Stereocontrolled synthesis of (S)-9-cis-4-oxo-13,14-dihydroretinoic acid

Article abstract of DOI:10.1016/j.tet.2011.12.056

(S)-9-cis-4-Oxo-13,14-dihydroretinoic acid (S)-1, a new major endogenous vitamin A metabolite that activates retinoic acid receptor signaling both in vitro and in vivo, has been synthesized stereoselectively by Horner-Wadsworth-Emmons condensation and Stille cross-coupling as bond forming reactions.

Full text of DOI:10.1016/j.tet.2011.12.056

Tetrahedron 68 (2012) 1756e1761
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Stereocontrolled synthesis of (S)-9-cis-4-oxo-13,14-dihydroretinoic acid
ꢀ
ꢀ
ꢀ
*
*
Marta Domínguez, Susana Alvarez, Rosana Alvarez , Angel R. de Lera
ꢀ
Departamento de Química Organica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 October 2011
Received in revised form 14 December 2011
Accepted 20 December 2011
Available online 24 December 2011
(S)-9-cis-4-Oxo-13,14-dihydroretinoic acid (S)-1, a new major endogenous vitamin A metabolite that
activates retinoic acid receptor signaling both in vitro and in vivo, has been synthesized stereoselectively
by HornereWadswortheEmmons condensation and Stille cross-coupling as bond forming reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Retinoids
Polyenes
Total synthesis
Stille reaction
Vitamin A
1. Introduction
other retinoid metabolites have shown that (S)-1 is an endogenous
ligand for at least two RAR subtypes (a and b), induces in vivo mor-
Vitamin A (retinol) and its analogs (retinoids) are essential in
many physiological processes, such as vision, immunity, the regu-
lation of embryonic development (e.g., limbs, nervous system, heart,
and kidney), cell differentiation, proliferation, and apoptosis.1,2 Most
of these cellular processes (the exception being vision, where 11-cis-
retinal is the active retinoid bound to the apo-protein opsin as an
inverse agonist)3,4 are mediated by the binding (and activation) of
vitamin A metabolites all-trans-retinoic acid and its 9-cis isomer to
retinoic acid (RARs) and retinoid X receptors (RXRs)5 as well as to
a series of retinoid metabolizing enzymes.2 All-trans-retinoic acid is
transformed into additional metabolites to help establish a delicate
control of the homeostasis of retinoid levels in the organs.6 Studies
of retinoid metabolism and gene expression are used to identify
novel pathways regulated by as yet uncharacterized active com-
pounds in order to establish whether retinoid receptors are exclu-
sively activated by all-trans-retinoic acid (or its 9-cis isomer), or
whether other endogenous ligands can also regulate gene expres-
sion.6 In this regard, 9-cis-retinoic acid, though it binds to and ac-
tivates both RARs and RXRs, is unlikely to be a bona fide physiological
ligand based on the results of pharmacological and genetic studies
in mouse epidermis keratinocytes7 and mouse embryos.2,8
phological changes in chicken limb buds in a similar way to all-
trans-retinoic acid and regulates gene transcription in the
same organdalbeit with lower potency than all-trans-retinoic acid.10
The identification of this metabolite in several tissues of mice, rats,
and humans is remarkable since a 9-cis-configured isomer of retinoic
acidhasbeendetectedfor the first timeendogenouslyinconsiderable
concentrations. Furthermore, this compound is a member of the
growing group of endogenous dihydroretinoids,11e13 which are pre-
sumably biosynthesized from vitamin A through a hydrogenation
reaction mediated by the enzyme retinol saturase (RetSat).14
Furtheranalysis of thesignalingpathways regulated by(S)-9-cis-4-
oxo-13,14-dihydroretinoic acid (S)-1 has been hampered by the scar-
city of this material in the organisms. We report herein the first
stereoselective synthesis of 1, which features the construction of the
polyene side chain through a palladium-catalyzed Csp2eCsp2 cross-
coupling15 and a Csp2]Csp2 condensation reaction. For the former
group, the Stille cross-coupling reaction was selected based on our
previous comprehensive studies on the scope and limitations of this
process for the synthesis of retinoids, and the findings that the re-
actions generally take place with retention of configuration of the
coupling partners.16e18 Both the JuliaeKocienski19,20 and the Hor-
nereWadswortheEmmons condensations21 were selected for double
bond formation starting from the corresponding components (Fig. 1).
Recently, an endogenous retinoid metabolite with the 9-cis con-
figuration, namely (S)-9-cis-4-oxo-13,14-dihydroretinoic acid (S)-1,
has been isolated from the liver of mice, rats, and humans.9 Experi-
ments aimed at elucidating the biological relevance of 1 relative to
2. Results and discussion
ꢀ
In order to explore alternative routes to the target compound,
we considered two key disconnections, C6eC7 and C8eC9, for the
* Corresponding authors. E-mail addresses: rar@uvigo.es (R. Alvarez), qolera@
uvigo.es (A.R. de Lera).
