howard hughes medical institute - wiley-vch · added n-buli (73 mmol, 2.5m in hexanes). the...

Supporting Information

for

Angew. Chem. Int. Ed. Z19567

© Wiley-VCH 200269451 Weinheim, Germany

Micalizio and Schreiber S1

An Alkynylboronic Ester Annulation: Development ofSynthetic Methods For Application to Diversity-

Oriented Organic Synthesis

Glenn C. Micalizio and Stuart L. Schreiber

Angew. Chem.

Howard Hughes Medical InstituteHarvard Institute of Chemistry and Cell Biology (ICCB)

Department of Chemistry and Chemical Biology,Harvard University, Cambridge, Massachusetts 02138

Supporting Information

Materials and Methods. Except as otherwise noted, reactions were carried out undernitrogen with dry, freshly purified solvents. Solvents were purified by passage through asolvent column prior to use.1 NMR spectra were recorded at either 500 MHz or 300MHz using a Varian I-500 or a Varian M-300 instrument respectively. 1H NMRchemical shifts are reported relative to residual CHCl3 (7.26 ppm). 13C NMR data wererecorded at 125 MHz using a Varian I-500 instrument. 13C chemical shifts are reportedrelative to the central line of CDCl3 (77.0 ppm). 11B NMR data were recorded at 96 MHzusing a Varian M-300 instrument. Infrared spectra were recorded using a Nicolet 5PCFT-IR spectrometer (thin film). Mass spectra were obtained with JEOL AX 505, JEOLSX-102 and Micromass ESI-LCT spectrometers.

1 The solvent columns are composed of activated alumina (A-2) and supported copper redox catalyst (Q-5reactant). See: Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.Organometallics 1996, 15, 1518.


32 9

Me MeB

i PrO

i PrO

i) n-BuLi, Et2Oii) (iPrO)3B

iii) HCl 68%

(1-Pentyn-1-yl)diisopropoxyborane (9): To a –78 °C solution of 1-pentyne (32)(5.55 g, 81.4 mmol) in 35 mL of anhydrous diethyl ether was dropwise added n-BuLi (81mmol, 2.5M in hexanes). The solution was stirred at –78 °C for 30 min, after which timethe solution was transferred via cannula to a –78 °C solution of triisopropylborate (18.7mL, 81 mmol) in diethyl ether (180 mL). The resulting heterogeneous solution was thenwarmed to rt over ca. 1 h. The solution was cooled to –78 °C and HCl was addeddropwise via syringe (35 mL of a 2M solution in diethyl ether). The solution waswarmed to rt, then diethyl ether was removed via distillation, following which,distillation at reduced pressure afforded 9.36 g (68%) of the desired alkynylboronic ester9: 1H NMR (500 MHz, CDCl3/CD3OD (3/1)) δ 3.82 (m, 2 H), 2.10 (t, J = 7.1 Hz, 2 H),1.41 (tq, J = 7.3, 7.2 Hz, 2 H), 1.00 (d, J = 5.9 Hz, 12 H), 0.84 (t, J = 6.3 Hz, 3 H); 13CNMR (125 MHz, CDCl3/CD3OD (3/1)) δ 63.5, 24.4, 21.5, 21.0, 12.9; 11B NMR (96MHz, CDCl3/CD3OD (3/1)) δ 22.2.

33 10

Bi PrO

i PrO


iii) HCl 25%Ph Ph

(5-Phenyl-1-pentyn-1-yl)diisopropoxyborane (10): To a –78 °C solution of 5-phenyl-1-pentyne (33) (9.49 g, 65.8 mmol) in 50 mL of anhydrous diethyl ether wasdropwise added n-BuLi (65.8 mmol, 2.5M in hexanes). The solution was stirred at –78°C for 30 min, after which time the solution was transferred via cannula to a –78 °Csolution of triisopropylborate (15 mL, 66 mmol) in diethyl ether (75 mL). The resultingheterogeneous solution was warmed to –20 °C, then HCl was added dropwise via syringe(64 mmol, 2M solution in diethyl ether). The solution was warmed to rt, then diethylether was removed via distillation, following which, distillation at reduced pressureafforded 4.3 g (25%) of the desired alkynylboronic ester 10: 1H NMR (500 MHz,CDCl3/CD3OD (3/1)) δ 7.13-7.02 (m, 5 H), 3.83-3.78 (m, 2 H), 2.58 (t, J = 7.6 Hz, 2 H),2.14 (t, J = 7.1 Hz, 2 H), 1.71 (tt, J = 7.6, 7.1 Hz, 2 H), 1.01 (d, J = 6.3 Hz, 12 H); 13CNMR (125 MHz, CDCl3/CD3OD (3/1)) δ 141.0, 128.2, 128.1, 125.6, 63.5, 34.3, 29.7,24.4, 18.4; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 22.3.

