Tetrahydrofuran → Diisopropylamine

A solution of keto ester 22a (1.79 g, 3.63 mmol, 1.0 equiv) in THF (15 mL) was added via cannula to a freshly prepared solution of lithium diisopropylamide [LDA; formed by addition of n-BuLi (2.83 mL, 1.6 M solution in hexanes, 4.58 mmol, 1.25 equiv) to a solution of diisopropylamine (0.61 mL, 4.36 mmol, 1.2 equiv) in THF (30 mL) at −10° C. and stirring for 30 min] at −78° C. After 15 min the reaction mixture was allowed to warm to −40° C. and was stirred for 45 min. The reaction mixture was cooled to −78° C. and a solution of aldehyde 7 (0.740 g, 5.8 mmol, 1.6 equiv) in THF (15 mL) was added dropwise. The resulting mixture was stirred for 15 min, then warmed to −40° C. for 30 min, cooled back to −78° C. and then quenched by slow addition of saturated aqueous NH4Cl solution (10 mL). The reaction mixture was warmed to 25° C., diluted with EtOAc (10 mL) and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and subjected to flash chromatographic purification (silica gel, 5 E 20% EtOAc in hexanes) to afford a mixture of aldol products 23 (926 mg, 42%) and 24 (724 mg, 33%), along with unreacted starting keto ester 22a (178 mg, 10%). 23: Rf=0.40 (silica gel, 18% EtOAc in hexanes); [α]22D −11.4 (c 1.00, CHCl3); IR (film) nmax 3518, 2962, 2932, 2858, 1722, 1644, 1294, 1182, 1114, 989, 702 cm−1; 1H NMR (600 MHz, CDCl3) d 7.67-7.63 (m, 4H, SiC(CH3)3(C6H5)2), 7.45-7.40 (m, 2H, SiC(CH3)3(C6H5)22), 7.40-7.35 (m, 4H, SiC(CH3)3(C6H5)2), 7.03 (d, 1H, J=15.8 Hz, CH═CHCOO), 5.92 (d, J=15.8 Hz, 1H, CH═CHCOO), 5.84-5.76 (m, 1H, CH2CH═CH2), 5.76-5.68 (m, 1H, CH2CH═CH2), 5.14-5.09 (m, 1H, CO2CH), 5.08 (d, J=17.2 Hz, 1H, CH2CH═CH2), 5.04 (d, J=10.1 Hz, 1H, CH2CH═CH2), 4.99 (d, J=18.9 Hz, 1H, CH2CH═CH2), 4.92 (d, J=10.2 Hz, 1H, CH2CH═CH2), 3.76-3.69 (m, 2H, CH2OTPS), 3.29 (d, J=8.9 Hz, 1 H, CHOH(CHCH3)), 3.16 (s, 1H, CHOH(CHCH3)), 3.13 (qd, J=7.0, 1.8 Hz, 1H, CH3CH(C═O)), 2.52-2.45 (m, 1H), 2.42-2.35 (m, 1H), 2.09-1.97 (m, 2H), 1.76-1.68 (m, 1H), 1.52-1.43 (m, 2H), 1.30 (s, 3H, C(CH3)2), 1.30 (s, 3H, C(CH3)2), 1.30-1.25 (m, 1H), 1.12-1.00 (m, 1H), 1.03 (s, 9H, SiC(CH3)3(C6H5)2), 1.01 (d, J=7.1 Hz, 3H, CH3CH(C═O), 0.77 (d, J=6.8 Hz, 3H, CH3CHCH2; 13C NMR (150.9 MHz, CDCl3) d 217.0, 165.2, 150.1, 138.9, 135.4, 135.4, 135.4, 133.1, 133.1, 129.6, 129.6, 127.6, 127.5, 121.5, 117.9, 114.2, 74.9, 73.8, 64.4, 51.6, 41.5, 35.5, 35.2, 34.3, 32.2, 26.8, 26.2, 23.3, 23.3, 19.4, 15.6, 10.4; HRMS (FAB), calcd for C38H54CsO5Si (M+Cs+) 751.2795, found 751.2766. 24: Rf=0.30 (silica gel, 18% EtOAc in hexanes); [α]22D −1.33 (c 0.60, CHCl3); IR (film) nmax 3521, 2962, 2932, 2858, 1722, 1644, 1294, 1182, 1113, 988, 702 cm−1; 1H NMR (600 MHz, CDCl3) d 7.68-7.63 (m, 4H, SiPh2), 7.45-7.40 (m, 2H, SiC(CH3)3(C6H5)2), 7.40-7.35 (m, 4H, SiC(CH3)3(C6H5)2), 7.03 (d, 1H, J=15.8 Hz, CH═CHCOO), 5.90 (d, J=15.8 Hz, 1H, CH═CHCOO), 5.82-5.68 (m, 2H, 2×CH2CH═CH2), 5.14-5.08 (m, 1H, CO2CH), 5.09 (d,. J=16.9 Hz, 1H, CH2CH═CH2), 5.05 (d, J=10.1 Hz, 1H, CH2CH═CH2), 4.99 (d, J=17.1 Hz, 1H, CH2CH═CH2), 4.95 (d, J=10.1 Hz, 1H, CH2CH═CH2), 3.76-3.69 (m, 2H, CH2OTPS), 3.44 (dd, J=6.6, 3.9 Hz, 1H, CHOH(CHCH3)), 3.13-3.08 (m, 1H, CH3CH(C═O)), 2.69 (bs, 1H, CHOH(CHCH3)), 2.53-2.47 (m, 1H), 2.43-2.37 (m, 1H), 2.07-1.95 (m, 2H), 1.48-1.25 (m, 5H), 1.31 (s, 3H, C(CH3)2), 1.29 (s, 3H C(CH3)2), 1.05 (d, J=7.0 Hz, 3H, CH3CH(C═O)), 1.03 (s, 9H, SiC(CH3)3(C6HS)2), 0.92 (d, J=6.6 Hz, 3H, CH3CHCH2); 13C NMR (150.9 MHz, CDCl3) d 216.1, 165.2, 150.3, 138.5, 135.5, 135.4, 135.4, 133.1, 133.1, 129.6, 129.6, 127.6, 127.6, 121.4, 117.9, 114.6, 75.1, 73.8, 64.4, 51.5, 42.6, 35.5, 35.1, 33.9, 32.6, 26.8, 26.0, 23.6, 23.3, 19.4, 15.0, 12.3; HRMS (FAB), calcd for C38H54CsO5Si (M+Cs+) 751.2795, found 751.2771.

ORD record

ord-9ac86848024f4a44a819b1dbc78e03f5

Source dataset

uspto-grants-2002_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06441186B1