N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition of ketenes and 3-aroylcoumarins: Highly enantioselective synthesis of dihydrocoumarin-fused dihydropyranones

Article abstract of DOI:10.1039/c2ob26804c

The N-heterocyclic carbene-catalyzed [4 + 2] cyclization of ketenes and 3-aroylcoumarins has been developed to give the corresponding dihydrocoumarin-fused multisubstituted dihydropyranones in high yield with good diastereoselectivity and high enantiosele

Full text of DOI:10.1039/c2ob26804c

Organic &
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N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition
of ketenes and 3-aroylcoumarins: highly
enantioselective synthesis of dihydrocoumarin-fused
dihydropyranones†
Cite this: Org. Biomol. Chem., 2013, 11,
158
Teng-Yue Jian, Xiang-Yu Chen, Li-Hui Sun and Song Ye*
Received 14th September 2012,
Accepted 12th October 2012
The N-heterocyclic carbene-catalyzed [4 + 2] cyclization of ketenes and 3-aroylcoumarins has been devel-
oped to give the corresponding dihydrocoumarin-fused multisubstituted dihydropyranones in high yield
with good diastereoselectivity and high enantioselectivity.
DOI: 10.1039/c2ob26804c
www.rsc.org/obc
Introduction
Results and discussion
Compounds with two or more heterocycles fused play a vital
role in natural and unnatural bioactive compounds.1 Cou-
marins are present in large quantities in human diets and,
more importantly, they are the active molecules in many tra-
ditional herbal medicines.2 Thus the synthesis of coumarin
and its derivatives attracts intensive attention.3 In this paper,
we wish to report an N-heterocyclic carbene-catalyzed cyclo-
addition reaction of ketenes with aroylcoumarins for the con-
struction of dihydrocoumarin-fused dihydropyranones.
Initially, the reaction of phenyl(ethyl)ketene (1a) and
3-benzoyl-2H-chromen-2-one (2a) was investigated under NHC
catalysis (Table 1). We were encouraged to find that the
Table 1 Screening of NHC catalysts and optimization of reaction conditions
Since Staudinger’s discovery of ketenes in the early 1900s,4
their cycloaddition reactions have become a powerful method-
ology for the construction of cyclic compounds.5,6 Over the
past decades, N-heterocyclic carbene (NHC) catalysis has been
very successful for a variety of reactions.7 We,8 independently
with Smith et al.,9 demonstrated that N-heterocyclic carbenes
(NHCs) were efficient catalysts for the formal cycloaddition
reactions of ketenes. In 2008 and later, we reported the NHC-
catalyzed enantioselective [4 + 2] cycloaddition of ketenes with
activated enones, giving the corresponding dihydropyranones
in good yield with high enantioselectivity.10 We envisaged that
3-aroylcoumarin may act as the oxodiene for the NHC-cata-
lyzed [4 + 2] cycloaddition of ketenes, and thus provide a facile
enantioselective access to coumarin-fused dihydropyranones.
4–5
Cs2CO3
(Y)
Yieldb eec
T (°C) (%)
(%) dre
Entry (X)a
Solvent
1
2
3
4
5
6
7
8
9
4a (10)
4b (10) 20
4c (10) 20
4d (10) 20
5 (10) 20
4d (10) 20
4d (10) 20
4d (10) 20
4d (12) 10
20
DCM
DCM
DCM
DCM
DCM
THF
rt
rt
rt
rt
rt
rt
49
77
82
81
88
67
89
91
87
29d
8 : 1
6 : 1
7 : 1
10 : 1
8 : 1
8 : 1
6d
18d
80
67
10
87
83
91
Toluene rt
Toluene 0 °C
Toluene 0 °C
8 : 1
10 : 1
12 : 1
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China. E-mail: songye@iccas.ac.cn; Fax: (+86) 10 6255 4449;
a NHC 4′–5′ was generated from its precursor 4–5 (10–12 mol%) in the
presence of Cs2CO3 (10–20 mol%) in the noted solvent at room
temperature for 30 min. b Isolated yield of pure cis-3aa. c Determined
by HPLC. d ent-3aa was isolated as the major enantiomer for entries
1–3. e Determined by 1H NMR (300 MHz) of the reaction mixture.
