Asymmetric sequential aza-diels-alder and o-michael addition: Efficient construction of chiral hydropyrano[2,3-b]pyridines

Article abstract of DOI:10.1002/cjoc.201200942

An asymmetric aza-Diels-Alder and O-Michael addition sequence has been developed to construct chiral hydropyrano[2,3-b]pyridine derivatives with good yields and excellent stereoselectivity, by starting with N-Ts-1-aza-1,3- butadienes and aliphatic aldehydes tethered to an α,β-unsaturated ketone motif. A tandem O-Michael addition reaction was completed via acid catalysis.

Full text of DOI:10.1002/cjoc.201200942

FULL PAPER
DOI: 10.1002/cjoc.201200942
Asymmetric Sequential Aza-Diels-Alder and O-Michael
Addition: Efficient Construction of Chiral
Hydropyrano[2,3-b]pyridines
Yin, Xiang(尹祥)
Zhou, Qingqing(周清清)
Dong, Lin(董琳)
Chen, Yingchun*(陈应春)
Key Laboratory of Drug-Targeting and Drug Delivery Systems of the Ministry of Education, West China School of
Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
An asymmetric aza-Diels-Alder and O-Michael addition sequence has been developed to construct chiral hy-
dropyrano[2,3-b]pyridine derivatives with good yields and excellent stereoselectivity, by starting with N-Ts-1-aza-
1,3-butadienes and aliphatic aldehydes tethered to an α,β-unsaturated ketone motif. A tandem O-Michael addition
reaction was completed via acid catalysis.
Keywords asymmetric organocatalysis, aza-Diels-Alder, O-Michael addition, hemiaminal, pyrano[2,3-b]-
pyridines
Introduction
quential aza-Diels-Alder and Friedel-Crafts reaction as
well as an asymmetric aza-Diels-Alder reaction[7] fol-
lowed by a tandem cation-olefin reaction,[8] which both
involve a highly electrophilic N-Ts iminium ion formed
in situ under acidic conditions. Our continuing interest
in this highly efficient methodology prompted us to ap-
ply hydroxyl group of hemiaminal to construct hexahy-
dro-2H-pyrano[2,3-b]pyridine via a new aza-Diels-
Alder and intramolecular O-Michael addition[9] se-
quence, as outlined in Scheme 2.
O- and N-heterocycles are very important structural
motifs in numerous natural products.[1] Among them,
the structure of octahydro-2H-pyrano[2,3-b]pyridine
was found in various kinds of compounds that exhibited
broad biological activities as illustrated in Scheme 1.[2]
Hence, the synthesis of such complex and diversely
structured heterocycles has attracted wide attention in
the field of medicinal and synthetic organic chemistry.[3]
Scheme 1 Selected compounds containing an octahydro-2H-
pyrano[2,3-b]pyridine motif
Scheme 2 Proposed aza-Diels-Alder/O-Michael addition se-
quence
O
NTs
CO2Et
aza-Diels-Alder
Chiral amine
H3C
R1
+
R
R
O
N
O
N
O
NH
2
3
O
O
O
O
NH
CH3
R
O
OH
N
N
H
O
*
O-Michael
OH
*
*
Compound for prevention
of AIDS virus
*
Nitaramine
Huperzine S
NTs
NTs
CO2Et
*
*
R1
CO2Et
R1
*
Recently, our group developed chiral secondary
amine-catalyzed asymmetric inverse-electron-demand
aza-Diels-Alder reaction towards stereoselective syn-
thesis of piperidine derivatives from N-sulfonyl-1-aza-
1,3-butadienes and aliphatic aldehydes.[4,5] Based on this
methodology, more complex heterocyclic compounds
were synthesized by further transformations of the he-
miaminal intermediates.[6] Moreover, we reported a se-
5
4
Experimental
General methods
NMR data were obtained for 1H at 400 MHz, and for
13C at 100 MHz. Chemical shifts were reported relative
*
E-mail: ycchenhuaxi@yahoo.com.cn; Tel.: 0086-028-85502609; Fax: 0086-028-85502609
Received September 24, 2012; accepted October 30.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200942 or from the author.
Chin. J. Chem. 2012, 30, 2669—2675
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2669

Yin et al.
FULL PAPER
to tetramethylsilane with the solvent resonance as the
internal standard in CDCl3 solution. ESI HRMS was
recorded on a Bruker Apex-2. In each case, enanti-
omeric ratio was determined by HPLC analysis on a
chiral column in comparison with authentic racemates,
using a Daicel Chiralcel AD-H or IC, OD Column (250
mm×4.6 mm). UV detection was monitored at 220 nm
or 254 nm. Optical rotation data were examined in
CHCl3 solution at 20 ℃. Column chromatography was
performed on silica gel (200—300 mesh) eluting with
ethyl acetate and petroleum ether. TLC was performed
on glass-backed silica plates. UV light and I2 were used
to visualize products. All chemicals were used without
purification as commercially available unless otherwise
noted. 1-Aza-1,3-butadienes[10] and the secondary amine
catalyst[11] were prepared according to the literature
procedures. The aliphatic aldehydes were also synthe-
sized according to the literature procedures.[12]
1H NMR (400 MHz, CDCl3) δ: 7.95 (d, J＝7.6 Hz, 2H),
7.87 (d, J＝8.0 Hz, 2H), 7.58 (t, J＝7.6 Hz, 1H), 7.47 (t,
J＝7.6 Hz, 2H), 7.28—7.24 (m, 2H), 7.12 (d, J＝8 Hz,
2H), 6.98 (d, J＝7.6 Hz, 2H), 6.15 (d, J＝3.2 Hz, 1H),
5.27 (d, J＝2.4 Hz, 1H), 4.22—4.17 (m, 3H), 3.49 (dd,
J＝11.2, 3.2 Hz, 1H), 3.42 (dd, J＝16.8, 5.6 Hz, 1H),
3.03 (dd, J＝16.4, 6.4 Hz, 1H), 2.43 (s, 3H), 2.35 (s,
3H), 1.84—1.81 (m, 1H), 1.67—1.60 (m, 4H), 1.18 (t,
J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 197.5,
164.4, 143.7, 137.7, 137.0, 136.9, 136.6, 133.2, 129.4,
129.3, 128.8, 128.5, 128.4, 128.1, 127.3, 126.1, 84.7,
75.7, 61.4, 44.8, 39.0, 37.0, 25.6, 24.5, 21.6, 21.0, 13.9;
ESI-HRMS calcd for C33H35NO6S ＋ Na 596.2083,
found 596.2081.
