Tetraenylstannanes in the synthesis of retinoic acid and its ring- modified analogues

Full text of DOI:10.1021/jo980097w

J . Org. Chem. 1998, 63, 4135-4139
4135
In some of the most active known retinoids, the
unstable polyolefinic chain of 1a is stabilized by the
inclusion of some of its double bonds in aromatic rings.
However, our structure-activity studies have recently
led us to investigate a synthetically more challenging
series of ring-modified retinoic acid analogues (1b-f), all
of them with the unaltered side-chain of 1a .
Tetr a en ylsta n n a n es in th e Syn th esis of
Retin oic Acid a n d Its Rin g-Mod ified
An a logu es
Beatriz Dom´ınguez, Beatriz Iglesias, and
Angel R. de Lera*
Departamento de Quı´mica Fı´sica y Quı´mica Orga´nica,
Facultad de Ciencias, Universidad de Vigo,
36200 Vigo (Spain)
Traditional routes to retinoids, based on olefin elonga-
tion procedures (Wittig, Horner-Wadsworth-Emmons,
and J ulia reactions),2a are recently being replaced by
more stereoselective approaches.4-6 Use of the Suzuki
reaction5 for the synthesis of retinoic acid analogues with
unmodified side chains is limited by the instability of the
corresponding conjugated alkenylboronic acids. The
popular Stille reaction6 is more versatile: alkenylstan-
nanes remain unaltered upon treatment with a variety
of reagents under a diversity of reaction conditions, and
recent improvements7 using alternative catalysts, co-
catalysts, and solvents can allow the use of reaction
conditions that are considerably milder that those orig-
inally reported.6
Received J anuary 21, 1998
Retinoids (vitamin A and its structural and functional
analogues) are currently the subject of intense biological
interest stimulated by the discovery and characterization
of retinoid receptors1 and the subsequent consideration
of retinoic acids as nonsteroidal small-molecule hor-
mones. The retinoid families of nuclear proteins [RARs
(retinoic acid receptors) and RXRs (retinoid X receptors)]
comprising subtypes RARR,â,γ and RXRR,â,γ) act as
ligand-inducible transcription factors in the proliferation
and differentiation of mammalian cells. trans-Retinoic
acid (1a ) is the natural ligand for RAR, and its isomer
9-cis-retinoic acid (2) has high affinity for, and activates,
both RAR and RXR.
The effects of retinoids on cell differentiation and
proliferation have spurred the synthesis and biological
evaluation of numerous retinoic acid analogues.2 Since
the subtypes within each receptor family, which are
encoded by separate genes, show some differences in
tissue distribution, synthetic retinoids selective for in-
dividual subtypes would be important tools for better
delineation of the multiple effects of retinoids in mam-
malian cells.3
Since we are interested in modifying only the cyclo-
hexenyl ring of retinoic acid, we decided to use the
polyenic functionalized stannane 5 (Scheme 1) as the
common Stille coupling partner of vinyltriflates 8a -f
(which can be prepared regioselectively from the com-
mercially available cyclohexanones 78) in a new synthesis
of retinoic acid (1a ) and the ring-modified analogues 1b-
f. This paper reports our results.
Tetraenylstannane 5 was prepared in good yield and
with excellent stereoselectivity by Horner-Wadsworth-
Emmons condensation, at -78 °C, of known stannane 39
and the carbanion derived from the treatment of phos-
phonate 410 with n-BuLi and 1,3-dimethyl-3,4,5,6-tet-
rahydro-2(1H)-pyrimidinone (DMPU) in THF at 0 °C11
(Scheme 1). Treatment of 2,2,6-trimethylcyclohexanone
(7a ) with LDA at -78 °C, followed by N-phenyltriflimide,
(4) (a) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32, 6683.
(b) Bienayme, H.; Yezeguelian, C. Tetrahedron 1994, 50, 3389. (c) Trost,
B. M.; Harms, A. E. Tetrahedron Lett. 1996, 37, 3971. (d) Trost, B. M.;
Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter, G. J . Am. Chem. Soc.
1997, 119, 698. (e) Lipshutz, B. H.; Lindsley, C. J . Am. Chem. Soc.
1997, 119, 4555.
(5) (a) de Lera, A. R.; Torrado, A.; Iglesias, B.; Lo´pez, S. Tetrahedron
Lett. 1992, 33, 6205. (b) Torrado, A.; Iglesias, B.; Lo´pez, S.; de Lera,
A. R. Tetrahedron 1995, 51, 2435. (c) Torrado, A.; Lo´pez, S.; Alvarez,
R.; de Lera, A. R. Synthesis 1995, 285. (d) de Lera, A. R.; Iglesias, B.,
Rodr´ıguez, J .; Alvarez, S.; Lo´pez, S.; Villanueva, X.; Padro´s, E. J . Am.
Chem. Soc. 1995, 117, 8220.
(6) (a) Stille, J . K. Pure Appl. Chem. 1985, 57, 1771. (b) Stille, J . K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c) Mitchell, T. N. Synthesis
1992, 803. (d) Sato, T. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier: Oxford,
1995; Vol. 11, Chapter 8, pp 355-387.
