Synthesis of all-E- and 9Z-heteroaryl-retinoic acid applying palladium catalyzed coupling reaction of (arylvinyl)tributyl stannane with vinyl triflate

Article abstract of DOI:10.1055/s-2001-18104

Palladium catalyzed cross coupling reactions of (arylvinyl)tributyl stannanes with vinyl triflates resulted in the production of stereochemically pure trisubstituted E- and Z-olefins in very good yields. These olefins were transformed to the corresponding all-E- and 9Z- heteroaryl-retinoic acid analogs via Horner-Emmons reaction and subsequent basic hydrolysis in excellent yields.

Full text of DOI:10.1055/s-2001-18104

LETTER
1759
Synthesis of all-E- and 9Z-Heteroaryl-retinoic Acid Applying Palladium
Catalyzed Coupling Reaction of (Arylvinyl)tributyl Stannane with Vinyl
Triflate
S
ynthesis of all-
E
-
k
a
nd9
Z
-Hete
i
r
oaryl-r
m
etinoic
A
cid ori Wada,* Govindarajuru Babu, Sayaka Shimomoto, Masayoshi Ito*
Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
E-mail: a-wada@kobepharma-u.ac.jp
Received 28 August 2001
step in our synthetic strategy is based on the coupling re-
action of two segments B and C. Segment C was obtained
from ethyl acetoacetate by the reported method8 and the
separation of two stereoisomers was easily performed by
Abstract: Palladium catalyzed cross coupling reactions of (arylvi-
nyl)tributyl stannanes with vinyl triflates resulted in the production
of stereochemically pure trisubstituted E- and Z-olefins in very
good yields. These olefins were transformed to the corresponding
all-E- and 9Z- heteroaryl-retinoic acid analogs via Horner–Emmons column chromatography (Scheme 1).
reaction and subsequent basic hydrolysis in excellent yields.
Key words: retinoid X receptors, heteroaryl-retinoic acid, coupling
reaction, vinyl triflate, (arylvinyl)tributyl stannane
7
9
7
11
CO2H
1
10
1
8
10
11
12
14
18
all-E-Retinoic acid
It is well known that all-E-retinoic acid and 9Z-retinoic
acid (Scheme 1) are the ligand molecules for retinoic acid
receptors (RAR , , ) and retinoid X receptors (RXR ,
, ), respectively.1 They are members of the nuclear re-
ceptor superfamily and exhibit significant biological
functions which include cell differentiation, cell prolifer-
ation, embryonic development etc. through gene tran-
scription.2 In biological system, RXRs form functional
heterodimers with other proteins of the nuclear receptors
such as the RARs, the thyroid hormone receptor (TR), the
vitamin D receptor (VDR) and the peroxisome prolifera-
tor-activated receptors (PPAR). These heterodimers bind
to co-activator or co-repressor proteins with changing
their conformation depending on the nature of the ligand
molecule, and then activate or repress a wide variety of
gene transcription. Currently great efforts have been
found for the preparation of receptor-selective retinoids in
order not only to define the functions of each receptor but
also to develop the therapeutic agents.3 In connection with
our study on the stereoselective synthesis of retinoids,4,5
we wish to report a convenient synthesis of all-E- and 9Z-
heteroaryl-retinoic acid analogs 12 and 14 (Scheme 3),
which replace the 2,6,6-trimethylcyclohexene ring of ret-
inoic acid by the heterocyclic rings in order not only to de-
crease a hydrophobic character of analogs but also to
investigate the interaction between the ligand and the re-
ceptor protein, by the application of a stereoselective, pal-
ladium catalyzed cross coupling reaction of (arylvinyl)-
tributyl stannanes with E- and Z-vinyltriflates.6,7
CO2H
9Z-Retinoic Acid
9
CO2H
Ar
Ar = heteroaromatics
9
CHO
CO2Et
Ar
(EtO)2P(O)CH2
A
O
O
SnBu3
CHO
Ar
CO2Et
Ar
TfO
OEt
B
C
Scheme 1
Our synthetic approach toward heteroaryl-retinoic acids
starts from the synthesis of (arylvinyl)tributyl stannanes 3
(Scheme 2). The arylaldehydes 1 were transformed to the
acetylenes 2 by the standard procedure using carbon tetra-
bromide and triphenylphosphine and subsequent treat-
ment with n-butyllithium.9 Hydrostannylation10 of 2 with
n-Bu3SnH in the presence of a catalytic amount of AIBN
at 50 °C for 12–16 hours afforded the corresponding
(arylvinyl)tributyl stannanes 311 in moderate to good
yields.