Tel: (+86) 10 6264 1156
†Electronic supplementary information (ESI) available. CCDC 901312. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26804c
158 | Org. Biomol. Chem., 2013, 11, 158–163
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Table 2 Variation of ketenes
Table 3 Variation of 3-aroylcoumarinsa
a Reaction conditions as Table 2.
withdrawing substituents (4-Br, 4-ClC6H4) are well tolerated,
giving cycloadducts (3ea and 3fa) in high yield with high
enantioselectivity, while an electron-donating group (4-MeC6H4)
led to some loss of yield and enantioselectivity (3ga). It should
be noted that reaction of ketene containing an o-chlorophenyl
group gave only a trace of cycloaddduct (3ha). Interestingly,
ketene 1i derived from cycloheptanecarbonyl chloride worked
very well, giving the desired cycloadduct 3ia in 83% yield with
98% ee, while benzyl(ethyl)ketene (1j) resulted in decreased
yield and low diastereo- and enantioselectivity (3ja).
Several 3-aroylcoumarins were also tested for the reaction
(Table 3). Both an electron-donating group (4-MeC6H4) and
electron-withdrawing groups (4-BrC6H4, 4-ClC6H4) on the aroyl
are tolerated, giving the desired cycloadduct in high yield with
good diastereo- and enantioselectivity (3ab, 3ac and 3ad).
However, aroyl groups with meta- or ortho-substituents
(3-ClC6H4, 2-ClC6H4) led to decreased enantioselectivity albeit
in high yield and good to high diastereoselectivity (3ae and
3af). 6-Halocoumarin derivatives (X = Cl, Br) also worked as
well as the parent one (3ag and 3ah).
desired [4 + 2] cycloadduct 3aa was isolated in 49% yield with
29% ee and 8 : 1 dr in the presence of 10 mol% NHC 4a′,8a,11
generated from L-pyroglutamic acid derived triazolium salt 4a
and 20 mol% of Cs2CO3 (entry 1). NHC 4b′ with a less bulky
TMS group and NHC 4c′ with a bulky N-(2-isopropyl)phenyl
group resulted in better yields but decreased enantioselectivity
(entries 2 and 3). NHC 4d′ with a free hydroxyl group12 led to a
reversed but high enantioselectivity (80% ee) for this reaction
(entry 4). Tetracyclic NHC 5′, derived from aminoindanol, also
worked well in the reaction, giving the cycloadduct 3aa in 88%
yield with 67% ee and 8 : 1 dr (entry 5).
Solvent screening revealed that the reaction performed
better in toluene than in DCM or THF in terms of enantio-
selectivity (87% ee vs. 80% ee or 10% ee, entries 4, 6–7). Lower-
ing the reaction temperature to 0 °C benefits the yield but with
decreased enantioselectivity (entry 8). Careful examination
revealed that excess Cs2CO3 could also promote the reaction,
giving the cycloadduct as a racemate. Thus the reaction
employing 10 mol% of Cs2CO3 and 12 mol% triazolium NHC
precursor 4d resulted in an improved enantioselectivity (91%
ee) and diastereoselectivity (12 : 1 dr) (entry 9).
The absolute stereochemistry of cycloadduct (+)-3fa was
unambiguous established by the X-ray analysis† of its crystal
(Fig. 1),13 and that of all other cycloadducts is proposed by
analogy. The crystal of (+)-3fa was prepared from a solution in
DCM–ether (90 : 10) with a trace of petroleum ether.
Based on the dramatic effect of the free hydroxyl group of
the NHC catalyst, and the diastereo- and enantioselectivity
observed,14 a likely transition state is proposed as in Fig. 2.
The enolate generated by addition of the NHC to ketene favors
its Z-isomer, which minimizes the steric repulsion. The hydro-
gen-bonding between the hydroxy group of the NHC–ketene
adduct and aroyl group of the coumarin derivative directs the
With the optimized reaction condition in hand, the reaction
scope was then briefly investigated (Table 2). It was found that
aryl(alkyl)ketenes with ethyl, methyl and n-propyl all worked
well to give the corresponding cycloadduct (3aa, 3ba and 3ca)
in high yield with high enantioselectivity and diastereoselectiv-
ity. However, ketenes with a bulky isobutyl group resulted in
decreased yield and enantioselectivity (3da). Electron-
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0 °C, ketene 1a (146 mg, 1 mmol) and 3-aroylcoumarin 2a
(125 mg, 0.5 mmol) were added. After stirring for 24 h, the
reaction mixture was diluted with diethyl ether and passed
through a short silica pad. The solvent was removed under
reduced pressure and the residue was purified by chromato-
graphy on silica gel (ethyl acetate–petroleum ether, typically
1 : 100) to give the desired product.
