Efficient Synthesis of 11-cis-Retinoids

Borhan, Babak; Souto, Marı́a L.; Um, Joann M.; Zhou, Bishan; Nakanishi, Koji

doi:10.1002/(sici)1521-3765(19990401)5:4<1172::aid-chem1172>3.0.co;2-q

Cited by 34 publications

(50 citation statements)

References 18 publications

(32 reference statements)

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“…1 H-NMR Spectra: Bruker DMX 500 or 400 MHz instrument, the residual protic solvent (CDCl 3 or C 6 D 6 ) as internal reference. 13 C-NMR Spectra: at 75 MHz on a Bruker DMX 300 instrument. Low-resolution and high-resolution (HR) FAB-MS: JEOL JMS-DX303 HF mass spectrometer, with a glycerol matrix and Xe ionizing gas.…”

Section: Experimental Partmentioning

confidence: 99%

“…Although the isomerization proceeded efficiently, and retinochrome could be recycled, this chemoenzymatic preparation was not suited for securing the quantity needed for the planned photo-cross-linking studies. However, we recently managed to devise a general synthetic method for preparation of various (11Z)-retinal analogs via semi-hydrogenation of 11-yne precursors with activated Zn (Scheme 2) [13]. Application of this protocol in the present studies was critical in achieving the synthesis of photoaffinity analog 1.…”

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“…Synthesis of the 11-yne precursor 2 has been demonstrated previously [13]. The crucial semi-hydrogenation of the acetylene is mediated by activated Zn powder in aqueous MeOH to secure the protected (11Z)-retinol analog 3 with high stereoselectivity (Scheme 3).…”

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“…Semi-Hydrogenation of 11-Yne Precursors of (11Z)-Retinal Analogs. Most other semi-hydrogenation methods fail to deliver the desired compound, usually because of over-hydrogenation of tetrasubstituted CC bonds [13].…”

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Synthesis of a Photoaffinity-Labeled (11Z)-Retinal: Identification of Retinal/Rhodopsin Cross-Linked Sites along the Visual-Transduction Path

Souto

Borhan

et al. 2000

HCA

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Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthdayThe retinal chromophore (11Z)-3-diazo-4-oxoretinal (1) with two photo-labile moieties has been synthesized by semi-hydrogenation of an 11-yne precursor with activated Zn in aqueous media. Incorporation of 1 into opsin yielded diazoketo rhodopsin (DK-Rh), which, upon bleaching, gave rise to intermediates bathoRh, lumi-Rh, meta-Rh, and meta-II-Rh corresponding to those of native Rh but at lower temperatures. Photoaffinity labeling of DK-Rh and these bleaching intermediates showed that the ionone ring cross-linked to Trp265 of helix F in DK-Rh and batho intermediate, and to Ala169 of helix D in lumi, meta-I, and meta-II intermediates. These results demonstrate the occurrence of large conformational changes along the visual transduction path, which, in turn, is responsible for activation of the G-protein.Introduction. ± Rhodopsin (Rh) is a seven-transmembrane a-helical G-ProteinCoupled Receptor (GPCR) composed of 348 amino acids and the chromophore, (11Z)-retinal, which is bound to Lys296 as a protonated Schiff base [1] [2]. It is found in the outer segment of vertebrate rods, and is the photoreceptor that mediates dim vision. Visual transduction is triggered by photons which isomerize the (11Z)-chromophore to (all-E); this isomerization triggers a chain of conformational changes in the opsin, which induces an enzymatic cascade leading to vision [2 ± 4]. Scheme 1 depicts the intermediates present in the visual transduction process of Rh, identified by flash photolysis and various low-temperature spectroscopic measurements [4] [5]. Light irradiation of Rh results in (11Z) 3 (11E) isomerization of the chromophore. This yields photo-Rh (femtosecond process), which is converted into batho-Rh, a primary product that can be sequestered at À 1408; in contrast to Rh, l max 500 nm, batho-Rh absorbs at 543 nm and is considered to adopt a highly-strained (11E)-double bond [1] [3]. As shown in Scheme 1, batho-Rh relaxes thermally to further photo intermediates, i.e., lumi-Rh, that is in equilibrium with the blue-shifted intermediate, and then to meta-I-Rh and meta-II-Rh.We have been interested in tracing the path of photo-isomerization and to identify the relative position of the chromophore with respect to Rh at each photointermediate. Results to date have shown that the C(3) of the ionone ring is in close contact with helix F of Rh in the dark prior to photo isomerization [4] [5]. However, the contacts made by the chromophore after light activation, which subsequently lead to visual transduction, remain to be clarified. Recent site-directed spin labeling of rhodopsin mutants (and disulfide cross-linking) [6] have demonstrated that movements

