Unusual highly regioselective direct aldol additions with a moisture-resistant and highly efficient titanium catalyst

Article abstract of DOI:10.1021/ol052637z

The extremely robust and water-stable tetranuclear complex Ti ₄(μ-BINOLato)₆(μ₃-OH)₄ was found to catalyze the direct aldol addition with high regioselectivities at the more steric α-encumbered side of unsymmetr

Full text of DOI:10.1021/ol052637z

ORGANIC
LETTERS
2
006
Vol. 8, No. 2
81-284
Unusual Highly Regioselective Direct
Aldol Additions with a
2
Moisture-Resistant and Highly Efficient
Titanium Catalyst
Rainer Mahrwald* and Bernd Schetter
Humboldt-UniVersit a¨ t zu Berlin, Institut f u¨ r Chemie, Brook-Taylor-Strasse 2,
12489 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
Received October 31, 2005
ABSTRACT
4 6 3 4
The extremely robust and water-stable tetranuclear complex Ti (µ-BINOLato) (µ -OH) was found to catalyze the direct aldol addition with high
regioselectivities at the more steric
r-encumbered side of unsymmetrical ketones. As few as 0.2 mol % loadings with this cluster were enough
to afford complete conversions. The reaction proceeds very smoothly without a significant amount of byproducts. The formation of quaternary
stereocenters is described.
1
The aldol addition is one of the most powerful methods for
especially Lewis acid catalysts, are sensitive to air and/or
moisture, making extended expenditures in handling neces-
sary. On the other hand, quenching the reactions with water
often causes the decomposition of the moisture-sensitive
catalysts, and the decomposition products, such as BINOL,
for example, make the purification of the reaction products
more difficult. The recovery of the catalyst is in these cases
impossible as well. Other catalysts are produced in situ,
making reproducible reaction conditions difficult, as well as
2
the formation of carbon-carbon bonds. Especially since the
mid-1990s, various methods for direct aldol additions have
been developed. Many of them are catalyzed by various
kinds of metal complexes. However, most of these catalysts,
3
4
(
1) (a) Kane, R. Ann. Phys. Chem., Ser. 2 1838, 44, 475. (b) Wurtz, A.
Bull. Soc. Chim. Fr. 1872, 17, 436-442. Wurtz, A. Ber. Dtsch. Chem. Ges.
872, 5, 326. Borodin, A. Ber. Dtsch. Chem. Ges. 1873, 6, 982-985.
2) (a) Heathcock, C. H. (Chapter 1.6); Kim, B. M.; Williams, S. F.;
Masamune, S. (Chapter 1.7); Rathke, M. W.; Weipert, P. (Chapter 1.8);
Paterson, I. (Chapter 1.9); Gennari, C. (Chapter 2.4) In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1993; Vol. 2. (b) Braun, M. In Houben-Weyl, Methoden
der Organischen Chemie; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart 1996; Vol. E21b, pp 1603-1666.
1
(
R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 7386-7387. (j)
Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki,
T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466-2467. (k) Mahrwald,
R.; Ziemer, B.; Trojanov, S. Tetrahedron Lett. 2001, 6843-6845. (l) Evans,
D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002,
124, 392-393. (m) Markert, M.; Mahrwald, R. Synthesis 2004, 1429-
1433. (n) Rohr, K.; Herre, R.; Mahrwald, R. Org. Lett. 2005, 7, 4499-
4501.
(
1
c) Machajewski, T. D.; Wong, C. H. Angew. Chem. Int. Ed. 2000, 39,
352-1374. (d) Mahrwald, R. Curr. Org. Chem. 2003, 4, 1713-1723. (e)
Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, Germany,
004. (f) Schetter, B.; Mahrwald, R. In Quaternary Stereocenters-Challenges
2
and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, Germany, 2005; pp 51-81.
(4) For an overview, see: (a) Acid catalysis: Yamamoto, H.; Futatsugi,
K. Angew. Chem. 2005, 117, 1958-1977. Mikami, K.; Terada, M. In Lewis
Acids in Organic Synthesis; Hisashi, Y., Ed.; Wiley-VCH: Weinheim,
Germany 2000. (b) Titanium complexes: Mikami, K.; Matsumoto, Y.;
Shiono, T. In Science of Synthesis; Bellus, D., Jacobsen, N. E., Ley, S. V.,
Noyori, R., Regitz, M., Reider, P. J., Schaumann, E., Shinkai, I., Thomas,
E. J., Trost, B. M., Eds.; Thieme: Stuttgart, 2003. Product class 10:
Organometallic Complexes of Titanium. (c) Applications to organic
synthesis: Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.;
Wiley-VCH: Weinheim, Germany, 2002.
(
3) (a) Mahrwald, R. Chem. Ber. 1995, 128, 919-921. (b) Mahrwald,
R.; Costisella, B. Synthesis 1996, 1087-1089. (c) Mahrwald, R.; Costisella,
B.; G u¨ ndogan, B. Tetrahedron Lett. 1997, 38, 4543-4544. (d) Mahrwald,
R.; G u¨ ndogan, B. Synthesis 1998, 262-264. (e) Mahrwald, R. Chem. ReV.
1
999, 99, 1097-1120. (f) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai,
H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. (g) Trost, B.
M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-12004. (h) Mahrwald,
R.; Ziemer, B. Tetrahedron Lett. 2002, 43, 4459-4461. (i) List, B.; Lerner,
1
0.1021/ol052637z CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/27/2005

