Stereoselective Titanium-mediated Aldol reactions of a chiral lactate-derived Ethyl Ketone with Ketones

Article abstract of DOI:10.1021/ol403461b

Aldol reactions of titanium enolates of lactate-derived ethyl ketone 1 with other ketones proceed in a very efficient and stereocontrolled manner provided that a further equivalent of TiCl₄ is added to the reacting mixture. The scope of these reactions encompasses simple ketones such as acetone or cyclohexanone as well as other ketones that contain potential chelating groups such as pyruvate esters or α- and β-hydroxy ketones.

Full text of DOI:10.1021/ol403461b

Letter
pubs.acs.org/OrgLett
Stereoselective Titanium-Mediated Aldol Reactions of a Chiral
Lactate-Derived Ethyl Ketone with Ketones
Sandra Alcoberro,† Alejandro Gomez-Palomino,† Ricard Sola,† Pedro Romea,*,† Felix Urpí,*,†
́
̀
̀
and Merce Font-Bardia‡
†Departament de Química Organ
̀
̀
ica and ‡Departament de Cristal·lografia, Mineralogia i Dipos
̀
its Minerals, Universitat de Barcelona,
08028 Barcelona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: Aldol reactions of titanium enolates of lactate-derived
ethyl ketone 1 with other ketones proceed in a very efficient and
stereocontrolled manner provided that a further equivalent of TiCl4 is
added to the reacting mixture. The scope of these reactions
encompasses simple ketones such as acetone or cyclohexanone as
well as other ketones that contain potential chelating groups such as
pyruvate esters or α- and β-hydroxy ketones.
he breathtaking accomplishments on the asymmetric aldol
titanium(IV) Lewis acid provides highly stereoselective aldol
additions to aldehydes.13 Specifically, the use of 2 equiv of
TiCl4 has proven to be crucial for attaining notable levels of
stereocontrol in aldol reactions from methyl,14 ethyl,15 and
even isopropyl chiral ketones.16 Herein, we describe the
successful application of these ideas to the substrate-controlled
aldol reactions of lactate-derived ethyl ketone 117 (Table 1)
with other ketones, which now provides new access to the
stereoselective synthesis of aldol adducts possessing two
contiguous tertiary and quaternary stereocenters.
Preliminary experiments showed that the reaction of the
titanium enolates of 1 with acetone (2a) did not occur at low
temperatures. Higher temperatures and 2 equiv of TiCl4 were
required to obtain diastereoselectively (dr 95:5) the aldol
adduct 3a with a 35% yield (compare entries 1−4 in Table 1).
Longer reaction times increased the yield without eroding the
diastereoselectivity, and 75% of adduct 3a was finally isolated
after 15 h at −20 °C (entry 5 in Table 1). Cyclohexanone (2b)
produced similar results (entry 6 in Table 1), but unfortunately,
acetophenone (2c) and 3-methyl-2-butanone (2d) possessing
different R1 and R2 groups afforded the corresponding adducts
3c and 3d as an equimolar mixture of two diastereomers in
moderate yields (entries 7 and 8 in Table 1). These results
proved the feasibility of our approach but also highlighted the
daunting challenge of aldol additions to nonactivated ketones.
We therefore paid special attention to pyruvate esters, which
are often chosen as model substrates because the ester group
enhances the electrophilicity of the ketone and the structural
differences between the carboxylate and the methyl groups
facilitate the π-facial discrimination of the carbonyl bond.
Needless to say, they can also form rigid and highly activated
complexes with bidentate Lewis acids that are ideally suited for
diastereoselective reactions with nucleophiles.
