Acyloins from Morita-Baylis-Hillman adducts: an alternative approach to the racemic total synthesis of bupropion

Article abstract of DOI:10.1016/j.tetlet.2008.04.040

In this Letter, we describe an easy and straightforward strategy for the preparation of acyloins (α-hydroxyketones) from Morita-Baylis-Hillman adducts, based on a Curtius rearrangement. Different acyloins were obtained with good overall yield (>40% for three steps). To exemplify the synthetic usefulness of this strategy, total synthesis of (±)-bupropion, a dopamine, and nor-epinefrine reuptake inhibitor has been accomplished in eight steps with an overall yield of 25%.

Full text of DOI:10.1016/j.tetlet.2008.04.040

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3744–3748
Acyloins from Morita–Baylis–Hillman adducts: an alternative
approach to the racemic total synthesis of bupropion
*
´
Giovanni W. Amarante, Patrıcia Rezende, Mayra Cavallaro, Fernando Coelho
Laboratory of Synthesis of Natural Products and Drugs, DQO/IQ/Unicamp, PO Box 6154, 13084-971 Campinas, SP, Brazil
Received 8 February 2008; revised 4 April 2008; accepted 7 April 2008
Available online 10 April 2008
Abstract
In this Letter, we describe an easy and straightforward strategy for the preparation of acyloins (a-hydroxyketones) from Morita–
Baylis–Hillman adducts, based on a Curtius rearrangement. Different acyloins were obtained with good overall yield (>40% for three
steps). To exemplify the synthetic usefulness of this strategy, total synthesis of ( )-bupropion, a dopamine, and nor-epinefrine reuptake
inhibitor has been accomplished in eight steps with an overall yield of 25%.
Ó 2008 Elsevier Ltd. All rights reserved.
Acyloins or a-hydroxyketones are a functional group
that plays an important role in organic synthesis. This
structural moiety is widespread in compounds of natural
origin as well as in advanced intermediates en route differ-
ent target molecules.1,2 The anti-inflammatory agent corti-
sone acetate (1), the anti-cancer agents daunorubicin and
daunomycinone (2 and 3),3 the natural flavouring agents
(4 and 5),4 or the male pheromone compounds of the long-
horn beetles Hylotropus bajulus (‘old-house borer’) (6 and
7)5 are examples of drugs or biologically active com-
pounds which present the acyloin moiety in their structures
(Fig. 1).
The biological, synthetic, and commercial relevancies of
acyloins have motivated the development of different
approaches to synthesize them, both in racemic and enan-
tioselective pure forms. Conventionally, a-hydroxy ketones
are prepared by the acyloin condensation reaction,6 oxida-
tion of enolates,7 or reduction of a-diketones or esters.1,8
Recently, a method based on ketohydroxylation of alkenes
was developed to afford acyloins.7c,9 Alternatively, radical
oxidation of a 1,3-dicarbonyl compound with cerium salt
could also be used as a method for the preparation of acy-
loins.10 Most recently, a skeletal rearrangement of symmet-
rically a,a-disubstituted a-amino aldehyde has been
reported as an elegant new strategy for preparing
acyloins.11
Morita–Baylis–Hillman (MBH) is an exquisite organic
chemical transformation which provides highly functional-
ized carbonyl compounds.12 The resulted MBH adducts
have found vast application as a versatile building block
to generate either bioactive compounds13 or useful syn-
thetic intermediates.14
We have been involved in a research program aimed at
the synthesis of some oxazolidinones with anti-microbial
properties from MBH adducts.13b To obtain the desired
oxazolidinones we decided to prepare ene-carbamates from
MBH adducts and use them as a substrate for the synthesis
of the required oxazolidinones, via a nucleophilic attack of
an alkoxy ion on the carbonyl group of the ene-carbamate.
The most direct way to prepare the latter was via a Curtius
rearrangement of a hydrolyzed MBH adduct, followed by
the treatment of the intermediate ene-isocyanate with an
alcohol (methanol or t-butanol). During the preparation
of the required ene-carbamates we have observed the for-
mation of an acyloin as a byproduct. The acyloin was likely
formed due to the presence of water in the alcohol used to
transform the ene-isocyanate into the corresponding
ene-isocarbamate.
*
Corresponding author. Tel.: +55 19 3521 3085; fax: +55 19 3521 3023.
E-mail address: coelho@iqm.unicamp.br (F. Coelho).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.040