(7) Farina, V. Pure Appl. Chem. 1996, 68, 73.
(8) Ritter, K. Synthesis 1993, 735.
(9) Yokokawa, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1993,
34, 6559.
* To whom correspondence should be addressed, phone: (34) 86
812316, fax: (34) 86 812382, e-mail: qolera@uvigo.es.
(1) For reviews, see: (a) Evans, R. M. Science 1988, 240, 889. (b)
Mangelsdorf, D. A.; Evans, R. M. Cell 1995, 83, 841. (c) Katzenellen-
bogen, J . A.; Katzenellenbogen, B. S. Chem. Biol. 1996, 3, 529.
(2) (a) Dawson, M. I.; Okamura, W. H., Eds. Chemistry and Biology
of Synthetic Retinoids; CRC Press: Boca Raton, FL, 1990. (b) Rosen,
J .; Day, A.; J ones, T. K.; J ones, E. T. T.; Nadzan, A. M.; Stein, R. B. J .
Med. Chem. 1995, 38, 4855.
(10) (a) Ahmad, I.; Gedye, R. N.; Nechvatel, A. J . Chem. Soc. (C)
1968, 185. (b) Pattenden, G.; Weedon, B. C. L. J . Chem. Soc. (C) 1968,
1984. (c) Bergdahl, M.; Hett, R.; Friebe, T.; Gangloff, A. R.; Iqbal, J .;
Wu, Y.; Helquist, P. Tetrahedron Lett. 1993, 34, 7371. (d) Helquist,
P.; Bergdahl, M.; Hett, R.; Gangloff, A. R.; Demillequand, M.; Cottard,
M.; Mader, M. M.; Friebe, T. L.; Iqbal, J .; Wu, Y.; Åkermark, B.; Rein,
T.; Kann, N. Pure Appl. Chem. 1994, 66, 2063. (e) Mata, E. G.; Thomas,
E. J . J . Chem. Perkin Trans. 1 1995, 785.
(3) For a recent review, see: Curley, R. W.; Robarge, M. J . Curr.
Med. Chem. 1996, 3, 325.
(11) Bennani, Y. L.; Boehm, M. F. J . Org. Chem. 1995, 60, 1195.
S0022-3263(98)00097-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/15/1998

4136 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Ta ble 1. Op tim iza tion of Rea ction Con d ition s for th e
Sch em e 1a
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g of
Tetr a en ylsta n n a n e 5 a n d Vin yl Tr ifla te 8a
T
t
yield
yield
entry 8a :5
solvent
cat.a additive (°C) (h) 9a b (%) 10c (%)
1
2
3
4
5
6
7
8
1.0:1.1 NMP
1.1:1.0 NMP
A
A
B
A
C
A
B
A
-
70
70
25 2.5
60 2.5
80
70
70
70
2
2
62
68
77f
56f
g
61
-
g
30d
29
23
48
g
39
78
58
-
1.0:1.1 NMP
1.0:1.1 NMP
1.0:1.1 DMF/THF
1.1:1.0 NMP
1.1:1.0 NMP
1.1:1.0 NMP
LiCle
LiCle
-
3
1
5
1
BHTh
-
CuIi
a
A )2.5 mol % Pd2(dba)3, 20 mol % AsPh3; B ) 2.5 mol %
b
Pd2(dba)3; C ) 5 mol % PdCl2(CH3CN)2. Yield based on starting
triflate 8a . c Yield based on starting stannane 5. The same ratio
d
was obtained with five freeze-thaw deoxygenation cycles and slow
addition of stannane 5 (ca. 2 h, syringe pump). e 3 equiv. f Mixture
g
h
i
of isomers. Decomposition. 25 mol %. 5 mol %.
a
Reagents and conditions: (a) LDA, THF, -78 °C, 2 h; then
N-phenyltriflimide, THF, 0 °C, 12 h. (b) i-Pr2NH, MeMgBr; then
N-phenyltriflimide, THF, 0 °C, 12 h. (c) n-BuLi, DMPU, THF, 0
°C, 20 min; then aldehyde 3, -78 °C, 3 h. (d) DIBALH, THF, -78
°C, 30 min.
found 8a to react sluggishly with arylstannanes in the
presence of AsPh3), omitting AsPh3 allowed room-tem-
perature coupling, but the LiCl reduced the isomeric
purity of the polyene products, and omitting both AsPh3
and LiCl led to the homodimer 10 alone, with no 9a
(entry 7). An alternative palladium catalyst led to
extensive decomposition (entry 5).
