Figure 3. Mechanism and reaction pathways for formation of â- (2) and R-epimer (3) products.
â-epimer thioamide 1 could be correlated to the rate of
formation of intermediate 8. Thus, the analysis was simplified
to the comparison of linear least-squares analysis of Hammett
constants versus log[(RR/âR)/(RH/âH)] for RR/âR as the ratio
of â-product 2 to R-product 3 having the para-substituents
R for each phenyl ketone.
The Pearson correlation coefficient of R2 ) 0.98 in the
linear least-squares analysis gives credence to the assumption
of the Hammett free-energy relationship in this system. The
positive slope of the line is also consistent with the
interpretation that electron-withdrawing groups slow the
reaction rate of formation of intermediate 8. As a matter of
comparison, the F constant derived from the Hammett plot
indicates that the rate of intermediate 8 formation is
somewhat more sensitive to para-substituent effects as
compared to the substituent effects on benzoic acid acidities,
the classical Hammett analysis comparator (F ) 1.76 vs F
) ∼1).
also been reported.14 This observation in conjunction with
the fact that no epimerization is seen with the electron-
donating p-methoxyphenyl ketone argues against tautomer
formation via cation intermediate 8.
Unlike the results reported for thiazoles derived from
amino acid building blocks, in this shikimic acid system
protonation of the re face of enamine 6 is favored kinetically
as the least hindered path of attack. However, this result does
not rule out reversion along these reaction pathways after
protonation of the C5 position.
To understand the kinetic control of the protonation
pathway of this sequence, the R-thioamide (5S) 15 was
examined for epimerization to â-thiazoles (5R) upon cy-
clization. The R- and â-thioamides are available in four steps
from (4R,5S) epoxide 10.15 Of several standard conditions
attempted for cyanide opening of epoxide 10, only Et2AlCN
was found to provide useful quantities of both cyano-alcohol
regioisomers (11:1 of 5(R)-cyano- to 4(R)-cyano-alcohol
products).16 These regioisomers were easily separated by
silica gel flash column chromatography. It was necessary to
saturate the 1,2 double bond under standard palladium-
catalyzed hydrogenation conditions prior to cyano-to-thio-
amide transformation in order to avoid side reactions of this
double bond with the thiolating reagent (TMS)2S.17 Different
ratios of R-thioamide epimers were formed depending upon
the commercial source of (TMS)2S as shown in Scheme 2.
Consideration of these data validates the supposition
proposed by Holzapfel et al.13 Apparently, the rate of cation
formation predominates for electron-donating substituents,
thereby accelerating the dehydration of the thiazoline ring
to form thiazole product with retention stereochemistry at
C-5 (1). However, with increasing electron-withdrawing
nature of the phenyl ring substitutions, the rate of the imine-
enamine tautomerization (5 to 6) becomes competitive with
the rate of thiazoline dehydration (5 to 2). Holzapfel et al.
have shown that imine-enamine tautomerization is likely
catalyzed by HBr generated in situ and occurs prior to cation
formation; unepimerized product for p-methoxy substitution
further supports this conclusion. The decrease in overall
reaction yield is consistent with a slower product formation
via reaction pathways that are open to the formation of other
side products.
(14) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397-5400.
(15) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman,
H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.;
Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545-
4550. Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H.-J.; Oberhauser, T.;
Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Goeckel,
V.; Goetzoe, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Roeckel-
Staebler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. DeVel. 1999,
3, 266-274.
(16) Nagata, W.; Yoshioka, M.; Okumura, T. Tetrahedron Lett. 1966,
847-852.
(17) Lin, P.-L.; Ku, W.-S.; Shiao, M.-J. Synthesis, 1992, 12, 1219-1220.
Acid-catalyzed epimerization of stereogenic centers ad-
jacent to thiazolines via imine-enamine tautomerization has
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