Cinchona alkaloid-catalyzed enantioselective direct aldol reaction of N-Boc-oxindoles with polymeric ethyl glyoxylate

Article abstract of DOI:10.1002/adsc.201100499

The first enantioselective direct aldol addition of N-Boc-oxindoles to polymeric ethyl glyoxylate is presented. The reaction is performed by using as low as 0.1 mol% (DHQ)₂PHAL and gives access to α- hydroxycarboxylate derivatives bearing adjacent secondary alcohol and quaternary stereocenters with high levels of diastereo- and enantiocontrol. The use of ethyl glyoxylate in its polymeric form represents an important advantage for synthetic applications and allows us to directly install a C₂ unit ready to be converted in useful building blocks. A further one-pot protection/deprotection sequence catalyzed by Zn(ClO₄) ₂·6 H₂O preserved the α-hydroxycarboxylates from racemization by means of a parasitic alcohol-catalyzed retroaldol reaction. Copyright

Full text of DOI:10.1002/adsc.201100499

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DOI: 10.1002/adsc.201100499
Cinchona Alkaloid-Catalyzed Enantioselective Direct Aldol
Reaction of N-Boc-Oxindoles with Polymeric Ethyl Glyoxylate
Fabio Pesciaioli,a Paolo Righi,a Andrea Mazzanti,a Chiara Gianelli,a
Michele Mancinelli,a Giuseppe Bartoli,a and Giorgio Bencivennia,*
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; phone: (+39)-051-209-3624; e-mail: giorgio.bencivenni2@unibo.it
Received: June 14, 2011; Revised: June 28, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100499.
Abstract: The first enantioselective direct aldol ad-
dition of N-Boc-oxindoles to polymeric ethyl glyox-
ylate is presented. The reaction is performed by
using as low as 0.1 mol% (DHQ)2PHAL and gives
access to a-hydroxycarboxylate derivatives bearing
adjacent secondary alcohol and quaternary stereo-
centers with high levels of diastereo- and enantio-
control. The use of ethyl glyoxylate in its polymeric
form represents an important advantage for syn-
thetic applications and allows us to directly install a
C2 unit ready to be converted in useful building
blocks. A further one-pot protection/deprotection
forming several bonds in a single operation in order
to reduce many purification steps, to minimize the
generation of chemical wastes and to save time are
necessary requirements for modern chemistry.[2]
Recently, oxindole derivatives containing a quater-
nary stereocenter at the C-3 position became the tar-
gets of several intriguing asymmetric transformations
because of their well documented importance as ef-
fective biologically active compounds.[3] Thus many
efforts have been devoted in the realization of orga-
nocatalyzed enantioselective Mannich, Michael addi-
tion, amination, hydroxylation, alkylation and cascade
reactions with the aim to install the oxindole scaffold
in the final products.[4] Although the aldol reaction
represents one of the most powerful tools for the real-
sequence catalyzed by ZnACTHUNTRGNEUNG(ClO4)2·6H2O preserved
the a-hydroxycarboxylates from racemization by
means of a parasitic alcohol-catalyzed retroaldol re-
action.
À
ization of C C bonds, the direct organocatalytic aldol
reaction of oxindoles with aldehydes for the stereo-
controlled generation of adjacent quaternary and sec-
ondary alcohol stereocenters remains unexplored.[5]
Herein we report the efficient direct aldol addition of
Keywords: acid derivatives; aldol reaction; asym-
metric catalysis; Cinchona alkaloids; hydrogen
bonding
3-substituted alkyloxindoles with
a commercially
available toluene solution of polymeric ethyl glyoxy-
late for the synthesis of a-hydroxycarboxylate deriva-
tives.[6] The reaction furnishes new oxindole deriva-
In the last years, asymmetric organocatalysis has tives (Scheme 1) with almost total stereocontrol of
proved to be amongst the most powerful approaches the newly forged adjacent quaternary and secondary
for the direct enantioselective construction of optical- alcohol stereocenters and is performed using a load-
ly active frameworks, starting from commercial or ing as low as 0.1 mol% of commercially available Cin-
readily available compounds.[1] However, the need of chona alkaloid catalyst. Moreover, the direct use of
always more efficient processes able to address most polymeric ethyl glyoxylate represents an important
of the principles of green chemistry[2] opens up new advantage for synthetic applications because it avoids
scenarios and challenges for organocatalysis. In this the need to prepare and use the extremely reactive
field the realization of organocatalyzed enantioselec- monomer form that rapidly polymerizes and reacts
tive transformations that give access to important with water to generate the hydrated form.[8] Moreover
chiral building blocks with relevant synthetic applica- the use of ethyl glyoxylate allows one to directly in-
tions or remarkable biological activities by means of stall a C2 unit ready to be converted into useful build-
new efficient activation modes and under a low cata- ing blocks.
