Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: An organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent

Article abstract of DOI:10.1039/c5ob00492f

An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABA_B receptor agonist baclofen.

Full text of DOI:10.1039/c5ob00492f

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Stereoselective reaction of 2-carboxythioesters-
1,3-dithiane with nitroalkenes: an organocatalytic
strategy for the asymmetric addition of a
glyoxylate anion equivalent†
Cite this: Org. Biomol. Chem., 2015,
13, 5591
Received 12th March 2015,
Accepted 7th April 2015
Elisabetta Massolo,a Maurizio Benaglia,*a Andrea Genoni,a Rita Annunziata,a
DOI: 10.1039/c5ob00492f
www.rsc.org/obc
Giuseppe Celentanob and Nicoletta Gaggero*b
An efficient organocatalytic methodology has been developed to tion of a nucleophilic acyl anion synthon,4 N-heterocyclic carb-
perform the stereoselective addition of 2-carboxythioesters-1,3- enes are known for their ability to reverse the polarity of
dithiane to nitroalkenes. Under mild reaction conditions γ-nitro- aldehydes, to generate acyl anion equivalents that have been
β-aryl-α-keto esters with up to 92% ee were obtained, realizing a widely employed in benzoin and Stetter-type reactions.5 More
formal catalytic stereoselective conjugate addition of the glyoxy- traditional methods involve the use of metalated amino-
late anion synthon. The reaction products are versatile starting nitriles6 and 1,3-dithiane-protected glyoxylates,7 prepared by
materials for further synthetic transformations; for example, the deprotonation with stoichiometric amounts of a strong base.8
simultaneous reduction of the nitro group and removal of the It must be noted that all of these methods suffer from
dithiane ring was accomplished, allowing the preparation of a intrinsic limitations and problems (limited general applica-
GABAB receptor agonist baclofen.
bility, low yields, modest stereoselectivity, and strongly
depending on reactant substrates); in addition, examples of
direct synthesis of enantiomerically enriched keto esters are
still very rare, especially those related to the preparation of
enantiopure β-aryl-α-keto esters, where the strong acidity of the
proton in the β position represents a real issue for any success-
ful stereoselective methodology.
With the goal to develop a metal-free catalytic strategy for
the synthesis of chiral β-substituted-α-keto esters, we decided
to study the addition of 1,3-dithiane-2-carboxy derivatives to
nitroalkenes. Surprisingly, a catalytic stereoselective version of
this powerful transformation seems to be unknown.9 Here
we wish to report the first enantioselective organocatalytic
conjugate addition of 2-carboxythioesters-1,3-dithiane to
nitroalkenes.
Introduction
Chiral α-keto esters are considered products of great impor-
tance, as starting materials for the preparation of highly func-
tionalized compounds via synthetic manipulation of their
functional groups.1 They also find successful applications in
biochemistry and are an integral part of several biologically
active natural compounds.2 Therefore, it is not surprising that
the stereoselective synthesis of chiral α-keto esters is still the
object of intense studies. Recently a novel approach was pro-
posed by Johnson, who described a copper(II)-catalyzed aerobic
oxidation reaction as a key step for the preparation of β-substi-
tuted α-keto esters, in a procedure where acetoacetate esters
were used as glyoxylate anion synthons.3
At the beginning of our investigation the chemical reactivity
of different 2-carboxyester 1,3-dithianes was investigated in the
presence of
(Scheme 1)10.
a cinchona-derived bifunctional catalyst A
However, most of the reported synthesis of chiral α-keto
esters rely on the umpolung strategy that allows the introduc-
Commercially available 1,3-dithiane-2-ethylcarboxylate 2 in
the presence of 20 mol% of quinine-thiourea derivative A did
not react at all with nitrostyrene. The corresponding S-phenyl
thioester 4 showed poor reactivity, affording the corresponding
addition product 5 in low yields, even after prolonged reaction
aDipartimento di Chimica, Universita’ degli Studi di Milano, via Golgi 19, I-20133
Milano, Italy. E-mail: maurizio.benaglia@unimi.it; Fax: +390250314159
bDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano,
via Mangiagalli, 25, Milano, Italy
†Electronic supplementary information (ESI) available: Experimental details for
times, although in
a remarkable 89% enantioselectivity
nitrostyrene derivatives synthesis, catalysts preparation and organocatalytic reac-
tions. Characterization details for Michael addition products and Baclofen syn-
thesis. Determination of absolute configuration of the reaction products.
1H-NMR, 13C-NMR and 19F-NMR spectra and HPLC chromatograms on the
chiral stationary phase of addition products. See DOI: 10.1039/c5ob00492f
(entries 2 and 3, Table 1). As expected 2-pyridylthioester 6
afforded adduct 7 in higher yields; unfortunately the reaction
product turned out to be not very stable, thus preventing the
determination of its enantiomeric excess. Finally the use of
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Scheme 1 Preliminary studies of organocatalytic addition of dithianes to nitrostyrene.
