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

Article abstract of DOI:10.1016/j.tetlet.2009.12.046

Good levels of 1,4-syn asymmetric induction are obtained in the TiCl₄-mediated aldol reaction of methyl α-silyloxy 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 syntheses of natural products.

Full text of DOI:10.1016/j.tetlet.2009.12.046

Tetrahedron Letters 51 (2010) 942–945
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,4-syn-Asymmetric induction in the titanium-mediated aldol reactions
of chiral methyl
a-silyloxy ketones
*
*
Adriana Lorente, Miquel Pellicena, 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-syn asymmetric induction are obtained in the TiCl4-mediated aldol reaction of methyl
Received 4 November 2009
Revised 4 December 2009
Accepted 9 December 2009
Available online 13 December 2009
a
-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the sub-
strate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural
products.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective reactions
Acetate aldol reactions
Titanium enolates
Chiral ketones
In spite of the large number of highly stereoselective aldol
methodologies1 developed during the last decades and their suc-
cessful application to the synthesis of natural products,2 the acetate
aldol reaction3 is still a matter of concern.1,4 Indeed, the lack of
mechanistic models to understand the stereochemical outcome
of these reactions5,6 makes it difficult to use them for coupling
large fragments in advanced steps of a synthesis.7 Particularly, it
is remarkable to note the scarce number of studies on aldol reac-
liminary experiments with mild (i-PrO)2TiCl2 and (i-PrO)TiCl3
Lewis acids furnished low yields of the desired 1,4-syn aldol 4a. In-
deed, the experimental conditions optimized for related ethyl ke-
tones13c afforded aldol 7 as the major component of the reaction
mixtures (see entries 1 and 2 in Table 1). Such unexpected results
suggest that the enolization step is slow enough to allow the
resulting enolate to attack the activated ketone and deliver the
self-condensation adduct 7. Even the stronger TiCl4 produced a sig-
nificant amount of this adduct at À78 °C (see entry 3 in Table 1).
Lowering the enolization temperature to À94 °C increased the
overall yield (71%) of aldols 4 and 5 (1,4-syn and 1,4-anti,
respectively) and minimized the formation of 7 (see entry 4 in
Table 1).15 However, it was then clear that tiny amounts of
hemiacetal 6a were also formed during the aldol reaction and
could be isolated after chromatographic purification as a single
diastereomer. Hence, assuming that 6a arises from 4a, the
tions from protected
we established that the titanium-mediated aldol reactions of chiral
a
-hydroxy methyl ketones.8,9 In this context,
a
-benzyloxy methyl ketones provide the corresponding 1,4-anti
adducts in good yields and diastereomeric ratios.10 More recently,
Kalesse and co-workers reported that the enol borinates and the
alkaline enolates from related
a-silyloxy ketones show the same
1,4-anti asymmetric induction.11,12 Thus, considering the impor-
tance of this transformation and taking advantage of our experi-
ence with chiral ethyl
a
-hydroxy ketones,13 we envisaged that
the appropriate choice of the titanium(IV) Lewis acid and the
hydroxyl protecting group might give access to 1,4-syn-selective
aldol reactions. Herein, we document that a-tert-butyldimethylsi-
O
O
OH
1) (i-PrO)TiCl3, i-Pr2NEt
2) RCHO
R1
R1
1
Ref. 10
R
4
lyloxy methyl ketones 1–3 represented in Scheme 1 impart such
asymmetric induction, which can be useful to design more flexible
syntheses of structurally complex natural products.
At first, we surveyed the influence of the titanium Lewis acid on
the stereochemical outcome of the aldol reactions from lactate-
derived ketone 114 and isobutyraldehyde (a). Disappointingly, pre-
BnO
BnO
1,4-anti aldol
OH
O
O
1) TiL4, i-Pr2NEt
2) RCHO
R1
R1
TBSO
1,4-syn aldol
1
This study
4
R
TBSO
1 R1: Me 2 R1: Bn 3 R1: i-Pr
* Corresponding authors. Tel.: +34 934039106; fax: +34 933397878 (P.R.); tel.:
+34 934021247; fax: +34 933397878 (F.U.).
Scheme 1. Asymmetric induction in titanium-mediated aldol reactions from chiral
a-hydroxy methyl ketones.
E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.046

