Lewis acid-catalyzed enantiospecific [3 + 2] annulations of γ-butyrolactone fused cyclopropanes with aromatic aldehydes: Synthesis of chiral furanolignans

Article abstract of DOI:10.1039/c8ob00455b

An enantiospecific [3 + 2] annulation of γ-butyrolactone fused cyclopropanes with aromatic aldehydes was realized under Lewis acid catalysis. This method provides facile access to a series of chiral furanolignan derivatives bearing multiple contiguous stereogenic centers in good-to-excellent yields, exclusive diastereoselectivities and excellent enantiopurities under mild reaction conditions. Elaboration work on the product of this reaction delivers stereoisomeric analogues of (+)-virgatusin and suggests a structural revision might be necessary for a previously reported isolated natural product.

Full text of DOI:10.1039/c8ob00455b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE
Lewis acid-catalyzed enantiospecific [3+2] annulations of γ-
butyrolactone fused cyclopropanes with aromatic aldehydes:
synthesis of chiral furanolignans
Received 00th January 20xx,
Accepted 00th January 20xx
Yue Shen,a,b Peng-Fei Yang,a Gaosheng Yang,a,* Wen-Long Chena and Zhuo Chaia
DOI: 10.1039/x0xx00000x
An enantiospecific [3+2] annulation of γ-butyrolactone fused cyclopropanes with aromatic aldehydes was realized under
Lewis acid catalysis. This method provides a facile access to a series of chiral furanolignan derivatives bearing multiple
contiguous stereogenic centers in good-to-excellent yields, exclusive diastereoselectivities and excellent enantiopurities
under mild reaction conditions. Elaboration work on the product of this reaction delivers stereoisomeric analogues of (+)-
virgatusin and suggests a structural revision might be necessary for a previously reported isolated natural product.
www.rsc.org/
advances have been achieved in the catalytic asymmetric
annulations of racemic 2-monosubstituted 1,1-diester
cyclopropanes via either kinetic resolution or dynamic kinetic
Introduction
The furanolignans featuring
a
densely substituted chiral
family of natural
asymmetric transformations (DyKATs), providing facile access
to a variety of useful chiral cyclic compounds.6 Racemic
polysubstituted D–A cyclopropanes like 2,3-disubstituted 1,1-
diester cyclopropanes, however, have rarely succumbed to
direct catalytic asymmetric transformations, despite their
great potential in the construction of structures bearing
multiple contiguous stereocenters.
tetrahydrofuran skeleton belong to
a
products possessing a vast structural diversity with a range of
biological activities such as antioxidant, antimicrobial, anti-
inflammatory and anticancer activities (Figure 1).1 The
presence of multiple contiguous stereocenters is arguably one
of the most challenging parts in constructing such a type of
structures. While numerous synthetic methods have been
developed for their construction,2–4 enantioselective ones
remain somewhat limited.3–4 The use of a chiral auxiliary group
such as the Evans’ chiral oxazolidiones has been a common
strategy in installing the requisite chirality in these molecules,
which usually requires multi-step manipulations.4
In this regard, the development of catalytic enantiospecific
transformations of readily available enantioenriched 2,3-
disubstituted D–A cyclopropanes has proved to be an efficient
alternative strategy,7 as exemplified by Johnson and co-
workers in an elegant total synthesis of (+)-polyanthellin A.7a
The same group have also first demonstrated the ingenious
employment of
a
chiral 2,3-disubsituted-1,1-diester
cyclopropane 10d, which was synthesized following Wang’s
organocatalytic asymmetric Michael addition-intramolecular
alkylation between an enal and bromomalonate,8 in a five-step
synthesis of (+)-virgatusin (Scheme 1).7b Notably, Zhang and
co-workers have first disclosed a single example on the
enantiospecific [3+2] annulation between benzaldehyde and a
chiral γ-butyrolactone fused cyclopropane with a fairly good
yield; the chiral fused cyclopropane was prepared by a Co(II)-
catalyzed asymmetric intramolecular cyclopropanation of
alkenes developed by the same group.9 Our group have very
recently revealed that γ-butyrolactone fused cyclopropanes
could have higher reactivity in Lewis acid-promoted
annulations with heterocumulenes, as compared to their
parent 2,3-disubsituted-1,1-diester cyclopropanes.10a Inspired
by these works, we then presumed that the use of chiral γ-
Figure 1. Representative natural chiral furanolignans.
On the other hand, the annulations of donor-acceptor (D–A)
cyclopropanes with various dipolarophiles have evolved into a
powerful strategy for fast construction of
functionalized cyclic structures.5 In this field, very impressive
a range of
a.Key Laboratory of Functionalized Molecular Solids, Ministry of Education, Anhui
Key Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation
Base), College of Chemistry and Materials Science, Anhui Normal University,
Wuhu, Anhui 241000, China. E-mail: gshyang@mail.ahnu.edu.cn
b.Department of Biology and Chemical Engineering, Bozhou University, Bozhou,
Anhui 236800, China.
butyrolactone fused cyclopropanes 1, which could be prepared
†Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data for new compounds, x-ray data for 3ak and 4dn (CCDC
1824774 and 1824775), copies of 1H, 13C NMR spectra and HPLC traces (PDF). See
DOI: 10.1039/x0xx00000x
in two steps from the chiral cyclopropanes 10, in the Lewis
acid-catalyzed [3+2] annulations would provide access to a
range of biologically interesting chiral furanolignans with
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stereochemical features complementary to that obtained in 1 mol % led to a significantly prolonged reaction time while
Johnson’s reaction system (Scheme 1). Herein, we report the maintaining the excellent yield (entry 13). Performing the
details of this study.
