Highly stereoselective aldol reactions of titanium enolates from lactate-derived chiral ketones.

Article abstract of DOI:10.1021/ol0274054

[reaction: see text] Highly stereoselective titanium-mediated aldol reactions based on lactate-derived ketones are reported. The stereochemical outcome of the process depends on the protecting group (PMB or Bn) and the Lewis acid (i-PrOTiCl(3) or TiCl(4))

Full text of DOI:10.1021/ol0274054

ORGANIC
LETTERS
2003
Vol. 5, No. 4
519-522
Highly Stereoselective Aldol Reactions
of Titanium Enolates from
Lactate-Derived Chiral Ketones
Joan G. Solsona, Pedro Romea,* Fe`lix Urp´ı,* and Jaume Vilarrasa
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, Mart´ı i Franque´s 1-11,
08028 Barcelona, Catalonia, Spain
furpi@qo.ub.es; promea@qo.ub.es
Received December 4, 2002
ABSTRACT
Highly stereoselective titanium-mediated aldol reactions based on lactate-derived ketones are reported. The stereochemical outcome of the
process depends on the protecting group (PMB or Bn) and the Lewis acid (i-PrOTiCl3 or TiCl4) used in the enolization step, the corresponding
anti−syn or syn−syn aldols being prepared in high yields and with diastereomeric ratios up to 99:1.
Metal enolates involved in stereoselective aldol reactions
need to be easily obtained in quantitative yield with a well
defined geometry. Furthermore, the metal still has to be
amenable to coordination by the carbonyl group in such a
way that the resulting ate complex can evolve through an
ordered transition state leading to the desired aldol products
with predictably high levels of stereoselection.1
Titanium enolates fulfill these requirements. Titanium(IV)
is available from inexpensive sources and permits the
incorporation of a large array of ligands to tune its acidity,
and the resulting enolates are fairly reactive.2 Despite these
and other advantages,1e,2 formation of titanium enolates from
the corresponding carbonyl precursors using a titanium(IV)
Lewis acid and a tertiary amine3 has often been hampered
by the need to strictly control the experimental conditions.
However, over the past few years there has been an in-
creasing number of cases showing their potential to the point
that slight changes on the enolization conditions modify the
stereochemical outcome of the process.3j,l
In this context, we have reported that putative Z titanium
enolates of R-silyloxy ketones (PG ) TBS, M ) Ti, in
Scheme 1) afford stereoselectively 2,4-syn-4,5-syn-aldols
(syn-syn) through the transition state shown in eq 1 (see
Scheme 1).4 Therefore, we envisaged that the corresponding
2,4-anti-4,5-syn-aldols (anti-syn) might be obtained instead
if the reaction could take place through a chelated transition
(2) For reviews dealing with titanium complexes, see: (a) Duthaler, R.
O.; Hafner, A. Chem. ReV. 1992, 92, 807. (b) Cozzi, P. G.; Solari, E.;
Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Chem. Ber. 1996, 129, 1361.
(3) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866. (b) Evans, D. A.; Rieger, D. L.;
Bilodeau, M. T.; Urp´ı, F. J. Am. Chem. Soc. 1991, 113, 1047. (c)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Borgia, A. L. J. Org. Chem. 1992,
57, 6339. (d) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H. C.; Huang, T.-Y.
J. Am. Chem. Soc. 1993, 115, 2613. (e) Luke, G. P.; Morris, J. J. Org.
Chem. 1995, 60, 3013. (f) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc.
1996, 118, 2527. (g) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe,
M.; Kise, N. J. Org. Chem. 1996, 61, 2809. (h) Gonza´lez, A.; Aiguade´, J.;
Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (i) Yoshida, Y.;
Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett. 1997, 38, 8727.
(j) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883. (k) Adrian, J. C., Jr.; Barkin, J. L.; Fox, R. J.; Chuck, J. L.;
Hunter, A. D.; Nicklow, R. A. J. Org. Chem. 2000, 65, 6264. (l) Crimmins,
M. T.; King, B. W.; Tabet, E. A.; Chaudhury, K. J. Org. Chem. 2001, 66,
894. (m) Guz, N. R.; Phillips, A. J. Org. Lett. 2002, 4, 2253.
(1) See, for instance: (a) Mekelburger, H. B.; Wilcox, C. S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, p 99. (b) Heathcock, C. H. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, p 133 and 181. (c) Kim, B. M.; Williams, S. F.; Masamune,
S. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, p 239. (d) Rathke, M. W.; Weipert,
P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, p 277. (e) Paterson, I. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, p 301. (f) Caine, D. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3, p 1. (g) Braun, M. Houben-Weyl. Methods of Organic Chemistry.
StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; Vol. E21b, p
1603.
10.1021/ol0274054 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/28/2003