gave the corresponding triflate 8a .12 The same procedure
was employed for the synthesis of triflates 8b, 8c,12b 8e,12b
and 8f13 starting from the corresponding ketone precur-
sors. Treatment of 2-methylcyclohexanone (7d ) with less
than 1 equiv of bromomagnesium diisopropylamide at 0
°C, followed by treatment with N-phenyltriflimide, af-
forded 8d as the only isolable regioisomer.14
Table 1 shows the results of preliminary studies of the
coupling reaction affording the parent ethyl retinoate
9a .15 Several recent modifications of the Stille protocol
were examined. The catalyst system affording best
conversion was Farina’s “soft” palladium Pd2(dba)3 with
AsPh3 as ligand and N-methyl-2-pyrrolidinone (NMP) as
solvent;16 the optimal proportions of catalyst and ligand
were found to be 2.5% Pd2(dba)3 (5% Pd) and 20% AsPh3
(entries 1 and 2). As in the intramolecular reactions
reported by Piers, and in contrast to other intermolecular
reactions, LiCl was not necessary for coupling 5 to 8a .17
We tried using LiCl (3 equiv), with and without ligand
(entries 3 and 4). However, since temperatures of 70 °C
were required for appreciable coupling (Farina18a too
In all coupling reactions, substantial amounts of the
red homodimer 10 were obtained through a competitive
process that was only slightly depressed by using excess
triflate (1.1:1, entry 2). Homocoupling of vinylstannanes
(and even bromides) was first described by Stille,18b and
although Stille described it as insensitive to the presence
or absence of oxygen,18c Farina reported it to be due to
an oxidative process, caused by oxygen in the medium,18a
that could be minimized by using both AsPh3 and LiCl
or by careful degassing. In this work, careful deoxygen-
ation of reaction flasks and solvents (five freeze-thaw
cycles) failed to reduce stannane homocoupling signifi-
cantly, even if stannane was slowly added with a syringe
pump as the reaction progressed.19 Nor did the presence
of a radical scavenger (25 mol % 2,6-di-tert-butyl-4-
methylphenol, BHT) either reduce homocoupling or
improve product yield (entry 6). Rather, it seems that
factors related to substrate reactivity favor the formation
of 10 (see below).
(12) (a) Scott, W. J .; Crisp, G. T.; Stille, J . K. J . Am. Chem. Soc.
1984, 106, 4630. (b) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan,
K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.;
Murray, C. K. J . Org. Chem. 1986, 51, 279.
(13) (a) Stang, P. J .; Dueber, T. E. Org. Synth. 1974, 54, 79. (b)
Stang, P. J .; Treptow, W. Synthesis 1980, 283.
Unlike Stille reactions with PPh3 as palladium ligand,
in which copper salts20 seem to enhance efficiency by
scavenging this ligand, reactions with low-donicity AsPh3
(14) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1984,
106, 7500.
(15) Trost, B. M.; Fortunak, J . M. D. Tetrahedron Lett. 1981, 22,
3459.
(16) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(17) (a) Piers, E.; Friesen, R. W. J . Org. Chem. 1986, 51, 3405. (b)
Piers, E.; Friesen, R. W.; Keay, B. A. Tetrahedron 1991, 47, 4555.
(18) (a) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J . Org.
Chem. 1993, 58, 5434. (b) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc.
1987, 109, 813. (c) Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1986,
108, 3033.
(19) Kang, S.-K.; Kim, J .-S.; Choi, S.-C. J . Org. Chem. 1997, 62,
4208.
(20) (a) Liebeskind, L. S.; Fengl, R. W. J . Org. Chem. 1990, 55, 5539.
(b) Go´mez-Bengoa, E.; Echavarren, A. M. J . Org. Chem. 1991, 56, 3947.
(c) Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J . Org. Chem. 1991,
56, 6488. (d) Saa´, J . M.; Martorell, G. J . Org. Chem. 1993, 58, 1963.
(e) Piers, E.; Wong, T. J . Org. Chem. 1993, 58, 3609. (f) Farina, V.;
Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J . Org. Chem.
1994, 59, 5905. (g) Roth, G. P.; Farina, V.; Liebeskind, L. S.; Pen˜a-
Cabrera, E. Tetrahedron Lett. 1995, 36, 2191. (h) Takeda, T.; Ka-
basawa, Y.; Fujiwara, T. Tetrahedron 1995, 51, 2515.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4137
Sch em e 2a
Ta ble 2. Gen er a lized P a lla d iu m -Ca ta lyzed
Cr oss-Cou p lin g of Tetr a en ylsta n n a n e 5 a n d Vin yl
Tr ifla tes 8 for th e Syn th esis of Rin g-Mod ified Retin oid s 9
a
Reagents and conditions: (a) 2.5 mol % Pd2(dba)3, 20 mol %
T
t
yield
yield
AsPh3, NMP, 40 °C, 2 h. (b) TPAP, NMO, CH2Cl2, 0 to 25 °C, 2 h.
(c) MnO2, KCN, MeOH, 0 °C, 2 h. (d) 1:4 2 M aqueous KOH/EtOH,
reflux, 10 min.
entrya R1
R2
Me Me Me
Me Me
R3 (°C) (h) product 9b (%) 10c (%)
1
2
3
4
5
6
70
50
50
50
25
25
2
2
2
3
9a
9b
9c
9d
9e
9f
62
30
22
35
18
17
-
H
82
H
H
H
H
Me Me
56d,e
76
Finally, basic hydrolysis of ethyl retinoate (9a ) and the
analogues 9b-f afforded the corresponding acids 1a -f.
In conclusion, tetraenylstannanes 5 and 6 were pre-
pared and used for retinoid synthesis. Although limited
in scope, this study highlights the importance of steric
effects due to the electrophile, which has hitherto largely
been ignored in studies of Stille reactions of vinyl
systems. The occurrence of homocoupling, probably due
to the low reactivity of hindered triflates, can severely
limit the usefulness of highly conjugated stannanes.