5
mechanistic studies. Last but not least, many catalysts are
only accessible by complicated multistep reaction sequences
6
or need rare and expensive metals as reactive centers. Recent
research is focused on the development of stable and storable
catalysts, and the first remarkable results have been presented
7
by Kobayashi et al., who presented stable rare-earth and
zirconium catalysts for Mannich, aza-Diels-Alder, and
Mukaiyama aldol reactions, and Bull et al., who described a
moisture-stable titanium triflate for aza-Diels-Alder reac-
tions.8
During our ongoing studies of the mechanisms of titanium-
(IV)-alkoxide-mediated direct aldol additions, we explored
the catalytic potental of Mikami’s tetranuclear titanium
9
cluster. Mikami’s catalyst is crystalline and stable even
against boiling 1 N HCl and 1 N LiOH in dioxane and easy
i
to synthesize from Ti(O Pr)
4
, R-BINOL, or S-BINOL and
6
10
water. We also synthesized this cluster with rac-BINOL
and found that all six BINOL molecules which are incor-
porated in each cluster have the same stereochemistry. No
clusters appeared in crystalline form with a mixed stereo-
chemistry of the incorporated BINOLs. Therefore, the
clusters obtained from rac-BINOL are identical to those
produced with R-BINOL or S-BINOL (Figure 1).
Figure 1. Crystal structure of the tetranuclear titanium complex
rac-Ti (µ-BINOLato) (µ -OH) ; hydrogen atoms are omitted for
clarity.
4
6
3
4
13
ketone. In many cases, only one regioisomer was obtained.
Methyl groups of alkan-2-ones were found to be unaffected
under these reaction conditions. Therefore, the Wieland-
Miescher ketone 4 avoids the typically aldol cyclization to
the CD bicyclic steroidal intermediate 6 (Scheme 1).14 The
To test the applicability of this titanium complex, we
reacted several aldehydes with symmetrical and unsym-
metrical ketones. In fact, the catalyst was able to promote
the direct aldol addition between aldehydes 1 and ketones 2
in a remarkably clean way even with very low catalyst
11
12
loadings to give the aldols 3 (Table 1). This reaction was
found to be highly regioselective. Aldol addition is strongly
preferred at the sterically more encumbered R-side of the
Scheme 1. Regioselective Formation of Diketone 5
(
5) (a) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117,
2
3
363-2364. (b) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995,
6, 1861-1864. (c) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami,
K. Inorg. Chim. Acta 1999, 267-272. (d) Delas, C.; Szymoniak, J.; Lefranc,
H.; Mo ¨ı se, C. Tetrahedron Lett. 1999, 40, 1121-1122. (e) De Rosa, M.;
Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 2000, 11, 3187-3195.
(
f) Davis, J. T.; Balsells, J.; Caroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3,
6
99-702. (g) Zimmer, R.; Peritz, A.; Czerwonka, R.; Schefzig, L.; Reissig,
H.-U. Eur. J. Org. Chem. 2002, 3419-3428. (h) Villano, R.; De Rosa, M.;
Salerno, C.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 2002, 13,
1
949-1952. (i) Mahrwald, R. Org. Lett. 2000, 2, 4011-4012. (j) Villano,
R.; Acocella, M.; De Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron:
Asymmetry, 2004, 15, 2422-2424;
(6) (a) Sawamura, M.; Ito, Y. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (b) Ito, Y.; Sawamura,
M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405-6406. Ito, Y.;
Sawamura, M.; Hayashi, T. Terahedron Lett. 1987, 28, 6215-6218. (c)
Sawamura, M.; Ito, Y. Catal. Asymmetric Synth. 1993, 367-388.
bicyclic dione 5 is formed and strongly preferred with a high
degree of diastereoselectivity (>95:5). Dione 5 posseses two
(
7) (a) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 12236-12237. (b) Kobayashi, S.; Ueno, M.; Mizuki,
Y.; Ishitani, H.; Yamashita, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5
476-5481.
8) Bull, S. D.; Davidson, M. G.; Johnson, A. L.; Robinson, D. E. J. E.
Chem. Commun. 2003, 1750-1751.
9) Mikami, K.; Ueki, M.; Matsumoto, Y.; Terada, M. Chirality 2001,
3, 541-545.
10) The experimental procedure was the same as that given by Mikami
(
(11) So far, the catalyst loadings for similar reactions range usually
between 2 and 20 mol %; recently, Ding et al. presented an enantioselective
carbonyl-ene reaction with comparable low catalyst loadings: Yuan, Y.;
Zhang, X.; Ding, K. Angew. Chem. 2003, 42, 5478-5480.
(
1
(
(12) Typical experimental procedure: 1 equiv of aldehyde and 1.5 equiv
of ketone were mixed at room temperature. If problems with the solubility
occurred, small amounts of CH2Cl2 were used as solvent. A portion 0.2
mol % of the catalyst was added. The procedure of the reaction was
monitored by TLC, and when the turnover was complete, the reaction
mixture was diluted with diethyl ether; the reaction was then quenched with
aqueous NH4Cl. The organic layer was separated, dried (MgSO4), and
filtered, and the ether was removed in vacuo. CC (hexane/ethyl acetate)
afforded the pure aldols. Yields have not been optimized. Large amounts
of recovered aldehyde indicate the necessity of the employment of longer
reaction times or higher reaction temperatures in some cases.
et al. The catalyst was obtained as dark red rectangular crystals. A single-
crystal structure analysis was made of a suitable crystal. The complex was
found to crystallize in the cubic space group F-43c. a ) b ) c ) 32.348
Å; R1 ) 0.049, wR2 ) 0.118. Crystallographic data have been deposited
at the Cambridge Crystal Data Center (CCDC 279234). This material can
be obtained upon request to CCDC, 12 Union Road, Cambridge, 1EZ, U.K.
(http://www.ccdc.cam.ac.uk; e-mail at deposit@ccdc.cam.ac.uk). The struc-
ture was refined with SHELX97 (Sheldrick, G. M. SHELX97: Program
for crystal structure refinement; Universit a¨ t G o¨ ttingen: G o¨ ttingen, Ger-
many).
282
Org. Lett., Vol. 8, No. 2, 2006