ꢀ
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.056

M. Domínguez et al. / Tetrahedron 68 (2012) 1756e1761
1757
C6-C7 Stille
C8-C9 Stille
C11-C12 Modified Julia
7
9
HWE
SnBu3
6
X
I
C8-C9
Bu3Sn
8
11
5
12
13
C6-C7
OH
OTES
O
(S)-4
-1
(S)
9
CO2Et
2
X = OTf
3 X = I
CO2Et
(S)-10
CO2H
O
EtO2C
CHO
8
I
EtO2C
Bu3Sn
CHO
(S)-
R
R
OH
OTES
5
8
(S)-
12a
, R = SO2BT
, R = SO2PT
11
6a, R = SO2BT
12b
6b
, R = SO2PT
13, R = P(O)(OMe)2
7, R = P(O)(OMe)2
Fig. 1. Retrosynthetic analysis of (S)-9-cis-4-oxo-13,14-dihydroretinoic acid (S)-1 (BT¼benzothiazolyl, PT¼1-phenyl-1H-tetrazolyl).
application of the Stille transform. In the first alternative the long
side chain is attached to a cyclohexenyl ring, whereas the second
approach uses unsaturated fragments of similar size. The first ap-
Formation of allylsulfones 12a,b required a two-step sequence that
involved a tineiodine exchange reaction followed by oxidation of the
allylsulfides with a peroxymolybdate reagent and H2O2 at ꢀ10 ꢁC.25
A comprehensive survey of bases and reaction temperatures was
required to optimize the construction of the trans C4]C5 double
bond by a JuliaeKocienski olefination26 using (S)-8.12,22 In agree-
ment with the Z-selectivity observed in the JuliaeKocienski olefi-
nation of allylsulfones with unsaturated aldehydes,27,28 the 4Z,6Z
isomer was obtained as the major product in all cases, although the
overall Z-selectivity was moderate (entries 1e6). The 4Z,6E isomer
was also obtained in all cases, probably due to isomerization of the
starting sulfone 11 prior to the condensation reaction. Regarding the
nature of the base, we found that HMDS derivatives afforded higher
isomer ratios (entries 2e6) than LDA (entry 1). Within the disilazide
series, the stereoselectivity appears to show a slight dependence on
the size of the base counterion, and the most covalent system
LiHMDS afforded the best ratio of the 4E,6Z isomer (entry 4). The use
of either a cosolvent (entry 5) or a higher temperature (entry 6) did
not result in any improvement in the selectivity.
proach could be achieved by the condensation of
a cyclo-
hexenyltriflate 2 (or the equivalent iodide 3) and trienylstannane
(S)-4, whereas the latter would involve coupling of a dienyliodide
(S)-10 and dienylstannane 9. In both cases, the C11eC12 double
bond would be formed by either a JuliaeKocienski olefination be-
tween sulfones 6/12 and the already known enantiopure aldehyde
(S)-812,22 or by HWE condensation of phosphonates 7/13 with (S)-8.
Ketone 5 was obtained in good yield by a syn non-aldol aldol
rearrangement of the cyclic a-alkylepoxy silyl ether as described by
Jung and Allen.23 However, the synthesis of triflate 2 or iodide 3
faced insurmountable difficulties, with either decomposition,
elimination of the silyl ether (using precursor ketone 5) or
unreacted starting material observed under the reaction conditions
surveyed. Dienylstannane (S)-10 was therefore selected as the
coupling partner in the Stille reaction with 9.
Dienylstannane 9 was uneventfully prepared in 86% yield by
radical-induced addition of tributyltin hydride to the previously de-
scribed enynol 11 (Scheme 1).17,24 The synthesis of (S)-10 was based on
a JuliaeKocienski olefination19,20 between the allylsulfones 12 and
enantiopure aldehyde (S)-8. The preparation of 12a,b started from (Z)-
stannanyl alcohol 14, which was converted into stannylated benzo-
thiazolyl- and 1-phenyl-1H-tetrazolyl-allylsulfides 15a and 15b, re-
spectively, by Mitsunobu reaction with the corresponding thiols.
1-Phenyl-1H-tetrazolyl-allylsulfones (PT-sulfones) represent
a useful alternative to benzothiazolyl-allylsulfones (BT-sulfones)
because of the enhanced stability of the PT-sulfone anions and their
higher E-selectivities in JuliaeKocienski olefinations with alde-
hydes.19,20,29 In fact, complete E selectivity has been described on
using PT-allylsulfone and an
a
-chiral aldehyde.30 The use of PT-
sulfone 12b improved the E selectivity in the newly formed dou-
ble bond in all cases, but once again the 4Z,6Z isomer was the major
product (entries 6e9). KHMDS proved to be the best base for this
olefination and afforded a 1.25:1 E/Z ratio of isomers at the newly
formed double bond of 10, with the other isomers not detected. An
improvement in the selectivity was not observed when KHMDS was
replaced with LiHMDS. The use of Barbier-like conditions (entry 9)
also had a detrimental effect on the stereoselectivity (Table 1).
Moreover, since the four double bond isomers of ester 10 could
not be base-line separated by HPLC, the reaction mixtures of dif-
ferent runs were isomerized to the final 0.2:1:0.2 4Z,6Z/4E,6Z/4E,6E
ratio, as monitored by 1H NMR, by treatment with catalytic
amounts of I2 in CD2Cl2 or in C6D6. Unfortunately, the separation by
HPLC of the desired 4E,6Z isomer from this mixture was also
unsuccessful.31
The lack of selectivity in the JuliaeKocienski olefination led us to
change our strategy and we turned our attention to the Hor-
nereWadswortheEmmons reaction as the key step in the synthesis
of dienyliodide (S)-10 (Scheme 2). Following conversion of alcohol
16 into the allylic chloride, the Arbuzov reaction of the latter with
neat trimethyl phosphite and an excess of sodium iodide provided
Scheme 1. Reagents and conditions: (a) Bu3SnH, AIBN, toluene, 130 ꢁC, 45 min, 86%.