Despite attempts to characterize intermediates by NMR,
Farina18a was unable to propose a detailed mechanism
for the homocoupling process. We are currently examin-
ing this secondary reaction in more detail.
H
Me
H
Me
H
H
1
70
92
0.5
a
Reactions were carried out with 2.5 mol % Pd2(dba)3, 20 mol
% AsPh3 and 1:1.1 triflate/stannane in NMP. bYield based on
starting triflate 8. c Yield based on starting stannane 5. Mixture
d
of isomers. e Lower temperatures also afforded mixtures of iso-
mers, and longer reactions times were required.
as ligand have been reported to be enhanced by copper
through the generation of an organocopper species7 which
might accelerate the rate-limiting transmetalation step
of the catalytic cycle. In this work, however, addition of
5 mol % copper iodide (entry 8) or excess CuCN4e led to
extensive decomposition.
Table 2 lists the results of applying the optimized
reaction conditions (entry 1 of Table 1) to the remaining
cyclohexenyl triflates, whose lesser steric hindrance of
the reaction is reflected in the lower temperatures needed
to achieve high conversion rates. In all but one case
(entry 3) good to excellent yields of the desired ethyl
retinoate analogues were obtained, and the yield of the
undesired octaene 10 was reduced (to zero in the case of
entry 6). Clearly the homocoupling is significant only
when the reactivity of the triflate is low and requires
more vigorous reaction conditions.
The coupling reaction of the 2,6-dimethyl triflate
analogue 8c was less successful. Extensive isomerization
of both the starting stannane and the retinoate product
was observed even after short reaction times. Reverse-
phase HPLC monitoring showed very rapid catalytic
turnover and deactivation within 5-10 min, even at the
lowest temperature inducing coupling. Treatment of
triflate 8c under the standard reaction conditions at 40
°C with the more reactive alcoholic tetraenylstannane 6
(obtained by DIBALH reduction of ester 5, Scheme 1)
afforded 1-demethylretinol (12) in excellent yield, but
efficiency was lost during conversion of 12 to an alkyl
ester: tetrapropylammonium prerruthenate (TPAP)/N-
methylmorpholine N-oxide (NMO) oxidation21 of 12 to
1-demethylretinal (13),22 followed by treatment of 13
under Corey’s conditions (MnO2/KCN/MeOH),23 afforded
the methyl ester 14 in 33% isolated yield from 8c.
Exp er im en ta l Section 24
Gen er a l Exp er im en ta l P r oced u r es. Proton (1H NMR)
and carbon (13C NMR) magnetic resonance spectra were
recorded in CDCl3 or C6D6. The tin-proton and tin-carbon
coupling constants (J Sn-H and J Sn-C) are given as an average
of the 117Sn and 119Sn values. Infrared spectra (IR) were
recorded in 0.1-mm path length sodium chloride cavity cells.
High-resolution mass spectra (HRMS) data were recorded at
an ionizing voltage of 70 eV.
Analytical thin-layer chromatography was performed on
Merck silica gel plates with F-254 indicator. Visualization was
accomplished by UV light, iodine, or a 15% ethanolic phos-
phomolybdic acid solution. Flash chromatography was per-
formed using E. Merck silica gel 60 (230-400 mesh).
All reactions were performed under a dry argon atmosphere
in oven- and/or flame-dried glassware. Transfer of anhydrous
solvents or mixtures was accomplished with oven-dried sy-
ringes or cannula. Solvents and reagents were distilled before
use: dichloromethane from calcium hydride, and tetrahydro-
furan from sodium benzophenone ketyl. “Brine” refers to
saturated aqueous solution of NaCl.
All reactions involving retinoids as final products or starting
materials were performed under subdued red light.
6,6-D im e t h y l-1-[(t r iflu o r o m e t h a n e s u lfo n y l)o x y ]-
cycloh ex-1-en e (8b). A solution of diisopropylamine (0.46
mL, 3.3 mmol) in THF (3.8 mL) was cooled to 0 °C and treated
with n-BuLi (2.94 M in hexanes, 1.12 mL, 3.3 mmol). The
mixture was stirred at this temperature for 30 min and then
cooled to -78 °C. A solution of 2,2-dimethylcyclohexanone (7b,
0.38 g, 3.0 mmol) in THF (3.8 mL) was slowly added, and the
reaction mixture was stirred at -78 °C for an additional 2 h.
N-phenyltriflimide (1.15 g, 3.21 mmol) in THF (3.8 mL) was
then added, and the mixture was allowed to warm to 0 °C and
was stirred at this temperature for 12 h. The solvent was then
(21) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc. Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V.
Aldrichim. Acta 1990, 23, 13.
(22) Courtin, J . M. L.; Verhagen, L.; Biesheuvel, P. L.; Lugtenburg,
J .; van der Bend, R. L.; van Dam, K. Rec. Trav. Chim. Pays-Bas 1987,
106, 112.
(23) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616.
