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Synthesis of Biotinylated Retinoids for Cross-Linking and Isolation of Retinol Binding Proteins

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Synthesis of Biotinylated Retinoids for Cross-Linking and Isolation of Retinol Binding Proteins Tetrahedron 58 (2002) 6577–6584 Synthesis of biotinylated retinoids for cross-linking and isolation of retinol binding proteins Nasri Nesnas,a Robert R. Randob,* and Koji Nakanishia,* aDepartment of Chemistry, Columbia University, New York, NY 10027, USA bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA Received 11 June 2002; accepted 21 June 2002 This article is dedicated to Professor Yoshito Kishi on his receipt of the Tetrahedron Prize Abstract—The synthesis of (3R )-3-[Boc-Lys(biotinyl)-O ]-11-cis-retinol bromoacetate and 3-[Boc-Lys(biotinyl)-O ]-all trans-retinol chloroacetate is described. These biotinylated retinoids are instrumental in labeling the retinol binding proteins (RBPs) via a nucleophilic displacement of the haloacetate by a residue in the binding site of the protein. The covalently linked biotin will allow for a facile isolation and purification of the protein on a streptavidin column thus rendering the protein ready for a tryptic digest followed by mass spectrometric analysis. The 11-cis retinoid was synthesized via metal reduction of an alkyne intermediate generated from a Horner–Wadsworth–Emmons (HWE) reaction whereas the all-trans was synthesized via two consecutive HWE couplings. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction some are involved in catalyzing esterification, hydrolysis, and isomerization of retinols at various stages in the visual Retinoids are derivatives of vitamin A (all trans-retinol) cycle. A summary of the mammalian visual cycle is which can generally be synthesized for studies directed to a presented in Fig. 2. The visual protein, rhodopsin, is better understanding of human and non-human vision. We comprised of the protein opsin (ca. 348 amino acids in hereby report the synthesis of (3R )-3-[Boc-Lys(biotinyl)- bovine) and 11-cis-retinal covalently linked via a schiff base O ]-11-cis-retinol bromoacetate (1) and 3-[Boc-Lys(bio- with Lys296 residue. Vision begins with the absorption of tinyl)-O ]-all trans-retinol chloroacetate (2)(Fig. 1). These light by rhodopsin causing the isomerization of 11-cis- retinoids can act as ligands for proteins known as retinol retinylidene to all trans-retinylidene. This occurs over binding proteins (RBPs) present in the retinal pigment several states of rhodopsin leading to a meta II state epithelial (RPE) cells.1 These RBPs are believed to be (unprotonated schiff base) which is responsible for responsible for the transport of retinols in RPE cells and G-protein activation ultimately leading to neural signaling.2 Figure 1. The target retinoid biotinylated structures. Keywords: biotinylated retinoids; biotin; retinol binding proteins; RBP. * Corresponding author. Tel.: þ1-212-854-2169; fax: þ1-212-932-8273; e-mail: [email protected] 0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(02)00667-1 6578 N. Nesnas et al. / Tetrahedron 58 (2002) 6577–6584 Figure 2. The mammalian visual cycle. This isomerization is accompanied by various confor- the transformation while the retinoid 1 may prove helpful mational changes of the protein which in turn trigger the for isolating RBPs that act in the later stages of pigment binding of G-protein. These photo intermediates have been regeneration. The features of the target molecules are well studied through photoaffinity labeling experiments, outlined in Fig. 3 as exemplified through retinoid 2. The all protein digestion and mass spectrometric characterization.3 trans retinol portion of the structures acts as a ligand for the The meta II state is then protonated generating meta III (see binding site of the RBP. The chloroacetyl moiety acts as a Fig. 2) which undergoes hydrolysis regenerating the protein potent electrophile for a nearby residue to carry out a opsin and all trans-retinal. To complete the visual cycle, the nucleophilic displacement of the halogen forming a all trans-retinal needs to be re-isomerized back to 11-cis- covalent bond with a residue in the active site of the retinal. This is achieved through a cascade of several events protein. This nucleophilic displacement resulting in a involving proteins such as dehydrogenase which initially covalent bond with the protein is referred to as the labeling reduces all trans-retinal to all trans-retinol (vitamin A). The step of the protein. The ultimate result is that the RBPs latter is then isomerized to 11-cis-retinol through the action which inherently bind retinol (hence the name) will be of numerous RBPs which we are interested in further specifically labeled with these structures bearing an investigating.1 The actions of these proteins include the extended tether (Boc-Lys) to a biotin. The latter will esterification of vitamin A with a palmitoyl group followed allow for the facile isolation of the protein via affinity