reaction at either a lower or higher reaction temperature is
detrimental to the reaction yield (entries 14 and 15). The
efficiency of the reaction could be further improved with an
appropriately reduced amount of solvent (entry 16), which
sets up the optimal reaction conditions as follows: 2.5 mol %
of Sc(OTf)3 as catalyst in 2.0 mL of 1,2-DCE at 40 °C. Notably, in
all the cases examined above, the desired product 3aa was
obtained invariably as a single diastereomer. Moreover, the
requirement of only a barely excess of benzaldehyde 2a (1.1
eq) for obtaining an excellent yield highlights the high
reactivity of this type of fused D–A cyclopropanes.
trans
s
CO2Me
CO2Me
n
BnO2
C
a
r
piperonal
CO2Me
t
MeO
OMe
BnO2
C
(2.0 equiv)
3
2
4
5
4 steps
O
AlCl3 (15 mol%)
Ar1
Johnson's work
(2009)
CO2Me
O
CH2Cl2, rt
O
MeO
Ar1
10d
80% ee
Ar1 = 3,4-diMeOC6H3
80% ee
(98% ee after a
recrystallization)
O
MeO
O
(+)-virgatusin
R
O
Ar2CHO
(1.1 equiv)
Sc(OTf)3
2 steps
O
O
R
O
O
CO2Me
OHC
2 steps
H
CO2Me
Ar2
(2.5 mol %)
CO2Me
This work
H
CO2Me
1,2-DCE
40 °C
Ar1
O
Ar1
O
3
10
MeO
Ar1
99% ee
O
1
73–98% yield
Readily available via
asymmetric
organocatalysis
98-99% ee
O
OMe
(after recrystallization)
23 examples
all cis-isomers
Scheme 1. Enantiospecific [3+2] annulations of 2,3-disubstituted D–A cyclopropanes
with aromatic aldehydes
Table 2. Scope of aldehydes 2a
Results and discussion
Using the [3+2] annulation of racemic cyclopropane 1a and
benzaldehyde 2a as model reaction, we first optimized several
reaction parameters such as Lewis acid catalyst, solvent and
reaction temperature (Table 1). While Sc(OTf)3 proved to be
the most efficient catalyst for the reaction in 1,2-
dicholoroetheane (1,2-DCE) at 40 °C, the triflate salts of other
metals including iron(III), tin(II) and aluminum(III) also
provided excellent yields, albeit with longer reaction times
(Table 1, entries 1–4). Surprisingly, the use of Yb(OTf)3,
Mg(OTf)2 and Zn(OTf)2 gave no formation of the desired
product with most of the starting material cyclopropane 1a
being recovered (entries 6–8).
Entry
2 (Ar)
t (h)
2.5
3 (yield %)b
3aa (97)
3ab (98)
3ac (97)
3ad (98)
3ae (97)
3af (95)
3ag (96)
3ah (90)
3ai (90)
1
2
2a (Ph)
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (3-MeOC6H4)
2e (2-MeOC6H4)
2f (3,4-diMeOC6H3)
2g (4-FC6H4)
4.0
3
1.5
4
2.0
5
1.5
6
0.5
7
10.0
28.0
24.0
24.0
30.0
10.0
24.0
8
2h (4-ClC6H4)
2i (3-ClC6H4)
9
10
11
12
13
2j (2-ClC6H4)
3aj (90)
2k (4-BrC6H4)
2l (4-F3CC6H4)
2m (4-O2NC6H4)
3ak (88, X-ray)
3al (85)
Table 1. Optimization of reaction conditionsa
NR
aReaction scale: 0.5 mmol, [1a]0 = 0.25 M. bIsolated yield.
Having established the optimum reaction conditions for the
annulation with the racemic γ-butyrolactone fused
cyclopropane 1a, (+)-1a of 99% enantiomer excess (ee) was
examined in the reaction (Table 2, entry 1). To our delight, the
reaction proceeded efficiently to provide the enantiomerically
enriched product 3aa in excellent yield and with complete
enantiospecificity (100% es). Then, a series of substituted
Entry
1
Lewis acid
Sc(OTf)3
Fe(OTf)3
Sn(OTf)2
Al(OTf)3
Cu(OTf)2
Yb(OTf)3
Mg(OTf)2
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Solvent
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
CH2Cl2
Time (h)
4
Yield (%)b
97
96
91
93
22
-
2
8
3
22
30
40
40
40
40
5
4
5
6
benzaldehydes
2 were subjected to the reaction with (+)-1a to
7
-
probe the reaction scope. In general, aldehydes bearing
electron-donating groups on the benzene ring (entries 2–6)
displayed appreciably higher reactivities in the reaction than
those with electron-withdrawing ones (entries 7–12), which is
similar to previous studies on related D–A cyclopropanes. The
differentiated placement of the substituent showed no
obvious influence on the reactivity of the aldehyde. However,
the aldehyde 2m bearing a strongly electron-withdrawing nitro
group was inert to the reaction, with only the starting material
being recovered (entry 13). It’s worth mentioning that almost
all the reactions examined have proceeded with 100% es to
provide a series of chiral tetrahydrofurans containing four
contiguous stereocenters including a quaternary carbon center
in good to excellent yields and with exclusive
diastereoselectivities.