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Section: Experimental Partmentioning

confidence: 99%

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confidence: 97%

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confidence: 99%

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confidence: 99%

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Synthesis of a Photoaffinity-Labeled (11Z)-Retinal: Identification of Retinal/Rhodopsin Cross-Linked Sites along the Visual-Transduction Path

Souto

Borhan

et al. 2000

HCA

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“…8) In the past decade, methods dealing with a stereoselective synthesis of 11Z-retinal have been developed. [9][10][11] In connection with our stereoselective synthesis of retinoid compounds, 1,[12][13][14][15] we describe herein a convenient and stereoselective synthesis of 11Z-3,4-didehydroretinal (2) (Chart 1).…”

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A Convenient and Stereoselective Synthesis of 11Z-3,4-Didehydroretinal by Horner-Emmons Reaction Using Diphenyl Phosphonate

Wada

Wang

Ito

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the visual pigment rhodopsin, the chromophore 11Z-retinal (1, vitamin A 1 aldehyde) binds to the e-amino group of a lysine residue of the apoprotein opsin through a protonated Schiff base.2) Rhodopsin is the G-protein-coupled photoreceptor in the retina of vertebrates that initiates the visual signal transduction cascade in dim light.3) It is a representative G-protein-coupled receptors (GPCRs), and is a member of the superfamily of the seven transmembrane helix proteins, a biologically very significant class of signal mediators.4,5) Some pigments, especially those of fresh water animals, contain 11Z-3,4-didehydroretinal (2, vitamin A 2 aldehyde) as well as 11Z-retinal (1) as the chromophore.6,7) For study of the mechanism of the visual process, a supply of a sufficient amount of the chromophore in pure 11Z-form is essential for the preparation of the pigment. Only one report for the stereoselective synthesis of 11Z-3,4-didehydroretinal (2) using hydrogenation of the acetylenic precursor by Lindlar catalyst has appeared in the literature. 8) In the past decade, methods dealing with a stereoselective synthesis of 11Z-retinal have been developed. [9][10][11] In connection with our stereoselective synthesis of retinoid compounds, 1,12-15) we describe herein a convenient and stereoselective synthesis of 11Z-3,4-didehydroretinal (2) (Chart 1). Results and DiscussionPreviously, we reported a highly stereoselective synthesis of 11Z-retinal (1) from the b-ionone-tricarbonyliron-complex (3) by controlling the stereochemistry of the newly produced double bond via the nitrile (4). 13) Our first approach for the preparation of 11Z-3,4-didehydroretinal (2) was an application of this methodology. However, all our attempts were unsuccessful. Treatment of 3,4-didehydro-b-ionone (7) 16) with dodecacarbonyltriiron in benzene afforded a complex mixture, and the desired tricarbonyliron-complex (8) was not obtained in good yield. The attempted conversion of the silyloxytricarbonyliron-complex (5), derived from 3-silyloxy-bionone, 17) into the 3,4-didehydro-b-ionone-tricarbonylironcomplex (8) was not achieved. Further more, our trials of transformation of the tricarbonyliron-complex (6), prepared according to our reported procedure, 13) into the 3,4-didehydroretinal (2), including the introduction of double bond at the 3 position, was not successful under the various reaction conditions (Chart 2).In the literature, two Horner-Emmons condensations, resulting in the formation of a new double bond predominantly A convenient synthesis of 3,4-didehydroretinal was developed. The Horner-Emmons reaction between 3,4-didehydro-b b-ionone and diphenyl phosphonate in the presence of crown ether gave the retinonitrile as an isomeric mixture, in which the newly produced double bond was predominantly 11Z-form. After separation of the 11Z-form retinonitrile, it was converted into the corresponding retinal in good yield without isomerization of the double bonds.