As the conversion of -ionylideneacetaldehyde analog A
to the corresponding retinoic acid has been already estab-
lished using Horner–Emmons or Wittig reaction,3,4 key
Stille coupling reaction of 3a with (E)-vinyl triflate 58 in
the presence of a catalytic amount of tris(dibenzylidene-
acetone)dipalladium(0)-chloroform adduct (Pd2(dba)3-
CHCl3) with triphenylarsine (AsPh3)12 provided the 9E-
ester 6a in 72% yield.13 Under the same conditions, the
coupling reaction of 3a with (Z)-triflate 5’8 also proceeded
smoothly to afford the 9Z-ester 8a13 in 78% yield
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1759,1762,ftx,en;Y16601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1760
A. Wada et al.
LETTER
(83-42%)
SnBu3
(96-72%)
(54-22%)
CHO
7
9
Ar
Ar
Ar
R
1) Ph3P, CBr4
2) n-BuLi
AIBN, Bu3SnH
Ar
3a-e
2a-e
Pd2(dba)3-CHCl3 ,
Ph3As, / DMF, r.t.
1a-e
1) DIBALH
2) TPAP
NMO
6a-e: R=CO2Et
7a-e: R=CHO
1, 2, 3, 6, 7, 8, 9
(61- 92%)
5'
(54-86%)
S
a
b
7
9
Ar
S
R
1) DIBALH
2) TPAP
NMO
8a-e: R=CO2Et
9a-e: R=CHO
(45-76%)
O
c
d
OTf
O
O
ref. 8
CO2Et
CO2Et
TfO
N
OEt
Et3N, Tf2O
5
/ CH2Cl2, -78 °C
SO2Ph
4
5'
e
N
Scheme 2
(Scheme 2). The esters 6a and 8a were converted to the al- dehydes,16 and it was found that this coupling reaction
dehydes 7a and 9a without isomerization of double bond proceeded stereospecifically with retention of the config-
by DIBALH reduction and subsequent oxidation using uration of the double bonds.
tetra-n-propylammonium perruthenate (TPAP) and N-
As we could develop a stereocontrolled synthesis of -io-
nylideneacetaldehyde analogs, our attention was focused
on the synthesis of heteroaryl-retinoic acid analogs. The
Horner–Emmons reaction of aldehyde 7a with C-5 phos-
methylmorpholine N-Oxide (NMO)14 in 58% and 68%
yields, respectively.15 The structures of 7a and 9a were
determined on the basis of their spectral data by the com-
parison of those of the corresponding -ionylideneacetal-
13
7, 9, 11, 12, 13, 14
9
7
CO2X
(71- 92%)
7a-e
Ar
14
S
i) n-BuLi, 10,
a
b
DMPU / THF
ii) recrystallization
11a-e: X=Et
KOH, EtOH
(80-87%)
12a-c, e: X=H
S
O
(EtO)2P
CO2Et
O
10
c
d
9
7
Ar
(75- 88%)
9a-e
N
i) n-BuLi, 10,
DMPU / THF
ii) recrystallization
13
SO2Ph
CO2X
e
13a-e: X=Et
14a, b, e: X=H
KOH, EtOH
(80%-quant.)