Ethyl-2-(2-oxo-2-phenylethyl)-5-m-tolyl-8-tosyl-
3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyridine-7-
carboxylate (5c) 79% yield; [α]2D0 ＋51.1 (c 0.47 in
CHCl3); 99% ee, determined by HPLC analysis [Daicel
chiralcel AD, n-hexane/i-PrOH＝60/40, 1.0 mL/min,
λ＝220 nm, t(major)＝9.78 min, t(minor)＝11.96 min];
1H NMR (400 MHz, CDCl3) δ: 7.96 (d, J＝8.0 Hz, 2H),
7.87 (d, J＝8.4 Hz, 2H), 7.58 (t, J＝7.2 Hz, 1H), 7.47 (t,
J＝7.6 Hz, 2H), 7.27—7.25 (m, 2H), 7.18 (t, J＝8.0 Hz,
1H), 7.07 (d, J＝7.2 Hz, 1H), 6.88 (d, J＝6.4 Hz, 2H),
6.16 (d, J＝2.8 Hz, 1H), 5.28 (d, J＝1.6 Hz, 1H), 4.23
—4.18 (m, 3H), 3.50 (dd, J＝7.2, 3.2 Hz, 1H), 3.44 (dd,
J＝16.4, 6.4 Hz, 1H), 3.05 (dd, J＝16.8, 6.4 Hz, 1H),
2.41 (s, 3H), 2.33 (s, 3H), 1.81—1.79 (m, 1H), 1.68—
1.59 (m, 4H), 1.19 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 197.5, 164.5, 143.7, 140.7, 138.5,
137.0, 136.5, 133.2, 129.5, 129.0, 128.6, 128.5, 128.2,
128.1, 127.3, 126.0, 125.8, 84.7, 75.7, 61.5, 44.8, 39.3,
36.8, 25.6, 24.5, 21.6, 21.4, 13.9; ESI-HRMS calcd for
C33H35NO6S＋Na 596.2083, found 596.2085.
General procedure for sequential aza-Diels-Alder
and O-Michael addition reaction
The reaction was carried out with 1-azadiene 3 (0.1
mmol) and aldehyde 2 tethered to an α,β-unsaturated
motif (0.2 mmol) in the presence of α,α-diphenylpro-
linol O-TMS ether 1 (6.8 mg, 0.02 mmol) and
o-fluorobenzoic acid (OFBA, 2.8 mg, 0.02 mmol) in
MeCN/H2O (10∶1, 1 mL) at 30 ℃. After completion
(monitored by TLC analysis), TFA (trifluoroacetic acid,
0.1 mL) was added, and the reaction was monitored by
TLC. Then the solvents were removed and the residue
was purified by flash chromatography on silica gel (pe-
troleum ether/ethyl acetate) to give fused heterocycle 5,
as outlined in Scheme 2.
Ethyl-2-(2-oxo-2-phenylethy)-5-phenyl-8-tosyl-
3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyridine-7-
carboxylate (5a) 90% yield; [α]2D0 ＋52.1 (c 0.63 in
CHCl3); 99% ee, determined by HPLC analysis [Daicel
chiralcel IC, n-hexane/i-PrOH＝60/40, 1.0 mL/min, λ＝
220 nm, t(major)＝59.10 min, t(minor)＝40.81 min]; 1H
NMR (400 MHz, CDCl3) δ: 7.95 (d, J＝7.6 Hz, 2H),
7.87 (d, J＝8.0 Hz, 2H), 7.58 (t, J＝7.6 Hz, 1H), 7.47 (t,
J＝7.6 Hz, 2H), 7.32—7.24 (m, 5H), 7.09 (d, J＝6.8 Hz,
2H), 6.17 (d, J＝3.2 Hz, 1H), 5.28 (d, J＝2.4 Hz, 1H),
4.22—4.17 (m, 3H), 3.53 (dd, J＝10.8, 3.2 Hz, 1H),
3.43 (dd, J＝16.6, 5.8 Hz, 1H), 3.04 (dd, J＝16.2, 6.6
Hz, 1H), 2.41 (s, 3H), 1.86—1.83 (m, 1H), 1.68—1.67
(m, 4H), 1.18 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 197.4, 164.4, 143.7, 140.8, 137.0, 136.6,
133.2, 129.4, 128.7, 128.5, 128.3, 128.2, 127.2, 125.8,
84.6, 75.7, 61.4, 44.8, 39.4, 37.1, 25.6, 24.4, 21.5, 13.8;
ESI-HRMS calcd for C32H33NO6S＋K 598.1666, found
598.1667.
