Highly enantioselective synthesis of α-diazo-β-hydroxy esters using a bifunctional titanium complex

Article abstract of DOI:10.1055/s-0029-1217322

A bifunctional titanium catalyst system has been developed for the asymmetric direct-type aldol reaction of ethyl diazoacetate with aldehydes, which produced the desired products in good yields (up to 83%) with excellent enantioselectivities (up to 94% ee

Full text of DOI:10.1055/s-0029-1217322

CLUSTER
1655
Highly Enantioselective Synthesis of a-Diazo-b-hydroxy Esters Using a
Bifunctional Titanium Complex
S
a
ynthesis of
a
-Diazo-
b
-h
e
ydroxy Es
n
ters tao Wang,a Ke Shen,a Xiaolei Hu,a Jun Wang,a Xiaohua Liu,a Xiaoming Feng*a,b
b
Received 18 November 2008
diazo-b-hydroxy carbonyl compounds is highly desirable.
Herein, we wish to report a highly enantioselective direct-
type aldol reaction of ethyl diazoacetate with aldehydes
catalyzed by a bifunctional titanium complex readily pre-
Abstract: A bifunctional titanium catalyst system has been devel-
oped for the asymmetric direct-type aldol reaction of ethyl diazo-
acetate with aldehydes, which produced the desired products in
good yields (up to 83%) with excellent enantioselectivities (up to
94% ee). A wide range of aromatic, heteroaromatic and aliphatic al- pared from (S)-BINOL, cinchonine, Ti(Oi-Pr)4, and H2O
dehydes were found to be suitable substrates in the presence of (S)-
BINOL (5 mol%), cinchonine (5 mol%), Ti(Oi-Pr)4 (5 mol%) and
under mild conditions.
H2O (15 mol%). On the basis of the experimental results and previ-
ous reports, a possible working model has been proposed to explain
the origin of the activation and asymmetric induction.
1a: R1 = R2 = H
R2
R1
1b: R1 = Me, R2 = H
1c: R1 = I, R2 = H
1d: R1 = CH2OH, R2 = H
1e: R1 = Ph, R2 = H
1f: R1 = P(O)Ph2, R2 = H
1g: R1 = H, R2 = Br
1h: R1 = H, R2 = I
OH
OH
Key words: asymmetric catalysis, combinational chemistry, titani-
um, aldol reaction, diazo esters
R2
R1
The aldol reaction is currently considered as one of the
most powerful and efficient methods for carbon–carbon
bond formation, and hence, much effort has been devoted
to the development of catalytic asymmetric aldol reac-
tion.1 However, most of these methods depend on the con-
densation of silyl enol ethers with carbonyl compounds
(Mukaiyama aldol reaction) using stoichiometric amounts
of bases and silicon sources. Therefore, development of
direct-type catalytic asymmetric aldol reaction has been
recently attracting much attention.2 In such cases, a-
diazo-b-hydroxy esters are valuable precursors for the
synthesis of amino acids and alcohols.3 Moreover, the car-
bene species generated from a-diazo carbonyl compounds
can undergo diverse transformations, including cyclopro-
panation, X–H (X = C, N, O, S, etc.) insertion, ylide for-
mation, and 1,2-migration.4 Accordingly, their facile
preparation using the direct-type aldol reaction of a-diazo
esters with aldehydes have been widely investigated.5 A
further extension of this chemistry is the catalytic asym-
metric version.6 In 2003, the Wang group achieved the
first example of catalytic asymmetric direct-type aldol re-
action of aldehydes with ethyl diazoacetate and obtained
high enantioselectivities (up to 87% ee).6a Subsequently,
a similar level of enantioselectivity (up to 81% ee) was
carried out by Arai and co-workers in the condensation of
aldehydes with tert-butyl diazoacetate using a phase-
transfer catalyst.6b,c Therefore, the development of a more
efficient catalyst for the enantioselective synthesis of a-
H
N
N
HO
HO
H
R
R
N
N
2a: R = H
2b: R = OMe
2c: R = H
2d: R = OMe
Figure 1 Ligands screened in this study
In our work directed toward the development of efficient
bifunctional titanium catalyst based on cinchona alkaloids
in asymmetric synthesis,7 we initially tested the reaction
of ethyl diazoacetate with benzaldehyde in THF at 0 °C in
the presence of 5 mol% cinchonine 2a–Ti(Oi-Pr)4 com-
plex. The reaction proceeded sluggishly to give the de-
sired product in only 17% yield and 23% ee after 3 days
(Table 1, entry 1). The combination of several chiral
ligand components into a highly efficient catalyst have
been achieved in various catalytic asymmetric process-
es.7–9 Enlightened by the concept, (S)-BINOL (1a)10 was
introduced in the reaction system. Gratifyingly, when 1a
was combined with 2a–Ti(Oi-Pr)4 complex, the reaction
proceeded smoothly to give the desired product in 47%
yield with 78% ee after 3 days at 0 °C (Table 1, entry 2).
Encouraged by the initial results, other experimental pa-
rameters were assessed (see Supporting Information), to
our delight, when 15 mol% H2O was surveyed as the ad-
ditive, the enantioselectivity could be indeed increased to
92% ee with 46% yield (Table 1, entry 3). This result in-
dicated that H2O11 may be able to coordinate to the metal
SYNLETT 2009, No. 10, pp 1655–1658
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217322; Art ID: Y01508ST
© Georg Thieme Verlag Stuttgart · New York