Racemic samples for the standard of chiral HPLC spectra
were prepared using 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c]-
[1,2,4]triazolium chloride as the catalyst.
(1S,10bS)-1-ETHYL-1,4-DIPHENYL-1,10b-DIHYDROPYRANO[3,4-c]CHROMENE-
2,5-DIONE (3aa). Yield: 172.4 mg (87%), white solid, mp
130–132 °C, Rf = 0.67 (petroleum ether–ethyl acetate, 5 : 1);
[α]2D5 +158.4 (c 1.2, CHCl3), HPLC analysis: 91% ee [Daicel
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
90 : 10, 1.0 mL min−1, 254 nm, 16.3 min (major), 25.9 min
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.48–7.42 (m, 3H),
7.40–7.37 (m, 4H), 7.25–7.24 (m, 1H), 7.19–7.02 (m, 3H), 7.04
(d, J = 8.1 Hz, 1H), 6.73 (dd, J = 6.6 Hz, J = 1.8 Hz, 2H), 4.67
(s, 1H), 2.40–2.32 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR
(300 MHz, CDCl3) δ 170.0, 164.0, 158.1, 151.7, 136.5, 131.6,
131.4, 130.0, 129.9, 129.4, 128.9, 128.3, 127.9, 126.0, 124.1,
117.1, 116.8, 104.1, 56.5, 40.2, 29.6, 10.2. IR (KBr) ν 3044, 1951,
1774, 1612, 1321, 785, 515, 468. HRMS (EI) m/z: M+ Calc. for
C26H20O4, 396.1362, Found 396.1366.
Fig. 1 X-ray structure of cycloadduct (+)-3fa.
(1S,10bS)-1-METHYL-1,4-DIPHENYL-1,10b-DIHYDROPYRANO[3,4-c]CHRO-
MENE-2,5-DIONE (3ba). Yield: 161.4 mg (85%), white solid, mp
90–92 °C, Rf = 0.56 (petroleum ether–ethyl acetate, 5 : 1); [α]D25
+167.3 (c 1.0, CHCl3), HPLC analysis: 87% ee [Daicel CHIRAL-
PAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10,
1.0 mL min−1, 254 nm, 12.3 min (major), 19.4 min (minor)].
1H NMR (300 MHz, CDCl3) δ 7.49–7.45 (m, 1H), 7.42–7.27
(m, 6H), 7.25–7.21 (m, 1H), 7.20–7.17 (m, 3H), 7.0–7.06 (m, 1H),
6.81–6.77 (m, 2H), 4.53 (s, 1H), 1.94 (s, 3H). 13C NMR
(300 MHz, CDCl3) δ 170.8, 164.2, 157.9, 151.5, 137.4, 131.5,
131.3, 130.1, 129.8, 129.4, 129.0, 128.3, 127.9, 125.5, 124.1,
117.7, 116.7, 104.5, 52.0, 42.6, 25.0. IR (KBr) ν 3024, 1855,
1774, 1642, 1221, 775, 550, 468. HRMS (EI) m/z: M+ Calc. for
C25H18O4, 382.1205, Found 382.1212.
(1S,10bS)-1,4-DIPHENYL-1-PROPYL-1,10b-DIHYDROPYRANO[3,4-c]CHRO-
MENE-2,5-DIONE (3ca). Yield: 178.1 mg (87%), white solid, mp
122–124 °C, Rf = 0.70 (petroleum ether–ethyl acetate, 5 : 1);
[α]2D5 +241 (c 1.5, CHCl3), HPLC analysis: 91% ee [Daicel CHIR-
ALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15,
1.0 mL min−1, 254 nm, 11.5 min (major), 15.9 min (minor)].
