Rohr et al.
integrity of the substrates is not affected. 1,3-anti-Configured
Tishchenko products were isolated as a single stereoisomer.
Similar results were obtained in samarium-catalyzed Tishchenko
reductions of ꢀ-hydroxy ketones. In these reactions the config-
uration of substrates remains unaffected.18
Conclusions
With these experiments we have demonstrated the utility of
chiral BINOL-titanium/cinchona alkaloid complexes in asym-
metric aldol-Tishchenko reactions. Several aspects of the
substituent architecture of the starting aldol adducts dictate the
stereochemical outcome of these reactions:
• By application of propionate aldol adducts (R2 ) Me),
diastereomeric mixtures of 1,2-anti, 1,3-anti- and 1,2-syn, 1,3-
anti-configured Tishchenko products can be isolated with good
enantioselectivities (ee’s up to 86%). An initial equilibration
of starting aldol adducts is overlapped by the competing
Tishchenko reaction. For this reason the exact ratio of equilibra-
tion of the aldol adducts cannot be determined. This retro aldol
reaction was monitored by NMR experiments and works with
reaction rates similar to those of the Tishchenko reaction.
• By deploying racemic and diastereomeric mixtures of
starting aldol adducts (R2 ) Et, iPr) Tishchenko products can
be obtained with high degrees of enantio- and diastereoselec-
tivities (ee’s up to 80-88%, de ) 100%). A full equilibration
by retro aldol reactions can be observed during these reactions.
• When used with oxygen-functionalized optically pure aldol
adducts the aldol-Tishchenko products were isolated as a single
stereoisomer (de ) 100%, ee ) 100%). An equilibration of the
starting aldol adducts could not be detected under these reaction
conditions. These transformations offer a simple access to chiral
stereotetrads and stereopentads of aliphatic and enolizable
aldehydes.
FIGURE 1. Proposed transition state model. Ti ) Ti(OtBu)4 or
BINOLTi(OtBu)2/cinchona alkaloids.
FIGURE 2. Possible mechanistic reaction pathway. Ti ) Ti(OtBu)4
or BINOLTi(OtBu)2/cinchonine.
Figure 1). 1,2-syn-, 1,3-anti-Configured products were isolated
as the main products (see results of Tables 1-4). Also, these
results indicate that the 1,3-diaxial interactions are very weak
and can be overriden by steric interactions of R2, R3 and of the
titanium complex. For similar observations in asymmetric aldol
additions of mandelic acid esters see, ref 15.
Further investigations on catalytic execution and determina-
tion of structure of titanium complexes are in progress.
Experimental Section
Starting Materials. The deployed aldol adducts 2a-k were
synthesized by aldol reactions in the presence of TiCl419 or TiCl4/
Et3N.20
It is assumed that a fast and reversible retro aldol intercon-
version of syn- and anti-configured aldol adducts occurs in the
presence of titanium complexes via the intermediate titanium
enolates (R2 ) Et and iPr, Scheme 4).16 Subsequent stereose-
lective Tishchenko reaction is irreversible and fixes the con-
figuration of the aldol adduct mixture with the rate constants k2
and k3 (Figure 2). The rate differences determine the configura-
tive outcome of the reaction. The exclusive formation of 1,2-
anti, 1,3-anti-configured Tishchenko products can be explained
by the fast reaction with aldehyde R4-CHO via transition state
B (k1, k-1 > k3 . k2, Figures 1 and 2).
(1R,2R,3R)-1-Cyclohexyl-3-hydroxy-2-methyl-pentyl Cyclohex-
anecarboxylate (3a) and (1R,2S,3R)-1-Cyclohexyl-3-hydroxy-2-
methyl-pentyl Cyclohexanecarboxylate (4a). Ti(OtBu)4 (2.0 mL,
5.0 mmol), cinchonine (1.5 g, 5.0 mmol) and (R)-BINOL (1.4 g,
5.0 mmol) were dissolved in dry dichloromethane and stirred for
2-3 h at rt. The solvents were removed in vacuo, and the residue
was co-evaporated three times with dry toluene. The remaining
brown-orange solid was dissolved in 20 mL of dry dichlormethane.
Next, 990 mg of aldol adduct 2a (5.0 mmol) and 6.0 mL of freshly
distilled cyclohexanecarboxaldehyde 1a (50.0 mmol) were dissolved
in 20.0 mL of CH2Cl2 under inert conditions. This solution was
carefully added to the prepared titanium(IV) complex. The reaction
was continuously monitored by thin layer chromatography. At the
end of the reaction, the reaction mixture was diluted with dieth-
ylether, filtered over Celite, and extracted successively by saturated
In the case of substituent R2 ) Me, the ratio of equilibration
rates and Tishchenko reaction rates become more equal (k1, k-1
> k2 . k3). Thus the syn-configuration of starting aldol adducts
can be preserved in the Tischenko products substantially. These
considerations are consistent with previous reports.6d,e,17
When used with oxygen-substituted aldol adducts, an equili-
bration was not observed (k1 and k-1 f 0). The stereochemical
(17) (a) Reutrakul, V.; Jarataroonphong, J.; Tuchinda, P.; Kuhakarn, C.;
Kongsaeree, P.; Prabpai, S.; Pohmakotr, M. Tetrahdron Lett. 2006, 47, 4753–
4757. (b) Schneider, C.; Klapa, K.; Hansch, M. Synlett 2005, 91–94.
(18) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447–
6449.
(19) (a) Mahrwald, R.; Guendogan, B. J. Am. Chem. Soc. 1998, 120, 413–
414. (b) Mahrwald, R. Chem. Ber. 1995, 128, 919–921.
(20) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047–1049.
(16) For similar equilibrations in the propionate series during aldol-
Tishchenko reactions see the following. (a) Total synthesis of rapamycin: Yang,
W.; Digits, C. A.; Hatada, M.; Narual, S.; Rozamus, L. W.; Huestis, C. M.;
Wong, J.; Dalgarno, D.; Holt, D. A. Org. Lett. 1999, 1, 2033–2035. (b)
Intramolecular aldol-Tishchenko reaction in the total synthesis of octalactine: Aird,
J. I.; Hulme, A. N.; White, J. W. Org. Lett. 2007, 9, 631–634.
3748 J. Org. Chem. Vol. 74, No. 10, 2009
Rohr, Kerstin