N
Scheme 3
Synlett 2001, No. 11, 1759–1762 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of all-E- and 9Z-Heteroaryl-retinoic Acid
1761
phonate 10 using n-BuLi as a base in the presence of 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DM-
PU)17 first at –78 °C and then at 0 °C gave the ester 11 as
a mixture of the double bond isomers in good yield. Pure
all-E-isomer was obtained by recrystallization of the
crude product from ether-n-hexane, and this compound
was transformed to the corresponding all-E-heteroaryl-re-
tinoic acid 12a by basic-hydrolysis in excellent yield. In a
similar fashion, the 9Z-aldehyde 9a was converted to the
corresponding 9Z-retinoic acid analog 14a in good yield18
(Scheme 3).
Table 2 Yields of Reactions for the Synthesis of 9Z-Heteroaryl-re-
tinoic Acids
Run Substituent Ar
Yield
of 8
Yield
of 9
Yield of
13 (%,
13E/13Z)
Yield
of 14
(%)
(%)a)
(%)b)
1
2
2-thienyl
78
68
76
62/13
77/9
96
2-benzo[b]thienyl 91
quant
.
d)
d)
3
4
2-benzo[b]furyl
61
92
50c)
60
-
–
e)
N-SO2Ph-3-in-
dolyl
74/10
77/8
–
By adopting the same methodology used for the thiophen-
ecarbaldehyde 1a, other heteroaromatic aldehydes 1b–e
were also transformed to the corresponding ethyl all-E
and 9Z-retinoate analogs (11b–e and 13b–e) in good to
excellent yields except for 13c.19 The esters 11b,c,e and
13b,e were converted to the corresponding acids and these
results are summarized in Tables 1 and 2.
5
3-pyridyl
92
45
80
a) Pd2(dba)3-CHCl3, AsPh3 and 5 in DMF at r.t.
b) Yield in 2 steps.
c) As a mixture of Z- and E -isomer (Z:E = 2:1).
d) Not performed.
e) Not obtained.
Table 1 Yields of Reactions for the Synthesis of all-E-Heteroaryl-
retinoic Acids
logical evaluation of these new analogs is currently in
progress.
Run Substituent Ar
Yield
of 6
(%)a)
Yield
of 7
Yield of
11 (%,
13E/13Z) (%)
Yield
of 12
(%)b)
Acknowledgement
1
2
3
4
5
2-thienyl
72
91
88
58
86
63
54
57
79/13
81c)
80
87
87
This work was supported in part by the Kobe Pharmaceutical Uni-
versity Collaboration Fund and The Science Research Promotion
Fund from the Japan Private School Promotion Foundation. We
thank the Kobe Pharmaceutical University for a postdoctoral fel-
lowship (to G. B.).
2-benzo[b]thienyl
2-benzo[b]furyl
61/10
63/27
85/7
d)
N-SO2Ph-3-indolyl 96
3-pyridyl 75
–
83
References and Notes
a) Pd2(dba)3-CHCl3, AsPh3 and 5 in DMF at r.t.
b) Yield in 2 steps.
(1) Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. In The
Retinoids; Sporn, M. B.; Roberts, A. B.; Goodman, D. S.,
Eds.; Raven: New York, 1994, 2nd ed., 319.
c) 13Z-isomer was not detected at all.
d) Not obtained.
(2) (a) Heyman, R. A.; Mangelsdorf, D. J.; Dyck, J. A.; Stein, R.
B.; Eichele, G.; Evans, R. M.; Thaller, C. Cell 1992, 68,
397. (b) Hong, W. K.; Sporn, M. B. Science 1997, 278, 1073.
(3) (a) Beard, R. L.; Klein, E. S.; Standeven, A. M.; Escobar,
M.; Chandraratna, R. A. S. Bioorg. Med. Chem. Lett. 2001,
11, 765. (b) Njar, V. C. O.; Nnane, I. P.; Broddie, A. M. H.