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New Transmembrane Polyene Bolaamphiphiles as Fluorescent Probes in Lipid Bilayers

Quesada¹,

Acuña²,

Amat‐Guerri³

2001

Angew. Chem.

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The former view of the cell lipid membrane as a somewhat random and disordered distribution of lipids and proteins has given way to one characterized by a complex lateral organization, with nm-sized domains in which specific lipids and proteins are assembled to carry out a particular process. [1] The study of the morphology, composition, regulation, and persistence time of these structures is an experimental challenge that has been taken up by fluorescence probe methods. In the case of lipid ± lipid and lipid ± protein interactions, the dependence of the resonant transfer of electronic excitation on the proximity of donor and acceptor probe molecules can provide very useful information in the 10-nm range. [2] We have previously developed a series of fluorescent fatty acids that contain five conjugated double bonds at the end of a flexible linear chain. [3] These probes accurately report the changes in order and dynamics of the lipid environment in artificial and natural membranes. Furthermore, the large spectral overlap of the polyene absorption with the tryptophan fluorescence from membrane proteins and peptides is very convenient for energy-transfer experiments. However, the mobility of the energy-accepting polyene group in fluid bilayers may introduce some uncertainty into the distance evaluation. This would also be the case in other possible applications of the probes, such as the detection of oxidizing radicals by fluorescence quenching. To restrict the mobility of the chromophore, a linear structure with two polar terminal groups, that is, a bolaform amphiphile similar to the membrane lipids of Archaebacteria [4] would be ideal, with the additional advantage of precisely locating the sensing group of the probe in the bilayer. Bolaamphiphiles can be constructed with the appropriate length to reach both external membrane surfaces with the distal polar groups, and with a sensitive group in the lipophilic central part of the molecule. [5] Some transmembrane bolaamphiphiles have been produced previously for altering specific membrane properties: for example, compounds with p-benzoquinone or anthraquinone groups to change the redox behavior, [6] or conjugated polyenes derived from the natural product bixine to modify the charge-transfer rate across the bilayer. [7] Furthermore, bolaamphiphiles that contain photochemically reactive benzophenone [8] or diazirine [9] groups, or emitting fluorene [10] or anthracene groups, [11] have been also synthesized. A different but interesting fluorescent bolaform structure was also produced by linking two rhodamine 101 dye molecules with a C 32 linear chain. [12] Herein we describe the synthesis of symmetrical bolaamphiphiles with four, five, or six conjugated double bonds in the center of the molecule, with terminal methyl ester (4) or carboxylic acid (5) groups (Scheme 1), and with the appropriate length for spanning the lipid bilayer (Figure 1). The intermediates in the synthesis of the former compounds are conjugated polyenediyne diesters 3 that might also be useful t...

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Efficient Synthesis of 11-cis-Retinoids

Cited by 34 publications

References 18 publications

Synthesis of a Photoaffinity-Labeled (11Z)-Retinal: Identification of Retinal/Rhodopsin Cross-Linked Sites along the Visual-Transduction Path

Synthesis of a Photoaffinity-Labeled (11Z)-Retinal: Identification of Retinal/Rhodopsin Cross-Linked Sites along the Visual-Transduction Path

A Convenient and Stereoselective Synthesis of 11Z-3,4-Didehydroretinal by Horner-Emmons Reaction Using Diphenyl Phosphonate

New Transmembrane Polyene Bolaamphiphiles as Fluorescent Probes in Lipid Bilayers

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