Ozonolysis of Morita-Baylis-Hillman adducts originated from aromatic aldehydes: an expeditious diastereoselective approach for the preparation of α,β-dihydroxy-esters

Article abstract of DOI:10.1016/j.tetlet.2007.10.149

We disclose herein ozonolysis of Morita-Baylis-Hillman adducts originated from aromatic aldehydes. This efficient reaction provides α-ketoesters with different substitution patterns on the aromatic ring. Diastereoselective reduction of the corresponding α-ketoester obtained in the oxidative cleavage step provides α,β-dihydroxy-esters with excellent degree of anti diastereoselection. The method is simple and easy to execute and is therefore a valuable alternative to prepare either α-ketoesters or α,β-dihydroxy-esters.

Full text of DOI:10.1016/j.tetlet.2007.10.149

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 145–148
Ozonolysis of Morita–Baylis–Hillman adducts originated
from aromatic aldehydes: an expeditious diastereoselective
I
approach for the preparation of a,b-dihydroxy-esters
Carlos A. M. Abella, Patr ´ı cia Rezende, Michele F. Lino de Souza and Fernando Coelho*
Laboratory of Synthesis of Natural Products and Drugs—Unicamp/IQ/DQO, PO Box 6154, 13084-971 Campinas, SP, Brazil
Received 22 December 2006; revised 30 October 2007; accepted 31 October 2007
Available online 4 November 2007
Abstract—We disclose herein ozonolysis of Morita–Baylis–Hillman adducts originated from aromatic aldehydes. This efficient reac-
tion provides a-ketoesters with different substitution patterns on the aromatic ring. Diastereoselective reduction of the correspond-
ing a-ketoester obtained in the oxidative cleavage step provides a,b-dihydroxy-esters with excellent degree of anti diastereoselection.
The method is simple and easy to execute and is therefore a valuable alternative to prepare either a-ketoesters or a,b-dihydroxy-
esters.
Ó 2007 Elsevier Ltd. All rights reserved.
8
In the last years, the Morita–Baylis–Hillman reaction
MBH) has attracted much attention as a simple and
straightforward alternative to form a new C–C r
But Doutheau and co-workers. described in 2005 a suc-
cessful oxidative cleavage of the double bond of some
MBH adducts originated from aliphatic aldehydes.
One of the ozonolyzed adducts was used as starting
material for the preparation of (S)-4,5-dihydroxy-2,3-
pentadione (DPD).
(
1
,2
bond. The resulted MBH adducts have found vast
application as a versatile building block to generate
3
either bioactive compounds or useful synthetic interme-
4
diates. The synthetic versatility of these adducts comes
from the three functionalities present in the same mole-
cular backbone, disposed in a unique fashion.
This impressive achievement stimulated us to revisit the
ozonolysis reaction of MBH adducts originated from
aromatic aldehydes. We are interested in this particular
oxidative cleavage mainly for two reasons. First, this
strategy seems to us to be a very efficient way to access
highly functionalized a-ketoesters, which could be used
as starting materials for the synthesis of diols, a-amino-
We have been involved in a research program aimed at
5
the synthesis of isoquinolinones from MBH adducts.
Our interest was focused on preparing b-ketoesters from
these adducts (3 or 4) and their use as starting material
for the synthesis of functionalized isoquinolinones
9
esters, or even tricarbonyl compounds. Secondly, the
(
Fig. 1).
double bond oxidation of MBH adducts originated
from aromatic aldehydes is troublesome and requires
special attention to avoid the extensive degradation
The simplest way to prepare the required a-ketoesters
from MBH adducts was via ozonolysis. Unfortunately,
however, the oxidation reaction failed to work as
required and we were able to isolate products resulting
from the complete degradation of the aromatic ring.
These results forced us to abandon this approach.
6
already observed by us and others. The success on the
ozonolysis of MBH adducts could also contribute to
extend the scope of this interesting reaction described
by Doutheau.
