Nonlinear effects and auto-induction in the asymmetric aldol condensation of synthetic equivalents of acetoacetic esters

Article abstract of DOI:10.1016/S0957-4166(02)00539-6

Positive nonlinear effects, (+)-NLEs, have been detected in the Ti(IV)/BINOL complex-mediated catalytic asymmetric aldol reaction of three different masked acetoacetate esters. The use of a different procedure for the catalyst preparation disclosed the oc

Full text of DOI:10.1016/S0957-4166(02)00539-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1949–1952
Nonlinear effects and auto-induction in the asymmetric aldol
condensation of synthetic equivalents of acetoacetic esters
Rosaria Villano, Margherita De Rosa, Concetta Salerno, Annunziata Soriente and Arrigo Scettri*
Dipartimento di Chimica, Universita` degli Studi di Salerno, I-84081 Baronissi, Salerno, Italy
Received 26 July 2002; accepted 3 September 2002
Abstract—Positive nonlinear effects, (+)-NLEs, have been detected in the Ti(IV)/BINOL complex-mediated catalytic asymmetric
aldol reaction of three different masked acetoacetate esters. The use of a different procedure for the catalyst preparation disclosed
the occurrence of aldol condensation of Chan’s diene through an auto-inductive process. © 2002 Elsevier Science Ltd. All rights
reserved.
In recent years the detection of positive nonlinear
effects, (+)-NLE, in asymmetric reactions has repre-
sented the main target of several research groups since
important preparative results can be achieved in the
presence of enantiomerically enriched catalysts and,
furthermore, useful information concerning the struc-
ture of the effective catalytic species and the mechanism
of the reaction, can be obtained.
Since the presence of (+)-NLEs has been pointed out1
in a variety of asymmetric reactions promoted by dif-
ferent Ti(IV)/BINOL complexes, we decided to investi-
gate the reactivity of compounds 1–3 in the presence of
an enantiomerically enriched catalyst.
In the first experiments benzaldehyde and Chan’s diene
3 (Table 1) were chosen as representative reagents and
the reaction was performed under the conditions
involved in the previously reported procedure by using
Ti(OiPr)4/(R)-BINOL (1:1), prepared in situ from (R)-
BINOL of varying enantiomeric excess (e.e.).
Consequently, the presence of (+)-NLE has been
pointed out in a variety of synthetically useful asym-
metric reactions,1 including the additions of dialkylzinc
reagents to aldehydes,2 glyoxylate-ene reactions,3 het-
ero-Diels–Alder reactions,4 aldol-type condensations,5
sulfide oxidation,6 and conjugate addition reactions.7
When the e.e. of the aldol product 6 was plotted against
the e.e. of the BINOL, an evident (+)-NLE could be
observed as shown in Fig. 1.
In the course of research devoted to the achievement of
efficient and highly enantioselective approaches to com-
pounds of the type 6, which are key-intermediates in
the synthesis of important bio-active compounds, we
have found8 that the aldol condensation of the syn-
thetic equivalents of acetoacetic ester 1–3 (Scheme 1)
can be conveniently performed in the presence of a
chiral Ti(OiPr)4/BINOL complex under stoichiometric
and catalytic conditions.
Furthermore, in the case of the silyloxydiene 1, the
occurrence of a process of auto-induction by self-
assembly of the chiral ligands was demonstrated.9
* Corresponding author. Tel.: +39-089-965374; fax: +39-089-965296;
e-mail: scettri@unisa.it
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00539-6