(24) The purity of all new compounds was judged by a combination
of HPLC and 1H and 13C NMR analysis before mass spectra were
recorded and is indicated in the Supporting Information by copies of
the 1H NMR/13C NMR spectra of selected compounds.

4138 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
removed in vacuo and the resulting residue was diluted with
hexane and washed with 10% HCl. The aqueous layer was
extracted with hexane, and the combined organic layers were
washed with 10% HCl, 10% NaOH, and H2O, dried (MgSO4),
and concentrated. The residue was distilled under vacuum
(50 °C/0.1 mmHg) to obtain 0.56 g of 8b (72%) as a colorless
oil. 1H NMR (400.13 MHz, C6D6) δ 5.66 (t, J ) 4.1 Hz, 1H),
2.1-2.2 (m, 2H), 1.6-1.7 (m, 4H), 1.15 (s, 6H); 13C NMR
(100.61 MHz, CDCl3) δ 156.3, 118.8, 116.6, 39.5, 35.4, 26.7,
25.3, 18.9.
Eth yl 5-Dem eth ylr etin oa te (9b). In accordance with the
general procedure described above, a mixture of Pd2(dba)3 (5
mg, 0.005 mmol), AsPh3 (13.5 mg, 0.044 mmol), triflate 8b (57
mg, 0.22 mmol), and stannane 5 (120 mg, 0.24 mmol) in NMP
(3.3 mL) was stirred at 50 °C for 2 h. The residue was purified
by chromatography (SiO2, 98:2 hexane/ethyl acetate) to afford
57 mg (82%) of 9b25 as a yellow oil and 11 mg (22%) of 10.
Eth yl 1,1-Did em eth ylr etin oa te (9d ). In accordance with
the general procedure described above, a mixture of Pd2(dba)3
(6.9 mg, 0.0075 mmol), AsPh3 (18.4 mg, 0.06 mmol), triflate
8d (67 mg, 0.3 mmol), and stannane 5 (163 mg, 0.33 mmol) in
NMP (4.4 mL) was stirred at 50 °C for 3 h. The residue was
purified by chromatography (SiO2, 98:2 hexane/ethyl acetate)
to afford 68 mg (76%) of 9d 25 as a yellow oil and 12 mg (18%)
of 10.
Eth yl 1,5-Did em eth ylr etin oa te (9e). In accordance with
the general procedure described above, a mixture of Pd2(dba)3
(5.7 mg, 0.006 mmol), AsPh3 (15.3 mg, 0.05 mmol), triflate 8e
(61 mg, 0.25 mmol), and stannane 5 (136 mg, 0.275 mmol) in
NMP (3.3 mL) was stirred at room temperature for 1 h. The
residue was purified by chromatography (SiO2, 98:2 hexane/
ethyl acetate) to afford 52 mg (70%) of 9e25 as a yellow oil and
10 mg (17%) of 10.
Eth yl 1,1,5-Tr id em eth ylr etin oa te (9f). In accordance
with the general procedure described above, a mixture of Pd2-
(dba)3 (3.6 mg, 0.004 mmol), AsPh3 (9.6 mg, 0.031 mmol),
triflate 8f (36 mg, 0.156 mmol), and stannane 5 (85 mg, 0.172
mmol) in NMP (2.3 mL) was stirred at room temperature for
30 min. The residue was purified by chromatography (SiO2,
98:2 hexane/ethyl acetate) to afford 41 mg (92%) of 9f25 as a
yellow oil.
R et in oic Acid (1a ). Gen er a l P r oced u r e for E st er
Hyd r olysis. A solution of ethyl retinoate (9a ; 20 mg, 0.061
mmol) in 1.9 mL of a 1:4 mixture of 2 M aqueous KOH and
ethanol was refluxed for 10 min. The solution was cooled to
room temperature and diluted with Et2O (5 mL) and brine (5
mL). The organic layer was washed with H2O, and the
combined aqueous layers were acidified with 5% HCl to give
a solution which was extracted with Et2O. The combined
organic extracts were washed with H2O and brine and then
dried (MgSO4) and concentrated. The residue was purified on
silica gel (95:5 CH2Cl2/MeOH) to afford 13 mg of 1a (71%) as
a yellow solid (mp 178-180 °C, EtOH). Physical and spec-
troscopic data matched those of commercially available retinoic
acid.
Eth yl (2E,4E,6E,8E)-3,7-Dim eth yl-9-(tr i-n -bu tylstan n yl)-
n on a -2,4,6,8-tetr a en oa te (5). A solution of diethyl 3-(ethoxy-
carbonyl)-2-methylprop-2-enylphosphonate 4 (1.07 g, 4.05
mmol) in THF (4 mL) was cooled to 0 °C and treated with
DMPU (1 mL, 8.32 mmol) and n-BuLi (1.66 M in hexanes, 2.3
mL, 3.82 mmol). The mixture was stirred at this temperature
for 20 min and then cooled to -78 °C. A solution of aldehyde
39 (0.87 g, 2.25 mmol) in THF (4 mL) was slowly added, and
the reaction mixture was stirred at -78 °C for 3 h. The
mixture was allowed to warm to 0 °C to complete the reaction.
Saturated aqueous NH4Cl was added, and the reaction mixture
was extracted with Et2O. The combined organic layers were
washed with H2O and brine, dried (MgSO4), and concentrated.