6
7
OR OR
OR OR
OR
O
O
O
O
O
O
R2
NR1
O
NR1
Br
O
Br
CO2Et
q
In memoriam of Professor Helena Ferraz for the outstanding
1
, R= protecting groups
R1= alkyl or aryl group
2
2 2
3, R= protecting group; R = CO H
contributions she gave to the Brazilian Chemical Community.
4, R= protecting group; R = CH OR
2
2
*
Corresponding author. Tel.: +55 19 3521 3085; fax: +55 19 3521
023; e-mail: coelho@iqm.unicamp.br
3
Figure 1. Isoquinolinones from a-keto esters or keto alcohols.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.149

146
C. A. M. Abella et al. / Tetrahedron Letters 49 (2008) 145–148
In this Letter, we describe a successful ozonolysis reac-
tion of several MBH adducts prepared from aromatic
aldehydes. We also exemplified the synthetic versatility
of a-ketoesters by their diastereoselective transforma-
tion into a,b-dihydroxy-esters.
for this particular adduct, is run to the point that all
starting material is consumed, only 10% product yield
is obtained. The oxidation of acetylated derivative (18)
works equally well, with the same experimental behavior
observed for the silylated derivatives. Table 2 summa-
rizes all results, and all spectroscopic data are compati-
1
1
The MBH adducts were prepared according to a meth-
ble with the structure of the a-ketoester compounds.
1
0a,b
odology we described some years ago.
Assuming
an eventual chemical instability of the a-keto-b-hydroxy
esters obtained in the oxidative step, we decided to pro-
tect the secondary hydroxyl group of all MBH adducts
using TBS or acetate as protecting groups. The results
concerning the reaction of MBH as well as those refer-
ring to the protective step are summarized in Table 1.
Trying to simplify the method we decided to test the
ozonolysis reaction directly over the unprotected MBH
adducts.
To our delight therefore, the reaction works efficiently
for all cases tested, and we were also able to obtain
the desired a-ketoesters in moderate to good yields after
just a few minutes (Table 2, entries 8–12). Even for
MBH adducts having electron rich aromatic rings, the
reaction works with just a low level of overoxidation.
Having all protected Morita–Baylis–Hillman adducts in
hand, we submitted them to ozonolysis. Basically, the
ozonolysis reactions were performed using two different
solvents (methanol and dichloromethane) at À78 °C.
For both solvents, the oxidation works properly and
provides the a-keto-b-hydroxy esters in moderate to
good yields after a few minutes (15–20 min). This reac-
tion is very time sensitive. If it is run overtime, extensive
degradation occurs and only the product of overoxida-
tion is isolated. The reaction should be followed care-
fully, by TLC for instance, and after a few minutes
only the ozonolyzed product is observed (a more polar
spot is detected).
In this stage of the work we have developed a simple and
direct approach to prepare a-ketoesters having an
aromatic ring with different substituent patterns. The
method is fast and is a valuable alternative to prepare
1
2
this type of a-ketoesters. To demonstrate its synthetic
versatility we have performed some chemical trans-
formations on these synthetic versatile compounds.
A wide range of important compounds in organic
1
3
chemistry comprise the 1,2-diol unit.
