1,4-Asymmetric induction in the titanium-mediated aldol reactions of α-benzyloxy methyl ketones

Article abstract of DOI:10.1016/j.tetlet.2008.06.120

Good levels of 1,4-anti asymmetric induction are obtained in the TiCl₃(i-PrO)-mediated aldol reaction of α-benzyloxy methyl ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient synthesis.

Full text of DOI:10.1016/j.tetlet.2008.06.120

Tetrahedron Letters 49 (2008) 5265–5267
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,4-Asymmetric induction in the titanium-mediated aldol reactions
of a-benzyloxy methyl ketones
*
*
Miquel Pellicena, Joan G. Solsona, Pedro Romea , Fèlix Urpí
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1–11, 08028 Barcelona, Catalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Good levels of 1,4-anti asymmetric induction are obtained in the TiCl3(i-PrO)-mediated aldol reaction of
Received 26 May 2008
Revised 20 June 2008
Accepted 24 June 2008
Available online 2 July 2008
a
-benzyloxy methyl ketones with achiral aldehydes. Such methodology represents a new approach to the
substrate-controlled acetate aldol reaction, which can be useful to design more efficient synthesis.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective reactions
Acetate aldol reactions
Titanium enolates
Chiral ketones
The ubiquitous presence of b-hydroxycarbonyl and 1,3-diol
subunits in natural products has motivated the development of a
plethora of synthetic strategies, being especially important those
associated to the aldol reaction.1 The intensive research carried
out in this area during the last decades has given rise to a large
number of highly stereoselective methodologies, which have been
successfully applied to the construction of structurally complex
molecular architectures.2 Regardless of these advances, the acetate
aldol reaction3 is still a matter of concern.1,4 Particularly, the lack of
refined models to understand the mechanistic details of such reac-
tions5,6 makes difficult to use them for coupling large fragments in
advanced steps of a synthesis.7 Indeed, the lack of knowledge of the
O
O
O
O
BnO
PMBO
BnO
BnO
1
2
3
4
Figure 1.
cently documented the structure of the titanium enolate from
alkoxy ketones,10 and have proved that the stereochemical out-
come of the aldol reaction from chiral -benzyloxy ethyl ketones
relies on the titanium Lewis acid employed in the enolization
step.11 Bearing in mind these precedents, we speculated that the
appropriate choice of the enolization conditions for the lactate-de-
rived methyl ketone 1 would afford a well organized enolate that
might provide the structural elements required to achieve a highly
substrate-controlled reaction.
a-
a
stereochemical bias imparted by
a-alkoxy groups in titanium-
mediated aldol reactions of methyl ketones is remarkable.8 Consid-
ering the importance of such transformation, we have surveyed the
reactivity of the chiral a-benzyloxy methyl ketones shown in Fig-
ure 1. Herein, we document the 1,4-anti induction provided by
the titanium enolates from these ketones, which can be useful to
design more efficient syntheses of complex natural products.
The significance of the titanium enolates has unceasingly in-
creased since Evans established that they can be prepared by sim-
ple enolization with a titanium(IV) Lewis acid and a tertiary
amine,9 and they are nowadays recognized as one of the most use-
ful tools for the stereoselective construction of carbon–carbon
bonds. Unfortunately, the poor knowledge on their structure has
hampered further synthetic advances. In this context, we have re-
Thus, we first evaluated the influence of the enolization condi-
tions on the titanium-mediated aldol addition of ketone 112 to iso-
butyraldehyde. The results are summarized in Table 1.
As expected, the stereochemical outcome of these reactions was
highly dependent on the titanium Lewis acid used in the enoliza-
tion. Thereby, almost no diastereoselectivity was observed with
TiCl4 (see entries 1 and 2 in Table 1), but better levels of stereocon-
trol favoring the anti adduct 5a were achieved with 2 equiv of TiCl4
(see Table 1, entry 3) or softer Lewis acids as TiCl3(i-PrO) or TiCl2-
(i-PrO)2 (see entries 4 and 5 in Table 1). The configuration of 5a
was established through conversion of an 85:15 mixture of
diastereomers into the (S) 3-hydroxy-4-methylpentanoic acid, 713
(Scheme 1).