by an isomerization of the resulting palimitate through a chromatography through an avidin column. This technique possible hydrolytic mechanism. One such protein that has proved to be successful in the isolation and identification of been already under investigation is known as lecithin retinol mammalian LRAT using biotinylated affinity labeling acyl transferase (LRAT).4,5 To regenerate the visual agents.6 The biotin affinity labeling approach was important pigment, 11-cis-retinol undergoes oxidation via a dehydro- here because membrane bound LRAT was not susceptible to genase rendering 11-cis-retinal ready for incorporation into purification due to its instability when solubilized in opsin forming the Schiff base rhodopsin. detergent. In the interest of isolating and investigating the RBPs One important advantage that is featured in the target involved in the transport and transformation of all trans- structures needs to be emphasized. The biotin allows for the retinol to the 11-cis-retinol the target molecules 1 and 2 successful isolation of the protein due to its remarkable were synthesized. The all trans biotinylated retinoid 2 is binding to streptavidin with association constants often needed as a ligand for RBPs involved in the earlier stages of exceeding 1015 M21.6,7 However, this often presents a challenge for the scientist who is interested in isolating the protein via breaking this association. The above structure features a labile ester of the primary alcohol at C-15 of the retinol hydroxyl which can be easily cleaved in basic media (pH,11). 1.1. Retrosynthetic analysis of 1 and 2 Scheme 1 represents the two approaches for the installation of a biotin on one end of the retinoid and a haloester on the other end. Structure 7 represents the general formula for retinoids 1 and 2. Structure 3 represents the retinoid backbone with some orthogonal protection on the hydroxy groups at C-3 and C-15. Route A will entail installing the Boc-Lys(biotinyl)-OH (B-OH) first directly after deprotec- tion of the C-3 alcohol (unless prior steps involve releasing the 3-hydroxy) and then attachment of the haloacid via an EDC coupling reaction. Route B, however, will require the Figure 3. A schematic diagram of structure 2 in the binding site of a representative RBP featuring key elements of the structure and their role in release of the primary alcohol at C-15, attachment of the protein labeling and isolation. haloester, and finally deprotection of the 3-hydroxy N. Nesnas et al. / Tetrahedron 58 (2002) 6577–6584 6579 Scheme 1. Retrosynthetic analysis using two poteintal route A and B. biological assays since the biotin linker is not directly involved in the binding of the protein. We have in fact generated 3-hydroxy-b-ionone 9 from two independent routes and have arbitrarily proceeded with (R )-9 for the synthesis of 1 and the racemic 9 for the synthesis of 2. The stereoselective route for the generation of (R )-9 was needed for another purpose that will be published elsewhere. Scheme 4 presents that two routes for the generation of 9. The non-stereoselective route will involve the introduction of a double at the C-3,412 followed by hydroboration 13 ^ 14 Scheme 2. treatment to afford ( )-9. The stereoselective route will involve the stereoselective reduction of 18 followed by a followed by esterification with B-OH. The first route is second reduction of the unhindered carbonyl resulting in favored as the labile haloester which is attached last will not 17.15 The latter can be transformed into (R )-9 via triflation16 need to endure the steps presented in Route B. However, followed by a Heck reaction.17 both routes were used as will become apparent in due course owing to the nature of the retinoid precursor 3 for each of the two target molecules, the cis and the trans. The retrosynthesis of 4a is outlined in Scheme 2. The 11-cis double bond can be generated via a zinc metal reduction of the alkyne intermediate 8.8 The latter can be constructed via Scheme 4. a Horner–Wadsworth–Emmons (HWE) coupling of the 3-hydroxy-b-ionone (R )-9 and phosphonate 10 followed by 2. Results and discussion a Sonogashira coupling8 with vinyl iodide 11, which can be obtained from a reduction of 12 followed by iodination with The synthesis of the racemic 3-hydroxy-b-ionone (^)-9 9 14 I2. from b-ionone 16 was carried out according to Scheme 5. Treatment of the latter with N-bromosuccinimide (NBS) The 3-hydroxy-b-ionone can also be used in the synthesis of under basic and refluxing conditions yielded a 4-bromo 4b as shown in the retrosynthetic analysis in Scheme 3. Two derivative which eliminated when heated in pyridine for 2 h consecutive HWE couplings: the first between (^)-9 and 14 affording 3,4-dehydro-b-ionone 19 in a 50% overall yield.12 followed by DIBAH reduction to generate an aldehyde Protection of the ketone occurred smoothly with ethylene ready for the second coupling with phosphonate 15 thus glycol in benzene catalyzed by p-toluenesulfonic acid in the 13 generating 13.
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