1H NMR (300 MHz, CDCl3) δ 7.54–7.40 (m, 7H), 7.38–7.15
(m, 4H), 7.05 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 6.0 Hz, 2H), 4.66
(s, 1H), 2.35 (t, J = 8.7 Hz, 2H), 1.96–1.86 (m, 1H), 1.36–1.23
(m, 1H), 1.02 (t, J = 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3)
δ 170.1, 164.0, 158.1, 151.6, 136.6, 131.6, 131.4, 130.0, 129.8,
Fig. 2 Proposed model for stereochemical outcome.
facial selectivity. The endo transition state of the Diels–Alder
reaction is favored and results in the cis-cycloadduct observed.
Conclusions
In summary, N-heterocyclic carbenes were found to be efficient
catalysts for the [4 + 2] cycloaddition of ketenes and 3-aroylcou-
marins. When the NHC derived from L-pyroglutamic acid and
featuring a free hydroxyl group was used as the catalyst, the
desired dihydrocoumarin-fused dihydropyranones were
obtained in high yield with good to high diastereo- and
enantioselectivity.
Experimental
Typical procedure for NHC-catalyzed [4 + 2] cycloaddition of
ketenes with 3-aroylcoumarins
An oven-dried 50 mL Schlenk tube equipped with a stir bar 129.3, 128.8, 128.2, 127.9, 125.9, 124.1, 117.7, 116.8, 104.1,
was charged with triazolium salt 4d (27.3 mg, 0.06 mmol) and 56.1, 40.5, 38.9, 18.7, 14.4. IR (KBr) ν 3030, 1961, 1834, 1644,
anhydrous Cs2CO3 (17 mg, 0.05 mmol). This tube was closed 1331, 765, 545, 455. HRMS (EI) m/z: M+ Calc. for C27H22O4,
with a septum, evacuated, and back-filled with argon. To this 410.1518, Found 410.1523.
mixture was added freshly distilled toluene (5 mL) and stirred
(1S,10bS)-1-ISOBUTYL-1,4-DIPHENYL-1,10b-DIHYDROPYRANO[3,4-c]CHRO-
for 30 min at room temperature. After stirring for 10 min at MENE-2,5-DIONE (3da). Yield: 166.7 mg (78%), white solid, mp
160 | Org. Biomol. Chem., 2013, 11, 158–163
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121–123 °C, Rf = 0.40 (petroleum ether–ethyl acetate, 5 : 1); 480. HRMS (EI) m/z: M+ Calc. for C27H22O4, 410.1518, Found
[α]2D5 +241.3 (c 1.0, CHCl3), HPLC analysis: 70% ee [Daicel 410.1523.
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
(S)4′-PHENYL-2′H-SPIRO[CYCLOHEPTANE-1,1′-PYRANO[3,4-c]CHROMENE]-
85 : 15, 1.0 mL min−1, 254 nm, 10.2 min (major), 15.5 min 2′,5′(10b′H)-DIONE (3ia). Yield: 155.4 mg (83%), white solid, mp
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.47–7.35 (m, 7H), 95–97 °C, Rf = 0.50 (petroleum ether–ethyl acetate, 5 : 1); [α]D25
7.26–7.20 (m, 4H), 7.10 (d, J = 8.7 Hz, 1H), 6.94–6.91 (m, 2H), +142.1 (c 1.0, CHCl3), HPLC analysis: 98% ee [Daicel CHIRAL-
4.58 (s, 1H), 2.30–2.17 (m, 2H), 2.04–1.95 (m, 1H), 1.09 (d, J = PAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10,
7.5 Hz, 3H), 0.33 (d, J = 6.6 Hz, 3H). 13C NMR (300 MHz, 1.0 mL min−1, 254 nm, 16.9 min (major), 28.5 min (minor)].
CDCl3) δ 170.4, 164.0, 158.5, 151.5, 136.1, 131.5, 131.3, 130.1, 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.50–7.32
130.0, 129.7, 128.9, 128.4, 127.9, 126.6, 124.0, 117.7, 117.2, (m, 5H), 7.16–7.09 (m, 2H), 4.27 (s, 1H), 2.32–2.24 (m, 1H),
104.1, 54.8, 45.7, 42.3, 25.9, 25.5, 23.6. IR (KBr) ν 3030, 1871, 2.04–2.02 (m, 1H), 2.02–2.00 (m, 1H), 1.80–1.08 (m, 8H),
1674, 1512, 1221, 780, 535. HRMS (EI) m/z: M+ Calc. for 0.87–0.85 (m, 1H). 13C NMR (300 MHz, CDCl3) δ 172.0, 160.0,
C28H24O4, 424.1675, Found 424.1682.
