T. Thaima et al. / Tetrahedron xxx (xxxx) xxx
19
(49.4 mg, 79%). 1H NMR analysis revealed the presence of two
biphenyl axis rotamers in
60:40 ratio. Rf ¼ 0.37
and H-200A), 2.17* (dt, J ¼ 14.0, 9.3 Hz, 0.46H, H-200B), 1.55e1.18 (m,
4H, H-5000 and H-6000), 0.87 (s, 4.86H, (CH3)3CSi), 0.83* (s, 4.14H,
(CH3)3CSi), ꢃ0.00 (s, 1.62H, CH3Si), ꢃ0.04* (s, 1.38H, CH3Si), ꢃ0.08
(s, 1.62H, CH3Si), ꢃ0.16* (s, 1.38H, CH3Si). 13C NMR (125 MHz, the
a
(MeOH:CH2Cl2 ¼ 3:97). IR (neat): nmax 3519, 2929, 2224, 1600, 1515,
1250, 1035, 694 cm-1 ½a D25
ꢄ
þ 36 (c 0.74, CHCl3). 1H NMR (500 MHz,
the asterisk* denotes the signal of the minor rotamer, CDCl3):
asterisk* denotes the signal of the minor rotamer, CDCl3): d 159.7
d
7.44* (dd, J ¼ 8.6, 2.1 Hz, 0.4H, H-4), 7.38* (d, J ¼ 2.1 Hz, 0.4H, H-2),
(C-6), 159.1* (C-6), 149.2 (C-40), 149.15* (C-40), 147.5 (C-50), 147.2* (C-
50), 137.4* (ArC), 136.9 (ArC), 136.3 (C-300), 136.1* (C-20), 135.8 (C-20),
135.7 (ArC), 135.67* (ArC), 135.6 (C-300), 135.4* (C-2), 135.3 (C-2),
133.3 (C-5), 133.1* (C-5), 132.4* (C-2000), 132.2 (C-1), 131.3* (C-1),
131.1 (C-4000), 131.0* (C-4000), 130.2 (C-2000), 128.8* (0.92 ꢂ ArCH), 128.7
(1.08 ꢂ ArCH), 128.69 (1.08 ꢂ ArCH), 128.5* (0.92 ꢂ ArCH), 128.2
(0.54 ꢂ ArCH), 128.1* (0.46 ꢂ ArCH), 128.0 (C-10), 127.8* (C-10), 127.4
(0.54 ꢂ ArCH), 127.2* (0.46 ꢂ ArCH), 126.8 (1.08 ꢂ ArCH), 126.4*
(0.92 ꢂ ArCH), 126.3 (1.08 ꢂ ArCH), 126.1* (0.92 ꢂ ArCH), 119.2*
(C^N), 119.0 (C^N), 118.2* (C-400), 117.5 (C-400), 113.1* (C-60), 112.8
(C-60), 112.79 (C-5), 110.2* (C-30), 110.1 (C-30), 104.2 (C-3), 103.6* (C-
3), 76.2* (C-4000), 75.9 (C-4000), 70.4 (PhCH2O), 69.9* (PhCH2O), 63.2
(C-7000), 63.1* (C-7000), 60.3 (C-3000), 59.1* (C-3000), 56.3* (OCH3), 56.2
(OCH3), 56.1 (OCH3), 56.05* (OCH3), 54.4 (C-100), 54.1* (C-100), 43.8*
(C-200), 42.3 (C-200), 30.4* (C-6000), 30.2 (C-6000), 28.9* (C-5000), 28.8 (C-
5000), 26.03 ((CH3)3CSi), 26.0* ((CH3)3CSi), 18.2 ((CH3)3CSi), 18.16*
((CH3)3CSi), ꢃ4.08 (CH3Si), ꢃ4.1* (CH3Si), ꢃ4.48* (CH3Si), ꢃ4.5
(CH3Si). HRMS (ESI): m/z calcd for C45H57N2O5Si [M þ H]þ:
733.4037; found: 733.4037.
