Chiral methyl trans -2,2-dichloro-3-methylcyclopropanecarboxylate upon exposure to thiophenolate nucleophile

Substitution of the β -halogen atoms in methyl (1 R ,3 S )-2,2-dichloro-3-methylycyclopropane-carboxylate with sodium thiophenolate leads to the di(phenylthio) ester (1 RS ,3 S )- 4 as a mixture of diastereomers. The c is - trans isomerisation of methyl (1 RS ,3 S )-3-methyl-2,2-bis(phenylthio)- cyclopropanecarboxylate 4 , basic hydrolysis and subsequent crystallization gave the corresponding acid (1 R ,3 S )- 5 in high diastereomeric and enantiomeric purity. On the other hand, ring opening of the ester (1 RS ,3 S )- 4 under acidic conditions leads to methyl 3-methyl-4,4-di(phenylthio)prop-3-enoate ( 8 ) or the chiral S -phenyl thioester methyl (3 S )-3-methyl-4-oxo-4- (phenylthio)butanoate ( 7 ).


Introduction
3][14][15] For example, they were utilized in the asymmetric synthesis of pyrethroids 1,2 and other natural products, 3,4 stereoregular oligocyclopropanes, 5 chiral biaryls, 6 and liquid crystals. 7In a recent article we efficiently resolved racemic trans-2,2dichloro-3-methylcyclopropanecarboxylic acid into enantiomers 1. 10 Further, the chiral acid (1R,3S)-1 was used in the construction of the methyl branched chain of the pine sawfly sex pheromone. 11-Halogen atoms in esters, amides or nitriles of 1 may easily be substituted with nucleophiles and this property gives an additional method of functionalization of cyclopropane compounds. 16,17These transformations could proceed with preservation or cleavage of the cyclopropane ring, depending on the nature of the nucleophilic reagent.The reactions of gemdihalocyclopropanes with sulfur nucleophiles are known to give sufficiently stable dithiocyclopropanes. [16][17][18][19][20] Recently, numerous examples of stereoselective substitution in monobromocyclopropanes with heteroatomic nucleophiles have been described. 21,22In continuation of our research, 10,11 the substitution of halogens by thiophenoxy groups in the chiral acids 1 has become the object of investigation.The stereochemistry of the dithiocyclopropanes obtained and the process of the cyclopropane ring opening were studied.
At first, the acid (1R,3S)-1 (ee 99%) was converted in the usual way into the methyl ester (1R,3S)-2. 10This last was reacted with a methanolic solution of sodium thiophenolate in accordance with prior procedure (Scheme 1). 20This reaction proceeds quickly via an elimination-addition mechanism with formation of the proposed intermediate 3. 16,17 After a short boiling time, complete substitution of the halogens and formation of an equimolar mixture of diastereomeric esters 4 was detected by TLC and NMR.However, continued heating under reflux significantly decreased the amount of the cis-ester 4.After 10 h, the ratio of diastereomers reached an equilibrium value 92.5/7.5 with a preference for the trans-ester 4 (established by 1 H NMR and GC).Basic hydrolysis of the resulting mixture led to the acid (1R,3S)-5 containing the diastereomer (1S,3S)-5 as the main impurity.In the final step, acid (1R,3S)-5 was successfully separated from byproducts by a two-fold crystallization from CCl 4 .
An assignment of the compounds to cis-and trans-isomer was in agreement with the values of vicinal coupling constants of cyclopropane protons in 1 H NMR (J 9.4 Hz and 6.7 Hz for cisand trans-ester 4, J 9.6 Hz and 7.0 Hz for cis-and trans-acid 5).In GC analysis retention times were 38.3 min for trans-ester 4 and 38.8 min for cis-ester 4.
Acid (1R,3S)-5 is easily obtained as a single diastereomer and a stable crystalline compound.This short reaction sequence does not require the isolation of intermediate ester 4 and seems to be a convenient way for the modification of the readily available compounds 1.Since the configuration of С-3 atom is not affected, the methyl substituent preserves the chirality of the initial compounds 1.
An alternative route to optically pure acids 5 could be realized via the resolution of the racemic acid but this attempt appeared to be less effective.In view of our previous results, 10 when individual enantiomers of acid 1 had been easily obtained from racemate by crystallization of the (R)-and (S)-α-phenylethylamine salts, the same procedure was applied to acid 5. First, racemic acid 5 was obtained from correspondent ester (±)-2, as well as chiral (1R,3S)-5 (Scheme 3).However, in contrast to chiral compound, crystallizations of racemic acid 5 from CCl 4 failed to isolate pure trans-isomer.Successive crystallization using (S)-(-)-α-phenylethylamine gave partially resolved trans-acid (1S,3R)-5.In the series of experiments the highest ee (~70%) was achieved after three crystallizations of the salt from EtOH (aqueous acetone also was used as solvent but this gave worse results).The configuration and ee of (1S,3R)-5 were estimated by a comparison of its optical rotation with the value for pure (1R,3S)-5.Finally, the process of the ring cleavage of dithiocyclopropanes obtained was investigated, because the derivatives of acids 5, as well as acids 1, could be the precursors of useful 1,4-bifunctional chiral compounds with an isopentane skeleton. 10,11Ester (1RS,3S)-4, as described above, demonstrates high stability during long-term heating under basic conditions (Scheme 1), but similar gem-diphenylthiocyclopropyl ketones are known to be easily transformed into S-phenylalkanethioate or ketene diphenylthioacetals under acidic catalysis. 23,24he experiments showed that ester (1RS,3S)-4 was unreactive in aqueous formic acid and even in a refluxing mixture of acetone and hydrochloric acid.However, the ring-opening reaction proceeded easily upon the treatment of (1RS,3S)-4 with aqueous TFA to give diester (3S)-7 (Scheme 4).The ee for compound (3S)-7 was at least 85% (see Experimental Section).On the other hand, treatment of (1RS,3S)-4 with anhydrous TFA caused isomerization to ketene dithioacetal 8.The last was smoothly hydrolyzed to give racemic compound 7.It should be noted that the formation of 8 was also detected by NMR and TLC in the reaction of (1RS,3S)-4 with aqueous TFA, but then the final product 7 was not completely racemic.Thus, there are two competing pathways for the ring opening of dithiocyclopropane (1RS,3S)-4, and the formation of ketene dithioacetal 8 caused the decrease in optical purity of (3S)-7.

Supporting information available
NMR spectra are available free of charge via the Internet at http://www.arkat-usa.org.

Scheme 3 .
Scheme 3. Route to chiral acid 5 by resolution of racemate.