Scheme 1. Mechanistic Models for Stereoselective syn-Aldol Reactions Based on Lactate-Derived Ketones
state as shown in eq 2 (see Scheme 1).5 The purpose of this
Letter is to report our findings on the titanium-mediated aldol
reactions from lactate-derived ketones 1 and 2 (see Figure
1) in which the R-hydroxy group is protected as PMB and
Bn ethers, respectively.6
ing anti-syn aldols11 (see Scheme 2) in high yields and with
excellent diastereomeric ratios, even in the case of a sterically
undemanding aldehyde such as propanal (98:2). The results
are summarized in Table 1.
Table 1. (i-PrO)TiCl3-Mediated Aldol Reactions of 1
entry
aldehyde
R
dra 3:4
yield (%)b
1
2
3
4
5
6
a
b
c
d
e
f
i-Pr
i-Bu
Et
H2CdCH(Me)
Ph
99:1
98:2
98:2
94:6
97:3
95:5
83
83
82
83
85
88
Figure 1.
4-ClC6H4
a Determined by HPLC. b Isolated yield of 3.
Taking into account the sensitivity of the PMB group
to acidic media,7 we first evaluated (i-PrO)2TiCl2- and
(i-PrO)TiCl3-mediated aldol reactions of 1 with isobutyral-
dehyde (a). As expected, the poor Lewis acid character of
(i-PrO)2TiCl2 produced low conversions when the enolization
was conducted under the standard conditions ((i-PrO)2TiCl2,
i-Pr2NEt, CH2Cl2, -78 °C).8 This drawback was overcome
using the more powerful Lewis acid (i-PrO)TiCl3 and,
although it was not possible to avoid a partial cleavage of
the PMB group (<10%),9 the anti-syn aldol 3a (see Scheme
2) was obtained stereoselectively (dr 99:1) in 83% yield. This
Encouraged by these findings we addressed our attention
to the ketone 2 containing the more stable benzyl group. In
this case, the aforementioned reaction conditions did not
produce any cleavage of the protecting group and the yields
were again high, the diastereoselectivity being slightly eroded
(compare entries 1-6 in Tables 1 and 2). However, when
(i-PrO)TiCl3 was replaced by TiCl4, the stereochemical
course of the reaction was surprisingly reversed, since the
Scheme 2 a
Table 2. Titanium-Mediated Aldol Reactions of 2
entry aldehyde
R
Lewis acid dra 5:6 yield (%)b
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
a
b
c
d
e
f
i-Pr
i-Bu
Et
(i-PrO)TiCl3 97:3
(i-PrO)TiCl3 94:6
(i-PrO)TiCl3 98:2
86
91
90
81
96
97
74
95
92
77
91
96
H2CdCH(Me) (i-PrO)TiCl3 92:8
Ph
4-ClC6H4
i-Pr
i-Bu
Et
H2CdCH(Me) TiCl4
Ph
4-ClC6H4
(i-PrO)TiCl3 92:8
(i-PrO)TiCl3 91:9
a Reaction conditions: (a) (i-PrO)TiCl3, i-Pr2NEt, CH2Cl2, -78
°C. (b) RCHO, -78 °C.
TiCl4
TiCl4
TiCl4
17:83
18:82
31:69
4:96
experimental procedure10 was subsequently generalized to
other aldehydes, which allowed us to isolate the correspond-
10
11
12
TiCl4
TiCl4
7:93
9:91
(4) (a) Figueras, S.; Mart´ın, R.; Romea, P.; Urp´ı, F.; Vilarrasa, J.
Tetrahedron Lett. 1997, 38, 1637. (b) Esteve, C.; Ferrero´, M.; Romea, P.;
Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 5083.
a Determined by HPLC. b Overall isolated yield.
520
Org. Lett., Vol. 5, No. 4, 2003