Ethyl-5-(3-methoxyphenyl)-2-(2-oxo-2-phenyl-
ethyl)-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,
3-b]pyridine-7-carboxylate (5d) 58% yield; [α]D20
＋42.7 (c 0.59 in CHCl3); 95% ee, determined by HPLC
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝10.99 min, t(minor)
1
＝12.58 min]; H NMR (400 MHz, CDCl3) δ: 7.95 (d,
J＝8.0 Hz, 2H), 7.86 (d, J＝8.0 Hz, 2H), 7.57 (t, J＝7.2
Hz, 1H), 7.46 (t, J＝7.6 Hz, 2H), 7.24—7.20 (m, 3H),
6.79 (d, J＝8.4 Hz, 1H), 6.68 (d, J＝7.2 Hz, 1H), 6.62
(s, 1H), 6.15 (d, J＝3.2 Hz, 1H), 5.28 (d, J＝2.0 Hz,
1H), 4.22—4.17 (m, 3H), 3.80 (s, 3H), 3.50 (dd, J＝6.8,
3.2 Hz, 1H), 3.42 (dd, J＝16.4, 5.6 Hz, 1H), 3.03 (dd,
J＝16.8, 6.4 Hz, 1H), 2.40 (s, 3H), 1.86—1.83 (m, 1H),
1.70—1.51 (m, 4H), 1.18 (t, J＝7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 197.5, 164.4, 159.8, 143.7, 142.4,
137.0, 136.6, 133.2, 129.7, 129.5, 128.5, 128.3, 128.2,
128.0, 127.2, 125.6, 120.9, 114.6, 84.7, 75.7, 61.4, 55.2,
44.8, 39.4, 36.8, 25.6, 24.5, 21.6, 13.9; ESI-HRMS
calcd for C33H35NO7S＋Na 612.2032, found 612.2034.
Ethyl-5-(4-methoxyphenyl)-2-(2-oxo-2-phenyl-
ethyl)-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,
3-b]pyridine-7-carboxylate (5e) 80% yield; [α]D20
＋50.2 (c 0.81 in CHCl3); 92% ee, determined by HPLC
Ethyl-2-(2-oxo-2-phenylethyl)-5-p-tolyl-8-tosyl-
3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyridine-7-
carboxylate (5b) 77% yield; [α]2D0 ＋62.9 (c 0.69 in
CHCl3); 99% ee, determined by HPLC analysis [Daicel
chiralcel AD, n-hexane/i-PrOH＝60/40, 1.0 mL/min,
λ＝220 nm, t(major)＝10.35 min, t(minor)＝15.33 min];
2670
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2669—2675

Efficient Construction of Chiral Hydropyrano[2,3-b]pyridines
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝13.19 min, t(minor)
＝27.18 min]; H NMR (400 MHz, CDCl3) δ: 7.95 (d,
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝6.44 min, t(minor)
＝8.77 min]; H NMR (400 MHz, CDCl3) δ: 7.94 (d,
1
1
J＝7.2 Hz, 2H), 7.87 (d, J＝8.0 Hz, 2H), 7.58 (t, J＝7.2
Hz, 1H), 7.47 (t, J＝7.6 Hz, 2H), 7.26—7.24 (m, 2H),
7.01 (d, J＝8.4 Hz, 2H ), 6.83 (d, J＝8.8 Hz, 2H ), 6.15
(d, J＝3.2 Hz, 1H), 5.27 (d, J＝2.4 Hz, 1H), 4.23—4.17
(m, 3H), 3.80 (s, 3H), 3.48 (dd, J＝10.4, 3.2 Hz, 1H),
3.42 (dd, J＝16.4, 6.0 Hz, 1H), 3.03 (dd, J＝16.8, 6.4
Hz, 1H), 2.41 (s, 3H), 1.84—1.80 (m, 1H), 1.68—1.65
(m, 4H), 1.18 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 197.5, 164.5, 158.8, 143.7, 137.0, 136.6,
133.2, 132.7, 129.5, 129.4, 128.6, 128.2, 128.1, 127.3,
126.2, 114.1, 84.7, 75.7, 61.4, 55.3, 44.8, 38.7, 37.2,
25.6, 24.5, 21.6, 13.9; ESI-HRMS calcd for
C33H35NO7S＋Na 612.2032, found 612.2034.
J＝7.2 Hz, 2H), 7.84 (d, J＝8.4 Hz, 2H ), 7.57 (t, J＝
6.8 Hz, 1H), 7.46 (t, J＝7.2 Hz, 1H), 7.26—7.23 (m,
2H), 7.19 (d, J＝5.2 Hz, 1H ), 6.94 (dd, J＝4.8, 3.2 Hz,
1H), 6.83 (d, J＝2.8 Hz, 1H ), 6.13 (d, J＝3.2 Hz, 1H),
5.28 (d, J＝2.4 Hz, 1H), 4.23—4.19 (m, 3H), 3.89 (dd,
J＝10.8, 3.2 Hz, 1H), 3.41 (dd, J＝16.8, 6.0 Hz, 1H),
3.02 (dd, J＝16.4, 6.0 Hz, 1H), 2.40 (s, 3H), 1.86—1.65
(m, 4H), 1.52—1.48 (m, 1H), 1.19 (t, J＝7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 197.3, 164.3, 143.7,
143.3, 136.9, 136.5, 133.2, 129.5, 128.5, 128.1, 128.0,
127.2, 127.0, 125.5, 124.4, 84.5, 75.6, 61.5, 44.7, 37.1,
34.2, 25.5, 24.8, 21.6, 13.8; ESI-HRMS calcd for
C30H31NO6S2＋Na 588.1490, found 588.1489.
