An efficient asymmetric domino reaction of amino aldehyde to β,γ-unsaturated α-keto esters using trans-perhydroindolic acid as a chiral organocatalyst

Article abstract of DOI:10.1002/cjoc.201200839

An efficient asymmetric domino reaction of amino aldehyde to β,γ-unsaturated α-keto esters was achieved by using trans-perhydroindolic acid 1d as a chiral organocatalyst with excellent asymmetric behavior. Under the optimal reaction conditions, products with more than 99% de and up to 93% ee were obtained in high chemical yield (up to 98%) for a series of β,γ-unsaturated α-keto esters. The methodology provided an efficient route to dihydropyran derivatives containing many substituent groups (including amino groups).

Full text of DOI:10.1002/cjoc.201200839

FULL PAPER
DOI: 10.1002/cjoc.201200839
An Efficient Asymmetric Domino Reaction of Amino Aldehyde
to β,γ-Unsaturated α-Keto Esters Using trans-Perhydroindolic
Acid as a Chiral Organocatalyst
Shen, Jiefenga(申杰峰)
An, Qianjinb(安前进)
Liu, Delongb(刘德龙)
Liu, Yangangb(刘燕刚)
Zhang, Wanbin*,a,b(张万斌)
a School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai 200240, China
b School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
An efficient asymmetric domino reaction of amino aldehyde to β,γ-unsaturated α-keto esters was achieved by
using trans-perhydroindolic acid 1d as a chiral organocatalyst with excellent asymmetric behavior. Under the opti-
mal reaction conditions, products with more than 99% de and up to 93% ee were obtained in high chemical yield
(up to 98%) for a series of β,γ-unsaturated α-keto esters. The methodology provided an efficient route to dihydro-
pyran derivatives containing many substituent groups (including amino groups).
Keywords asymmetric domino reaction, β,γ-unsaturated α-keto esters, trans-perhydroindolic acid, organocatalyst
Introduction
its isomers 1b—1d (Figure 1). These molecules are
unique in that they possess a rigid bicyclic structure,
with the two H atoms attached to the bridgehead C at-
oms being trans to each other. So, they can be used as
efficient organocatalysts for asymmetric Michael addi-
tions of aldehydes to nitroolefins.[4f] They were also
used in asymmetric domino reactions of aldehyde esters
with β,γ-unsaturated α-keto esters possessing excellent
asymmetric catalytic behavior (up to 99% ee, de and
yield).[4g] Encouraged by the excellent catalytic ability
of these proline-like molecules, we therefore utilised
them in asymmetric domino Michael addition/cyclisa-
tion reactions of amino aldehyde to β,γ-unsaturated
α-keto esters.
Dihydropyran derivatives exhibit interesting bio-
logical activities and are structural subunits in numerous
natural products and bioactive molecules;[1] they also
serve as versatile and important building blocks in or-
ganic synthesis.[2] Several syntheses have been reported
towards the preparation of this important structural mo-
tif,[3] however, the majority of reported procedures in-
volve the synthesis of products with few substituents,
and only one procedure involves the consturction of
dihydropyrans containing amino groups, which is very
important functional group and could be further func-
tionalized.[3c] A convenient and enantioselective ap-
proach to highly substituted dihydropyran derivatives
(containing amino groups) is therefore desirable.
Experimental
Our group have been developing novel and easily
accessible organocatalysts for use in asymmetric trans-
formations.[4] Recently our attention turned to the use of
trans-perhydroindolic acid (1a) (a key intermediate used
in the synthesis of the ACE inhibitor trandolapril)[5] and
General
1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded using a Varian MERCURY
plus-400 spectrometer with TMS as an internal stan-
H
H
H
H
CO2H
CO2H
CO2H
CO2H
N
N
N
N
H
H
H
H
H
H
H
H
1a
1b
1c
1d
Figure 1 Trandolapril intermediate 1a and its byproducts 1b—1d.
*
E-mail: wanbin@sjtu.edu.cn; Tel.: 0086-021-54743265; Fax: 0086-021-54743265
Received August 18, 2012; accepted September 11, 2012; published online October 30, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200839 or from the author.
Chin. J. Chem. 2012, 30, 2681—2687 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shen et al.