T
addition to aldehydes reported over the last decades have
placed the aldol reaction among the most important trans-
formations in organic synthesis.1 In contrast, parallel additions
to ketones are much less common.2 Ironically, a milestone in
organic synthesis such as the proline-catalyzed Eder−Sauer−
Wiechert−Hajos−Parrish reaction3 involves an intramolecular
aldol addition to a ketone, but apart from this case,4
stereoselective and intermolecular aldol reactions in which a
ketone acts as the electrophilic partner are hitherto scarce. The
reasons for this lack of a synthetic methodology are
thermodynamic and structural; especially important in
hindering the development of such processes are the attenuated
reactivity of ketones and the similarity of the two groups
flanking the carbonyl bond compared to aldehydes.5,6 Thus, it
is not surprising that most of the approaches reported up to
now deal with asymmetric acetate aldol additions (R = H, in
Scheme 1) to α-keto esters and other activated ketones.7,8
Scheme 1. Aldol Additions to Ketones
Despite these achievements, the simultaneous installation of a
tertiary and a quaternary stereocenter associated with the
propionate counterparts (R = CH3, in Scheme 1) still remains
elusive,9 and the few procedures reported so far are only
suitable for a very small group of ketones.7a,10,11
Considering that stereocontrol of these reactions may be
achieved by using reactive and well-ordered intermediates, we
envisaged that titanium enolates from chiral α-hydroxy ketones
might permit such challenging transformations.12 Indeed,
previous reports from our laboratory have established that an
appropriate choice of the hydroxyl protecting group and the
Received: November 29, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403461b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Titanium-Mediated Aldol Additions of Lactate-Derived Ethyl Ketone 1 to Nonactivated Ketones 2
a
b
entry
TiCl4 equiv (n)
ketone
R1
R2
Treac (°C)
timereac (h)
aldol
dr
yield (%)
1
2
3
4
5
6
7
8
1.1
2.2
1.1
2.2
2.2
2.2
2.2
2.2
2a
2a
2a
2a
2a
2b
2c
2d
Me
Me
Me
Me
Me
Me
−78
−78
−20
−20
−20
−20
−20
−20
3
3
3a
3a
3a
3a
3a
3b
3c
3d
Me
Me
3
nd
<5
35
75
75
50
39
Me
3
95:5
Me
15
15
72
72
95:5
(CH2)5
Me
95:5
c
c
Ph
50:50
Me
i-Pr
50:50
a
b
c
Established by 1H NMR analysis. Overall isolated yield. Only two of up to four diastereomers are observed in the reaction mixture by 1H NMR
analysis.
Table 2. Titanium-Mediated Aldol Additions of Lactate-Derived Ethyl Ketone 1 to α-Keto Esters 4
a
b
entry
α-keto ester
R1
Et
R2
TiCl4 (n equiv)
Treac (°C)
aldol
dr
yield (%)
1
4a
4a
4a
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Me
Me
−78
−20
−78
−20
−20
−20
−20
−20
−20
−20
−20
−20
−78
5a
5a
5a
5a
5b
5c
5d
5e
5f
83:17
82:18
97:3
97:3
97:3
97:3
98:2
98:2
98:2
98:2
98:2
85:15
85:15
(46)
(87)
88
2
Et
3
Et
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
4
Et
87
5
Me
Bn
i-Pr
t-Bu
Et
91
6
84
7
84
8
79
9
PhCH2CH2
i-Bu
91
10
11
12
13
4g
4h
4i
Et
5g
5h
5i
86
Et
PhCH2
i-Pr
68
Et
68 (80)
c
4i
Et
i-Pr
5i
52 (62)
a
b
c
Established by 1H NMR and HPLC analysis. Isolated yield of diastereomer 5. Overall yield is shown in parentheses. 30% of ketone 1 is recovered.
Since previous tests had shown the crucial role of Lewis acid,
Table 2). However, the diastereoselectivity was sensitive to the
steric hindrance of the R2 group. Ethyl esters 4f and 4g without
bulky substituents (R2 = PhCH2CH2 and i-Bu, respectively)
gave a single diastereomer (dr 98:2) in excellent yields (entries
9 and 10 in Table 2), as did the easily enolizable α-keto ester 4h
(R2 = PhCH2), which furnished aldol 5h with a 68% yield
(entry 11 in Table 2). In contrast, sterically hindered ethyl 3-
methyl-2-oxobutanoate (4i, R2 = i-Pr) produced an 85:15
mixture of two diastereomers at both −20 and −78 °C with a
moderate-to-good overall yield (entries 12 and 13 in Table 2).