151.8, 131.7, 131.4, 130.2, 129.7, 129.5, 128.3, 127.9, 124.0,
(1S,10bS)-1-(4-BROMOPHENYL)-1-ETHYL-4-PHENYL-1,10b-DIHYDROPYRANO- 117.7, 103.0, 49.2, 43.4, 34.8, 30.6, 30.5, 28.8, 24.8, 23.1. IR
[3,4-c]CHROMENE-2,5-DIONE (3ea). Yield: 206.4 mg (87%), white (KBr) ν 3030, 1816, 1658, 1356, 1262, 760. HRMS (EI) m/z: M+
solid, mp 140–141 °C, Rf = 0.65 (petroleum ether–ethyl acetate, Calc. for C24H22O4, 374.1518, Found 374.1526.
5 : 1); [α]2D5 +231.4 (c 1.5, CHCl3), HPLC analysis: 91% ee [Daicel
(1R,10bS)-1-BENZYL-1-ETHYL-4-PHENYL-1,10b-DIHYDROPYRANO[3,4-c]-
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = CHROMENE-2,5-DIONE (3ja). Yield: 155.1 mg (76%), white solid,
90 : 10, 1.0 mL min−1, 254 nm, 15.6 min (major), 18.9 min mp 89–91 °C, Rf = 0.60 (petroleum ether–ethyl acetate, 5 : 1);
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.55–7.38 (m, 7H), [α]D25 +173.1 (c 1.0, CHCl3), HPLC analysis: 48% ee [Daicel
7.32–7.20 (m, 3H), 7.05 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 5.7 Hz, CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
2H), 4.67 (s, 1H), 2.37–2.29 (m, 2H), 1.19 (t, J = 6.9 Hz, 3H). 13
C
85 : 15, 1.0 mL min−1, 254 nm, 12.9 min (major), 15.4 min
1
NMR (300 MHz, CDCl3) δ 169.5, 164.0, 158.0, 151.65, 135.6, (minor)]. H NMR (300 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 1H),
132.0, 131.6, 131.3, 130.2, 129.9, 129.3, 128.0, 127.7, 124.3, 7.39 (d, J = 6.9 Hz, 2H), 7.40–7.09 (m, 10H), 7.02 (d, J = 7.8 Hz,
122.5, 117.8, 116.4, 103.9, 56.2, 39.9, 29.6, 10.1. IR (KBr) 1H), 4.33 (s, 1H), 4.04 (d, J = 15.0 Hz, 1H), 3.11 (d, J = 15.3 Hz,
ν 2980, 1836, 1658, 1556, 1262, 755. HRMS (EI) m/z: M+ Calc. 1H), 2.01–1.91 (m, 1H), 1.88–1.75 (m, 1H), 0.90 (t, J = 7.2 Hz,
for C26H19Br79O4, 474.0467, Found 474.0475, M+ Calc. for 3H). 13C NMR (300 MHz, CDCl3) δ 169.3, 161.1, 160.9, 151.3,
C26H19Br81O4, 476.0446, Found 474.0443.
135.9, 132.1, 131.1, 129.8, 129.3, 129.1, 128.8, 128.1, 127.9,
(1S,10bS)-1-(4-CHLOROPHENYL)-1-ETHYL-4-PHENYL-1,10b-DIHYDROPYRANO- 127.3, 124.1, 118.9, 118.1, 101.4, 49.6, 39.2, 37.0, 26.0, 8.7. IR
[3,4-C]CHROMENE-2,5-DIONE (3fa). Yield: 187.2 mg (87%), white (KBr) ν 2990, 1766, 1556, 1455, 1262, 779. HRMS (EI) m/z: M+
solid, mp 119–122 °C, Rf = 0.70 (petroleum ether–ethyl acetate, Calc. for C27H22O4, 410.1518, Found 410.1523.