8
-
9
95
91
89
91
97
90
90
97
10
11
12
13c
14d
15e
16f
CHCl3
40
40
40
14
20
2.5
2.5
CCl4
toluene
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
aUnless note otherwise, reactions were performed with (±)-1a (0.5 mmol) and 2a
(0.55 mmol) in 5.0 mL of solvent. Isolated yield. 1 mol % of Sc(OTf)3 was used.
dRun at 20 °C. eRun at 60 °C. fRun in 2.0 mL of solvent.
b
c
The use of several other solvents led to inferior yields
(entries 9–12). Reducing the catalyst loading from 2.5 mol % to
2 | J. Name., 2012, 00, 1-3
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The absolute configuration of the product 3ak was racemic sample. The diol 5dn could be transformed to 6dn, a
confirmed by single crystal X-ray crystallographic analysis. The stereoisomer of (+)-virgatusin, via a single-step treatment with
absolute configurations of other products were assigned by NaH and CH3I; to 7dn, an analogue of fargesin, via a single-step
analogy.
Subsequently, the reaction scope with respect to chiral γ- fragransin C1, via a tandem mesylation-reduction sequence.
butyrolactone fused cyclopropanes was examined (Figure 2). The stereochemical purity of the starting materials could be
The presence of an electron-donating group (R) at the para maintained during almost all of these manipulations.
position of the benzene ring in cyclopropanes seems to be Moreover, both the relative and absolute configurations of
favorable in terms of reaction rate as demonstrated in the these products are highly complementary to that obtained
formation of the products 3ba 3ea and 3fa. Herein, the with the corresponding non-fused chiral D–A cyclopropane in
strongly electron-withdrawing substituent NO2 is well Johnson’s work despite the same chirality source (all from (2S,
tolerated, although large excess of benzaldehyde, an 3R)-10d), highlighting the great influence of the fused lactone
treatment with NaH and TsCl; and to 9dn, an analogue of
1
1
,
a
increased catalyst loading and a prolonged reaction time were moiety on the reactivity of the cyclopropane. Notably, the
required to provide excellent yield. Placing a substituent at the structure of 9dn has previously been assigned to a natural
ortho position somewhat slowed down the reaction (3ca), product with insect growth inhibitive activity firstly isolated
while the presence of two substituents at the 3,4-positions of from Machilus japonica; however, the spectroscopic data and
the benzene ring was well tolerated (3da). Notably, a series of specific rotation value reported in the literature11a differ
chiral tetrahydrofurans
(
3bf
–
3dq
)
containing multiple significantly from those of ours, which suggests a revision of
substituents on both benzene rings, which are widely present the original structure assigned to the isolated natural product
in biologically active furanolignans, were obtained in almost may be necessary.
enantiopure forms as single diastereomers.
Conclusions
In summary, we have developed a stereoselective way to a
range of chiral furanolignans bearing multiple adjacent
stereogenic centers in almost optically pure forms. The high
yields, simple manipulations and mild conditions render this
method
a good complement to previous ones in the
construction of structurally diverse chiral furanolignans with
biological relevance.
Experimental
General remarks
Figure 2. Scope of Cyclopropanes 1. See Table 2 for general reaction conditions. aRun
with 10.0 equiv of benzaldehyde 2a in the presence of 10 mol % of Sc(OTf)3.
All the [3+2] annulation reactions were carried out with flame-
dried Schlenk-type glassware using a Schlenk line. All reagents
were purchased from commercial suppliers and purified by
standard techniques unless specified otherwise. Flash column
chromatography was performed using silica gel (200–400
mesh). For thin-layer chromatography (TLC), silica gel plates
(HSGF 254) were used and compounds were visualized by
irradiation with UV light. 1H NMR (500 MHz) and 13C NMR (125
MHz) spectra were recorded in CDCl3. All chemical shifts (δ)
are given in ppm relative to TMS (δ = 0 ppm) as internal
standard. Data are reported as follows: chemical shift,
multiplicity, coupling constants and integration. Melting points
were uncorrected. High resolution mass spectral (HRMS) data
were obtained with an ionization mode of ESI and a TOF
analyzer.
O
O
O
CO2Me
O
O
O
MeO
MeO
MeO
O
O
O
9dn
(99 ee%)
33% yield over 2 steps
7dn
(97 ee%)
3dn
(99% ee)
O
MeO
O
O
MeO
MeO
NaCl
DMSO-H2
reflux
1). Et3N, MsCl
THF, rt
O
89%
NaH, TsCl
THF, 0
74%
C
2) Super-H
THF, 60
O
C
O
HO
OH
MeO
OMe
NaH, CH3
I
LiAlH4 (4eq)
THF, 0
98% yield
THF, rt
91%
C
O
MeO
O
O
O
4dn
(99% ee)
(relative configuration
confirmed by x-ray)
MeO
MeO
O
O
O
MeO
6dn
(99 ee%)
5dn
O
O
MeO
MeO
(99% ee)
Scheme 2. Product transformations
To illustrate the utility of the [3+2] annulation products, the
transformations of 3dn to several chiral furanolignan
analogues were studied (Scheme 2). Selective Krapcho
decarboxylation of the pendant methyl carboxylate group
provided an 89% yield of 4dn, which could be converted into
the diol 5dn in an almost quantitative yield after reduction
with LiAlH4. The relative configuration of the compound 4dn
has been confirmed by a single crystallographic analysis of its
Typical procedure for the enantiospecific [3+2] annulation
To a solution of γ-butyrolactone fused cyclopropanes
1 (0.5
mmol) and aromatic aldehydes 2 (0.55 mmol) in 2.0 mL of dry
1,2-dichloroethane was added Sc(OTf)3 (0.0125 mmol). The
reaction mixture was stirred at 40 °C and monitored by TLC.
