Synthesis of 3-substituted 1,5-aldehyde esters via an organocatalytic highly enantioselective conjugate addition of new carbonylmethyl 2-pyridinylsulfone to enals

Article abstract of DOI:10.1039/c1cc15714k

A highly enantioselective organocatalytic protocol for conjugate addition of new nucleophilic carbonylmethyl 2-pyridinylsulfone to enals has been developed in good yields and with high enantioselectivities. The resulting Michael adducts are versatile building blocks for a variety of organic transformations.

Full text of DOI:10.1039/c1cc15714k

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COMMUNICATION
Synthesis of 3-substituted 1,5-aldehyde esters via an organocatalytic
highly enantioselective conjugate addition of new carbonylmethyl
2-pyridinylsulfone to enalswz
Jing Deng,a Fei Wang,b Wenzhong Yan,a Jin Zhu,a Hualiang Jiang,a Wei Wang*ac and
Jian Li*a
Received 15th September 2011, Accepted 24th October 2011
DOI: 10.1039/c1cc15714k
A highly enantioselective organocatalytic protocol for conjugate
addition of new nucleophilic carbonylmethyl 2-pyridinylsulfone
to enals has been developed in good yields and with high
enantioselectivities. The resulting Michael adducts are versatile
building blocks for a variety of organic transformations.
Despite the fact that chiral 3-substituted 1,5-aldehyde esters
are versatile building blocks in organic synthesis, for example,
they can be conveniently transformed into synthetically and
biologically interesting lactones and lactams,1 their synthesis
Scheme 1 Design of carbonylmethyl sulfones 1 as nucleophiles for
remains elusive.2 Conjugate additions to enals represent a
organocatalytic Michael reactions of enals.
straightforward approach to the substances and in the past
products. Toward this end, a series of carbonylmethyl sulfones
13 including new carbonylmethyl 2-pyridinylsulfone 1a (CMPS)
several years impressive organocatalytic approaches have been
reported.3 It is noteworthy that in general in these processes,
activated methylenes such as malonates,4 1,3-ketoesters,5 nitro-
alkanes,6 bis-sulfones,7 and active thioesters8 as nucleophiles
are commonly used.9 However, the introduction of a more
synthetically useful mono-ester (e.g. CH2CO2Me) moiety is an
unmet synthetic issue.
1
have been developed and explored for the purpose. We have
found that the new reagent 1a is the most effective nucleophile in
the organocatalytic Michael addition reaction with enals. Notably,
high enantioselectivities (89–>99% ee) are achieved. Moreover,
the Michel adducts can be conveniently transformed into new
functional molecules and the sulfone group can be removed
under mild reactions without affecting enantioselectivity of the
products. Herein we disclose the results.
We envision that introducing a temporary ‘‘mask’’ group such
as a sulfone moiety10–12 instead of a carbonyl can function as a
nucleophile, which can be viewed as a CH2CO2Me synthon
(Scheme 1). The introduction of the sulfone group kills two
birds with one stone. It activates the a-carbon of ester allowing
for an effective nucleophilic conjugate addition. Moreover, the
experience of ours9 and several others10–12 in this area shows
that the moiety can be readily removed under mild reaction
conditions without affecting enantioselectivity of the end
In our initial efforts, three different methoxycarbonylmethyl
heterocyclic sulfones 1a–c, which bear 2-pyridinyl, phenyl and
benzothiazoyl sulfone groups, were screened in the reaction
with trans-cinnamaldehyde 2a in the presence of diphenylprolinol
silyl ether 4a (10 mol%),14 a commonly used promoter in
conjugate addition to enals in THF at rt (Table 1, entries 1–3).
We were pleased to find that the novel methoxycarbonylmethyl
2-pyridinylsulfone 1a showed the highest activity among them
tested. Even without a base, the reaction proceeded smoothly
to provide the desired product 3a in 72% yield and with 95%
ee and 8.3 : 1 dr after 48 h (Table 1, entry 1). Screening of
solvents revealed that the yield, enantio- and diastereoselectivities
of the products varied dramatically (entries 1, 4–6). Among
the solvents probed, toluene was of choice for the process
(entry 4). In this instance, a high yield (86%), excellent ee
(>99%) and good dr (14.3 : 1) were achieved. It was noteworthy
that methylene dichloride gave the better dr (20 : 1), but at the
expense of the enantioselectivity (91% ee) and yield (53%)
(entry 5). When methanol was employed, the yield (90%) was
a School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: jianli@ecust.edu.cn; Fax: +86 21-64252584;
Tel: +86 21-64252584
b Chinese Pharmacopoeia commission, Building 11, Fahua Nanli,
Beijing, 100061, China
c Department of Chemistry and Chemical Biology, University of
New Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA.
E-mail: wwang@unm.edu; Fax: +1 505-277-2609
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for the compounds 3a–3t, 5–8. CCDC
844031. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc15714k
c
148 Chem. Commun., 2012, 48, 148–150
This journal is The Royal Society of Chemistry 2012