This motif
The ozonolysis works efficiently with most MBH
adducts leading to different a-keto-b-hydroxy esters
with a variety of substituents on the aromatic ring. Even
for those examples having either no substituent, or elec-
tron-donating substituents on aromatic ring (Table 2,
entries 1, 2 and 3) the reaction works efficiently, without
any trace of oxidative degradation of the aromatic
Table 2. Ozonolysis of the protected and unprotected MBH adducts
°
1) O
3
, -78
C
OR
1
O
MeOH or CH
2 2
Cl
OR1
O
7-20 min
R
O
R
O
°
2
) S(CH , -78
3
)
2
C
O
1
2
ring. In the particular case of piperonal (Table 2, entry
), the reaction is stopped as soon as the sign of decom-
R= aryl; R
R= aryl: R
R= aryl; R
1
1
1
= TBS,12-17
= Ac, 18
= H (5, 7, 9, 10, 26)
R= aryl; R = TBS, 19-24
2
1
R= aryl: R = Ac, 25
1
position was detected by TLC (ca 7 min) with recovery
and recycling of the starting material. If this reaction,
R= aryl; R = H (27-31)
1
a,b,c
Entry
Protected MBH adducts
a-Ketoesters
(%)
1
2
3
4
5
6
7
12, R = phenyl
13, R = piperonyl
14, R = 4-OCH -phenyl
3
15, R = 3,5-difluorophenyl
16, R = 6-Br-piperonyl
19 (67)
20 (68)
21 (79)
22 (77)
23 (85)
24 (82)
25 (71)
Table 1. Preparation of the protected MBH adducts
TBSOTf
OH
O
OR
1
O
Et N
DABCO, )))
3
RCHO
R
O
R
O
O
O
or
CH COCl
2
17, R = 4-NO -phenyl
3
18, R = 4-CH SO -phenyl
3
2
Et
N
R= aryl; R = TBS, 12-17
1
R= aryl: R = Ac, 18
5
-11
3
R= aryl
1
Unprotected MBH adducts
a,b,c
Entry Aldehyde
MBH
(%) Protected
d
8
9
10
11
12
5, R = phenyl
26 (75)
b,c
adduct (%)
d
7, R = 4-OCH
9, R = 6-Br-piperonyl
10, R = 4-NO -phenyl
26, R = 3-Cl-phenyl
3
-phenyl
27 (85)
d
1
2
3
4
5
6
7
Benzaldehyde
Piperonal
Anisaldehyde
3,5-F,F-Benzaldehyde
6-Br-Piperonal
5 (70)
6 (73)
7 (80)
8 (80)
9 (85)
10 (99)
12 (92)
13 (96)
14 (98)
15 (77)
16 (95)
17 (97)
18 (80)
28 (82)
d
2
29 (70)
d
30 (83)
a
Typically, a solution of the adduct in methanol or dichloromethane
was treated with ozone at À78 °C for a few minutes (the solution
should not become blue), after that, 10 equiv of dimethyl sulfide was
added to the reaction medium at À78 °C, and finally, the reaction
was left to achieve room temperature and stirred for about 16 h.
The yields refers to isolated and purified products.
All spectroscopic data are compatible with the proposed structures.
Products proved to be unstable at room temperature, however, they
are stable for a long time in a refrigerator.
4-NO
4-CH
2
-Benzaldehyde
SO
3
2
-Benzaldehyde 11 (93)
a
The Morita–Baylis–Hillman reactions were performed using methyl
acrylate as solvent in an ultrasound bath (1000 W, 40 Hz).
The yield refers to isolated and purified product.
All spectral data are compatible for each compound, according to
data available in the literature.
b
c
b
c
d

C. A. M. Abella et al. / Tetrahedron Letters 49 (2008) 145–148
147
occurs in many natural products, such as sugars, and
also has an important role as ligand in asymmetric syn-
thesis. Owing to their synthetic relevance, extensive ef-
forts have been made to develop a general synthetic
tool to stereoselectively produce 1,2-diols. Among the
methods, we can cite the catalytic asymmetric dihydr-
It is well-known that b-hydroxy ketone can be reduced
with excellent diastereoselectivity when the hydroxyl
group is free. Under this condition, the reduction takes
place via a chelate intermediate normally with excellent
diastereoselection. We therefore reduced the a-keto-
esters prepared from the direct ozonolysis of the unpro-
tected MBH adducts. Owing to the relative instability of
these compounds we decided to reduce them immedi-
ately after the evaporation of dimethyl sulfide. Fortu-
nately, an excellent diastereoselectivity was obtained in
all cases (Table 3, entries 4–8).
1
5
1
4
oxylation (AD) of olefins, the stereoselective reduc-
1
5
16
tion of ketoesters, hydroxylation of b-ketoesters
1
7
and aldol condensation.
The importance of a,b-dihydroxy-esters in natural prod-
ucts chemistry and organic synthesis calls for the avail-
ability of as many as possible alternative methods to
prepare these key compounds. As MBH adducts can
be promptly prepared and as we demonstrated their easy
transformation into a-ketoesters, our strategy seems to
be an interesting alternative for the synthesis of a,b-
dihydroxy-esters.