Upon completion, the reaction mixture was cooled down to
room temperature followed by the addition of 10.0 mL of
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(petroleum ether/ethyl acetate). 1H NMR (CDCl3, 500 MHz): δ 7.46–
7.39 (m, 4H), 7.38–7.29 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.08 (s, 1H),
6.88 (dd, J = 8.2, 2.2 Hz, 1H), 5.74 (s, 1H), 5.32 (d, J = 4.7 Hz, 1H),
4.12 (t, J = 9.0 Hz, 1H), 4.01–3.91 (m, 2H), 3.90 (s, 3H), 3.82 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 171.1, 168.9, 159.5, 137.1, 135.8,
129.5, 128.9, 128.2, 125.6, 118.8, 113.6, 112.6, 85.0, 81.0, 66.4,
66.3, 55.2, 53.7, 51.2. HRMS (ESI-TOF) calcd for C21H21O6 ([M + H]+)
369.1338, found 369.1330.
saturated sodium bicarbonate aqueous solution. Then the
mixture was extracted with dichloromethane (10.0 mL
× 3),
and the combined organic layers were dried with anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude
products were purified by flash chromatography to give the
pure products.
(1R,3R,3aR,6aR)-Methyl 4-oxo-1,3-diphenylhexahydrofuro
[3,4-c]furan-3a-carboxylate (3aa). Purified by column
chromatography (petroleum ether/ethyl acetate = 6/1) to
afford a colorless oil in 97% yield (164 mg) and 99% ee. The ee
was determined by HPLC analysis using a Chiralcel AD-H
column (95/5 hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210
(1R,3R,3aR,6aR)-Methyl 3-(2-anisyl)-4-oxo-1-phenylhexahydro
furo[3,4-c]furan-3a-carboxylate (3ae). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 97% yield (179 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AS-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 14.4 (major),
nm; tR = 16.4 (major), 19.0 (minor) min). [α]20 = +24.7 (c =
D
10.9 (minor) min). [α]20 = –59.7 (c = 0.52, CHCl3). 1H NMR (CDCl3,
1
0.59, CHCl3). H NMR (CDCl3, 500 MHz): δ 7.53 (d, J = 7.3 Hz,
D
500 MHz): Mp: 139–140 °C (petroleum ether/ethyl acetate). 1H
NMR (CDCl3, 500 MHz): δ 7.57 (d, J = 7.3 Hz, 1H), 7.50–7.38 (m, 4H),
7.38–7.28 (m, 2H), 7.00 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H),
5.95 (s, 1H), 5.45 (d, J = 4.9 Hz, 1H), 3.99 (t, J = 9.5 Hz, 1H), 3.91 (s,
3H) , 3.86 (dd, J = 9.5, 6.8 Hz, 1H), 3.81 (s, 3H). 3.79–3.71 (m, 1H).
13C NMR (CDCl3, 125 MHz): δ 170.7, 169.8, 156.8, 136.0, 129.7,
128.8, 128.1, 126.0, 125.6, 124.4, 120.6, 110.3, 82.8, 81.1, 65.7,
64.1, 55.3, 53.3, 52.6. HRMS (ESI-TOF) calcd for C21H21O6 ([M + H]+)
369.1338, found 369.1331.
2H), 7.48–7.31 (m, 8H), 5.77 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H),
4.13 (t, J = 9.2 Hz, 1H), 4.03–3.92 (m, 2H), 3.90 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 171.1, 168.9, 135.9, 135.5, 128.9, 128.8,
128.5, 128.2, 126.4, 125.6, 85.2, 81.1, 66.7, 66.3, 53.7, 51.1.
HRMS (ESI-TOF) calcd for C20H19O5 ([M + H]+) 339.1232, found
339.1239.
(1R,3R,3aR,6aR)-Methyl 4-oxo-1-phenyl-3-(p-tolyl)hexahy
drofuro[3,4-c]furan-3a-carboxylate (3ab). Purified by column
chromatography (petroleum ether/ethyl acetate = 4/1) to
afford a white solid in 98% yield (173 mg) and 99% ee. The ee
was determined by HPLC analysis using a Chiralcel OD-H
column (9/1 hexane/i-PrOH; flow rate 0.75 mL/min; λ = 210
(1R,3R,3aR,6aR)-Methyl
3-(3,4-dimethoxyphenyl)-4-oxo-1-
phenylhexahydrofuro[3,4-c]furan-3a-carboxylate (3af). Purified by
column chromatography (petroleum ether/ethyl acetate = 3/1) to
afford a white solid in 95% yield (189 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (4/1
nm; tR = 29.0 (major), 21.6 (minor) min). [α]20 = –78.9 (c =
D
0.59, CHCl3). Mp: 160–161 °C (petroleum ether/ethyl acetate). hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 17.3 (major),
20.4 (minor) min). [α]20 = –28.7 (c = 0.59, CHCl3). Mp: 109–110 °C
1H NMR (CDCl3, 500 MHz): δ 7.50–7.38 (m, 6H), 7.38–7.32 (m,
1H), 7.20 (d, J = 7.9 Hz, 2H), 5.73 (s, 1H), 5.32 (d, J = 4.8 Hz,
1H), 4.13 (t, J = 9.2 Hz, 1H), 4.01–3.91 (m, 2H), 3.89 (s, 3H),
2.35 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.3, 169.0, 138.6,
135.9, 132.5, 129.2, 128.9, 128.2, 126.4, 125.6, 85.3, 81.1,
66.7, 66.4, 53.6, 51.1, 21.3. HRMS (ESI-TOF) calcd for C21H21O5
([M + H]+) 353.1389, found 353.1379.