5 : 1); [α]2D5 +211.3 (c 1.4, CHCl3), HPLC analysis: 90% ee [Daicel
(1S,10bS)-1-ETHYL-1-PHENYL-4-p-TOLYL-1,10b-DIHYDROPYRANO[3,4-c]-
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = CHROMENE-2,5-DIONE (3ab). Yield: 178.5 mg (87%), white solid,
90 : 10, 1.0 mL min−1, 254 nm, 8.6 min (major), 10.7 min mp 95–97 °C, Rf = 0.61 (petroleum ether–ethyl acetate, 5 : 1);
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.55–7.51 (m, 2H), [α]D25 +256.4 (c 1.5, CHCl3), HPLC analysis: 87% ee [Daicel
7.50–7.48 (m, 2H), 7.44–7.39 (m, 3H), 7.27–7.22 (m, 1H), 7.16 CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
(d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.7 Hz, 85 : 15, 1.0 mL min−1, 254 nm, 12.3 min (major), 16.2 min
2H), 4.67 (s, 1H), 2.38–2.29 (m, 2H), 1.20 (t, J = 6.9 Hz, 3H). 13
C
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.49–7.46(m, 3H),
NMR (300 MHz, CDCl3) δ 169.6, 164.0, 158.1, 151.6, 135.1, 7.42–7.36 (m, 1H), 7.25–7.15 (m, 6H), 7.03 (d, J = 8.1 Hz, 1H),
134.3, 131.6, 131.4, 130.2, 129.9, 129.4, 129.1, 128.0, 127.4, 6.71 (d, J = 6.6 Hz, 2H), 4.64 (s, 1H), 2.39–2.31 (m, 3H), 1.18
124.3, 117.8, 116.4, 103.9, 56.1, 40.0, 29.7, 10.1. IR (KBr) ν (t, J = 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 170.2, 164.2,
3010, 1856, 1648, 1556, 1262, 775. HRMS (EI) m/z: M+ Calc. for 158.3, 151.6, 142.2, 136.4, 130.0, 129.9, 129.4, 128.8, 128.6,
C26H19ClO4, 430.0972, Found 430.0979.
128.5, 128.2, 126.0, 124.0, 117.6, 116.8, 103.2, 56.8, 40.2, 29.5,
(1S,10bS)-1-ETHYL-4-PHENYL-1-p-TOLYL-1,10b-DIHYDROPYRANO[3,4-c]- 21.7, 10.1. IR (KBr) ν 3030, 1851, 1674, 1512, 1322, 775, 525,
CHROMENE-2,5-DIONE (3ga). Yield: 157.2 mg (77%), white solid, 458. HRMS (EI) m/z: M+ Calc. for C27H22O4, 410.1518, Found
mp 121–123 °C, Rf = 0.60 (petroleum ether–ethyl acetate, 5 : 1); 410.1522.
[α]2D5 +153.3 (c 1.1, CHCl3), HPLC analysis: 66% ee [Daicel
(1S,10bS)-4-(4-BROMOPHENYL)-1-ETHYL-1-PHENYL-1,10b-DIHYDROPYRANO-
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = [3,4-c]CHROMENE-2,5-DIONE (3ac). Yield: 205.5 mg (87%), white
85 : 15, 1.0 mL min−1
254 nm, 14.9 min (major), solid, mp 127–129 °C, Rf = 0.61 (petroleum ether–ethyl acetate,
,
18.5 min (minor)]. 1H NMR (300 MHz, CDCl3) δ 7.55–7.37 5 : 1); [α]D25 +163 (c 1.0, CHCl3), HPLC analysis: 80% ee [Daicel
(m, 8H), 7.25–7.23 (m, 1H), 7.05–6.95 (m, 2H), 6.61 (d, J = CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
7.5 Hz, 2H), 4.64 (s, 1H), 2.35–2.30 (m, 2H), 2.22 (s, 3H), 90 : 10, 1.0 mL min−1, 254 nm, 15.2 min (major), 21.7 min
1.19 (t, J = 6.9 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 170.3, (minor)]. 1H NMR (300 MHz, CDCl3) δ 7.54–7.48 (m, 3H),
164.1, 158.4, 151.8, 138.1, 133.5, 131.8, 131.5, 130.0, 129.7, 7.43–7.37 (m, 3H), 7.27–7.16 (m, 4H), 7.04 (d, J = 8.1 Hz, 1H),
129.5, 128.0, 126.0, 124.2, 117.8, 117.0, 104.2, 56.3, 40.3, 29.8, 6.71 (d, J = 6.6 Hz, 2H), 4.64 (s, 1H), 2.39–2.31 (m, 3H), 1.18
21.1, 10.3. IR (KBr) ν 3026, 1851, 1674, 1512, 1221, 765, 565, (t, J = 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 169.7, 162.7,
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158.0, 151.5, 136.3, 131.4, 131.2, 130.3, 130.0, 129.4, 128.9, (minor)]. 1H NMR (300 MHz, CDCl3) δ 7.54–7.48 (m, 4H),
128.3, 126.1, 125.9, 124.2, 117.7, 116.5, 104.6, 56.4, 40.2, 29.5, 7.47–7.31 (m, 3H), 7.25–7.18 (m, 3H), 6.99 (d, J = 8.7 Hz, 1H),
10.1. IR (KBr) ν 3030, 1851, 1774, 1542, 1221, 785, 468. HRMS 6.76–6.73 (m, 2H), 4.62 (s, 3H), 2.36 (q, J = 7.2 Hz, 2H), 1.20 (t,
(EI) m/z: C26H19Br79O4, 474.0467, Found 474.0475, M+ Calc. for J = 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 169.5, 164.5,
C26H19Br81O4, 476.0446, Found 474.0443.
