Synthesis of tropic acid

Total synthesis of hyoscyamine requires two different schemes, the first is the synthesis of tropine and the other is the synthesis of (-) tropic acid. 

Several schemes for the total synthesis of tropic acid are known [For these schemes refer to the analytical profiles of atropine (26) and of scopolamine (35)]. 

Other methods of synthesis of tropic acid have been placed in patents (41,42 ).(-)-Tropic acid can be obtained by resolution of (t)-tropic acid (37). 

The addition of hydrogen chloride to atropic acid, followed by the replacement of the chlorine atom (Na2C03) by a hydroxyl group (213), or the addition of hypochlorous acid to the unsaturated acid followed by the reductive elimination of the chlorine (Zn-Fe + NaOH) (82) completed the synthesis of tropic acid but gave no clear insight into the position of the hydroxyl in the tropic acid molecule (V or VI). Although both V and VI... 

This synthetic tropidine was converted into bromodihydrotropidine by hydrogen bromide in aeetie aeid, and the solution heated with 10 per cent, sulphurie acid at 200-10°, when it passed into -tropine,and, sinee this may be partially converted into tropine by oxidation to tropinone and reduction of the latter by zinc dust and hydriodic acid, this series of reactions affords a complete synthesis of tropine and of the tropeines. Combining the formula given above for tropine with that of tropic acid, atropine and hyoscyamine are represented as follows ... 

Chiral 3-hydroxyacid esters and 3-,5-acetoxyacid esters have been identified in tropical fruits and other products (J 4). These compounds are intermediates in B-oxidation and de novo synthesis of fatty acids, but exhibit opposite configuration at the carbinol carbon. 

Scheme 13.1. Degradation and partial synthesis determining the structure of tropic acid. After Ladenburg, A. Riigheimer, L. Chem. Ber., 1880,13, 373.

The structure of tropic acid was worked out as shown in Scheme 13.1, and the synthesis (Scheme 13.2) was accomplished by Ladenburg and Rugheimer later the same year. ... 

For the synthesis, as shown in Scheme 13.2, when acetophenone was treated with phosphorus pentachloride, first with cooling and then warming to 40°C to complete the reaction, the corresponding benzylic dichloride (1,1-dichloro-l-phenylethane) was obtained in good yield. Dissolution of the dichloride in ethanol followed by addition of ethanolic potassium cyanide (KCN) and standing for 48 h at room temperature resulted in a solution from which potassium chloride (KCl) precipitated and which had a strong odor of hydrogen cyanide (HCN).The ethanol was removed by distillation, and the residue was treated at room temperature for 8h with barium hydroxide [Ba(OH)2]. Acidification resulted in the isolation of tropic acid in low yield. 

Nearly 40 years later, when additional amounts of tropic acid were sought, an alternative synthesis was developed by Muller. As shown in Scheme 13.3, when the ethyl ester of phenylacetic acid was allowed to condense with ethyl formate in ether and in the presence of sodium metal and the resulting condensation products was reduced with aluminum amalgam, the corresponding ethyl ester of tropic acid was isolated. Hydrolysis of the ester was accomplished (again) with barium hydroxide (Scheme 13.3). The question of stereochemistry was not addressed. 

Scheme 13.11. The synthesis and resolution of the enantiomers of tropic acid. After McKenzie, A. Wood, J. K. /. Chem. Soc., 1919,115,828.

Boehmite (OC-Aluminum Oxide-Hydroxide). Boehmite, the main constituent of bauxite deposits in Europe, is also found associated with gibbsite in tropical bauxites in Africa, Asia, and Austraha. Hydrothemial transformation of gibbsite at temperatures above 150 °C is a common method for the synthesis of weU-cry stalhzed boehmite. Higher temperatures and the presence of alkali increase the rate of transfomiation. Boehmite ciy stals of 5—10 ]liii size (Fig. 3) are produced by tliis method. Fibrous (acicular) boehmite is obtained under acidic hydrothemial conditions (6). Excess water, about 1% to 2% higher than the stoichiometric 15%, is usually found in hydrothemiaHy produced boehmite. 

Recently a convenient method for the synthesis of maleimide-terminated imide oligomers has been described (38). Aromatic diamine, biphenyl tetracar-boxylic dianhydride and maleic anhydride are reacted in DMAc/Xylene at 50 °C to form the amic acid oligomer which was subsequently cyclodehydrated by refluxing in the presence of pyridine as a catalyst. Water is removed azeo-tropically over a period of three hours. The maleimide terminated imide oligomer is isolated by precipitation in water or a non-solvent. The molar ratio of the monomers can be varied widely to tailor the molecular weight and... 

Hydroxyacid esters are contained in several subtropical fruits like pineapple (26), passion fruit (27) and mango (2 ). 3-Hydroxyacid derivatives are formed as intermediates during de novo synthesis and P -oxidation of fatty acids, but the two pathways lead to opposite enantiomers. S-(+)-3-Hydroxyacyl-CoA-esters result from stereospecific hydration of 2,3-trans-enoyl-CoA during P -oxidation R-(-)-3-hydroxyacid derivatives are formed by reduction of 3-ketoacyl-S-ACP in the course of fatty biosynthesis. Both pathways may be operative in the production of chiral 3-hydroxyacids and 3-hydroxyacid esters in tropical fruits. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

Isolated from Datura ferox L. 29), this product was hydrolyzed to (— )-3a,6/S-tropanediol and ( —)-tropic acid. A synthesis of XXI was achieved by hydrogenolytic cleavage (30) of A — )-hyoscine (XXII), obtained by total synthesis, and followed by separation of the diastereo-isomeric S( — )-tropoyltropanediols with dibenzoyltartaric acid. Feeding D. stramonium L. seedlings with hyoscyamine-(methyl-i4C) brought about its conversion to the 6 3-hydroxy derivative-(methyl-i C) 31). 

Stypodiol, epistypodiol and stypotriol are secondary diterpene metabolites produced by the tropical brown algae Stypopodium zonaie. These compounds display diverse biological properties, including strong toxic, narcotic, and hyperactive effects upon the reef-dwelling fish. In the laboratory of A. Abad an efficient stereoselective synthesis of stypodiol and its C14 epimer, epistypodiol, was accomplished from (S)-(+)-carvone. The key transformations in the synthesis of these epimeric compounds were an intramolecular Diels-Alder reaction, a sonochemical Barbier reaction and an acid-catalyzed quinol-tertiary alcohol cyclization. 

Atropine can be synthesized from tropi-none and tropic acid as starting materials. Tropinone can be prepared by Robinson s synthesis (68) and reduced under proper conditions to tropine. ( )-Tropic acid can be prepared from ethyl phenylacetate (69, 70) or acetophenone (71). The 0-acetyl derivative of tropyl chloride reacts with tropine to yield O-acetyl of atropine hydrochloride, from which the acetyl group hydrolyzes spontaneously in aqueous solution (72). 

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