34 11

Me MeB

i PrO

i PrO


iii) HCl 72%

Me Me

(3-Methyl-1-butyn-1-yl)diisopropoxyborane (11): To a –78 °C solution of 3-methyl-1-butyne (34) (5.0 g, 73 mmol) in 50 mL of anhydrous diethyl ether was dropwiseadded n-BuLi (73 mmol, 2.5M in hexanes). The solution was stirred at –78 °C for 30min, after which time the solution was transferred via cannula to a –78 °C solution of


triisopropylborate (17 mL, 74 mmol) in diethyl ether (160 mL). The reaction vessel wasthen removed from the –78 °C and stirred for ca 3 h, after which time the solution wasrecooled to –78 °C and HCl was added dropwise via syringe (72 mmol, 2M solution indiethyl ether). The solution was warmed to rt, then diethyl ether was removed viadistillation, following which, distillation at reduced pressure afforded 10.1 g (72%) of thedesired alkynylboronic ester 11: 1H NMR (500 MHz, CDCl3/CD3OD (3/1)) δ 3.79 (sept,J = 6.2, Hz, 2 H), 2.48 (sept, J = 6.8 Hz, 1 H), 1.04 (d, J = 6.8 Hz, 6 H), 1.00 (d, J = 5.9Hz, 12 H); 13C NMR (125 MHz, CDCl3/CD3OD (3/1)) δ 63.5, 24.4, 22.2, 20.8; 11B NMR(96 MHz, CDCl3/CD3OD (3/1)) δ 22.4.

35 19

Bi PrO

i PrO


iii) HCl

O O

(3-Allyloxy-1-propyn-1-yl)diisopropoxyborane (19): To a –78 °C solution ofthe allyl propargyl ether 35 (2.05 g, 21.3 mmol) in 25 mL of anhydrous diethyl ether wasdropwise added n-BuLi (21 mmol, 2.5M in hexanes). The solution was stirred at –78 °Cfor 30 min, after which time the solution was transferred via cannula to a –78 °C solutionof triisopropylborate (4.9 mL, 21 mmol) in diethyl ether (25 mL). The solution wasstirred at –78 °C for 30 min, the solution was then slowly warmed to rt, and stirred atambient temperature for ca. 1 h. The solution was cooled to –78 °C and HCl was addeddropwise via syringe (21 mmol, 2M solution in diethyl ether). The solution was warmedto rt, then diethyl ether was removed via distillation, following which, distillation atreduced pressure afforded ca. 3 mL of the desired alkynylboronic ester 19: 1H NMR (500MHz, CDCl3/CD3OD (3/1)) δ 5.77-5.69 (m, 1 H), 5.15 (dd, J = 17.1, 1.0 Hz, 1 H), 5.06(dd, J = 10.3, 1.0 Hz, 1 H), 4.07 (s, 2 H), 3.93 (d, J = 5.9 Hz, 2 H), 3.82-3.77 (m, 2 H),1.00 (d, J = 6.3 Hz, 12 H); 13C NMR (125 MHz, CDCl3/CD3OD (3/1))δ 133.2, 117.8, 70.4, 63.5, 57.1, 24.4; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 22.1.

8 12

BnOOH

BnOO

BMeOH

9 MeB

i PrO

i PrO

RuPhH

ClCl

PCy3

NN MesMes

7

PhH, 65 °C65%

2-Hydroxy-3-(1’-penten-2’-yl)-6-benzyloxymethyl-3,4-dihydro-1,2-oxaborole(12): To the homoallylic alcohol 8 (130 mg, 0.676 mmol) was added the alkynylboronicester 9 (299 mg, 1.52 mmol) via syringe. The mixture was diluted with benzene (10 mL),then the Grubbs’ catalyst (7) (68 mg, 0.08 mmol, 12 mol%) was added. The vessel waspurged with argon, then heated at 65 °C under nitrogen for 18h. The crude reactionmixture was directly purified by flash column chromatography [120 g SiO2; eluted with0.67% CH3OH in CH2Cl2 (500 mL), then 1.0% CH3OH in CH2Cl2 (500 mL)] to afford


134 mg (69%) of the cyclic dialkenylboronic acid 12: 1H NMR (500 MHz,CDCl3/CD3OD (3/1)) δ 7.21-7.12 (m, 5 H), 6.47 (dd, J = 4.4, 4.4 Hz, 1 H), 4.97 (d, J =2.4 Hz, 1 H), 4.69 (s, 1 H), 4.47 (s, 2 H), 4.12-4.06 (m, 1 H), 3.48-3.40 (m, 2 H), 2.21-2.13 (m, 2 H), 2.08-2.01 (m, 2 H), 1.28-1.20 (m, 2 H), 0.73 (t, J = 7.3 Hz, 3 H); 13C NMR(125 MHz, CDCl3/CD3OD (3/1)) δ 148.7, 140.4, 137.7, 128.1, 127.40, 127.37, 111.6,73.1, 72.8, 71.8, 36.7, 30.0, 21.0, 13.4; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 26.5;IR (thin film from CDCl3/CD3OD (3/1)) 3403, 3064, 3029, 2956, 2929, 2869, 1612,1496, 1453, 1391, 1313, 1248, 1207, 1098, 1028 cm–1; LRMS (ApCI) calcd forC17H24BO3, 287.2 (M+H)+; observed 287.1 m/z.