Table 1
a
Regioselectivity was generally below the detection limit of 300 MHz H NMR (>95:5). 70% of the thiophenecarbaldehyde was recovered. c 75% of
1
b
d
the benzaldehyde was recovered. 40% of the phenylpropargylaldehyde was recovered.
quaternary stereocenters with defined relative configurations
endo-CH
and exo-OH, Figure 2).15
Because Mikami’s catalyst is highly resistant against air,
moisture, and acids, neither drying of the reagents and the
solvents nor the application of protection gas techniques was
necessary. Although the reaction stopped after adding 1 equiv
of water, the aldol reaction proceeded after water removal
(
3
(molsieve A3 after separation of the aqueous layer), indicat-
ing that the catalyst remained stable and active. It was even
possible to recover unchanged catalyst from the reaction
mixture.
Optimization of the reaction conditions indicated that
reaction temperatures of 55 °C reduce the reaction times to
4
6
2
8 h (entry 2a, Table 1). If the reaction was carried out at
3 °C, satisfactory yields were obtained after 12 h (entry
b, Table 1). Higher amounts of the aldehyde and higher
catalyst loadings also resulted in a reduction of reaction time.
In contrast to the TiCl
-mediated aldol addition,13 this
4
Figure 2. Crystal structure of the bicyclic dione 5.
reaction is even applicable to higher functionalized ene
compounds. Hydroxyacetone 10 reacts with aldehydes to give
the protected aldols 11 and 12 (Table 3) with a high degree
Other quaternary carbon atoms were also synthesized with
R-methylcyclopentanone 7a and R-methylcyclohexanone 7b
(Table 2). Surprisingly, the regioselectivity depends strongly
(15) The relative stereochemistry was unambiguously determined by
single-crystal structure analysis. Substance 5 crystallizes in the orthorhombic
space group Pna21. a ) 12.024 Å, b ) 10.6931 Å, c ) 7.1249 Å; R1 )
upon the nature of the cyclic ketone in these reactions.
0
.025, wR2 ) 0.061. Crystallographic data have been deposited at the
(
13) Mahrwald, R.; G u¨ ndogan, B. J. Am. Chem. Soc. 1998, 120, 413-
14.
14) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.
Cambridge Crystal Data Center (CCDC 279235). This material can be
obtained upon request to CCDC, 12 Union Road, Cambridge, 1EZ, U.K.
(http://www.ccdc.cam.ac.uk; e-mail at deposit@ccdc.cam.ac.uk).
4
(
Org. Lett., Vol. 8, No. 2, 2006
283