FULL PAPER
dard. HRMS was performed at the Analysis Center of
Shanghai Jiao Tong University. Enantioselectivity was
measured by high performance liquid chromatography
(HPLC) using Daicel Chiralcel AD-H, OD-H, AS-H,
OJ-H and OZ-H column with hexane/i-propyl alcohol as
eluent. Column chromatography was performed using
100—200 mesh silica gel. All commercially available
substrates were used as received. β,γ-Unsaturated α-keto
esters (2)[6] and 4-methyl-N-(3-oxopropyl)benzenesul-
fonamide (3)[7] were prepared according to literature
procedures.
Isopropyl 2-hydroxy-3-(4-methylphenylsulfonamido)-
methyl-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylate
1
(4c): White solid. m.p. 140—141 ℃; H NMR (400
MHz, CDCl3) δ: 7.57 (d, J＝8.2 Hz, 2H), 7.36—7.01 (m,
6H), 6.10 (d, J＝2.4 Hz, 1H), 5.70 (s, 1H), 5.11—5.08
(m, 1H), 3.61—3.57 (m, 1H), 3.03—2.98 (m, 1H),
2.83—2.78 (m, 1H), 2.39 (s, 3H), 2.14—2.10 (m, 1H),
1.27—1.23 (m, 6H); 13C NMR (100 MHz, CDCl3) δ:
163.4, 143.5, 141.2, 140.0, 136.6, 129.9, 129.1, 128.7,
127.7, 127.4, 115.5, 93.1, 69.8, 42.5, 42.3, 37.2, 29.9,
21.9; HRMS (ESI) calcd for C23H27NNaO6S [M＋Na＋]
468.1514, found 468.1460. HPLC conditions: the enan-
tiomeric excess and diastereoselective excess were de-
termined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝88∶12, UV 254 nm, 0.8 mL/min, tR1＝24.21
min (major) and tR2＝26.56 min (minor); ee＝92%; de
＞99%.
Methyl 4-(4-fluorophenyl)-2-hydroxy-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
carboxylate (4e): White solid. m.p. 66—67 ℃; 1H
NMR (400 MHz, CDCl3) δ: 7.66—7.53 (m, 2H), 7.31—
7.18 (m, 2H), 7.11—7.08 (m, 2H), 7.02—6.98 (m, 2H),
6.09 (d, J＝2.4 Hz, 1H), 5.65 (s, 1H), 3.79 (s, 3H),
3.62—3.58 (m, 1H), 3.06—2.92 (m, 2H), 2.81—2.76
(m, 1H), 2.47—2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 163.5, 143.8, 139.8, 136.5, 130.6, 128.8,
127.3, 116.0, 115.8, 93.2, 52.8, 42.6, 41.9, 36.2, 30.0,
21.8; HRMS (ESI) calcd for C21H22FNNaO6S [M＋Na＋]
458.1044, found 458.1050. HPLC conditions: the enan-
tiomeric excess and diastereoselective excess were de-
termined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝87∶13, UV 254 nm, 1.0 mL/min, tR1＝24.84
min (major) and tR2＝29.13 min (minor); ee＝92%; de
＞99%.
Methyl 4-(2-chlorophenyl)-2-hydroxy-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
carboxylate (4f): White solid. m.p. 70—71 ℃; 1H
NMR (400 MHz, CDCl3) δ: 7.57 (d, J＝8.2 Hz, 2H),
7.26—7.19 (m, 6H), 6.02 (d, J＝2.8 Hz, 1H), 5.70 (s,
1H), 3.77 (s, 3H), 3.12—3.09 (m, 1H), 2.96—2.77 (m,
2H), 2.39 (s, 3H), 2.34—2.19 (m, 1H); 13C NMR (100
MHz, CDCl3) δ: 163.8, 143.6, 140.4, 138.5, 136.6,
134.4, 130.1, 129.9, 128.7, 127.7, 127.2, 114.6, 92.6
52.7, 42.2, 34.7, 31.1, 21.7; HRMS (ESI) calcd for
C21H22ClNNaO6S [M＋Na＋] 474.0749, found 474.0760.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 1.0 mL/min, tR1＝24.76 min (major) and tR2＝
31.77 min (minor); ee＝83%; de＞99%.
General procedure for the Michael addition
The catalyst 1d (1.69 mg, 0.01 mmol), DABCO
(2.24 mg, 0.02 mmol), enone 3 (0.1 mmol) and alde-
hyde 4 (0.2 mmol) were added to a screw-capped vial
containing n-butanol (1 mL) at room temperature. The
reaction mixture was stirred at the same temperature
until complete consumption of enone 3 (monitored by
TLC). The solvent was then evaporated and the residue
was purified by flash column silica-gel chromatography
(PE/EA, V∶V＝4∶1) to provide the corresponding
Michael adducts. Diastereoselectivity (de) and the enan-
tiomeric excess (ee) were determined by HPLC analysis
of the pure product.