D
(petroleum ether/ethyl acetate). 1H NMR (CDCl3, 500 MHz): δ 7.48–
7.39 (m, 4H), 7.39–7.31 (m, 1H), 7.09 (dd, J = 8.3, 1.8 Hz, 1H), 7.01
(d, J = 1.8 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.71 (s, 1H), 5.31 (d, J =
4.7 Hz, 1H), 4.14 (t, J = 9.1 Hz, 1H), 4.01–3.92 (m, 2H), 3.90 (s, 3H),
3.89 (s, 3H), 3.88 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.2, 169.0,
149.3, 148.9, 135.9, 128.9, 128.2, 127.9, 125.6, 118.9, 111.0, 109.9,
85.2, 81.0, 66.7, 66.2, 55.9, 55.8, 53.7, 51.1. HRMS (ESI-TOF) calcd
for C22H23O7 ([M + H]+) 399.1444, found 399.1443.
(1R,3R,3aR,6aR)-Methyl
3-(4-anisyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ac). Purified by
column chromatography (petroleum ether/ethyl acetate = 3/1)
to afford a white solid in 97% yield (179 mg) and 99% ee. The
ee was determined by HPLC analysis using a Chiralcel OD-H
column (4/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm;
(1R,3R,3aR,6aR)-Methyl 3-(4-fluorophenyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ag). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 96% yield (171 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AS-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 14.6 (major),
tR = 24.3 (major), 16.3 (minor) min). [α]20 = –71.3 (c = 0.50,
D
9.9 (minor) min). [α]20 = +67.7 (c = 0.66, CHCl3). Mp: 151–152 °C
CHCl3). Mp: 156–157 °
C (petroleum ether/ethyl acetate). 1H
D
(petroleum ether/ethyl acetate). 1H NMR (CDCl3, 500 MHz): δ 7.55–
7.48 (m, 2H), 7.47–7.33 (m, 5H), 7.14–7.03 (m, 2H), 5.74 (s, 1H),
5.33 (d, J = 4.8 Hz, 1H), 4.14 (t, J = 8.9 Hz, 1H), 4.00–3.91 (m, 2H),
3.90 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.1, 168.8, 162.9 (d, 1JC–
F = 247.0 Hz), 135.7, 131.3, 128.9, 128.3, 128.2, 125.6, 115.5 (d, 2JC–F
= 21.7 Hz), 84.6, 81.3, 66.8, 66.2, 53.7, 51.0. HRMS (ESI-TOF) calcd
for C20H18FO5 ([M + H]+) 357.1138, found 357.1137.
NMR (CDCl3, 500 MHz): δ 7.54–7.39 (m, 6H), 7.38–7.32 (m,
1H), 6.93 (d, J = 8.7 Hz, 2H), 5.71 (s, 1H), 5.31 (d, J = 4.8 Hz,
1H), 4.13 (t, J = 9.1 Hz, 1H), 4.01–3.92 (m, 2H), 3.89 (s, 3H),
3.81 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.3, 169.0, 159.9,
136.0, 128.9, 128.2, 127.8, 127.5, 125.6, 113.9, 85.2, 81.0,
66.7, 66.3, 55.2, 53.6, 51.0. HRMS (ESI-TOF) calcd for C21H21O6
([M + H]+) 369.1338, found 369.1334.
(1R,3R,3aR,6aR)-Methyl 3-(4-chlorophenyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ah). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 90% yield (168 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel OD-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 21.1 (major),
(1R,3R,3aR,6aR)-Methyl
3-(3-anisyl)-4-oxo-1-phenylhexahy
drofuro[3,4-c]furan-3a-carboxylate (3ad). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 98% yield (181 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (95/5
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 23.2 (major),
13.9 (minor) min). [α]20 = +94.1 (c = 0.59, CHCl3). Mp: 165–166 °C
29.6 (minor) min). [α]20 = +56.0 (c = 0.12, CHCl3). Mp: 126–127 °C
D
D
(petroleum ether/ethyl acetate). 1H NMR (CDCl3, 500 MHz): δ 7.52–
4 | J. Name., 2012, 00, 1-3
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ARTICLE
7.33 (m, 9H), 5.73 (s, 1H), 5.33 (d, J = 4.7 Hz, 1H), 4.14 (t, J = 8.7 Hz, chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
1H), 3.98–3.91 (m, 2H), 3.90 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ white solid in 79% yield (145 mg) and 99% ee. The ee was
171.0, 168.8, 135.7, 134.6, 134.0, 128.9, 128.7, 128.3, 127.9, 125.6, determined by HPLC analysis using a CHIRALPAK IC column (4/1 i-
84.5, 81.3, 66.8, 66.2, 53.8, 51.0. HRMS (ESI-TOF) calcd for PrOH/hexane; flow rate 1.0 mL/min; λ = 254 nm; tR = 21.3 (major),
C20H18ClO5 ([M + H]+) 373.0843, found 373.0840.