Ethyl-5-(3-bromophenyl)-2-(2-oxo-2-phenyl-
ethyl)-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,
3-b]pyridine-7-carboxylate (5f) 62% yield; [α]D20
＋59.6 (c 1.00 in CHCl3); 96% ee, determined by HPLC
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝11.20 min, t(minor)
Ethyl-2-(2-(4-methoxyphenyl)-2-oxoethyl)-5-
phenyl-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano-
[2,3-b]pyridine-7-carboxylate (5i) 66% yield; [α]D20
＋37.1 (c 0.35 in CHCl3); 93% ee, determined by HPLC
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝24.86 min, t(minor)
1
1
＝18.43 min]; H NMR (400 MHz, CDCl3) δ: 7.95 (d,
＝33.93 min]; H NMR (400 MHz, CDCl3) δ: 7.94 (d,
J＝7.2 Hz, 2H), 7.86 (d, J＝8.4 Hz, 2H), 7.58 (t, J＝7.2
Hz, 1H), 7.49—7.42 (m, 4H), 7.25 (d, J＝9.2 Hz, 2H),
6.99 (d, J＝8.0 Hz, 2H), 6.10 (d, J＝3.2 Hz, 1H), 5.28
(d, J＝2.4 Hz, 1H), 4.23—4.16 (m, 3H), 3.51 (dd, J＝
10.8, 3.2 Hz, 1H), 3.41 (dd, J＝16.4, 6.4 Hz, 1H), 3.02
(dd, J＝16.4, 6.0 Hz, 1H), 2.41 (s, 3H), 1.85—1.82 (m,
1H), 1.68—1.59 (m, 4H), 1.18 (t, J＝7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 197.4, 164.2, 143.7, 140.0,
137.0, 136.6, 133.2, 131.8, 130.2, 129.8, 129.4, 128.6,
128.5, 128.2, 127.2, 124.8, 121.1, 84.5, 75.7, 61.5, 44.7,
38.9, 37.1, 25.5, 24.4, 21.6, 13.8; ESI-HRMS calcd for
C32H32BrNO6S＋Na 660.1031, found 660.1032.
J＝9.2 Hz, 2H), 7.87 (d, J＝8.0 Hz, 2H), 7.32—7.25 (m,
5H), 7.09 (d, J＝6.8 Hz, 2H), 6.94 (d, J＝8.8 Hz, 2H),
6.17 (d, J＝3.2 Hz, 1H), 5.27 (d, J＝2.8 Hz, 1H), 4.23
—4.18 (m, 3H), 3.88 (s, 3H), 3.53 (dd, J＝14.8, 3.2 Hz,
1H), 3.37 (dd, J＝16.0, 6.6 Hz, 1H), 3.00 (dd, J＝16.4,
6.8 Hz, 1H), 2.42 (s, 3H), 1.86—1.83 (m, 1H), 1.68—
1.65 (m, 4H), 1.19 (t, J＝6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 196.0, 164.4, 163.6, 143.7, 140.8,
136.6, 130.2, 129.5, 129.1, 128.8, 128.7, 128.3, 128.2,
127.3, 125.9, 113.7, 84.7, 75.9, 61.4, 55.5, 44.5, 39.5,
37.1, 25.7, 24.5, 21.6, 13.9; ESI-HRMS calcd for
C33H35NO7S＋Na 612.2032, found 612.2032.
Ethyl-5-(4-bromophenyl)-2-(2-oxo-2-phenyl-
ethyl)-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-
b]pyridine-7-carboxylate (5g) 93% yield; [α]D20
＋47.9 (c＝0.52 in CHCl3); 99% ee, determined by
HPLC analysis [Daicel chiralcel AD, n-hexane/i-PrOH
＝60/40, 1.0 mL/min, λ＝220 nm, t(major)＝14.95 min,
Ethyl-2-(2-(4-chlorophenyl)-2-oxoethyl)-5-phenyl-
8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]-
pyridine-7-carboxylate (5j) 62% yield; [α]D20
＋33.7 (c 0.30 in CHCl3); 97% ee, determined by HPLC
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝70/30,
1.0 mL/min, λ＝220 nm, t(major)＝19.44 min, t(minor)
1
1
t(minor)＝26.97 min]; H NMR (400 MHz, CDCl3) δ:
＝30.24 min]; H NMR (400 MHz, CDCl3) δ: 7.89 (d,
7.95 (d, J＝7.6 Hz, 2H), 7.86 (d, J＝8.4 Hz, 2H), 7.58 (t,
J＝7.2 Hz, 1H), 7.49—7.42 (m, 4H), 7.25 (d, J＝8.4 Hz,
2H), 6.98 (d, J＝8.4 Hz, 2H), 6.10 (d, J＝2.8 Hz, 1H),
5.27 (d, J＝2.4 Hz, 1H), 4.23—4.16 (m, 3H), 3.51 (dd,
J＝10.8, 3.2 Hz, 1H), 3.41 (dd, J＝16.4, 6.0 Hz, 1H),
3.02 (dd, J＝16.8, 6.0 Hz, 1H), 2.41 (s, 3H), 1.84—1.81
(m, 1H), 1.71—1.51 (m, 4H), 1.17 (t, J＝7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 197.4, 164.3, 143.8,
140.0, 136.9, 136.5, 133.3, 131.8, 130.2, 129.5, 128.6,
128.2, 127.2, 124.8, 121.2, 84.5, 75.7, 61.5, 44.7, 38.9,
37.1, 25.6, 24.4, 21.6, 13.8; ESI-HRMS calcd for
C32H32BrNO6S＋Na 660.1031, found 660.1032.
