Stereocontrolled synthesis and configurational assignment of (R)-all-trans-11,12-dihydro-3-hydroxyretinol

Article abstract of DOI:10.1016/j.tetlet.2019.150972

The synthesis of (R)-all-trans-11,12-dihydro-3-hydroxyretinol and putative metabolites of the side-chain functional group has been achieved in a stereocontrolled manner via the Suzuki-Hiyama cross-coupling reaction of an enantiopure (hydroxycyclohexenyl)alkenyliodide and non-conjugated pinacolboranedienoate, which allowed the absolute configuration of this natural product to be confirmed.

Full text of DOI:10.1016/j.tetlet.2019.150972

Accepted Manuscript
Stereocontrolled Synthesis and Configurational Assignment of (R)-all-
trans-11,12-Dihydro-4-Hydroxy-Retinol
Aurea Rivas, Rosana Alvarez, Angel R. de Lera
PII:
S0040-4039(19)30723-3
https://doi.org/10.1016/j.tetlet.2019.150972
150972
DOI:
Article Number:
Reference:
TETL 150972
Tetrahedron Letters
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Revised Date:
Accepted Date:
13 June 2019
17 July 2019
22 July 2019
Please cite this article as: Rivas, A., Alvarez, R., de Lera, A.R., Stereocontrolled Synthesis and Configurational
Assignment of (R)-all-trans-11,12-Dihydro-4-Hydroxy-Retinol, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.150972
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Stereocontrolled Synthesis and Configurational Assignment of
(R)-all-trans-11,12-Dihydro-4-Hydroxy-Retinol
Leave this area blank for abstract info.
Aurea Rivas,a Rosana Alvarez,a,* and Angel R. de Lera a,*
C6-C7
11
7
CO2Me
PinB
9
OH
12
C8-C9
+
HO
C8-C9
I
(R)-11,12-dihydro-3-hydroxyretinol
HO

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Stereocontrolled Synthesis and Configurational Assignment of (R)-all-trans-11,12-
Dihydro-4-Hydroxy-Retinol
Aurea Rivas,a Rosana Alvarez,a,* and Angel R. de Lera a,*
a Departamento de Química Orgánica, Facultade de Química, CINBIO and IIS Galicia Sur, Universidade de Vigo, E-36310 Vigo, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of (R)-all-trans-4-hydroxy-11,12-dihydroretinol and putative metabolites of the
side-chain functional group has been achieved in a stereocontrolled manner via the Suzuki-
Hiyama cross-coupling reaction of an enantiopure (hydroxycyclohexenyl)alkenyliodide and non-
conjugated pinacolboranedienoate, which allowed the absolute configuration of this natural
product to be confirmed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Retinoids
Vitamin A
Suzuki-Hiyama
Total synthesis
dihydroretinol saturase (RetSat).25 RetSat saturates all-trans-
1. Introduction
retinol
1
to enantiospecifically give (R)-all-trans-13,14-
All-trans-retinol (vitamin A 1, Fig. 1) is considered to be a
multifunctional vitamin1 due to its physiological role in a variety
of processes such as vision, reproduction, embryonic growth and
development, cell differentiation, proliferation and apoptosis,
immune competence, maintenance of epithelial tissue and control
dihydroretinol (R)-7.23 A related enzyme in zebrafish catalyzes
the saturation of the C7=C8 bond in addition to the C13=C14
bond of all-trans-retinol 1 to produce both (R)-7 and all-trans-
7,8-dihydroretinol 9. These metabolites undergo oxidation by
SDR/MDR dehydrogenases leading to the formation of (R)-all-
trans-13,14-dihydroretinoic acid (R)-8 and all-trans-7,8-
dihydroretinoic acid 10 (Fig. 1). For all-trans-13,14-
dihydroretinoic acid 8 these pathways are similar to those
involved in the formation of the parent all-trans-retinoic acid 3
from 1.
of brain function.2-6 In developing countries, vitamin
A
deficiency is associated with child and maternal mortality,7,8 as
well as with xerophthalmia and night blindness.8
Most of these biological processes linked to vitamin A are in
fact due to the interaction of several of its metabolites with their
cognate receptors. Both 11-cis-retinal (4, Fig. 1) and all-trans-
retinal (2, Fig. 1) are chromophores of the visual pigments,9-12
whereas all-trans-retinoic acid (3, Fig. 1) and 9-cis-retinoic acid
(6, Fig. 1) are ligands for the RAR and RXR families of nuclear
receptors.13,14 These and additional metabolites, collectively
termed retinoids,15-17,3,4 are generated in vivo by redox changes
affecting the functional groups (retinal, retinoic acid), the allylic
positions and the conjugated polyene chain and/or by
isomerization of selected double bonds. Vitamin A and its
analogs are generally stored in the liver as retinyl esters of long
chain fatty acids (such as palmitates) through the action of
lecithin:retinol acyl transferase (LRAT) enzymes.18 Retinoid
metabolizing
enzymes,19,20
such
as
NAD-dependent
dehydrogenases (retinol dehydrogenases, RDHs) of the cytosolic
medium-chain (MDR) and the membrane-bound short-chain
(SDR) dehydrogenases/reductases,21,20 and the aldo-keto
reductases (AKR)22 further collaborate to maintain the
physiological levels of the retinoids in vivo.
The group of endogenous dihydroretinoids (Fig. 1)23-25 are
produced in vivo by the action of all-trans-retinol:13,14-