1656
W. Wang et al.
CLUSTER
center, forming a favorable chiral geometry around the ac- Interestingly, these products were obtained in R-form with
tive center, which led to an increase of enantioselectivity. a changeover in absolute stereochemistry. It suggested
that the environment of asymmetric induction was quite
distinct from the complex of 1a, 2a, and Ti(Oi-Pr)4. On
Further BINOL derivatives (Figure 1) were screened with
the results summarized in Table 1. Diminished yields and
the other hand, evaluating other chiral 6,6¢-substituents
enantioselectivities were observed from the use of (S)-
BINOL derivatives did not provide a significant improve-
BINOL derivatives that possess large substituents at the
3,3¢-positions (Table 1, entries 4–8).
ment in yield and enantioselectivity (Table 1, entries 9
and 10). Also, when other cinchona alkaloids were com-
bined with 1a–Ti(Oi-Pr)4 complex, the reaction was cata-
lyzed, with similar yields, but the ee values were not
improved (Table 1, entries 11–13). When replacing (S)-
BINOL with (R)-BINOL, lower ee value was obtained
with a turnover of enantioselectivity (Table 1, entry 14). It
might be that (S)-BINOL possessed a better conformation
to match cinchonine than (R)-BINOL. These results indi-
cated that the rational assembling the component ligands
with metal ions to generate highly efficient chiral catalysts
was crucial for high reactivity and enantioselectivity of
this reaction. In further studies, the catalyst loading was
also examined, however, the results were not satisfactory
(Table 1, entries 15 and 16). Cooling the reaction temper-
ature to –20 °C slightly improved the ee value of 5a with
lower yield (Table 1, entry 17) and performing the reac-
tion at 25 °C afforded 55% yield with merely 74% ee
(Table 1, entry 18). The low isolated yield could be over-
come to some extent by prolonging the reaction time, and
the enantioselectivity was remained (Table 1, entry 19 vs.
3). Hence, the optimal reaction conditions were selected
as: 5 mol% catalyst (1a/2a/Ti(Oi-Pr)4 = 1:1:1), 15 mol%
H2O, 0.15 mmol benzaldehyde, 0.45 mmol ethyl diazo-
acetate in 0.5 mL THF for six days at 0 °C.
Table 1 Catalytic Asymmetric Addition of Ethyl Diazoacetate to
Benzaldehyde under Indicated Conditions
OH
O
O
catalyst (5 mol%)
0 °C, THF
PhCHO
+
Ph
OEt
OEt
N2
N2
3a
4
5a
Entrya Ti(Oi-Pr)4 1a–h
2a–d
(mol%) (d)
Time Yield ee
(mol%) (mol%)
(%)b (%)c
1d
2d
3
5
5
none
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2b (5)
2c (5)
2d (5)
3
3
3.5
3
5
3
3
3
3
3
3
3
3
3
3
5
3
3
6
17
47
46
27
27
16
13
9
23 (S)
1a (5)
1a (5)
1b (5)
1c (5)
1d (5)
1e (5)
1f (5)
1g (5)
1h (5)
1a (5)
1a (5)
1a (5)
78 (S)
92 (S)
15 (R)
57 (R)
18 (R)
8 (R)
5
4
5
5
5
6
5
7
5
8
5
20 (R)
80 (S)
72 (S)
85 (S)
46 (S)
40 (S)
37 (R)
87 (S)
89 (S)
94 (S)
74 (S)
91 (S)
9
5
42
45
45
33
40
38
42
36
14
55
62
10
5
Under the optimal reaction conditions, a wide range of ar-
omatic, aliphatic, and heteroaromatic aldehydes reacted
with 4 to afford the corresponding aldol adducts in good
yields with excellent enantioselectivities, the results were
listed in Table 2. Halogen-substituted benzaldehydes
gave similar results compared with benzaldehyde
(Table 2, entries 2–8). Among them, 2-chlorobenzalde-
hyde gave the best enantioselectivity (up to 94% ee;
Table 2, entry 3). Besides, aromatic aldehydes with an
electron-donating group gave the corresponding product
in lower yields with high enantioselectivities (up to 93%
ee; Table 2, entries 9–12). Introducing a strong electron-
withdrawing group (CN, CF3, NO2) on the para or meta
position of benzaldehyde provided relatively low enantio-
selectivities with moderate yields (Table 2, entries 13–
15). For the heteroaromatic and aliphatic aldehydes, the
catalytic system was also efficient (up to 83% yield and
86% ee; entries 16–19). The 3- or 4-picolinaldehyde and
2-furylaldehyde bearing a heterocycle gave good results
(up to 86% ee; Table 2, entries 16–18). Hexanal was con-
verted into the corresponding product in 64% ee with 74%
yield (Table 2, entry 19).
11
12
13
14
15
16
17e
18f
19
5
5
5
5
(R)-BINOL (5) 2a (5)
10
1a (10)
1a (2.5)
1a (5)
2a (10)
2a (2.5)
2a (5)
2.5
5
5
5
1a (5)
2a (5)
1a (5)
2a (5)
a Unless specified otherwise, reaction conditions: catalyst (5 mol%;
1/2/Ti(Oi-Pr)4 = 1:1:1), H2O (15 mol%), benzaldehyde (0.15 mmol)
in THF (0.5 mL) at 0 °C under Ar atmosphere, ethyl diazoacetate (3.0
equiv).
b Isolated yield.
c Determined by HPLC analysis (Chiralcel AD-H). The absolute con-
figuration was determined by comparison with the reported value of
optical rotation.6a,
d The amount of 15 mol% H2O was not added and 1.2 equiv ethyl di-
azoacetate.
On the basis of the experimental investigation and previ-
ous reports,6,7,12 a proposed working model for this aldol
reaction was depicted in Figure 2. A complex catalyst that
bound simultaneously the electrophile and the nucleo-
phile was presented.12 The benzaldehyde was activated by
e Reaction temperature was –20 °C.
f Reaction temperature was 25 °C.
Synlett 2009, No. 10, 1655–1658 © Thieme Stuttgart · New York