* Corresponding authors. Tel.: +34 93 4021247/4039106; fax: +34 93 3397878
(F.U.).
E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.120

5266
M. Pellicena et al. / Tetrahedron Letters 49 (2008) 5265–5267
Table 1
Table 2
Titanium-mediated aldol reaction of 1 and isobutyraldehyde
TiCl3(i-PrO)-Mediated aldol reaction of lactate-derived ketones 1 and 2
O
O
OH
O
OH
O
O
OH
O
OH
a
a
+
+
R
R
BnO
BnO
BnO
PGO
PGO
5 PG: Bn
8 PG: PMB
PGO
6 PG: Bn
9 PG: PMB
1
5a
6a
1 PG: Bn
2 PG: PMB
Entry
TiL4
dr (5a:6a)a
Yieldb (%)
1
2
3
4
5
TiC4
TiCl4 + THF
TiCl4 + TiCl4
TiCl3(i-PrO)
TiCl2(i-PrO)2
57:43
51:49
71:29
85:15
73:27
90
71
77
80
80
Entry Ketone PG
Aldehyde
R
dr
dr
Yieldb
(%)
(5:6)a
(8:9)a
1
2
1
1
1
1
1
1
2
2
2
2
Bn
Bn
a
b
c
d
e
f
a
c
e
f
i-Pr
t-Bu
i-Bu
Pr
85:15
93:7
85:15
80:20
83:17
77
72
76
67
66
58
80
81
70
65
3
Bn
a
The diastereomeric ratio was established through HPLC analysis of the reaction
mixture.
4
Bn
5
Bn
Ph
b
Isolated yield of the aldol mixture.
6
Bn
H2C@C(CH3) 69:31
i-Pr
i-Bu
Ph
7
8
9
10
PMB
PMB
PMB
PMB
86:14
83:17
82:18
75:25
H2C@C(CH3)
a
The diastereomeric ratio was established through NMR analysis of the reaction
mixture.
b
O
OH
O
OH
Isolated yield of the aldol mixture.
a,b
HO
BnO
5a
7
a
-benzyloxy methyl ketones. Indeed, the diastereoselectivity and
7 (70% ee) [α]D —25.3 (c 1.2, CHCl3)
Evans13a [α]D —42.1 (c 1.8, CHCl3)
Yan13b [α]D —40.7 (c 3.0, CHCl3)
the yields achieved with ketones 3 and 4 are much better to that
obtained from 1 and 2 (compare, for instance, the data corre-
sponding to methacrolein in entries 6 and 10 in Table 2, and en-
tries 3 and 6 in Table 3),15,17 so, although a theoretical model is
still elusive, the stereocontrol imparted by model ketones 1–4
can be used for coupling large fragments in advanced steps of a
synthesis.
Scheme 1. Reagents and conditions: (a) H2, Pd/C, EtOH, rt; (b) NaIO4, MeOH/H2O
2:1, rt; 50% overall yield.
As the most promising result was obtained with TiCl3(i-PrO), we
carried out an exhaustive evaluation on the reaction conditions
with this Lewis acid. Unfortunately, attempts to improve the dia-
stereoselectivity by lowering the reaction temperature and by
altering times were unsuccessful, but we were pleased to observe
that the amount of aldehyde could be safely reduced to 1.2 equiv
without a significant erosion of the yield.14 Next, these experimen-
tally simple conditions were applied to the reaction of lactate-de-
rived methyl ketones 1 and 212 with a broad array of aldehydes.
The results are summarized in Table 2.