2
Tetrahedron
20
13
19
9
16
17
3
differing by the presence and geometry of the double bonds and
15
11
their location along the C20-carbon skeletons.6
R
1
18
In this context, 11,12-dihydro-3-hydroxyretinol 14 has
recently been isolated from the red alga Laurencia nipponica
collected in Muroran, Hokkaido, Japan.30 It showed moderate (5–
10 g/cm2) antifouling activity against larvae of the barnacle
Amphibalanus amphitrite diatoms. Due to the limited amounts of
natural product isolated, it was not possible to determine the
absolute configuration of natural product 14.
R
1
2
3
, R = CH2OH, all-trans-retinol
, R = CHO, all-trans-retinal
, R = COOH, all-trans-retinoic acid
4
5,
, R = CHO
R = CH2OH
9
R
13
7
8
, R = CH2OH
, R = COOH
Results and Discussion
6
CO2H
Since the putative biogenetic precursors6 should be
hydroxycarotenoids and these natural products with hydroxyl
substituents at C3 are of the R configuration,31 we assumed this to
be the absolute configuration of natural product 14. Given our
interest in the synthesis and biological evaluation of retinoids and
related polyenes,6 we set out to develop a stereoselective
synthesis of the proposed enantiomer 14 in order to confirm the
structure and make the compound available for further biological
evaluation. Moreover, structural similarities of the C7-C15
skeleton with that of vitamin A 1 suggested the C6-C7 and C8-
C9 single bonds to be reasonable disconnections (Scheme 1).
Alternatively, a Pd-catalyzed cross-coupling reaction of non-
7
9
9
R
8
13
13
9
, R = CH2OH
O
10
, R = COOH
11
CO2H
CO2H
12
11
OH
OH
12
3
HO
14
, (R)-11,12-dihydro-3-hydroxyretinol
13
, caulerpol
conjugated
trienylboronate
15
and
enantiopure
hydroxycyclohexenyliodide 16 or that of non-conjugated
dienylboronate 17 and dienyliodide 18 would eventually lead to
the target skeleton. Iodides 16 and 18 can efficiently be derived
from enantiopure actinol 20.32 Boronate 15 could be obtained
from the dienal resulting from allylic oxidation of a protected
derivative of geraniol 19, whereas 17 would result from the
acyclic cross-metathesis of 21 and 2-propenylboronate.33
Figure 1. Structures of natural retinoids and di(tetra)hydroretinoids.
The absolute configurations of 11 and 13 have not yet been
determined.
Additionally, we have recently discovered 9-cis-13,14-
dihydroretinoic acid 11 as the first endogenous and
physiologically relevant retinoid that acts as a RXR ligand in
mammals.26 The putative metabolite (S)-9-cis-4-oxo-13,14-
dihydroretinoic acid (S)-12 (Fig. 1) has been endogenously
detected (in liver and other tissues) and also isolated from the
liver of mice, rats and humans.27,28
We started with the C6-C7 disconnection, and constructed
boronate 15, which contains the side chain of the natural product
(see ESI). Enal 2234 was efficiently (78% yield) converted into
dienylpinacolboronate
15
upon
treatment
with
dichloromethylpinacolboronate and CrCl2 in THF.24
A formal tetrahydroretinol named caulerpol 13 has also been
reported to be present in the green algae Caulerpa brownie,29
which indicates the existence of additional derivatives in Nature
I
+
C6-C7
C6-C7
PinB
OAc
RO
15
7
16
9
OH
C8-C9
I
HO
C8-C9
+
CO2Me
PinB
14
, (R)-11,12-dihydro-3-hydroxyretinol
HO
17
18
O
+
R
HO
19
21
22
20
, R = CH2OH
, R = CO2Me
, R = CHO
Scheme 1. Retrosynthetic analysis of (R)-3-hydroxy-11,12-dihydroretinol 14.
Unfortunately, all attempts to perform the Suzuki-Miyaura
cross-coupling of 15 and 1632 proved inefficient, with by-