Bioorg. Med. Chem. Lett. 2000, 10, 1905. (c) Kikuchi, K.;
Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.;
Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10,
619. (d) Viligonda, V.; Garst, M. E.; Chandraratna, R. A. S.
Bioorg. Med. Chem. Lett. 1999, 9, 589. (e) Wong, M. F.;
Repa, J. J.; Clagett-Dame, M.; Curley, R. W. J. r. Bioorg.
Med. Chem. Lett. 1997, 7, 2313. (f) Yu, K.-L.; Chen, S.;
Ostrowski, J.; Tramposch, K. M.; Reczek, P. R.; Mansuri,
In the case of indolylesters 11d and 13d, our first attempts
to isolate N-unsubstituted acids by basic-hydrolysis20
were unsuccessful. Therefore, the ester 11d was convert-
ed to the N-methylated acid 16 by the sequence of desulfo-
nylation, methylation and subsequent basic-hydrolysis
(Scheme 4).
In conclusion, we have stereoselectively synthesized the
trisubstituted E- or Z- olefin using a modified Stille cou-
pling reaction of (arylvinyl)tributyl stannane with E- or Z-
vinyl triflate and have achieved the synthesis of previous-
ly unreported heteroaryl-retinoic acid analogs. The bio-
CO2X
CO2Et
(31%)
N
N
i) TBAF / THF , 50 °C
ii) NaH / DMSO , 0 °C
then MeI
Me
SO2Ph
15: X=Et
16: X=H
KOH, EtOH
(82%)
11d
Scheme 4
Synlett 2001, No. 11, 1759–1762 ISSN 0936-5214 © Thieme Stuttgart · New York

1762
A. Wada et al.
LETTER
M. M.; Starrett, J. E. Jr Bioorg. Med. Chem. Lett. 1996, 6,
2859. (g) Trost, B. M.; Harms, A. E. Tetrahedron Lett. 1996,
37, 3971. (h) Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M.
R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.;
Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. J. Med.
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2930. (j) Vaezi, M. F.; Alam, M.; Sani, B. P.; Rogers, T. S.;
Simpson-Herren, L.; Wille, J. J.; Hill, D. L.; Doran, T. I.;
Brouillette, W. J.; Muccio, D. D. J. Med. Chem. 1994, 37,
4499.
6a: IR (CHCl3)cm–1: 2960, 1702, 1608; 1H NMR (300 MHz,
CDCl3) : 1.29 (3 H, t, J = 7 Hz), 2.37 (3 H, s), 4.18 (2 H, q,
J = 7 Hz), 5.86 (1 H, s), 6.63 (1 H,d, J = 16 Hz), 7.01 (1 H,
dd, J = 3.5, 5 Hz), 7.05 (1 H, d, J = 16 Hz), 7.09 (1 H, d,
J = 3.5 Hz), 7.24 (1 H, d, J = 5 Hz); 13C NMR (75 MHz,
CDCl3) : 13.5, 14.3, 59.7, 119.5, 125.9, 126.9, 127.7, 127.8,
131.4, 141.9, 151.6, 167.0; HRMS (EI) C12H14O2S: requires
220.0715, found 220.0721.
8a: IR (CHCl3) cm–1: 2984, 1697, 1612; 1H NMR (300 MHz,
CDCl3) : 1.31 (3 H, t, J = 7 Hz), 2.08 (3 H, s), 4.19 (2 H, q,
J = 7 Hz), 5.71 (1 H, s), 7.00 (1 H, dd, J = 3.5, 5.5 Hz), 7.03
(1 H, d, J = 15 Hz), 7.13 (1 H, d, J = 3.5 Hz), 7.25 (1 H, d
J = 5.5 Hz), 8.20 (1 H, d J = 15 Hz); 13C NMR (75 MHz,
CDCl3) : 14.3, 20.7, 59.8, 117.6, 125.6, 126.3, 127.7, 127.8,
128.1, 142.5, 150.0, 166.3; HRMS (EI) C12H14O2S: requires
220.0715, found 220.0722.