In summary, the titanium-mediated aldol reaction from chiral
-benzyloxy methyl ketones is highly sensitive to the titanium Le-
wis acid used in the enolization step. High yields and a remarkable
1,4-anti induction have been obtained for aliphatic, aromatic, and
a
a
,b-unsaturated aldehydes when the reaction is carried out with
TiCl3(i-PrO). Thus, the titanium-based methodology disclosed
herein represents a new approach to the substrate-controlled ace-
tate aldol reaction, which can be helpful to design more efficient
synthesis.
These results prove that the lactate-derived methyl ketone 1 af-
fords the 1,4-anti aldol adducts 5 from aliphatic, aromatic, and a,b-
unsaturated aldehydes in good yields and diastereomeric ratios
(see entries 1–6 in Table 1).15 Significantly, the steric bulk dictates
the diastereoselectivity for aliphatic aldehydes a–d (compare en-
tries 1–4 in Table 2), which ranges from dr 93:7 for pivalaldehyde
(b) to dr 80:20 for butanal (d). The level of stereocontrol was
Table 3
TiCl3(i-PrO)-mediated aldol reaction of a-benzyloxy methyl ketones 3 and 4
O
O
OH
O
OH
a
R'
R'
R'
+
R
R
evenly high for benzaldehyde, but became poorer for the
a,b-
BnO
BnO
BnO
unsaturated methacrolein (see entries 5–6 in Table 2). Moreover,
the PMB-protected ketone 2 delivered parallel results with model
aldehydes (see entries 7–10 in Table 2). Eventually, the anti config-
uration of the major diastereomer was confirmed through analysis
of the spectroscopic data for 5e8c and chemical correlation of aldol
8a.16
3 R': Bn
4 R': i-Bu
10 R': Bn
12 R': i-Bu
11 R': Bn
13 R': i-Bu
Entry Ketone R0
Aldehyde
R
dr
dr
Yieldb
(10:11)a (12:13)a (%)
1
2
3
4
5
6
3
3
3
4
4
4
Bn
Bn
Bn
i-Bu
i-Bu
i-Bu
a
e
f
a
e
f
i-Pr
Ph
85:15
88:12
92
96
78
93
94
85
Since structurally simple ketones 1 and 2 enable highly stereo-
controlled reactions, we were interested in gaining insight into the
H2C@C(CH3) 83:17
i-Pr
Ph
bias imparted by related
a-benzyloxy methyl ketones containing
85:15
75:25
81:19
more bulky chains. Therefore, we tried the aldol reaction of ke-
tones 3 and 412 (see Fig. 1) with some representative aldehydes.
The results are summarized in Table 3.
These results confirm that the titanium aldol chemistry opti-
mized for lactate-derived ketones can be safely expanded to other
H2C@C(CH3)
a
The diastereomeric ratio was established through NMR analysis of the reaction
mixture.
b
Isolated yield of the aldol mixture.

M. Pellicena et al. / Tetrahedron Letters 49 (2008) 5265–5267
5267
Org. Chem. 1999, 64, 8193; (c) Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc.
2000, 122, 8837; (d) Fürstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006,
128, 9194.
Acknowledgments
Financial support from the Spanish Ministerio de Ciencia y Tec-
nología and Fondos FEDER (Grant CTQ2006-13249/BQU), and the
Generalitat de Catalunya (2005SGR00584), as well as doctorate
studentship to J.G.S. (Universitat de Barcelona) are acknowledged.
9. (a) Evans, D. A.; Urpí, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem.
Soc. 1990, 112, 8215; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpí, F. J. Am.
Chem. Soc. 1991, 113, 1047.
10. Moreira, I. P. R.; Bofill, J. M.; Anglada, J. M.; Solsona, J. G.; Nebot, J.; Romea, P.;
Urpí, F. J. Am. Chem. Soc. 2008, 130, 3242.
