Stereocontrolled synthesis of (S)-9-cis- and (S)-11-cis-13,14-dihydroretinoic acid

Article abstract of DOI:10.1016/j.tet.2016.05.006

The 9-cis and 11-cis stereoisomers of 13,14-dihydroretinoic acid with S configuration, (S)-7 and (S)-9, respectively, have been synthesized stereoselectively. The former has been recently characterized as the first endogenous natural ligand of the retinoid X receptor (RXR). The Julia-Kocienski reaction of allyl sulfones and aldehydes was used as connective step and afforded the Z isomer of a trienyl ester accounting for the entire side chain of the targets. A highly selective and unidirectional iodine-induced isomerization of a Z,Z,E triene to the desired E,Z,E isomer was required prior to the synthesis of (S)-7 via a Suzuki cross-coupling. The same approach to (S)-9 led to substantial isomerization when the Suzuki cross-coupling was used as the last bond-forming reaction. As alternative, the two bond-forming steps were exchanged and the synthesis of (S)-9 was completed using the Z-selective Julia-Kocienski reaction.

Full text of DOI:10.1016/j.tet.2016.05.006

Tetrahedron xxx (2016) 1e7
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Stereocontrolled synthesis of (S)-9-cis- and (S)-11-cis-13,14-
dihydroretinoic acid
*
*
ꢀ
Belen Vaz, Rosana Alvarez , Angel R. de Lera
ꢀ
Departamento de Química Organica and CINBIO, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The 9-cis and 11-cis stereoisomers of 13,14-dihydroretinoic acid with S configuration, (S)-7 and (S)-9,
respectively, have been synthesized stereoselectively. The former has been recently characterized as the
first endogenous natural ligand of the retinoid X receptor (RXR). The Julia-Kocienski reaction of allyl
sulfones and aldehydes was used as connective step and afforded the Z isomer of a trienyl ester ac-
counting for the entire side chain of the targets. A highly selective and unidirectional iodine-induced
isomerization of a Z,Z,E triene to the desired E,Z,E isomer was required prior to the synthesis of (S)-7
via a Suzuki cross-coupling. The same approach to (S)-9 led to substantial isomerization when the Suzuki
cross-coupling was used as the last bond-forming reaction. As alternative, the two bond-forming steps
were exchanged and the synthesis of (S)-9 was completed using the Z-selective Julia-Kocienski reaction.
Ó 2016 Published by Elsevier Ltd.
Received 26 February 2016
Received in revised form 28 April 2016
Accepted 4 May 2016
Available online xxx
Keywords:
Retinoids
Synthesis
Suzuki
Julia-Kocienski
1. Introduction
which binds to the apoprotein opsin as a protonated Schiff base to
trigger the visual cycle upon light absorption.11 Fig 1.
Vitamin A (retinol, 1) and its metabolites (native retinoids) are
essential in many physiological processes, such as vision, immunity,
the regulation of embryonic development, the control of cell dif-
ferentiation, cell proliferation and apoptosis.1 With the exception of
vision, most of these cellular processes have been traditionally
considered to be mediated by the binding (and activation) of vita-
min A metabolites all-trans-retinoic acid 2 and its 9-cis isomer 3 to
retinoic acid receptors (RARs) and retinoid X receptors (RXRs),
which are members of the nuclear receptor superfamily.2e5
In addition to all-trans-retinoic acid 2, vitamin A is transformed
into additional metabolites that collectively help establish a deli-
cate control of the homeostasis of retinoid levels.1,6 In this regard,
a group of endogenous dihydroretinoids, including all-trans-13,14-
dihydroretinoic acid 5, have been recently added to the vitamin A
metabolite pool.7e9 It has been shown that the formation of 5 in-
volves the formal hydrogenation of all-trans-retinol 1 mediated by
the enzyme retinol saturase (RetSat)10 and further two-stage oxi-
dation of the polar group of 4 to metabolite 5 mediated by retinol
dehydrogenases (ADH/SDR) and retinal dehydrogenases (RADH).8,9
Naturally-occurring 5 was shown to be the R enantiomer, which is
consistent with its higher binding affinity to RARs and trans-
activation activity in comparison with its antipode.8
More controversial is the endogenous presence of 9-cis-retinoic
acid 3 in cells and tissues.12 Although originally described in the liver
and kidney,13 and later in rat epididymal tissue and spermatozoa,14
its detection in various organs has been questioned,15e20 perhaps
Some double bond stereoisomers of the parent polyene6 also
play fundamental roles in biological systems. The best known of
those is 11-cis-retinal 6, the chromophore of the visual pigments,
* Corresponding authors. Tel.: þ34 986 812316; fax: þ34 986 811940; e-mail
addresses: rar@uvigo.es (R. Alvarez), qolera@uvigo.es (A.R. de Lera).
Fig. 1. Vitamin A1 and selected metabolites of biological significance.
http://dx.doi.org/10.1016/j.tet.2016.05.006
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2
B. Vaz et al. / Tetrahedron xxx (2016) 1e7
with the exception of pancreas.21,22 Pharmacological and genetic
studies in mouse epidermis keratinocytes23 and mouse embryos24,25
added functional evidence to the analytical data and together con-
curred that 9-cis-retinoic acid 3 is unlikely a bona fide physiological
ligand but rather a pharmacological ligand for both RARs and RXRs.12
Studies of retinoid metabolism and gene expression are of major
interest to aid in the identification of novel pathways regulated by
yet uncharacterized endogenous ligands that can also alter gene
expression.6 Retinoid metabolites with 9-cis configuration, namely
9-cis-13,14-dihydroretinoic acid (S)-726 and its 4-oxo derivative (S)-
827,28 have been recently isolated from several organs and charac-
terized as retinoid receptor ligands. Although compounds with the
structure of 9-cis-13,14-dihydroretinoic acid 7 (its absolute con-
figuration was not determined) and its taurine conjugate were
detected in rats, the animals had been fed with high doses of 9-cis-
retinoic acid 3, making interpretation of their putative role as an
endogenous retinoid doubtful.29 In contrast 9-cis-13,14-
dihydroretinoic acid 7 was detected in normally fed animals, and
found to bind and transactivate RXR (as well as RAR) in various
assays and to display similar transcriptional activity as other RXR
ligands in cultured human dendritic cells.26 Intriguingly (S)-8 was
parent system,39 requires the reaction of enantiopure trienyliodide
(S)-15 and boronic acid 16 (Scheme 1). The synthesis of (S)-15 started
with (Z)-stannyldienol 1139,45 which was transformed into the
benzothiazolyl allyl sulfide 12 by Mitsunobu reaction with the cor-
responding thiol and subsequently oxidized to sulfone 13 with H2O2
and a peroxymolybdate reagent46 at ꢀ10 ꢁC (yields decreased at
higher temperatures: 0 ꢁC, 61%; 25 ꢁC, 48%). The Julia-Kocienski
olefination41e43 was performed using a slight excess of base
(NaHMDS, 1.15 equiv) and 1.7 equiv of enantiopure aldehyde (S)-
10.8,44 As anticipated from previous findings on the stereochemical
outcome of the reactions between allyl sulfones and unsaturated
aldehydes47,48 the newly formed olefin of trienyl ester (S)-14 is of Z-
geometry, which was confirmed by NOE experiments. Treatment of
the precursor stannane with a solution of iodine in CH2Cl2 produced
the iodide (S)-15 via Sn-I exchange and iodine-promoted isomeri-
zation of the Z,Z,E triene to the desired E,Z,E geometric isomer (as
confirmed by NOE experiments). Immediate work-up and Suzuki
reaction with the freshly prepared boronate 1639 afforded the ex-
pected ethyl (9Z)-13,14-dihydroretinoate (S)-17 in good yield. Sa-
ponification of (S)-17 led to the corresponding carboxylic acid (S)-7
in good yield with preservation of the 9Z geometry of the tetraene.