lyst loading are highly desirable. Indeed, the realiza-
In a preliminary stage of the project we began to
tion of new chemical transformations carried out by study the reaction of tert-butyl 3-methyl-2-oxoindo-
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Scheme 1. Direct aldol reaction of 3-alkyl-N-Boc-oxindoles with polymeric ethyl glyoxylate.
line-1-carboxylate (1a)[9] with polymeric ethyl glyoxy-
We found that hydroquinine 1,4-phthalazinediyl di-
late (2) in THF 0.2M in the presence of 10 mol% of ether (DHQ)2PHAL E was extremely efficient, pro-
commercially available or readily prepared Cinchona viding the desired a-hydroxycarboxylate with a dia-
alkaloid derivatives as catalyst at room temperature stereomeric ratio of 97:3 [Scheme 2 a)] as determined
1
(Scheme 2).
by H NMR in favour of 3a.[10] However, the same
sample analyzed by HPLC on a chiral stationary
Scheme 2. a) Observed diastereoisomers and relative ratio after and before HPLC analysis. b) Hypothesized mechanism for
the racemization pathway.
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Cinchona Alkaloid-Catalyzed Enantioselective Direct Aldol Reaction of N-Boc-Oxindoles
Table 1. Optimization studies for the direct aldol reaction of N-Boc-3-methyloxindole 1a and toluene solution of polymeric
ethyl glyoxylate 2.[a]
Entry[a]
Catalyst (mol%)
Solvent
Conversion [%][b]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
A (10)
B (10)
C (10)
D (10)
E (10)
E (10)
E (10)
E (10)
E (10)
E (10)
E (10)
E (5)
THF
THF
THF
THF
THF
Et2O
CH2Cl2
1,4-dioxane
AcOEt
dry THF
THF
THF
THF
THF
THF
full
full
full
full
full
full
full
full
full
full
full
full
full
full
–
66:34
92:8
95:5
88:12
95:5
95:5
85:15
93:7
91:9
92:8
95:5
95:5
97:3
97:3
–
30
77
80
66
85
80
67
84
83
82
74
87
90
90
–
9
10
11[d]
12
13
14
15
E (1)
E (0.5)
no catalyst
[a]
Unless otherwise noted all reactions were performed at room temperature with 1a (0.1 mmol), 2 (50% in toluene,
0.1 mmol), catalyst (10 mol%), solvent (500 mL), Zn(ClO4)2·6H2O (5 mol%), Ac2O (50 mL).
Determined by H NMR analysis of the crude mixture.
Determined by HPLC analysis on a chiral stationary phase.
Reaction performed at 08C.
AHCTUNGTRENNUNG
[b]
[c]
[d]
1
phase showed a much lower diastereomeric ratio, in- hydroxy-3-methylindole and the ethyl glyoxylate.[12]
consistent with the one determined by NMR. In the Moreover, as established by NMR analysis,[10] the
attempt to gain more insight into this discrepancy, fur- presence of a hydrogen bond between the secondary
ther NMR measurements showed that the purified OH and the oxygen of the amidic carbonyl group of
product as such or as a CDCl3 solution maintains in- the oxindole moiety enhances the acidity of the hy-
definitely the 97:3 3a:epi-3a diastereomeric ratio over droxy proton, thus promoting the action of the alco-
time. Then, a sample of the isolated crude product hol.
