Stereoselective Titanium Mediated Aldol Reactions of a Chiral Lactate Derived Ethyl Ketone with Ketones

Transcription

1 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia StereoselectiveTitanium MediatedAldol ReactionsofaChiralLactate DerivedEthyl KetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà, PedroRomea,FèlixUrpí,andMercèFont Bardia DepartamentdeQuímicaOrgànica DepartamentdeCristal lografia,mineralogiaidipòsitsminerals, UniversitatdeBarcelona,08028Barcelona,Catalonia,Spain 1. GeneralExperimentalMethods S2 2. GeneralProcedurefortheAldolReaction S2 3. PhysicalandSpectroscopicDataforAldolAdducts S3 4. Proofof stereochemistry S Hand 13 CNMRSpectraofAldolAdducts S12 S1

2 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia 1.GeneralExperimentalMethods Unlessotherwisenoted,reactionswereconductedinoven driedglasswareunderinertatmosphereof N 2 with anhydrous solvents. The solvents and reagents were dried and purified when necessary accordingtostandardprocedures.commerciallyavailablereagentswereusedasreceived.analytical thin layerchromatography(tlc)wascarriedoutonmercksilicagel60f 254 platesandanalyzedbyuv (254nm)andstainedwithp anisaldehyde;r f valuesareapproximate.specificrotations([α] D )were determinedat20 ConaPerkin Elmer241MCpolarimeter.IRspectra(AttenuatedTotalReflectance, ATR) were recorded on a Nicolet 6700 FT IR Thermo Scientific spectrometer and only the more representative frequencies (ν) are reported in cm 1. 1 H NMR (400 MHz) and 13 C NMR (100.6 MHz) spectrawererecordedonavarianmercury400.chemicalshifts(δ)arequotedinppmandreferenced tointernaltms(δ0.00for 1 HNMR)orCDCl 3 (δ77.0for 13 CNMR);couplingconstants(J)arequotedin Hz;dataarereportedasfollows:s,singlet;d,doublet;t,triplet;q,quartet;hept,heptuplet;m,multiplet (andtheircorrespondingcombinations);wherenecessary,2dtechniques(noesy,cosy,hsqc)were alsousedtoassistonstructureelucidation.highresolutionmassspectra(hrms)wereobtainedwith an Agilent 1100 spectrometer by the Unitat d Espectrometria de Masses, Universitat de Barcelona. Columnchromatographieswerecarriedunderlowpressure(flash)conditionsandperformedonSDS silicagel60(35 70µm). 2.GeneralProcedurefortheAldolReaction NeatTiCl 4 (0.12mL,1.1mmol)iscarefullyaddedtoasolutionof1(192mg,1.0mmol)inCH 2 Cl 2 (5 ml)at 78 CunderN 2 andtheresultantyellowsuspensionisstirredfor5min.then,anhydrousi Pr 2 NEt(0.19mL,1.1mmol)isaddeddropwiseandtheensuingdarkredsolutionisstirredfor30min at 78 C,followedbyadditionofneatTiCl 4 (0.12mL,1.1mmol).Afterstirringfor5min,ketone(1.5 mmol)a sisaddedandthereactionmixtureisstirredat 20 C. ThereactionisquenchedbytheadditionofasaturatedsolutionofNH 4 Cl(5mL)withvigorousstirring andthelayersareseparated.themixtureispartitionedinet 2 Oandwaterandtheaqueouslayeris extracted with Et 2 O. The combined organic extracts are washed with sat NaHCO 3 and brine, dried (MgSO 4 ), filtered, and concentrated. Eventually, the residue is analyzed by 1 H NMR and purified by flashcolumnchromatographytoaffordthealdoladducts. S2