G. W. Amarante et al. / Tetrahedron Letters 49 (2008) 3744–3748
3745
O
O
OH
O
O
OH
O
OAc
O
OH
OH
OH
O
O
OH
O
O
OH OH
O
H3C
O
Daunomycinone (3)
Cortisone acetate (1)
H2N
OH
Daunorubicin (2)
OH
O
OH
O
OH
(R)
(R)
O
OH
O
5
6
7
4
herbaceous flavor
property
melted cheese
flavor property
Fig. 1. Some examples of biologically active compounds presenting the acyloin moiety in their structures.
The importance of acyloins in natural products chemis-
Table 1
Preparation of the protected MBH adducts
try and organic synthesis calls for the availability of as
many alternative methods to prepare these key compounds
as possible. Thus we decided to systematically check the
possibility of preparing acyloins from MBH adducts. We
disclose herein our results on the utilization of MBH
adducts as substrates for the synthesis of acyloins. The syn-
thetic usefulness of this new acyloin preparation method
was demonstrated by performing the total synthesis of
( )-buproprion.
The MBH adducts were prepared according to a meth-
odology we described some years ago.15 Assuming an
increase of the polarity of the ene-isocyanates, which could
make the isolation procedure difficult, the MBH adducts
were transformed into the corresponding silyl ethers by
the treatment of the MBH adducts with TBSCl or
TBSOTf. Results from the preparation of MBH adducts
as well as those referring to the protective step are summa-
rized in Table 1.
Having all silylated Morita–Baylis–Hillman adducts in
hand, we submitted them to an ester group hydrolysis, in
order to obtain the acids which would be used as substrates
for the Curtius rearrangement step. Then, the silylated
MBH 16–23 were treated with LiOH in a mixture of CH3
CN–H2O(1:1), at 50–60 °C, to afford the acids with almost
quantitative yields. The only exception was the hydrolysis
of the silylated ester 16. In this particular case we obtained
a yield of only 91%. Likely this yield is due to the fact that
the acid derived from 16 is a small polar molecule with a
good water solubility, despite the presence of the TBS
group in its structure.
Acids 24–31 were submitted to the Curtius rearrange-
ment.16 Thus they were reacted initially with chloroethyl
formate at 5 °C in the presence of triethylamine for
5 min, followed by a treatment with NaN3 to provide the
intermediate acylazides.
TBSOTf
CH2Cl2, Et3N
OR1
O
OH
O
DABCO, )))
RCHO
R
O
R
O
or
TBSCl,
Imidazole, DMF
O
O
R= alkyl or aryl
R1= TBS, 16-23
8-15
R= alkyl or aryl
Entry
R
MBHa,b,c (%)
Protected adductb,c (%)
1
2
3
4
5
6
7
8
H
Hexyl
Phenyl
4-CH3O-Phenyl
3-Cl-Phenyl
Thiazolyl
2-O2N-Phenyl
Thiophene
8, 70
9, 76
16, 67d
17, >99e
18, >99e
19, >99e
20, >99e
21, >99d
22, 97e
10, 75
11, 73
12, 89
13, 98
14, 99
15, 90
23, 90d
a
The Morita–Baylis–Hillman reactions were performed using methyl
acrylate as solvent in an ultrasonic bath (1000 W, 40 Hz).
b
The yield refers to isolated and purified product.
All spectral data for each compound are compatible to data available
c
in the literature.16
d
TBSOTf is used as silylating reagent.
TBSCl is used as silylating reagent.
e
After solvent removal, acylazides were thermally rear-
ranged by refluxing them in toluene for 2 h to afford the
ene-isocyanates. The entire sequence of reactions was per-
formed without any purification steps.17 The only proce-
dure used between each step was simply solvent removal.
After evaporation, the crude ene-isocyanates were refluxed
in water. To our delight, after 12 h the acyloins were
smoothly formed with very good overall yields. In Table
2 we summarize the entire sequence as well as the overall
yield obtained in the preparation of the acyloins from the
silylated acids 24–31.