The residue was purified by chromatography on silica gel (93:
5:2 hexane/ethyl acetate/Et3N) to afford 0.82 g of 5 (73%) as a
yellow oil. IR (NaCl, cm-1) ν 1713 (m); 1H NMR (400.13 MHz,
C6D6) δ 6.93 (dd, J ) 19.2 Hz, 3J Sn-H ) 62.7 Hz, 1H), 6.89 (dd,
2
J ) 15.1, 11.4 Hz, 1H), 6.61 (dd, J ) 19.2 Hz, J Sn-H ) 97.7
Hz, 1H), 6.18 (d, J ) 15.1 Hz, 1H), 6.13 (d, J ) 11.4 Hz, 1H),
5.98 (s, 1H), 4.11 (q, J ) 7.1 Hz, 2H), 2.46 (s, 3H), 1.82 (s,
3H), 1.6-1.7 (m, 6H), 1.4-1.5 (m, 6H, 3 × CH2), 1.0-1.1 (m,
9H), 0.99 (t, J ) 7.3 Hz, 9H); 1H NMR (400.13 MHz, CDCl3) δ
3
6.98 (dd, J ) 15.0, 11.4 Hz, 1H), 6.63 (d, J ) 19.2 Hz, J Sn-H
2
) 61.4 Hz, 1H), 6.43 (d, J ) 19.2 Hz, J Sn-H ) 63.6 Hz, 1H),
6.32 (d, J ) 15.0 Hz, 1H), 6.17 (d, J ) 11.4 Hz, 1H), 5.78 (s,
1H), 4.17 (q, J ) 7.1 Hz, 2H), 2.36 (s, 3H), 1.95 (s, 3H), 1.5-
1.6 (m, 6H), 1.2-1.4 (m, 9H), 0.8-1.0 (m, 15H); 13C NMR
(100.61 MHz, CDCl3) δ 167.1, 152.5, 150.1 (5J Sn-C ) 10.4 Hz),
140.0, 136.0, 131.2 (1J Sn-C ) 213.9 Hz), 131.0, 130.4, 118.9,
59.7, 29.1 (3J Sn-C ) 20.4 Hz), 27.3 (2J Sn-C ) 54.0 Hz), 14.7,
13.8, 13.7, 12.4, 9.53 (1J Sn-C ) 336.5 Hz). HRMS m/z (M+)
calcd for C21H35O2118Sn 437.1653, found 437.1666.
E t h yl R et in oa t e (9a ). Gen er a l P r oced u r e for St ille
Rea ction s. A solution of Pd2(dba)3 (3.4 mg, 0.004 mmol) in
NMP (1.4 mL) was treated with AsPh3 (9 mg, 0.029 mmol)
and, after 5 min, with a solution of triflate 8a (40 mg, 0.147
mmol) in NMP (0.2 mL). After stirring for 10 min, a solution
of stannane 5 (80 mg, 0.161 mmol) in NMP (0.2 mL) was
added. The resulting solution was stirred at 70 °C for 2 h.
After cooling, saturated aqueous KF solution (2 mL) was
added, and the mixture was stirred for 30 min and extracted
with Et2O. The combined organic extracts were washed with
H2O and saturated aqueous KF solution, dried over MgSO4,
and concentrated to dryness. The residue was purified by
chromatography (SiO2, 98:2 hexane/ethyl acetate) to afford 30
mg (62%) of 9a 15 as a yellow oil and 10 mg (30%) of diethyl
(2E,4E,6E,8E,10E,12E,14E,16E)-3,7,12,16-tetramethyloctadeca-
2,4,6,8,10,12,14,16-octaene-1,18-dioate (10) as a red solid
(mp: 150-158 °C). Data for 9a : 1H NMR (400.13 MHz,
CDCl3) δ 7.00 (dd, J ) 15.0, 11.2 Hz, 1H), 6.29 (d, J ) 15.0
Hz, 1H), 6.28 (d, J ) 16.1 Hz, 1H), 6.15 (d, J ) 11.2 Hz, 1H),
6.14 (d, J ) 16.1 Hz, 1H), 5.78 (s, 1H), 4.17 (q, J ) 7.1 Hz,
2H), 2.36 (d, J ) 1.0 Hz, 3H), 2.0-2.1 (m, 2H), 2.00 (s, 3H),
1.72 (s, 3H), 1.4-1.6 (m, 4H), 1.29 (t, J ) 7.1 Hz, 3H), 1.03 (s,
6H); 13C NMR (100.61 MHz, CDCl3) δ 167.2, 152.8, 139.5,
137.6, 137.2, 135.1, 130.9, 130.0, 129.4, 128.5, 118.5, 59.7, 39.4,
34.2, 33.0, 28.9, 21.8, 19.1, 14.3, 13.7, 12.9. Data for 10: IR
5-Dem eth ylr etin oic Acid (1b). Application of the general
procedure for ester hydrolysis to ethyl 5-demethylretinoate
(9b) afforded, after chromatography on silica gel (95:5 CH2-
Cl2/MeOH), an 83% yield of 5-demethylretinoic acid (1b) as a
yellow solid (mp 83-85 °C, EtOH).25
1,1-Did em eth ylr etin oic Acid (1d ). Application of the