19.1 (minor) min). [α]20 = –14.7 (c = 0.59, CHCl3). Mp: 158–159 °C
D
(petroleum ether/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 7.51 (d,
J = 7.3 Hz, 2H), 7.44–7.31 (m, 5H), 6.95 (d, J = 8.7 Hz, 2H), 5.75 (s,
1H), 5.29 (d, J = 5.0 Hz, 1H), 4.13 (t, J = 9.4 Hz, 1H), 4.00 (dd, J = 9.6,
6.3 Hz, 1H), 3.90 (s, 3H), 3.89–3.84 (m, 1H), 3.83 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 171.2, 169.0, 159.4, 135.6, 128.8, 128.5, 127.8,
126.8, 126.5, 114.3, 85.1, 81.0, 66.6, 66.4, 55.4, 53.6, 51.3. (ESI-TOF)
calcd for C21H21O6 ([M + H]+) 369.1338, found 369.1334.
(1R,3R,3aR,6aR)-Methyl 3-(3-chlorophenyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ai). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 90% yield (168 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 7.2 (major),
8.2 (minor) min). [α]20 = +104.3 (c = 0.33, CHCl3). Mp: 135–136 °C
D
1
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.51
(1R,3R,3aR,6aR)-Methyl (4-anisyl)-3-(3,4-dimethoxyphenyl)-1-4-
(s, 1H), 7.49–7.29 (m, 8H), 5.73 (s, 1H), 5.33 (d, J = 4.9 Hz, 1H), 4.14 oxohexahydrofuro[3,4-c]furan-3a-carboxylate (3bf). Purified by
(t, J = 9.1 Hz, 1H), 4.01–3.87 (m, 5H). 13C NMR (CDCl3, 125 MHz): δ column chromatography (petroleum ether/ethyl acetate = 2/1) to
170.9, 168.7, 137.5, 135.5, 134.4, 129.7, 128.9, 128.3, 126.5, 125.6, afford a colorless oil in 95% yield (204 mg) and 99% ee. The ee was
124.8, 84.2, 81.3, 66.8, 66.2, 53.8, 51.0. HRMS (ESI-TOF) calcd for determined by HPLC analysis using a Chiralcel AD-H column (2/1
C20H18ClO5 ([M + H]+) 373.0843, found 373.0835.
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 14.9 (major),
1
24.7 (minor) min). [α]20 = +109.7 (c = 0.34, CHCl3). H NMR (CDCl3,
D
(1R,3S,3aR,6aR)-Methyl 3-(2-chlorophenyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3aj). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 90% yield (168 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel OD-H column (9/1
hexane/i-PrOH; flow rate 0.75 mL/min; λ = 210 nm; tR = 41.3 (major),
33.0 (minor) min). [α]20D = –124.7 (c = 0.80, CHCl3). Mp: 220–221 °C
(petroleum ether/ethyl acetate).1H NMR (CDCl3, 500 MHz): δ 7.63
(dd, J = 7.6, 1.5 Hz, 1H), 7.49–7.27 (m, 8H), 6.13 (s, 1H), 5.50 (d, J =
4.8 Hz, 1H), 4.07 (t, J = 9.5 Hz, 1H), 3.98–3.88 (m, 4H), 3.86–3.78 (m,
1H). 13C NMR (CDCl3, 125 MHz): δ 170.6, 169.3, 135.5, 134.0, 132.9,
129.9, 129.6, 128.9, 128.2, 127.4, 127.1, 125.5, 83.3, 81.2, 66.0,
64.8, 53.8, 52.6. HRMS (ESI-TOF) calcd for C20H18ClO5 ([M + H]+)
373.0843, found 373.0843.
500 MHz): δ 7.32 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H),
7.00 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.3 Hz,
1H), 5.69 (s, 1H), 5.26 (d, J = 5.0 Hz, 1H), 4.14 (t, J = 9.4 Hz, 1H), 3.99
(dd, J = 9.6, 6.3 Hz, 1H), 3.96–3.78 (m, 13H). 13C NMR (CDCl3, 125
MHz): δ 171.3, 169.0, 159.4, 149.3, 148.8, 127.94, 127.87, 126.8,
118.9, 114.3, 111.0, 109.9, 85.1, 80.8, 66.7, 66.2, 55.9, 55.8, 55.3,
53.6, 51.2. HRMS (ESI-TOF) calcd for C23H25O8 ([M + H]+) 429.1549,
found 429.1550.
(1R,3R,3aR,6aR)-Methyl 1-(4-anisyl)-3-(4-chlorophenyl)-4-oxo
hexahydrofuro[3,4-c]furan-3a-carboxylate (3bh). Purified by
column chromatography (petroleum ether/ethyl acetate = 6/1) to
afford a white solid in 73% yield (147 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (9/1
hexane/i-PrOH; flow rate 0.75 mL/min; λ = 210 nm; tR = 25.6 (major),
27.6 (minor) min). [α]20D = –170.7 (c = 0.20, CHCl3). Mp: 167–168 °C
(1R,3R,3aR,6aR)-Methyl 3-(4-bromophenyl)-4-oxo-1-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ak). Purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
white solid in 88% yield (184 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 8.8 (major),
1
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.45
(d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H),
6.95 (d, J = 8.5 Hz, 2H), 5.71 (s, 1H), 5.28 (d, J = 4.8 Hz, 1H), 4.14 (t, J
= 9.4 Hz, 1H), 3.97 (dd, J = 9.1, 6.5 Hz, 1H), 3.89 (s, 3H), 3.88–3.78
(m, 4H). 13C NMR (CDCl3, 125 MHz): δ 171.1, 168.8, 159.5, 134.6,
134.1, 128.7, 127.9, 127.6, 126.8, 114.3, 84.4, 81.2, 66.8, 66.2, 55.4,
53.7, 51.1. HRMS (ESI-TOF) calcd for ([M + NH4]+) 420.1214, found
420.1205.