reported as an endogenous ligand for at least two RAR subtypes (
a
and ) but not for RXR. This compound induced in vivo morpho-
b
logical changes in chicken limb buds similarly to all-trans-retinoic
acid 2 and regulated gene transcription in the same organ although
with lower potency than 2.27,28 Thus far, the detailed metabolic
pathway for formation of 9-cis-13,14-dihydroretinoids is unknown.
In order to aid in the characterization of endogenous retinoids,
their metabolic formation and their function, we started a program
aimed at the development of stereoselective approaches to dihy-
droretinoids of potential biological interest. We have reported the
synthesis of all-trans-13,14-dihydroretinoic acid 5 in both enantio-
meric forms and showed that the R enantiomer is the endogenous
ligand.8 The stereoselective synthesis of the S enantiomers (the
configuration of the presumably oxidation metabolite 8) of the 9-cis
and 11-cis stereoisomers of this compound (7 and 9) is shown below.
Scheme 1. Reagents and conditions: (a) PPh3, BTSH, DIAD, CH2Cl2, 25 ꢁC, 2 h (95%). (b)
(NH4)6Mo7O24$4H2O, 30% H2O2, EtOH, ꢀ10 ꢁC, 17 h (66%). (c) NaHMDS, THF, ꢀ78 ꢁC,
30 min (93%). (d) I2, CH2Cl2, 25 ꢁC, 30 min (90%). (e) Pd(PPh3)4, 10% aq TlOH, THF, 25 ꢁC,
3 h (78%). (f) 2M KOH, MeOH, 80 ꢁC, 45 min; then H3Oþ (84%).
2. Results and discussion
Central to the construction of the polyene side chain of retinoids1a
is the choice of the synthetic tactic. This may involve either the use of
monofunctionalized components to perform Csp2]Csp2 bond con-
struction by carbonyl condensation reactions (Wittig, HWE, Julia) or
the use of mono and bis-functionalized alkenyl linchpins30 to con-
nect components of complementary reactivity by palladium-
catalyzed Csp2eCsp2 cross-coupling reactions.31 In practice, func-
tionalized alkenyl reagents (as halogens or metal derivatives such as
boron, tin, silicon, etc.) containing anion-stabilizing allyl groups
(phosphonates, sulfones.) provide higher versatility to the synthetic
scheme, as in general greater orthogonality is expected compared to
the use of bis-functionalized alkenyl reagents.32 Thus, the Suzuki
cross-coupling reaction33e35 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 in general the
reaction takes place with retention of configuration of the coupling
partners,36e40 whereas the Julia-Kocienski reaction41,42 was consid-
ered for double bond formation starting from the corresponding
functionalized components. For both targets, the disconnection of
the C6eC7 bond by application of the Suzuki transform with cyclo-
hexenyl boron derivative 16 and a trienyliodide was selected as key
step. Prior to this step, the C11]C12 double bond was conceived to be
formed by a Julia-Kocienski olefination41e43 between a sulfone and
the already described enantiopure aldehyde (S)-10,8,44 which will be
the source of the enantiopure compounds along the sequence.
For the preparation of (S)-9-cis-13,14-dihydroretinoic acid (S)-7
the application of the Suzuki coupling reaction, as developed for the
Scheme 2. Reagents and conditions: (a) 1. n-BuLi, THF, ꢀ78 ꢁC; 2. B(O-i-Pr)3. (b)
IPPh3CH2I, NaHMDS, THF, ꢀ78 ꢁC; 2. (S)-10, THF, HMPA, ꢀ78 ꢁC. (c) Pd(PPh3)4, 10% aq
TlOH, THF, 25 ꢁC, 3 h (15% for (S)-21 from (S)-20; 71% for 29þfrom 27; 33% for (S)-21
from (S)-26). (d) 2M KOH, MeOH, 80 ꢁC, 45 min; then H3O (91%). (e) PPh3, BTSH,
DIAD, CH2Cl2, 30 min (93% for 23). (f) (NH4)6Mo7O24$4H2O, 30% H2O2, EtOH, ꢀ10 ꢁC,
17 h, 25 ꢁC, 30 min (61% for 24; 60% for 28; 40% for 30). (g) NaHMDS, THF, ꢀ78 ꢁC,
30 min (89% for (S)-25; 89% for (S)-21; 34% for (S)-26). (h) NIS, CH3CN, 0 ꢁC, 1.5 h (84%
for 27). (i) I2, CH2Cl2, 25 ꢁC, 30 min (33% for (S)-26).
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B. Vaz et al. / Tetrahedron xxx (2016) 1e7
3
As a first approach to the synthesis of the 11-cis isomer (S)-9 we
had considered a Suzuki coupling between the trienyl boronate 19
and the Z-vinyliodide (S)-20. However, the instability of both
building blocks led us to complete the sequence without their
isolation.39 The Z-configured vinyliodide (S)-20 was prepared suc-
cessfully from the enantiopure aldehyde (S)-10 through a Stork
olefination. The crude reaction was immediately used in the next
Suzuki coupling without further purification. Starting from the
known trienyliodide precursor 18,38 the preparation of boronate 19
was carried out by treatment with nBuLi at ꢀ78 ꢁC and subsequent
reaction with B(OiPr)3. After 1 h, Pd(PPh3)4 was added followed by
a solution of the Z iodide (S)-20 obtained before in THF and, finally
a 10% aqueous TlOH solution. This series of transformations pro-
vided the expected ethyl (11Z)-13,14-dihydroretinoate (S)-21, al-
though in a disappointing 15% yield (Scheme 2).