Methyl 2-hydroxy-3-(4-methylphenylsulfonamido)-
methyl-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylate
1
(4a): White solid. m.p. 147—148 ℃; H NMR (400
MHz, CDCl3) δ: 7.58 (d, J＝8.2 Hz, 2H), 7.37—7.02 (m,
6H), 6.13 (d, J＝2.4 Hz, 1H), 5.68 (d, J＝2.4 Hz, 1H),
3.77 (s, 3H), 3.63—3.48 (m, 1H), 3.13—2.96 (m, 1H),
2.83—2.80 (m, 1H), 2.40 (s, 3H), 2.17—2.06 (m, 1H);
13C NMR (100 MHz, CDCl3) δ: 164.1, 143.6, 140.9,
139.7, 136.5, 129.9, 129.1, 128.6, 127.6, 127.3, 116.0,
93.1, 53.2, 42.5, 42.1, 37.2, 21.8; HRMS (ESI) calcd for
C21H23NNaO6S [M＋Na＋]: 440.1138, found 440.1148.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝82∶18, UV
254 nm, 0.65 mL/min, tR1＝21.97 min (major) and
tR2＝27.20 min (minor); ee＝93%; de＞99%.
Ethyl 2-hydroxy-3-(4-methylphenylsulfonamido)-
methyl-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylate
(4b): White solid. m.p. 95—96 ℃; 1H NMR (400 MHz,
CDCl3) δ: 7.59—7.56 (m, 2H), 7.44—7.04 (m, 6H),
6.13 (d, J＝2.4 Hz, 1H), 5.67 (d, J＝2.0 Hz, 1H),
4.26—4.21 (m, 2H), 3.62—3.57 (m, 1H), 3.14—2.92
(m, 1H), 2.89—2.72 (m, 1H), 2.40 (d, 3H), 2.11 (m, 1H),
1.27 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
163.7, 143.3, 141.0, 139.8, 136.5, 129.9, 129.0, 128.6,
127.6, 127.3, 115.7, 93.1, 61.9, 42.5, 42.1, 37.2, 21.7,
14.3; HRMS (ESI) calcd for C22H25NNaO6S [M＋Na＋]
454.1295, found 454.1269. HPLC conditions: the enan-
tiomeric excess and diastereoselective excess were de-
termined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝88∶12, UV 254 nm, 0.5 mL/min, tR1＝47.56
min (major) and tR2＝51.20 min (minor); ee＝91%; de
＞99%.
Methyl 4-(4-chlorophenyl)-2-hydroxy-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
1
carboxylate (4g): White solid. m.p. 148—149 ℃; H
NMR (400 MHz, CDCl3) δ: 7.57 (d, J＝8.2 Hz, 2H),
7.27—7.21 (m, 4H), 7.09—7.05 (m, 2H), 6.07 (d, J＝
2.4 Hz, 1H), 5.66 (s, 1H), 3.79 (s, 3H), 3.63—3.58 (m,
1H), 3.24—3.18 (m, 1H), 3.02—2.98 (m, 1H), 2.82—
2.70 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3)
2682
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2681—2687

An Efficient Asymmetric Domino Reaction of Amino Aldehyde to β,γ-Unsaturated α-Keto Esters
δ: 163.8, 143.8, 143.7, 139.7, 139.5, 136.3, 133.4, 129.9,
129.2, 128.7, 127.3, 115.2, 93.1 52.8, 42.5, 36.4, 31.1,
21.8; HRMS (ESI) calcd for C21H22ClNNaO6S [M＋
Na＋] 474.0749, found 474.0754. HPLC conditions: the
enantiomeric excess and diastereoselective excess were
determined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝85∶15, UV 254 nm, 0.7 mL/min, tR1＝26.45
min (major) and tR2＝29.49 min (minor); ee＝92%; de
＞99%.