8 13

BnOOH

BnOO

BOH

10B

i PrO

i PrO

RuPhH

ClCl

PCy3

NN MesMes

7

PhH, 65 °C66%

Ph

Ph

2-Hydroxy-3-(5’-phenyl-1’-penten-2’-yl)-6-benzyloxymethyl-3,4-dihydro-1,2-oxaborole (13): To the homoallylic alcohol 8 (100 mg, 0.520 mmol) was added thealkynylboronic ester 10 (350 mg, 1.10 mmol) via syringe. The mixture was diluted withbenzene (10 mL), then the Grubbs’ catalyst (7) (66 mg, 0.08 mmol, 15 mol%) was added.The vessel was purged with argon, then heated at 65 °C under nitrogen for 28h. Thecrude reaction mixture was then directly purified by flash column chromatography [120 gSiO2; eluted with 1.0% CH3OH in CH2Cl2 (500 mL), then 1.5% CH3OH in CH2Cl2 (500mL)] to afford 125 mg (66%) of the cyclic dialkenylboronic acid 13: 1H NMR (500MHz, CDCl3/CD3OD (3/1)) δ 7.23-7.00 (m, 10 H), 6.45 (dd, J = 4.4, 4.4 Hz, 1 H), 5.00(d, J = 2.4 Hz, 1 H), 4.72 (s, 1 H), 4.47 (s, 2 H), 4.12-4.07 (m, 1 H), 3.48-3.41 (m, 2 H),2.48-2.42 (m, 2 H), 2.21-2.13 (m, 4 H), 1.59-1.53 (m, 2 H); 13C NMR (125 MHz,CDCl3/CD3OD (3/1)) δ 148.5, 142.3, 140.6, 137.7, 128.07, 128.05, 127.8, 127.4, 127.3,125.2, 111.8, 73.0, 72.8, 71.8, 35.1, 34.1, 30.0, 29.7; 11B NMR (96 MHz, CDCl3/CD3OD(3/1)) δ 26.4; IR (thin film from CDCl3/CD3OD (3/1)) 3403, 3084, 3062, 3026, 2932,2860, 1947, 1873, 1806, 1611, 1496, 1453, 1391, 1320, 1246, 1206, 1093, 1028 cm–1;LRMS (ApCI) calcd for C23H28BO3, 363.2 (M+H)+; observed 363.2 m/z.

8 14

BnOOH

BnOO

BHO

11 MeB

i PrO

i PrO

RuPhH

ClCl

PCy3

NN MesMes

7

PhH, 65 °C73%

Me Me

Me


2-Hydroxy-3-(3’-methyl-1’-buten-2’-yl)-6-benzyloxymethyl-3,4-dihydro-1,2-oxaborole (14): To the homoallylic alcohol 8 (131 mg, 0.681 mmol) was added thealkynylboronic ester 11 (299 mg, 1.52 mmol) via syringe. The mixture was diluted withbenzene (10 mL), then the Grubbs’ catalyst (7) (68 mg, 0.08 mmol, 12 mol%) was added.The vessel was purged with argon, then heated at 65 °C under nitrogen for 18h. Thecrude reaction mixture was then directly purified by flash column chromatography [120 gSiO2; eluted with 0.67% CH3OH in CH2Cl2 (500 mL), then 1.0% CH3OH in CH2Cl2 (500mL)] to afford 142 mg (73%) of the cyclic dialkenylboronic acid 14: 1H NMR (500MHz, CDCl3/CD3OD (3/1)) δ 7.21-7.11 (m, 5 H), 6.40 (dd, J = 4.2, 4.2 Hz, 1 H), 4.74 (d,J = 2.0 Hz, 1 H), 4.62 (dd, J = 1.7, 1.7 Hz, 1 H), 4.46 (s, 2 H), 4.13-4.08 (m, 1 H), 3.47-3.40 (m, 2 H), 2.45-2.39 (m, 1 H), 2.20-2.11 (m, 2 H), 0.85 (d, J = 6.3 Hz, 3 H), 0.81 (d,J = 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3/CD3OD (3/1)) δ 156.3, 140.6, 137.7,128.1, 127.42, 127.39, 107.5, 73.1, 72.8, 72.0, 31.0, 30.0, 21.6, 21.2; 11B NMR (96 MHz,CDCl3/CD3OD (3/1)) δ 26.4; IR (thin film from CDCl3/CD3OD (3/1)) 3404, 3087, 3030,2959, 2927, 2869, 1611, 1496, 1454, 1384, 1320, 1229, 1094, 1028 cm–1; LRMS (TOFMS ES+) calcd for C17H24BO3, 287.2 (M+H)+; observed 287.2 m/z.

15 16

Ph

OH

Ph

OBOH

9B

i PrO

i PrO

RuPhH

ClCl

PCy3

NN MesMes

7

PhH, 65 °C72%

Me

Me

2-Hydroxy-3-(1’-penten-2’-yl)-6-phenyl-3,4-dihydro-1,2-oxaborole (16): Tothe homoallylic alcohol 15 (116 mg, 0.783 mmol) was added the alkynylboronic ester 9(322 mg, 1.64 mmol) via syringe. The mixture was diluted with benzene (10 mL), thenthe Grubbs’ catalyst (7) (75 mg, 0.09 mmol, 11 mol%) was added. The vessel waspurged with argon, then heated at 65 °C under nitrogen for 23h. The crude reactionmixture was then directly purified by flash column chromatography [120 g SiO2; elutedwith 0.25 % CH3OH in CH2Cl2 (1 L)] to afford 136 mg (72%) of the cyclicdialkenylboronic acid 16: 1H NMR (500 MHz, CDCl3/CD3OD (3/1)) δ 7.27-7.12 (m, 5H), 6.55 (dd, J = 5.9, 2.4 Hz, 1 H), 5.07 (d, 2.0 Hz, 1 H), 4.94 (dd, J = 11.7, 3.9 Hz, 1 H),4.74 (s, 1 H), 2.40 (ddd, J = 17.6, 5.9, 3.9 Hz, 1 H), 2.27 (ddd, J = 17.7, 12.2, 2.4 Hz, 1H), 2.15-2.05 (m, 2 H), 1.34-1.24 (m, 2 H), 0.76 (t, J = 7.3 Hz, 3 H); 13C NMR (125MHz, CDCl3/CD3OD (3/1)) δ 148.5, 142.7, 140.8, 128.0, 127.0, 125.1, 112.0, 74.6, 36.6,36.4, 21.1, 13.5; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 26.7; IR (thin film fromCDCl3/CD3OD (3/1)) 3065, 3029, 2957, 2930, 2871, 1613, 1495, 1453, 1391, 1319,1305, 1243, 1180, 1114, 1072, 1052, 1029 cm–1; HRMS (TOF MS ES+) calcd forC15H20BO2, 243.1556 (M+H)+; observed 243.1548 m/z.