An analogous synthetic route to the one developed for (9Z)-
13,14-dihydroretinoic acid (S)-7 was then explored. The Z-selective
Julia-Kocienski olefination of allyl sulfones with aldehydes was
selected,47,48 and the Suzuki coupling was postponed to the last
step to complete the assembly of the skeleton. Thus, the synthesis
of the polyenic structure started from previously described E-
stannyldienol 22 through its transformation into the benzothiazolyl
sulfide 23 and subsequent oxidation to the desired sulfone 24. The
Julia-Kocienski olefination was performed as before with aldehyde
(S)-10, giving rise exclusively to the trienyl ester (S)-25 with Z-ge-
ometry of the newly formed double bond in 89% yield. During the
subsequent Sn-I exchange, however, partial isomerization of the Z-
olefin to the more stable all-trans triene was observed, as deduced
from the analysis of the coupling constants in the 1H NMR spectra.
The ca. 1:1 mixture of isomeric trienyliodides (S)-26 was subjected
to the Suzuki coupling reaction conditions with 16,39 affording
ethyl 13,14-dihydroretinoate (S)-21 as a mixture of 11Z and all-trans
isomers in the same ratio.
compounds available for further research. The synthetic routes are
different to the approach to (S)-9-cis-4-oxo-13,14-dihydroretinoic
acid (S)-8 described previously.49 Efforts are underway to uncover
the occurrence and possible physiological functions of cis isomers
other than the already validated retinoid receptor ligand (S)-8.
3. Experimental section
For general procedures, see Supplementary data.
3.1. (2Z,4E)-1-(Benzothiazol-2-yl)sulfanyl-5-(tri-n-butyl-
stannyl)-3-methylpenta-2,4-diene 12
A solution of (2Z,4E)-3-methyl-5-(tri-n-butylstannyl)penta-2,4-
dien-1-ol 11 (0.915 g, 2.36 mmol), 2-mercaptobenzothiazole
(0.592 g, 3.54 mmol) and PPh3 (1.10 g, 3.85 mmol) in THF (13 mL)
was stirred for 5 min at 0 ꢁC. A solution of DIAD (0.703 mL,
3.54 mmol) in THF (4.6 mL) was added dropwise and the mixture
was stirred for 30 min at 25 ꢁC. The solvent was removed and the
residue was purified by column chromatography (silica gel, 97:3
hexane/Et3N) to afford 1.20 g (95%) of a colorless oil identified as
(2Z,4E)-1-(benzothiazol-2-yl)sulfanyl-5-(tri-n-butylstannyl)-3-
methylpenta-2,4-diene 12. 1H NMR (400 MHz, C6D6):
d 7.93 (d,
J¼8.2, 1H), 7.35 (d, J¼19.1 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.10 (t,
J¼7.7 Hz, 1H), 6.90 (t, J¼7.6 Hz, 1H), 6.55 (d, J¼19.2 Hz, 1H), 5.54 (t,
J¼8.0 Hz, 1H), 4.26 (d, J¼8.1 Hz, 2H), 1.75 (s, 3H), 1.67e1.52 (m, 6H),
1.44e1.30 (m, 6H), 1.04e0.89 (m, 15H) ppm. 13C NMR (100 MHz,
C6D6):
126.2 (d),124.3 (d),122.3 (d),121.9 (d),121.2 (d), 30.8 (t), 29.6 (t, 3x),
27.8 (t, 3x), 20.0 (q),14.0 (q, 3x), 9.9 (t, 3x) ppm. IR (NaCl): 2955 (s,
d 166.6 (s), 154.1 (s), 142.8 (d), 138.8 (s), 135.9 (s), 132.3 (d),
n
CeH), 2923 (s, CeH), 2870 (m, CeH), 2850 (m, CeH), 1460 (s), 1427
(s) cmꢀ1. HRMS (ESIþ) m/z calcd for C25H40NS2120Sn, 538.1620;
found, 538.1621.
As the isomerization occurred during Sn-I exchange, we con-
sidered the possibility of running the one-pot Julia olefination with
the iododienyl sulfone 28, which was prepared from sulfide 27
(itself derived from the stannyldienol 22 in 93% yield using Mit-
sunobu conditions) in good yield following the same methodology
described before, but adjusting the amount of oxidant to 10 equiv
and using 0.2 mol equivalents of the peroxomolybdate reagent.
Under the same conditions used before (100 mol equiv of 35% H2O2,
0.4 mol equiv (NH4)6Mo7O24$4H2O) the yield dropped to 23% and
the dienyl sulfone was obtained as a mixture of isomers. Un-
fortunately, the trienyliodide (S)-26 obtained by this route in 34%
yield in the olefination reaction slowly isomerized to the all-trans
isomer (1.7:1 Z/E ratio; significant changes were detected by 1H
NMR after 1 h, at which time a Z/E ratio of 1.4:1 was measured).
Moreover, the Suzuki coupling of the mixture of iodides (S)-26 with
the corresponding cyclohexenylboronate 16 did not afford the ex-
pected ethyl retinoate (S)-21.
Finally, we decided to postpone the construction of the Z-olefin
to the last step of the sequence. Therefore, the benzothiazolyl sul-
fide 23 was converted into the corresponding dienyliodide 27 by
treatment with NIS in CH3CN (99% yield) and subjected to the
Suzuki coupling reaction with 16, which produced the expected
trienyl sulfide 29 in good yield (71%). Careful oxidation at 0 ꢁC
provided the all-trans trienyl sulfone 30, although in moderate
yield (40%). Finally, the Z-selective Julia-Kocienski reaction of 30
and (S)-10 led to the expected tetraene (S)-21 as a mixture of Z/E
isomers in a 5:1 ratio, which were successfully separated by HPLC.
Although saponification again required high temperatures (80 ꢁC),
the yield of (S)-9 was satisfactory (91%) and the original 11Z ge-
ometry was preserved in the carboxylic acid (Scheme 2).
3.2. (2Z,4E)-1-(Benzothiazol-2-yl)sulfonyl-5-(tri-n-butyl-
stannyl)-3-methylpenta-2,4-diene 13
To a solution of (2Z,4E)-1-(benzothiazol-2-yl)sulfanyl-5-(tri-n-
butylstannyl)-3-methylpenta-2,4-diene 12 (0.48 g, 0.89 mmol) in
EtOH (9 mL), at ꢀ10 ꢁC, was added
a
solution of
(NH4)6Mo7O24$4H2O, (0.44 g, 0.36 mmol) in aqueous hydrogen
peroxide (35%, 7.7 mL, 89.1 mmol). After stirring for 17 h at ꢀ10 ꢁC,
the mixture was quenched with H2O and extracted with Et2O (3x).
