Highly convergent, stereospecific synthesis of 11-cis-retinoids by metal-catalyzed cross-coupling reactions of (Z)-1-alkenylmetals

Article abstract of DOI:10.1021/jo701664r

(Chemical Equation Presented) A stereospecific synthesis of 11-cis-retinoids has as its key step the hitherto unexplored palladium-catalyzed cross-coupling of trans-tnenyl electrophiles and (1Z,3E)-penta-1,3-dienyl boronates (a Suzuki-Miyaura reaction) or

Full text of DOI:10.1021/jo701664r

S1
SUPPORTING INFORMATION
HIGHLY CONVERGENT, STEREOSPECIFIC
SYNTHESIS OF 11-CIS-RETINOIDS BY
METAL-CATALYZED CROSS-COUPLING
REACTIONS OF Z-ALKENYLMETALS
Susana López,* Javier Montenegro and Carlos Saá
Departamento de Química Orgánica, Facultade de Química,
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SPAIN
qosuslop@usc.es
Table of Contents.
General Methods.......................................................................................................................................S2
Experimental Procedures for Significant Intermediates......................................................................S2-S4
Tables of Spectroscopic Data ............................................................................................................ S5-S7
NMR Spectra of All Compounds......................................................................................................S8-S33

S2
General Methods. Solvents were dried according to published methods and distilled before use.1
All other reagents were commercial compounds of the highest purity available. Reactions were carried
out under atmosphere of argon in flame-dried glassware with magnetic stirring. Visualization of
analytical thin-layer chromatography (TLC) was accomplished with phosphomolybdic acid ethanolic
solution (10%) stain followed by heating. Proton (1H) and carbon (13C) magnetic resonance spectra
(NMR) were recorded using CDCl3 as solvent. Chemical shifts (δ) are expressed in parts per million
(ppm) relative to tetramethylsilane as internal reference. 13C multiplicities were assigned with the aid of
the DEPT pulse sequence.
Experimental Procedures.
All the solutions employed were degassed by argon bubbling during 15 min. Reactions and
purification of the final products were carried out in the absence of light.
(7E,9E,11Z,13E)-9,13-Bis-demethyl-tert-butyldiphenylsilyl retinyl ether (12). Suzuki reaction: To a
suspension of Pd(PPh3)4) (30 mg, 0.026 mmol) and pinacol dienylboronate 4a (174 mg, 0.39 mmol) in
THF (4 mL) was added, via cannula, a solution of trienyl iodide 2a (50 mg, 0.16 mmol) in THF (2 mL).
A solution of TlOH (10 % in water, 1.7 mL, 0.81 mmol) was added dropwise, and the stirring was
continued for 5 h. The mixture was filtered through a short pad of neutral alumina and concentrated.
Flash chromatography of the crude (Al2O3, hexane) yielded 58 mg (74%) of 12 as an unstable pale
yellow oil. Stille reaction: To a solution trienyl iodide 2a (50 mg, 0.17 mmol) and
tributyldienylstannane 5a (152 mg, 0.24 mmol) in DMF (4 mL) was added, in one portion,
PdCl2(CH3CN)2 (4 mg, 0.016 mmol). The reaction mixture was stirred for 8h, filtered through a short
pad of neutral alumina (IV, hexane) and concentrated. Flash chromatography of the crude (Al2O3,
1
hexane) afforded 54 mg (70% yield) of 12. H NMR (400 MHz, CDCl3) δ 1.04 (s, 6H), 1.09 (s, 9H),
1Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th Ed; Butterworth-Heinemann: Oxford, 1996.