3 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia 3.PhysicalandSpectroscopicDataforAldolAdducts (2S) 2 Benzyloxy 5 hydroxy 4,5 dimethyl 3 hexanone(3a) Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 188mg(75%yield)of3a.Colorlessoil.R f (hexanes/etoac85:15)0.20.[α] 20 D+19.9(c1.0,CHCl 3 ).IR (film)ν3479(br),2977,2937,2879,1719,1455,1371,1205,1143,1114cm 1. 1 H NMR(400MHz, CDCl 3 ) δ (5H, m, ArH), 4.62 (1H, d, J = 11.7 Hz, PhCH x H y O), 4.56 (1H, d, J = 11.7 Hz, PhCH x H y O),4.05(1H,q,J=6.9Hz,CHOBn),3.06(1H,q,J=7.1Hz,COCHCH 3 ),1.37(3H,d,J=6.9Hz, BnOCHCH 3 ),1.22(3H,s,CCH 3 ),1.18(3H,s,CCH 3 ),1.13(3H,d,J=7.1Hz,COCHCH 3 ). 13 CNMR(100.6 MHz,CDCl 3 )δ217.5(c),137.6(c),128.5(ch),127.9(ch),127.7(ch),80.3(ch),72.1(c),71.7(ch 2 ), 48.9 (CH), 29.8 (CH 3 ), 26.0 (CH 3 ), 16.3 (CH 3 ), 12.6 (CH 3 ). HRMS (+ESI): m/z calc. for C 15 H 22 NaO 3 [M+Na] + : ;found: (2S) 2 Benzyloxy 4 (1 hydroxycyclohexyl) 3 pentanone(3b) Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 219mg(75%yield)of3b.Colorlessoil.R f (hexanes/etoac85:15)0.30.[α] 20 D+3.5(c1.0,CHCl 3 ).IR (film)ν3504(br),2977,2934,2860,1701,1454,1371,1264,1164,1103,1069cm 1. 1 H NMR(400 MHz,CDCl 3 )δ (5H,m,ArH),4.62(1H,d,J=11.8Hz,PhCH x H y O),4.56(1H,d,J=11.8Hz, PhCH x H y O),4.02(1H,q,J=6.9Hz,CHOBn),3.21(1H,s,OH),3.05(1H,q,J=7.1Hz,COCHCH 3 ), (10H,m,(CH 2 ) 5 ),1.36(3H,d,J=6.9Hz,BnOCHCH 3 ),1.11(3H,d,J=7.1Hz,COCHCH 3 ). 13 CNMR (100.6MHz,CDCl 3 )δ218.6,137.6,128.5,127.9,127.7,80.3,72.6,71.7,47.9,37.5,34.0,25.7,21.9,21.5, 16.3,11.5.HRMS(+ESI):m/zcalc.forC 18 H 26 NaO 3 [M+Na] + : ;found: (3R,4S,5S)Ethyl5 benzyloxy 2 hydroxy 2,3 dimethyl 4 oxohexanoate(5a). Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 269mg(87%yield)of5a.Colorlessoil.R f (hexanes/etoac80:20)0.30.hplc(hexanes/etoac85:15) t R =11.8min.[α] 20 D 42.8(c1.1,CHCl 3 ).IR(ATR)ν3503(br),2984,2940,2877,1725,1455,1370, 1253,1125,1096cm 1. 1 HNMR(400MHz,CDCl 3 )δ (5H,m,ArH),4.58(1H,d,J=12.0Hz, S3