7.35 (d, J ¼ 2.1 Hz, 0.6H, H-2), 7.34e7.03 (m, 11.6H, H-4, H-30 and
ArH), 6.89 (d, J ¼ 8.6 Hz, 0.6H, H-5), 6.55* (s, 0.4H, H-60), 6.51* (d,
J ¼ 9.1 Hz, 0.4H, H-5), 6.49 (s, 0.6H, H-60), 6.22 (d, J ¼ 16.0 Hz, 0.6H,
H-1000), 6.09* (d, J ¼ 16.0 Hz, 0.4H, H-1000), 5.71* (dd, J ¼ 16.0, 9.1 Hz,
0.4H, H-2000), 5.64 (dd, J ¼ 16.0, 8.6 Hz, 0.6H, H-2000), 5.60e5.48 (m,
1H, H-300), 5.09e5.00 (m, 1.2H, PhCH2O), 5.00e4.79 (m, 2.8H, H-400
and PhCH2O), 3.95 (s, 1.8H, OCH3), 3.92* (s, 1.2H, OCH3), 3.81* (s,
1.2H, OCH3), 3.77 (s, 1.8H, OCH3), 3.65e3.52 (m, 3.4H, H-100, H-4000
and H-7000), 3.45 (t, J ¼ 6.5 Hz, 0.6H, H-100), 3.22 (dd, J ¼ 8.8, 3.4 Hz,
0.6H, H-3000), 3.11* (dd, J ¼ 9.1, 4.2 Hz, 0.4H, H-3000), 2.46e2.25 (m, 2H,
H-200), 1.83 (s, 2H, OH and NH), 1.71e1.39 (m, 4H, H-5000 and H-6000),
0.88 (s, 5.4H, (CH3)3CSi), 0.80* (s, 3.6H, (CH3)3CSi), 0.06 (s, 1.8H,
CH3Si), 0.04* (s, 1.2H, CH3Si), 0.01 (s, 1.8H, CH3Si), ꢃ0.01* (s, 1.2H,
CH3Si). 13C NMR (125 MHz, the asterisk* denotes the signal of the
minor rotamer, CDCl3):
d
159.6 (C-6), 159.0* (C-6), 149.0* (C-40),
148.9 (C-40),147.3 (C-50),137.3* (ArC),136.9 (ArC),136.1* (ArC),136.0
(C-300), 135.8 (ArC), 135.7* (C-300), 135.67 (C-20), 135.5 (C-2), 135.2*
(C-2), 135.1* (C-20), 133.1 (C-4), 132.9* (C-4), 132.1* (C-1000), 132.0 (C-
1), 131.9* (C-1), 131.3 (C-1000), 130.4 (C-2000), 129.3 (C-2000), 128.7*
(0.8 ꢂ ArCH), 128.69 (1.2 ꢂ ArCH), 128.6 (1.2 ꢂ ArCH), 128.5* (0.8 ꢂ
ArCH), 128.1 (0.6 ꢂ ArCH), 128.09* (0.4 ꢂ ArCH), 127.6 (C-10), 127.5*
(C-10), 127.4 (ArCH), 126.7 (1.2 ꢂ ArCH), 126.5* (1.6 ꢂ ArCH), 126.4
(1.2 ꢂ ArCH), 119.2 (C^N), 119.16* (C^N), 117.4* (C-400), 117.3 (C-400),
113.2* (C-5), 112.9 (C-5), 112.7* (C-60), 112.4 (C-60), 110.4 (C-30),
110.3* (C-30), 103.8 (C-3), 103.7* (C-3), 75.9 (C-4000), 75.4* (C-4000),
70.3 (PhCH2O), 70.1* (PhCH2O), 64.7 (C-3000), 63.1 (C-7000), 62.9* (C-
7000), 61.9* (C-3000), 56.6 (C-100), 56.1 (OCH3), 56.03 (OCH3), 56.0*
(OCH3), 55.96* (OCH3), 55.4* (C-100), 41.1 (C-200), 40.8* (C-200), 30.8*
(C-6000), 29.4 (C-6000), 29.2 (C-5000), 28.4* (C-5000), 26.1 ((CH3)3CSi),
26.0* ((CH3)3CSi), 18.2 ((CH3)3CSi), 18.18* ((CH3)3CSi), ꢃ4.0*
(CH3Si), ꢃ4.1 (CH3Si), ꢃ4.2* (CH3Si). HRMS (ESI): m/z calcd for
4.26. Synthesis of 6-(Benzyloxy)-2'-((S)-1-((2S,3R)-3-((tert-
butyldimethylsilyl)oxy)-2-((E)-styryl)piperidin-1-yl)but-3-en-1-yl)-
40,50-dimethoxy-[1,10-biphenyl]-3-carbonitrile (31a)
Piperidine 31a was prepared from compound 30a (0.655 g,