Methyl 4-(2,6-dichlorophenyl)-2-hydroxy-3-(4-meth-
ylphenylsulfonamido)methyl-3,4-dihydro-2H-pyran-
1
6-carboxylate (4k): White solid. m.p. 174—175℃; H
NMR (400 MHz, acetone-d6) δ: 7.52—7.25 (m, 6H),
6.61—6.48 (m, 1H), 5.96 (d, J＝2.4 Hz, 1H), 5.78 (s,
1H), 4.4—4.45 (m, 1H), 3.71 (s, 3H), 3.16—3.09 (m,
1H), 2.89—2.78 (m, 1H), 2.60—2.49 (m, 1H), 2.38 (s,
3H); 13C NMR (100 MHz, acetone-d6) δ: 162.9, 143.2,
140.8, 137.3, 136.7, 135.6, 130.8, 129.7, 128.8, 127.1,
112.9, 91.7, 51.4, 42.4, 38.8, 34.6, 20.7; HRMS (ESI)
calcd for C21H21Cl2NNaO6S [M＋Na＋] 508.0359, found
508.0374. HPLC conditions: the enantiomeric excess
and diastereoselective excess were determined by HPLC
(Chiralcel AD-H), Hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 1.0 mL/min, tR1＝37.28 min (major) and tR2＝
49.13 min (minor); ee＝92%; de＞99%
Methyl 4-(2-bromophenyl)-2-hydroxy-3-((4-methyl-
phenylsulfonamido)methyl)-3,4-dihydro-2H-pyran-6-
1
carboxylate (4h): White solid. m.p. 82—83 ℃; H
NMR (400 MHz, CDCl3) δ: 7.59—7.55 (m, 2H), 7.35—
6.92 (m, 6H), 6.02 (d, J＝2.8 Hz, 1H), 5.70 (s, 1H),
3.78 (s, 3H), 3.15—3.08 (m, 2H), 2.99—2.76 (m, 1H),
2.40 (s, 3H), 2.37—2.20 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 163.8, 143.6, 140.3, 136.5, 133.4, 129.9,
129.3, 129.1, 128.2, 127.61, 127.4, 125.2, 114.6, 92.6,
52.7, 42.2, 37.4, 21.7; HRMS (ESI) calcd for
C21H22BrNNaO6S [M＋Na＋] 518.0243, found 518.0259.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 1.0 mL/min, tR1＝25.93 min (major) and tR2＝
34.75 min (minor); ee＝91%; de＞99%.
Methyl 4-(3-bromophenyl)-2-hydroxy-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
carboxylate (4i): White solid. m.p. 88—89 ℃; 1H NMR
(400 MHz, CD3OD) δ: 7.68—6.99 (m, 8H), 5.91 (d, J＝
2.6 Hz, 1H), 5.60 (d, J＝2.0 Hz, 1H), 3.74 (s, 3H), 3.33
—3.26 (m, 1H), 2.98—2.92 (m, 1H), 2.55—2.49 (m,
1H), 2.37 (s, 3H), 2.13—1.94 (m, 1H); 13C NMR (100
MHz, CD3OD) δ: 163.8, 144.5, 143.6, 140.6, 136.5,
131.2, 130.4, 130.1, 129.6, 127.3, 126.9, 113.6, 91.9,
51.6, 43.2, 41.5, 37.8, 20.48; HRMS (ESI) calcd for
C21H22BrNNaO6S [M＋Na＋] 518.0243, found 518.0251.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 0.85 mL/min, tR1＝23.87 min (major) and tR2＝
29.81 min (minor); ee＝85%; de＞99%.
Methyl 4-(4-bromophenyl)-2-hydroxy-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
carboxylate (4j): White solid. m.p. 77—79 ℃; 1H
NMR (400 MHz, CDCl3) δ: 7.59 (d, J＝8.2 Hz, 2H),
7.41 (d, J＝8.2 Hz, 2H), 7.27—7.23 (m, 2H), 7.04—
6.99 (m, 2H), 6.09 (d, J＝2.6 Hz, 1H), 5.64 (s, 1H),
5.20—5.16 (m, 1H), 3.80 (s, 3H), 3.63—3.58 (m, 1H),
3.15—2.88 (m, 1H), 2.79—2.75 (m, 1H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 163.8, 143.8, 140.1,
136.4, 132.2, 130.4, 129.9, 127.3, 121.4 (s), 115.1, 93.0,
52.8, 42.4, 36.5, 29.9, 21.8; HRMS (ESI) calcd for
C21H22BrNNaO6S [M＋Na＋] 518.0243, found 518.0405.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 0.85 mL/min, tR1＝27.58 min (major) and tR2＝
30.24 min (minor); ee＝92%; de＞99%.