was dissolved in a hexane-isopropyl alcohol mixture
In order to avoid the racemization, we decided to
and this solution was analyzed as such by HPLC on a protect the alcoholic moiety of compound 3a by ace-
chiral stationary phase at regular intervals over 48 h. tylation. Thus, after evaporation of the solvent, treat-
During this time, the 3a:epi-3a diastereoisomer ratio ment of the crude reaction mixture with
initially observed by NMR underwent a complete in- ZnACTHUNGTRNEG(UN ClO4)2·6H2O (5 mol%) and acetic anhydride at
version and at the end it was 3:97. This phenomenon room temperature gave compound 4a in which the
was also accompanied by a rapid racemization of tert-butyloxycarbonyl group was removed, thus pro-
both diastereoisomers 3a and epi-3a.[11] [Scheme 2 a)]. viding a one-pot easy and highly efficient protection-
Based on the above findings and on the fact that deprotection sequence.[13] Neither diastereomeric con-
using either Dabco or K2CO3 as the catalyst furnished version nor racemization was observed when com-
epi-3a as the major diastereoisomer, we suppose that pound 4a was exposed to isopropyl alcohol and the
the chiral Cinchona alkaloid-catalyzed reaction is diastereomeric ratio of 4a determined by HPLC ex-
under catalyst control forming the kinetic diastereo- actly matched the value obtained by NMR.
isomer 3a which in hexane-isopropyl alcohol solution
The real efficiency of the proposed catalysts was
undergoes a conversion to the thermodynamic diaste- evaluated on the protected compound 4a. The results
reoisomer epi-3a. Since this conversion is also accom- outlined in Table 1 show that commercially available
panied by racemization, as depicted in Scheme 2 b), bis-Cinchona alkaloid (DHQ)2PHAL (E) was the
we think that isopropyl alcohol may promote two best catalyst providing the best result with dr=95:5
consecutive reaction pathways: the retroaldol reaction and 85% ee (Table 1, entries 1–5). Tetrahydrofuran
À
and the racemic C C bond formation between the 2- (THF) revealed to be the solvent of choice and inter-
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Table 2. Direct aldol reaction of N-Boc-3-alkyloxindoles and polymeric ethyl glyoxylate.[a]
Entry[a]
4
R
R1
R2
R3
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
a
d
Me
n-butyl
i-butyl
Bn
p-Cl-C6H4CH2
p-CF3-C6H4CH2
p-MeO-C6H4CH2
m-MeO-C6H4CH2
Bn
Bn
Bn
Bn
Bn
Me
Bn
H
H
H
H
H
H
H
H
Me
Me
F
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
Me
H
F
71
75
65
83
80
84
82
87
85
76
75
78
65
77
70
97:3
98:2
97:3
99:1
98:2
97:3
99:1
99:1
98:2
97:3
97:3
98:2
98:2
95:5
97:3
90
94
80
96
96
96
96
98
95
96
90
94
95
93
95
9
10
11
12
13
14[e]
15[f]
H
H
H
H
H
H
H
[a]
Unless otherwise noted all reactions were performed at room temperature with 1a–m (0.2 mmol), 2 (50% in toluene,
0.2 mmol), (DHQ)2PHAL (0.5 mol%, 100 mL of 0.01M THF solution), THF (900 mL), ZnACHTUNGTRNEUNG(ClO4)2·6H2O (5 mol%), Ac2O
(100 mL).
Sum of diastereoisomers.
Determined by H NMR analysis of the crude mixture.
Determined by HPLC analysis on chiral stationary phase.
Reaction performed using 0.5 mol% of (DHQD)2PHAL.
Reaction performed on 2 mmol scale using 0.1 mol% of E.