(b) PPh3, BTSH or PTSH, DIAD, THF, ꢀ10 ꢁC, 3 h, (15a, 72%; 15b, 98%). (c) I2, CH2Cl2,
25 ꢁC, 2 min. (d) (NH4)6Mo7O24$4H2O, 30% H2O2, EtOH, ꢀ10 ꢁC, 4 h (12a, 84%; 12b, 88%,
both steps). (BT¼benzothiazolyl, PT¼1-phenyl-1H-tetrazolyl).

1758
M. Domínguez et al. / Tetrahedron 68 (2012) 1756e1761
Table 1
Optimization of C4]C5 double bond formation via a JuliaeKocienski olefination
Entry
Conditions
Isomer ratio
Yield (%)
4Z,6Z
4E,6Z
4Z,6E
4E,6E
1
2
3
4
5
6
7
8
9
12a (1.0 equiv), (S)-8 (1.5 equiv), LDA (1.2 equiv), THF, ꢀ78 to 25 ꢁC
2.54
2.1
2.5
1.62
1.6
1.6
1.25
1.34
2
1
1
1
1
1
1
1
1
1
0.54
0.36
0.15
0.19
0.32
0.19
0
0.15
0.07
0
78
60
37
35
93
45
15
72
42
12a (1.0 equiv), (S)-8 (1.5 equiv), KHMDS (1.1 equiv), THF, ꢀ78 ꢁC, 1.5 h
12a (1.0 equiv), (S)-8 (1.5 equiv), NaHMDS (1.1 equiv), THF, ꢀ78 ꢁC, 3 h
12a (1.0 equiv), (S)-8 (1.5 equiv), LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 40 min
12a (1 equiv), (S)-8 (1.5 equiv), LiHMDS (1.2 equiv), HMPA (1.5 equiv), THF, ꢀ78 ꢁC, 30 min
12a (1.0 equiv), (S)-8 (1.2 equiv), LiHMDS (1.2 equiv), THF, ꢀ78 to 25 ꢁC, 1 h (Barbier)
12b (1.0 equiv), (S)-8 (2.1 equiv), KHMDS (2 equiv), THF, ꢀ78 ꢁC, 5 h
0
0.07
0.1
0
0.11
0.1
12b (1.0 equiv), (S)-8 (1.1 equiv), LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 2 h
12b (1.0 equiv), (S)-8 (1.2 equiv), LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 40 min (Barbier)
0.13
0.26
phosphonate 13 in 61% overall yield.32 HWE olefination between
the allylic phosphonate 13 and enantiopure (S)-8 using NaHMDS as
base provided the iodide (S)-10 in 38% yield33 as a mixture of 4E,6Z/
4Z,6Z isomers in a 14:1 ratio; the mixture was separated by HPLC.34
The high E selectivity (14:1 E/Z) in the formation of (S)-10 with
a semi-stabilized phosphonate is notable, but is in agreement with
previous findings.32
1ꢂ25 cm), which afforded enantiomeric excess values of 91% for
(S)-1 and 80% for (R)-1.
3. Conclusion
In summary, we have developed a short synthesis of (S)-9-cis-4-
oxo-13,14-dihydroretinoic acid (S)-1 and its antipode in a stereo-
selective manner. Although (S)-1 was claimed to be the native
retinoid,9,10 to the best of our knowledge, this is the first time that
both enantiomers have been synthesized and characterized, mak-
ing these compounds available for research. Endogenous
dihydroretinoids11e13 have so far been implicated in the regulation
of lipid accumulation in mice through the nuclear receptor
EtO2C
CHO
I
(S)-8
b
I
R
PPARg 37,38
Further biological characterization of (S)-9-cis-4-oxo-
.
16, R = OH
CO2Et
c
13,14-dihydroretinoic acid is ongoing.
a
(S)-10
13, R = P(O)(OMe)2
4. Experimental section
4.1. General
SnBu3
OH
9
All reagents were commercial compounds of the highest purity
available. All reactions were carried out under an argon atmosphere,
and those not involving aqueous reagents were carried out in oven-
dried glassware. All solvents and anhydrous solutions were trans-
ferred by syringe and cannula, which were previously dried in an
oven for at least 12 h and kept in a desiccator over KOH. THF, CH2Cl2,
and DMF were dried using a PuresolvÔ solvent purification system.
Et3N was dried by distillation over CaH2. For reactions at low tem-
perature, ice-wateror CO2eacetone systems wereused. Fordifferent
temperatures, a HaaKe EK90 Immersion Cooler (ꢀ90 to ꢀ15 ꢁC) was
used. Analytical TLC was performed on aluminum plates with Merck
Kieselgel 60F254 and visualized by UV irradiation (254 nm) or by
stainingwith a solution of phosphomolybdic acidor p-anisaldehyde.
Flash column chromatography was carried out using Merck Kie-
selgel 60 (230e400 mesh) under pressure. UV/vis spectra were
recorded on a Cary 100 Bio spectrophotometer in MeOH as solvent.
IR spectra were obtained on a JASCO FTIR 4200 spectrophotometer,
from a thin film deposited onto NaCl glass. Mass spectra were ob-
tained on a Micromass GC-TOF instrument operating at 70 eV by
electron ionization. HRMS were recorded on a VG Autospec in-
strument. 1H NMR spectra were recorded in CDCl3 and C6D6 or
(CD3)2CO at 25 ꢁC on a Bruker AMX-400 spectrometer operating at
400.16 MHz with residual protic solvent as the internal reference
(CDCl3, dH¼7.26 ppm; C6D6, dH¼7.16; (CD3)2CO, dH¼2.05 ppm);
Y
X
CO2R
19, Y/X = H, OH, R = Et
(S)-20, Y/X = O, R = Et
(S)-1, Y/X = O, R = H
d
e
Scheme 2. Reagents and conditions: (a) i. MsCl, DMAP, CH2Cl2, 25 ꢁC, 24 h. ii. P(OMe)3,
NaI, 70 ꢁC, 4 h, 61%. (b) NaHMDS, THF, ꢀ78 ꢁC, 3 h, 38%. (c) (NBu4)(Ph2PO2), Pd(PPh3)4,
CuTC, DMF, 25 ꢁC, 1.15 h, 91%. (d) MnO2, Na2CO3, CH2Cl2, 0e25 ꢁC, 5 h, 84%. (d) 2 M
KOH, MeOH, 80 ꢁC, 30 min, 73%.