The configuration of the aldols 5 was firmly established by X-
ray diffraction of lactone 6,19 prepared from 5a by removing the
benzyl protecting group followed by lactonization of the
resultant hydroxy ester (Scheme 2).20
Aiming to expand the scope of the process, we next evaluated
the reactivity of protected α- and β-hydroxy methyl ketones
7.21 As for α-keto esters, the outcome of the reactions of alkoxy
ketones 7a−c turned out to be closely related to the amount of
Lewis acid used in the process. Indeed, preliminary studies
showed that the yield steadily increased when a further
equivalent of TiCl4 was added to the reaction mixture
(compare entries 1−6 in Table 3). This was particularly
remarkable for β-benzyloxy ketone 7c, which emphasizes the
we initially assessed the influence of the equivalents of TiCl4
and the temperature on the aldol addition of 1 to ethyl pyruvate
(4a). We were pleased to observe that the reaction proceeded
at −78 °C without requiring a supplementary amount of Lewis
acid, albeit with a moderate yield and moderate diastereose-
lectivity (46% and dr 83:17, entry 1 in Table 2). Interestingly,
the yield was enhanced by performing the reaction at −20 °C
without adverse effect on the diastereoselectivity (87% and dr
82:18, entry 2 in Table 2). Following thorough optimization, it
was finally established that the addition of a further equivalent
of TiCl4 to the reaction mixture produced aldol 5a in high
yields with complete stereocontrol (dr 97:3) both at −78 and
−20 °C (entries 3 and 4 in Table 2); this suggested that the
success with these reactions required the addition of this
second equivalent of TiCl4. Encouraged by these findings, we
decided to assess the scope of this reaction in the substitution
pattern on the α-keto ester backbone.
To that end, we applied the optimized conditions to a range
of α-keto esters (4 in Table 2).18 Aldol additions to pyruvate
esters 4a−e (R2 = Me) produced all the adducts 5a−e in
diastereomeric ratios up to 98:2 with a 80−90% yield
irrespective of the steric bulk of the R1 group (entries 4−8 in
B
dx.doi.org/10.1021/ol403461b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketones such as acetone or cyclohexanone as well as α-keto
esters and α- or β-hydroxy ketones. This highlights the crucial
role of chelating groups in π-facial discrimination of the
carbonyl bond.
Scheme 2. Configuration of Aldols 5
ASSOCIATED CONTENT
* Supporting Information
■
S
Physical and spectroscopic data for aldol adducts 3a,b, 5a−i,
and 8a−d and proof of the stereochemistry of 5a and 8c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
Table 3. Titanium-Mediated Aldol Additions of 1 to α- and
β-Hydroxy Methyl Ketones 7
*E-mail: pedro.romea@ub.edu.
*E-mail: felix.urpi@ub.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
Competitividad (Grant No. CTQ2012-31034) and the
Generalitat de Catalunya (2009SGR825) is acknowledged.
■
́
a
b
entry ketone
R
aldol TiCl4 (n equiv)
dr
yield (%)
1
2
3
4
5
6
7
8
9
7a
7a
7b
7b
7c
7c
7d
7e
7f
OMe
8a
90:10
95:5
44
OMe
8a
8b
8b
8c
8c
8d
8e
8f
1.1
1.1
63
DEDICATION
Dedicated to the memory of Francisco San
■
OBn
97:3
60
́
chez Baeza.
OBn
97:3
88
CH2OBn
CH2OBn
OTBS
OTBDPS
55:45
92:8
(8)
(80)
77
REFERENCES
1.1
1.1
1.1
1.1
■
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73:27
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1
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C
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cyclization reaction.
D
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