15 17

Ph

OH

Ph

OB

HO

11 MeB

i PrO

i PrO

RuPhH

ClCl

PCy 3

NN MesMes

7

PhH, 65 °C72%

Me

Me

Me

2-Hydroxy-3-(3’-methyl-1’-buten-2’-yl)-6-phenyl-3,4-dihydro-1,2-oxaborole(17): To the homoallylic alcohol 15 (116 mg, 0.783 mmol) was added the alkynylboronicester 11 (322 mg, 1.64 mmol) via syringe. The mixture was diluted with benzene (10mL), then the Grubbs’ catalyst (7) (76 mg, 0.09 mmol, 11 mol%) was added. The vesselwas purged with argon, then heated at 65 °C under nitrogen for 23h. The crude reactionmixture was then directly purified by flash column chromatography [120 g SiO2; elutedwith 0.25 % CH3OH in CH2Cl2 (1 L)] to afford 136 mg (72%) of the cyclicdialkenylboronic acid 17: 1H NMR (500 MHz, CDCl3/CD3OD (3/1)) δ 7.27-7.12 (m, 5H), 6.50 (dd, J = 6.1, 2.2 Hz, 1 H), 4.96 (dd, J = 11.7, 3.9 Hz, 1 H), 4.85 (d, J = 1.5 Hz, 1H), 4.69 (s, 1 H), 2.54-2.46 (m, 1 H), 2.40 (ddd, J = 17.6, 5.9, 3.9 Hz, 1 H), 2.27 (ddd, J =17.6, 11.7, 2.4 Hz, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H); 13C NMR(125 MHz, CDCl3/CD3OD (3/1)) δ 156.1, 142.7, 141.0, 128.0, 127.0, 125.1, 107.8, 74.7,36.3, 30.9, 21.7, 21.3; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 26.6; IR (thin filmfrom CDCl3/CD3OD (3/1)) 3433, 3087, 3064, 3030, 2960, 2928, 2871, 1605, 1495, 1454,1383, 1320, 1306, 1258, 1230, 1180, 1156, 1097, 1073, 1052, 1029 cm–1; HRMS (TOFMS ES+) calcd for C15H20BO2, 243.1556 (M+H)+; observed 243.1547 m/z.

15 20Ph

OH

Ph

OB

HO

19 OB

i PrO

i PrO

RuPhH

Cl

Cl

PCy3

NN MesMes

7

PhH, 65 °C66%

O

2-Hydroxy-3-(3’,4’-dihydrofuran-3’-yl)-6-phenyl-3,4-dihydro-1,2-oxaborole(20): To the homoallylic alcohol 15 (112 mg, 0.756 mmol) was added the alkynylboronicester 19 (255 mg, 1.14 mmol) via syringe. The mixture was diluted with benzene (10mL), then the Grubbs’ catalyst (7) (75 mg, 0.09 mmol, 12 mol%) was added. The vesselwas purged with argon, then heated at 65 °C under nitrogen for 22h. The crude reactionmixture was then directly purified by flash column chromatography [120 g SiO2; elutedwith 0.25 % CH3OH in CH2Cl2 (1 L), then 0.5% CH3OH in CH2Cl2 (500 mL), then 1.0%CH3OH in CH2Cl2 (500 mL), then 1.5% CH3OH in CH2Cl2 (500 mL)] to afford 121 mg(66%) of the bicyclic dialkenylboronic acid 20: 1H NMR (500 MHz, CDCl3/CD3OD(3/1)) δ 7.26-7.12 (m, 5 H), 6.31-6.30 (m, 1 H), 6.18 (s, 1 H), 4.96 (dd, J = 11.7, 3.9 Hz,1 H), 4.64-4.60 (m, 4 H), 2.43 (ddd, J = 18.1, 5.9, 4.4 Hz, 1 H), 2.35-2.29 (m, 1 H); 13C


NMR (125 MHz, CDCl3/CD3OD (3/1)) δ 142.8, 142.3, 137.4, 128.4, 127.5, 125.5, 123.7,76.8, 75.1, 74.9, 36.6; 11B NMR (96 MHz, CDCl3/CD3OD (3/1)) δ 26.2; IR (thin filmfrom CDCl3/CD3OD (3/1)) 3269, 2929, 2872, 2845, 1630, 1604, 1584, 1495, 1468, 1442,1416, 1383, 1362, 1325, 1313, 1273, 1222, 1202, 1139, 1115, 1061 cm–1; HRMS (TOFMS ES+) calcd for C14H16BO3, 243.1192 (M+H)+; observed 243.1199 m/z.