The combined organic layers were washed with brine (3x) and
dried (Na2SO4), and the solvent was removed. The residue was
purified by column chromatography (C18-silica gel, MeOH) to af-
ford 0.33 g (66%) of a colorless oil identified as (2Z,4E)-1-(benzo-
thiazol-2-yl)sulfonyl-5-(tri-n-butylstannyl)-3-methylpenta-2,4-
diene 13. 1H NMR (400 MHz, C6D6):
d
7.99 (d, J¼8.2 Hz, 1H), 7.07 (d,
J¼19.2 Hz, 1H), 7.05 (t, J¼7.7 Hz, 1H), 7.01 (d, J¼8.2 Hz, 1H), 6.87 (t,
J¼7.7 Hz, 1H), 6.48 (d, J¼19.2 Hz, 1H), 5.32 (t, J¼8.0 Hz, 1H), 4.21 (d,
J¼8.1 Hz, 2H), 1.63 (s, 3H), 1.62e1.54 (m, 6H), 1.45e1.33 (m, 6H),
1.02e0.93 (m, 15H) ppm. 13C NMR (100 MHz, C6D6):
d 166.5 (s),
152.3 (s),142.6 (s),141.2 (d), 136.42 (s), 133.9 (d),126.8 (d),126.6 (d),
124.5 (d),121.7 (d),111.6 (d), 53.1 (t), 29.2 (t, 3x), 27.4 (t, 3x),19.9 (q),
13.7 (q, 3x), 9.6 (t, 3x) ppm. IR (NaCl):
n 2955 (s, CeH), 2923 (s,
CeH), 2850 (m, CeH), 1467 (m), 1333 (s), 1151 (s) cmꢀ1. HRMS
(ESIþ): m/z calcd for C25H39NNaO2S2120Sn, 592.1338; found:
592.1334. UV (MeOH): lmax 239 nm.
3.3. Ethyl (3S,4Z,6Z,8E)-3,7-dimethyl-9-(tri-n-butylstannyl)
nona-4,6,8-trienoate (S)-14
In summary we achieved the synthesis of (S)-9-cis-13,14-
dihydroretinoic acid (S)-7 and (S)-11-cis-13,14-dihydroretinoic
A cooled (ꢀ78 ꢁC) solution of (2Z,4E)-1-(benzothiazol-2-yl)sul-
fonyl-5-(tri-n-butylstannyl)-3-methylpenta-2,4-diene 13 (0.115 g,
0.20 mmol) in THF (9 mL) was treated with NaHMDS (0.23 mL, 1M
acid (S)-9 in
a stereoselective manner, thus making these
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B. Vaz et al. / Tetrahedron xxx (2016) 1e7
in THF, 0.23 mmol). After stirring for 30 min at this temperature,
a solution of ethyl (S)-3-methyl-4-oxobutanoate (S)-10 (0.044 g,
0.30 mmol) in THF (4.5 mL) was added and the resulting mixture
was stirred for 1 h at ꢀ78 ꢁC and then allowed to reach 25 ꢁC for 3 h.
Et2O and water were added at low temperature and the mixture
was warmed up to room temperature. It was then diluted with Et2O
and the layers were separated. The aqueous layer was extracted
with Et2O (3x), the combined organic layers were dried (Na2SO4)
and the solvent was removed. The residue was purified by column
chromatography (C-18 silica gel, MeOH) to afford 0.94 g (93%) of
11.2 Hz, 1H), 6.28 (d, J¼16.0 Hz, 1H), 5.96 (d, J¼11.1 Hz, 1H), 5.51 (dd,
J¼15.0, 7.8 Hz,1H), 3.94 (q, J¼7.2 Hz, 2H), 2.77 (dt, J¼14.1, 7.1 Hz,1H),
2.21 (dd, J¼14.8, 7.3 Hz, 1H), 2.11 (dd, J¼14.8, 7.2 Hz, 1H), 1.95 (t,
J¼6.1 Hz, 2H), 1.90 (s, 3H), 1.79 (s, 3H), 1.63e1.53 (m, 2H), 1.50e1.43
(m, 2H),1.11 (s, 6H), 0.95 (t, J¼7.1 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H) ppm.
13C NMR (100 MHz, C6D6):
d 171.6 (s), 138.5 (s), 137.9 (d), 133.0 (s),
130.9 (d), 129.3 (d), 129.2 (s), 128.2 (d), 127.9 (s), 125.1 (d), 60.0 (t),
41.8 (t), 39.8 (t), 34.5 (s), 34.4 (d), 33.2 (t), 29.2 (q, 2x), 22.0 (q), 20.7
(q), 20.3 (q),19.7 (t),14.4 (q) ppm. IR (NaCl): n 2961 (s, CeH), 2929 (s,
CeH), 2866 (m, CeH), 1737 (s, C]O), 1455 (m), 1372 (m), 1167
(m) cmꢀ1. HRMS (ESIþ): m/z calcd for C22H35O2, 331.2632; found,
331.2625. UV (MeOH): lmax 287 nm (ε¼20,000 L molꢀ1 cmꢀ1).
a pale yellow oil identified as ethyl (3S,4Z,6Z,8E)-3,7-dimethyl-9-
28
(tri-n-butylstannyl)nona-4,6,8-trienoate 14. [
a
]
D
þ11.5 (c 1.22,
MeOH). 1H NMR (400 MHz, C6D6):
d
7.50 (d, J¼19.1 Hz,
3JSnH¼65.1 Hz, 1H), 6.74 (t, J¼11.4 Hz, 1H), 6.54 (d, J¼19.2 Hz,
2JSnH¼71.9 Hz,1H), 6.47 (d, J¼11.9 Hz, 1H), 5.20 (t, J¼10.4 Hz, 1H),
3.93 (q, J¼7.1 Hz, 2H), 3.39e3.24 (m, 1H), 2.30e2.03 (m, 2H), 1.91 (s,
3H), 1.71e1.50 (m, 6H), 1.41e1.31 (m, 6H), 1.06e0.84 (m, 18H) ppm.