(4) (a) Wada, A.; Hiraishi, S.; Ito, M. Chem. Pharm. Bull. 1994,
42, 757. (b) Wada, A.; Tanaka, Y.; Fujioka, N.; Ito, M.
Bioorg. Med. Chem. Lett. 1996, 6, 2049. (c) Wada, A.;
Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J. Org.
Chem. 1997, 62, 4343. (d) Wada, A.; Fujioka, N.; Tanaka,
Y.; Ito, M. J. Org. Chem. 2000, 65, 2438.
(14) Griffith, W. P.; Ley, S. V.; Whitecombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625.
(5) (a) Wada, A.; Nomoto, Y.; Tano, K.; Yamashita, E.; Ito, M.
Chem. Pharm. Bull. 2000, 48, 1391. (b) Wada, A.;
Fukunaga, K.; Ito, M. Synlett 2001, 800.
(6) Several similar cross coupling reactions for the
stereoselective synthesis of retinoids have already been
reported; for all-E-retinoids see: (a) Torrado, A.; Iglesias,
B.; López, S.; de Lera, A. R. Tetrahedron 1995, 51, 2435.
(b) Torrado, A.; López, S.; Alvarez, R.; de Lera, A. R.
Synthesis 1995, 285. (c) Thibonnet, J.; Abarbri, M.;
Duchêne, A.; Parrain, J.-L. Synlett 1999, 141.
(d) Dominguez, B.; Iglesias, B.; de Lera, A. R. J. Org. Chem.
1998, 63, 4135.
(7) (a) For 9Z-retinoic acid see: Pazos, Y.; de Lera, A. R.
Tetrahedron Lett. 1999, 40, 8287. (b) For 11Z-retinal
see:Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Wada, A.;
Ito, M. Angew. Chem. Int. Ed. 1998, 37, 320.
(8) (a) Saulnier, M. G.; Kadow, J. F.; Tun, M. M.; Langley, D.
R.; Vyas, D. M. J. Am. Chem. Soc. 1989, 111, 8320.
(b) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(10) (a) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem.
1990, 55, 1857. (b) Betzer, J.-F.; Delaloge, F.; Muller, B.;
Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62, 7768.
(11) Stannylcupration of 2 with lithium
(15) Spectral data are as follows; 7a: IR (CHCl3)cm–1: 3012,
1658, 1600; 1H NMR (300 MHz) : 2.34 (3 H, s), 6.05 (1 H,
d, J = 8 Hz), 6.72 (1 H, d, J = 16 Hz), 7.04 (1 H, dd, J = 3.5,
5 Hz), 7.16 (1 H, d J = 3.5 Hz), 7.22 (1 H, d, J = 16 Hz), 7.32
(1 H, d J = 5 Hz), 10.14 (1 H, d, J = 8 Hz); 13C NMR (75
MHz, CDCl3) : 12.9, 126.9, 128.0, 128.5, 128.7, 129.6,
130.6, 141.5, 153.8, 191.0; HRMS (EI) C10H10O2S: requires
178.0452, found 178.0457. 9a: IR (CHCl3) cm–1: 3012,
1658, 1605; 1H NMR (300 MHz) : 2.16 (3 H, s), 5.92 (1 H,
d, J = 8 Hz), 7.05 (1 H, dd, J = 3.5, 5 Hz), 7.12 (1 H, d,
J = 16 Hz), 7.17 (1 H, d J = 3.5 Hz), 7.32 (1 H, d, J = 5 Hz),
7.64 (1 H, d, J = 16 Hz), 10.26 (1 H, d, J = 8 Hz); 13C NMR
(75 MHz, CDCl3) : 21.0, 122.7, 127.0, 128.0, 128.3, 128.9,
129.5, 141.5, 153.6, 189.7; HRMS (EI) C10H10O2S: requires
178.0452, found 178.0450.