Methyl 2-hydroxy-3-((4-methylphenylsulfonamido)-
methyl)-4-p-tolyl-3,4-dihydro-2H-pyran-6-carboxylate
1
(4l): White solid. m.p. 155—156 ℃; H NMR (400
MHz, CDCl3) δ: 7.59 (d, J＝8.2 Hz, 2H), 7.27—7.16 (m,
2H), 7.10 (d, J＝7.6 Hz, 2H), 7.01 (d, J＝7.8 Hz, 2H),
6.11 (d, J＝2.4 Hz, 1H), 5.64 (s, 1H), 3.77 (s, 3H),
3.58—3.51 (m, 1H), 3.50—3.39 (m, 1H), 3.10—2.95
(m, 1H), 2.84—2.79 (m, 1H), 2.40 (s, 3H), 2.34 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 164.0, 143.6, 139.6,
137.9, 137.3, 136.6, 129.8, 128.4, 127.3, 116.3, 93.2,
52.7, 42.8, 36.8, 29.9, 21.8, 21.3; HRMS (ESI) calcd for
C22H25NNaO6S [M＋Na＋] 454.1295, found 454.1294;
HPLC conditions: The enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 0.8 mL/min, tR1＝25.30 min (major) and tR2＝
28.39 min (minor); ee＝92%; de＞99%.
Methyl 2-hydroxy-4-(3-methoxyphenyl)-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
1
carboxylate (4m): White solid. m.p. 89—90 ℃; H
NMR (400 MHz, CDCl3) δ: 7.58—7.52 (m, 2H), 7.24—
7.16 (m, 3H), 6.80 (m, 1H), 6.74—6.65 (m, 2H), 6.10 (d,
J＝2.4 Hz, 1H), 5.68 (s, 1H), 3.79 (s, 3H), 3.74 (s, 3H),
3.60—3.41 (m, 1H), 3.16—2.98 (m, 1H), 2.85—2.61
(m, 1H), 2.38 (s, 3H), 2.15—2.10 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ: 164.1, 160.1, 143.6, 142.7, 139.6,
136.5, 129.9, 127.2, 120.9, 115.9, 114.1, 113.1, 93.0,
55.5, 52.7, 42.3, 41.5, 37.3, 21.7; HRMS (ESI) calcd for
C22H25NNaO7S [M＋Na＋] 470.1244, found 470.1254.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝88∶12, UV
254 nm, 0.8 mL/min, tR1＝35.24 min (major) and tR2＝
48.87 min (minor); ee＝82%; de＞99%.
Methyl 2-hydroxy-4-(4-methoxyphenyl)-3-(4-methyl-
phenylsulfonamido)methyl-3,4-dihydro-2H-pyran-6-
1
carboxylate (4n): White solid. m.p. 63—64 ℃; H
NMR (400 MHz, CDCl3) δ: 7.58 (d, J＝8.2 Hz, 2H),
7.29—7.17 (m, 2H), 7.04 (d, J＝8.8 Hz, 2H), 6.82 (d,
J＝8.6 Hz, 2H), 6.13—6.05 (m, 1H), 5.64 (d, J＝2.4 Hz,
1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.60—3.44 (m, 1H),
3.05—2.98 (m, 1H), 2.84—2.79 (m, 1H), 2.40 (s, 3H),
Chin. J. Chem. 2012, 30, 2681—2687
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shen et al.
FULL PAPER
2.13—2.01 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
159.1, 143.4, 140.1, 136.6, 133.6, 129.3, 129.2, 126.9,
115.1, 114.0, 91.9, 54.6, 51.5, 43.5, 41.6, 37.2, 20.3;
HRMS (ESI) calcd for C22H25NNaO7S [M ＋Na ＋]
470.1244, found 470.1235. HPLC conditions: the enan-
tiomeric excess and diastereoselective excess were de-
termined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝85∶15, UV 254 nm, 0.80 mL/min, tR1＝29.07
min (major) and tR2＝32.19 min (minor); ee＝85%;
de＞99%.
tioselectivity (Entries 1, 2). Their diastereomers 1c and
1d both provided good enantioselectivities and yields
(Entries 3, 4). It was interesting that only one pair of
peaks of product was found during the HPLC experi-
mentals. trans-Perhydroindolic acids are comparably
more efficient than L-proline (Entry 5), thus the catalyst
1d was used in subsequent reactions.
