The Journal of Organic Chemistry
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δ 7.69−7.58 (m, 2H), 7.48−7.31 (m, 13H), 5.78 (ddt, J = 7.0, 10.3,
17.2 Hz, 1H), 5.12 (d, J = 11.3 Hz, 1H), 5.09 (dd, J = 1.3, 17.2 Hz,
1H), 5.06 (dd, J = 1.3, 10.3 Hz, 1H), 4.97 (d, J = 11.7 Hz, 1H), 4.78
(d, J = 11.3 Hz, 1H), 4.76 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 7.9 Hz,
1H), 4.37−4.26 (br s, 1H), 4.19 (dd, J = 2.1, 7.9 Hz, 1H), 3.53 (ddd,
J = 5.0, 9.3, 14.1 Hz, 1H), 3.30−3.24 (m, 1H), 2.51−2.39 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 170.7 (CO), 137.5 (C), 137.1 (C),
136.8 (2 × CH), 135.6 (CH), 130.1 (CH), 129.0 (2 × CH), 128.5
(t, J = 288.8 Hz, CF2), 128.4 (4 × CH), 128.1 (2 × CH), 128.0 (2 ×
CH), 127.9 (CH), 127.8 (CH), 125.4 (d, J = 3.4 Hz, C), 117.1
(CH2), 90.2 (dd, J = 22.7, 28.4 Hz, C), 87.6 (CH), 78.7 (d, J = 3.1 Hz,
CH), 74.2 (CH2), 73.3 (CH2), 40.2 (CH2), 32.3 (CH2); 19F NMR
(470 MHz, CDCl3) δ −81.57 (d, J = 216.7 Hz, 1F), −80.43 (d, J =
216.7 Hz, 1F); IR (neat) νmax 3272br, 1694s, 1683s, 1456s, 1360m,
1148m, 1097m, 1069s, 749m, 693s cm−1; MS m/z (%) relative intensity
525 (M+, trace), 290 (6), 230 (21), 181 (11), 91 (100), 77 (6), 65 (14);
HRMS (ESI-TOF) calcd for C29H29F2NO4SNa [M + Na]+ 548.1683,
found 548.1697. anti-9: mp 57−58 °C; [α]24D +60.9° (c 1, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.63−7.60 (m, 2H), 7.52−7.48 (m, 1H),
7.46−7.35 (m, 10H), 7.33−7.31 (m, 2H), 5.82 (ddt, J = 6.9, 10.2,
17.1 Hz, 1H), 5.15−5.05 (m, 2H), 5.10 (d, J = 11.8 Hz, 1H), 4.85 (d,
J = 11.8 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.1 Hz, 1H),
4.42 (d, J = 4.9 Hz, 1H), 4.39 (s, 1H), 4.17 (d, J = 4.9 Hz, 1H), 3.76
(ddd, J = 5.7, 9.5, 14.2 Hz, 1H), 3.42 (ddd, J = 5.7, 9.5, 14.2 Hz, 1H),
2.59−2.40 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 171.5 (CO), 137.2
(C), 136.7 (3 × CH), 136.0 (C), 135.2 (CH), 130.2 (CH), 129.2 (3 ×
CH), 128.7 (t, J = 287.9 Hz, CF2), 128.6 (3 × CH), 128.5 (4 × CH),
128.1 (CH), 124.7 (C), 116.7 (CH2), 88.7 (t, J = 26.0 Hz, C), 78.3
(CH), 78.0 (CH), 73.6 (CH2), 72.6 (CH2), 40.9 (CH2), 32.6 (CH2);
19F NMR (470 MHz, CDCl3) δ −84.91 (d, J = 209.9 Hz, 1F), −82.08
25.6 (3 × CH3), 18.1 (C), 17.9 (C), 9.5 (d, J = 8.9 Hz, CH3), −4.2
(CH3), −4.7 (CH3), −5.0 (2 × CH3); 19F NMR (470 MHz, CDCl3)
δ −129.38 (dd, J = 23.0, 230.8 Hz, 1F), −125.89 (d, J = 230.8 Hz, 1F);
IR (KBr) νmax 3375br, 2930m, 1693s, 1473m, 1252m, 1110s, 838s
cm−1; MS m/z (%) relative intensity 451 (M+, trace), 394 (100), 346
(31), 234 (37), 212 (26), 206 (14), 73 (19); HRMS (ESI-TOF) calcd
for C20H39F2NO4Si2Na [M + Na]+ 474.2283, found 474.2256.