4 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia PhCH x H y O),4.56(1H,d,J=12.0Hz,PhCH x H y O),4.19(1H,dq,J=10.8,7.2Hz,CO 2 CH x H y CH 3 ),4.14(1H, dq,j=10.8,7.2hz,co 2 CH x H y CH 3 ),4.09(1H,q,J=6.8Hz,CHOBn),3.87(1H,brs,OH),3.48(1H,q,J= 7.2 Hz, COCHCH 3 ), 1.35 (3H, d, J = 6.8 Hz, BnOCHCH 3 ), 1.35 (3H, s, CCH 3 ), 1.26 (3H, t, J = 7.2 Hz, CO 2 CH 2 CH 3 ), 1.22 (3H, d,j = 7.2Hz, COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 )δ (C), (C), 137.6(C),128.5(CH),127.9(CH),127.8(CH),79.3(CH),75.8(C),71.4(CH 2 ),61.5(CH 2 ),46.9(CH), 22.8 (CH 3 ), 16.3 (CH 3 ), 14.1 (CH 3 ), 10.9 (CH 3 ). HRMS (+ESI): m/z calc. for C 17 H 24 NaO 5 [M+Na] + : ;found: (3R,4S,5S)Methyl5 benzyloxy 2 hydroxy 2,3 dimethyl 4 oxohexanoate(5b). Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 268mg(91%yield)of5b.Colorlessoil.R f (hexanes/etoac80:20)0.35.hplc(hexanes/etoac85:15) t R =14.6min.[α] 20 D 44.4(c1.05,CHCl 3 ).IR(ATR)ν3493(br),2985,2949,1723,1453,1369,1251, 1121, 1090 cm 1. 1 H NMR (400 MHz, CDCl 3 ) δ (5H, m, ArH), 4.58 (1H, d, J = 11.6 Hz, PhCH x H y O),4.55(1H,d,J=11.6Hz,PhCH x H y O),4.08(1H,q,J=6.8Hz,CHOBn),3.92(1H,brs,OH), 3.70 (3H, s, CO 2 Me), 3.48 (1H, q, J = 7.2 Hz, COCHCH 3 ), 1.36 (3H, s, CCH 3 ), 1.35 (3H, d, J = 6.8 Hz, BnOCHCH 3 ), 1.22 (3H, d,j = 7.2 Hz, COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 ) δ 217.0, 176.5, 137.5, 128.5,127.9,127.8,79.4,76.0,71.4,52.5,46.9,22.8,16.3,10.8.HRMS(+ESI):m/zcalc.forC 16 H 26 NO 5 [M+NH 4 ] + : ;found: (3R,4S,5S)Benzyl5 benzyloxy 2 hydroxy 2,3 dimethyl 4 oxohexanoate(5c). Thereactionwasperformedfrom1(176mg,0.9mmol)accordingtothegeneralproceduretoafford 286mg(84%yield)of5c.Colorlessoil.R f (hexanes/etoac80:20)0.30.hplc(hexanes/etoac85:15) t R =11.1min.[α] 20 D 43.4(c1.05,CHCl 3 ).IR(ATR)ν3499(br),3031,2983,2939,2876,1720,1454, 1369,1244,1118,1090cm 1. 1 H NMR(400MHz,CDCl 3 )δ (10H,m,ArH),5.17(1H,d,J= 12.4Hz,CO 2 CH x H y Ph),5.10(1H,d,J=12.4Hz,CO 2 CH x H y Ph),4.50(2H,s,PhCH 2 O),4.04(1H,q,J=6.8 Hz,CHOBn),3.94(1H,brs,OH),3.49(1H,q,J=7.2Hz,COCHCH 3 ),1.36(3H,s,CCH 3 ),1.26(3H,d,J=6.8 Hz,BnOCHCH 3 ),1.21(3H,d,J=7.2Hz,COCHCH 3 ). 13 CNMR(100.6MHz,CDCl 3 )δ216.6,175.9,137.6, 135.4, 128.5, 128.4, 128.3, 128.2, 127.9, 127.8, 79.2, 75.9, 71.3, 67.1, 46.9, 22.8, 16.1, HRMS (+ESI):m/zcalc.forC 22 H 30 NO 5 [M+NH 4 ] + : ;found: S4

5 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia (3R,4S,5S)Isopropyl5 benzyloxy 2 hydroxy 2,3 dimethyl 4 oxohexanoate(5d). Thereactionwasperformedfrom1(193mg,1.0mmol)accordingtothegeneralproceduretoafford 271mg(84%yield)of5d.Colorlessoil.R f (hexanes/etoac80:20)0.35.hplc(hexanes/etoac90:10) t R =15.4min.[α] 20 D 41.1(c1.0,CHCl 3 ).IR(ATR)ν3506(br),2981,2937,2876,1716,1453,1374, 1253, 1101 cm 1. 1 H NMR (400 MHz, CDCl 3 ) δ (5H, m, ArH), 5.00 (1H, hept, J = 6.4 Hz, CO 2 CH(CH 3 ) 2 ),4.59(1H,d,J=12.0Hz,PhCH x H y O),4.55(1H,d,J=12.0Hz,PhCH x H y O),4.10(1H,q,J= 6.8 Hz, CHOBn), 3.81 (1H, br s, OH), 3.46 (1H, q, J = 7.2 Hz, COCHCH 3 ), 1.35 (3H, d, J = 7.2 Hz, BnOCHCH 3 ),1.34(3H,s,CCH 3 ),1.24(3H,d,J=6.4Hz,CO 2 CHCH 3 ),1.23(3H,d,J=6.4Hz,CO 2 CHCH 3 ), 1.21 (3H, d,j = 7.2 Hz, COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 ) δ 216.2, 175.7, 137.6, 128.4, 127.9, 127.8, 79.2, 75.6, 71.4, 69.2, 47.1, 22.7, 21.6 ( 2), 16.2, HRMS (+ESI): m/z calc. for C 18 H 27 O 5 [M+H] + : ;found: (3R,4S,5S)tert Butyl5 benzyloxy 2 hydroxy 2,3 dimethyl 4 oxohexanoate(5e). Thereactionwasperformedfrom1(193mg,1.0mmol)accordingtothegeneralproceduretoafford 266mg(79%yield)of5e.Colorlessoil.R f (hexanes/etoac85:15)0.30.hplc(hexanes/etoac90:10) t R =11.6min.[α] 20 D 39.5(c1.05,CHCl 3 ).IR(ATR)ν3501(br),2979,2936,2876,1714,1454,1367, 1256, 1122 cm 1. 1 H NMR (400 MHz, CDCl 3 ) δ (5H, m, ArH), 4.58 (1H, d, J = 12.0 Hz, PhCH x H y O),4.56(1H,d,J=12.0Hz,PhCH x H y O),4.11(1H,q,J=6.8Hz,CHOBn),3.72(1H,brs,OH), 3.42(1H,q,J=7.2Hz,COCHCH 3 ),1.45(9H,s,C(CH 3 ) 3 ),1.36(3H,d,J=6.8Hz,BnOCHCH 3 ),1.32(3H,s, CCH 3 ), 1.20 (3H, d,j = 7.2 Hz, COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 )δ215.9, 175.4, 137.7, 128.4, ( 2), 81.9, 79.1, 75.7, 71.4, 47.2, 27.8, 22.8, 16.2, HRMS (+ESI): m/z calc. for C 19 H 32 NO 5 [M+NH 4 ] + : ;found: (3R,4S,5S)Ethyl5 benzyloxy 2 hydroxy 3 methyl 2 (2 phenylethyl) 4 oxohexanoate(5f). Thereactionwasperformedfrom1(193mg,1.0mmol)accordingtothegeneralproceduretoafford 362mg(91%yield)of5f.Colorlessoil.R f (hexanes/etoac90:10)0.15.hplc(hexanes/etoac90:10) t R =13.4min.[α] 20 D 23.8(c1.0,CHCl 3 ).IR(ATR)ν3510(br),3027,2980,2935,2868,1718,1453, 1368,1241,1184,1092,1026cm 1. 1 HNMR(400MHz,CDCl 3 )δ (10H,m,ArH),4.58(1H,d,J S5