A. Lorente et al. / Tetrahedron Letters 51 (2010) 942–945
943
Table 1
Influence of the titanium Lewis acid on the aldol reaction of ketone 1 with isobutyraldehyde (a)
O
OH
O
OH
O
O
O
O
OH
a, b
HO
+
+
+
TBSO
4a (1,4-syn)
TBSO
5a (1,4-anti)
TBSO
TBSO
OTBS
TBSO
1
6a
7
a) 1.1 eq TiL4, 1.1 eq i-Pr2NEt, CH2Cl2, Tenol, 30 min. b) 1.5 eq i-PrCHO (a), –78 °C, 30 min
Entry
TiL4
Tenol (°C)
Yield 7a (%)
Yield 6aa (%)
Yield 4a and 5aa (%)
dr (4a+6a:5a)b
1
2
3
4
(i-PrO)2TiCl2
(i-PrO)TiCl3
TiCl4
À78
À78
À78
À94
68
29
15
—
—
5
27
65
71
75:25
76:24
74:26
77:23
ndc
ndc
5
TiCl4
a
b
c
Isolated yield.
Determined by 1H NMR analysis on isolated products.
Not determined.
diastereoselectivity on the formation of 4a was established as dr
77:23 (see entry 4 in Table 1).
tive aldehydes as isobutyraldehyde (a), benzaldehyde (f), and
methacrolein (g). The results are summarized in Table 3. Impor-
tantly, the potential hemiacetal from isobutyraldehyde was never
observed and aldols 8–11 were isolated in excellent yields. On
the other hand, the diastereoselectivity of these reactions turned
out to be highly sensitive to the steric hindrance of the R1 chain
in such a way that the most bulky group produced the best
diastereomeric ratios. Actually, aldol reactions from lactate- and
phenylalanine-derived ketones (1 and 2, respectively) with isobu-
tyraldehyde and methacrolein afford the same diastereoselectivi-
ties (compare entries 1 and 7 in Table 2 with entries 1 and 3 in
Table 3), while the more bulky valine-derived ketone 3 produced
a significant improvement on the corresponding diastereomeric ra-
tios (see entries 4 and 6 in Table 3). In turn, benzaldehyde shows a
closer dependence on the R1 group and its diastereomeric ratios in-
crease steadily from 1 to 3 (compare entry 6 in Table 2 with entries
2 and 5 in Table 3).
This optimized experimental procedure16 was next applied to
other aliphatic, aromatic, and
a,b-unsaturated aldehydes. The re-
sults summarized in Table 2 prove that the TiCl4-mediated aldol
reactions of lactate-derived ketone 1 with aliphatic aldehydes
a–e are fairly diastereoselective. Indeed, the desired 1,4-syn aldols
4 were isolated in good yields and diastereomeric ratios were
close to 80:20 irrespective of the steric hindrance and the pres-
ence of other functional groups on the aldehyde (see entries 1–
5 in Table 2). Interestingly, significant amounts of hemiacetals
6b and 6c from isovaleraldehyde and butanal (b and c, respec-
tively, see entries 2 and 3 in Table 2) were isolated after chro-
matographic purification, but the corresponding hemiacetals
from related aldehydes d and e were never observed (see entries
4 and 5 in Table 2). Conjugated aldehydes did not form such kind
of hemiacetals either (see entries 6 and 7 in Table 2). Unfortu-
nately, the diastereoselectivity for these aldehydes was rather
poor, being particularly low with benzaldehyde (dr 55:45, see en-
try 6 in Table 2).
The 1,4-syn asymmetric induction provided by these ketones
was initially proved by conversion of aldol 4a into (R)-3-hydro-
xy-4-methylpentanoic acid (see Eq. 1 in Scheme 2). Later, the same
strategy was applied to aldols 10a and 10f obtained from the aldol
reactions of ketone 3 with isobutyraldehyde (a) and benzaldehyde
(f), respectively (see Eq. 2 in Scheme 2).
Having established the feasibility of this substrate-controlled
methodology on lactate-derived ketone 1, we were interested in
gaining insight into the bias imparted by other a-silyloxy ketones
containing more bulky chains. Hence, we studied the aldol reaction
The asymmetric induction imparted by the titanium enolates of
of methyl ketones 2 and 314 (see Scheme 1) with some representa-
the
a
-tert-butyldimethylsilyloxy methyl ketones 1–3 can be
Table 2
Titanium-mediated aldol reaction from lactate-derived ketone 1
R
O
OH
O
OH
O
O
O
a, b
HO
+
+
R
R
R
TBSO
4 (1,4-syn)
TBSO
5 (1,4-anti)
TBSO
TBSO
1
6
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.5 eq RCHO, –78 °C, 30 min
Entry
Aldehyde
R
Yield 6a (%)
Yield 4 and 5a (%)
dr (4+6:5)
1
2
3
4
5
6
7
a
b
c
d
e
f
i-Pr
i-Bu
Pr
CH2CH2OTIPS
CH2CH2NPhth
Ph
5
19
18
—
—
—
71
63
65
72
68
75
80
77:23b
76:24b
76:24b
77:23c
80:20c
55:45c
65:35c
g
C(CH3)@CH2
—
a
b
c
Overall isolated yield.
Determined by 1H NMR analysis on isolated products.
Determined by 1H NMR analysis of the reaction mixture.