(1R,2R,7S,8aR)- and (1R,2R,7R,8aR)-1,2-Bis(tert-butyldime-
thylsilyloxy)-8,8-difluoro-8a-hydroxy-7-methylhexahydroin-
dolizin-3(5H)-one (trans-11, cis-11). According to the general
procedure B, radical cyclization of syn-7 (3.44 g, 6 mmol) followed by
the removal of tin byproduct and flash column chromatography (SiO2,
10% EtOAc in hexanes) gave trans-11 (0.95 g, 34% yield) and cis-11
(0.33 g, 12% yield) as white solids. trans-11: mp 211−212 °C; [α]24
D
+28.5° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.33 (dd, J = 2.7,
7.0 Hz, 1H), 4.19 (dd, J = 1.1, 7.0 Hz, 1H), 3.95 (dd, J = 5.1, 13.3 Hz,
1H), 3.00 (dt, J = 3.4, 13.3 Hz, 1H), 2.83 (s, 1H), 2.46−2.38 (m, 1H),
1.66−1.59 (m, 1H), 1.53 (dq, J = 5.1, 13.3 Hz, 1H), 1.07 (d, J = 6.8
Hz, 3H), 0.95 (s, 9H), 0.94 (s, 9H), 0.24 (s, 3H), 0.19 (s, 3H), 0.17 (s,
3H), 0.16 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.7 (CO), 120.5
(dd, J = 247.5, 258.9 Hz, CF2), 85.5 (dd, J = 26.4, 35.1 Hz, C), 84.2
(CH), 76.8 (d, J = 4.3 Hz, CH), 34.9 (CH2), 33.9 (t, J = 22.3 Hz,
CH), 30.2 (d, J = 6.3 Hz, CH2), 25.8 (3 × CH3), 25.7 (3 × CH3), 18.2
(C), 17.8 (C), 11.9 (t, J = 3.8 Hz, CH3), −4.1 (CH3), −4.3 (CH3),
−4.6 (CH3), −4.7 (CH3); 19F NMR (470 MHz, CDCl3) δ −130.04
(dd, J = 26.8, 251.3 Hz, 1F), −117.89 (d, J = 251.3 Hz, 1F); IR (KBr)
νmax 3411br, 2930m, 1686s, 1463w, 1361w, 1252m, 1137m, 1094m,
838s cm−1; MS m/z (%) relative intensity 465 (M+, trace), 408 (100),
360 (26), 248 (22), 226 (11), 198 (11), 151 (10), 73 (15); HRMS
(ESI-TOF) calcd for C21H41F2NO4Si2Na [M + Na]+ 488.2440, found
1
488.2455. cis-11: mp 248−249 °C; [α]25 +1.9° (c 0.5, CHCl3); H
(d, J = 209.9 Hz, 1F); IR (KBr) νmax 3441br, 1715s, 1641w, 1455m,
1410m, 1353m, 1000s, 1018m, 749s, 698s cm−1; MS m/z (%) relative
intensity 525 (M+, trace), 400 (28), 385 (11), 302 (31), 181 (45), 91
(100), 77 (6), 65 (12); HRMS(ESI-TOF) calcd for C29H29F2NO4SNa
[M + Na]+ 548.1683, found 548.1697.