10.7 (minor) min). [α]20 = –58.6 (c = 0.59, CHCl3). Mp: 186–187 °C
D
1
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.52
(d, J = 8.5 Hz, 2H), 7.49–7.32 (m, 7H), 5.71 (s, 1H), 5.33 (d, J = 4.7 Hz,
1H), 4.14 (t, J = 8.6 Hz, 1H), 4.00–3.91 (m, 2H), 3.90 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 171.1, 168.7, 135.6, 134.5, 131.6, 128.9, 128.3,
128.1, 125.5, 122.8, 84.4, 81.3, 66.8, 66.2, 53.8, 50.9. HRMS (ESI-
TOF) calcd for C20H18BrO5 ([M + H]+) 417.0338, found 417.0336.
(1R,3R,3aR,6aR)-Methyl 1-(2-anisyl)-4-oxo-3-phenylhexahydro
furo[3,4-c]furan-3a-carboxylate (3ca). Purified by column
chromatography (petroleum ether/ethyl acetate = 7/1) to afford a
white solid in 85% yield (156 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AS-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm; tR = 11.4 (major),
(1R,3R,3aR,6aR)-Methyl 4-oxo-1-phenyl-3-(4-(trifluoromethyl)
phenyl)hexahydrofuro[3,4-c]furan-3a-carboxylate (3al). Purified by
column chromatography (petroleum ether/ethyl acetate = 5/1) to
afford a white solid in 85% yield (173 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel OD-H column (9/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm; tR = 20.8 (major),
9.9 (minor) min). [α]20 = –29.7 (c = 0.60, CHCl3). Mp: 125–126 °C
D
1
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.69
(d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H),
7.34 (t, J = 7.7 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H),
5.75 (s, 1H), 5.37 (d, J = 5.1 Hz, 1H), 4.10 (t, J = 9.1 Hz, 1H), 4.07–
4.00 (m, 1H), 3.96–3.88 (m, 4H), 3.86 (s, 3H). 13C NMR (CDCl3, 125
MHz): δ 171.7, 169.3, 155.2, 135.7, 129.2, 128.7, 128.4, 127.0,
126.6, 124.4, 120.9, 110.0, 84.4, 78.1, 67.0, 66.3, 55.4, 53.6, 49.7.
HRMS (ESI-TOF) calcd for C21H21O6 ([M + H]+) 369.1338, found
369.1331.
13.4 (minor) min). [α]20 = +29.1 (c = 0.50, CHCl3). Mp: 128–129 °C
D
(petroleum ether/ethyl acetate). 1H NMR (CDCl3, 500 MHz): δ 7.74–
7.62 (m, 4H), 7.52–7.34 (m, 5H), 5.80 (s, 1H), 5.36 (d, J = 4.9 Hz, 1H),
4.16 (t, J = 8.8 Hz, 1H), 4.02–3.92 (m, 2H), 3.91 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 170.9, 168.7, 139.5, 135.5, 130.8 (q, 2JC–F = 32.4
1
Hz), 129.0, 128.4, 126.9, 125.6, 125.4, 124.1 (q, JC–F = 272.3 Hz),
84.3, 81.5, 66.8, 66.3, 53.8, 51.0. HRMS (ESI-TOF) calcd for
C21H18F3O5 ([M + H]+) 407.1106, found 407.1100.
(1R,3R,3aR,6aR)-Methyl
1-(3,4-dimethoxyphenyl)-4-oxo-3-
phenylhexahydrofuro[3,4-c]furan-3a-carboxylate (3da). Purified by
column chromatography (petroleum ether/ethyl acetate = 2/1) to
(1R,3R,3aR,6aR)-Methyl 1-(4-anisyl)-4-oxo-3-phenylhexahydro
furo[3,4-c]furan-3a-carboxylate (3ba). Purified by column
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Journal Name
afford a white solid in 77% yield (153 mg) and 99% ee. The ee was AD-H column (1/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm;
determined by HPLC analysis using a CHIRALPAK IC column (4/1 tR = 10.3 (major), 23.6 (minor) min). [α]20D = +20.0 (c = 0.33, CHCl3).
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 48.9 (major), 1H NMR (CDCl3, 500 MHz): δ 6.98–6.87 (m, 3H), 6.73 (s, 2H), 5.68 (s,
39.5 (minor) min). [α]20 = +87.7 (c = 0.51, CHCl3). Mp: 187–188 °C
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.51
1H), 5.27 (d, J = 5.0 Hz, 1H), 4.18 (t, J = 9.4 Hz, 1H), 4.00 (dd, J = 9.6,
D
6.4 Hz, 1H), 3.97–3.80 (m, 19H). 13C NMR (CDCl3, 125 MHz): δ 171.1,
1
169.0, 153.2, 149.4, 148.9, 138.3, 131.0, 128.3, 117.7, 111.4, 108.8,
103.8, 85.2, 80.8, 66.7, 66.2, 60.9, 56.1, 56.00, 55.95, 53.7, 51.2.