11. (a) Solsona, J. G.; Romea, P.; Urpí, F.; Vilarrasa, J. Org. Lett. 2003, 5, 519; (b)
Solsona, J. G.; Romea, P.; Urpí, F. Tetrahedron Lett. 2004, 45, 5379; (c) Nebot, J.;
Figueras, S.; Romea, P.; Urpí, F.; Ji, Y. Tetrahedron 2006, 62, 11090; (d)
Rodríguez-Cisterna, V.; Villar, C.; Romea, P.; Urpí, F. J. Org. Chem. 2007, 72,
6631.
12. For the preparation of ketones 1–4, see: Ferreró, M.; Galobardes, M.; Martín, R.;
Montes, T.; Romea, P.; Rovira, R.; Urpí, F.; Vilarrasa, J. Synthesis 2000, 1608.
13. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (b) Yan,
T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60,
3301.
References and notes
1. (a) Braun, M. In Houben-Weyl. Methods of Organic Chemistry. Stereoselective
Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1995; Vol. E21b, p 1603; (b) Cowden, C. J.; Paterson, I. Org.
React. 1997, 51, 1; (c) Mahrwald, R. Chem. Rev. 1999, 99, 1095; (d) Alcaide, B.;
Almendros, P. Eur. J. Org. Chem. 2002, 1595; (e) Palomo, C.; Oiarbide, M.; García,
J. M. Chem. Soc. Rev. 2004, 33, 65; (f)Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004.
14. Typical experimental procedure: Freshly distilled Ti(i-PrO)4 (80
lL, 0.27 mmol)
2. (a) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237; (b) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506.
was added dropwise to a solution of TiCl4 (90 L, 0.82 mmol) in CH2Cl2 (1 mL)
l
at 0 °C under N2. The white mixture was stirred for 15 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) to a
solution of 1 (178 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
30 min at ꢁ78 °C. After the dropwise addition of the aldehyde (1.2 mmol),
stirring was continued for 30 min at ꢁ78 °C. The reaction was quenched by the
addition of saturated NH4Cl (5 mL), diluted with Et2O (80 mL) and washed with
H2O (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The combined
organic extracts were dried (MgSO4) and concentrated. The resulting oil was
analyzed by NMR and purified by flash chromatography (hexanes/EtOAc).
15. Unfortunately, the separation of aldol adducts by column chromatography
turns out to be painful and they are isolated as a mixture of diastereomers.
16. The configuration of aldol 8a was secured through conversion into (S) 5-
hydroxy-6-methyl-3-heptanone, see: Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C.
F., III. J. Am. Chem. Soc. 2001, 123, 5260.
3. The term acetate aldol reaction refers to any aldol transformation involving
unsubstituted enolates, which encompasses the reactions from acetate esters
or methyl ketones.
4. Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24.
5. In contrast to other aldol reactions that proceed through closed transition
states, both chair- and boatlike transition state models have been invoked to
rationalize the stereochemical outcome of such reactions. For theoretical
calculations on boron-mediated aldol reactions of ethyl and methyl ketones,
see: Bernardi, A.; Gennari, C.; Goodman, J. M.; Paterson, I. Tetrahedron:
Asymmetry 1995, 6, 2613.
6. For an insightful analysis of some key structural elements that control the
stereochemical outcome of boron-mediated acetate aldol reactions, see: Paton,
R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253.
7. For recent examples illustrating the complexity of acetate aldol reactions, see:
(a) Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int. Ed. 2007, 46,
6699; (b) Fürstner, A.; Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Porée, F.-H.;
Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46,
9265.
17. The single exception of this trend has been observed for the aldol reaction of 4
and benzaldehyde (see entry
5 in Table 3). The reasons of the low
diastereoselectivity (dr 75:25) obtained in this case are still unclear and
warrants further investigation on the structural issues that determine the
stereochemical outcome of such transformations.
8. For studies on stereoselective aldol reactions from a-hydroxy methyl ketones,
see: (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.;
Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540; (b) Palomo, C.; Oiarbide, M.;
Aizpurua, J. M.; González, A.; García, J. M.; Landa, C.; Odriozola, I.; Linden, A. J.