D
NMR (500 MHz, CDCl3) δ 4.30 (dd, J = 2.7, 6.3 Hz, 1H), 4.11 (dd,
J = 1.0, 6.3 Hz, 1H), 3.94−3.90 (m, 1H), 3.17 (dt, J = 3.7, 12.9 Hz,
1H), 2.82 (s, 1H), 2.42−2.35 (m, 1H), 2.05−1.97 (m, 1H), 1.54−1.51
(m, 1H), 1.29 (d, J = 7.4 Hz, 3H), 0.94 (s, 18H), 0.23 (s, 3H), 0.18 (s,
3H), 0.17 (s, 3H), 0.15 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.1
(CO), 120.0 (dd, J = 244.4, 261.1 Hz, CF2), 87.1 (dd, J = 26.4, 36.4
Hz, C), 84.3 (CH), 76.8 (d, J = 3.6 Hz, CH), 35.8 (t, J = 23.1 Hz,
CH), 31.3 (CH2), 28.2 (d, J = 5.6 Hz, CH2), 25.8 (3 × CH3), 25.7
(3 × CH3), 18.2 (C), 17.8 (C), 13.3 (dd, J = 3.9, 7.9 Hz, CH3), −4.1
(CH3), −4.3 (CH3), −4.6 (CH3), −4.7 (CH3); 19F NMR (470 MHz,
CDCl3) δ −116.14 (dd, J = 6.6, 256.2 Hz, 1F), −109.25 (dd, J = 14.1,
256.2 Hz, 1F); IR (KBr) νmax 3387br, 2961s, 1709s, 1453m, 1388m,
1260s, 1156s, 1067s, 844s cm−1; MS m/z (%) relative intensity 466
(M+ + 1, 2), 448 (12), 408 (100), 360 (24), 248 (23), 200 (24), 73
(25); HRMS (ESI-TOF) calcd for C21H41F2NO4Si2Na [M + Na]+
488.2440, found 488.2424.
(1R,2R,6R,7aR)- and (1R,2R,6S,7aR)-1,2-Bis(tert-butyldime-
thylsilyloxy)-7,7-difluoro-7a-hydroxy-6-methyltetrahydro-1H-
pyrrolizin-3(2H)-one (cis-10 and trans-10). General Procedure B.
An argon gas was bubbled through a solution of syn-6 (2.24 g, 4 mmol)
in dry toluene (25 mL) for 30 min, and then a mixture of Bu3SnH
(1.9 mL, 7.1 mmol) and AIBN (0.10 g, 0.6 mmol) in dry toluene
(15 mL) was added dropwise at reflux over a 1 h period. After the com-
pletion of the reaction, volatiles were evaporated and the tin byproduct
were removed by column chromatography (SiO2, hexanes (300 mL)
then EtOAc) to give a crude product, which was then purified by flash
column chromatography (SiO2, 10% EtOAc in hexanes) to afford cis-10
(0.67 g, 37% yield) as a white solid and trans-10 (0.27 g, 15% yield) as
a pale yellow solid. cis-10: mp 211−212 °C; [α]25D +2.8° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 4.14 (d, J = 2.1 Hz, 1H), 4.03 (d, J =
(1R,2R,6R,7aR)- and (1R,2R,6S,7aR)-1,2-Bis(benzyloxy)-7,7-
difluoro-7a-hydroxy-6-methyltetrahydro-1H-pyrrolizin-3(2H)-
one (cis-12 and trans-12). According to the general procedure B,
radical cyclization of syn-8 (2.05 g, 4 mmol) followed by the removal
of tin byproduct and preparative thin-layer chromatography (SiO2,
10% EtOAc in hexanes ×6) gave cis-12 (0.63 g, 39% yield) as a
2.1 Hz, 1H), 3.97 (dd, J = 8.1, 11.5 Hz, 1H), 3.96 (s, 1H), 2.95 (t, J =
11.5 Hz, 1H), 2.54−2.45 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (s,