The versatile protocol for Stille cross-coupling reactions de-
€
scribed by Furstner et al., which is applicable to both unhindered
and sterically hindered alkenyl triflates and iodides,35 was used to
react vinylstannane
9 and dienyliodide (S)-10 with catalytic
amounts of Pd(PPh3)4 and copper-thiophene carboxylate (CuTC) in
DMF in the presence of (NBu4)(Ph2PO2) as a tin scavenger. This
reaction afforded, after 30 min at 25 ꢁC, tetraenol 19 in excellent
yield (93%), as a mixture of diastereomers. Oxidation of 19 to the
corresponding ketone with MnO2 under basic conditions and hy-
drolysis of the ester (S)-20 with aqueous KOH in MeOH produced
the desired (S)-9-cis-4-oxo-13,14-dihydroretinoic acid (S)-1 in 73%
yield.36 The general scheme was also used to prepare enantiomer
(R)-1 with equal efficiency. The enantiomeric excess of the target
compounds was determined by Chiral HPLC (Chiralpak IA
chemical shifts (d) are given in parts per million (ppm) and coupling
constants (J) are given in Hertz (Hz). The proton spectra are reported
as follows:
d (multiplicity, coupling constant J, number of protons).
13C NMR spectra were recorded in CDCl3, C6D6 or (CD3)2CO at 25 ꢁC
on the same spectrometer at 101.62 MHz with the central peak of
CDCl3
(
dC¼77.2 ppm), C6D6
(
dC¼128.0 ppm), and (CD3)2CO
(dC¼29.84 ppm) as the internal reference. DEPT-135 pulse sequence

M. Domínguez et al. / Tetrahedron 68 (2012) 1756e1761
1759
was used to aid in the assignment of signals in the 13C NMR spectra.
For compound 13, the second multiplicity in parenthesis refers to
JCeP splitting, and includes the coupling constant value. Optical ro-
tation values were determined in a Jasco P-1020 polarimeter.
J¼15.2, 9.7 Hz, 1H, H5), 5.71 (d, J¼9.4 Hz, 1H, H6), 5.60 (dd, J¼15.3,
7.5 Hz, 1H, H4), 3.96 (q, J¼7.1 Hz, 2H, OCH2CH3), 2.71 (sept, J¼6.9 Hz,
1H, H3), 2.23 (s, 3H, C7eCH3), 2.17 (dd, J¼15.0, 7.3 Hz, 1H, H2), 2.08
(dd, J¼15.0, 7.1 Hz, 1H, H2), 0.98 (t, J¼7.1 Hz, 3H, OCH2CH3), 0.90 (d,
J¼6.8 Hz, 3H, C3eCH3) ppm. 13C NMR (101 MHz, C6D6)
d 171.4 (s),
4.1.1. (E)-2,4,4-Trimethyl-3-(2-(tributylstannyl)vinyl)cyclohex-2-enol
9. To a solution of 3-ethynyl-2,4,4-trimethylcyclohex-2-enol 11
(0.038 g, 0.233 mmol) and AIBN (0.0032 g, 0.0233 mmol) in toluene
(5.6 mL) was added n-Bu3SnH (0.271 g, 0.930 mmol) and the mix-
ture was heated under reflux (130 ꢁC) for 45 min. The solvent was
evaporated and the residue was purified by column chromatogra-
phy (silica gel, 90:10 hexane/EtOAc) to afford 0.091 g (86%) of
141.0 (d), 134.6 (d), 131.8 (d), 100.1 (s), 60.1 (t), 41.4 (t), 34.0 (d), 33.7
(q), 19.9 (q), 14.4 (q) ppm. HRMS (ESIþ): calcd for C11H17O2I
([MþH]þ), 309.0346; found, 309.0358. IR (NaCl):
n 2978 (m, CeH),
2854 (w, CeH), 1734 (s, C]O), 1371 (m), 1179 (m) cmꢀ1. UV
(MeOH): lmax 248 nm.
4.1.4. Ethyl
(R,4E,6Z)-7-iodo-3-methylocta-4,6-dienoate
(R)-
a
colorless oil identified as (E)-2,4,4-trimethyl-3-(2-(tributyl-
10. Following the general procedure for the HWE olefination, the
reaction of dimethyl (Z)-(3-iodobut-2-en-1-yl)phosphonate 13
(0.123 g, 0.423 mmol) with ethyl (3R)-3-methyl-4-oxobutanoate
(R)-8 (0.047 g, 0.325 mmol) and NaHMDS (0.423 mL, 0.423 mmol,
1 M in THF) in THF (6.19 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.0445 g (44%) of
a colorless oil identified as a mixture of 4E,6Z/4Z,6Z isomers of (R)-
ethyl 7-iodo-3-methylocta-4,6-dienoate (R)-10 in a 10:1 ratio.