Table 1 Asymmetric domino reaction with different catalystsa
O
Catalyst (10 mol%)
DMAP (10 mol%)
Methyl 2-hydroxy-3-(4-methylphenylsulfonamido)-
methyl-4-(naphthalen-2-yl)-3,4-dihydro-2H-pyran-6-
OMe
O
Ph
TsHN
+
1
O
i-PrOH, r.t.
carboxylate (4o): White solid. m.p. 89—91 ℃; H
3
2a
NMR (400 MHz, CDCl3) δ: 7.92—7.76 (m, 2H), 7.57 (s,
1H), 7.54—7.50 (m, 1H), 7.28—7.23 (m, 1H), 7.22 (d,
J＝8.2 Hz, 1H), 6.86 (d, J＝8.2 Hz, 1H), 6.05 (d, J＝
2.6 Hz, 1H), 5.65 (d, J＝2.2 Hz, 1H), 3.77 (s, 3H),
3.49—3.44 (m, 1H), 2.95—2.89 (m, 1H), 2.53—2.49
(m, 1H), 2.29—2.25 (m, 1H), 2.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 143.6, 140.0, 138.4, 129.8, 128.9,
128.0, 127.9, 127.9, 127.9, 127.9, 115.7, 93.1, 52.7,
42.3, 37.4, 30.0, 21.7; HRMS (ESI calcd for
C25H25NNaO6S [M＋Na＋] 490.1295, found 490.1308.
HPLC conditions: the enantiomeric excess and di-
astereoselective excess were determined by HPLC
(Chiralcel AD-H), hexane/i-PrOH, V∶V＝87∶13, UV
254 nm, 1.0 mL/min, tR1＝26.22 min (major) and tR2＝
32.22 min (minor); ee＝88%; de＞99%.
Methyl 4-(furan-2-yl)-2-hydroxy-3-(4-methylphenyl-
sulfonamido)methyl-3,4-dihydro-2H-pyran-6-carboxyl-
ate (4p): White solid. m.p. 101—102 ℃; 1H NMR (400
MHz, CDCl3) δ: 7.66 (d, J＝8.2 Hz, 2H), 7.33—7.29 (m,
1H), 7.28—7.22 (m, 2H), 6.36—6.23 (m, 1H), 6.10 (d,
J＝2.8 Hz, 2H), 5.64 (s, 1H), 3.77 (s, 3H), 3.19—2.88
(m, 4H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
163.4, 153.4, 143.7, 142.3, 140.1, 136.8, 129.9, 127.3,
112.7, 110.7, 107.4, 92.8, 52.7, 42.3, 31.5, 29.9, 21.7;
HRMS (ESI) calcd for C19H21NNaO7S [M ＋Na ＋]
430.0931, found 430.0928. HPLC conditions: the enan-
tiomeric excess and diastereoselective excess were de-
termined by HPLC (Chiralcel AD-H), hexane/i-PrOH,
V∶V＝87∶13, UV 254 nm, 0.8 mL/min, tR1＝32.89
min (major) and tR2＝40.31 min (minor); ee＝92%; de
＞99%.
OH
O
TsHN
OMe
Ph
O
4a
Entry
Catalyst
Time/h
24
Yieldb/%
eec/%
－51
52
1
2
3
4
5
1a
1b
83
82
90
92
81
24
1c
24
－78
79
1d
24
L-proline
24
27
a Reactions were conducted with (E)-methyl 2-oxo-4-phenylbut-
3-enoate (0.1 mmol) and 4-methyl-N-(3-oxopropyl)benzene-
sulfonamide (0.2 mmol) by using10 mol% catalyst and DMAP in
i-PrOH at room temperature. b Isolated yield. Determined by
c
chiral HPLC with more than 99% de.
The influence of solvent on the reaction was then
investigated in the presence of 10 mol% 1d at room
temperature in i-PrOH (Table 2). In low polarity sol-
vents such as toluene and Et2O, low yields and enanti-
oselectivities were obtained (Entries 1, 2). When using
moderately polar solvents such as CH2Cl2 and CHCl3,
no obvious improvement in reactivity was observed
(Entries 3, 4). If DMF was used as the solvent, the reac-
tion activity and enantioselectivity were improved sig-
nificantly (Entry 5). Therefore we envisaged alcohol
solvents would be most suitable for the asymmetric
domino reaction. The reaction was performed in MeOH,
EtOH and n-PrOH with excellent asymmetric catalytic
results being obtained (Entries 6—8). A range of other
alcohol solvents i-PrOH, n-BuOH, iso-pentanol and
tert-pentanol were also examined, and n-BuOH pro-
vided the most promising result (Entry 10). n-BuOH
was therefore used as the solvent of choice in the fol-
lowing reactions.