18 21

OH OB

HO

19 OB

i PrO

i PrO

RuPhH

Cl

Cl

PCy3

NN MesMes

7

PhH, 65 °C67%

O

TIPSO TIPSO

2-Hydroxy-3-(3’,4’-dihydrofuran-3’-yl)-6-triisopropylsilanyloxymethyl-3,4-dihydro-1,2-oxaborole (21): To the homoallylic alcohol 18 (128 mg, 0.495 mmol) wasadded the alkynylboronic ester 19 (171 mg, 0.763 mmol) via syringe. The mixture wasdiluted with benzene (7 mL), then the Grubbs’ catalyst (7) (62 mg, 0.07 mmol, 14 mol%)was added. The vessel was purged with argon, then heated at 65 °C under nitrogen for22h. The crude reaction mixture was then directly purified by flash columnchromatography [120 g SiO2; eluted with 0.5 % CH3OH in CH2Cl2 (1 L), then 1.0%CH3OH in CH2Cl2 (750 mL)] to afford 117 mg (67%) of the bicyclic dialkenylboronicacid 21: 1H NMR (500 MHz, CDCl3/CD3OD (3/1)) δ 6.25 (dd, J = 4.4, 4.4 Hz, 1 H),6.10 (s, 1 H), 4.60-4.56 (m, 4 H), 3.99-3.94 (m, 1 H), 3.66 (dd, J = 9.8, 4.9 Hz, 1 H), 3.58(dd, J = 10.0, 6.1 Hz, 1 H), 2.26 (m, 2 H), 0.99-0.77 (m, 21 H); 13C NMR (125 MHz,CDCl3/CD3OD (3/1)) δ 142.1, 137.2, 122.8, 76.4, 74.8, 73.2, 66.1, 29.8, 17.5, 11.6; 11BNMR (96 MHz, CDCl3/CD3OD (3/1)) δ 26.2; IR (thin film from CDCl3/CD3OD (3/1))3329, 2942, 2891, 2866, 2077, 1779, 1751, 1671, 1629, 1587, 1463, 1411, 1398, 1356,1338, 1310, 1257, 1216, 1193, 1134, 1105, 1070, 1012 cm–1; HRMS (TOF MS ES+)calcd for C18H34BO4Si, 353.2319 (M+H)+; observed 353.2315 m/z.

12

BnOO

BMeOH i) H2O2, NaOH, THF

ii) Ac2O, DMAP, Et3N CH2Cl2 69%

22

BnOOAc

MeO

1-Benzyloxy-2-acetoxy-6-propyl-6-hepten-5-one (22): To a rt solution of thedialkenylboronic acid 12 (151 mg, 0.528 mmol) in THF (5 mL) was simultaneouslyadded H2O2 (300 µL, 30% in H2O) and NaOH (1 mL, 1N). The solution was stirred for 5min, then more H2O2 (300 µL) and NaOH (1 mL, 1N) were added and the solution wasstirred an additional 15 min. The solution was then diluted with CH2Cl2 and washed withNaHCO3 (sat), dried over Na2SO4, then concentrated to ca. 10mL. To this solution wasadded DMAP (13 mg, 0.11 mmol), then triethylamine (1 mL) and acetic anhydride (560µL, 5.9 mmol) were added simultaneously via syringe. The solution was stirred at rt for30 min, then diluted with ethyl acetate and washed successively with NaHCO3 (sat) 2X,


then brine. The organic layer was dried over Na2SO4, filtered and concentrated to afforda crude oil which was purified by flash column chromatography [120 g SiO2; eluted with18 : 1 hexanes : EtOAc (1 L), then 13 : 1 hexanes : EtOAc (500 mL), then 9 : 1 hexanes :EtOAc (1 L)] to afford 116 mg (69%) of the γ-acetoxy enone 22: 1H NMR (500 MHz,CDCl3) δ 7.35-7.27 (m, 5 H), 5.94 (s, 1 H), 5.70 (s, 1 H), 5.09-5.05 (m, 1 H), 4.57 (A ofAB, J = 12.2 Hz, 1 H), 4.50 (B of AB, J = 12.2 Hz, 1 H), 3.55-3.50 (m, 2 H), 2.71 (app t,J = 7.6 Hz, 2 H), 2.23 (app t, J = 7.6 Hz, 2 H), 2.06 (s, 3 H), 2.03-1.88 (m, 2 H), 1.45-1.38 (m, 2 H), 0.90 (t, J = 7.6 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 200.7, 170.7,148.6, 137.9, 128.4, 127.7, 127.6, 123.8, 73.1, 72.0, 71.0, 33.4, 32.9, 25.6, 21.5, 21.1,13.8; IR (thin film from CDCl3) 3064, 3030, 2960, 2932, 2871, 1738, 1678, 1626, 1496,1454, 1414, 1373, 1240, 1098, 1047, 1028 cm–1; HRMS (TOF MS ES+) calcd forC19H27O4, 319.1909 (M+H)+; observed 319.1901 m/z.

