M. A. Arrica et al. / Tetrahedron Letters 43 (2002) 5137–5139
5139
Li
OCH2OLi
Li
OCH2OLi
AlkylX or CO2
Li
anti-5a, syn-5b, syn-5c, major
stereoisomers of 6a and 6b-8b
1
Ar
Ar
R
R
2 syn
2 anti
Scheme 2. Epimerization and kinetic resolution of intermediates 2.
preferentially and stereoselectively with carbon elec-
trophiles, either under retention or inversion of configu-
ration,2,3,7,8 i.e. that reaction of our intermediates with
carbon electrophiles requires an activation energy higher
than the energy of epimerization.
2. Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282–2316.
3. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552–560.
4. Azzena, U. J. Chem. Soc., Perkin Trans. 1 2002, 360–
365.
A final remark concerns the relative stereochemistry of
the major stereoisomers of recovered lactones (anti 5a;
syn 5b; syn 5c; Table 1, entries 3, 7 and 13, respectively),
as this evidences a strong influence of the substitution
pattern on the kinetic resolution of organolithiums 2.
Indeed, a comparison between intermediates 2a (Ar=
C6H5; R=CH3) and 2b (Ar=4-(CH3O)C6H4; R=CH3)
shows that the presence of a para-methoxy substituent
on the aromatic ring led to an inversion of the stereochem-
ical outcome of the carboxylation reaction. From this
point of view, it is worth noting that such a substituent
on the aromatic ring is known to bias the relative stability
of benzylithium derivatives;17,18 accordingly, it could
affect either the relative reactivity of intermediates 2
and/or the relative stereochemistry of the electrophilic
substitution (inversion versus retention).
5. Kato, T.; Maumoto, S.; Sato, T.; Kuwajima, I. Synlett
1990, 671–672.
6. Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Nor-
mant, J. F. Chem. Eur. J. 1999, 5, 2055–2068.
7. Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1999,
55, 2609–2624.
8. Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1996,
52, 10025–10042.
9. Similarly CH3Li does not add to styrene: Wei, X.;
Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 2000, 1109–1116.
10. Azzena, U.; Pilo, L. Synthesis 1999, 664–668.
11. Drukker, E. A.; Beets, M. G. J. Recl. Trav. Chim.
Pays-Bas 1951, 70, 29–34.
12. Delmas, M.; Gaset, A. Synthesis 1980, 871–872.
13. Smissman, E. E.; Schnettler, R. A.; Portoghese, P. S. J.
Org. Chem. 1965, 30, 797–801.
14. Tateiwa, J.-i.; Hashimoto, K.; Yamauchi, T.; Uemura,
S. Bull. Chem. Soc. Jpn. 1996, 69, 2361–2368.
15. Brunner, M.; Alper, H. J. Org. Chem. 1997, 62, 7565–
7568 and references cited therein.
16. Azzena, U. Trends Org. Chem. 1997, 6, 55–65 and ref-
erences cited therein.
Furthermore, a comparison between intermediates 2a
(Ar=C6H5; R=CH3) and 2c (Ar=C6H5; R=C4H9)
shows that steric bulk at the homobenzylic position
influences, besides stereoselectivity, the relative stereo-
chemistry of the major stereoisomer recovered upon
carboxylation, a finding not observed in the related
carbometalation procedure.19
17. Schlosser, M.; Maccaroni, P.; Marzi, E. Tetrahedron
1998, 54, 2763–2770.
18. Azzena, U.; Carta, S.; Melloni, G.; Sechi, A. Tetra-
hedron 1997, 53, 16205–16212.
In conclusion, our results show that reductive metalation
of 4-aryl-5-methyl-1,3-dioxanes is a suitable procedure
for the synthesis of 2-methyl-3-substituted-3-phenyl-
propan-1-ols with satisfactory to good diastereoselectiv-
19. Carbolithiations of cinnamyl methyl ether with different
alkyllithiums, followed by reaction with the same elec-
trophile, result in the formation of major stereoisomers
with the same relative stereochemistry; see Ref. 7. For
related examples involving carbolithiation of a cinnamyl
acetal, see Ref. 6.
ities, thus circumventing
a
drawback of the
carbometalation of cinnamyl derivatives.20
References
20. All new compounds gave analytical and spectral (1H
and 13C NMR, IR, MS) data in agreement with the
assigned structures.
1. Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 535–
544.