(16) (a) Dugger, R. W.; Heathcock, C. H. Synth. Commun. 1980,
10, 509. (b) Robeson, C. D.; Cawley, J. D.; Weisler, L.;
Stern, M. H.; Eddinger, C. C.; Chechak, A. J. J. Am. Chem.
Soc. 1955, 77, 4111.
(17) Bennani, Y. L. J. Org. Chem. 1996, 61, 3542.
(18) Spectral data are as follows; 12a: IR (CHCl3) cm–1: 3300–
2600, 1683, 1590; 1H NMR (300 MHz) : 2.04 (3 H, s), 2.37
(3 H, s), 5.83 (1 H, s), 6.32 (1 H, d, J = 11 Hz), 6.38 (1 H, d,
J = 15 Hz), 6.72 (1 H, d, J = 16 Hz), 6.85 (1 H, d, J = 16
Hz), 6.99 (1 H, dd, J = 3.5, 5 Hz), 7.03 (1 H, d, J = 3.5 Hz),
7.08 (1 H, dd, J = 11, 15 Hz), 7.19 (1 H, d, J = 5 Hz), COOH
signal was not present; 13C NMR (75 MHz, CDCl3) : 12.9,
14.0, 118.0, 122.6, 124.7, 126.3, 127.7, 131.3, 131.5, 132.7,
135.8, 139.2, 143.1, 155.0, CO signal was not present;
HRMS (EI) C15H16O2S: requires 260.0870, found 260.0860.
14a: IR (CHCl3) cm–1: 3300–2600, 1681, 1590; 1H NMR
(500 MHz) : 2.03 (3 H, s), 2.38 (3 H, s), 5.81 (1 H, s), 6.13
(1 H, d, J = 11 Hz), 6.29 (1 H, d, J = 15 Hz), 6.82 (1 H, d,
J = 15 Hz), 6.99 (1 H, dd, J = 3.5, 5 Hz), 7.05 (1 H, d,
J = 3.5 Hz), 7.16 (1 H, d, J = 5 Hz), 7.20 (1 H, d, J = 15 Hz),
7.21 (1 H, dd, J = 11, 15 Hz), COOH signal was not present;
13C NMR (125 MHz, CDCl3) : 14.1, 20.8, 117.3, 122.7,
123.9, 124.6, 125.0, 126.7, 127.8, 129.7, 130.1, 135.1,
142.9, 154.0, CO signal was not present; HRMS (EI)
C15H16O2S: requires 260.0870, found 260.0872.
butyltributylstannylcyanocuprate at –78 °C in THF also
afforded the(arylvinyl)tributyl stannane 3 in good yield. 1H
NMR data of 3a are as follows; (300 MHz, CDCl3) 0.8–1.6
(27 H, m), 6.59 (1 H, d, J = 19 Hz), 6.8–7.0 (2 H, m), 6.95 (1
H, d, J = 19 Hz), 7.13 (1 H, d, J = 5 Hz).
(12) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(13) Typical coupling procedure: To a stirred solution
of(arylvinyl)tributyl stannane (3, 1 mmol), vinyl triflate (5 or
5’, 1.5 mmol) and AsPh3 (20 mol%, 60 mg) in DMF (2 mL)
was added Pd2(dba)3-CHCl3 adduct (2.5 mol%, 26 mg) all at
once at r.t. under nitrogen. After stirring for an additional 2
h, the reaction was quenched with saturated aq KF solution
(3 mL) and extracted with Et2O (10 mL 3). The extracts
were washed with aq sat. NaCl solution (10 mL) and then
dried over Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by column
chromatography on silica gel to afford the coupled ester.
(19) It was difficult to obtain the 9Z-aldehyde 9c in pure form due
to its easy isomerization.
(20) Nagarathnam, D. J. Heterocyclic Chem. 1992, 29, 953.
Synlett 2001, No. 11, 1759–1762 ISSN 0936-5214 © Thieme Stuttgart · New York