Table 1 Chemical activity of 2-substituted 1,3-dithianes
Therefore we turned our attention to the variation of
different structural elements of quinine-derived catalyst A; for
example with the cinchonidine derivative C, lacking the
methoxy group on the quinolone ring, a little decrease in
enantioselection was observed (75% vs. 87%). A modification
of the same alkoxy group was deleterious for enantioselectivity
(see entries 4 and 5, catalysts D and E). Compounds F–I clearly
demonstrated the crucial role exerted by the thiourea moiety
which cannot be replaced by alternative hydrogen bond donor
groups. In addition, when squaramides L–N,15 derived from
quinine or trans-diamine-cyclohexane, were tested, very low
enantioselectivities were obtained.
Entrya
X
Product
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
OEt
SPh
SPh
SPy
3
5
5
7
9
24
24
72
24
24
—
16
25
41
71
—
89
87
n.d.
87
SCH2CF3
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of
dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were
determined after chromatographic purification. c Enantiomeric excess
determined by HPLC on a chiral stationary phase.
Once compound A was selected as a catalyst of choice, a few
reaction parameters were optimized (Table 3).
2-S-trifluoroethyl carboxy-thioester-1,3-dithiane 8 gave the best
results; after 24 hours at RT the stable conjugate addition
product 9 was obtained in 71% yield and 87% ee.11
The reaction tolerates different solvents, although only
dichloromethane guaranteed the same level of ee as toluene
(80% ee at RT). Lowering the reaction temperature to 0 °C had
a positive effect, allowing isolating the product in 92% ee;
lower temperatures did not give satisfactory results. It is note-
worthy that the loading of the catalyst could be decreased to
10 mol% and even to 5 mol% with only a marginal loss of
enantioselectivity, albeit with diminished chemical yield. The
general applicability of the methodology was then investigated
(Scheme 3, eqn (a)).
The use of 1,1,1-trifluoroethyl thioester was documented
for the first time by Barbas in an organocatalytic Michael re-
action.12 Later, our group took advantage of low pKa of the
protons in the α position of the carboxy group in the trifluoro-
ethyl thioesters to realize the first organocatalytic direct aldol
reaction between a thioester and an aromatic aldehyde.13 Due
to its favorable reactivity profile (entry 5, Table 1), thioester 8
was selected as a reagent of choice and its addition to nitros-
tyrene was studied in the presence of different chiral bifunc-
tional organocatalysts (Scheme 2).
In the model reaction performed in toluene for 24 hours at
room temperature 2 mol eq. of thioester 8 were reacted with
1 mol eq. of nitrostyrene in the presence of 0.2 mol eq. of a
catalyst. Based on the good results obtained with catalyst A,
another successful thiourea-based bifunctional catalyst, Take-
moto catalyst B,14 was tested; the product was isolated in
higher yield but lower enantioselectivity than the cinchona-
derived catalyst A (entries 1 and 2 of Table 2, 67% ee for cata-
lyst B vs. 87% ee for A).
Differently substituted nitro alkenes were easily prepared11
and reacted with dithiane 8 in the presence of catalyst A
(Table 4).
The reaction works with nitrostyrenes substituted both in
ortho and in para positions, with electron rich or poor substi-
tuents, leading to products with enantioselectivities ranging
typically between 70% and 92%. Typically less reactive alkyl
nitro alkenes16 did not react under the present conditions
(entries 10 and 11); however, 4-nitro-1-phenyl butadiene
reacted smoothly to afford product 17, bearing a styryl moiety
in 61% yield and 71% ee (eqn (b), Scheme 3).
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Scheme 2 Chiral organocatalysts investigated in the 1,3-dithiane addition to nitrostyrene.
Table 3 Solvent screening for the organocatalyzed addition of dithiane
8 to nitrostyrene
Table 2 Screening of chiral organocatalysts in the 1,3-dithiane addition
to nitrostyrene
Entrya
Solvent
Temp. (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
Toluene
DCM
CH3CN
Hexane
Et2O
Toluene
Toluene
Toluene
Toluene
25
25
25
25
25
0
−20
25
25
71
55
80
75
73
60
61
55
47
87
80
41
57
67
92
66
81
80
Entrya
Catalyst
Yieldb (%)
eec (%)
7
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
I
71
81
55
53
41
53
55
73
15
51
47
57
87
67
75
51
37
<5
31
37
<5
21
7
8d
9e
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of
dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were
determined after chromatographic purification c Enantiomeric excess
determined by HPLC on a chiral stationary phase. d Reaction run with
10 mol% of a catalyst. e Reaction run with 5 mol% of a catalyst.
9
10
11
12
L
M
N
<5
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of
dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were
determined after chromatographic purification. c Enantiomeric excess
determined by HPLC on a chiral stationary phase.
In order to establish the absolute configuration of the
addition products, compound 11 was treated with powdered
zinc and 6 M HCl17 to afford enantiomerically enriched lactam
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Scheme 3 Organocatalytic 1,3-dithiane addition to different nitroalkenes.