J＝8.4 Hz, 2H), 7.85 (d, J＝8.0 Hz, 2H), 7.43 (d, J＝
8.0 Hz, 2H ), 7.32—7.23 (m, 5H), 7.09 (d, J＝7.2 Hz,
2H), 6.17 (d, J＝2.8 Hz, 1H), 5.27 (d, J＝2.0 Hz, 1H),
4.23—4.16 (m, 3H), 3.51 (dd, J＝10.8, 3.2 Hz, 1H),
3.38 (dd, J＝16.4, 6.0 Hz, 1H), 2.99 (dd, J＝16.4, 6.0
Hz, 1H), 2.41 (s, 3H), 1.87—1.85 (m, 1H), 1.68—1.65
(m, 4H), 1.19 (t, J＝6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 196.5, 164.4, 143.7, 140.8, 139.6, 136.5,
135.4, 129.7, 129.4, 128.8, 128.5, 128.3, 128.1, 127.3,
127.2, 125.7, 84.6, 75.6, 61.5, 44.8, 39.5, 37.0, 25.6,
24.4, 21.6, 13.9; ESI-HRMS calcd for C32H32ClNO6S＋
Na 616.1537, found 616.1539.
Ethyl-2-(2-oxo-2-phenylethyl)-5-(thiophen-3-yl)-
8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]-
pyridine-7-carboxylate (5h) 88% yield; [α]D20
＋21.8 (c 0.77 in CHCl3); 96% ee, determined by HPLC
Ethyl-2-(2-(naphthalen-2-yl)-2-oxoethyl)-5-phe-
nyl-8-tosyl-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-
b]pyridine-7-carboxylate (5k) 61% yield; [α]D20
＋26.4 (c 0.47 in CHCl3); 95% ee, determined by HPLC
Chin. J. Chem. 2012, 30, 2669—2675
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2671

Yin et al.
FULL PAPER
analysis [Daicel chiralcel AD, n-hexane/i-PrOH＝60/40,
1.0 mL/min, λ＝220 nm, t(major)＝22.83 min, t(minor)
＝39.48 min]; H NMR (400 MHz, CDCl3) δ: 8.49 (s,
λ＝220 nm, t(major)＝10.17 min, t(minor)＝14.59 min];
1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J＝7.6 Hz, 2H),
7.81 (d, J＝7.6 Hz, 2H), 7.56 (t, J＝7.6 Hz, 1H), 7.44 (t,
J＝7.6 Hz, 2H), 7.34—7.31 (m, 2H), 7.22 (d, J＝7.2 Hz,
2H), 7.10 (d, J＝8.0 Hz, 2H), 6.35 (d, J＝7.2 Hz, 1H),
5.83 (d, J＝6.8 Hz, 1H), 4.60 (t, J＝7.2 Hz, 1H), 4.38—
4.32 (m, 1H), 4.29—4.23 (m, 1H), 3.56—3.54 (m, 1H),
3.21 (dd, J＝17.6, 6.0 Hz, 1H), 3.00—2.95 (m, 1H),
2.94 (dd, J＝17.6, 6.8 Hz, 1H), 2.58—2.51 (m, 1H),
2.25 (s, 3H), 1.72—1.64 (m, 1H), 1.31 (t, J＝7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 197.8, 164.4,
143.5, 139.3, 137.4, 136.6, 133.1, 132.5, 129.0, 128.8,
128.5, 128.3, 128.1, 127.6, 127.2, 121.9, 86.3, 74.6,
61.6, 48.2, 45.8, 39.7, 36.2, 21.5, 14.1; ESI-HRMS
calcd for C31H31NO6S＋Na 568.1770, found 568.1772.
1
1H), 8.03 (dd, J＝8.8, 1.6 Hz, 1H), 7.96 (d, J＝8.0 Hz,
1H), 7.90—7.85 (m, 4H), 7.64—7.55 (m, 2H), 7.33—
7.28 (m, 3H), 7.20 (d, J＝8.0 Hz, 2H), 7.18 (d, J＝6.8
Hz, 2H), 6.19 (d, J＝3.6 Hz, 1H), 5.30 (d, J＝2.8 Hz,
1H), 4.27—4.23 (m, 1H), 4.15 (q, J＝4.0 Hz, 2H), 3.61
—3.55 (m, 2H), 3.16 (dd, J＝16.4, 6.4 Hz, 1H), 2.37 (s,
3H), 1.89—1.87 (m, 1H), 1.74—1.61 (m, 4H), 1.12 (t,
J＝6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 164.6,
144.0, 141.8, 141.0, 136.6, 129.5, 128.7, 128.6, 128.5,
128.3, 128.2, 127.7, 127.2, 126.1, 125.7, 84.5, 77.9,
61.5, 44.9, 39.5, 37.1, 25.7, 24.5, 21.5, 13.8;
ESI-HRMS calcd for C36H35NO6S ＋ Na 632.2083,
found 632.2085.
Synthetic transformations of the products
Ethyl-2-(2-oxopropyl)-5-phenyl-8-tosyl-3,4,4a,5,8,
8a-hexahydro-2H-pyrano[2,3-b]pyridine-7-carboxyl-
ate (5l) 81% yield; [α]2D0 ＋31.6 (c 0.55 in CHCl3);
96% ee, determined by HPLC analysis [Daicel chiralcel
AD, n-hexane/i-PrOH＝70/30, 1.0 mL/min, λ＝220 nm,
The ketone functional group could be chemoselec-
tively reduced to the corresponding methylene group
without affecting the enamide functionality, as illus-
trated in Scheme 3.
