Chiral acetals bromination

Asymmetric halogenation of chiral acetals has been realized by C. Giordano (refs. 2-7). Using alkyl esters of optically active tartaric acids as chiral auxiliaries, a high diastereoselectivity is obtained even at room temperature. The results are best explained by a fast electrophilic addition of bromine on the electron rich enol ether, originating from an acid-catalyzed equilibrium with the chiral acetal. If (2R, 3R)-tartaric acid is involved, a S-configuration prevails at the new stereogenic center. Finally, cautious hydrolysis provides a set of 2-bromo alkyl aryl ketones, which can be obtained in enantiomerically pure form after crystallization (Fig. 2) ... 

A number of processes involving chiral acetals have been examined in the synthesis of pharmaceutically important compounds. In one example, a synthesis of the antiinflammatory drug naproxen (80) includes a diastereoselective bromination reaction to furnish bromide 78 (dr 93 7, Scheme 6.15) [45]. Intramolecular rearrangement gives ester 79 with >99 1 diastereo-selectivity after recrystallization. Subsequent acidic cleavage of the auxiliary followed by reduction (H2 Pd-C) of the bromide that is adventitiously introduced on the naphthyl core afforded naproxen (80). 

Penzien and Schmidt reported the first absolute asymmetric transformation in a chiral crystal. [10] They showed that enone 4,4 -dimethylchalcone 1, although being achiral itself, crystallizes spontaneously in the chiral space group P2 2 2 (Scheme 1). When single crystals of this material are treated with bromine vapor in a gas-solid reaction, the chiral dibromide 2 is produced in 6-25% ee. In this elegant experiment, it is the reaction medium, the chiral crystal lattice, that provides the asymmetric influence favoring the formation of one product enantiomer over the other, and the chemist has merely provided a non-chiral solvent (ethyl acetate) for the crystallization and a nonchiral reagent (bromine) for the reaction. 

Tartaric acid has been used as a chiral auxiliary in a patented route to (S)-naproxen (20) (Scheme 23.3).45" 9 In initial studies, the acetal 21 was used to allow a stereoselective bromination that resulted in a 91 9 ratio of the (RRS)- and (RRR)-bromo derivatives 22 and 23. The bromo acetal diesters could be completely separated. Debromination of 22, followed by acid hydrolysis, led to formation of (S)-naproxen (20) in 80% yield, >99% ee, and recovery of the auxiliary. Conversely, debromination and hydrolysis of 23 gave only 12% yield of (R)-naproxen and 86% ee. In this case, the hydroxy acetal 24 was the major product (68%). However, the auxiliary was recovered in enantiomerically pure form. 

BusSnH. Internal addition of amine to allylic acetates, catalyzed by Pd(PPh3)4, leads to cyclic products via a 8 2 reaction.Three-membered cychc amines (aziridines) can be prepared from chiral conjugated amides via bromination and reaction with an amine. Four-membered cychc amines (azetidines) have been prepared in a different way ... 

We also felt that the relative solubilities of the diastereomeric amides (or their crystal lattice energies) might be related to the sense of steric bulk disymmetry about that central backbone. If one could perform a chemical reaction, such as addition to the double bond, that could alter the distribution of steric bulk, one could hope to invert diastereomer solubility. Addition of a symmetrical reagent, such as bromine, avoids positional isomerism and the stability of the bromonium ion ensures stereoselectivity. Thus each diastereomeric amide gave only one bromine adduct. The solubilities were indeed dramatically altered and, since bromine is easily removed (Zn, acetic acid) it became possible to use the amide mixture that had been recovered from purification to claim the more soluble diastereomer as its bromine adduct. A process was established to obtain both enantiomeric cyclohexene acids using only one chiral amine. 

Dimethyl-l,5,7-octatrien-3-ol [(15) = R-isomer)] has been found naturally in both chiral forms. The 3S-(+)-enantiomorph occurs in Japanese Ho leaf oil (whence its trivial name, hbtrienol), while the R-isomer has been isolated from black tea and green tea. The R-isomer (15) was synthesised from R-linalyl acetate (10) by bromination with iV-bromosuccinimide, giving three allylically brominated acetates (11), (12), and (13), which all lead to the acetate... 

Because of the inherent difficulty of inducing chirality in the acetate enolate reaction, alternative approaches have been developed. A general approach is to synthesize a-substituted aldols and then reductively remove the a-substituent. Yan reported a one-step bromination-aldolization which provided a-bromo aldols in excellent yield and diastereoselectivity (Scheme 2.4) [22]. They then demonstrated that the a-bromo substituent could be reduc-... 

Shortly before, Oppolzer and coworkers had reported the chlorination and bromination of chiral esters 496 via the silyl ketene acetals 497, also shown in Scheme 4.104 [236]. Excellent diastereoselectivity was reached, and the halo-genated esters 498 were obtained as pure diastereomers upon recrystallization. 

Lactate esters of the 5 -carbon phenylpyrazoles 2 and JV485 were prepared from common intermediate 23 (Figure 5). Conversion of the S -methyl group of phenylpyrazole 23 to carboxylic acid 24 was achieved by Mid-Century oxidation with molecular oxygen in the presence of cobalt and manganese catalysts (77). Halogenation of 24 with chlorine gas or bromine in acetic acid gave 25 which can be esterified to provide either JV 485 or other derivatives such as chiral lactate ester 26. 

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