14

BnOO

B

MeHO i) H2O2, NaOH, THF

ii) Ac2O, DMAP, Et3N CH2Cl2 76%

23

BnOOAc

Me

O

Me

Me

1-Benzyloxy-2-acetoxy-6-isopropyl-6-hepten-5-one (23): To a rt solution of thedialkenylboronic acid 14 (111 mg, 0.388 mmol) in THF (5 mL) was simultaneouslyadded H2O2 (500 µL, 30% in H2O) and NaOH (1 mL, 1N). The solution was stirred for10 min, then was diluted with CH2Cl2 and washed with NaHCO3 (sat), dried overNa2SO4, then concentrated to ca. 10mL. To this solution was added DMAP (12 mg, 0.10mmol), then triethylamine (1 mL) and acetic anhydride (560 µL, 5.9 mmol) were addedsimultaneously via syringe. The solution was stirred at rt for 1 h, then diluted with ethylacetate and washed successively with NaHCO3 (sat) 2X, then brine. The organic layerwas dried over Na2SO4, filtered and concentrated to afford a crude oil which was purifiedby flash column chromatography [120 g SiO2; eluted with 18 : 1 hexanes : EtOAc (1 L),then 13 : 1 hexanes : EtOAc (500 mL), then 9 : 1 hexanes : EtOAc (1 L)] to afford 94 mg(76%) of the γ-acetoxy enone 23: 1H NMR (500 MHz, CDCl3) δ 7.35-7.26 (m, 5 H),5.91 (s, 1 H), 5.68 (d, J = 1 Hz, 1 H), 5.10-5.05 (m, 1 H), 4.57 (A of AB, J = 12.2 Hz, 1H), 4.50 (B of AB, J = 11.7 Hz, 1 H), 3.56-3.50 (m, 2 H), 2.93-2.85 (m, 1 H), 2.71 (app t,J = 7.6 Hz, 2 H), 2.06 (s, 3 H), 2.03-1.88 (m, 2 H), 1.01 (d, J = 6.8 Hz, 3 H), 1.008 (d, J =6.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 200.8, 170.6, 155.0, 137.9, 128.4, 127.7,127.6, 121.1, 73.1, 72.0, 71.0, 33.9, 27.7, 25.6, 21.9, 21.1; IR (thin film from CDCl3)3064, 3031, 2962, 2931, 2871, 1738, 1678, 1627, 1497, 1454, 1415, 1372, 1240, 1098,1046, 1028 cm–1; HRMS (TOF MS ES+) calcd for C19H27O4, 319.1909 (M+H)+; observed319.1903 m/z.

14

O BHO

BnO

OHBnO C

24d.r. 4:1

O

O

O

PhMe, 80 °C79%

OH

MeMe

Me Me


(+/–)(7R,4R)-3-Isopropyl-8-benzyloxy-1,7-dihydroxy-3,4-octadiene (24): Asolution of the dialkenylboronic acid 14 (142 mg, 0.496 mmol) and 1,3,5-trioxane (101mg, 1.12 mmol) in benzene (8 mL) was heated at 80 °C for 16h. The solution wasdiluted with ethyl acetate and washed with NaHCO3 (sat) then brine. The organic layerwas dried over Na2SO4, filtered and concentrated to afford a crude oil (1H NMR of whichindicated a 4 : 1 mixture of diastereomeric products). Purification of the crude oil viaflash column chromatography [60 g SiO2; eluted with 30% EtOAc in hexanes (500 mL),then 50% EtOAc in hexanes (500 mL)] afforded 114 mg (79%) of a 4 : 1 mixture ofdiastereomeric allenes 24: (major diastereomer) 1H NMR (500 MHz, CDCl3) δ 7.36-7.28 (m, 5 H), 5.20-5.15 (m, 1 H), 4.57-4.52 (m, 2 H), 3.88-3.83 (m, 1 H), 3.78-3.66 (m,2 H), 3.49 (dd, J = 9.5, 3.7 Hz, 1 H), 3.37 (dd, J = 9.3, 7.3 Hz, 1 H), 3.16 (s, 2 H), 2.22-2.06 (m, 5 H), 1.02-1.00 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 200.6, 137.8, 128.4,127.7, 108.3, 89.9, 74.2, 73.3, 73.3, 70.0, 60.3, 34.2, 33.7, 31.3, 21.6, 21.5; IR (thin filmfrom CDCl3) 3382, 3063, 3030, 2959, 2926, 2868, 1958, 1496, 1454, 1381, 1363, 1205,1098, 1073, 1045, 1029 cm–1; HRMS (TOF MS ES+) calcd for C18H27O3, 291.1960(M+H)+; observed 291.1959 m/z; (minor diastereomer) selected peaks 1H NMR (500MHz, CDCl3) δ � �� 4.00-3.96 (m, 1 H), 3.42 (dd, J = 9.3, 7.3 Hz, 1 H); 13CNMR (125 MHz, CDCl3) δ 199.5, 109.2, 73.8, 69.0, 60.2, 33.8, 32.9, 21.8, 21.6.