1
t(major)＝11.48 min, t(minor)＝14.05 min]; H NMR
Scheme 3 Chemoselective reduction of ketone group
(400 MHz, CDCl3) δ: 7.91 (d, J＝8.4 Hz, 2H), 7.35—
7.28 (m, 5H), 7.09 (d, J＝6.4 Hz, 2H), 6.16 (d, J＝2.8
Hz, 1H), 5.23 (d, J＝2.4 Hz, 1H), 4.24—4.17 (m, 2H),
4.00—3.98 (m, 1H), 3.49 (dd, J＝10.4, 3.2 Hz, 1H),
2.79 (dd, J＝16.0, 7.2 Hz, 1H), 2.50 (dd, J＝16.0, 5.2
Hz, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 1.88—1.85 (m, 1H),
1.69—1.63 (m, 4H), 1.21 (t, J＝6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 206.4, 164.4, 147.0, 143.8, 140.8,
136.6, 129.5, 128.5, 128.2, 127.3, 125.8, 84.5, 75.4,
61.4, 39.4, 37.0, 31.7, 30.8, 25.4, 24.4, 21.6, 13.9;
ESI-HRMS calcd for C27H31NO6S ＋ Na 520.1770,
found 520.1772.
Ethyl-2-(2-oxo-2-phenylethyl)-4-phenyl-7-tosyl-
2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyridine-6-car-
boxylate (5m) 28% yield; [α]2D0 ＋62.0 (c 0.34 in
CHCl3); 95% ee, determined by HPLC analysis [Daicel
chiralcel OD, n-hexane/i-PrOH＝60/40, 1.0 mL/min,
λ＝220 nm, t(major)＝14.78 min, t(minor)＝12.87 min];
1H NMR (400 MHz, CDCl3) δ: 7.92 (d, J＝6.8 Hz, 2H),
7.88 (d, J＝8.4 Hz, 2H), 7.58 (t, J＝7.6 Hz, 1H), 7.48—
7.45 (m, 2H), 7.31 (t, J＝7.2 Hz, 2H), 7.26—7.25 (m,
2H), 7.16 (d, J＝6.8 Hz, 2H), 6.44 (d, J＝6.0 Hz, 1H),
5.83 (d, J＝5.6 Hz, 1H), 4.73—4.69 (m, 1H), 4.29—
4.20 (m, 2H), 3.50—3.44 (m, 2H), 3.04 (dd, J＝16.8,
8.0 Hz, 1H), 2.69 (dd, J＝7.6, 5.2 Hz, 1H), 2.41 (s, 3H),
2.31—2.25 (m, 1H), 1.94—1.86 (m, 1H), 1.26 (t, J＝7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 197.7, 164.2,
143.6, 140.3, 137.1, 136.7, 133.7, 133.4, 129.3, 128.9,
128.6, 128.1, 127.8, 127.6, 127.3, 126.1, 86.5, 73.6,
61.6, 45.0, 44.5, 41.8, 37.4, 21.6, 14.0; ESI-HRMS
calcd for C31H31NO6S＋Na 568.1770, found 568.1772.
Ethyl-2-(2-oxo-2-phenylethyl)-4-phenyl-7-tosyl-
2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyridine-6-car-
boxylate (5m') 18% yield; [α]2D0 ＋52.0 (c 0.20 in
CHCl3); 95% ee, determined by HPLC analysis [Daicel
chiralcel AD, n-hexane/i-PrOH＝60/40, 1.0 mL/min,
O
Ph
Ph
.
O
Et3SiH, BF3 Et2O
O
DCM, Ar
NTs
CO2Et
NTs
CO2Et
Ph
Ph
6
5a
Ethyl-2-phenethyl-5-phenyl-8-tosyl-3,4,4a,5,8,8a-
hexahydro-2H-pyrano[2,3-b]pyridine-7-carboxylate
(6) 54% yield; [α]D20 ＋98.3 (c 0.51 in CHCl3); 98%
ee, determined by HPLC analysis [Daicel chiralcel AD,
n-hexane/i-PrOH＝60/40, 1.0 mL/min, λ＝220 nm,
1
t(major)＝5.60 min, t(minor)＝6.11 min]; H NMR
(400 MHz, CDCl3) δ: 8.07 (d, J＝8.4Hz, 2H ), 7.37 (d,
J＝8.0 Hz, 2H), 7.32—7.11 (m, 8H), 7.01 (d, J＝6.4 Hz,
2H), 6.21 (d, J＝3.2 Hz, 1H), 5.12 (d, J＝2.8 Hz, 1H),
4.25 (qd, J＝7.2, 1.2 Hz, 2H), 3.53 (dd, J＝10.8, 3.6 Hz,
1H), 3.40—3.35 (m, 1H), 2.74—2.69 (m, 1H), 2.64—
2.56 (m, 1H), 2.43 (s, 3H), 1.96—1.87 (m, 2H), 1.71—
1.64 (m, 1H), 1.56—1.46 (m, 2H), 1.37—1.28 (m, 2H),
1.25 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
164.6, 144.0, 141.8, 141.0, 136.6, 129.5, 128.7, 128.6,
128.5, 128.3, 128.2, 127.7, 127.2, 126.1, 125.7, 84.5,
77.9, 61.5, 39.5, 37.4, 37.2, 31.3, 25.8, 24.5, 21.6, 13.9;
ESI-HRMS calcd for C32H35NO5S ＋ Na 568.2134,
found 568.2136.
The enamide group could be reduced in methanol by
Pd/C-catalyzed hydrogenation at high pressure (4.5
MPa), but in poor diastereoselectivity. The ketone group
was also converted to methylene group simultaneously,
giving separable diastereomers 7 and 7' (Scheme 4).