syn-syn aldols 6 were obtained as the major diastereomers
the diastereomeric ratios of the (i-PrO)TiCl3-mediated aldol
reactions of 1 and 2 are due to the unequal chelating abilities
of PMB and Bn protecting groups. However, the reversal of
the stereochemistry observed in these ketones (compare
entries 1-6 and 7-12 in Table 2 and see ref 13), depending
on the Lewis acid used in the enolization step, requires
further analysis because the strong chelating ability of TiCl4
does not agree with the process evolving through an open
transition state as shown in eq 1 (see Scheme 1).14 As a
consequence, these results are not easily rationalized using
the pathways depicted in Scheme 1, which suggests that this
mechanistic model has to be reevaluated.
(see Scheme 3 and Table 2).12,13 In this case, it is worth
Scheme 3 a
a Reaction conditions: (a) (i-PrO)TiCl3 or TiCl4, i-Pr2NEt,
CH2Cl2, -78 °C. (b) RCHO, -78 °C.
Keeping in mind that the structure of titanium enolates
has not been unambiguously established, any attempt to
rationalize their behavior is rather speculative. However,
evidence arising from structural studies gives support to a
chelated and octahedral geometry for the titanium(IV)-ate
complexes (I and II in Scheme 4) involved in those reactions.
Given that ligands on such titanium complexes are placed
around the metal center according to a sequence based on
stereoelectronic considerations,15 it can be anticipated that
thermodynamic and kinetic properties of ate complexes I
and II derived from (i-PrO)TiCl3 or TiCl4 may be highly
influenced by the replacement of i-PrO- by Cl-.
Therefore, assuming that each ate complex goes through
a different cyclic transition state to the corresponding syn
aldol product (see Scheme 4), if both diastereomeric com-
plexes, I and II, do not rapidly establish equilibrium and do
not interconvert directly by any octahedral isomerization, the
stereochemical outcome of the process could be dependent
on the ate complex formation step.16 Thus, ligands not only
tune the titanium acidity but may also have a dramatic
influence on the stereochemistry of the ate complex and, as
a consequence, of the syn aldol product (see Scheme 4).17,18
Further investigations into the mechanism of this process
are currently underway.
noting the different diastereoselectivities displayed by ali-
phatic (a-c) and conjugated (d,f) aldehydes (compare entries
7-12 in Table 2), which suggests that this variability is
mainly rooted in stereoelectronic grounds.
Due to the coordinating capability of (i-PrO)TiCl3 and
TiCl4, it is expected that both Lewis acids produce chelated
enolates such as that shown in eq 2 (see Scheme 1). Then,
it might be argued that the slight differences existing among
(5) For stereoselective aldol reactions based on chiral hydroxy ketones
involving chelated transition states, see: (a) Van Draanen, N. A.; Ars-
eniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56,
2499. (b) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233. (c)
Choudhury, A.; Thornton, E. R. Tetrahedron Lett. 1993, 34, 2221. (d)
Palomo, C.; Gonza´lez, A.; Garc´ıa, J. M.; Landa, C.; Oiarbide, M.; Rodr´ıguez,
S.; Linden, A. Angew. Chem., Int. Ed. 1998, 37, 180. (e) Perkins, M. V.;
Sampson, R. A. Org. Lett. 2001, 3 123. (f) Paterson, I.; Temal-La¨ıb, T.
Org. Lett. 2002, 4, 2473.
(6) Ferrero´, M.; Galobardes, M.; Mart´ın, R.; Montes, T.; Romea, P.;
Rovira, R. Urp´ı, F.; Vilarrasa, J. Synthesis 2000, 1608.
(7) Greene, T. W.; Wuts, R. G. M. In ProtectiVe Groups in Organic
Synthesis; Wiley & Sons: New York, 1999.
(8) Isolated yield of 3a and 4a (see Scheme 2) ) 55%. Diastereomeric
ratio (3a:4a) ) 84:16.
(9) When (i-PrO)TiCl3 and i-Pr2NEt were added to ketone 1 at -90 °C,
and the enolization and the further aldol reaction with isobutyraldehyde
were carried out at -78 °C, the cleavage of the PMB was reduced to less
than 5%.
(10) Typical Experimental Procedure. Freshly distilled Ti(i-PrO)4 (83
µL, 0.28 mmol) was added dropwise to a solution of TiCl4 (92 µL, 0.84
mmol) in CH2Cl2 (1 mL) at 0 °C under N2. The yellow mixture was stirred
for 10 min at 0 °C and 10 min at room temperature. It was diluted with
CH2Cl2 (1 mL), and the resulting colorless solution was added dropwise
(it was rinsed with 2 × 0.5 mL) for 10-15 min to a solution of 1 (195 mg,
1 mmol) in CH2Cl2 (2 mL) at -78 °C under N2, followed by i-Pr2NEt
(0.19 mL, 1.1 mmol). The resulting dark red solution was stirred for 1.5 h
at -78 °C. After the dropwise addition of 1.5 equiv of aldehyde, stirring
was continued for 30 min at -78 °C. The reaction was quenched by the
addition of saturated NH4Cl (5 mL) and vigorously stirred at room
temperature. The mixture was diluted with Et2O (200 mL) and washed with
H2O (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The aqueous
phases were extracted with Et2O (75 mL), and the combined organic extracts
were dried (MgSO4) and concentrated. The resulting oil was analyzed by
HPLC and purified by flash chromatography (hexanes/EtOAc).
(11) Stereochemistry of 3f was established by X-ray diffraction analysis;
see Supporting Information. The stereochemistry of 3a was confirmed by
chemical correlation.
In summary, we have described highly stereoselective aldol
reactions based on the titanium enolates of lactate-derived
(14) Aforementioned reversal of stereoselectivity is not observed when
the equivalent TBS-protected ketone is submitted to the same reaction
conditions. As expected, the titanium-mediated aldol reaction of this ketone
with aliphatic or aromatic aldehydes affords the corresponding syn-syn
aldols (see eq 1 in Scheme 1) in high yields with dr > 96:4 irrespective of
the Lewis acid (TiCl4 or (i-PrO)TiCl3) used in the enolization. These results
suggest that the fickle behavior observed in the titanium-mediated aldol
reactions of 1 and 2 is related to the formation of a chelated enolate, whose
more rigid architecture has a crucial influence on the stereodetermining
step of the process.
(15) Gau, H.-M.; Lee, C.-S.; Lin, C.-C.; Jiang, M.-K.; Ho, Y.-C.; Kuo,
C.-N. J. Am. Chem. Soc. 1996, 118, 2936.
(16) This hypothesis is supported by the lithium-mediated aldol reaction
of 2, which affords the corresponding anti-syn aldol (i.e., 5a:6a ) 72:28,
46% yield). Given that the stererochemical outcome of this reaction is
rationalized using the model shown in eq 2 (Scheme 1), it is clear that the
stereodetermining step of the TiCl4-mediated aldol reactions of 2 cannot
be linked to the carbon-carbon bond formation step.
(17) For related discussions on the structure of titanium complexes
involved in stereoselective Diels-Alder reactions, see: (a) Seebach, D.;
Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.; Ku¨hnle, F. N. M.
J. Org. Chem. 1995, 60, 1788. (b) Haase, C.; Sarko, C. R.; DiMare, M. J.
Org. Chem. 1995, 60, 1777. (c) Gothelf, K. V.; Jorgensen, K. A. J. Org.
Chem. 1995, 60, 6847. (d) Garc´ıa, J. I.; Mart´ınez-Merino, V.; Mayoral, J.
A. J. Org. Chem. 1998, 63, 2321.
(12) Stereochemistry of 5f was established by X-ray diffraction analysis;
see Supporting Information. The stereochemistry of 5a and 6a was
confirmed by chemical correlation.
(13) Same reversal of the stereochemistry was observed in the case of
ketone 1 when enolization was carried out with TiCl4/i-Pr2NEt. For instance,
TiCl4-mediated aldol reaction of 1 with benzaldehyde (e) afforded a mixture
of 3e and 4e (see Scheme 2) in low yield (58%) and with a poor
diastereomeric ratio (3e:4e ) 25:75), the syn-syn aldol being the major
diastereomer. This result is opposite to that obtained with (i-OPr)TiCl3
(compare with entry 5 in Table 1), which proves the crucial role played by
the Lewis acid on the stereochemical outcome of these reactions.
(18) For related examples on the impact of additives on titanium-mediated
aldol reactions, see for instance, refs 3k-m and: Nakamura, S.; Hayakawa,
T.; Nishi, T.; Watanabe, Y.; Toru, T. Tetrahedron 2001, 57, 6703.
Org. Lett., Vol. 5, No. 4, 2003
521