16Ph

O BOH Me

Ph

OH

C

25d.r. 6 :1

O

O

O

PhMe, 60 °C78%

OH

Me

(+/–)(7R,4S)-3-Propyl-7-phenyl-1,7-dihydroxy-3,4-heptadiene (25): Asolution of the dialkenylboronic acid 16 (150 mg, 0.62 mmol) and 1,3,5-trioxane (123mg, 1.37 mmol) in benzene (5 mL) was heated at 60 °C for 24h. The solution wasdiluted with ethyl acetate and washed with NaHCO3 (sat) then brine. The combinedaqueous layers were extracted with EtOAc (2X). The combined organic layer was driedover Na2SO4, filtered and concentrated to afford a crude oil (1H NMR of which indicateda 6 : 1 mixture of diastereomeric products). Purification of the crude oil via flash columnchromatography [60 g SiO2; eluted with 20% EtOAc in hexanes (500 mL), then 30%EtOAc in hexanes (500 mL), then 38% EtOAc in hexanes (400 mL)] afforded 119 mg(78%) of a 6 : 1 mixture of diastereomeric allenes 25: (major diastereomer) 1H NMR(500 MHz, CDCl3) δ 7.34-7.23 (m, 5 H), 5.21-5.15 (m, 1 H), 4.65 (dd, J = 7.3, 5.4 Hz, 1H), 3.78 (br s, 2 H), 3.73-3.66 (m, 1 H), 3.57-3.53 (m, 1 H), 2.39-2.34 (m, 2 H), 2.14-2.03(m, 2 H), 1.89-1.86 (m, 2 H), 1.45-1.34 (m, 2 H), 0.89 (t, J = 7.6 Hz, 3 H); 13C NMR (125MHz, CDCl3) δ 202.1, 144.4, 128.24, 127.3, 125.7, 101.7, 89.2, 73.5, 60.0, 40.3, 35.3,35.2, 20.6, 13.8; IR (thin film from CDCl3) 3342, 3086, 3062, 3029, 2956, 2931, 2872,1962, 1603, 1493, 1453, 1427, 1377, 1337, 1283, 1200, 1085, 1054 cm–1; HRMS (TOFMS ES+) calcd for C16H23O2, 247.1698 (M+H)+; observed 247.1703 m/z; (minordiastereomer) selected peaks 1H NMR (500 MHz, CDCl3) δ � � �� dd, J =6.8, 4.4 Hz, 1 H), 0.93 (t, J = 7.3 Hz, 3 H)� 13C NMR (125 MHz, CDCl3) δ 200.7, 144.2,128.17, 127.1, 125.74, 102.6, 88.9, 72.2, 59.8, 38.7, 35.4, 35.1, 20.8, 13.81.


15Ph

OH Ph

OH

C

25d.r. 6 :1

OH

Me

i) 9, 7 (5.5 mol%) PhH, 60 °C ii ) trioxane, PhMe, 60 °C 56%

To the homoallylic alcohol 15 (325 mg, 2.19 mmol) was added thealkynylboronic ester 9 (456 mg, 2.32 mmol) via syringe. The mixture was diluted withbenzene (20 mL), then the Grubbs’ catalyst (7) (100 mg, 0.12 mmol, 5.5 mol%) wasadded. The vessel was purged with argon, then heated at 60 °C under nitrogen for 2h.The crude reaction mixture was filtered through a pad of basic alumina (using EtOAc forwashing). The solution was concentrated, diluted with EtOAc and washed with NaHCO3(sat) then brine. The organic layer was dried over Na2SO4, filtered and concentrated toafford a crude oil which was diluted with toluene (10 mL) and 1,3,5-trioxane (300 mg,3.3 mmol) was added. The solution was heated at 60 °C for 16h, then purified directly byflash column chromatography [120 g SiO2; eluted with 20% EtOAc in hexanes (1 L),then 30% EtOAc in hexanes (1 L), then 40% EtOAc in hexanes (500 mL)] to afford 303mg (56%) of a 6 : 1 mixture of diastereomeric trisubstituted allenes 25: (see above forspectroscopic data).

Structure assignment for the functionalized allene 25:

Ph

OH

C

25d.r. 6:1

TBDPSCl

imidazole, DMF86%

OH

Me

Ph

OH

C

30d.r. 6:1

OTBDPS

Me

(+/–)(7R,4S)-1-t-Butyldiphenylsilanyloxy-3-propyl-7-phenyl-7-hydroxy-3,4-heptadiene (30): To a rt solution of the diol 25 (282 mg, 1.14 mmol) in DMF (10 mL)was added TBDPSCl (286 mL, 1.10 mmol) and imidazole (150 mg, 2.20 mmol). Thesolution was stirred at rt for 16h, then diluted with EtOAc and washed with NaHCO3 (sat)then brine. The organic layer was dried over Na2SO4, filtered and concentrated to afforda crude oil which, after purification via flash column chromatography [120 g SiO2; elutedwith 2.5% EtOAc in hexanes (1 L), then 5.0% EtOAc in hexanes (1 L), then 10% EtOAcin hexanes (500 mL)] afforded 476 mg (86%) of the allenic alcohol 30: 1H NMR (500MHz, CDCl3) δ 7.76-7.71 (m, 4 H), 7.47-7.40 (m, 6 H), 7.36-7.26 (m, 5 H), 5.05-5.01 (m,1 H), 4.68 (dd, J = 6.6, 6.6 Hz, 1 H), 3.78 (app t, J = 7.1 Hz, 2 H), 2.41-2.38 (m, 2 H),2.23-2.20 (m, 3 H), 1.89-1.86 (m, 2 H), 1.40-1.31 (m, 2 H), 1.10 (s, 9 H), 0.89 (t, J = 7.3Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ �02.7, 143.8, 135.6, 134.8, 133.9, 129.6,129.5, 128.2, 127.7, 127.6, 127.3, 125.9, 125.8, 101.3, 87.4, 73.8, 62.7, 39.7, 35.7, 34.8,26.8, 26.5, 20.8, 20.7, 19.1, 13.8; IR (thin film from CDCl3) 3383, 3070, 3049, 3029,2998, 2957, 2930, 2894, 2857, 1961, 1888, 1822, 1589, 1492, 1472, 1463, 1454, 1428,1390, 1361, 1331, 1307, 1260, 1191, 1156, 1111, 1029, 1007 cm–1; HRMS (TOF MSES+) calcd for C32H41O2Si, 485.2876 (M+H)+; observed 485.2876 m/z.


