Crotonic acid, 3-formyl

As shown in Scheme 1, isotretinoin (1) was first synthesized by Garbers et al. in 1968 utilizing a key Wittig condensation. Phosphonium salt 8 was prepared from direct treatment of vinyl p-ionol 7 with triphenylphosphonium bromide (PhsPaHBr) in ethanol. Subsequent addition of an excess of sodium ethoxide to 8 was followed by an ethanol solution of cij-3-formyl crotonic acid (9) to produce isotretinoin (1,2-cjs-vitamin A acid. 

CH3OH) across the carbon-carbon double bond of crotonic acid [( )-2-butenoic acid] followed by potassium bromide treatment of the initial adduct to yield the corresponding mercuric bromide and then the formation of 2-bromo-3-methoxybutanoic acid by the addition of bromine (Br2) to the latter. Acidification to the free acid, followed by amination (NH3), formylation with the equivalent of acetic-formic anhydride, hydrogen bromide (HBr) ether cleavage, and a final pH adjustment with ammonium hydroxide produced the desired amino acid. 

LLJ The ester of crotonic acid with (2-formyl)phenylethanol was treated with Li-tetramethyl-piperidide in a toluene/THF solution (10 1) in the presence of the Lewis acid Al-tris(2,6-di-phenyl)phenoxide at —48 °C for 1 h. After workup, a product A was isolated in 70% yield. 

The reactions of ethyl acrylate and ethyl crotonate were studied (117) in the presence of ethyl orthoformate using 1 1 CO/H2 and 250 and 200 atm pressure. For ethyl acrylate, the distribution of products corresponded to j3-hydroformylation 78.2%, (y,y-diethoxybutyrate and j3-formylpropionic acid), and a-hydroformylation 21.7%, (a-methyl-j8-ethoxyacrylate and -methyl-j3,/3-diethoxypropionate). For ethyl crotonate, y-hydroformyla-tion occurred to the extent of 67-73% (8,8-diethoxyvalerate and y-formyl-butyrate) and a-hydroformylation to the extent of only 13.6% (a-ethyl-/ -ethoxyacrylate and j3-ethyl-j8-diethoxypropionate). 

Vitamin A acid, especially used in the treatment of acne for some years, can also be obtained by Wittig reaction. Thus, olefination of phosphorane 506, with y-formyl-crotonic ester 509 as well as the reversed Wittig olefination, i.e. the conversion of aldehyde 511 and ylide 512 yields the ester 510 of vitamin A acid 255), according to Scheme 86. 

---