Synthesis and Use of Stable Isotope Enriched Retinals in the Field of Vitamin A

Abstract

Abstract:The role of vitamin A and its metabolites in the life processes starting with the historical background and its up to date information is discussed in the introduction. Also the role of 11Z-retinal in vision and retinoic acid in the biological processes is elucidated. The essential role of isotopically enriched systems in the progress of vision research, nutrition research etc. is discussed. In part B industrial commercial syntheses of vitamin A by the two leading companies Hoffmann-La Roche (now DSM) and BASF are discussed. The knowledge obtained via these pioneering syntheses has been essential for the further synthetic efforts in vitamin A field by other scientific groups. The rest of the paper is devoted to the synthetic efforts of the Leiden group that gives an access to the preparation of site directed high level isotope enrichment in retinals. First the synthesis of the retinals with deuterium incorporation in the conjugated side chain is reviewed. Then, 13 C-labeled retinals are discussed. This is followed by the discussion of a convergent synthetic scheme that allows a rational access to prepare any isotopomer of retinals. The schemes that provide access to prepare any possible isotope enriched chemically modified systems are discussed. Finally, nor-retinals and bridged retinals that give access to a whole (as yet incomplete) library of possible isotopomers are reviewed.

Synthesis of highly 13C enriched carotenoids: access to carotenoids enriched with 13C at any position and combination of positions.

“…The Schemes described in this paper allow access to any biologically and commercially important carotenoid in well defined 13 C enriched form up to the U-13 C enriched system. Combined with the reactions reviewed in the 13 C enriched retinal papers all apo-carotenoids are now also accessible in any 13 C enriched form (Dawadi & Lugtenburg, 2010).…”

“…The anion 79 is expected to form the phosphate ester 80 upon treatment with diethyl phosphonyl chloride. Subsequent reaction with base should give 3-oxo-β-cyclocitronitrile 81 (Dawadi & Lugtenburg, 2010). Application of the reduction and enzymatic conversion in Scheme 14 gives the building blocks for the end groups of zeaxanthin and lutein with one of the diasteromeric methyl groups in the form of a protected aldehyde, which will allow a site-directed 13 C introduction.…”

Rhodopsins: An Excitingly Versatile Protein Species for Research, Development and Creative Engineering

“…With the start of the genome era, recombinant DNA technology (genome mining, DNA and c-DNA sequence information and comparison, DNA sequence modification) became accessible and have now become common experimental tools ( Khorana, 1979 ; Khorana et al, 1987 ). Likewise, total synthesis of retinal isomers and a plethora of derivatives has improved significantly ( Dawadi and Lugtenburg, 2010 ; Liu and Liu, 2011 ; Álvarez et al, 2014 ; El-Tahawy et al, 2020 ).…”

Isorhodopsin: An Undervalued Visual Pigment Analog

“…In infrared absorbance spectra, the coupled HOOPs are always active, but again their intensity strongly depends on the torsion in the ethylenic bond. Assignment of vibrational bands to structural elements is assisted by selective 13 C or 2 H labeling of the chromophore via organic synthesis, and can subsequently also validate physical computation [71,78,106,108,[112][113][114]. Furthermore, solid-state NMR spectroscopy can also provide detailed structural information on the chromophore and its interaction with the binding pocket environment, using properly labeled and/or otherwise modified retinals [55,69,74,76,89,102,[113][114][115][116][117][118][119][120][121][122].…”

“…Early on, it was realized that investigating the effects of modified retinals on pigment properties would enable significant information to be unraveled. For instance, data such as incorporation rates, spectral properties, photochemistry, G-protein activation, etc., could provide intimate insight into aspects such as binding pocket restraints, spectral tuning, and photoactivation mechanisms [45,58,63,72,112,123,[126][127][128][129][130][131][132]. The majority of these analogs are based on the 11-cis isomer, but analogs of other isomers have also been studiedpredominantly the 9-cis isomer (e.g., [45,101,105,113,123,126,127,131,133,134]).…”