944
A. Lorente et al. / Tetrahedron Letters 51 (2010) 942–945
Table 3
Titanium-mediated aldol reactions from ketones 2 and 3
O
OH
O
OH
O
a, b
R1
R1
R1
+
R
R
TBSO
TBSO
TBSO
2 R1: Bn
8 R1: Bn
10 R1: i-Pr
1,4-syn
9 R1: Bn
11 R1: i-Pr
1,4-anti
3 R1: i-Pr
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.5 eq RCHO, –78 °C, 30 min
Entry
Ketone
R1
Aldehyde
R
dr (8:9)a
dr (10:11)a
Yieldb (%)
1
2
3
4
5
6
2
2
2
3
3
3
Bn
Bn
Bn
i-Pr
i-Pr
i-Pr
a
f
g
a
f
i-Pr
Ph
C(CH3)@CH2
i-Pr
Ph
77:23
75:25
68:32
95
94
93
85
84
83
96:4
83:17
90:10
g
C(CH3)@CH2
a
Determined by 1H NMR analysis of the reaction mixture.
Overall isolated yield of aldols 8–9 or 10–11.
b
reocenter pointing toward the inside of the ring (compare transi-
tion states I and II in Scheme 3). We are aware that other boat-
like transition states (as III and IV in Scheme 3) might also be sug-
gested to explain the stereochemical outcome of such acetate aldol
reactions. However, transition state IV leading to 1,4-syn diastereo-
mers should be particularly irrelevant for the most hindered ke-
tone 3. Hence, these boat-like transition states probably do not
play a significant role in the titanium-mediated aldol reactions of
O
OH
O
OH
a, b
(1)
(2)
HO
TBSO
4a
12a (54% ee) [α]D +18.1 (c 1.0, CHCl3)
Palomo8c
[α]D +41.7 (c 1.0, CHCl3)
O
OH
O
OH
a, b
the aforementioned
In summary, the substrate-controlled titanium-mediated aldol
reactions from chiral -tert-butyldimethylsilyloxy methyl ketones
with aliphatic, aromatic, and ,b-unsaturated aldehydes furnish
a
-silyloxy ketones 1–3.17
R
HO
R
TBSO
10a R: i-Pr
10f R: Ph
12a (92% ee) [α]D +33.9 (c 0.9, CHCl3)
12f (66% ee) [α]D +10.7 (c 1.2, EtOH)
a
a
Palomo8c
[α]D +15.5 (c 0.9, EtOH)
the corresponding 1,4-syn aldols in high yields. Remarkably, the
diastereoselectivity is very sensitive to the steric hindrance of the
starting ketone, particularly important being the stereochemical
control achieved with the valine-derived ketone 3. In any case,
these results complement the 1,4-anti asymmetric induction ob-
a) HF, CH3CN, rt. b) NaIO4, CH3OH/H2O 2:1, rt
Scheme 2. Proof of the 1,4-syn asymmetric induction.
served for related a
-benzyloxy methyl ketones10 and can be help-
rationalized invoking the six-membered chair-like transition state
I represented in Scheme 3. In such scenario, the antiperiplanar dis-
tribution of both TBSO–C and C–OTi bonds would act as the key
element that determines the configuration of the major 1,4-syn
diastereomer since the preferred transition state places the less
ful to design more efficient syntheses of natural products.
Acknowledgments
Financial support from the Spanish Ministerio de Educación y
Ciencia and Fondos FEDER (Grant CTQ2006-13249/BQU and Grant
CTQ2009-09692/BQU), and the Generalitat de Catalunya (2005
SGR00584 and 2009SGR825), as well as doctorate studentship to
M. P. (Ministerio de Educación y Ciencia) is acknowledged.
sterically demanding substituent (H vs Me, Bn, i-Pr) of the
a-ste-
H
R
H
O
TBSO
TBSO
R1
R
O
TiLn
TiLn
References and notes
O
O
R1
II
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, pp 1603–1666; (b) Cowden, C. J.; Paterson,
I. Org. React. 1997, 51, 1–200; (c) Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120;
(d) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595–1601; (e) Palomo, C.;
Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2004, 33, 65–75; (f)Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004.
2. (a) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237–4313; (b) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506–7525; (c) Brodmann, T.;
Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Synlett 2009, 174–192.
3. The term acetate aldol reaction refers to any aldol transformation involving
unsubstituted enolates, which encompasses the reactions from acetate esters
or methyl ketones.
I
favored
O
OH
4
O
OH
R1
R
1
R
1
R1
4
TBSO
TBSO
1,4-syn
1,4-anti
H
H
R
R
TBSO
TBSO
O
Ln
O
4. Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24–37.
O
TiLn
Ti
III
O
R1
R1
5. In contrast to other aldol reactions that proceed through closed transition
states, both chair- and boat-like 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, 2613–2636.
IV
Scheme 3. Transition states for acetate aldol reactions from chiral
methylsilyloxy methyl ketones.
a
-tert-butyldi-

