June 1998
SYNLETT
635
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For the more hindered (still configurationally unstable) compounds 4b
and 4c with substituents (R = OMe, Me) next to the biaryl axis,
however, only low (or even no) asymmetric inductions were observed.
Thus, the reduction of the hydroxy aldehydes 4 is a worthy complement
to that of the lactones 1, which gave best enantiomeric ratios for the
5
methoxy- and methyl-substituted compounds 1b and 1c, respectively.
Scheme 3
good enantioselectivities, the steric demand of the substituents ortho to
the biaryl axis should be strongly differentiated. Investigations on the
apparently existing mechanistic differences between the atroposelective
hydroxy aldehyde and lactone reductions, and their use in
stereoselective biaryl synthesis, are in progress.
Acknowledgements: This work was supported by the Deutsche
Forschungsgemeinschaft (SFB 347 'Selektive Reaktionen Metall-
aktivierter Moleküle') and by the Fonds der Chemischen Industrie
(graduate research fellowship to M. B. and financial support). We
gratefully acknowledge engaged experimental assistance by Heike
Endress.
For these enantioselective reductions by dynamic kinetic resolution, a
high interconversion rate between the atropo-enantiomeric forms of 4 is
an important precondition. A too slow enantiomerization as a possible
reason for the missing stereoselectivities was excluded by quenching
(0.1 N HCl) the reduction of 4c at < 20% conversion, thus checking for
References and Notes
19
a possible kinetic, non-dynamic resolution alone, which again gave
(1) "Novel Concepts in Directed Biaryl Synthesis", part 72, for part
only a low asymmetric induction (er = 56 : 44) for 5c. The derivative 4d,
which is configurationally stable due to the high steric demand of the
tBu substituent, was reduced with a slightly better er of 40 : 60 at < 20%
conversion.
14
71, see ref.
(2) Bringmann, G.; Schupp, O. S. Afr. J. Chem. 1994, 47, 83.
(3) Bringmann, G.; Busse, H.; Dauer, U.; Güssregen, S.; Stahl, M.
Tetrahedron 1995, 51, 3149.
Interestingly, with a substoichiometric amount (20 mol-%) of 6 as the
reductant (Scheme 2, method B, and Table 1), a reversal of the
asymmetric induction was found for 4a and 4b, now yielding the atropo-
(4) Bringmann, G.; Hartung, T.; Göbel, L.; Schupp, O.; Ewers, C. L.
J.; Schöner, B.; Zagst, R.; Peters, K.; von Schnering, H. G.;
Burschka, C. Liebigs Ann. Chem. 1992, 225.
16
enantiomer 5-A as the main isomer, which is also formed in the
5,17
(5) Bringmann, G.; Hartung, T. Angew. Chem. 1992, 104, 782;
Angew. Chem. Int. Ed. Engl. 1992, 31, 761. Bringmann, G.;
Hartung, T. Tetrahedron 1993, 49, 7891.
borane reduction of the lactones 1.
Especially in the reduction of 4a
with THF as the solvent the er was significantly inverted from 8 : 92 to
20
82 : 18, now in favor of the M-enantiomer, 5a-A. This strong
dependence of the asymmetric induction on the quantity of the reductant
suggests the existence of two competing mechanistic pathways with
opposite stereocontrol. Thus, by the choice of reaction conditions,
optionally either of the two enantiomers of 5a can be obtained in high
asymmetric inductions, using the same chiral auxiliary, (S)-2.
(6) Seebach, D.; Jaeschke, G.; Gottwald, K.; Matsuda, K.; Formisano,
R.; Chaplin, D. A.; Breuning, M.; Bringmann, G. Tetrahedron
1997, 53, 7539.
(7) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C-P.; Singh, V. K. J.
Am. Chem. Soc. 1987, 109, 7925.
One of the reasons for the bad asymmetric inductions for medium-sized
ortho-substituents (R = OMe, Me) might be the lacking steric difference
to the other ortho-substituent, OH. Reduction of 7c, a configurationally
stable tBDMS derivative of 4c, under the same conditions gave a good
enantioselectivity of 80 : 20 at < 20% conversion (method B, kinetic
resolution only). This shows that a strongly differentiated steric demand
of the two ortho substituents at the benzene moiety is a good
precondition for a high stereocontrol, which is fulfilled for 4a (H vs.
OH) and 7c (Me vs. OtBDMS). This is furthermore underlined by the
comparatively good asymmetric induction obtained for 4d (see Table 1).
(8) Bringmann, G.; Reuscher, H. Angew. Chem. 1989, 101, 1725;
Angew. Chem. Int. Ed. Engl. 1989, 28, 1672. Bringmann, G.;
Walter, R.; Ewers, C. L. J. Synlett 1991, 581. Bringmann, G.;
Holenz, J.; Weirich, R.; Rübenacker, M.; Funke, C.; Boyd, M. R.;
Gulakowski, R. J.; François, G. Tetrahedron 1998, 54, 497.
Bringmann, G.; Pabst, T.; Busemann, S.; Peters, K.; Peters, E.-M.
Tetrahedron 1998, 54, 1425.
(9) Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1998, 9,
667.
(10) Bringmann, G.; Hartung, T. Liebigs Ann. Chem. 1994, 313.
(11) Bringmann, G.; Schöner, B.; Peters, K.; Peters, E.-M.; von
In conclusion, the oxazaborolidine-assisted catecholborane reduction of
configurationally unstable biaryl hydroxy aldehydes 4 provides a novel
approach to axially chiral biaryl alcohols 5 with enantiomeric ratios of
up to 92 : 8. Depending on the relative amount of the achiral reductant,
optionally any of the two atropisomers of 5 can be obtained with the
same chiral auxiliary (S)-2, which suggests the existence of two
competing reaction pathways with divergent stereocontrol. To achieve
Schnering, H. G. Liebigs Ann. Chem. 1994, 439.
(12) Bringmann, G.; Breuning, M.; Endress, H.; Vitt, D.; Peters, K.;
Peters, E.-M. Tetrahedron, in press.
(13) Bringmann, G.; Vitt, D. J. Org. Chem. 1995, 60, 7674.
(14) Bringmann, G.; Vitt, D.; Kraus, J.; Breuning, M. Tetrahedron, in
press.