CLUSTER
Synthesis of a-Diazo-b-hydroxy Esters
1657
tivated and deprotonated to generate the active
nucleophile which would attack the activated benzalde-
hyde from the Re face, thus the corresponding a-diazo-b-
hydroxy ester was obtained with S configuration.
Table 2 Substrate Scope for the Catalytic Asymmetric Aldol Reac-
tion of Aldehydes with Ethyl Diazoacetate
OH
O
O
catalyst (5 mol%)
0 °C, THF, 6 d
+
RCHO
R
OEt
OEt
In summary, the asymmetric direct-type aldol reaction of
aldehydes with ethyl diazoacetate has been achieved by a
bifunctional titanium complex catalyst giving the corre-
sponding a-diazo-b-hydroxy esters in good yields (up to
83%) with good to excellent enantioselectivities (up to
94% ee) under mild conditions. Based on the experimen-
tal results and previous reports, a possible working model
has been presented to explain the origin of the activation
and asymmetric induction. Further efforts should be di-
rected to clarify the precise mechanism of this reaction as
well as to improve the reactivity and enantioselectivity of
the asymmetric version.
N2
N2
3a–s
4
5a–s
Entrya
1
R
Product13 Yield (%)b ee (%)c
Ph
5a
5b
5c
5d
5e
5f
62
70
54
67
78
47
41
48
48
41
51
42
54
63
61
53
83
40
74
91 (S)d
90
94
89
87
80
86
83
93
88
88
83
82
75
75
86
77
81
64
2
4-FC6H4
3
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2,4-Cl2C6H3
4-MeC6H4
3-MeC6H4
3-PhOC6H4
4-PhC6H4
3-O2NC6H4
4-F3CC6H4
4-NCC6H4
3-pyridyl
4-pyridyl
2-furyl
4
5
6
7
5g
5h
5i
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
8
9
Acknowledgment
10
11
12
13
14
15
16
17
18
19
5j
The authors appreciate the National Natural Science Foundation of
China (No. 20732003) and the Ministry of Education (No.
20070610019) for financial support. We also thank Sichuan Univer-
sity Analytical & Testing Center for NMR analysis.
5k
5l
5m
5n
5o
5p
5q
5r
5s
References and Notes
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C5H11
a Conditions: catalyst (5 mol%; 1a/2a/Ti(Oi-Pr)4 = 1:1:1), H2O (15
mol%), aldehyde (0.15 mmol) in THF (0.5 mL) at 0 °C under Ar
atmosphere, ethyl diazoacetate (3.0 equiv).
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b Isolated yield.
c Determined by HPLC on a Chiralcel AD-H, OD-H, OJ-H column
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d The absolute configuration was determined by comparison with the
reported value of optical rotation.6a
O
L
Ti
= cinchonine
*
*
O
O
N
N
O
*
*
(3) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley-Interscience: New York, 1998.
L
O
O
H
= (S)-BINOL
EtOOC
O
H
N2
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2008, 64, 6577.
Ph
L = H2O or solvent
Figure 2 Proposed working model for the asymmetric aldol reac-
tion of ethyl diazoacetate with benzaldehyde
Ti(IV), while tertiary amine of the ligand 2a might act as
the Lewis base to activate the nucleophile (ethyl diazo-
acetate). In this transition state, ethyl diazoacetate was ac-
Synlett 2009, No. 10, 1655–1658 © Thieme Stuttgart · New York