3.6. (9Z,13S)-13,14-Dihydroretinoic acid (S)-7
To a solution of ethyl (9Z,13S)-13,14-dihydroretinoate (S)-17
(0.023 g, 0.069 mmol) in MeOH (4.7 mL) was added KOH (2M
aqueous solution, 1.1 mL, 2.27 mmol) and the reaction mixture was
stirred for 45 min at 80 ꢁC. After cooling down to 25 ꢁC, CH2Cl2 and
brine were added and the layers were separated. The aqueous layer
was washed with H2O (3x). The combined aqueous layers were
acidified with 10% HCl and extracted with CH2Cl2 (3x). The com-
bined organic layers were dried (Na2SO4) and the solvent was re-
moved. The residue was purified by column chromatography (silica
gel, gradient from 95:5 to 90:10 CH2Cl2/MeOH) to afford 0.017 g
13C NMR (100 MHz, C6D6):
d 171.5 (s), 143.5 (d), 136.1 (d), 135.7 (s),
130.9 (d), 124.1 (d), 123.2 (d), 60.1 (t), 42.1 (t), 29.6 (t, 3x), 29.5 (d),
27.7 (t, 3x), 20.9 (q), 20.6 (q), 14.3 (q), 14.0 (q, 3x), 9.9 (t, 3x) ppm. IR
(NaCl):
n 2957 (s, CeH), 2924 (s, CeH), 2871 (m, CeH), 2851 (m,
CeH), 1737 (s, C]O), 1459 (m), 1160 (m) cmꢀ1. HRMS (ESIþ): m/z
calcd for C25H46NaO2120Sn, 521.2416; found, 521.2408. UV (MeOH):
lmax 285 nm.
3.4. Ethyl (3S,4E,6Z,8E)-9-iodo-3,7-dimethylnona-4,6,8-
trienoate (S)-15
(84%) of
dihydroretinoic acid (S)-7. [
(400 MHz, (CD3)2CO):
a
pale yellow oil identified as (9Z,13S)-13,14-
ꢀ6.9 (c 0.26, MeOH). 1H NMR
24
a
]
D
d
6.66 (d, J¼16.0 Hz, 1H), 6.60 (dd, J¼15.0,
To
a
solution of ethyl (3S,4Z,6Z,8E)-3,7-dimethyl-9-(tri-n-
11.1 Hz, 1H), 6.18 (d, J¼16.0 Hz, 1H), 5.93 (d, J¼11.1 Hz, 1H), 5.65 (dd,
J¼15.0, 7.5 Hz, 1H), 2.73 (dt, J¼13.2, 7.0 Hz, 1H), 2.40e2.24 (m, 2H),
2.05e1.99 (m, 2H), 1.91 (s, 3H), 1.72 (s, 3H), 1.66e1.57 (m, 2H),
1.53e1.43 (m, 2H), 1.08 (d, J¼6.7 Hz, 3H), 1.03 (s, 6H) ppm. 13C NMR
butylstannyl)nona-4,6,8-trienoate (S)-14 (0.060 g, 0.120 mmol) in
CH2Cl2 (5.3 mL) was added dropwise a solution of iodine (0.046 g,
0.180 mmol) in CH2Cl2 (2.8 mL) and the resulting mixture was
stirred for 30 min at 25 ꢁC. A saturated aqueous solution of Na2S2O3
was added and the reaction mixture was extracted with Et2O (3x),
the combined organic layers were dried (Na2SO4) and the solvent
was removed. The residue was purified by column chromatography
(silica gel, 97:3 hexane/Et3N) to afford 0.036 g (90%) of a pale yellow
(100 MHz, (CD3)2CO): d 173.5 (s), 138.9 (s), 138.8 (d), 133.4 (s), 131.1
(d), 129.8 (s), 129.7 (d), 128.5 (d), 125.4 (d), 41.8 (t), 40.3 (t), 34.9 (s),
34.6 (d), 33.6 (t), 29.4 (q), 22.1 (q), 20.7 (q), 20.6 (q), 20.0 (t) ppm. IR
(NaCl):
n 2957 (s, CeH), 2923 (s, CeH), 2855 (m, CeH), 1709 (s, C]
O), 1446 (m), 1290 (m) cmꢀ1. HRMS (ESIþ): m/z calcd for C20H31O2,
303.2319; found, 303.2313. UV (MeOH): lmax 289 nm
(ε¼17,600 L molꢀ1 cmꢀ1).
oil identified as ethyl (3S,4E,6Z,8E)-9-iodo-3,7-dimethylnona-4,6,8-
23
trienoate (S)-15. [
C6D6):
a]
ꢀ16.7ꢁ (c 0.72, MeOH). 1H NMR (400 MHz,
D
d
7.65 (d, J¼14.5 Hz, 1H), 6.28 (dd, J¼14.9, 11.3 Hz, 1H), 6.05
(d, J¼14.5 Hz, 1H), 5.64 (d, J¼11.1 Hz, 1H), 5.44 (dd, J¼15.0, 7.8 Hz,
1H), 3.95 (q, J¼7.1 Hz, 2H), 2.71e2.58 (m, 1H), 2.15 (dd, J¼14.9,
7.1 Hz, 1H), 2.06 (dd, J¼14.9, 7.3 Hz, 1H), 0.97 (t, J¼7.2 Hz, 3H), 0.88
3.7. Ethyl (11Z,13S)-13,14-dihydroretinoate (S)-21
NaHMDS (0.43 mL,1M in THF, 0.43 mmol) was added to a cooled
(ꢀ78 ꢁC) solution of (iodomethyl)triphenylphosphonium iodide
(0.230 g, 0.43 mmol) in THF (8.0 mL). After stirring for 20 min at this
temperature, HMPA (0.15 mL) was added followed by a solution of
ethyl (S)-3-methyl-4-oxobutanoate (S)-10 (0.050 g, 0.35 mmol) in
THF (2.0 mL) and the resulting mixture was stirred for 1.5 h at
ꢀ78 ꢁC. Water was then added at low temperature and the mixture
was warmed up to room temperature. It was then diluted with
hexane and the layers were separated. The aqueous layer was
extracted with hexane (4x), the combined organic layers were dried
(Na2SO4) and the solvent was removed. The residue obtained was
used without further purification in the following Suzuki reaction.
To a solution of (10E,30E)-2-(4-iodo-3-methylbuta-10,30-dienyl)-
1,3,3-trimethylcyclohex-1-ene 18 (0.060 g, 0.190 mmol) at ꢀ78 ꢁC
was added n-BuLi (1.43 M in hexanes, 0.318 mL, 0.455 mmol)
dropwise. After 20 min at this temperature, triisopropylborate
(0.241 mL, 1.044 mmol) was added and the mixture was stirred for
an additional 30 min at 25 ꢁC. After this time, Pd(PPh3)4 (0.022 g,
0.019 mmol) was added and the reaction mixture was stirred for
5 min at 25 ꢁC. Then, a solution of the iodide obtained above in THF
(1.5 mL) was transferred via cannula to the reaction mixture fol-
lowed by TlOH (10% aqueous solution, 1.2 mL, 0.722 mmol). The
resulting mixture was stirred for 7 h before the reaction was diluted
with Et2O. The mixture was filtered through a short pad of CeliteÒ
(d, J¼6.8 Hz, 3H) ppm. 13C NMR (100 MHz, C6D6):
d 171.9 (s), 142.7
(d), 140.4 (d), 132.7 (s), 130.9 (d), 124.6 (d), 78.5 (d), 60.5 (t), 41.8 (t),
34.5 (d), 20.4 (c), 19.9 (c), 14.7 (c) ppm. IR (NaCl):
n 2972 (m, CeH),
2932 (m, CeH), 1731 (s, C]O), 1666 (m), 1180 (m) cmꢀ1. HRMS
(ESIþ): m/z calcd for C13H19INaO2, 357.0322; found, 357.0316. UV
(MeOH): lmax 275 nm.