These isomers were separated by HPLC (preparative NovaPakÔ
stannyl)vinyl)cyclohex-2-enol 9. 1H NMR (400 MHz, C6D6)
d
6.67 (d,
0
0
J¼19.7 Hz, 1H, H2 ), 6.14 (d, J¼19.7 Hz, 1H, H1 ), 3.86e3.79 (m, 1H,
H1), 1.94 (s, 3H, C2eCH3), 1.8e1.7 (m, 2H, 2H6), 1.7e1.5 (m, 6H,
SnCH2CH2CH2CH3), 1.5e1.3 (m, 6H, SnCH2CH2CH2CH3), 1.3e1.2 (m,
2H, 2H5), 1.10 (s, 3H, C4eCH3), 1.05 (s, 3H C4eCH3), 1.1e1.0 (m, 6H,
SnCH2CH2CH2CH3), 1.0e0.9 (m, 9H, SnCH2CH2CH2CH3) ppm. 13C
NMR (101 MHz, C6D6) d 146.3 (d), 144.6 (s), 133.6 (d), 129.6 (s), 69.9
(d), 35.0 (t), 34.5 (s), 29.7 (t, 3ꢂ), 29.2 (t), 29.1 (q), 27.7 (t, 3ꢂ), 27.6
(q), 18.8 (q), 14.0 (q, 3ꢂ), 10.0 (t, 3ꢂ) ppm. HRMS (ESIþ): calcd for
silica
6
m
m
19ꢂ300 mm, 99:1 hexane/EtOAc, 4 mL/min,
C23H44NaOSn ([MþNa]þ), 479.2310; found, 479.2306. IR (NaCl):
n
tR¼56.5 min (4Z,6E) isomer). ½a D21
þ4.29 (c 0.8, MeOH).
ꢃ
3600e3000 (br, OeH), 2957 (s, CeH), 2926 (s, CeH), 2854 (m,
CeH), 1457 (m), 1022 (m), 995 (m) cmꢀ1
.
4.1.5. Ethyl (4R,13S)- and (4S,13S)-9-cis-4-hydroxy-13,14-
dihydroretinoate 19. A degassed solution of ethyl (S,4E,6Z)-7-iodo-
3-methylocta-4,6-dienoate (S)-10 (0.040 g, 0.13 mmol) and (E)-
4.1.2. Dimethyl (Z)-(3-iodobut-2-en-1-yl)phosphonate 13. To a solu-
tion of alcohol 16 (1.41 g, 7.09 mmol) and DMAP (1.13 g, 9.22 mmol)
in CH2Cl2 (102.5 mL) was added methanesulfonyl chloride (1.18 mL,
15.25 mmol) and the mixture was stirred at rt for 23 h. The reaction
mixture was filtered through silica gel, eluting with hexanes, and the
solvent was evaporated. The residue was used in the next step
without further purification. To a solution of the allylic chloride in
trimethyl phosphite (15.4 mL) was added sodium iodide (1.19 g,
7.9 mmol) and the mixture was stirred at 70 ꢁC for 4 h. The solution
was poured into H2O, extracted with EtOAc (3ꢂ) and the combined
organic layers were dried (Na2SO4), filtered and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel, 50:50 to 0:100 hexane/EtOAc gradient) to afford 1.302 g
(61%) of a colorless oil identified as dimethyl (Z)-(3-iodobut-2-en-1-
2,4,4-trimethyl-3-(2-(tributylstannyl)vinyl)cyclohex-2-enol
9
(0.054 g, 0.118 mmol) in DMF (0.45 mL) was added to a solution of
tetra-n-butylammoniumdiphenylphosphinate (0.06 g, 0.13 mmol)
in DMF (0.5 mL). The reaction mixture was cooled to 0 ꢁC and
copper-thiophene carboxylate (CuTC, 0.0248 g, 0.13 mmol) was
added followed by Pd(PPh3)4 (14 mg, 0.0118 mmol). The reaction
mixture was stirred for 3 h at 25 ꢁC and the reaction was quenched
with H2O at 0 ꢁC and extracted with Et2O (3ꢂ). The combined or-
ganic layers were washed with H2O (3ꢂ), dried (Na2SO4) and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, 90:7:3 hexane/EtOAc/Et3N) to afford
37.8 mg (91%) of a pale yellow oil identified as ethyl (4R,13S)- and
(4S,13S)-9-cis-4-hydroxy-13,14-dihydroretinoate 19. Spectroscopic
data of the mixture of diastereomers (these could only be separated
yl)phosphonate 13. 1H NMR (400 MHz, CDCl3)
d
5.51 (dt, J¼7.3 Hz,
3JHeP¼6.7 Hz, 1H, H2), 3.78 (s, 3H, OMe), 3.75 (s, 3H, OMe), 2.74 (dd,
J¼7.3 Hz,2JHeP¼21.9 Hz,2H,2H1), 2.55(d, 5JHeP¼5.0 Hz, 3H,C3eCH3)
by Chiral HPLC): 1H NMR (400 MHz, (CD3)2CO)
d
6.67 (d, J¼16.1 Hz,
1H, H8), 6.57 (dd, J¼14.9, 11.3 Hz, 1H, H11), 6.16 (d, J¼16.1 Hz, 1H,
H7), 5.94 (d, J¼10.9 Hz, 1H, H10), 5.62 (dd, J¼15.0, 7.6 Hz, 1H, H12),
4.07 (q, J¼7.1 Hz, 2H, OCH2CH3), 4.0e3.9 (m,1H, H4), 3.7e3.6 (m,1H,
OH), 2.73 (sept, J¼6.9 Hz,1H, H13), 2.4e2.2 (m, 2H, 2H14), 1.91 (s, 3H,
CeCH3), 1.9e1.8 (m, 1H, H2 or H3), 1.83 (s, 3H, CeCH3), 1.8e1.6 (m,
2H, H2þH3), 1.4e1.3 (m, 1H, H2 or H3), 1.19 (t, J¼7.1 Hz, 3H,
OCH2CH3), 1.06 (d, J¼6.8 Hz, 3H, C13eCH3),1.03 (s, 3H, C1eCH3), 1.01
ppm. 13C NMR (101 MHz, CDCl3)
d
124.8 (d), (d, 2JCeP¼10.0 Hz),105.8
(s) (d, 3JCeP¼18.0 Hz), 52.7 (q, 2ꢂ), 34.3 (t) (d, 1JCeP¼141.2 Hz), 33.9
(q) ppm. HRMS (ESI): calcd forC6H12IO3P ([MþH]þ), 321.9461;found,
312.9459. IR (NaCl): n 2952 (m, CeH), 2848 (w, CeH),1256 (m), 1028
(s, P]O) cmꢀ1. UV (MeOH): lmax 249 nm.