Table 1 Optimization of the reaction conditionsa
Table 2 Scope of enantioselective Michael addition of b-methyl ester
or b-keto pyridine sulfones (1) with a,b-unsaturated aldehydes (2)a
Entry R1
R2
3
Yieldb (%) drc
eed (%)
1
2
OMe Ph
3a 90
3b 83
3c 55
3d 54
3e 65
3f 55
3g 51
3h 80
3i 88
3j 92
3k 82
3l 87
3m 95
>30 : 1 100
OMe 4-MeOC6H4
OMe 2-Furyl
OMe C3H7
OMe C4H9
OMe C6H13
OMe C7H15
OMe 2-ClC6H4
OMe 4-MeC6H4
OMe 4-ClC6H4
OMe 2-FC6H4
OMe 4-EtC6H4
OMe 4-NO2C6H4
OMe 3-MeO-4-AcOPh 3n 76
OMe 4-AcOC6H4 3o 85
OMe 4-MeOCOC6H4 3p 88
3 : 1
100
89
92
94
94
90
100
3e
4f,g
5f
1.7 : 1
1.8 : 1
1.8 : 1
1.6 : 1
1.8 : 1
7.7 : 1
Entry
1
Cat. Solvent Additive Yieldb (%) drc
eed (%)
6f
1
1a 4a
1b 4a
1c 4a
1a 4a
1a 4a
1a 4a
1a 4a
1a 4a
1a 4a
1a 4b
1a 4c
1a 4d
1a 4d
1a 4d
THF
THF
THF
Toluene None
CH2Cl2 None
MeOH None
None
None
None
72
54
0
86
53
90
8.3 : 1
2.3 : 1
—
95
91
—
7f
2
3e
4
8
9
14.3 : 1 100
>30 : 1 100
5
6
7
8
20 : 1
1.7 : 1
6.7 : 1
2.5 : 1
14.3 : 1 100
>30 : 1 100
>30 : 1 100
>30 : 1 100
>30 : 1 100
>30 : 1 100
91
77
>99
100
10
11
12
13
14
15
16
17
18
19
20
2.1 : 1
2 : 1
6.3 : 1
5.8 : 1
3 : 1
100
100
100
100
97
Toluene PhCO2H 87
Toluene LiCl
Toluene Et3N
Toluene None
Toluene None
Toluene None
Toluene None
Toluene None
91
80
40
88
90
90
90
9
10
11
12
13f
14g
14.3 : 1 100
1.5 : 1
4.8 : 1
100
100
OMe 4-Ph-Ph
OMe 1-Naphth
Ph Ph
C2H5 Ph
3q 83
3r 85
3s 76
3t 94
>30 : 1 100
>30 : 1 100
>30 : 1 100
a
Unless stated otherwise, the reaction was carried out with 1
(0.2 mmol), 2a (0.4 mmol), catalyst 4 (0.02 mmol) and additive
a
b
c
Unless stated otherwise, see ESI. Isolated yield. Determined by
1H NMR of products. Determined by HPLC analysis (Chiralcel AD
d
b
c
(0.02 mmol) in 1 mL of solvent at rt for 48 h. Isolated yield. The
diastereoisomeric ratios were determined by 1H NMR of products.
e
and AS) by converting to the corresponding methylacetal. At 0 1C.
10% K2CO3 and 20% catalyst 4d used. Reaction time: 72 h.
f
g
d
Determined by HPLC analysis (Chiralcel AD) by converting to the
e
corresponding methylacetal. Reaction time: 72 h. 2a (0.3 mmol)
g
was used. 2a (0.24 mmol) was used.
f
alkyl a,b-unsaturated aldehyde (entries 4–7). Excellent enantio-
selectivities (90–94% ee) were obtained despite relative low yields
(50–65%) with 20 mol% 4d and K2CO3 as additive. The low
reaction yields are mainly due to an significant side 1,2-addition-
dehydration reaction between 1a and 2.15 In addition to sulfone
ester (1a), the ketones arylcarbonylmethyl 2-pyridinylsulfone (1d)
and alkylcarbonylmethyl 2-pyridinylsulfone (1e) also efficiently
participate in the conjugate process to generate 1,5-ketoaldehydes
(entries 19 and 20). Again, high yields (76 and 94%) and excellent
diastereo- and enantioselectivity (>30 : 1 dr and >99% ee) were
achieved. It should be pointed out that although poor diastereo-
selectivities were seen in some cases, the removal of the sulfone
group would eliminate a stereogenic center. We found that
(see below) the high enantioselectivity arises from the b-carbon,
which is directly controlled by the 4d-mediated conjugate addition.
The absolute configuration of the Michael adducts was deter-
mined and confirmed by a single crystal X-ray crystallographic
analysis of the derivative 3j (Fig. S1, ESIz).16
improved but the enantioselectivity (77%) decreased signifi-
cantly (entry 6). The effect of additives on reactions was also
examined (entries 7–9). Among the acids, bases and salts
probed, it appeared that they were not beneficial. PhCO2H
and LiCl resulted in decreased dr (entries 7 and 8), while
Et3N reduced the yield (entry 9). Survey of catalysts revealed
that the more bulky catalysts 4b–d could promote this reaction
by further improving the dr value to an excellent level (dr >
30 : 1) (entries 10–12). Among them, catalyst 4d was the best
for the process (Table 1, entry 12). In this case, a high yield
(90%), high ee (>99%) and excellent dr (>30 : 1) were
obtained. Reducing the loading of 2a from 2.0 equiv. to
1.2 equiv. gave a similar result (entry 14).
Having established optimal reaction conditions, we sub-
sequently explored the scope of the Michael addition of CMPS 1
to structurally diverse a,b-unsaturated aldehydes. As shown in
Table 2, a number of trans-cinnamaldehydes bearing electron-
donating and electron-withdrawing substituents were success-
fully applied in the Michael reaction. The corresponding
Michael adducts 3a–o were isolated with high to excellent
enantioselectivities (89–>99% ee) and in good to excellent
yields (54–95%) (entries 1–18). It seems that independent of
the electronic characteristics of the substituents attached to the
phenyl ring are the enantioselectivities of the processes. Also
significant is that heteroaromatic enals could effectively engage
in the conjugate addition process with high efficiency (entry 3)
when the reaction was performed at 0 1C. Furthermore, the
4d-promoted Michael process was expanded to the less reactive
Finally, to demonstrate the synthetic utility of the Michael
adducts 3, a series of organic transformations were performed
using 3a as an example (Scheme 2). Reduction of the aldehyde
or reductive aminations followed by spontaneous cyclization
led to synthetically valuable chiral lactone 5 and lactam 6,
respectively (eqn (1)). These two classes of compounds have
important biological activities1 and serve as important building
blocks in organic synthesis. Moreover, the sulfone can be removed
conveniently under mild conditions (eqn (2)). Protection of the
aldehyde moiety to corresponding acetal 30a, and subsequent
reductive removal of the 2-pyridinylsulfonyl group under the
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 148–150 149