S3
1.4-1.5 (m, 4H), 1.6-1.7 (m, 2H), 1.74 (s, 3H), 2.04 (t, J = 6.2 Hz, 2H), 4.31 (d, J = 5.1 Hz, 2H), 5.80
(dt, J = 15.0, 5.1 Hz, 1H), 5.98 (dd, J = 10.7, 11.3 Hz, 1H), 6.04 (dd, J = 10.7, 11.3 Hz, 1H), 6.15 (dd, J
= 15.6, 10.0 Hz, 1H), 6.22 (d, J = 15.6 Hz, 1H), 6.32 (dd, J = 10.0, 14.6 Hz, 1H), 6.59 (dd, J = 14.6,
13
10.7 Hz, 1H), 6.78 (dd, J = 15.0, 10.7 Hz, 1H), 7.3-7.4 (m, 6H), 7.6-7.7 (m, 4H) ppm. C NMR (100
MHz, CDCl3) δ 19.2 (C), 19.3 (CH2), 21.7 (CH3), 26.8 (3xCH3), 28.9 (2xCH3), 33.2 (CH2), 34.1 (C),
39.7 (CH2), 64.3 (CH2), 125.4 (CH), 126.3 (CH), 127.6 (4xCH), 128.2 (CH), 129.4 (CH), 129.6 (2xCH),
130.3 (C), 132.4 (CH), 132.9 (CH), 133.3 (CH), 133.6 (2xC), 134.7 (CH), 135.6 (4xCH), 137.4 (C)
ppm. MS ESI-TOF m/z (%) 496 (2), 301 (28), 279 (100). HRMS (CI) calcd. for C34H44OSi, 496.3161;
found, 496.3159.
(7E,9E,11Z,13E)-9-Demethyl-tert-butyldiphenylsilyl retinyl ether (13). Suzuki reaction: Following
the same procedure as described for compound 12, reaction of trienyl iodide 2a (56 mg, 0.18 mmol),
dienyl boronate 4b (179 mg, 0.4 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and TlOH (10 % in water, 0.8
mL, 0.37 mmol), in THF (5 mL) for 5 h, afforded 13 (82 mg, 90% yield) as an unstable pale yellow oil.
Stille reaction: Following the same procedure as described for compound 12, reaction of trienyl iodide
2a (50 mg, 0.16 mmol), tributyldienylstannane 5b (156 mg, 0.25 mmol) and PdCl2(CH3CN)2 (4.0 mg,
0.016 mmol) in DMF (4 mL), yielded 68 mg (83%) of 13. 1H NMR (750 MHz, CDCl3) δ 1.03 (s, 6H),
1.05 (s, 9H), 1.4-1.5 (m, 2H), 1.5-1.6 (m, 2H), 1.67 (s, 3H), 1.72 (s, 3H), 2.02 (t, J = 6.3 Hz, 2H), 4.35
(d, J = 6.2 Hz, 2H), 5.69 (t, J = 6.2 Hz, 1H), 5.78 (d, J = 11.7 Hz, 1H), 6.00 (t, J = 11.7 Hz, 1H), 6.11
(dd, J = 15.6, 10.7 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H ), 6.30 (dd, J = 14.4, 10.7 Hz, 1H), 6.69 (dd, J =
13
14.4, 11.7 Hz, 1H), 7.3-7.4 (m, 6H), 7.6-7.7 (m, 4H) ppm. C NMR (75 MHz, CDCl3) δ 17.0 (CH3),
18.8 (C), 19.2 (CH2), 21.8 (CH3), 26.8 (3xCH3), 28.9 (2xCH3), 33.3 (CH2), 34.1 (C), 39.8 (CH2), 61.1
(CH2), 127.6 (4xCH), 127.9 (CH), 128.8 (CH), 129.6 (2xCH), 130.4 (C), 131.1 (CH), 132.1 (CH), 132.7
(CH), 133.4 (CH), 133.9 (2xC), 134.5 (C), 135.5 (CH), 135.6 (4xCH), 137.5 (C) ppm. MS (CI) m/z (%):
510 (58), 495 (2), 433 (5), 255 (75), 199 (100). HRMS (CI) calcd. for C35H46OSi, 510.3318; found,
510.3317.