3746
G. W. Amarante et al. / Tetrahedron Letters 49 (2008) 3744–3748
Table 2
OTBS
OTBS
OH
OH
Preparation of acyloins from MBH adducts
a
b
OR1
OR1
O
OR1
O
O
OH
a
b
O
R
R
OH
R
O
Cl
Cl
Cl
( )-42
( )-36
( )-41
16-23
R= alkyl or aryl
R1= TBS
24-31
MBH acids
32-39
Acyloins
c
O
H
N
O
Reagents and conditions: (a) LiOH, CH3CN:H2O (1:1), 50−60 °C, 2 h 4 h,
>99%; (b) (i) ClCO2Et, 5 °C, 5 min; (ii) NaN3, rt, 2 h;(iii) PhCH3, reflux,
2 h; (iv) H2O, reflux, 12 h (for overall yields see table).
d
OH
Cl
Cl
Entry
Protected MBH adducts
Acyloinsa,b,c (%)
( )-Bupropion (40)
( )-43
1
2
3
4
5
6
7
8
a
16, R = H
17, R = Hexyl
18, R = Phenyl
19, R = 4-CH3O-Phenyl
20, R = 3-Cl-Phenyl
21, R = Thiazolyl
22, R = 2-O2N-phenyl
23, R = Thiophene
32, 57
33, 42
34, 50
35, 48
36, 45
37, 43
38, 46
39, 44
Scheme 1. Total synthesis of ( )-bupropion from an acyloin prepared
from an MBH adduct. Reagents and conditions: (a) NaBH4, MeOH, rt,
quantitative yield; (b) TBAF/THF, rt, 2 h, 97%; (c) IBX, DMSO, rt, 30 h,
85%; (d) (i) Tf2O, 2,6-lutidine, CH2Cl2, À40 °C, 30 min; (ii) t-BuNH2,
12 h, 75%.
The pharmaceutical importance of bupropion (40),
associated with our will of demonstrating the usefulness
of the method we have just developed for the preparation
of acyloins from MBH adducts stimulated us to propose
a new approach for the racemic total synthesis of 40.
The silylated acyloin 36 was used as substrate for our
synthesis. Thus, a-hydroxy ketone 36 was reduced with
NaBH4 in methanol to furnish the mono-silylated diol 41
in quantitative yield. Treatment of 41 with TBAF in
THF gave diol 42 in 97% yield (syn as major isomer—
2.5:1). In this stage of the synthesis, it was necessary to
regioselectively oxidize diol 42 to prepare the regioisomeric
acyloin 43. We tried several different experimental condi-
tions, however, the only successful one was that in which
IBX was used as an oxidizing agent. Thus acyloin 43 was
obtained in 85% yield after 30 h at room temperature.
Finally, the regioisomeric acyloin 43 was treated with triflic
anhydride and 2,6-lutidine in dichloromethane at À40 °C
to give a triflate intermediate that was then submitted in
situ to a nucleophilic substitution reaction using t-butyl-
amine as nucleophile, to afford bupropion (40) in 75% yield
(for the two steps) (Scheme 1).
In summary, this study clearly demonstrates that Mori-
ta–Baylis–Hillman adducts coming from both aliphatic
and aromatic aldehydes provide easy access to acyloins,
which are valuable intermediates in organic synthesis.
The total synthesis of ( )-bupropion has been accom-
plished in eight steps with an overall yield of 25% using
an acyloin prepared by the new strategy disclosed in this
Letter. As far as we know this is the first report relating
the preparation of acyloins from MBH adducts.
The yields refer to isolated and purified products.
Yields for three steps (including the protection step).
b
c
All spectroscopic data are compatible with the proposed structures.17
For a mechanism proposal see Reference section.18
In all cases the acyloins were obtained in good overall
yield from the silylated MBH adducts. For all cases the
yield for each step is good (ꢀ75–80% for each step). Differ-
ent types of acyloins were obtained and the method proved
to be quite general. Even heterocyclic MBH adducts (Table
2, entries 6 and 8) provide the corresponding acyloins with
good overall yields. The method is very simple and could
be easily performed without the need of using any critical
experimental conditions.
Tobacco addiction is a very serious health problem all
over the world. Unfortunately, the diseases associated with
the smoking habit (lung cancer, pulmonar emphysema, and
cardiovascular problems) have a severe negative impact on
the public health system of the majority of western world
countries.
Due to the gravity of the health problem caused by
tobacco addiction there are several types of medical and
behavioral therapies to circumvent and cure this addiction.
Most recently, the elucidation of the biochemical mecha-
nisms used by the human brain to develop addiction has
permitted the development of some efficient chemical sub-
stances which can effectively aid addiction treatment.19
Among these substances bupropion [( )-a-t-butylamino
3-chloropropiophenone] (40, Scheme 1) has an important
role. This compound is a potent inhibitor of dopamine
reuptake with subtle noradrenergic reuptake also.20 Bupro-
pion is an atypical antidepressant, which has been licensed
by FDA to treat the smoker’s abstinence syndrome.21
Owing to the pharmacological importance of bupropi-
on, several approaches to synthesize it have already been
developed.22 Bupropion is administered in its racemic
form, since it racemizes very quickly in the body when
administered in its enantiomerically pure form.
An asymmetric version of this approach could easily be
developed simply by using chiral Morita–Baylis–Hillman
adducts. Further studies aiming at the development of an
asymmetric version of this method, as well as its applica-
tion for the synthesis of natural products and commercially
valuable intermediates, are ongoing in our laboratory and
will be reported in due time.