A. Lorente et al. / Tetrahedron Letters 51 (2010) 942–945
6. For an insightful analysis of some key structural elements that control the 12. The Mukaiyama aldol reaction of the leucine-derived methyl
945
a
-OTES ketone
stereochemical outcome of boron-mediated acetate aldol reactions, see: Paton,
R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253–1263.
with isobutyraldehyde affords the corresponding syn aldol as
diastereomer (dr syn/anti 98:2) but in low yield (36%).
a single
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,
6699–6702; (b) Fürstner, A.; Bouchez, L. C.; Morency, L.; Funel, J.-A.; Liepins, V.;
Porée, F.-H.; Gilmour, R.; Laurich, D.; Beaufils, F.; Tamiya, M. Chem. Eur. J. 2009,
15, 3983–4010.
13. (a) Solsona, J. G.; Romea, P.; Urpí, F.; Vilarrasa, J. Org. Lett. 2003, 5, 519–522; (b)
Solsona, J. G.; Romea, P.; Urpí, F. Tetrahedron Lett. 2004, 45, 5379–5382; (c)
Nebot, J.; Figueras, S.; Romea, P.; Urpí, F.; Ji, Y. Tetrahedron 2006, 62, 11090–
11099; (d) Nebot, J.; Romea, P.; Urpí, F. J. Org. Chem. 2009, 74, 7518–7521.
14. For the synthesis of ketones 1–3, see: Ferreró, M.; Galobardes, M.; Martín, R.;
Montes, T.; Romea, P.; Rovira, R.; Urpí, F.; Vilarrasa, J. Synthesis 2000, 1608–1614.
15. The aldol reaction was also carried out at À94 °C. However, it turned out to be
too sluggish and required longer reaction times.
8. For studies on stereoselective aldol reactions from chiral
a-hydroxy methyl
ketones, see: (a) Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 3982–3983; (b)
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540–7552; (c) Palomo, C.; Oiarbide, M.;
Aizpurua, J. M.; González, A.; García, J. M.; Landa, C.; Odriozola, I.; Linden, A. J.
Org. Chem. 1999, 64, 8193–8200; (d) Denmark, S. E.; Stavenger, R. A. J. Am.
Chem. Soc. 2000, 122, 8837–8847; (e) Fürstner, A.; Kattnig, E.; Lepage, O. J. Am.
Chem. Soc. 2006, 128, 9194–9204.
16. Typical procedure: TiCl4 (120
methyl ketone 1 (202 mg, 1 mmol) in CH2Cl2 (5 mL) at À94 °C under N2,
followed by i-Pr2NEt (190 L, 1.1 mmol). The resulting dark red solution was
lL, 1.1 mmol) was added dropwise to a solution of
l
stirred for 30 min at À94 °C. After dropwise addition of the aldehyde
(1.5 mmol), stirring was continued for 30 min at À78 °C. The reaction was
quenched by the addition of saturated NH4Cl (5 mL), diluted with Et2O (50 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).
9. For studies on stereoselective aldol reactions from chiral a,b-dihydroxy methyl
ketones, see Ref. 7b and: (a) Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J.
J. Chem. Soc., Perkin Trans. 1 1999, 1163–1166; (b) Paterson, I.; Chen, D. Y.-K.;
Coster, M. J.; Aceña, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.;
Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross, R. D. Angew. Chem., Int.
Ed. 2001, 40, 4055–4060; (c) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.;
Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661–5663; (d) Deng, L.;
Ma, Z.; Zhao, G. Synlett 2008, 728–732; (e) Lu, L.; Zhang, W.; Carter, R. G. J. Am.
Chem. Soc. 2008, 130, 7253–7255.
17. At this point, it is worth mentioning that the boron-mediated aldol reactions
from mandelic-derived tert-butyldimethylsilyloxy methyl ketone provided a
roughly equimolar mixture of two diastereomeric aldol adducts, which was
assumed to be due to the competition between two boat-like transition states,
see: Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc. 1986,
108, 8279–8281. Therefore, it is clear the crucial role of the metal on the
transition states and the stereochemical outcome of such reactions.
10. Pellicena, M.; Solsona, J. G.; Romea, P.; Urpí, F. Tetrahedron Lett. 2008, 49, 5265–
5267.
11. Lorenz, M.; Bluhm, N.; Kalesse, M. Synthesis 2009, 3061–3066.