general procedure for ester hydrolysis to ethyl 1,1-didemeth-
ylretinoate (9d ) afforded, after chromatography on silica gel
(95:5 CH2Cl2/MeOH), a 92% yield of 1,1-didemethylretinoic
acid (1d ) as a yellow solid (mp 211-213 °C, EtOH).25
1,5-Did em eth ylr etin oic Acid (1e). Application of the
general procedure for ester hydrolysis to ethyl 1,5-didemeth-
ylretinoate (9e) afforded, after chromatography on silica gel
(95:5 CH2Cl2/MeOH), a 66% yield of 1,5-didemethylretinoic
acid (1e) as a yellow solid (mp 170-172 °C, EtOH).25
1,1,5-Tr id em eth ylr etin oic Acid (1f). Application of the
general procedure for ester hydrolysis to ethyl 1,1,5-tride-
methylretinoate (9f) afforded, after chromatography on silica
gel (95:5 CH2Cl2/MeOH), a 75% yield of 1,1,5-tridemethylre-
tinoic acid (1f) (mp 173-175 °C, EtOH).25
(2E,4E,6E,8E)-3,7-Dim eth yl-9-(tr i-n -bu tylsta n n yl)n on a -
2,4,6,8-tetr a en -1-ol (6). A cooled (-78 °C) solution of tet-
raenylstannane 5 (0.25 g, 0.5 mmol) in THF (1.7 mL) was
treated with DIBALH (1 M, 1 mL, 1 mmol) and stirred at -78
°C for 1 h. The reaction was quenched with a 2:3 MeOH/Et2O
mixture (2 mL) and allowed to reach room temperature. H2O
was added, and the mixture was extracted with Et2O. The
1
(NaCl, cm-1) ν 1698 (s), 1574 (m), 1150 (s); H NMR (400.13
MHz, CDCl3) δ 6.98 (dd, J ) 15.0, 11.5 Hz, 2H), 6.4-6.5 (m,
4H), 6.33 (d, J ) 15.1 Hz, 2H), 6.24 (d, J ) 11.5 Hz, 2H), 5.80
(s, 2H), 4.18 (q, J ) 7.1 Hz, 4H), 2.36 (s, 6H), 2.00 (s, 6H),
1.30 (t, J ) 7.1 Hz, 6H); 13C NMR (100.61 MHz, CDCl3) δ 167.6,
152.9, 139.6, 138.2, 136.6, 132.2, 131.1, 130.9, 119.6, 60.2, 14.8,
14.2, 13.4; HRMS m/z (M+) calcd for C26H34O4 410.2457, found
410.2463.
(25) Spectroscopic data are provided in the Supporting Information.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4139
combined organic extracts were washed with 10% NH4Cl and
brine, dried (MgSO4), and concentrated to yield 0.16 g of 6
(72%) as a yellow oil which was used in the next step without
Meth yl 1-Dem eth ylr etin oa te (14). To a cooled (0 °C)
solution of aldehyde 13 (40 mg, 0.148 mmol) in MeOH (1 mL)
was added a mixture of KCN (48 mg, 0.741 mmol) and MnO2
(257 mg, 2.96 mmol). After being stirred at 0 °C for 2 h, the
mixture was filtered, diluted with Et2O, and washed with
brine. The residue was purified on silica gel (98:2 hexane/
ethyl acetate) to afford 32 mg (72%) of 14 as a yellow oil. IR
(NaCl, cm-1) ν 1713 (m); 1H NMR (400.13 MHz, CDCl3) δ 7.02
(dd, J ) 15.0, 11.4 Hz, 1H), 6.73 (d, J ) 15.9 Hz, 1H), 6.30 (d,
J ) 15.9 Hz, 1H), 6.29 (d, J ) 15.0 Hz, 1H), 6.22 (d, J ) 11.4
Hz, 1H), 5.78 (s, 1H), 3.72 (s, 3H), 2.67 (br, 1H), 2.37 (s, 3H),
2.0-2.3 (m, 2H), 2.02 (s, 3H), 1.82 (s, 3H), 1.6-1.8 (m, 4H),
1.08 (d, J ) 7.0 Hz, 3H); 13C NMR (100.61 MHz, CDCl3) δ
167.6, 153.1, 140.3, 135.0, 134.7, 133.5, 131.2, 130.1, 129.8,
127.5, 117.8, 50.9, 33.4, 29.9, 27.7, 20.2, 19.7, 17.6, 13.8, 13.0;
HRMS m/z (M+) calcd for C20H28O2 300.2089, found 300.2085.