Table 4 General applicability of the catalytic methodology
18, which was determined to be in the (S) configuration by
comparison of optical rotation power values. Indeed final
hydrolysis with hydrochloridric acid afforded (S)-baclofen 19
(Scheme 4).18
Therefore, the method offers a straightforward access to a
direct precursor of baclofen-type derivatives, GABAB receptor
agonists used in the treatment of spasticity and alcohol
dependence.19
Entrya
R
Product
Yieldb (%)
eec (%)
1
Ph
Ph
4-CF3Ph
4-ClPh
4-CH3Ph
2-CH3Ph
4-OCH3Ph
2-OCH3Ph
2-OAcPh
i-Pr
9
9
71
60
41
81
71
43
75
80
55
—
—
87
92
53
86
73
67
73
71
85
—
—
2d
3
10
11
12
13
14
15
16
n.r.
n.r.
4
5
6
7
8
9
10
11
Finally, conversion of the addition products into the corres-
ponding α-ketothioesters was achieved by reaction with
N-bromosuccinimide in acetone (Scheme 5).20
CH2CH2Ph
For example, compounds 9–11 were quantitatively con-
verted to α-ketothioesters 20–22. Interestingly, upon treatment
of 20–22 with silver trifluoroacetate, β-nitro esters 23–25 were
obtained (Scheme 5).21
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of
dithiane, 0.02 mmol of catalyst A, 1 mL of toluene at 25 °C. b Yields
were determined after chromatographic purification. c Enantiomeric
excess determined by HPLC on a chiral stationary phase. d Reaction
run at 0 °C.
Scheme 4 Synthesis of baclofen.
Scheme 5 Synthesis of β-aryl-α-keto thioesters.
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Products: The Chiron Approach, Pergamon Press, New York,
1983, ch. 2.
3 K. M. Steward and J. S. Johnson, Org. Lett., 2011, 13, 2426.
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J. Zhang and Y. R. Chi, Angew. Chem., Int. Ed., 2012, 51,
1911.
Fig. 1 Proposed stereoselection model.
4 (a) D. Seebach, Angew. Chem., Int. Ed., 1979, 18, 239. For a
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F. Glorius, Chem. Soc. Rev., 2012, 41, 3511. For some recent
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The procedure afforded compounds 20–22 without
affecting the stereochemical integrity of the starting materials.
For instance, a sample of (R)-9 (53% ee) was quantitatively
transformed into α-ketothioester 20 through a 4 hour reaction
with NBS in acetone at 0 °C, and then reacted with CF3CO2Ag
in methanol to give the known (R)-β-nitro methylester 2322 in
70% yield, its absolute configuration reflecting that of the
starting compound 9 without appreciable variation of the
enantiomeric excess.23
In proposing a stereoselection model, the coordination of
both reaction partners to the bifunctional catalyst may be envi-
saged, the substrate nitro group being engaged in hydrogen
bonds by the thiourea moiety, and the charged quinuclidine
nitrogen possibly forming an ion pair with the nucleophile
(Fig. 1).
Accordingly, with the quinine-derived catalyst, the thioester
attack occurs on the nitroalkene Si face, affording the experi-
mentally observed (S)-configured product.
In conclusion, the enantioselective organocatalyzed conju-
gate addition of a newly activated thioester acting as an acyl
anion mimic has been performed. The use of chiral bifunc-
tional catalysts to control the stereochemical outcome through
a hydrogen bond network imposed by the thiourea moiety
afforded good yields and enantioselectivities up to 92%. This
methodology represents an entry to highly functionalized,
enantiomerically enriched products, such as γ-nitro-β-aryl-
α-keto thioesters, valuable precursors of a wide variety of chiral
organic compounds.
6 D. Enders, M. Bonten and G. Raabe, Angew. Chem., Int. Ed.,
2007, 46, 2314. For a recent contribution, see: K. S. Yang,
A. E. Nibbs, Y. E. Turkmen and V. H. Rawal, J. Am. Chem.
Soc., 2013, 135, 16050. See also: P. A. Evans, S. Oliver and
J. J. Chae, J. Am. Chem. Soc., 2012, 134, 19314.
7 limited examples, see: (a) M. Amat, M. Perez, N. Llor and
J. Bosch, Org. Lett., 2002, 4, 2787; (b) I. Coldham,
K. M. Crapnell, J.-C. Fernandez, J. D. Moseley and R. Rabot,
J. Org. Chem., 2002, 67, 6181; (c) T. Ichige, A. Miyake,
N. Kanoh and M. Nakata, Synlett, 2004, 1686 and references
cited therein.
Acknowledgements
M.
B.
thanks
COST
action
CM9505
“ORCA”
Organocatalysis. E. M. and A. G. thank the University of Milan
for PhD fellowships.
8 For
a recent catalytic, non-stereoselective, conjugate
addition of acyl anion equivalents derived from 2-silyl-1,3-
dithianes to unsaturated ketones, see: S. E. Denmark and
L. R. Cullen, Org. Lett., 2014, 16, 70. For a Pd-catalyzed
coupling of acetyltrimethylsilane, see: S. Ramgren and
N. K. Garg, Org. Lett., 2014, 16, 824.
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5596 | Org. Biomol. Chem., 2015, 13, 5591–5596
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