9H), 0.89 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H), 0.13 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ 174.5 (CO), 125.0 (t, J = 258.4 Hz, CF2), 95.1
(dd, J = 32.1, 20.9 Hz, C), 79.1 (CH), 78.9 (CH), 45.7 (d, J = 5.9 Hz,
CH2), 41.5 (t, J = 23.4 Hz, CH), 25.6 (3 × CH3), 25.5 (3 × CH3), 17.9
(C), 17.8 (C), 9.5 (d, J = 7.1 Hz, CH3), −4.7 (CH3), −4.9 (CH3), −5.1
(d, J = 1.8, CH3), −5.2 (CH3); 19F NMR (470 MHz, CDCl3)
δ −121.59 (dd, J = 19.3, 241.6 Hz, 1F), −119.13 (dd, J = 12.7, 241.6 Hz,
1F); IR (KBr) νmax 3354br, 2930s, 1694s, 1464m, 1261s, 1123s, 1059s,
844s cm−1; MS m/z (%) relative intensity 452 (M+ + 1, 1), 451 (M+,
trace), 394 (100), 346 (21), 234 (83), 212 (14), 206 (25), 73 (29);
HRMS (ESI-TOF) calcd for C20H39F2NO4Si2Na [M + Na]+ 474.2283,
colorless crystal and trans-12 (0.21 g, 13% yield) as a colorless oil. cis-
1
12: mp 145−146 °C; [α]23 +33.4° (c 2.0, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 7.38−7.31 (m, 10H), 4.88 (d, J = 11.5 Hz, 1H), 4.75
(d, J = 11.6 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.6 Hz,
1H), 4.19−4.16 (m, 2H), 4.10 (dd, J = 9.0, 11.9 Hz, 1H), 4.01 (s, 1H),
2.97 (dd, J = 6.3, 11.9 Hz, 1H), 2.66−2.50 (m, 1H), 1.28−1.26
(m, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4 (CO), 137.1 (C),
136.7 (C), 128.5 (2 × CH), 128.4 (2 × CH), 128.2 (3 × CH), 128.0
(CH), 127.9 (2 × CH), 125.1 (dd, J = 248.9, 269.8 Hz, CF2),
92.1 (dd, J = 24.6, 34.7 Hz, C), 84.7 (CH), 81.6 (CH), 73.2 (CH2),
73.0 (CH2), 46.8 (CH2), 40.5 (t, J = 23.7 Hz, CH), 13.7 (CH3); 19F
NMR (470 MHz, CDCl3) δ −125.59 (d, J = 236.9 Hz, 1F), −107.72
(dd, J = 23.0, 236.9 Hz, 1F); IR (KBr) νmax 3262br, 1728s, 1702m,
1457m, 1338m, 1203s, 1095s, 1062s, 756s, 701s cm−1; MS m/z (%)
relative intensity 404 (M+ + 1, trace), 191 (93), 171 (23), 151 (14),
136 (18), 111 (17), 91 (100), 77 (5), 65 (24); HRMS (ESI-TOF)
calcd for C22H23F2NO4Na [M + Na]+ 426.1493, found 426.1495.
found 474.2253. trans-10: mp 176−177 °C; [α]24 +97.4° (c 1,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.29 (d, J = 4.6 Hz, 1H), 4.14
(dd, J = 1.9, 4.6 Hz, 1H), 3.56 (dd, J = 9.2, 11.5 Hz, 1H), 3.41−3.33
(br s, 1H), 3.24 (dd, J = 8.5, 11.5 Hz, 1H), 3.04−2.93 (m, 1H), 1.16
(d, J = 7.0 Hz, 3H), 0.93 (s, 18H), 0.22 (s, 3H), 0.18 (s, 6H), 0.16 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 173.1 (CO), 123.6 (dd, J = 252.4,
266.6 Hz, CF2), 91.8 (dd, J = 24.8, 32.2 Hz, C), 80.9 (CH), 79.7 (CH),
46.1 (d, J = 7.3 Hz, CH2), 38.0 (t, J = 22.9 Hz, CH), 25.7 (3 × CH3),
8473
dx.doi.org/10.1021/jo301327s | J. Org. Chem. 2012, 77, 8465−8479