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Bu4N+Brꢀ (TBAB) in MeOH11e (see ESIz) gave 3-substituted
acetal 7, which was transformed into an aldehyde ester 8. It is
noteworthy that our initial attempt to form the methoxy-
carbonylmethylated product under basic conditions (Mg, TBAB,
MeOH) without protection of the aldehyde resulted in a signifi-
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In conclusion, we have developed a new nucleophilic reagent
CMPS 1a for the direct organocatalytic asymmetric Michael
addition to a wide range of a,b-unsaturated aldehydes in
moderate to excellent yields and with high enantioselectivities.
Moreover, as demonstrated, the Michael adducts serve as
versatile building blocks in a variety of transformations. The
application of the process in the synthesis of biologically
interesting molecules is being pursued in our laboratories.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Grants
90813005, 21002028 and 20902022, J. Li), National S&T Major
Project, China (Grant 2011ZX09102-005-02, J. Li), the 111 Project
(Grant B07023, J. Li and W. Wang), the Fundamental Research
Funds for the Central Universities (J. Li) and East China
University of Science & Technology (W. Wang).
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Notes and references
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2 To our knowledge, only two examples can be found in the literature
in asymmetric preparation: the use of catalytic asymmetric Diels–Alder
reactions: (a) D. A. Evans, J. S. Johnson and E. J. Olhava, J. Am.
Chem. Soc., 2000, 122, 1635; (b) D. A. Evans and J. S. Johnson, J. Am.
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C. Palomo, Chem.–Asian J., 2008, 3, 922.
3 For recent reviews on enantioselective Michael addition reactions,
see: (a) Catalytic asymmetric conjugate reactions, ed. A. Cordova,
Wiley-VCH, Weinheim, Germany, 2010; (b) J. L. Vicario, E. Reyes,
D. Dadia and L. Carrillo, in Catalytic asymmetric conjugate reactions,
ed. A. Cordova, Wiley-VCH, Weinheim, Germany, 2010, ch. 6, p. 619.
15 We observed 24% yield of byproduct generated from 1a and hex-2-enal.
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16 CCDC 844031 (3j).
c
150 Chem. Commun., 2012, 48, 148–150
This journal is The Royal Society of Chemistry 2012