157.6, 150.2, 136.1, 131.6, 131.3, 130.1, 129.9, 129.2, 129.0,
(1S,10bS)-4-(4-CHLOROPHENYL)-1-ETHYL-1-PHENYL-1,10b-DIHYDROPYRANO- 128.95, 128.4, 127.9, 125.9, 119.0, 118.5, 103.1, 56.5, 40.2, 29.4,
[3,4-c]CHROMENE-2,5-DIONE (3ad). Yield: 191.5 mg (89%), white 10.1. IR (KBr) ν 3040, 1972, 1774, 1610, 1221, 780, 468. HRMS
solid, mp 127–129 °C, Rf = 0.62 (petroleum ether–ethyl acetate, (EI) m/z: M+ Calc. for C26H19ClO4, 430.0972, Found 430.0979.
5 : 1); [α]2D5 +189.7 (c 1.3, CHCl3), HPLC analysis: 87% ee [Daicel
(1S,10bS)-9-BROMO-1-ETHYL-1,4-DIPHENYL-1,10b-DIHYDROPYRANO[3,4-
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = c]CHROMENE-2,5-DIONE (3ah). Yield: 201.4 mg (85%), white solid,
90 : 10, 1.0 mL min−1, 254 nm, 16.2 min (major), 25.8 min mp 131–133 °C, Rf = 0.60 (petroleum ether–ethyl acetate, 5 : 1);
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.46–7.41 (m, 3H), [α]D25 +213.3 (c 1.0, CHCl3), HPLC analysis: 82% ee [Daicel
7.40–7.36 (m, 3H), 7.28–7.14 (m, 4H), 7.05 (d, J = 7.5 Hz, 1H), CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
6.71 (d, J = 6.6 Hz, 2H), 4.66 (s, 1H), 2.40–2.32 (m, 3H), 1.19 (t, 90 : 10, 1.0 mL min−1, 254 nm, 16.1 min (major), 25.8 min
1
J = 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 169.8, 162.7, (minor)]. H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.61–7.34
158.1, 151.5, 137.7, 136.3, 131.3, 130.1, 130.2, 129.4, 128.9, (m, 6H), 7.25–7.17 (m, 3H), 6.93 (d, J = 8.7 Hz, 1H), 6.75 (d, J =
128.4, 128.3, 125.9, 124.3, 117.7, 116.6, 104.6, 56.5, 40.2, 29.6, 6.0 Hz, 2H), 4.61 (s, 1H), 2.35 (q, J = 6.9 Hz, 2H), 1.19 (t, J =
10.2. IR (KBr) ν 3040, 1851, 1674, 1512, 1221, 760, 545, 480. 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 169.5, 164.5, 157.5,
HRMS (EI) m/z: M+ Calc. for C26H19ClO4, 430.0972, Found 150.7, 136.0, 133.0, 132.0, 131.6, 131.3, 129.9, 128.9, 128.4,
430.0979.
127.9, 125.9, 119.4, 118.9, 116.5, 103.0, 56.4, 40.1, 29.4, 10.1.