In summary, this study clearly demonstrates that the
ozonolysis reaction of Morita–Baylis–Hillman adducts
stemmed from aromatic aldehydes works efficiently thus
providing access to valuable intermediates. This
approach is therefore complementary to the elegant
study conducted by Doutheau and co-workers.8
We started the reduction step using NaBH in methanol
at room temperature. However, an extensive over-
An asymmetric version of this approach could be easily
developed simply by using chiral Morita–Baylis–Hill-
man adducts. Further studies aiming at to the applica-
tion of this methodology for the synthesis of natural
products and commercially valuable intermediates are
ongoing in our laboratory. We also plan to study the
use these aromatic ketoesters as intermediates for a
reductive amination and for the preparation of tricar-
bonyl compounds.
4
7
reduction was observed, which formed the correspond-
ing triol in some cases. To circumvent this over
reduction, we used a more selective hydride, sodium
cyanoborohydride, which is indicated for the reduction
1
8
of imines. However, in the presence of a weakly acidic
medium, this hydride can easily reduce carbonyl
1
9
groups. Initially we reduced the a-ketoesters prepared
from the protected MBH adducts, but observed poor
diastereoselectivity (Table 3, entries 1–3). Likely this
result is due to the presence of the protecting group,
which compromises the carbonyl face selection by
the reducing agent. For all cases, anti isomers are the
favored ones. Table 3 summarizes the results for the
Acknowledgements
We thank Brazilian Science foundation for supporting
this work, more specifically CAMA and P.R. thank
Fapesp (03/12872-0 and 02/07649-3) for fellowship.
F.C. thanks Fapesp for a research grant (04/09475-0)
and CNPq for a research fellowship (CNPq 536425/
2
0
sodium cyanoborohydride reduction.
Table 3. Reduction of the b-hydroxy-a-keto esters
2004-5). We thank Professors Carol H. Collins and
a) NaBH
3
CN, r.t.,
Marcos Eberlin for helpful suggestions on English
grammar and style.
OR
1
O
MeOH
OR
1
O
1
OR O
+
R
O
or
R
O
R
O
°
O
b) NaBH
CH Cl
4
,-78
C
OH
syn
OH
anti
2
2
References and notes
R= aryl; R
R= aryl; R
1
1
= TBS (19, 22, 24)
= H (27-31)
R= aryl; R
R= aryl; R
1
1
= TBS (32-34)
= H (35-39)
1
. For comprehensive reviews on the Morita–Baylis–Hillman
reaction see: (a) Basavaiah, D.; Rao, A. J.; Satyanara-
yama, T. Chem. Rev. 2003, 103, 811–891; (b) Almeida, W.
P.; Coelho, F. Quim. Nova 2000, 23, 98–105; Chem. Abstr.
a
Entry R/a-ketoesters
(%)
dr syn/
anti
b
c
1
2
3
4
5
6
7
8
19, R = phenyl; R
22, R = 3,5-difluorophenyl, R
24, R = 4-nitrophenyl, R = TBS
27, R = phenyl, R = H
28, R = 4-OCH -phenyl, R
29, R = 6-bromopiperonyl, R
30, R = 4-NO -phenyl, R = H
31, 3-Cl-phenyl, R = H
1
= TBS
31 (70) 55:45
= TBS 32 (86) 60:40
2
000, 132, 236562e; (c) Ciganek, E. Org. React. 1997, 51,
d
1
2
01; (d) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
d
c
1
33 (93) 60:40
Tetrahedron 1996, 52, 8001–8062.
e
1
34 (70)
35 (61)
5:95
5:95
2
. For some new insights about the mechanism of the
Morita–Baylis–Hillman reaction see: (a) Santos, L. S.;
Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N.
Angew. Chem., Int. Ed. 2004, 43, 4330–4333; (b) Price, K.
E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J.
Org. Chem. 2005, 70, 3980–3987; (c) Aggarwal, V. K.;
Fulford, S. Y.; Llyod-Jones, G. C. Angew. Chem., Int. Ed.