6 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia =12.0Hz,PhCH x H y O),4.54(1H,d,J=12.0Hz,PhCH x H y O),4.20(1H,dq,J=10.8,7.2Hz,CO 2 CH x H y CH 3 ), 4.13(1H,dq,J=10.8,7.2Hz,CO 2 CH x H y CH 3 ),4.07(1H,q,J=6.8Hz,CHOBn),3.88(1H,brs,OH),3.50 (1H,q,J=7.2Hz,COCHCH 3 ),2.79(1H,td,J=12.8,4.8Hz,PhCH x H y CH 2 ),2.38(1H,td,J=12.8,4.8Hz, PhCH x H y CH 2 ),2.09(1H,td,J=12.8,4.8Hz,PhCH 2 CH x H y ),1.89(1H,td,J=12.8,4.8Hz,PhCH 2 CH x H y ), 1.34 (3H, d, J = 6.8 Hz, BnOCHCH 3 ), 1.28 (3H, t,j = 7.2 Hz, CO 2 CH 2 CH 3 ), 1.22 (3H, d, J = 7.2 Hz, COCHCH 3 ). 13 C NMR(100.6MHz,CDCl 3 )δ216.1,175.3,141.5,137.6,128.5,128.4( 2),127.9,127.8, 126.0, 79.1, 78.0, 71.4, 61.6, 47.2, 37.8, 29.7, 16.2, 14.3, HRMS (+ESI): m/z calc. for C 24 H 34 NO 5 [M+NH 4 ] + : ;found: (3R,4S,5S)Ethyl5 benzyloxy 2 hydroxy 2 isobutyl 3 methyl 4 oxohexanoate(5g). Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 303mg(86%yield)of5g.Colorlessoil.R f (hexanes/etoac90:10)0.25.hplc(hexanes/etoac90:10) t R =9.1min.[α] 20 D 43.8(c1.0,CHCl 3 ).IR(ATR)ν3513(br),2980,2954,2870,1718,1454,1367, 1224,1157,1026cm 1. 1 HNMR(400MHz,CDCl 3 )δ (5H,m,ArH),4.55(2H,s,PhCH 2 O),4.18 (1H,dq,J=10.8,7.2Hz,CO 2 CH x H y CH 3 ),4.12(1H,dq,J=10.8,7.2Hz,CO 2 CH x H y CH 3 ),4.06(1H,q,J=6.8 Hz, CHOBn), 3.79 (1H, d, J = 1.6 Hz, OH), 3.41 (1H, q, J = 7.2 Hz, COCHCH 3 ), (2H, m, CH x H y CH(CH 3 ) 2 ), (1H,m,CH x H y CH(CH 3 ) 2 ),1.33(3H,d,J=6.8Hz,BnOCHCH 3 ),1.26(3H,t,J= 7.2Hz,CO 2 CH 2 CH 3 ),1.20(3H,d,J=7.2Hz,COCHCH 3 ),0.96(3H,d,J=6.4Hz,CH 2 CH(CH 3 ) 2 ),0.85(3H, d, J= 6.4 Hz, CH 2 CH(CH 3 ) 2 ). 13 C NMR (100.6 MHz, CDCl 3 ) δ 216.3, 175.8, 137.6, 128.4, 127.8, 127.7, 79.3,78.3,71.3,61.4,47.7,44.2,24.1,23.9( 2),16.3,14.1,11.1.HRMS(+ESI):m/zcalc.forC 20 H 31 O 5 [M+H] + : ;found: (3R,4S,5S)Ethyl2 benzyl 5 benzyloxy 2 hydroxy 3 methyl 4 oxohexanoate(5h). Thereactionwasperformedfrom1(193mg,1.0mmol)accordingtothegeneralproceduretoafford 261mg(68%yield)of5h.Colorlessoil.R f (hexanes/etoac90:10)0.20.hplc(hexanes/etoac90:10) t R =13.4min.[α] 20 D 63.0(c1.05,CHCl 3 ).IR(ATR)ν3514(br),3030,2981,2935,1718,1495,1454, 1368,1254,1197,1088,1027cm 1. 1 HNMR(400MHz,CDCl 3 )δ (10H,m,ArH),4.55(2H,s, PhCH 2 O),4.10(1H,q,J=6.8Hz,CHOBn),4.00(1H,dq,J=10.7,7.2Hz,CO 2 CH x H y CH 3 ),3.96(1H,dq,J= 10.7,7.2Hz,CO 2 CH x H y CH 3 ),3.74(1H,brs,OH),3.58(1H,q,J=7.2Hz,COCHCH 3 ),3.12(1H,d,J=13.6 Hz,CCH x H y Ph),2.85(1H,d,J=13.6Hz,CCH x H y Ph),1.35(3H,d,J=7.2Hz,COCHCH 3 ),1.33(3H,d,J=6.8 Hz,BnOCHCH 3 ),1.08(3H,t,J=7.2Hz,CO 2 CH 2 CH 3 ). 13 CNMR(100.6MHz,CDCl 3 )δ215.8,174.5,137.7, 135.4,130.1,128.4,128.0,127.8,127.7,126.9,79.2,79.1,71.3,61.4,47.1,42.3,16.2,13.9,11.2.HRMS S6