1950
R. Villano et al. / Tetrahedron: Asymmetry 13 (2002) 1949–1952
Table 1. (+)-NLE in the aldol reaction of 3
Entry
(R)-BINOL e.e. (%)
6 e.e. (%)a
Yield (%)b
1
2
3
4
5
0
15
42
69
100
0
31c
74
82
78
72
94
66c
94c
\99c
3/PhCHO/Ti(OiPr)4/(R)-BINOL 2/1/0.08/0.08 molar ratios were used.
a E.e.s were determined by HPLC analysis using a CHIRALPAK AD column.
b Yields refer to isolated chromatographically pure compounds.
c The R enantiomer was predominant.
oligomers: the absence of ligand exchange prevents
trapping of the less abundant chiral auxiliary in ineffec-
tive heterochiral oligomers, thereby leading to the
observed linearity.
It is noteworthy that a similar dependence on the mode
of preparation of a catalyst1a has been observed previ-
ously in other important processes, such as the asym-
metric Diels–Alder reaction,10 allylation of aldehydes
with allylstannanes,11 and in the oxidation of sulfides.12
Conveniently, this finding can be exploited to obtain
information about the active species involved in the
catalytic cycle.
In the course of research related to a previous investiga-
tion on the addition of Et2Zn to benzaldehyde, pro-
moted by Ti(OiPr)4/BINOL complexes, Walsh13
reported three different solid state structures for tita-
nium BINOLate complexes obtained by reaction of
Ti(OiPr)4 and BINOL under carefully chosen stoichio-
metric ratios. In particular, the combination of equimo-
lar amounts of BINOL and titanium tetraisopropoxide,
followed by crystallization at −30°C, afforded crystals
characterized by a trimeric [(BINOLate)Ti(OiPr)2]3
structure and the involvement of this trimer in the
asymmetric addition of Et2Zn was considered unlike on
the ground of the absence of NLE under the reported
conditions.
Figure 1.
Rather interestingly, the mode of preparation of the
enantiomerically enriched catalyst was found to exert a
marked influence on the nonlinear effects: in fact, mix-
ing enantiopure Ti(IV)/(S)-BINOL and Ti(IV)/(R)-
BINOL in order to obtain the specific e.e.s reported in
Table 2, led to linearity (Fig. 2).
These results can be reasonably explained by the fact
that the complexes consist of stable homochiral
The detection of a (+)-NLE in the addition of Chan’s
diene in the presence of the chiral catalyst prepared in
situ from equimolar amounts of Ti(OiPr)4 and enan-
tiomerically enriched BINOL suggests that the
observed deviation from linearity could be attributed to
a concomitant auto-inductive process,1,9,14 i.e. the incor-
poration of the aldol 6 produced in the original cata-
lytic species by ligand exchange to give a more
enantioselective multi-component Ti complex.
Table 2. Aldol reaction of 3 in the presence of Ti(IV)/(S)-
BINOL+Ti(IV)/(R)-BINOL catalyst
Entry
(S)-BINOL e.e. (%)
6 e.e. (%)a
Yield (%)b
1
2
3
4
14
52
70
14 (S)
52 (S)
74 (S)
81
82
54
52
100
\99 (S)
3/PhCHO/[Ti(OiPr)4/(R)-BINOL]+[Ti(OiPr)4/(S)-BINOL]
2/1/0.08
Therefore in a set of experiments the catalytic species
was prepared by mixing, under the same conditions
involved in Table 2, pre-prepared solutions of Ti(IV)/
(S)-BINOL, Ti(IV)/(R)-BINOL and (R)-aldol 6.16
molar ratios were used.
a E.e.s were determined by HPLC analysis using a CHIRALPAK AD
column.
b Yields refer to isolated chromatographically pure compounds.

R. Villano et al. / Tetrahedron: Asymmetry 13 (2002) 1949–1952
1951
pared directly in situ from enantiomerically enriched
(R)-BINOL.17
Rather interestingly, in both cases, (+)-NLE could be
observed (Fig. 3) although a more complex curve was
obtained on plotting the e.e. of aldol 5 against the e.e.
of BINOL.
Further investigation will be devoted to verify if a
process of auto-induction is involved in the asymmetric
aldol condensation of silyloxydiene 2 and to ascertain
whether the linear relationship observed in the area of
BINOL e.e.=40% is a consequence of a loss of
efficiency of the above process.
In conclusion these results represent further confirma-
tion of the involvement of Ti/BINOL complexes in
enantioselective processes characterized by the presence
of (+)-NLE. In particular, in the case of Chan’s diene 3,
a different mode of preparation of the catalyst was
shown to determine the presence or the absence of
(+)-NLE. Furthermore, the occurrence of a concomi-
tant auto-inductive process in the aldol reaction of 3
was pointed out.
Figure 2.
The results, reported in Table 3 (compared with those
in Table 2), confirm that a significant amplification of
the e.e. can be obtained by favouring a process of
self-organization of the chiral ligands (i.e. BINOL and
the chiral aldol (R)-6) in the preliminary phase of
synthesis of the catalyst.
The critical influence exerted by the mode of prepara-
tion of the catalyst was further confirmed by carrying
out the aldol condensation in the presence of Ti(OiPr)4/
( )-BINOL/(R)-6: in this case completely racemic aldol
6 was isolated in 71% yield. Furthermore, when the
experiment of entry 2, Table 3, was repeated using the
opposite combination Ti(IV)/(R)-BINOL+Ti(IV)/(S)-
BINOL and (R)-6, in order to get a resulting 11% e.e.
of (R)-BINOL, amplification of e.e. was again observed
since 6 was obtained with 28% e.e. (yield=88%) and
the chiral induction was shown to be controlled by the
chiral auxiliary (BINOL) since in this case 6 was
obtained with the R enantiomer predominant.
Finally, the behaviour of silyloxydienes 1 and 2 was
examined in aldol condensations carried out on benz-
aldehyde, as a representative substrate, in the presence
of the usual 1/1 Ti(OiPr)4/(R)-BINOL complex, pre-
Table 3. (+)-NLE by [Ti(IV)/(S)-BINOL+Ti(IV)/(R)-
BINOL+(R)-6] system
Entry
S-BINOL
6 e.e. (%)a
6 e.e. (%)b
6 Yield (%)c
e.e. (%)
1
2
3
0
1 (R)
14 (S)
67 (S)
10 (S)
24 (S)
82 (S)
74
90
88
11 (S)
49 (S)
3/PhCHO/[Ti(OiPr)4/(R)BINOL]+[Ti(OiPr)4/(S)BINOL]/(R)-6 2/1/
0.08/0.08 molar ratios were used.
a E.e.s were determined by HPLC analysis using a CHIRALPAK AD
column.
b E.e.s of newly formed aldol 6 calculated according to Ref. 15.
c All yields refer to isolated chromatographically pure compounds
correct by the amount of added 6.
Figure 3.