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Seibert, K. A.; Abboud, K. A. J. Am. Chem. Soc. 2006,
128, 4174–4175.
c
3
1
= H
= H
e
d
c
1
36 (65) 10:90
2
1
37 (70) 18:82
d
1
38 (63)
5:95
a
Yields refer to purified and isolated compounds.
Spectral data for all compounds are compatible with the proposed
structures and relative stereochemistries (see, Ref. 11).
Diastereoselectivity was determined by comparison with known
compounds (after deprotection, if necessary—see Refs. 15b–f) or by
NMR (of the corresponding acetals).
The relative stereochemistry was ascertained by spectroscopic ana-
lysis of the corresponding acetals through NOE experiments.
Yield for two steps.
b
c
3. (a) Silveira, G. P. C.; Coelho, F. Tetrahedron Lett. 2005,
46, 6477–6481; (b) Coelho, F.; Rossi, R. C. Tetrahedron
Lett. 2002, 43, 2797–2800; (c) Gowrisankar, S.; Lee, K. Y.;
Kim, J. N. Tetrahedron Lett. 2005, 46, 4859–4863; (d)
d
e
2
1

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J = 4.2 Hz, 1H), 4.48 (d, J = 4.2 Hz, 1H), 3.71 (s, 3H),
1
3
2.77 (br s, 2H, exchangeable with D O). C NMR
2
4
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3
, 300 MHz): d 172.1, 140.6, 134.3, 129.5, 128.3,
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10 4
+
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Tetrahedron Lett. 1994, 35, 3329–3332.
18. For a recent review on reduction of C@N compounds with
hydride reagents, see: Hutchins, R. O.; Hutchins, M. K.
Reduction of C@N to CHNH by metal hydrides. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 8.
19. Zhao, Y.; Jiang, N.; Chen, S.; Peng, C.; Zhang, X.; Zou,
Y.; Zhang, S.; Wang, J. Tetrahedron 2005, 61, 6546–6552.
20. Lane, C. F. Synthesis 1975, 135–146.
1
unprotected a-ketoesters: (28)
H
NMR (CDCl3,
300 MHz): d 7.01 (s, 1H), 6.82 (s, 1H), 6.02 (s, 1H), 5.99
(
1
s, 2H), 3.82 (s, 3H), 2.3 (br s, exchangeable with D O,
2
13
H); C NMR (CDCl , 75.4 MHz): d 192.7, 163.0, 148.3,
3
1
48, 121.3, 116.2, 113.2, 108.3, 101.2, 77.5, 52.5. HRMS
+
(
ESI) calcd for C11
H
10BrO
6
[M+H] 316.9661; found
1
316.9652; (30) H NMR (CDCl
3
, 300 MHz): d 7.55–7.20
1
3
(
(
1
m, 4H aromatic), 5.82 (s, 1H), 3.85 (s, 3H); C NMR
CDCl , 125 MHz): d 191.7, 162.9, 140.1, 134.1, 129.5,
28.2, 126.5, 124.5, 76.2, 52.6. HRMS (ESI) calcd for
3
+
C H ClO [M+H] 229.0268; found 229.0233. Spectro-
10
scopic data for some representative anti diols (unknown
10
4
1
compounds): (36) H NMR (CDCl
3
, 250 MHz): d 7.03 (s,
H aromatic), 6.98 (s, 1H aromatic), 5.28 (d, J = 3.9 Hz,
H), 4.54 (d, J = 3.9 Hz, 1H), 3.70 (s, 3H), 2.06 (br s,
1
1
1
3
exchangeable with D
2
O). C NMR (CDCl
3
, 62.5 MHz): d
21. The relative stereochemistries of diols 24, 35, and 37 were
determined by comparison with data available in the
literature. The corresponding 1,2-ketals of diols 36 and 38
were used for stereochemical determinations.
1
7
3
72.4, 147.9, 147.5, 131.4, 112.6, 112.4, 108.1, 101.8, 74,
+
3.4, 58.4. HRMS (EI, 70 eV) calcd for C11
6
H11BrO [M]
1
17.9739; found 317.9723; (38)
H NMR (CDCl3,