S M J Org Chem 1982, 47, 1378– 1380 • Allylic epoxides: >95 Hanson, R M Chem Rev 1991, 91, 437–575, and references therein O Ph O CO2CH3 DIBAL-H CH2Cl2 –78 °C Ph O OH Nicolaou, K C.; Uenishi, J J Chem Soc., Chem Commun 1982, 1292–1293 OH M Movassaghi Myers Chem 115 Transformations of 2,3-Epoxy Alcohols • Internal nucleophiles may be used to open 2,3-epoxy alcohols: • The regioselectivity of epoxide opening can vary with the organometallic reagent O OH BnO O "M(CH3)n" OH + BnO H BnO NaIO4 THF:H2O O CH3 CH3 OH C5H11 10-12% 74-79% (CH3)3Al, CH2Cl2 ! 23 ºC 69-73% 13-14% CH3 H3C PhNCO, i-Pr2NEt, 68% O O Johnson, M R.; Nakata, T.; Kishi, Y Tetrahedron Lett 1979, 4343–4346 Roush, W R.; Adam, M H.; Peseckis, S M Tetrahedron Lett 1983, 1377–1380 • AE of allyl alcohol followed by in situ derivatization affords versatile chiral building blocks, such as glycidol tosylate (now commercially available) • Reactions of glycidol tosylate: OH Et2AlCN OTs BF3•OEt2 CH3CN, °C 91% O PhOH OTs OTs O O OH O TsNCO (dba)3Pd2•CHCl3 O H3C O O N Ts H3C (iPrO)3P THF, 23 °C 100% Ph H3C O N OPh O O Ph O Ph (H2CO)n Cs2CO3 OH Ph O CH3CN, 23 °C 95% O McCombie, S W.; Metz, W A Tetrahedron Lett 1987, 28, 383–386 O OH OH H3C HO OTs O BH3•THF 5% NaBH4 81% O Trost, B M.; Sudhakar, A R J Am Chem Soc 1987, 109, 3792–3794 NaH, DMF 84% O CH3 Ph N O H3C OTs PhCH3 96% O O t-BuOK, THF, 81% OH NC O Minami, N.; Ko, S S.; Kishi, Y J Am Chem Soc 1982, 104, 1109–1111 O OTs O C5H11 Corey, E J.; Hopkins, P B.; Munroe, J E.; Marfat, A.; Hashimoto, S.-I J Am Chem Soc 1980, 102, 7986–7987 O O 5% aq HClO4 71% OH (CH3)2CuLi Et2O, –20 ºC OH PhNCO, TEA OTs Klunder, J M.; Onami, T.; Sharpless, K B J Org Chem 1989, 54, 1295–1304 Hanson, R M Chem Rev 1991, 91, 437–475 H3C H CH3 O H CO2, Cs2CO3 DMF, 78 °C 3Å MS 78% O H3C Myers, A G.; Widdowson, K L Tetrahedron Lett 1988, 29, 6389–6392 H O CH3 OH M Movassaghi ... 115 Transformations of 2,3 -Epoxy Alcohols • C2 reduction of 2,3 -epoxy alcohols using Red-Al is highly selective when C4 is oxygenated • Regioselectivity of uncatalyzed nucleophilic opening of. .. 1292–1293 OH M Movassaghi Myers Chem 115 Transformations of 2,3 -Epoxy Alcohols • Internal nucleophiles may be used to open 2,3 -epoxy alcohols: • The regioselectivity of epoxide opening can vary with... NaSPh OH OH O BnO 76 OH O O OH O H3C OH NaN3 O OH 1.4 : 71 : 1.4 • Phenyl substitution at C3 of 2,3 -epoxy alcohols can lead to high C3-regioselectivity H OH Ph OH Ma, P.; Martin, V S.; Masamune,