S4
(7E,9E,11Z,13E)-13-Demethyl-tert-butyldiphenylsilyl retinyl ether (14). Suzuki reaction with iodide:
Following the same procedure as described for compound 12, reaction of trienyl iodide 2b (113 mg,
0.36 mmol), pinacol dienylboronate 4a (200 mg, 0.43 mmol), Pd(PPh3)4 (58 mg, 0.036 mmol) and
TlOH (10 % in water, 2.9 mL, 1.30 mmol), in THF (8 mL) for 5 h, afforded 147 mg (80% yield) of 14
as an unstable pale yellow oil. Suzuki reaction with triflate: To a suspension of Pd(PPh3)4 (34 mg, 0.029
mmol), K3PO4 (123 mg, 0.58 mmol) and pinacol dienylboronate 4a (199 mg, 0.44 mmol) in THF (4
mL) was added, via cannula, a solution of trienyl triflate 3 (100 mg, 0.29 mmol) in THF (2 mL), and the
reaction mixture was stirred for 5h, filtered through a short pad of neutral alumina (IV, hexane), and
concentrated. Flash chromatography of the crude (Al2O3, hexane) yielded 92 mg (63% yield) of 14.
Stille reaction with iodide: Following the same procedure as described for compound 12, reaction of
trienyl iodide 2b (50 mg, 0.16 mmol), tributyldienylstannane 5a (145.3 mg, 0.24 mmol) and
PdCl2(CH3CN)2 (4.0 mg, 0.016 mmol) in DMF (4 mL) afforded 47 mg (57%) of 14. Stille reaction with
triflate: To a solution of trienyl triflate 3 (113 mg, 0.334 mmol) and dienylstannane 5a (225 mg, 0.367
mmol) in NMP (4 mL) were added, each in one portion, Pd2(dba)3·CHCl3 (8.0 mg, 0.008 mmol) and
AsPh3 (20 mg, 0.067 mmol) and the reaction mixture was stirred for 12 h, filtered through a short pad of
neutral alumina, and concentrated. Flash chromatography of the crude (Al2O3, hexane) yielded 133 mg
(78%) of 14. 1H NMR (750 MHz, CDCl3) δ 1.04 (s, 6H), 1.09 (s, 9H), 1.4-1.5 (m, 4H), 1.6-1.7 (m, 4H),
1.73 (s, 3H), 1.94 (s, 3H), 2.03 (t, J = 6.2 Hz, 2H), 4.31 (d, J = 4.8 Hz, 2H), 5.82 (dt, J = 15.0, 4.8 Hz,
1H), 6.05 (t, J = 11.1 Hz, 1H), 6.12 (d, J = 16.1 Hz, 1H), 6.20 (d, J = 16.1 Hz, 1H), 6.33 (dd, J = 12.0,
11.1 Hz, 1H), 6.45 (d, J = 12.0 Hz, 1H), 6.83 (dd, J = 15.0, 11.1 Hz, 1H), 7.2-7.3 (m, 6H), 7.7-7.8 (m,
13
4H) ppm. C NMR (100 MHz, CDCl3) δ 12.3 (CH3), 19.2 (CH2), 19.3 (C), 21.7 (CH3), 26.8 (3xCH3),
29.0 (2xCH3), 33.1 (CH2), 34.3 (C), 39.6 (CH2), 64.3 (CH2), 124.9 (CH), 125.2 (CH), 125.4 (CH), 127.1
(CH), 127.7 (4xCH), 128.3 (CH), 128.7 (CH), 129.6 (2xCH), 133.1 (CH), 133.7 (2xC), 135.6 (4xCH),
136.5 (C), 137.8 (C), 137.9 (CH) ppm. MS (CI) m/z (%) 510 (88), 433 (7), 255 (66), 199 (100). HRMS
(CI) calcd. for C35H46OSi, 510.3318; found, 510.3312.

S5
Tables of spectroscopic data.