3.5. Ethyl (9Z,13S)-13,14-dihydroretinoate (S)-17
To a solution of ethyl (3S,4E,6Z,8E)-9-iodo-3,7-dimethylnona-
4,6,8-trienoate (S)-15 (0.036 g, 0.107 mmol) in THF (2.3 mL) was
added Pd(PPh3)4 (0.013 g, 0.011 mmol). After 5 min at room tem-
perature, 2,6,6-trimethylcyclohex-1-enylboronic acid 16 (0.027 g,
0.161 mmol) was added in one portion followed by TlOH (10%
aqueous solution, 0.75 mL, 0.407 mmol). After stirring for 3 h at
25 ꢁC, Et2O was added and the reaction mixture was filtered through
a short pad of CeliteÒ. The filtrate was washed with a saturated
aqueous solution of NaHCO3 and the organic layer was dried
(Na2SO4). The solvent was removed by evaporation and the residue
was purified by column chromatography (silica gel, 97:3 hexane/
Et3N) to afford 0.028 g (78%) of a pale yellow oil identified as ethyl
22
(9Z,13S)-13,14-dihydroretinoate (S)-17. [
a
]
D
ꢀ15.5 (c 0.51, MeOH).
1H NMR (400 MHz, C6D6):
d
6.90 (d, J¼16.0 Hz, 1H), 6.71 (dd, J¼14.9,
Please cite this article in press as: Vaz, B.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.006

B. Vaz et al. / Tetrahedron xxx (2016) 1e7
5
and washed with a saturated aqueous NaHCO3 solution. The or-
ganic layer was dried over Na2SO4 and evaporated, and the residue
was purified by flash chromatography (silica gel, 97:3 hexane/Et3N)
to afford 0.009 g (15%) of a pale yellow oil identified as ethyl
(s), 994 (s) cmꢀ1. HRMS (ESIþ): m/z calcd for C13H13INS2, 373.9529;
found, 373.9528. UV (MeOH): lmax 226, 257 nm.
3.10. (2E,4E)-1-(Benzothiazol-2-yl)sulfanyl-3-methyl-5-(2,6,6-
trimethylcyclohex-1-en-1-yl)penta-2,4-diene 29
(11Z,13S)-13,14-dihydroretinoate (S)-21. [
a
]
24 ꢀ52.5 (c 0.08, MeOH).
D
1H NMR (400 MHz, C6D6):
d
6.56 (d, J¼11.9 Hz, 1H), 6.35 (t,
J¼11.4 Hz, 1H), 6.30 (d, J¼16.1 Hz, 1H), 6.24 (d, J¼16.1 Hz, 1H), 5.24
(t, J¼10.4 Hz, 1H), 3.94 (q, J¼7.1 Hz, 2H), 3.37e3.25 (m, 1H),
2.25e2.11 (m, 2H), 1.95 (t, J¼6.3 Hz, 2H), 1.81 (s, 3H), 1.73 (s, 3H),
1.63e1.56 (m, 2H), 1.50e1.46 (m, 2H), 1.10 (s, 3H), 1.09 (s, 3H), 0.96
(d, J¼6.6 Hz, 3H), 0.95 (t, J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz,
To a solution of (2E,4E)-1-(benzothiazol-2-yl)sulfanyl-5-iodo-3-
methylpenta-2,4-diene 27 (0.042 g, 0.112 mmol) in THF (2.0 mL)
was added Pd(PPh3)4 (0.013 g, 0.011 mmol). After 5 min at 25 ꢁC,
2,6,6-trimethylcyclohex-1-enylboronic
acid
16
(0.028
g,
0.168 mmol) was added in one portion followed by TlOH (10%
aqueous solution, 0.8 mL, 0.427 mmol). After stirring for 15 h at
25 ꢁC, Et2O was added and the reaction mixture was filtered
through a short pad of CeliteÒ. The filtrate was washed with a sat-
urated aqueous NaHCO3 solution, the organic layer was dried
(Na2SO4) and the solvent was removed. The residue was purified by
column chromatography (silica gel, 97:3 hexane/Et3N) to afford
0.028 g (71%) of a pale yellow oil identified as (2E,4E)-1-(benzo-
thiazol-2-yl)sulfanyl-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-
C6D6):
d 171.5 (s), 138.9 (d), 138.3 (s), 136.2 (s), 136.2 (d), 129.0 (s),
127.0 (d), 125.6 (d), 124.7 (d), 60.1 (t), 42.2 (t), 39.9 (t), 34.5 (s), 33.2
(t), 29.8 (d), 29.2 (q), 21.9 (q), 20.9 (q), 19.8 (t), 14.3 (q), 12.4 (q) ppm.
IR (NaCl):
n 2958 (s, CeH), 2925 (s, CeH), 2860 (m, CeH), 1737 (s,
C]O), 1448 (m), 1170 (m) cmꢀ1. HRMS (ESIþ): m/z calcd for
C
22H35O2, 331.2632; found, 331.2630. UV (MeOH): lmax 290 nm
(ε¼23,600 L molꢀ1 cmꢀ1).
3.8. (11Z,13S)-13,14-Dihydroretinoic acid (S)-9
yl)penta-2,4-diene 29. 1H NMR (400 MHz, C6D6):
d
7.92 (d, J¼8.1 Hz,
1H), 7.23 (d, J¼8.0 Hz, 1H), 7.09 (t, J¼7.7 Hz, 1H), 6.90 (t, J¼7.6 Hz,
1H), 6.18 (d, J¼16.2 Hz, 1H), 6.09 (d, J¼16.2 Hz, 1H), 5.68 (t, J¼8.1 Hz,
1H), 4.09 (d, J¼8.1 Hz, 2H), 1.91 (t, J¼6.1 Hz, 2H), 1.73 (s, 3H), 1.66 (s,
3H),1.59e1.51 (m, 2H),1.46e1.42 (m, 2H),1.05 (s, 6H) ppm. 13C NMR
To
a solution of ethyl (11Z,13S)-13,14-dihydroretinoate 21
(0.009 g, 0.028 mmol) in MeOH (2.0 mL) was added KOH (2M
aqueous solution, 0.46 mL, 0.930 mmol) and the reaction mixture
was stirred for 30 min at 80 ꢁC. After cooling down to room tem-
perature, CH2Cl2 and brine were added and the layers were sepa-
rated. The aqueous layer was washed with H2O (3x). The combined
aqueous layers were acidified with 10% HCl and extracted with
CH2Cl2 (3x). The combined organic layers were dried (Na2SO4) and
the solvent was removed. The residue was purified by column
chromatography (silica gel, gradient from 95:5 to 90:10 CH2Cl2/
(101 MHz, C6D6):
d 166.7 (s), 154.0 (s), 138.9 (s), 137.9 (s), 137.5 (d),
136.0 (s), 129.2 (s), 127.4 (d), 126.2 (d), 124.3 (d), 124.0 (d), 121.9 (d),
121.2 (d), 39.8 (t), 34.4 (s), 33.1 (t), 31.9 (t), 30.5 (q), 29.1 (q), 21.8 (q),
19.7 (t), 12.4 (q) ppm. IR (NaCl):
2852 (s, CeH), 1459 (m) cmꢀ1. HRMS (ESIþ): m/z calcd for
22H28NS2, 370.1658; found, 370.1658. UV (MeOH): lmax 225,
n 2958 (s, CeH), 2922 (s, CeH),
C
275 nm.