[b]
[c]
[d]
[e]
[f]
1
estingly the reaction performed in dry THF caused a 4a–m was realized through a one-pot protection and
loss of diastereo- and enantioselectivity (Table 1, deprotection protocol without any precaution to ex-
entry 10). In order to improve the enantioselectivity clude water and air. As shown in Table 2, less hin-
the reaction was conducted at 08C and, whilst a good dered linear substituents at the C-3 position gave
level of diastereoselectivity was maintained, the enan- good results in term of yields and stereocontrol
tiomeric excess dramatically dropped to 74% (Table 2, entries 1 and 2). Interestingly, the reaction
(Table 1, entry 11). The decision to run the reaction proceeded smoothly also in the case of the more en-
with a minor amount of catalyst led to an increment cumbered oxindole 3c and compound 4c was isolated
in the stereocontrol without a detectable loss of reac- in 65% yield with a dr=97:3, albeit with a lower
tivity (Table 1, entries 12–14). Moreover without orga- value of enantiomeric excess. (Table 2, entry 3). More
nocatalyst no traces of product could be detected sterically demanding oxindoles bearing a benzyl sub-
(Table 1, entry 15). The reaction proceeded smoothly stituent at the C-3 position maintained high levels of
with catalyst E (0.5 mol%) at room temperature for diastereo- and enantiocontrol (Table 2, entries 4–13)
24 h and then for further 6 h hours with Zn- even when the stereoelectronic nature and the posi-
ACHTUNGTRENNUNG
The scope of the direct aldol reaction of various N- ring (Table 2, entries 5 and 6) and electron-releasing
Boc-oxindoles 1a–m, with polymeric ethyl glyoxylate methoxy substituents in para or meta positions
2 was then investigated using the optimized condi- (Table 2, entries 7 and 8), furnished the corresponding
tions (Table 2). The reaction perfectly maintained the products in excellent yields, essentially as a single dia-
high level of efficiency as regards all the substituents stereoisomer and with ee values ranging from 96 to
of the oxindolic structure despite the very low 98%. Except for the methyl group (Table 2, entry 9),
amount of catalyst and the synthesis of compounds the substitution on the aromatic ring of the oxindole
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Adv. Synth. Catal. 2011, 353, 2953 – 2959

Cinchona Alkaloid-Catalyzed Enantioselective Direct Aldol Reaction of N-Boc-Oxindoles
to polymeric ethyl glyoxylate using (DHQ)2PHAL as
catalyst. The reaction gives access to both enantio-
mers of oxindole-containing a-hydroxycarboxylate de-
rivatives bearing adjacent secondary alcohol and qua-
ternary stereocenters with excellent optical purity and
relevant diastereoselectivity using directly the com-
mercially available toluene solution of polymeric
ethyl glyoxylate. The present synthesis features some
important aspects which represent significant break-
throughs for the realization of always more efficient
routes for the synthesis of chiral building blocks. The
high efficiency of the reaction allows the use of as low
as 0.1 mol% of the catalyst at room temperature
maintaining an elevated level of stereocontrol. In ad-
dition, three reactions: aldol addition, O-acetylation
and N-deprotection can be performed in a one-pot
process without any need to exclude water, thus
saving energy, time and costly separation and purifica-
tion procedures. In particular, the protection/depro-
tection process, that has proved to be necessary to
prevent the racemization pathway, is realized using
Figure 1. X-ray structure of the N-tosyl derivative (2R,3’R)-5
(left) and absolute configuration of the corresponding pre-
cursor alcohol 3a (right).
proved to influence negatively the catalyst activity, the same catalyst and this aspect represents a great
leading to a general decrease of isolated product yield advantage from an economical point of view.
(Table 2, entries 10–13). Indeed, the presence of a
second methyl substituent at the C-7 of the oxindole
moiety gave compound 4j in 76% yield and with very Experimental Section
high enantioselectivity (Table 2, entry 10). Also
strongly electron-withdrawing fluorine and chlorine Typical Procedure
atoms did not change the stereochemical outcome of
the reaction and the corresponding products 4k, 4l
and 4m were isolated as almost single diastereoiso-
mers with 90%, 94% and 95% ee respectively
(Table 2, entries 11–13).
In an ordinary vial equipped with a Teflon-coated stir bar,
tert-butyl
3-methyl-2-oxoindoline-1-carboxylate
1a
(0.2 mmol, 49.4 mg) was dissolved in 900 mL of THF and
100 mL of a 0.01M solution of (DHQ)2PHAL (E) in THF
(0.001 mmol, 0.78 mg, 0.5 mol%) were added. After 5 min
ethyl glyoxylate 2 (0.2 mmol, 40 mL of a 50% toluene solu-
tion, 1.0 equiv.) was added. The resulting solution was
stirred at room temperature for 24 h then solvent was re-
moved under reduced pressure without heating and Ac2O
was added (1.06 mmol, 100 mL, 5.3 equiv.) followed by
Interestingly, the reaction performed using oxindole
1a with 0.5 mol% of (DHQD)2PHAL, the pseudo-
enantiomer of E, gave access to the enantiomer of
compound 4a (ent-4a) in 77% yield but with high dia-
stereo- and enantioselectivity: dr=95:5 and 93% ee
(Table 2, entry 14). Notably, when the catalyst loading
was further diminished to 0.1 mol% the reaction of
tert-butyl 3-benzyl-2-oxoindoline-1-carboxylate 1d
performed on a 2-mmol scale, maintained the same
level of enantioselectivity (95% ee) and furnished the
desired a-hydroxycarboxylate derivative in good yield
as single diastereoisomer (Table 2, entry 15). The ab-
solute configuration has been determined to be
2R,3’R by X-ray crystallographic analysis[14] of the cor-
responding N-tosylated oxindole derivative 5 obtained
by simple reaction of 4a with TsCl and NaH in
THF[11] (Figure 1). The same absolute configuration
could be assigned by analogy to the corresponding al-
cohol 3a thus suggesting that the Si face of the indole
enolate species generated by the interaction between
the oxindole 1a and (DHQ)2PHAL[5b], approaches
the Re face of the ethyl glyoxylate.