1952
R. Villano et al. / Tetrahedron: Asymmetry 13 (2002) 1949–1952
9. De Rosa, M.; Acocella, M. R.; Soriente, A.; Scettri, A.
Acknowledgements
Tetrahedron: Asymmetry 2001, 12, 1529–1531.
10. Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem.
Soc. 1994, 116, 2812–2820.
We thank MIUR for financial support.
11. Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Am.
Chem. Soc. 1995, 117, 2363–2364.
References
12. Brunel, J. M.; Luukas, T. O.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 1941–1946.
13. Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org.
Lett. 2001, 3, 699–702.
14. Szlosek, M.; Figade`re, B. Angew. Chem., Int. Ed. 2000,
39, 1799–1801.
1. (a) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto,
Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000,
112, 3532–3556; (b) Girard, C.; Kagan, H. B. Angew.
Chem., Int. Ed. 1998, 37, 2922–2959 and references cited
therein.
2. (a) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 9800–9809; (b) Mori, M.; Nakai,
T. Tetrahedron Lett. 1997, 38, 6233–6236.
3. (a) Terada, M.; Mikami, K.; Nakai, T. J. Chem. Soc.,
Chem. Commun. 1990, 1623–1624; (b) Mikami, K.; Ter-
ada, M. Tetrahedron 1992, 48, 5671–5680; (c) Kitamoto,
D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995, 36,
1861–1864.
15. Shengjian, L.; Yaozhong, J.; Aiqiao, M.; Giushu, Y. J.
Chem. Soc., Perkin Trans. 1 1993, 885–886.
16. Typical experimental procedure for asymmetric aldol
reaction in the presence of (R)-aldol 6 (entry 2, Table 3):
Two mixtures of (S)-1,1%-bi-2-naphthol (0.0445 mmol),
Ti(OiPr)4 (0.0445 mmol) and 4 A molecular sieves (195
,
mg) in THF (2.78 ml) and (R)-1,1%-bi-2-naphthol (0.0355
i
,
mmol), Ti(O Pr)4 (0.0335 mmol) and 4 A molecular sieves
4. Furuno, H.; Hanamoto, T.; Sugimoto, Y.; Inanaga, J.
Org. Lett. 2000, 2, 49–52.
(155 mg) in THF (2.22 ml) were separately stirred at rt
for 1 h under argon atmosphere. After mixing the two
suspensions together, (R)-6 (0.08 mmol) was added and
the mixture was stirred at rt for 0.5 h. The mixture was
cooled to −78°C and the aldehyde (1 mmol) was added
followed, after 30 min, by a solution of silyloxydiene 3 (2
mmol) in THF (1 ml). The mixture was stirred at −78°C
for 2 h and then at rt overnight. After cooling the
mixture at −78°C, TFA (0.4 ml) was added and the
solution was warmed to rt. After stirring at rt for 1 h
desilylation was complete and the reaction mixture was
diluted with ether and saturated aqueous NaHCO3 solu-
tion (3 ml) was added dropwise. The pure product 6 was
obtained by usual work-up and purification procedures8c
(90% yield, 24% e.e.).
5. (a) Evans, A. D.; Kozlowski, M. C.; Murry, J. A.;
Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R.
J. J. Am. Chem. Soc. 1999, 121, 669–685; (b) Yamashita,
Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 3292–3302.
6. Brunel, J. M.; Luukas, T. O.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 1941–1946.
7. (a) Tanaka, K.; Matsui, J.; Kawabata, Y.; Suzuki, H.;
Watanabe, A. J. Chem. Soc., Chem. Commun. 1991,
1632–1634; (b) Tanaka, K.; Matsui, J.; Suzuki, H. J.
Chem. Soc., Perkin Trans. 1 1993, 153–157; (c) Arnold, L.
A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878.
8. (a) Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A.
Tetrahedron: Asymmetry 2000, 11, 2255–2258; (b) De
Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron: Asymme-
try 2000, 11, 3187–3195; (c) Soriente, A.; De Rosa, M.;
Stanzione, M.; Villano, R.; Scettri, A. Tetrahedron:
Asymmetry 2001, 12, 959–963.
17. It is noteworthy that in the experiments performed with
silyloxydienes 1 and 2 in the presence of Ti(IV)/(R)-
BINOL (100% e.e.) complex, the corresponding aldols
(R)-4 and (R)-5 were respectively obtained in 93% yield
(>99% e.e.) and 81% yield (96% e.e.).