Naturally Occurring Retinoids

In the course of almost 50 years of synthetic retinoid chemistry up to the present time, a large number of processes for the synthesis of retinol (1) and its esters, such as retinyl acetate (9) and retinyl palmitate (113), have been developed. The most important large-scale industrial processes today are based on the work of Isler et al. at Hoffmann-La Roche, and of Pommer et al. at BASF. These two processes probably satisfy a large part of the world demand for retinol (1) (vitamin A), most of which is used for the production of animal feeds. 

The acetylene compound (7) was formed in the acid-catalyzed allylic 

A short time after Wittig and Geissler had discovered the olefination of ben-zophenone with methylene triphenylphosphorane, Pommer et al. synthesized retinoic acid (3) and, soon thereafter, retinyl acetate (9), using this new C—C bond-forming synthetic procedure (Pommer, 1960, 1977 Pommer and Thieme, 1983). Thus, they laid the foundations of the BASF industrial synthesis of retinyl acetate (Reif and Grassner, 1973). 

In addition to the possibility of synthesizing C20 retinoids by the ( ,5 + C5) method, syntheses based on a (C,3 + C7) (Pommer, 1960) or (C,q + C o) method (Pommer, 1960) and employing Wittig reactions were also worked out. The (Cj8 + C2) method with the C,g ketone (136) via a 

Homer-Wadsworth-Emmons reaction remained unimportant as a preparative route owing to the low reactivity of (136) (Pommer, 1960) toward phosphoryl anions. 

---

Tretinoin -naturally occurring retinoid -retinoic acid syndrome -fever -chest pain -hypoxia -pulmonary infiltrates -pleural/pericardial effusions -nausea and vomiting -mucocutaneous effects -arthralgias -headaches -increased triglycerides -xerostomia, exfoliation, chelitis... 

This naturally occurring retinoid (Solatene), a dimer of vitamin A, reduces free radical formation induced by... 

Spom, Roberts and Goodman81 have recently provided a broad overview of the field of the retinoids, based on the IUPAC-IUB Joint commission definition that Retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. (The work was updated in 1994) Whereas there is only a handful of naturally occurring retinoids using this definition, more than a thousand man-made retinoids are known. The IUPAC-IUB bulletin recommended that the term, retinal, not be used as a chemical designation but be reserved as an adjective referring to the retina. They suggested that retinaldehyde be used instead in scientific literature as the name of chemical related to vision. 

Widespread use of tretinoin and related naturally occurring retinoids is limited by undesirable side effects, which probably arise from their activation of multiple receptors. Recently, compounds selective for the retinoid X receptors... 

Naturally occurring retinoids are characterized by three distinct structural elements (Fig. 7.1) (l)a lipophilic terminus composed of a j3-ionone ring, (2) an isoprene side chain that is subject to both enzymatic and non-en-zymatic isomerization (Fig. 7.2), and (3)a polar terminus that is the subject of oxidative modifications (Figs. 7.1 and 7.2). All of these processes occur in vivo with the superimposed complexity of a multitude of binding and transport proteins and receptors possessing differential affinities for these naturally occurring retinoids. 

Furr, H.C. Amedee-Manesme, O. Olson, J.A. Gradient reversed-phase high-performance liquid chromatographic separation of naturally occurring retinoids. J.Chromatogr., 1984, 309, 299-307 [gradient rat human pig liver kidney extracted retinyl esters, tretinoin, vitEunin A]... 

Retinoids include all natural and synthetic derivatives of vitamin A (retinol) (Figure 102.3). The naturally-occurring retinoids (aU-rntwr-retinoic acid (RA), 9- r-RA, and 13-cw-RA) are interconverted in vivo, and therefore have overlapping effects and toxicity. Synthetic retinoids, such... 

Figure 102.3 The naturally occurring retinoids are Interconverted in vivo.

For numbering the carbon atoms of the naturally occurring retinoids retinol (1), retinaldehyde (2), and retinoic acid (3) and those derivatives whose carbon skeletons can be derived from these three retinoids, Chemical Abstracts has long used the numbering scheme laid down by lUPAC for carotenoids (lUPAC, 1973). 

The numbering scheme derived from the carotenoids and illustrated above for retinol (1) is not yet used in Chemical Abstracts for compounds whose carbon skeletons differ substantially from those of the naturally occurring retinoids. Thus, for example, the carboxylic acid (28) is given in Chemical Abstracts the systematic numbering scheme of a nonatetraenoic acid, substituted at the termi-... 

A large number of H-NMR and C-NMR spectra of geometric isomers of the naturally occurring retinoids and of their synthetic derivatives have been published (Schwieter a/., 1969 Englert eta/., 1978, Halley and Nelson, 1979a,b). This... 

Chemistry and Physical Properties of Retinoids V. NATURALLY OCCURRING RETINOIDS... 

For practical purposes, retinol and its esters are the only naturally occurring retinoids that fluoresce appreciably under normal conditions. Anhydroretinol (A8), retinoic acid, and retinaldehyde do not fluoresce in conventional assay procedures but may do so at very low temperatures or under special conditions. The possible use of fluorescence assay for other retinoids has not been effectively explored. 

The retinoids discussed so far in this chapter, all-rrons-retinol, retinaldehyde, and retinoic acid, together comprise the major portion of the naturally occuring retinoids. However, several isomers of retinol have been detected in fish liver oil, including 13-cis-, 9-cis-, and 9,13-di-cis-retinol (Roberson and Baxter, 1945, 1947 Brown et al., 1959), although the metabolism of these compounds... 

Figure 1 Some naturally occuring retinoids (a) all-fra/ii -retinol (b) all-frans-retinal (c) all-fran5 -retinoic acid (d) 13-cw-retinoic acid (e) all-frani-3,4-didehydroretinol (vitamin Aj alcohol) (f) 11-cw-retinal (g) all-franj-5,6-epoxyretinol (h) all-irani-anhydroret-inol (i) all-rran5 -4-oxoretinol (j) all-irans-retinoyl 5-glucuronide (k) all-frani-retinyl i-glucuronide (1) all-franj-retinyl palmitate.

JL Napoli, RL Horst. Quantitative analyses of naturally occurring retinoids. In CPF Redfern, ed. Retinoid Protocols. Totowa, NJ Humana Press, 1998, pp 29-... 

Using steady state tracer kinetic techniques in rats, Kurlandsky et al. determined how much of the all-rra 5-retinoic acid present in a given tissue was derived from the circulation [21]. Some of the findings of this study are summarized in Table 1. For the liver and brain, greater than 75% of the all-rran -retinoic acid present in these tissues was derived from the circulation (88.4% for brain and 78.2% for liver). The seminal vesicles, epididymis, kidney, epididymal fat, perinephric fat, spleen, and lungs derived, respectively, 23.1%, 9.6%, 33.4%, 30.3%, 24.5%, 19.0%, and 26.7% of their tissue all-rran -retinoic acid pools from the circulation. Only 2.3% and 4.8%, respectively, of the retinoic acid present in the pancreas and eyes was contributed by the circulation. For all rats studied, the testes did not take up any (<1%) all-tran -retinoic acid from the circulation. Kurlandsky et al. also reported a fractional catabolic rate for d -tmns-retinoic acid in plasma of 30.4 pools/hr and an absolute catabolic rate for all-tran -retinoic acid of 640 pmol/h [21]. These rates are very rapid compared to those of the only other naturally occurring retinoid that has been studied under normal physiological conditions, all-rra 5-retinol [22]. 

---