ZnACTHUNTGRNEGNU(ClO4)2·6H2O (5 mol%, 3.74 mg) and 2 drops of diethyl
ether. The resulting mixture was stirred for 6 h then diluted
with 2 mL of dichloromethane and flushed through a short
plug of silica gel, using dichloromethane/ethyl acetate 1:1 as
the eluent (100 mL). The solvent was removed under
vacuum and crude 4a (dr=97:3) was purified by flash
column chromatography using hexane/diethyl ether 2:3 as
the eluent mixture. Pure 4a was obtained in 71% yield as
sum of diastereoisomers and 90% ee on the major diastereo-
isomer. HPLC (Daicel Chiralpak AD-H column: 90/10
hexane/i-PrOH, flow rate 0.75 mLminÀ1, l=214, 254 nm):
t
minor =17.03 min, tmajor =23.47 min.
Acknowledgements
We acknowledge financial support from Bologna University
and from MIUR National Project “Stereoselezione in Sintesi
In conclusion, we have realized the first enantiose-
lective direct aldol addition of N-Boc-3-alkyloxindoles Organica, Metodologie ed Applicazioni”.
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[5] a) To the best of our knowledge only one example de-
scribing the organocatalyzed aldol-type reaction of 3-
substituted oxindoles with paraformaldehyde has been
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4872–4875; b) for the organocatalyzed direct aldol-type
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S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru,
M. Shiro, Angew. Chem. 2007, 119, 8820–8823; Angew.
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ide-ScACTHNURTGENNG(U OTf)3 complex catalyzed aldol-type reaction of
3-substituted oxindoles with phenylglyoxal derivatives
see: K. Shen, X. Liu, K. Zeng, W. Li, X. Hu, L. Lin, X.
Feng, Chem. Eur. J. 2010, 16, 3736–3742.
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[7] For a comprehensive review on the Cinchona alkaloids
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[9] Attempts to perform the reaction using 3-non-substitut-
ed N-Boc-alkyloxindole did not gave any traces of the
corresponding a-hydroxycarboxylate derivative.
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Adv. Synth. Catal. 2011, 353, 2953 – 2959

Cinchona Alkaloid-Catalyzed Enantioselective Direct Aldol Reaction of N-Boc-Oxindoles
[10] 1H NMR spectra recorded in CDCl3 show the OH
proton as a doublet with a 9.4 Hz coupling constant,
whereas the spectrum taken in a polar solvent like
CD3CN does not show this coupling. This strong hydro-
gen bond between the OH group and the oxindole car-
bonyl group allowed us to establish by NOE experi-
ments that the major diastereoisomer has the relative
configuration shown in the structure 3a.
[11] See the Supporting Information for more details.
[12] A similar retro-aldol process was reported to be work-
ing under basic conditions, see ref.[5b] There, exposure
of the compounds to 2-propanol for HPLC analysis
under neutral conditions had no effect on both diaster-
eo- and enantioselectivity.
[13] a) R. Dalpozzo, G. Bartoli, L. Sambri, P. Melchiorre,
Chem. Rev. 2010, 110, 3501–3551; b) G. Bartoli, M.
Bosco, R. Dalpozzo, E. Marcantoni, M. Massaccesi, L.
Sambri, Eur. J. Org. Chem. 2003, 4611–4617; c) G. Bar-
toli, M. Bosco, R. Dalpozzo, E. Marcantoni, M. Mas-
saccesi, S. Rinaldi, L. Sambri, Synlett 2003, 39–42.
[14] CCDC 828981 (5) contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
Adv. Synth. Catal. 2011, 353, 2953 – 2959
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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