7 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia (+ESI):m/zcalc.forC 23 H 32 NO 5 [M+NH 4 ] + : ;found: (3R,4S,5S)Ethyl5 benzyloxy 2 hydroxy 2 isopropyl 3 methyl 4 oxohexanoate(5i). Thereactionwasperformedfrom1(192mg,1.0mmol)accordingtothegeneralproceduretoafford 222 mg (66% yield) of 5i and 47 mg (14% yield) of a second stereoisomer (80% overall yield). Colorlessoil.R f (hexanes/etoac90:10)0.25.hplc(hexanes/etoac95:5)t R =19.1min.[α] 20 D 31.2(c 1.0,CHCl 3 ).IR(ATR)ν3493(br),2973,2938,2879,1717,1454,1370,1298,1238,1151,1098,1020 cm 1. 1 H NMR(400MHz,CDCl 3 )δ (5H,m,ArH),4.61(1H,d,J=12.0Hz,PhCH x H y O),4.46 (1H,d,J=12.0Hz,PhCH x H y O),4.39(1H,dq,J=10.7,7.2Hz,CO 2 CH x H y CH 3 ),4.29(1H,dq,J=10.7,7.2 Hz,CO 2 CH x H y CH 3 ),4.13(1H,q,J=6.8Hz,CHOBn),3.45(1H,q,J=7.2Hz,COCHCH 3 ),3.40(1H,s,OH), 2.12 (1H, hept, J = 6.8 Hz, CH(CH 3 ) 2 ), 1.37 (3H, t, J = 7.2 Hz, CO 2 CH 2 CH 3 ), 1.35 (3H, d, J = 6.8 Hz, BnOCHCH 3 ),1.21(3H,d,J=7.2Hz,COCHCH 3 ),0.96(3H,d,J=6.8Hz,CH(CH 3 ) 2 ),0.77(3H,d,J=6.8Hz, CH(CH 3 ) 2 ). 13 CNMR(100.6MHz,CDCl 3 )δ214.0,175.8,138.0,128.4,127.7( 2),80.5,80.2,71.4,62.1, 46.9, 31.8, 16.6, 16.5, 15.5, 14.1, HRMS (+ESI): m/z calc. for C 19 H 32 NO 5 [M+NH 4 ] + : ; found: (2S,4S,5R)2 Benzyloxy 5 hydroxy 6 methoxy 4,5 dimethyl 3 hexanone(8a). Thereactionwasperformedfrom1(200mg,1.04mmol)accordingtothegeneralproceduretoafford 188mg(0.67mmol,63%yield)of8a.Paleyellowoil.R f (hexanes/etoac70:30)0.45.[α] 20 D+46.6(c 1.1,CHCl 3 ).IR(ATR)ν3489(br),2981,2936,2881,1719,1454,1385,1370,1339,1192,1112cm 1. 1 HNMR(400MHz,CDCl 3 )δ (5H,m,ArH),4.65(1H,d,J=11.8Hz,PhCH x H y O),4.52(1H,d,J= 11.8Hz,PhCH x H y O),4.12(1H,q,J=7.0Hz,CHOBn),3.58(1H,brs,OH),3.31(3H,s,OCH 3 ),3.29(1H,d, J=9.3Hz,CH x H y OCH 3 ),3.23(1H,q,J=7.1Hz,COCHCH 3 ),3.18(1H,d,J=9.3Hz,CH x H y OCH 3 ),1.38(3H, d,j=7.0hz,bnochch 3 ),1.13(3H,s,CCH 3 ),1.08(3H,d,J=7.1Hz,COCHCH 3 ). 13 CNMR(100.6MHz, CDCl 3 )δ216.3,137.9,128.4,127.7( 2),80.6,79.6,74.3,71.6,59.1,44.6,21.0,16.6,12.3.HRMS(+ESI): m/zcalc.forc 16 H 24 NaO 4 [M+Na] + : ;found: S7