MeOH) to afford 0.008 g (91%) of a pale yellow oil identified as
26
(11Z,13S)-13,14-dihydroretinoic acid (S)-9.
[a
]
ꢀ34.1 (c 0.1,
3.11. (2E,4E)-1-(Benzothiazol-2-yl)sulfonyl-3-methyl-5-(2,6,6-
trimethylcyclohex-1-en-1-yl)penta-2,4-diene 30
D
MeOH). 1H NMR (400 MHz, (CD3)2CO):
d
6.42 (d, J¼11.9 Hz, 1H),
6.33 (ddd, J¼11.8, 10.5, 1.1 Hz, 1H), 6.21 (d, J¼16.2 Hz, 1H), 6.17 (d,
J¼16.2 Hz, 1H), 5.35 (t, J¼10.2 Hz, 1H), 3.29e3.11 (m, 1H), 2.29 (dd,
J¼7.1, 1.8 Hz, 3H), 2.03e1.98 (m, 2H), 1.91 (d, J¼1.1 Hz, 3H), 1.70 (q,
J¼0.9 Hz, 3H), 1.66e1.59 (m, 2H), 1.50e1.45 (m, 2H), 1.06 (d,
J¼6.7 Hz, 3H), 1.03 (s, 3H), 1.02 (s, 3H) ppm. 13C NMR (100 MHz,
To a solution of (2E,4E)-1-(benzothiazol-2-yl)sulfanyl-3-methyl-
5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-diene 29 (0.049 g,
0.137 mmol) in EtOH (1.4 mL) at 0 ꢁC, was added a solution of
(NH4)6Mo7O24$4H2O, (0.033 g, 0.027 mmol) in aqueous hydrogen
peroxide (35%, 0.2 mL, 2.5 mmol). After stirring for 2 h at 0 ꢁC, the
mixture was quenched with H2O and extracted with Et2O (3x). The
combined organic layers were washed with brine (3x) and dried
(Na2SO4), and the solvent was removed. The residue was purified
by column chromatography (silica gel, 90:7:3 hexane/EtOAc/Et3N)
to afford 0.022 g (40%) of a pale yellow oil identified as (2E,4E)-1-
(benzothiazol-2-yl)sulfonyl-3-methyl-5-(2,6,6-trimethylcyclohex-
(CD3)2CO):
d 173.4 (s), 139.2 (d), 138.7 (s), 137.2 (d), 136.6 (s), 129.6
(s), 127.3 (d), 126.0, (d) 124.9 (d), 42.1 (t), 40.5 (t), 35.0 (s), 33.7 (t),
30.9 (d), 30.5 (q), 29.4 (q), 22.1 (q), 21.2 (q), 20.1 (t), 12.5 (q) ppm. IR
(NaCl):
n 2957 (s, CeH), 2926 (s, CeH), 2860 (m, CeH), 1709 (s, C]
O), 1449 (m), 1287 (m) cmꢀ1. HRMS (ESIþ): m/z calcd for C20H31O2:
303.2319; found: 303.2313.
3.9. (2E,4E)-1-(Benzothiazol-2-yl)sulfanyl-5-iodo-3-
1-en-1-yl)penta-2,4-diene 30. 1H NMR (400 MHz, C6D6):
d 7.95 (d,
methylpenta-2,4-diene 27
J¼8.2 Hz, 1H), 7.02 (t, J¼8.1 Hz, 2H), 6.88 (t, J¼7.8 Hz, 1H), 6.05 (d,
J¼16.2 Hz, 1H), 5.95 (d, J¼16.2 Hz, 1H), 5.38 (t, J¼8.1 Hz, 1H), 4.06 (d,
J¼8.1 Hz, 2H), 1.86 (t, J¼6.2 Hz, 2H), 1.55 (s, 3H), 1.54e1.48 (m, 2H),
1.51 (s, 3H), 1.42e1.35 (m, 2H), 0.94 (s, 6H) ppm. 13C NMR (101 MHz,
To a solution of (2E,4E)-1-(benzothiazol-2-yl)sulfanyl-5-(tri-n-
butylstannyl)-3-methylpenta-2,4-diene50 23 (0.231 g, 0.430 mmol)
in CH3CN (2.5 mL) at 0 ꢁC, was added N-iodosuccinimide (0.126 g,
0.559 mmol) in one portion. After stirring for 1.5 h at 0 ꢁC, the
mixture was quenched with satd Na2S2O4 and NaHCO3(sat) and
extracted with Et2O (3x). The combined organic layers were
washed with H2O (1x) and dried (Na2SO4), and the solvent was
removed. The residue was purified by chromatography (C18-silica,
CH3CN) to afford 0.158 g (99%) of a colorless oil identified as (2E,4E)-
1-(benzothiazol-2-yl)sulfanyl-5-iodo-3-methylpenta-2,4-diene 27.
C6D6):
d 167.5 (s), 153.1 (s), 143.8 (s), 137.5 (s), 137.3 (s), 136.7 (d),
129.6 (s), 128.9 (d), 127.5 (d), 127.4 (d), 125.2 (d), 122.3 (d), 114.0 (d),
55.0 (t), 39.7 (t), 34.3 (s), 33.1 (t), 28.9 (q, 2x), 21.7 (q), 19.6 (t), 12.7
(q) ppm. IR (NaCl):
1467 (m), 1330 (s), 1149.4 (s) cmꢀ1. HRMS (ESIþ): m/z calcd for
22H28NO2S2, 402.1556; found, 402.1555. UV (MeOH): lmax 238,
n 2956 (s, CeH), 2926 (s, CeH), 2864 (m, CeH),
C
275 nm.