1-Dem eth ylr etin oic Acid (1c). Application of the general
procedure for ester hydrolysis to methyl 1-demethylretinoate
(14) afforded, after chromatography on silica gel (95:5 CH2-
Cl2/MeOH), a 78% yield of 1-demethylretinoic acid (1c) as a
yellow solid (mp 187-190 °C, EtOH). IR (NaCl, cm-1) ν 3600-
further purification. IR (NaCl, cm-1) ν 3500-3100 (br); 1H
3
NMR (400.13 MHz, C6D6) δ 6.95 (dd, J ) 19.2 Hz, J Sn-H
)
64.1 Hz, 1H), 6.62 (dd, J ) 15.1, 11.3 Hz, 1H), 6.50 (dd, J )
19.2 Hz, J Sn-H ) 69.0 Hz, 1H), 6.2-6.3 (m, 2H), 5.59 (t, J )
2
6.6 Hz, 1H), 4.01 (br, 2H), 1.89 (s, 3H), 1.65 (quintet, J ) 7.3
Hz, 6H), 1.59 (s, 3H), 1.40 (sextet, J ) 7.3 Hz, 6H), 1.05 (t, J
) 7.3 Hz, 6H), 0.94 (t, J ) 7.3 Hz, 9H); 13C NMR (100.61 MHz,
C6D6) δ 151.7 (4J Sn-C ) 10.2 Hz), 138.5, 136.8 (3J Sn-C ) 66.1
Hz), 135.9, 132.6, 132.5, 127.8, 125.1, 59.5, 29.7 (3J Sn-C ) 20.4
Hz), 27.9 (2J Sn-C ) 54.0 Hz), 14.1, 12.6, 12.4, 10.0 (1J Sn-C
334.2 Hz).
)
1-Dem eth ylr etin ol (12). The general procedure for Stille
reactions coupled triflate 8c (35 mg, 0.15 mmol) and stannane
6 (82 mg, 0.165 mmol) after the reaction mixture was stirred
at 40 °C for 2 h. The residue was purified by chromatography
(silica, 80:18:2 hexane/ethyl acetate/Et3N) to afford 42 mg
(98%) of 12 as a yellow oil, which was immediately used in
the next reaction (samples stored after their preparation
underwent extensive decomposition).
1
3200 (br), 1679 (s); H NMR (400.13 MHz, CDCl3) δ 7.06 (dd,
1-Dem eth ylr etin a l (13). To a solution of the alcohol 12
(88 mg, 0.323 mmol) in CH2Cl2 (4 mL) were added 4 Å
molecular sieves and NMO (76 mg, 0.647 mmol). After stirring
for 10 min and cooling to 0 °C, TPAP (5.7 mg, 0.016 mmol)
was added and the mixture was stirred for 1 h at 0 °C, allowed
to reach room temperature, stirred for an additional 1 h,
diluted with CH2Cl2, filtered, and washed with saturated
aqueous Na2SO3, brine, and saturated aqueous CuSO4. The
organic layer was dried over MgSO4, filtered, and concentrated.
The residue was purified by chromatography (silica, 93:5:2
hexane/ethyl acetate/Et3N) to afford 41 mg (47%) of 13 as a
yellow oil.22 IR (NaCl, cm-1) ν 1657 (s); 1H NMR (400.13 MHz,
C6D6) δ 10.02 (d, J ) 7.9 Hz, 1H), 6.86 (dd, J ) 15.0, 11.4 Hz,
1H), 6.81 (d, J ) 15.0 Hz, 1H), 6.41 (d, J ) 15.0 Hz, 1H), 6.08
(d, J ) 11.4 Hz, 1H), 6.07 (d, J ) 15.0 Hz, 1H), 6.00 (d, J )
7.9 Hz, 1H), 2.70 (br, 1H), 1.8-2.0 (m, 2H), 1.82 (s, 3H), 1.73
(s, 3H), 1.68 (s, 3H), 1.4-1.7 (m, 4H), 1.17 (d, J ) 7.0 Hz, 3H);
13C NMR (100.61 MHz, C6D6) δ 188.9, 153.7, 141.6, 135.5,
135.0, 134.5, 132.2, 131.0, 130.0, 128.8, 128.7, 34.0, 30.6, 28.6,
J ) 15.0, 11.5 Hz, 1H), 6.75 (d, J ) 16.0 Hz, 1H), 6.32 (d, J )
15.0 Hz, 1H), 6.31 (d, J ) 16.0 Hz, 1H), 6.22 (d, J ) 11.5 Hz,
1H), 5.80 (s, 1H), 2.68 (br, 1H), 2.38 (s, 3H), 2.0-2.2 (m, 2H),
2.04 (s, 3H), 1.83 (s, 3H), 1.5-1.8 (m, 4H), 1.08 (d, 3H, J ) 7.0
Hz); 13C NMR (100.61 MHz, CDCl3) δ 172.3, 155.8, 141.4,
135.7, 135.0, 133.9, 132.4, 130.5, 130.2, 128.2, 117.8, 33.9, 30.3,
28.2, 20.6, 20.2, 18.0, 14.4, 13.5; HRMS m/z (M+) calcd for
C
19H26O2 286.1933, found 286.1932.
Ack n ow led gm en t. We thank FIS (Contract 95/
1534, which also supported Dr. Iglesias) and the Xunta
de Galicia (grant XUGA30106B97) for financial support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 9b, 9d -f, and 1d -f, and copies of 1H/13C
NMR spectra of selected compounds described in the text (38
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
20.9, 20.1, 18.4, 13.4, 12.9; HRMS m/z (M+) calcd for C19H26
O
270.1984, found 270.1986.
J O980097W