4.1.3. Ethyl (S,4E,6Z)-7-iodo-3-methylocta-4,6-dienoate (S)-10. To
a cooled (ꢀ78 ꢁC) solution of dimethyl (Z)-(3-iodobut-2-en-1-yl)
phosphonate 13 (0.026 g, 0.09 mmol) in THF (0.76 mL) was added
NaHMDS (0.091 mL, 1 M in THF, 0.091 mmol) and the mixture was
stirred for 30 min. A solution of ethyl (S)-3-methyl-4-oxobutanoate
(S)-8 (0.009 g, 0.06 mmol) in THF (0.38 mL) was added and the
mixture was stirred for 3 h. After adding saturated aqueous NH4Cl
the mixture was extracted with Et2O (3ꢂ), the combined organic
layers were washed with brine (3ꢂ), dried (Na2SO4) and the solvent
was evaporated. The residue was purified by column chromatog-
raphy (silica gel, 99:1 hexane/EtOAc) to afford 0.007 g (38%) of
a colorless oil identified as a mixture of 4E,6Z/4Z,6Z isomers in
a 14:1 ratio. The isomers were separated by HPLC (preparative
(s, 3H, C1eCH3) ppm. 13C NMR (100 MHz, (CD3)2CO)
d 172.3 (s),
141.1 (s), 138.7 (d), 133.2 (s), 132.1 (s), 131.4 (d), 129.9 (d), 128.2 (d),
125.3 (d), 69.9 (d), 60.5 (t), 42.1 (t), 35.6 (t), 35.2 (s), 34.7 (d), 29.6
(t), 29.3 (q), 28.2 (q), 20.6 (q), 20.5 (q), 19.0 (q), 14.6 (q) ppm. HRMS
(ESIþ): calcd for C22H34NaO3 ([MþNa]þ), 369.2400; found,
369.2410. IR (NaCl): n 3650e3050 (br, OeH), 2961 (s, CeH), 2933 (s,
CeH), 2867 (m, CeH), 1737 (s, C]O), 1453 (m), 1373 (m), 1172 (m),
1029 (m), 963 (m) cmꢀ1. UV (MeOH): lmax 285 nm.
4.1.6. Ethyl (4R,13R)- and (4S,13R)-9-cis-4-hydroxy-13,14-
dihydroretinoate 19. Following the general procedure for the Stille
cross-coupling reaction, the reaction of (R)-10 (0.023 g,
0.074 mmol) with rac-(E)-2,4,4-trimethyl-3-(2-(tributylstannyl)vi-
NovaPakÔ silica 6
m
m 19ꢂ300 mm, 99:1 hexane/EtOAc, 4 mL/min,
nyl)cyclohex-2-enol
9
(0.0305 g, 0.067 mmol), tetra-n-buty-
tR¼56.5 min (4Z,6E) isomer).
lammoniumdiphenylphosphinate (0.034 g, 0.074 mmol), copper-
thiophene carboxylate complex (CuTC, 0.014 g, 0.074 mmol), and
Pd(PPh3)4 (7.7 mg, 0.0067 mmol) in DMF (0.54 mL) afforded, after
Data for ethyl (S,4E,6Z)-7-iodo-3-methylocta-4,6-dienoate (S)-
10. ½a 2D1
ꢃ
ꢀ4.57 (c 1.27, MeOH). 1H NMR (400 MHz, C6D6)
d 6.29 (dd,

1760
M. Domínguez et al. / Tetrahedron 68 (2012) 1756e1761
purification by column chromatography (silica gel, 90:7:3 hexane/
EtOAc/Et3N), 0.023 g (98%) of a pale yellow oil identified as ethyl
(4R,13R)- and (4S,13R)-9-cis-4-hydroxy-13,14-dihydroretinoate 19.
0.048 mmol) and KOH (0.77 mL, 1.54 mmol, 2 M) in MeOH
(3.32 mL) afforded, after purification by column chromatography
(silica gel, gradient from 98:2 to 95:5 CH2Cl2/MeOH), 10.4 mg (68%)
of
a
pale yellow oil identified as (R)-9-cis-4-oxo-13,14-
4.1.7. Ethyl
(S)-9-cis-4-oxo-13,14-dihydroretinoate
(S)-20. To
dihydroretinoic acid (R)-1. ½a D24
þ8.8 (c 0.275, MeOH).