8 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia (2S,4S,5R)2,6 Dibenzyloxy 5 hydroxy 4,5 dimethyl 3 hexanone(8b). Thereactionwasperformedfrom1(200mg,1.04mmol)accordingtothegeneralproceduretoafford 328mg(0.92mmol,88%yield)of8b.Paleyellowoil.R f (hexanes/etoac70:30)0.50.[α] 20 D+37.3(c 1.1,CHCl 3 ).IR(ATR)ν3487(br),3031,2979,2937,2865,1720,1454,1397,1370,1337,1210,1101 cm 1. 1 HNMR(400MHz,CDCl 3 )δ (10H,m,ArH),4.61(1H,d,J=11.8Hz,PhCH x H y O),4.52 (1H,d,J=12.1Hz,PhCH a H b O),4.48(1H,d,J=11.8Hz,PhCH x H y O),4.47(1H,d,J=12.1Hz,PhCH a H b O), 4.11(1H,q,J=6.9Hz,CHOBn),3.59(1H,brs,OH),3.37(1H,d,J=9.3Hz,CH x H y OBn),3.35(1H,q,J= 7.1Hz,COCHCH 3 ),3.26(1H,d,J=9.3Hz,CH x H y OBn),1.36(3H,d,J=6.9Hz,BnOCHCH 3 ),1.14(3H,s, CCH 3 ), 1.05 (3H, d,j = 7.1 Hz, COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 )δ 216.3, 137.9, 128.4, 127.7, 127.6, 80.6, 76.8, 74.4, 73.4, 71.6, 44.7, 20.9, 16.5, HRMS (+ESI): m/z calc. for C 22 H 28 NaO 4 [M+Na] + : ;found: (2S,4S,5S)2,7 Dibenzyloxy 5 hydroxy 4,5 dimethyl 3 heptanone(8c). Thereactionwasperformedfrom1(190mg,1.0mmol)accordingtothegeneralproceduretoafford 299mg(dr92:8,80%yield)of8c.Colorlessoil.R f (hexanes/etoac80:20)0.45.[α] 20 D+39.1(c1.0, CHCl 3 ).IR (ATR)ν 3485 (br),2974, 2930, 2867, 1720, 1453, 1366, 1090, 1027 cm 1. 1 H NMR (400 MHz,CDCl)δ (10H,m,ArH),4.63(1H,d,J=11.8Hz,PhCH x H y O),4.50(1H,d,J=11.6Hz, PhCH a H b O),4.46(1H,d,J=11.8Hz,PhCH x H y O),4.46(1H,d,J=11.6Hz,PhCH a H b O),4.19(1H,q,J=7.0 Hz, CHOBn), (2H, m, CH 2 OBn), 3.10 (1H, q, J = 7.0 Hz, COCHCH 3 ), (2H, m, CH 2 CH 2 OBn),1.31(3H,d,J=7.0Hz,BnOCHCH 3 ),1.18(3H,s,CCH 3 ),1.04(3H,d,J=7.0Hz,COCHCH 3 ). 13 C NMR (100.6 MHz, CDCl 3 ) δ 215.6, 138.1, 137.7, 128.5, 128.3, ( 2), 127.6, 80.8, 74.7, 73.5, 71.5,67.0,48.6,39.6,22.7,16.6,12.7.HRMS(+ESI):m/zcalc.forC 23 H 31 O 4 [M+H] + : ;found: (2S,4S,5R)2 Benzyloxy 6 tert butyldimethylsilyloxy 5 hydroxy 4,5 dimethyl 3 hexanone(8d). Thereactionwasperformedfrom1(200mg,1.04mmol)accordingtothegeneralproceduretoafford 306mg(0.80mmol,77%yield)of8d.Colorlessoil.R f (hexanes/etoac90:10)0.35.[α] 20 D+51.1(c1.0, CHCl 3 ).IR (ATR)ν3493(br),2952,2928,2856,1710,1454,1362,1251,1089,1006cm 1. 1 H NMR (400MHz,CDCl)δ (5H,m,ArH),4.65(1H,d,J=11.8Hz,PhCH x H y O),4.50(1H,d,J=11.8Hz, S8