Results and Discussion
1a—1d were first used in asymmetric domino Mi-
chael addition/cyclisation reactions of amino aldehyde
with β,γ-unsaturated α-keto esters to determine the ef-
fect the configuration of the catalysts had on the reac-
tions. Thus, the reaction of (E)-methyl 2-oxo-4-phe-
nylbut-3-enoate (2a) with 4-methyl-N-(3-oxopropyl)-
benzenesulfonamide (3) was carried out in the presence
of 10 mol% of catalyst 1a—1d and DMAP in i-PrOH at
room temperature.
Several bases were examined as additives in the re-
action. As shown in Table 3, a majority of the basic ad-
ditives (Entries 1 vs. 2—8) dramatically shortened the
length of the reaction time, providing excellent di-
astereoselectivity, good enantioselectivity, and good
yields. Acidic additives did not improve the reaction.
As shown in Table 1, catalyst 1a and its enantiomer
1b gave good yields of product but only moderate enan-
2684
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2681—2687

An Efficient Asymmetric Domino Reaction of Amino Aldehyde to β,γ-Unsaturated α-Keto Esters
Table 2 The influence of solvent on the asymmetric domino
mol% increased the enantioselectivity. Increasing the
reactiona
quantity of additive to 50 mol% decreased enantio-
selectivity and yield, however a reduction in reaction
time was observed.
1d (10 mol%)
DMAP (10 mol%)
+
2a
3
4a
With the above optimal reaction conditions in hand,
the asymmetric domino reaction was applied to a series
of aromatic β,γ-unsaturated α-keto esters (Table 4). At
first, the influence of the ester group on the reaction
outcome was examined (Entries 1—4). The methyl ester
(with little steric hindrance) gave the best result (Entry
1). The effects of substituents on the aromatic ring were
then investigated. β,γ-Unsaturated α-keto esters with
electron-withdrawing (Entries 5—11) and electon-
donating (Entries 12—14) substituents on the aromatic
group provided products in excellent yield and good
enantioselectivity. Excellent diasteroeslectivities and
enantioselectivies were also obtained when the phenyl
group was replaced with a naphthalene or furan ring
(Entries 15 and 16). The present catalytic system is
Solvent, r.t.
Entry
1
Solvent
Toluene
Et2O
Time/h
14 d
14 d
14 d
14 d
96
Yieldb/%
35
eec/%
60
60
2
41
3
CH2Cl2
CHCl3
DMF
37
57
68
70
4
43
5
92
6
MeOH
EtOH
96
98
82
7
72
79
85
85
8
n-PrOH
i-PrOH
n-BuOH
36
80
9
24
92
79
10
11
12
36
93
88
iso-Pentanol
36
87
87
Table 4 Asymmetric domino reaction for a seriesof the aro-
matic β,γ-unsaturatedα-keto esters with 1d as a catalysta
tert-Pentanol
72
83
78
a Reactions were conducted with 0.1 mmol of (E)-methyl 2-oxo-
4-phenylbut-3-enoate and 0.2 mmol of 4-methyl-N-(3-oxopro-
pyl)-benzenesulfonamide in the presence of 10 mol% 1d and
O
1d (10 mol%)
OR
DABCO (20 mol%)
O
Ar
TsHN
+
DMAP in a solvent at room temperature. b Isolated yield. De-
c
O
n-Butanol, r.t.
termined by chiral HPLC with more than 99% de.
3
2
OH
Table 3 The influence of additive on the asymmetric domino
TsHN
O
reactiona
OR
Ar
1d (10 mol%)
O
4
DMAP (10 mol%)
+
2a
3
4a
Entry
4
Ar
R
Tim/h Yieldb/% eec/%
Solvent, r.t.
