Stereocontrolled synthesis of (S)-9-cis- and (S)-11-cis-13,14-dihydroretinoic acid
Graphical abstract
Introduction
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 differentiation, 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 vitamin 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.2, 3, 4, 5
In addition to all-trans-retinoic acid 2, vitamin A is transformed into additional metabolites that collectively help establish a delicate 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.7, 8, 9 It has been shown that the formation of 5 involves the formal hydrogenation of all-trans-retinol 1 mediated by the enzyme retinol saturase (RetSat)10 and further two-stage oxidation 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 transactivation activity in comparison with its antipode.8
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, which binds to the apoprotein opsin as a protonated Schiff base to trigger the visual cycle upon light absorption.11 Fig 1.
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,15, 16, 17, 18, 19, 20 perhaps 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 concurred 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 characterized as retinoid receptor ligands. Although compounds with the structure of 9-cis-13,14-dihydroretinoic acid 7 (its absolute configuration 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 reported as an endogenous ligand for at least two RAR subtypes (α and β) but not for RXR. This compound induced in vivo morphological 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 dihydroretinoids of potential biological interest. We have reported the synthesis of all-trans-13,14-dihydroretinoic acid 5 in both enantiomeric 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.
Section snippets
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 Csp2Csp2 bond construction by carbonyl condensation reactions (Wittig, HWE, Julia) or the use of mono and bis-functionalized alkenyl linchpins30 to connect components of complementary reactivity by palladium-catalyzed Csp2–Csp2 cross-coupling reactions.31 In practice, functionalized alkenyl reagents (as halogens
Experimental section
For general procedures, see Supplementary data.
Acknowledgements
This work was supported by funds from the Spanish MINECO (SAF2013-48397-R-FEDER), Xunta de Galicia (Grant 08CSA052383PR from DXI+D+i; Consolidación 2013/007 from DXPCTSUG; INBIOMED-FEDER ‘Unha maneira de facer Europa’).
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