9 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia PhCH x H y O),4.15(1H,q,J=7.0Hz,CHOBn),3.48(1H,d,J=9.9Hz,CH x H y OTBS),3.35(1H,d,J=9.9Hz, CH x H y OTBS),3.34(1H,q,J=7.1Hz,COCHCH 3 ),1.37(3H,d,J=7.0Hz,BnOCHCH 3 ),1.11(3H,s,CCH 3 ), 1.04(3H,d,J=7.1Hz,COCHCH 3 ),0.90(9H,s,SiC(CH 3 ) 3 ),0.07(3H,s,SiCH 3 ),0.05(3H,s,SiCH 3 ). 13 C NMR(100.6MHz,CDCl 3 )δ216.1,138.0,128.4,127.7,80.9,74.7,71.5,69.3,44.3,25.8,20.1,18.2,16.6, 12.3, 5.4, 5.5.HRMS(+ESI):m/zcalc.forC 21 H 40 NO 4 Si[M+NH 4 ] + : ;found: Proofofstereochemistry 4.1.Aldoladductsfromα ketoesters Amixtureofaldol5a(927mg,3mmol)and10%Pd/C(800mg)inEtOH(20mL)isstirredatroom temperatureunderah 2 atmospherefor3h.thereactionmixtureisfilteredthroughapadofcelite (CH 2 Cl 2 )andthevolatilesareremovedinvacuotoprovide656mg(3mmol,quantitative)ofethyl2,5 dihydroxy 2,3 dimethyl 4 oxohexanoate as a colorless oil. IR (ATR) ν 3458 (br), 2982, 2940, 1710, 1248,1125,1106cm 1. 1 HNMR(400MHz,CDCl 3 )δ4.35(1h,qd,j=7.2,5.2hz,choh),4.20(2h,q,j= 7.2Hz,CO 2 CH 2 CH 3 ),3.74(1H,s,OH),3.27(1H,d,J=5.2Hz,OH),3.23(1H,q,J=7.2Hz,COCHCH 3 ),1.41 (3H,d,J=7.2Hz,HOCHCH 3 ),1.39(3H,s,CCH 3 ),1.28(3H,t,J=7.2Hz,CO 2 CH 2 CH 3 ),1.24(3H,d,J=7.2 Hz,CHCH 3 ). 13 CNMR(100.6MHz,CDCl 3 )δ ,76.1,73.4,61.9,46.6,22.5,19.2,14.0,11.2. AsolutionofthismaterialandCSA(71mg,0.3mmol)inCH 2 Cl 2 (15mL)isstirredatroomtemperature undern 2 foraweek.itiswashedwithsatnahco 3,dried(Na 2 SO 4 )andconcentrated.theresultantoil is purified by flash column chromatography (hexanes/etoac 60:40) to give 172 mg (1 mmol, 33% overall yield) of 3 hydroxy 3,4,6 trimehtyldihydro 2H pyran 2,5(6H)dione (6) as a white solid. Mp C. R f (hexanes/etoac 60:40) [α] 20 D (c 1.0, CHCl 3 ). IR (ATR) ν 3423 (br), 2992, 2943,1725,1367,1245,1104cm 1. 1 H NMR(400MHz,CDCl 3 )δ4.89(1h,q,j=6.8hz,co 2 CHCH 3 ), 3.16 (1H, s, OH), 2.82 (1H, q, J = 7.2 Hz, COCHCH 3 ), 1.61 (1H, d, J = 6.8 Hz, CO 2 CHCH 3 ), 1.52 (3H, s, CCH 3 ),1.23(3H,d,J=7.2Hz,COCHCH 3 ). 13 CNMR(100.6MHz,CDCl 3 )δ207.0,173.2,81.4,72.0,50.7, 24.6,19.1,10.6.MS(+ESI):m/zcalc.forC 8 H 8 O 3 [M+H] + :153.06;found: Theabsoluteconfigurationof6wasestablishedbyX rayanalysis.seenextortepfigure. S9