ꢃ
a cooled (0 ꢁC) solution of ethyl (4R,13S)- and (4S,13S)-9-cis-4-
hydroxy-13,14-dihydroretinoate 19 (0.0363 g, 0.0105 mmol) in
CH2Cl2 (4.13 mL) were added MnO2 (0.164 g, 1.88 mmol) and Na2CO3
(0.2 g,1.88 mmol) and the suspension was stirred for 5 h. The mixture
was filtered through Celite and the solvents were evaporated. The
residue was purified by column chromatography (silica gel, 95:3:2
hexane/EtOAc/Et3N) to afford 30.2 mg (84%) of a pale yellow oil
Chromatographic conditions for the separation and analysis of
(R)-1 and (S)-1: Chiralpak IA 1x25 cm, 30% tBuOMe in hexane with
0.1% trifluoroacetic acid (TFA); tR(S)-1¼26.5 min; tR(R)-1¼30.5 min.
Acknowledgements
This work was supported by the European Union LSHC-CT-
2005-518417 ‘Epitron’, MICINN-Spain (SAF2010-17935-FEDER),
Xunta de Galicia (Grant 08CSA052383PR from DXIþDþi; Con-
identified as ethyl (S)-9-cis-4-oxo-13,14-dihydroretinoate (S)-20. ½a D21
ꢃ
ꢀ42.68 (c 1.40, MeOH). 1H NMR (400 MHz, (CD3)2CO)
d 6.92 (d,
J¼16.2 Hz, 1H, H8), 6.63(dd, J¼14.8, 11.4 Hz, 1H, H11), 6.33 (d, J¼16.2 Hz,
1H, H7), 6.09 (d, J¼11.2 Hz, 1H, H10), 5.70 (dd, J¼17.9, 7.6 Hz, 1H, H12),
4.06 (q, J¼7.0 Hz, 2H, OCH2CH3), 2.74 (sept, J¼7.0 Hz, 1H, H13), 2.44 (t,
J¼6.8 Hz, 2H, 2H14), 2.32 (t, J¼7.0 Hz, 2H, 2H3),1.97 (s, 3H, CeCH3),1.86
(t, J¼6.8 Hz, 2H, 2H2),1.82 (s, 3H, CeCH3),1.20 (s, 6H, 2ꢂ C1eCH3),1.18
ꢀ
solidacion 2006/15 from DXPCTSUG; INBIOMED; Parga Pondal
ꢀ
~
Research Contract to M.D. and Angeles Alvarino Research Contract
to S.A.).
References and notes
(t, J¼7.1 Hz, 3H, OCH2CH3), 1.06 (d, J¼6.8 Hz, 3H, C13eCH3) ppm. 13
C
ꢀ
NMR (100 MHz, (CD3)2CO)
d 189.2 (s), 172.3 (s), 161.4 (s), 140.2 (d),
1. Niederreither, K.; Dolle, P. Nat. Rev. Gen. 2008, 9, 541e553.
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3. Palczewski, K. Annu. Rev. Biochem. 2007, 75, 743e767.
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133.6 (d), 132.6 (s), 132.5 (d),130.2 (s), 126.6 (d),125.1 (d), 60.5 (t), 41.9
(t), 38.1 (t), 36.2 (s), 34.8 (t), 34.7 (d), 27.9 (q), 27.8 (q), 20.4 (q), 20.2 (q),
14.6 (q), 14.0 (q) ppm. HRMS (ESIþ): calcd for C22H33O3 ([MþH]þ),
345.2424; found, 345.2415. IR (NaCl): v 2963 (m, CeH), 2928 (m, CeH),
1734 (s, C]O), 1664 (s, C]O) cmꢀ1. UV (MeOH): lmax 255, 327 nm.
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4.1.8. Ethyl (R)-9-cis-4-oxo-13,14-dihydroretinoate (R)-20. Following
the general procedure for alcohol oxidation by MnO2, the reaction of
ethyl (4R,13R)- and (4S,13R)-9-cis-4-hydroxy-13,14-dihydroretinoate
19 (0.0228 g, 0.066 mmol) with MnO2 (0.103 g, 1.18 mmol) and
Na2CO3 (0.126 g, 1.18 mmol) in CH2Cl2 (2.6 mL) afforded, after puri-
fication by column chromatography (silica gel, 95:3:2 hexane/EtOAc/
Et3N), 0.0166 g (73%) of a pale yellow oil identified as ethyl (R)-9-cis-
€
€
10. Schuchardt, J. P.; Wahlstrom, D.; Ruegg, J.; Giese, N.; Stefan, M.; Hopf, H.;
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4-oxo-13,14-dihydroretinoate (R)-20. ½a D21
þ34.0 (c 0.655, MeOH).
ꢃ
4.1.9. (S)-9-cis-4-Oxo-13,14-dihydroretinoic acid (S)-1. To a solution
of ethyl (S)-9-cis-4-oxo-13,14-dihydroretinoate 20 (28.7 mg,
0.083 mmol) in MeOH (5.75 mL) was added KOH (1.33 mL,
2.66 mmol, 2 M aqueous solution) and the reaction mixture was
stirred for 30 min at 80 ꢁC. After cooling down to 25 ꢁC, CH2Cl2 and
brine were added and the layers were separated. The organic layer
was washed with H2O (3ꢂ). The combined aqueous layers were
acidified with 10% HCl and extracted with CH2Cl2 (3ꢂ). The com-
bined organic layers were dried (Na2SO4) and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel, from 98:2 to 95:5 CH2Cl2/MeOH) to afford 19.3 mg (73%)
16. Domínguez, B.; Iglesias, B.; de Lera, A. R. Tetrahedron 1999, 55, 15071e15098.
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17. Domínguez, M.; Alvarez, R.; Martras, S.; Farres, J.; Pares, X.; de Lera, A. R. Org.
