Retinal synthesis

There are many synthetically useful conversion reactions of a,p-unsaturated nitriles to a,p-unsaturated aldehydes using DIBAL-H. To illustrate the value of the method, we have brought together all the examples concerned with chemistry of retinal. Thus, the applicability of the sequence combining the use of diethyl cyanomethylphosphonate with diethyl 3-cyano-2-methyl-2-prope-nylphosphonate, diethyl 3-cyano-2-butenylphosphonate, or diethyl 3-cyano-2-methyl-l-ethyl-2-propenylphosphonate has been studied intensively in retinal synthesis to prepare retinal analogues ... 

Posch, K. C., Boerman, M H E M, Burns, R D, and Napoli, J. L (1991) Holocellular retinol-bindmg protein as substrate for microsomal retinal synthesis. Biochemistry 30, 6224-6230. 

Posch KC, Boerman MHEM, Bums RD, Napoli JL (1991) Holo-cellular retinol binding protein as a substrate for microsomal retinal synthesis. Biochemistry 30 6224-6230... 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

Antiviral drugp interfere with viral reproduction by altering DNA synthesis. These drug are used in the treatment of herpes simplex infections of the eye, treatment in immunocompromised patients with cytomegalovirus (CMV) retinitis, and for the prevention of CMV retinitis in patients undergoing transplant. 

Chen, M, Forrester, JV, and Xu, H, 2007. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 84, 635-645. 

Dienes and polyenes have been a subject of great interest due to their important role in biology, materials science and organic synthesis. The mechanism of vision involves cis-trans photoisomerization of 11 -civ-retinal, an aldehyde formed from a linear polyene. Moreover, this kind of molecule exhibits high linear and non-linear electrical and optical properties. Short polyenes are also involved in pericyclic reactions, one of the most important classes of organic reactions. 

In the organic synthesis (Roche, BASF) two C2o molecules, retinal and retinulidene-triphenylphosphorane, are coupled according to the Wittig reaction to give /i-carotene in high yield [9]. A disadvantage is that triphenylphosphine oxide, formed in a stoichiometric amount, cannot be recycled economically to triphenylphosphine. 

Campbell, D. S. and Holt, C. E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 2001, 32, 1013-1026. 

The synthesis of the bis-P-cyclodextrin 35 is outlined in Fig. 14. Interestingly, however, the X-ray structure of 36, the de-tosylated 35, revealed that P-carotene would not be incorporated into both CD units due to the unfavorable orientation of the diamide linker which blocks the entrance to the second P-CD. In agreement with this result are experiments with the target Ru complex 37 which displayed central cleavage on P-carotene 1 5delding retinal 2 as the major product (Fig. 15) (19). 

Adverse effects that are not unequivocally related to inhibition of prostaglandin synthesis include hepatic effects (hepatitis, hepatic necrosis, cholestatic jaundice, increased serum aminotransferases), dermal effects (photosensitivities, Stevens-Johnson syndrome, toxic epidermal necrolysis, onycholysis), central nervous system (CNS) effects (headaches, dizziness, tinnitus, deafness, drowsiness, confusion, nervousness, increased sweating, aseptic meningitis), ocular effects (toxic amblyopia, retinal disturbances), and certain renal effects (acute interstitial nephritis, acute papillary necrosis). 

A stereoselective synthesis of all E retinal, via a condensation of a Cio chloroacetal with (3-eyelogerany 1 sulfone was described by Julia et al. [29]. The chloroacetal was reacted with the silylenol ether, using TiCl4/Ti(OMe)4, to give in 63% yield, the chloromethoxyacetal derivative as a mixture of E Z isomers (80/20). The aldehyde was converted in 97% yield into the corresponding acetal with HC(OMe)3 and camphorsulfonic acid in methanol, Fig. (6). 

A short synthesis of retinal was described by Taylor et al. [42] based on the addition of a C]3 vinylalane to a methylpyrylium salt. The 13Z-retinal (48%) was isomerised to all E retinal by a previous procedure [43]. P-Ionone was first converted into the alkyne and then into the vinylalane, using the Negishi methodology [44], Addition of an excess of this alane to 4-methylpyrilium tetrafluoroborate [45] gave 13Z-retinal, being isomerized to the all E isomer (L in benzene/ether), Fig. (18). 

Another work of Duhamel and Ancel [59] related this synthesis of retinal via (3-ionylideneacetaldehyde. Condensation of methallyl-magnesium chloride with diethyl phenyl orthoformate (EtC CHOPh) led after bromination of the ene-acetal, deshydrohalogenation (NaOH 50%), ethanol elimination with hexamethyldisilazane (HMDS) and ISiMes, to the bromo-dienol ether. This latter was submitted to bromine lithium exchange and the lithio enol ether was then condensed with p ionylideneacetaldehyde to give retinal, Fig. (28). 

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