(1S,10bS)-4-(3-CHLOROPHENYL)-1-ETHYL-1-PHENYL-1,10b-DIHYDROPYR- IR (KBr) ν 3030, 1816, 1658, 1556, 1462, 775. HRMS (EI) m/z:
ANO[3,4-c]CHROMENE-2,5-DIONE (3ae). Yield: 184.5 mg (86%), white C26H19Br79O4, 474.0467, Found 474.0475, M+ Calc. for
solid, mp 99–101 °C, Rf = 0.61 (petroleum ether–ethyl acetate, C26H19Br81O4, 476.0466, Found 474.0460.
5 : 1); [α]2D5 +241.2 (c 1.5, CHCl3), HPLC analysis: 66% ee [Daicel
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
85 : 15, 1.0 mL min−1, 254 nm, 9.4 min (major), 13.4 min
(minor)]. 1H NMR (300 MHz, CDCl3) δ 7.52–7.46 (m, 3H),
7.44–7.36 (m, 3H), 7.28–7.14 (m, 4H), 7.05 (d, J = 8.7 Hz, 1H),
6.71 (d, J = 6.6 Hz, 2H), 4.65 (s, 1H), 2.40–2.31 (m, 2H), 1.19 (t, J
= 7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 169.9, 162.8,
158.2, 151.6, 140.3, 137.8, 136.4, 131.5, 131.4, 130.2, 130.0,
129.5, 129.0, 128.5, 128.4, 126.0, 124.4, 117.8, 116.7, 104.7,
56.6, 40.3, 29.7, 10.3. IR (KBr) ν 3034, 1851, 1774, 1512, 1221,
790, 515, 468. HRMS (EI) m/z: M+ Calc. for C26H19ClO4,
430.0972, Found 430.0979.
Acknowledgements
Financial support from the Ministry of Science and Technology
of China (2011CB808600), National Natural Science Foun-
dation of China (No. 21072195, 20932008), and the Chinese
Academy of Sciences is gratefully acknowledged.
Notes and references
(1S,10bS)-4-(2-CHLOROPHENYL)-1-ETHYL-1-PHENYL-1,10b-DIHYDROPYR-
ANO[3,4-c]CHROMENE-2,5-DIONE (3af). Yield: 174.1 mg (81%), white
solid, mp 107–109 °C, Rf = 0.71 (petroleum ether–ethyl acetate,
5 : 1); [α]2D5 +106.8 (c 1.0, CHCl3), HPLC analysis: 42% ee [Daicel
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
85 : 15, 1.0 mL min−1, 254 nm, 19.0 min (major), 22.4 min
1 D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
2003, 103, 893.
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(minor)]. H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 1H),
7.43–7.28 (m, 3H), 7.27–7.23 (m, 5H), 7.08 (d, J = 5.1 Hz, 1H),
6.92–6.82 (br, 2H), 4.80 (s, 1H), 2.41–2.35 (t, J = 6.0 Hz, 3H),
1.25–1.23 (br, 3H). 13C NMR (300 MHz, CDCl3) δ 169.2, 159.9,
157.4, 151.6, 136.8, 133.7, 132.2, 131.2, 130.0, 129.7, 129.3,
128.9, 128.3, 127.9, 126.7, 126.2, 124.3, 116.7, 55.8, 38.8, 30.2,
10.3. IR (KBr) ν 3030, 1871, 1772, 1642, 1221, 780, 548, 468.
HRMS (EI) m/z: M+ Calc. for C26H19ClO4, 430.0972, Found
430.0979.
(1S,10bS)-9-CHLORO-1-ETHYL-1,4-DIPHENYL-1,10b-DIHYDROPYRANO[3,4-
C]CHROMENE-2,5-DIONE (3ag). Yield: 187.5 mg (87%), white solid,
mp 120–122 °C, Rf = 0.61 (petroleum ether–ethyl acetate, 5 : 1);
[α]2D5 +251.4 (c 1.5, CHCl3), HPLC analysis: 91% ee [Daicel
CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH =
90 : 10, 1.0 mL min−1, 254 nm, 14.8 min (major), 19.0 min
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13 The crystal was prepared from the solution of cis-3fa in
DCM–ether (90 : 10) with a trace of petroleum ether. CCDC
901312† contains the supplementary crystallographic data
for this paper.
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