1
2
4a
4b
4c
4d
4e
4f
C6H5
C6H5
Me
Et
24
12
12
12
12
12
12
12
24
12
12
12
12
36
12
12
94
88
90
87
92
88
93
89
89
94
90
90
90
96
91
90
93
91
92
-d
Entry
Additive
None
Time/h
8 d
48
Yieldb/%
82
eec/%
84
1
2
3
C6H5
i-Pr
Bn
Et3N
93
90
4
C6H5
3
DABCO
TMEDA
DIPEA
DMAP
24
93
90
5
p-FC6H4
o-ClC6H4
p-ClC6H4
o-BrC6H4
m-BrC6H4
p-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
92
83
92
84
85
92
92
92
82
85
88
92
4
36
89
87
6
5
48
97
87
7
4g
4h
4i
6
36
93
87
8
7
Cinchona alkali
NaOAc
36
87
89
9
8
36
80
81
10
4j
9
2-ClC6H4CO2H
DABCO
8 d
24
62
87
11 4k
12 4l
2,6-Cl2C6H4
11d
12e
94
93
p-CH3C6H4
DABCO
8
81
90
13 4m m-MeOC6H4 Me
a Reactions were conducted with 0.1 mmol (E)-methyl 2-oxo-4-
phenylbut-3-enoate and 0.2 mmol 4-methyl-N-(3-oxopropyl)-
benzenesulfonamideby using 10 mol% 1d in the presence of ad-
ditive in n-BuOH at room temperature. b Isolated yield. c Deter-
mined by chiral HPLC with more than 99% de. 20 mol%
DABCO was used. e 50 mol% DABCO was used.
14 4n
15 4o
16 4p
p-MeOC6H4
2-Nap.
Me
Me
Me
2-Furanyl
a Reactions were conducted with 0.1 mmol of (E)-methyl 2-oxo-
4-phenylbut-3-enoate and 0.2 mmol of 4-methyl-N-(3-oxopro-
pyl)-benzenesulfonamide by using 10 mol% 1d and 20 mol%
d
DABCO in n-BuOH at room temperature. b Isolated yield. De-
c
DABCO proved to be the best additive according to a
combination of enantioselectivity, reaction time and
yield. Increasing the quantity of additive from 10 to 20
d
termined by chiral HPLC with more than 99% de. The sample
could not be separated by chiral HPLC.
Chin. J. Chem. 2012, 30, 2681—2687
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2685

Shen et al.
FULL PAPER
Scheme 1 Proposed mechanism for the stereochemical outcome
1d (10 mol%)
O
OH
DABCO (20 mol%)
OMe
O
TsHN
Ph
+
TsHN
Ph
O
O
n-Butanol, r.t.
OMe
2
3
O
4
-H2O
1d
-1d
+H2O
H
H
H
H
O
H
H
O
O
N
H
O
N
H
N
OH
OH
H
H
H
O
H
H
O
O-
TsHN
Ph
TsHN
Ph
CO2Me
CO2Me
CO2Me
TsHN
therefore suitable for domino reactions with a range of
substituted β,γ-unsaturated α-keto esters. The aforemen-
tioned methodology provides an efficient synthetic
pathway to the synthesis of highly substituted dihydro-
pyran derivatives containing unusual amino group.
To determine the absolute configuration of the dom-
ino reaction product, X-ray crystallography studies were
performed. Unfortunately a single crystal of the corre-
sponding chiral product could not be obtained. Refer-
ring to our previous work in this area, the hemiacetal
hydroxyl group and the adjacent ester group should lie
on the opposite side of the phenyl ring.[4g]
prepared using mild reaction conditions.
Acknowledgement
This work was partly supported by the National
Natural Science Foundation of China (Nos. 20972095,
21172143 and 21172145), the Science and Technology
Commission
of
Shanghai
Municipality
(No.
09JC1407800), the Nippon Chemical Industrial Co., Ltd
and the Instrumental Analysis Center of Shanghai Jiao
Tong University. We thank Prof. Tsuneo Imamotoand
Dr. Masashi Sugiyafor helpful discussion.
Thus, a transition state model was proposed to ac-
count for the stereochemical outcome when using 1d as
the catalyst (Scheme 1). The aldehyde amine 3 reacts
with 1d to give a nucleophilic enamine intermediate
whilst the (E)-methyl 2-oxo-4-phenylbut-3-enoate (2a)
is directed toward the carboxylic acid group by a hy-
drogen bond (with the molecule lying behind the
enamine) enhancing the electrophilic character of 2a.
The resulting enamine attacks the double C—C bond of
2a (from above the plane of the alkene) to give the
imine-enol intermediate with the adjacent amino group
lying on the opposite side of the phenyl ring. Following
cyclization, front-side attack by H2O gives the desired
product 4 and catalyst 1d.
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2686
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2681—2687

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Chin. J. Chem. 2012, 30, 2681—2687
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2687