Carboxylic acids Claisen rearrangement

The discovery of the utility of the bis-chromone carboxylic acid derivative cromolyn sodium in the treatment of asthma and related allergies has led to an intensive, and thus far not very fruitful, effort to discover analogues which would show oral activity in contrast to the lead which must be administered by inhalation. Preparation of a typical analogue, proxicromil (63), starts with the O-allylated phenol 57. Claisen rearrangement leads to the corresponding C-allylated product 58. 

Allyl acrylates have been reacted with the combination of ClMe2SiH/ [(cod)RhCl]2/Me-DuPHOS (l,2-bis(2,5-dimethylphospholano)benzene) to bring about reduction of the ,/l-unsaturated ester followed by a Claisen rearrangement to the y,8-unsaturated carboxylic acid (Eq. 293)474 Other silanes did not perform as well in this sequence. 

Several applications of this methodology are known. For the determination of the relative configuration of the stereocenter and the axial chiral unit of 71, the product of a diastereoselective ester enolate Claisen rearrangement of 70, with AgBF4 a cycli-zation to 72 was initiated. Then the carboxylic acid was reduced to alcohol 73 and the position of the substituents was investigated by NMR and by the use of NMR shift-reagents (Scheme 15.16) [32], Control experiments ensured the stereospecifi-city of the cyclization and the reduction step. There are further examples of this strategy [33]. 

In the particular case in which the carbonyl group belongs to a carboxylic acid derivative, such as an ester (17) or an amide (18) (or other functional groups which may be converted into it by a FGI), then they may be disconnected according to the "orthoacetate-modification" of the retro-Claisen rearrangement (Schemes 7.7 and 7.8) developed mainly by Eschenmoser [7] and Ziegler [8], independently, in the synthesis of alkaloids, and Johnson in a very simple and yet highly stereoselective synthesis of squalene [9]. 

There are several variations of the Claisen rearrangement that make it a powerfid tool for the synthesis of y,<5-unsaturated carboxylic acids. The ortho ester modification of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the /-position of allylic alcohols.157 A mixed ortho ester is formed as an intermediate and undergoes sequential elimination and sigmatropic rearrangement. 

The ester Claisen rearrangement that converts optically active allyl alcohol (2 )-2-methyl-1-penten-3-ol into the a-substituted carboxylic acid 4 (for assignment, see p 452)144,145. 

The Claisen rearrangement of lactonic enolates provides a new route to cycloalkenes. Cyclocitral was converted to the lactone (642) through a multistep sequence, the lactone deprotonated with LDA in THF at -78 °C, and the enolate quenched with f-butyldimethyl-chlorosilane (80JA6889, 6891). The crude ketene acetal (643) was heated at 110 °C for 10 h, and the product treated with fluoride ion to afford a single acid. Replacement of the quaternary carboxyl group by hydroxyl was accomplished through use of the carboxy inversion reaction (Scheme 147). The product (645) of this last reaction was identical with an authentic sample of widdrol in all respects excluding its optical rotation. 

Another interesting variant of Claisen rearrangement has been introduced by Ireland [149], and used by his group in carbohydrate chemistry. The starting compound is again an allylic alcohol that is esterified by a suitable carboxylic acid. This ester is enolized in basic medium, and quenching of the intermediate enolate at low temperature gives a ketene silyl... 

The Johnson Claisen rearrangement,31 also called the ortho ester Claisen rearrangement, involves the reaction of an allylic alcohol with an ortho ester, often triethyl orthoacetate, in the presence of a carboxylic acid such as propionic acid, usually at temperatures between 120 and 140 JC (Scheme 3).1 The intermediate kctcnc acetal rearranges stereoselectively. 

Alkenyl-2-azetidinone systems could be converted to bicyclic (3-lactam carboxylic esters and hence carboxylic acids (Fig. 5) via tandem Ireland-Claisen rearrangement and subsequent alkene metathesis [250],... 

This gentle variant of the Claisen Rearrangement employs the allyl ester of a carboxylic acid instead of an allyl vinyl ether. The ester is converted to its silyl-stabilized enolate (silyl ketene acetal), which rearranges at temperatures below 100 °C. 

The immediate product of the rearrangement, a carboxylic acid silyl ester, cannot be isolated and is hydrolyzed during workup. The Ireland-Claisen Rearrangement thus offers ready access to chain-extended carboxylic acids. 

The product of a Ireland-Claisen rearrangement is a silyl ester. However, silyl esters generally are so sensitive toward hydrolysis that one usually does not attempt to isolate them. Instead, the silyl esters are hydrolyzed completely during work-up. Thus, Ireland-Claisen rearrangements de facto afford carboxylic acids and, more specifically, they afford y,5-unsaturated carboxylic acids. 

Ireland-Claisen rearrangements are extraordinarily interesting from a synthetic point of view for several reasons. First, the Ireland-Claisen rearrangement is an important C=C bondforming reaction. Second, Ireland-Claisen rearrangements afford y,<5-unsaturated carboxylic acids, which are valuable bifunctional compounds. Both of the functional groups of these acids can then be manipulated in a variety of ways. 

Protodesilylation, A new preparation of -unsaturated carboxylic acids involves the amide acetal Claisen rearrangement of a 3-(trimethylsilyl)allyl alcohol such as 1 to allylsilanes (2). Desilylation of 2 by usual methods results in formation of stereoisomers. However, use of liquid HF at low temperatures results only in (E)-3 in 88% yield. The HF-pyridine complex is not so stereoselective. Amides such as 3 can be converted into carboxylic acid esters by Meerwein s trialkyloxonium salts (—70% yield). 

---