Ph

OH

C

30d.r. 6:1

OTBDPS

Me

OPh Me

OTBDPS

i) Hg( NO3)2, CaCO3 DME

ii) NaBH4, CH3OH 23%

31d.r. 6:1

(+/–)(1S,6R)-2-Propyl-2-(1’-t-butyldiphenylsilanyloxy-eth-2’-yl)-6-phenyl-3,4-dihydropyran (31): To a rt solution of Hg(NO3)2 (110 mg, 0.34 mmol) and CaCO3 (37mg, 0.37 mmol) in DME (1 mL) was added the homoallenic alcohol 30 (150 mg, 0.309mmol) as a solution in 1.5 mL DME. The solution was stirred at rt for 10 min, then wastransferred via cannula to a –78 °C solution of NaBH4 (60 mg, 1.6 mmol) in CH3OH (5mL). The flask was then warmed to rt, diluted with EtOAc and washed successively withNaHCO3 (2X) then brine. The organic layer was dried over Na2SO4, filtered andconcentrated to afford a crude oil which, after purification via flash columnchromatography, afforded 35 mg (23%) of a 6 : 1 mixture of diastereomericdihydropyrans 31: (major diastereomer) 1H NMR (500 MHz, CDCl3) δ 7.72-7.25 (m,15 H), 5.87 (ddd, J = 10.1, 5.1, 2.8 Hz, 1 H), 5.66-5.63 (m, 1 H), 4.59 (dd, J = 8.8, 4.9Hz, 1 H), 3.88-3.78 (m, 2 H), 2.16-2.11 (m, 2 H), 2.09-2.03 (m, 1 H), 1.97-1.91 (m, 1 H),1.68-1.22 (m, 4 H), 1.06 (s, 9 H), 0.88 (t, J = 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3)δ 143.3, 135.60, 135.57, 133.9, 133.1, 133.0, 129.5, 128.23, 128.20, 127.6, 127.2, 126.1,125.9, 123.7, 76.9, 70.4, 60.3, 41.9, 41.0, 32.7, 26.8, 19.1, 16.8, 14.5; IR (thin film fromCDCl3) 3070, 3029, 2998, 2957, 2931, 2892, 2857, 1958, 1889, 1824, 1654, 1589, 1489,1472, 1464, 1454, 1428, 1390, 1361, 1341, 1307, 1260, 1212, 1190, 1112, 1085, 1063,1027 cm–1; HRMS (TOF MS ES+) calcd for C32H41O2Si, 485.2876 (M+H)+; observed485.2886 m/z; (minor diastereomer) selected peaks 1H NMR (500 MHz, CDCl3) δ �.78(ddd, J = 10.3, 5.9, 2.0 Hz, 1 H), 4.66 (dd, J = 10.3, 3.4 Hz, 1 H), 3.97-3.92 (m, 1 H),1.88-1.83 (m, 1 H), 1.07 (s, 9 H)� 13C NMR (125 MHz, CDCl3) δ 30.9, 17.1, 14.7.

Selected nOe’s for dihydropyran 31:

31major

OPh

OTBDPS

Me

HH H H H

31minor

OPh

Me

OTBDPS

HH H


Si O*

H

O

b)

R =Si*

26 27

28ca. 100 nmol compound/bead

10µL of 10 mM stock solut ion/bead

i Pr i Pr

i Pr i Pr

a) •

OHRO

Me

H OH

•

OHHO

Me

H OH

(a) To a rt solution of the resin bound aldehyde 26 (39 mg – 264 beads @ ca. 1.4mmol/g) in toluene (0.5 mL) was added the dialkenylboronic acid 16 (80 mg, 0.33 mmol)as a solution in 1.0 mL of toluene. The vessel was purged with argon, then heated at 80°C for 6d. The vessel was then cooled to rt, and the beads were washed successively withTHF (2X); THF:H2O (3:1)(1X); THF (2X).

(b) To the resin bound allene 27 was added HF•pyr/pyr/THF (5% HF•pyr + 5%pyr). The solution was agitated via shaking for 1h, after which time TMSOMe (500 µL)was added. The solution was agitated via shaking for an additional 30 min, then thesolution was filtered through a plug of glass wool and the beads were washedsuccessively with THF (5X) and CH2Cl2 (5X). The combined organics wereconcentrated to afford 3.6 mg of crude 28 as ca. a 3:1 mixture of diastereomers(corresponding to ca. 100 nmol/bead).


•HOOH

H

Me

OH

28 crude in CDCl3(d.r. ca. 3:1)

ca. 100 nmol/bead

howard hughes medical institute - wiley-vch · added n-buli (73 mmol, 2.5m in hexanes). the...

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