0.89 mmol) according to General Method for Mesylation-
Cyclization. Purification by column chromatography on silica gel
eluting with 15:85 EtOAc/hexanes gave the title compound 31a as a
pale yellow oil (0.573 g, 90%). 1H NMR analysis revealed the pres-
ence of two biphenyl axis rotamers in an 88:12 ratio. Rf ¼ 0.29
(EtOAc:hexanes ¼ 20:80). IR (neat): nmax 2925, 2852, 2223, 1599,
1516,1491,1094, 835, 747, 694 cm-1 ½a D
(500 MHz, the asterisk* denotes the signal of the minor rotamer,
CDCl3):
7.68 (dd, J ¼ 8.5, 2.2 Hz, 1H, H-4), 7.55 (d, J ¼ 2.2 Hz, 1H, H-
ꢄ
25 - 29 (c 2.4, CHCl3). 1H NMR
C
45H57N2O5Si [M þ H]þ: 733.4037; found: 733.4057.
d
4.25.2. Synthesis of 6-(benzyloxy)-2'-((S)-1-(((3S,4R,E)-4-((tert-
butyldimethylsilyl)oxy)-7-hydroxy-1-phenylhept-1-en-3-yl)amino)
but-3-en-1-yl)-40,50-dimethoxy-[1,10-biphenyl]-3-carbonitrile (30b)
Diol 30b was prepared from compound 29b (55.9 mg,
0.066 mmol) according to General Method for the Selective
Deprotection of a Primary TBS Ether. The crude product was puri-
fied by column chromatography on silica gel eluting with 0:100 to
1:99 MeOH/CH2Cl2 to afford the title compound 30b as a pale
yellow oil (37.1 mg, 77%). 1H NMR analysis revealed the presence of
2), 7.43e7.10 (m, 8H, ArH), 7.09* (s, 0.12H, H-5), 6.96* (s, 0.12H, H-
30), 6.85 (s, 0.88H, H-30), 6.83e6.78 (m, 2H, ArH), 6.81 (d, J ¼ 8.7 Hz,
0.88H, H-5), 6.66* (s, 0.12H, H-60), 6.61 (s, 0.88H, H-60), 6.44 (d,
J ¼ 15.9 Hz, 1H, H-20000), 5.66* e 5.53* (m, 0.12H, H-300), 5.32e5.21
(m, 0.88H, H-300), 5.16* (d, J ¼ 12.4 Hz, 0.12H, PhCHAHBO), 5.08* (d,
J ¼ 12.4 Hz, 0.12H, PhCHAHBO), 4.92* (t, J ¼ 17.0, 13.6 Hz, 0.12H, H-
400A), 4.85 (d, J ¼ 17.0 Hz, 0.88H, H-400A), 4.73* (dd, J ¼ 15.9, 9.4 Hz,
0.12H, H-400B), 4.57 (d, J ¼ 12.4 Hz, 0.88H, PhCH2O), 4.53 (d,
J ¼ 10.2 Hz, 0.88H, H-400B), 4.45 (d, J ¼ 12.4 Hz, 0.88H, PhCH2O),
4.48e4.41 (m, 1H, H-1000), 3.92* (s, 0.36H, OCH3), 3.91 (s, 2.64H,
OCH3), 3.84 (s, 2.64H, OCH3), 3.80* (s, 0.36H, OCH3), 3.78 (dd,
J ¼ 11.5, 3.4 Hz, 1H, H-100), 3.15e3.06 (m, 1.76H, H-3000), 2.95* e 2.88*
(m, 0.24H, H-3000), 2.77 (t, J ¼ 8.7 Hz,1H, H-2000), 2.63e2.56 (m, 1H, H-
6000A), 2.56e2.49 (m, 1H, H-200A), 2.48e2.38 (m, 1H, H-200B),
2.06e2.00 (m, 1H, H-6000B), 1.95e1.90 (m, 1H, H-4000A), 1.54e1.49 (m,
two biphenyl axis rotamers in
a
54:46 ratio. Rf ¼ 0.37
(MeOH:CH2Cl2 ¼ 3:97). IR (neat): nmax 3519, 2930, 2224, 1599, 1513,
1490, 1248, 1153,1035, 734, 745, 694 cm-1 ½a D25
ꢄ
- 64 (c 0.51, CHCl3).