Scheme 4. Proposed Mechanistic Model for Titanium-Mediated Aldol Reactions of Ketones 1 and 2
ketones 1 and 2. The protecting groups (PMB or Bn) and
y Cultura (DGESIC, Grant PM98-1272), the Ministerio de
Ciencia y Tecnolog´ıa and Fondos FEDER (Grant BQU2002-
01514), and the Generalitat de Catalunya (2001SGR00051),
as well as a doctorate studentship (Universitat de Barcelona)
to J.G.S. are acknowledged.
the titanium Lewis acid (i-PrOTiCl3 or TiCl4) employed in
the enolization determine the stereochemical outcome of the
process, affording the corresponding anti-syn or syn-syn
aldols in high yields and with diastereomeric ratios up to
99:1. A working hypothesis based on the crucial role played
by the stereochemistry of the ate complexes has been
proposed to account for the aforementioned results.
Supporting Information Available: Spectroscopic data
for aldols 3, 5, and 6, copies of 1H NMR spectra of 3a,d-e
and 5a,d-e, and X-ray crystal data for 3f and 5f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Dr. Xavier Solans and Dr.
Merce` Font-Bardia (Universitat de Barcelona) for X-ray
analyses. Financial support from the Ministerio de Educacio´n
OL0274054
522
Org. Lett., Vol. 5, No. 4, 2003