10 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia 4.2.Aldoladductsfromhydroxyketones Amixtureofaldol8c(56mg,0.15mmol)and10%Pd/C(43mg)inEtOH(5mL)isstirredunderaH 2 atmosphere at room temperature for 3 h. The reaction mixture is filtered through a pad of Celite (CH 2 Cl 2 )andthevolatilesareremovedinvacuotoprovideathickoilthatispurifiedbyflashcolumn chromatography (CH 2 Cl 2 /MeOH 95:5) to give 28 mg (0.15 mmol, 97% yield) of (2S,3S,4S) 2 ((S) 1 hydroxyethyl) 3,4 dimethyltetrahydro 2H pyran 2,4 diol (9) as a white solid. Mp C. R f (CH 2 Cl 2 /MeOH 95:5) [α] 20 D 27.1 (c 1.0, CHCl 3 ). IR (ATR) ν 3390 (br), 3252 (br), 2963, 2939, 2888,1459,1361,1299,1173,1139,1111,1087,1034cm 1. 1 HNMR(400MHz,CDCl 3 )δ5.03(1h,s, OH),4.14(1H,ddd,J=13.1,12.0,2.5Hz,OCH x H y ),3.80(1H,dq,J=8.8,6.4Hz,CH 3 CHOH),3.70(1H, ddd,j=12.0,5.5,1.2hz,och x H y ),2.34(1H,s,CCH 3 OH),2.03(1H,d,J=8.8Hz,CH 3 CHOH),1.99(1H,q,J =7.1Hz,OC(OH)CHCH 3 ),1.79(1H,td,J=13.1,5.5Hz,OCCH 2 CH x H y ), (1H,m,OCCH 2 CH x H y ), 1.27(3H,s,CCH 3 ),1.22(3H,d,J=6.4Hz,CH 3 CHOH),1.09(3H,d,J=7.1Hz,OC(OH)CHCH 3 ). 13 CNMR (100.6 MHz, CDCl 3 ) δ 99.6, 72.0, 69.9, 56.3, 40.1, 39.4, 28.7, 15.9, 8.3. HRMS (+ESI): m/z calc. for C 9 H 18 NaO 4 [M+Na] + : ;found: Analysesof1Dand2D NMRspectraareconsistentwithasinglechairconformer(seenextpage). S10

11 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S11

12 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia 5. 1 Hand 13 CNMRSpectraofAldolAdducts S12

13 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S13

14 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S14

15 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S15

16 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S16

17 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S17

18 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S18

19 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S19

20 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S20

21 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S21

22 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S22

23 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S23

24 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S24

25 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S25

26 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S26

27 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S27

28 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S28

29 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S29

30 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S30

31 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S31

32 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S32

33 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S33

34 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S34

35 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S35

36 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S36

37 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S37

38 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S38

39 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S39

40 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S40

41 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S41

42 StereoselectiveTitanium MediatedAldolReactionsofaChiralLactate DerivedEthylKetonewithKetones SandraAlcoberro,AlejandroGómez Palomino,RicardSolà,PedroRomea,FèlixUrpí,andMercèFont Bardia S42