S6

S7

S8
NMR Spectra.
O
B
O
OTBDPS
4a
1H NMR (300 MHz, CDCl3), Method A
7.00
6.50
6.00
5.50
ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
13C NMR (75 MHz, CDCl3), Method A
125.0
120.0
ppm (t1)
150
100
50
0
ppm (t1)
150
100
50
0
ppm (t1)

S9
O
B
O
OTBDPS
4b
1H NMR (300 MHz, CDCl3), Method C
8.0
ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
13C NMR (75 MHz, CDCl3), Method C
125.0
120.0
ppm (t1)
150
ppm (t1)
100
50
0
150
ppm (t1)
100
50
0

S10
Bu3Sn
OTBDPS
5a
1H NMR (300 MHz, CDCl3), Method B
7.00
ppm (t1)
6.75
6.50
6.25
6.00
5.75
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3), Method B
150
ppm (t1)
100
50
0
150
ppm (t1)
100
50
0

S11
Bu3Sn
OTBDPS
5b
1H NMR (300 MHz, CDCl3), Method B
7.00
ppm (t1)
6.50
6.00
5.50
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3), Method B
150
ppm (t1)
100
50
0
150
ppm (t1)
100
50
0

S12
Me3Sn
OTBDPS
6
1H NMR (300 MHz, CDCl3), Method D
7.00
6.50
6.00
ppm (f1)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
13C NMR (75 MHz, CDCl3), Method D
150
ppm (t1)
100
50
0
150
ppm (t1)
100
50
0

S13
150.0
145.0
140.0
135.0
130.0
ppm (t1)
150.0
145.0
140.0
135.0
130.0
ppm (t1)

S14
OTBDPS
7a
1H NMR (300 MHz, CDCl3)
8.0
ppm (t1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S15
OTBDPS
7b
1H NMR (300 MHz, CDCl3)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S16
O
O
B
OTBDPS
8a
1H NMR (300 MHz, CDCl3)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S17
145.0
140.0
135.0
130.0
ppm (t1)
145.0
140.0
135.0
130.0
ppm (t1)

S18
SnBu3
OTBDPS
9a
1H NMR (300 MHz, CDCl3)
6.200 6.150 6.100 6.050 6.000 5.950
ppm (t1)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S19
SnBu3
OTBDPS
9b
1H NMR (300 MHz, CDCl3)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S20
I
OTBDPS
10
1H NMR (300 MHz, CDCl3)
8.0
ppm (t1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
13C NMR (75 MHz, CDCl3)
150
100
50
0
ppm (t1)
150
100
50
0
ppm (t1)

S21
OTBDPS
11
1H NMR (300 MHz, CDCl3)
6.50
6.00
5.50
5.00
4.50
ppm (t1)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S22
Z
12
OTBDPS
1H NMR (400 MHz, CDCl3), Suzuki reaction
6.50
6.00
ppm (f1)
8.0
ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
13C NMR (100 MHz, CDCl3), Suzuki reaction
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S23
126.527
135.0
130.0
ppm (t1)
134.0
133.0
132.0
131.0
130.0
129.0
ppm (t1)

S24
Z
OTBDPS
13
1H NMR (750 MHz, CDCl3), Suzuki reaction
6.50
6.00
ppm (t1)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (75 MHz, CDCl3), Suzuki reaction
100
50
0
ppm (f1)
100
50
0
ppm (f1)

S25
135.0
130.0
ppm (f1)
137.0
136.0
135.0
134.0
133.0
132.0
131.0
130.0
129.0
128.0
ppm (f1)

S26
Z
14
OTBDPS
1H NMR (750 MHz, CDCl3), Suzuki reaction
6.50
6.00
ppm (t1)
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (100 MHz, CDCl3), Suzuki reaction
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S27
135.0
130.0
125.0
ppm (t1)
135.0
130.0
ppm (t1)

S28
Z
15
OTBDPS
1H NMR (750 MHz, CDCl3), Suzuki reaction
6.50 6.40 6.30 6.20 6.10 6.00 5.90 5.80
ppm (t1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (t1)
13C NMR (75 MHz, CDCl3), Suzuki reaction
100
50
0
ppm (t1)
100
50
0
ppm (t1)

S29
135.0
130.0
125.0
ppm (t1)
135.0
130.0
125.0
ppm (t1)

S30
Z
16
OH
1H NMR (400 MHz, CDCl3)
6.50 6.40 6.30 6.20 6.10 6.00 5.90 5.80 5.70
ppm (t1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
13C NMR (100 MHz, CDCl3)
100
50
0
ppm (t1)
100
50
0
ppm (t1)