1H NMR (500 MHz, the asterisk* denotes the signal of the minor
rotamer, CDCl3):
d 7.42e7.38 (m, 1.46H, H-2 and H-4), 7.36 (dd,
J ¼ 8.6, 2.1 Hz, 0.54H, H-4), 7.34e7.19 (m, 8.16H, ArH), 7.18e7.11 (m,
1.92H, H-30 and ArH), 7.02* (d, J ¼ 6.9 Hz, 0.92H, ArH), 6.86 (d,
J ¼ 8.6 Hz, 0.54H, H-5), 6.71* (d, J ¼ 9.2 Hz, 0.46H, H-5), 6.65* (s,
0.46H, H-60), 6.57 (s, 0.54H, H-60), 5.95 (d, J ¼ 16.1 Hz, 0.54H, H-1000),
5.92e5.85 (m, 1H, H-1000 and H-2000), 5.72* (dd, J ¼ 16.0, 7.1 Hz, 0.46H,
H-2000), 5.72e5.49 (m, 1H, H-300), 5.18* e 5.09* (m, 0.92H, H-400),
5.08e5.02 (m, 1.08H, PhCH2O), 5.02e4.96 (m, 1.08H, H-400), 4.95* e
4.86* (m, 0.92H, PhCH2O), 3.98* (s, 1.38H, OCH3), 3.97 (s, 1.62H,
OCH3), 3.86 (s, 1.62H, OCH3), 3.79* (s, 1.38H, OCH3), 3.62e3.54 (m,
2H, H-100 (minor), H-4000 (minor) and H-7000), 3.53e3.42 (m, 2H, H-100,
H-4000 and H-7000 (minor)), 2.84 (dd, J ¼ 7.3, 3.8 Hz, 0.54H, H-3000),
2.81* (dd, J ¼ 6.9, 2.9 Hz, 0.46H, H-3000), 2.45e2.25 (m, 1.54H, H-200
1H, H-5000A), 1.27e1.19 (m, 2H, H-4000 and H-5000B), 0.75 (s, 9H,
B
(CH3)3CSi), 0.01 (s, 2.64H, CH3Si), ꢃ0.09* (s, 0.36H, CH3Si), ꢃ0.10 (s,
2.64H, CH3Si), ꢃ0.20* (s, 0.36H, CH3Si). 13C NMR (125 MHz, the
asterisk* denotes the signal of the minor rotamer, CDCl3):
d 160.6*
(C-6), 159.1 (C-6), 147.6* (C-40), 147.4 (C-40), 147.3 (C-50), 147.1* (C-
50), 137.8 (C-2), 137.4 (ArC), 136.8* (ArC), 136.2 (C-300), 136.1* (ArC),
135.9 (ArC), 133.5 9 (C-20000), 133.3* 9 (C-20000), 132.5 (C-1), 132.4 (C-
4),131.7* (C-10),131.4 (C-10),131.3 (C-20),130.9 (C-10000),130.4* (C-20),
128.9* (0.24 ꢂ ArCH), 128.7* (0.24 ꢂ ArCH), 128.4 (3.52 ꢂ ArCH),
128.1* (0.12 ꢂ ArCH), 127.8 (0.88 ꢂ ArCH), 127.5* (0.12 ꢂ ArCH),
127.4 (0.88 ꢂ ArCH), 126.8 (1.76 ꢂ ArCH), 126.5 (2 ꢂ ArCH), 126.3*
Please cite this article as: T. Thaima et al., Progress toward the total synthesis of 9
b-hydroxyvertine: Construction of an advanced quinolizidine