G. W. Amarante et al. / Tetrahedron Letters 49 (2008) 3744–3748
3747
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Eberlin, M. N.; Dupont, J. J. Phys. Org. Chem. 2006, 19, 731–
735.
Acknowledgments
We thank the Brazilian science foundations for support-
ing this work. More specifically G.W.A, P.R., and M.C.
thank Fapesp (05/02373-2, 02/07659-3, and 07/55548-0)
for fellowships. F.C. thanks Fapesp for a research Grant
14. (a) Abella, C. A. M.; Rezende, P.; Souza, M. F. L.; Coelho, F.
Tetrahedron Lett. 2008, 49, 145–148; (b) Mateus, C. R.; Coelho, F. J.
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(06/06347-9) and CNPq for
a research fellowship
(301832/2007-2). The authors are grateful to Professors
Carol H. Collins and Marcos N. Eberlin for helpful sugges-
tions on English grammar and style.
References and notes
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17. Representative experimental procedure: To a solution of acid 20 (1 g,
3 mmol) in acetone (15 mL) were added, at 0 °C, ethyl chloroformate
(0.44 mL, 4.6 mmol) and triethylamine (0.88 mL, 6.1 mmol). After 5–
10 min (analysis by TLC shows the complete disappearance of
starting material), sodium azide (0.3 g, 4.6 mmol) was added under
strong stirring, and the resulting mixture was stirred strongly for 2 h.
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toluene (15 mL) and refluxed for 2 h. The solvent was evaporated and
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12 h. After, the aqueous phase was extracted with ethyl acetate and
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could be easily followed by IR spectroscopy, since the C@O IR
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intense and appear in different regions of the IR spectrum. All
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J = 7.0 Hz, 1H), 4.65 (br s, 1H, NH), 1.67 (d, J = 7.0 Hz, 3H), 1.44 (s,
9H); 13C NMR (CDCl3, 62.5 MHz) d: 195.7, 136, 135.2, 133.5, 130.1,
128.6, 126.5, 71.9, 58.1, 30.3, 17.
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OR1
O
O
OR1
O
OR1
O
ClCO2Et
Et3N
NaN3
R
O
OEt
R
N3
R
OH
acylazide
R= aryl and alkyl; R1 = TBS
Δ
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OR1
N
O
OR1
O
H
H2O
C
C
O
N
H
O
H
N
H
R
R
R
O
O
isocyanate
OR1
CO2
OR1
OR1
OR1
H3O
R
H
N
O
NH2
NH
O
R
R
R
H
acyloin
enamine
imine
or
alternatively
OR1
H
N
O
R
O
CO2
H
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