Ethyl-2-phenethyl-5-phenyl-8-tosyl-octahydro-
2H-pyrano[2,3-b]pyridine-7-carboxylate (7) 34%
yield; [α]2D0 ＋52.0 (c 0.20 in CHCl3); 97% ee, deter-
2672
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2669—2675

Efficient Construction of Chiral Hydropyrano[2,3-b]pyridines
Scheme 4 Hydrogenation of product 5a
Table 1 Optimizations of reaction conditions in sequential
Aza-Diels-Alder/O-Michael additiona
O
O
1 (20 mol%)
OFBA (20 mol%)
Solvent, 30 oC
NTs
Ph
+
O
Ph
Ph
Pd/C, H2 (4.5 MPa)
O
Ph
CO2Et
2a
3a
O
MeOH
NTs
O
O
Ph
CO2Et
Ph
TFA
OH
NTs
CO2Et
5a
Ph
Ph
NTs
CO2Et
Ph
O
O
4a
Ph
+
5a
NTs
NTs
F
Ph
Ph
OTMS
Ph
CO2Et
Ph
CO2Et
dr = 1:1
CO2H
N
7'
H
7
1
OFBA
mined by HPLC analysis [Daicel chiralcel AD,
Entry Solvent
t/h
24
Yieldb/% eec/%
n-hexane/i-PrOH＝90/10, 1.0 mL/min, λ＝220 nm,
1
2
3
4
5
6
THF
messy
4a, 55
4a, 60
4a, 55
4a, 45
4a, 60
5a, 90
—
99
99
99
99
99
99
1
t(major)＝12.80 min, t(minor)＝18.61 min]; H NMR
Dioxane
DCM
48
(400 MHz, CDCl3) δ: 7.85 (d, J＝8.0 Hz, 2H ), 7.32—
7.15 (m, 10H), 7.07 (d, J＝6.8 Hz, 2H ), 5.35 (d, J＝2.0
Hz, 1H), 4.27—4.16 (m, 3H), 3.44—3.41 (m, 1H), 3.08
(td, J＝11.6, 4.4 Hz, 1H), 2.43—2.38 (m, 3H), 2.35 (s,
3H), 2.22—2.10 (m, 3H), 1.60—1.56 (m, 1H), 1.54—
1.49 (m, 4H), 1.30 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 171.2, 143.3, 142.3, 142.0, 137.8,
129.2, 128.8, 128.4, 128.3, 128.2, 128.1, 126.9, 125.7,
85.8, 76.9, 61.6, 57.0, 38.8, 37.6, 37.0, 36.5, 30.8, 25.2,
24.7, 21.5, 13.9; ESI-HRMS calcd for C32H37NO5S＋
Na 570.2290, found 570.2289.
Ethyl-2-phenethyl-5-phenyl-8-tosyl-octahydro-
2H-pyrano[2,3-b]pyridine-7-carboxylate (7') 34%
yield; [α]2D0 ＋101.8 (c 0.40 in CHCl3); 95% ee, de-
termined by HPLC analysis [Daicel chiralcel AD,
n-hexane/i-PrOH＝90/10, 1.0 mL/min, λ＝220 nm,
t(major)＝9.19 min, t(minor)＝7.41 min]; 1H NMR
(400 MHz, CDCl3) δ: 7.89 (d, J＝8.4 Hz, 2H), 7.33—
7.25 (m, 6H), 7.23—7.18 (m, 4H), 7.04 (d, J＝7.2 Hz,
2H), 5.36 (d, J＝2.8 Hz, 1H), 4.87 (dd, J＝5.6, 2.0 Hz,
1H), 4.09—4.04 (m, 1H), 3.77—3.73 (m, 1H), 3.48 (td,
J＝12.4, 3.6 Hz, 1H), 3.38—3.33 (m, 1H), 2.52—2.43
(m, 2H), 2.43 (s, 3H), 2.00—1.85 (m, 2H), 1.71—1.60
(m, 3H), 1.49—1.47 (m, 2H), 1.36—1.25 (m, 2H), 1.00
(t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
170.8, 143.1, 143.0, 141.9, 138.4, 129.0, 128.7, 128.3,
128.1, 127.8, 127.5, 126.7, 125.8, 84.0, 77.6, 60.8, 52.6,
39.5, 37.4, 34.9, 34.1, 31.5, 25.4, 25.1, 21.5, 13.9;
ESI-HRMS calcd for C32H37NO5S ＋ Na 570.2290,
found 570.2290.
48
CHCl3
MeCN
Toluene
48
72
72
7d
MeCN/H2O
8＋2
a
Unless noted otherwise, reactions were performed with 0.2
mmol of 2a, 0.1 mmol of 3a, 20 mol% of 1 and 20 mol% of
OFBA in 1 mL solvent at 30 ℃. b Isolated product. c By chiral
HPLC analysis, d.r.＞95∶5. d After the completion of aza-DA
reaction, TFA (0.1 mL) was directly added to promote O-Michael
addition.
in 1,4-dioxane, DCM, CHCl3 in moderate yield (55%—
60%) in 48 h, while with excellent stereoselectivity
(Table 1, Entries 2—4). The reaction was quite sluggish
in CH3CN or toluene (Table 1, Entries 5 and 6). The
aza-Diels-Alder reaction proceeded more efficiently in a
mixture of CH3CN and water (10∶1), cleanly furnish-
ing the hemiaminal 4a in 8 h; more importantly, the fol-
lowing O-Michael reaction could be carried out by the
direct treatment with trifluoroacetic acid (TFA, 0.1 mL),
producing the desired ring-closed heterocycle 5a in ex-
cellent diastereoselectivity and high yield for 2 h (Table
1, Entry 7).