1658
W. Wang et al.
CLUSTER
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(13) General Procedure for the Asymmetric Aldol Reaction
of Ethyl Diazoacetate with Benzaldehyde
Ti(Oi-Pr)4 (1.0 M in toluene, 7.5 mL, 0.0075 mmol) was
added to a soln of 1a (2.2 mg, 0.0075 mmol), 2a (2.2 mg,
0.0075 mmol) in THF (0.5 mL), and the mixture was stirred
at 25 °C under Ar. This was followed by the addition of H2O
(1.0 M in THF, 22.5 mL, 0.0225 mmol). Benzaldehyde (0.15
mmol) was added after the contents were stirred for 30 min
at 25 °C. To this solution, ethyl diazoacetate (0.45 mmol)
was added under 0 °C. The reaction was vigorously stirred at
0 °C under Ar atmosphere and monitored by TLC, after 6 d,
the residue was purified by flash SiO2 chromatography
(PE–acetone, 10:1) to afford the corresponding a-diazo-b-
hydroxy ester 5a (20.5 mg, 62% yield) as a yellow oil with
91% ee; HPLC [Chiralpak AD-H column, hexane–2-PrOH
(90:10), 254 nm, 1.0 mL min–1]: tR(minor) = 6.906 min,
tR(major) = 7.774 min; [a]D25 +21.9 (c 0.42, CH2Cl2). Lit.6a
[a]D20 –9.5 (c 3.2, CH2Cl2) for R enantiomer in 87% ee. 1H
NMR (400 MHz, CDCl3): d = 7.28–7.45 (m, 5 H), 5.94 (s, 1
H), 4.31 (q, J = 7.2 Hz, 2 H), 2.99 (br s, 1 H), 1.32 (t, J = 7.2
Hz, 3 H) ppm.
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