1H NMR (400 MHz, C6D6):
d
7.89 (d, J¼8.1 Hz, 1H), 7.24 (d, J¼8.0 Hz,
3.12. Ethyl (11Z,13S)-13,14-dihydroretinoate (S)-21
1H), 7.10 (t, J¼7.7 Hz, 1H), 6.91 (t, J¼7.7 Hz, 1H), 6.76 (d, J¼14.7 Hz,
1H), 5.90 (d, J¼14.7 Hz, 1H), 5.33 (t, J¼8.0 Hz, 1H), 3.78 (d, J¼8.0 Hz,
A cooled (ꢀ78 ꢁC) solution of (2E,4E)-1-(benzothiazol-2-yl)sul-
fonyl-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-
diene 30 (0.012 g, 0.030 mmol) in THF (1.5 mL) was treated with
NaHMDS (0.034 mL, 1M in THF, 0.034 mmol). After stirring for
30 min at this temperature, a solution of ethyl (S)-3-methyl-4-
2H), 1.31 (s, 3H) ppm. 13C NMR (100 MHz, C6D6):
d 166.1 (s), 153.9
(s), 148.7 (d), 138.4 (s), 135.9 (s), 127.0 (d), 126.3 (d), 124.5 (d), 121.9
(d), 121.3 (d), 76.8 (d), 31.0 (t), 11.6 (q) ppm. IR (NaCl): 3061 (w,
CeH), 2954 (m, CeH), 2921 (m, CeH), 2854 (w, CeH), 1457 (s), 1424
n
Please cite this article in press as: Vaz, B.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.006

6
B. Vaz et al. / Tetrahedron xxx (2016) 1e7
oxobutanoate (S)-10 (0.007 g, 0.045 mmol) in THF (0.7 mL) was
added and the resulting mixture was stirred for 1 h at ꢀ78 ꢁC. Et2O
and water were added at low temperature and the mixture was
warmed up to room temperature. It was then diluted with Et2O and
the layers were separated. The aqueous layer was extracted with
Et2O (3x), the combined organic layers were dried (Na2SO4) and the
solvent was removed. The residue was purified by column chro-
matography (silica gel, 97:3 hexane/Et3N) to afford 0.009 g (89%) of
a pale yellow oil identified as a 5:1 mixture of 11Z/11E isomers of
ethyl (13S)-13,14-dihydroretinoate (S)-21. They were separated by
HPLC (Prep Nova Pak Silica HR, 98:2 hexane/EtOAc, 3 mL/min; tR
(Z)¼33 min; tR (E)¼35 min).
25 ꢁC, the reaction mixture was quenched with a saturated aqueous
Na2S2O4 solution and extracted with Et2O (3x). The combined or-
ganic layers were dried (Na2SO4), and the solvent was removed.
NMR analysis of the crude obtained showed a 1:1 ratio of E/Z iso-
mers of the expected iodide. The mixture was used in the next
Suzuki reaction without further purification.
To a solution of the mixture of iodides obtained above in THF
(0.8 mL) was added Pd(PPh3)4 (0.005 g, 0.004 mmol). After 5 min at
25 ꢁC, 2,6,6-trimethylcyclohex-1-enylboronic acid 16 (0.010 g,
0.058 mmol) was added in one portion followed by TlOH (10%
aqueous solution, 0.262 mL, 0.148 mmol). After stirring for 16 h at
25 ꢁC, Et2O was added and the reaction mixture was filtered
through a short pad of CeliteÒ. The filtrate was washed with satd
NaHCO3, the organic layer was dried (Na2SO4) and the solvent was
removed. The residue was purified by column chromatography
(silica gel, 97:3 hexane/Et3N) to afford 0.004 g (33%) of a pale yellow
oil identified as a 1:1 mixture of 11Z/11E isomers of ethyl (13S)-
13,14-dihydroretinoate (S)-21.
3.13. (2E,4E)-1-(Benzothiazol-2-yl)sulfonyl-5-iodo-3-
methylpenta-2,4-diene 28
To a solution of (2E,4E)-1-(benzothiazol-2-yl)sulfanyl-5-iodo-3-
methylpenta-2,4-diene 27 (0.056 g, 0.152 mmol) in EtOH (1.6 mL) at
0
ꢁC, was added a solution of (NH4)6Mo7O24$4H2O, (0.037 g,
0.030 mmol) in aqueous hydrogen peroxide (35%, 0.24 mL,
2.742 mmol). After stirring for 13 h at 0 ꢁC, the mixture was
quenched with H2O and extracted with Et2O (3x). The combined
organic layers were washed with brine (3x) and dried (Na2SO4), and
the solvent was removed. The residue was purified by re-
crystallization from acetone/hexane affording 0.036 g (60%) of
white crystals identified as (2E,4E)-1-(benzothiazol-2-yl)sulfonyl-
5-iodo-3-methylpenta-2,4-diene 28. 1H NMR (400 MHz, C6D6):
Acknowledgements
This work was supported by funds from the Spanish MINECO
(SAF2013-48397-R-FEDER), Xunta de Galicia (Grant 08CSA052383PR
ꢀ
from DXIþDþi; Consolidacion 2013/007 from DXPCTSUG;
INBIOMED-FEDER ‘Unha maneira de facer Europa’).
Supplementary data
d
7.94 (d, J¼8.1 Hz, 1H), 7.07 (d, J¼7.5 Hz, 1H), 7.06 (t, J¼7.5 Hz, 1H),
6.91 (t, J¼7.7 Hz, 1H), 6.65 (d, J¼14.7 Hz, 1H), 5.86 (d, J¼14.7 Hz, 1H),
5.11 (t, J¼8.1 Hz, 1H), 3.86 (d, J¼8.1 Hz, 2H), 1.14 (s, 3H) ppm. 13C
Supplementary data (General procedures, HPLC separation, NOE
experiments and copies of 1H NMR and 13C NMR spectra for all
compounds described in the text) associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2016.05.006.
NMR (100 MHz, C6D6): d 167.1 (s), 153.0 (s), 147.8 (d), 143.4 (s), 137.1
(s), 127.7 (d), 127.5 (d), 125.2 (d), 122.5 (d), 116.6 (d), 79.4 (d), 54.2
(t), 12.0 (q) ppm.
3.14. Ethyl (3S,4Z,6E,8E)-3,7-dimethyl-9-(tri-n-butylstannyl)
nona-4,6,8-trienoate (S)-25
References and notes
A cooled (ꢀ78 ꢁC) solution of (2E,4E)-1-(benzothiazol-2-yl)sul-
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fonyl-5-(tri-n-butylstannyl)-3-methylpenta-2,4-diene50
24
(0.030 g, 0.053 mmol) in THF (2.4 mL) was treated with NaHMDS
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Please cite this article in press as: Vaz, B.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.006