With the optimized reaction conditions in hand, we
next investigated the substrate scope and limitations for
the one-pot, sequential aza-Diels-Alder and O-Michael
addition. The results are summarized in Table 2. Firstly,
a series of N-Ts-1-aza-1,3-butadienes 3 were explored
in reactions with 7-oxo-7-phenyl-hept-5-enal 2a. In
general, N-Ts-1-azadienes carrying a diversely substi-
tuted aryl or heteroaryl groups could be well tolerated,
affording the corresponding hexahydro-2H-pyrano[2,3-
b]pyridine derivatives 5a—5h in excellent diastereo-
and enantioselectivity and with moderate to high yields
(Table 2, Entries 1—8). Unfortunately, 1-azadienes de-
rived from chalcones showed low reactivity with alde-
Results and Discussion
Our initial investigation was carried out with N-Ts-
1-azadienes 3a and readily available 7-oxo-7-phenyl-
hept-5-enal 2a catalyzed by α,α-diphenylprolinol
O-TMS ether 1 and o-fluorobenzoic acid (OFBA) at 30
℃. A mixture of products was generated in THF (Table
1, Entry 1). The hemianminal 4a was obtained smoothly
Chin. J. Chem. 2012, 30, 2669—2675
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2673

Yin et al.
FULL PAPER
hyde 2a in the amine-catalyzed aza-Diels-Alder step.[4]
On the other hand, the substitution effects of O-Michael
acceptor were also explored, and similar good results
were obtained for substrates 2 with diverse aryl groups
(Table 2, Entries 9—11). The reaction still proceeded
smoothly for Michael acceptor with an acetyl group
(Table 2, Entry 12), but the intramolecular O-Michael
addition did not occur for less electrophilic ethoxycar-
bonyl-substituted substrate (Table 2, Entry 13). In addi-
tion, 6-oxo-6-phenyl-hex-4-enal could be smoothly used
in the aza-Diels-Alder reaction with diene 3a, but the
O-Michael addition reaction was not satisfactory, and
separable diastereomeric hexahydrofuro[2,3-b]pyridines
5m and 5m' were isolated in 26% and 18% yield, re-
spectively, but still with excellent enantioselectivity
(Table 2, Entry 14). Nevertheless, the attempt to con-
struct fused oxepane ring was not successful with
8-oxo-8-phenyl-oct-6-enal (Table 2, Entry 15).
Conclusions
We have developed an asymmetric aza-Diels-Alder
and O-Michael addition sequence to synthesize fused
hexahydro-2H-pyrano[2,3-b]pyridine derivatives, which
relies on the assembly of N-Ts-1-aza-1,3-butadienes and
aliphatic aldehydes tethered to a α,β-unsaturated ketone
motif. This process exhibited good efficiency, and an
array of bicyclic frameworks bearing multiple function-
alities have been constructed with excellent stereoselec-
tivity under mild conditions. These enantiomerically
pure heterocycles might find applications in synthetic
and medicinal chemistry. The results will be reported in
due course.
Acknowledgement
We are grateful for the financial support from the
Natural Science Foundation of China (Nos. 20972101
and 21125206).
Table 2 Substrate scope and limitationsa
NTs
O
R1
CO2Et
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O
O
(1)
1 (20 mol%)
OFBA (20 mol%)
MeCN/H2O, 30 oC
(2) TFA
R
n
NTs
CO2Et
R1
5
Entry
1
R
R1
n
1
1
1
1
1
1
1
1
1
1
1
1
1
Yieldb/% eec/%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a, 90
5b, 77
5c, 79
5d, 58
5e, 80
5f, 62
5g, 93
5h, 88
5i, 66
5j, 62
5k, 61
5l, 81
99
99
99
95
92
96
99
96
93
97
95
96d
2
p-MePh
m-MePh
m-MeOPh
p-MeOPh
m-BrPh
p-BrPh
2-Thienyl
3
4
5
6
7
8
9
p-MeOPh
p-ClPh
Ph
Ph
10
11
12
13
1-Naphthyl Ph
Me
Ph
Ph
e
e
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—
—
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95
95
14
Ph
Ph
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a
—
—
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Chem. Soc. 2007, 129, 1480; (d) Sandrinelli, F.; Perrio, S.; Beslin, P.
J. Org. Chem. 1997, 62, 8626.
Reactions were performed with 0.2 mmol of 2, 0.1 mmol of 3,
20 mol% of 1 and 20 mol% of OFBA in MeCN/H2O (10∶1, 1
mL) at 30 ℃. Then TFA (0.1 mL) was directly added to promote
the O-Michael addition. b Isolated yield for two steps. c Deter-
mined by chiral HPLC analysis. d The absolute configuration of 5l
was determined by X-ray analysis.[13] The other products were
assigned by analogy. e The O-Michael addition failed to give the
desired ring-closed products.
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2669—2675

Efficient Construction of Chiral Hydropyrano[2,3-b]pyridines
[11] Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. 2005,
117, 4284; Angew. Chem. Int. Ed. 2005, 44, 4212.
[12] Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P.
M.; Gelbrich, T.; Hursthouse, M. B. Tetrahedron 2001, 57, 7771; (c)
Do, Y.-S.; Sun, R.; Kim, H. J.; Yeo, J. E.; Bae, S.-H.; Koo, S. J. Org.
Chem. 2009, 74, 917.
[13] CCDC-905671 (5l) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(Lu, Y.)
Chin. J. Chem. 2012, 30, 2669—2675
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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