3
products resulting from protiodeboronation and ester hydrolysis
being obtained under the reaction conditions.
oxidative metabolism of all-trans-retinol 2 to all-trans-retinoic
acid 3 also catalyze similar steps in the biogenesis of all-trans-4-
hydroxy-11,12-dihydroretinol 14 and putative metabolites.
Alternatively, the C8-C9 bond disconnection (Scheme 2)
involving the use of a similar Csp2-Csp2 cross-coupling reaction
between dienyliodide 18 and alkenylpinacolboronate 17 was
considered. The first component was obtained in good overall
Acknowledgments
We thank the Spanish MINECO (SAF2016-77620-R-
FEDER), Xunta de Galicia (Consolidación GRC ED431C
2017/61 from DXPCTSUG; ED-431G/02-FEDER "Unha
maneira de facer Europa" to CINBIO, a Galician research center
2016-2019; Contract to A. Rivas). We thank Dr. Thomas
Netscher (DSM, Switzerland) for his generous gift of actinol.
yield
from
cyclohexenyliodide
1632,35
(Scheme
1).
Pinacolboronate 17 was obtained from methyl geranoate 21
(which was synthesized in 87% yield by oxidation of geranial
using MnO2 and KCN in the presence of MeOH) by acyclic
cross-metathesis with 2-propenylboronate promoted by second-
generation Grubbs’ catalyst (50 ºC, 16 h) to afford 17 in 48%
yield as the Z isomer.36 Finally, the Suzuki-Miyaura cross-
coupling of alkenylboronate 17 and dienyliodide 18 under
Pd(PPh3)4 catalysis with 10% aqueous TlOH as the base in THF
afforded non-conjugated all-trans-tetraenoate 24 in 71% yield.
Functional group modification gave either (R)-3-hydroxy-11,12-
dihydroretinol 14 (DIBAL-H, THF, 73%) or (R)-3-hydroxy-
11,12-dihydroretinoic acid 25 (KOH, 63%). Comparison of the
specific rotation of synthetic 14 ([α]D18 -42.7 (c 0.064, CHCl3))
27
with that reported for the natural product ([α]D -61.9 (c 0.07,
CHCl3))30 allowed its absolute configuration to be confirmed.
To summarize, the stereoselective synthesis of (R)-all-trans-4-
hydroxy-11,12-dihydroretinol 14 and putative metabolite 25 has
been achieved via a Suzuki-Hiyama cross-coupling reaction of
dienyliodide 18 and non-conjugated pinacolboranedienoate 17
for the C8-C9 single bond construction. Biogenetically, (R)-all-
trans-4-hydroxy-11,12-dihydroretinol and metabolites (and / or
isomers) could be formed by enzymatic saturation of the
precursor all-trans-4-hydroxyretinol or alternatively generated by
saturation at the provitamin A / carotenoid level.37 It could be
hypothesized that enzymes similar to those involved in the
Cl
a)
Pd(PPh3)4 (7 mol%)
10% aq. TlOH
THF, 25 ºC, 2 h
OAc
Cl
BPin
PinB
OAc
OHC
OAc
CrCl2, THF, 25 ºC
16 h, 78%
22
15
TBDMSO
I
23
TBDMSO
16
5 steps
(ref. 32 and 35)
I
b)
PinB
R
Grubbs II cat.
(5 mol%)
HO
18
CO2Me
CO2Me
HO
PinB
Pd(PPh3)4 (7 mol%)
10% aq. TlOH
THF, 25 ºC, 2 h, 71%
50 ºC, 16 h, 48%
21
17
24
25
14
, R = CO2Me
, R = CO2H
, R = CH2OH
2 M KOH, MeOH
80 ºC, 15 min, 63%
DIBAL-H, THF
-78 ºC, 2 h, 73%
Scheme 2. a) Unsuccessful approach to (R)-3-hydroxy-11,12-dihydroretinol 14 via C6-C7 bond formation. b) Synthesis of (R)-3-hydroxy-
11,12-dihydroretinol 14 through the C8-C9 disconnection using
alkenylpinacolboronate 17.
a Suzuki-Miyaura cross-coupling of dienyliodide 18 and

4
Tetrahedron
26. Rühl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.;
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Szklenar, M.; Nagy, L.; de Lera, A. R.; Kręzel, W. PLoS Genet
2015, 11, e1005213.
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Stereocontrolled Synthesis and
Leave this area blank for abstract info.
Configurational Assignment of (R)-all-trans-
11,12-Dihydro-3-Hydroxyretinol
Aurea Rivas,a Rosana Alvarez,a,* and Angel R. de Lera a,*
CO2Et
PinB
9
OH
C8-C9
8
+
HO
C8-C9
I
(R)-11,12-dihydro-3-hydroxyretinol
HO
Academic Press: San Diego, 2002.
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template box below.
23. Moise, A. R.; Isken, A.; Domínguez, M.; de Lera , A. R.; von
Lintig, J.; Palczewski, K. Biochemistry 2007, 46, 1811-1820.
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Mol. Pharmacol. 2009, 76, 1228-1237.
Fonts or abstract dimensions should not be changed or altered.
-
Configurational assignment of a natural
product
HIGHLIGHTS

5
-
-
Total synthesis of a new retinoid
Synthetic route to investigate the
biological activity
-
Relationship with carotenoids and vitamin
A