Biomol. Chem. 2004, 2, 3368e3373.
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Biomol. Chem. 2006, 4, 155e164.
19. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563e2585.
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€
21. Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann. Chem. 1997,
of
a
pale yellow oil identified as (S)-9-cis-4-oxo-13,14-
1283e1301.
dihydroretinoic acid (S)-1. ½a D25
ꢃ
ꢀ10.7 (c 0.685, MeOH). 1H NMR
22. Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A. Tetrahedron 1995, 51,
12843e12858.
(400 MHz, (CD3)2CO)
d
6.93 (d, J¼16.2 Hz, 1H, H8), 6.65 (dd, J¼14.9,
23. Jung, M. E.; Allen, D. A. Org. Lett. 2008, 10, 2039e2041.
24. Yamano, Y.; Ito, M. Chem. Pharm. Bull. 2001, 49, 1662e1663.
25. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28, 1140e1142.
26. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,
1175e1178.
11.3 Hz, 1H, H11), 6.33 (d, J¼16.2 Hz, 1H, H7), 6.10 (d, J¼11.1 Hz, 1H,
H10), 5.74 (dd, J¼14.9, 7.4 Hz, 1H, H12), 2.74 (sept, J¼6.9 Hz, 1H, H13),
2.44 (t, J¼6.8 Hz, 2H, 2H14), 2.4e2.2 (m, 2H, 2H3), 1.97 (s, 3H,
CeCH3), 1.86 (t, J¼6.8 Hz, 2H, 2H2), 1.82 (s, 3H, CeCH3), 1.20 (s, 6H,
C1eCH3), 1.08 (d, J¼6.8 Hz, 3H, C13eCH3) ppm. 13C NMR (100 MHz,
27. Vaz, B.; Alvarez, R.; Souto, J. A.; de Lera, A. R. Synlett 2005, 294e298.
€
28. Sorg, A.; Bruckner, R. Synlett 2005, 289e293.
(CD3)2CO)
d 198.3 (s), 173.4 (s), 161.4 (s), 140.5 (d), 133.7 (d), 132.6
ꢀ
29. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26e28.
30. Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.; Ku-
(d), 132.5 (s), 130.2 (s), 126.6 (d), 125.1 (d), 41.6 (t), 38.4 (t), 36.3 (s),
34.8 (t), 34.5 (d), 27.9 (q), 27.8 (q), 20.2 (q), 14.0 (q) ppm. HRMS
(ESIþ): calcd for C20H29O3 ([MþH]þ), 317.2111; found, 317.2102. IR
ꢂ
wajima, I.; Omura, S. Org. Lett. 2001, 3, 2289e2291.
31. Some precedents in our lab suggested that an increase in the conjugation of the
sulfone could have a beneficial effect on the selectivity of the JuliaeKocienski
olefination. However, the inversion in the order of steps, i.e., postponing the
JuliaeKocienski olefination to the final step, also led to a mixture of Z,Z and E,Z
isomers in a 2:1 ratio.
32. Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Duan, J. J. W.; Hull, K.
G.; Iwashima, M.; Qiu, Y.; Spoors, P. G.; Salvatore, B. A. J. Am. Chem. Soc. 1999,
121, 10478e10486.
(NaCl):
n 3500e2500 (br, OeH), 2965 (m, CeH), 2928 (m, CeH),
1692 (s, C]O),1640 (s, C]O),1361 (m),1144 (m) cmꢀ1. UV (MeOH):
lmax 255 (
3
¼14,200 molꢀ1 L cmꢀ1), 323 (
3
¼8990 molꢀ1 L cmꢀ1) nm.
4.1.10. (R)-9-cis-4-Oxo-13,14-dihydroretinoic acid (R)-1. Following
the general procedure for ester hydrolysis with KOH, the reaction of
ethyl (R)-9-cis-4-oxo-13,14-dihydroretinoate (R)-20 (0.0166 g,
33. The low yields could be due to the nature of the chiral aldehyde (S)-8, since
a control HWE reaction with allylic phosphonate 13 and 2,6-dimethylhept-5-
enal afforded the condensation product in 69% yield.

M. Domínguez et al. / Tetrahedron 68 (2012) 1756e1761
1761
34. HPLC conditions: NovaPakÔ HR silica 6
m
m 19ꢂ300 mm, 99:1 hexane/EtOAc,
37. Schupp, M.; Lefterova, M. I.; Janke, J.; Leitner, K.; Cristancho, A. G.; Mullican, S.
E.; Qatanani, M.; Szwergold, N.; Steger, D. J.; Curtin, J. C.; Kim, R. J.; Suh, M.-j.;
Albert, M. R.; Engeli, S.; Gudas, L. J.; Lazar, M. A. Proc. Natl. Acad. Sci. U.S.A. 2009,
106, 1105e1110.
4 mL/min, tR¼41 min (4E,6Z), tR¼45 min (4Z,6Z).
€
35. Furstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.; Nevado, C.; Waser, M.;
Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2873e2875.
36. The reversal in the order of steps in this approach (first Stille and second HWE)
was unsuccessful. Although the Stille cross-coupling product was obtained in
72% yield, the HWE reaction did not take place with different bases.
38. Moise, A. R.; Lobo, G. P.; Erokwu, B.; Wilson, D. L.; Peck, D.; Alvarez, S.;
Domínguez, M.; Alvarez, R.; Flask, C. A.; de Lera, A. R.; von Lintig, J.; Palczewski,
K. FASEB J. 2010, 24, 1261e1270.