Table 2. Aldol Additions to R-Methylcycloalkanones
Table 3. Aldol Additions to Hydroxyacetone
overall
regioselectivity syn-8: syn-9: yield
ratio yield 11 syn-11: yield 12 syn-12:
entry ketone
R1
8:9
anti-8 anti-9
(%)
entry
R
1:10
(%)
anti-11
(%)
anti-12
1
2
3
4
5
6
7
8
9
0
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
Ph
Ph
>95:5a
66:34
94:6
52:48
55:45 72:28
51:49
52:48 70:30
65:35
85
d
c
1
2
3
Ph
Ph
1:1
5:1
1:1
22
88
trace
86:14
65:35
63
13:87
53
81
72
61
PhCtC
PhCtC
4-EtO-C
4-EtO-C
78:22
PhCtC
61
20:80
a
6
6
H
H
H
H
4
4
4
4
>95:5
no reaction
96:4
4-Cl-C
4-Cl-C
6
55:45 ndb
68
34
68
12
6
81:19
65:35 67:33
low catalyst loadings. The complimentary regioselectivity
is remarkable compared with the proline-catalyzed direct
3-MeO-C
3-MeO-C
6
H
H
4
4
96:4
75:25
67:33 ndb
63:37 65:35
e
1
6
aldol additions and the regioselective MgI -amine-promoted
2
a
Regioselectivity was generally below the detection limit of 300 MHz
1
d
f
b
c
17
H NMR (>95:5). Not determined. 28% of the aldehyde was recovered.
8% of the aldehyde was recovered. 78% of the aldehyde was recovered.
Relative stereochemistry determined by X-ray structure determination.
direct aldol addition. With aliphatic aldehydes, aldols could
be obtained as well under certain reaction conditions.
Because the outcome of this reaction is sensitive to the
reaction conditions and other reaction products could be
obtained in high yields as well under application of other
reaction conditions, these results will be reported in a separate
forthcoming paper.
e
3
of diastereoselectivity. In these cases, only one regioisomer
was detected as well.
The outcome of this reaction is tunable by the stoichiom-
etry of the reactants. By employing equimolar amounts of
aldehyde 1 and hydroxyacetone 10, we obtained the anti-
configured aldol adduct 12 (a hydroxyacetone acetal) as the
main product, whereas a 5-fold excess of the aldehyde 1
resulted in the syn-configured aldol 11 (an aldehyde acetal).
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft and the Konrad-Ade-
nauer-Stiftung. Enantiopure BINOL was a gift from Merck
KGaA, Darmstadt, Germany. Dr. Burkhard Ziemer, Gregor
Schnakenburg, and Petra Neubauer are gratefully acknowl-
edged for the X-ray structure analysis.
Additional experiments concerning the concept of chiral
amplification and chiral poisoning16 of the racemic catalyst
are ongoing. Recently, other multinuclear chiral titanium
clusters (e.g., a hexanuclear cluster with a chiral reactive
cave) have been synthesized in our laboratories, and the
catalytic properties will be explored.
In summary, herein, we demonstrate for the first time the
synthetic power of stable and storable titanium clusters for
the direct aldol addition, which is promoted with extremely
Supporting Information Available: NMR data of all
synthesized species and full characterization of novel com-
pounds as well as selected X-ray crystallographic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052637Z
(
16) (a) Keck, G. E.; Tarbet, K. H.; Kenneth H. J. Am. Chem. Soc. 1993,
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1
(17) Wei, H.-X.; Jasoni, R. L.; Shao, H.; Hu, J.; Par e´ , P. W. Tetrahedron
2004, 60, 11829-11835.
284
Org. Lett., Vol. 8, No. 2, 2006