HRMS (ESI-TOF) calcd for C25H29O10 ([M + H]+) 489.1761, found
489.1757.
(d, J = 7.3 Hz, 2H), 7.45–7.32 (m, 3H), 7.02–6.88 (m, 3H), 5.75 (s, 1H),
5.29 (d, J = 5.0 Hz, 1H), 4.16 (t, J = 9.4 Hz, 1H), 4.02 (dd, J = 9.6, 6.3
Hz, 1H), 3.97–3.84 (m, 10H). 13C NMR (CDCl3, 125 MHz): δ 171.2,
168.9, 149.4, 148.9, 135.5, 128.8, 128.5, 128.3, 126.5, 117.8, 111.4,
108.9, 85.2, 81.0, 66.7, 66.3, 56.1, 56.0, 53.6, 51.2. HRMS (ESI-TOF)
calcd for C22H23O7 ([M + H]+) 399.1444, found 399.1443.
(1R,3R,3aR,6aR)-Methyl 1-(4-fluorophenyl)-4-oxo-3-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3ea). Purified by column
chromatography (petroleum ether/ethyl acetate = 7/1) to afford a
white solid in 87% yield (155 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AS-H column (4/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm; tR = 14.9 (major),
(1R,3R,3aR,6aR)-Methyl 3-(benzo[d][1,3]dioxol-5-yl)-1-(3,4-di-
methoxyphenyl)-4-oxohexahydrofuro[3,4-c]furan-3a-carboxylate
(3dn). Purified by column chromatography (petroleum ether/ethyl
acetate = 2/1) to afford a colorless oil in 96% yield (212 mg) and
99% ee. The ee was determined by HPLC analysis using
a
10.0 (minor) min). [α]20 = +24.9 (c = 0.69, CHCl3). Mp: 178–179 °C
D
1
CHIRALPAK IC column (2/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ (petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 7.51
= 254 nm; tR = 40.0 (major), 33.4 (minor) min). [α]20 = –35.0 (c = (d, J = 7.2 Hz, 2H), 7.46–7.32 (m, 5H), 7.17–7.08 (m, 2H), 5.76 (s, 1H),
D
1.20, CHCl3). 1H NMR (CDCl3, 500 MHz): δ 7.05–6.86 (m, 5H), 6.82 (d, 5.30 (d, J = 4.8 Hz, 1H), 4.14 (t, J = 9.0 Hz, 1H), 3.99–3.86 (m, 5H). 13
C
1
J = 8.0 Hz, 1H), 5.97 (s, 2H), 5.65 (s, 1H), 5.25 (d, J = 4.9 Hz, 1H), 4.16 NMR (CDCl3, 125 MHz): δ 171.0, 168.8, 162.4 (d, JFC = 247.3 Hz),
3
(t, J = 9.4 Hz, 1H), 3.99 (dd, J = 9.7, 6.3 Hz, 1H), 3.96–3.83 (m, 10H). 135.3, 131.6, 128.9, 128.5, 127.3 (d, JFC = 8.1 Hz), 126.4, 115.9 (d,
13C NMR (CDCl3, 125 MHz): δ 171.3, 168.9, 149.3, 148.8, 147.9, 2JFC = 21.7 Hz), 85.2, 80.6, 66.5, 66.3, 53.7, 51.1. HRMS (ESI-TOF)
147.7, 129.2, 128.2, 120.2, 117.8, 111.3, 108.7, 108.4, 106.9, 101.2, calcd for C20H18FO5 ([M + H]+) 357.1138, found 357.1137.
85.1, 80.9, 66.7, 66.2, 56.04, 55.98, 53.7, 51.1. HRMS (ESI-TOF)
(1R,3R,3aR,6aR)-Methyl 1-(4-nitrophenyl)-4-oxo-3-phenylhexa
hydrofuro[3,4-c]furan-3a-carboxylate (3fa). Purified by column
calcd for C23H26NO9 ([M + NH4]+) 460.1608, found 460.1605.
(1R,3R,3aR,6aR)-Methyl 3-(4-acetoxy-3-methoxyphenyl)-1-(3,4- chromatography (petroleum ether/ethyl acetate = 2/1) to afford a
dimethoxyphenyl)-4-oxohexahydrofuro[3,4-c]furan-3a-carboxyl
white solid in 95% yield (182 mg) and 99% ee. The ee was
ate (3do). Purified by column chromatography (petroleum determined by HPLC analysis using a Chiralcel AD-H column (2/1
ether/ethyl acetate = 2/1) to afford a colorless oil in 85% yield (207 hexane/i-PrOH; flow rate 1.0 mL/min; λ = 210 nm; tR = 9.6 (major),
11.2 (minor) min). [α]20 = –77.7 (c = 0.79, CHCl3). Mp: 181–182 °C
mg) and 99% ee. The ee was determined by HPLC analysis using a
D
1
Chiralcel AS-H column (2/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ
(petroleum ether/ethyl acetate). H NMR (CDCl3, 500 MHz): δ 8.31
(d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H),
7.47–7.33 (m, 3H), 5.79 (s, 1H), 5.40 (d, J = 4.9 Hz, 1H), 4.16 (t, J =
9.4 Hz, 1H), 4.05–3.99 (m, 1H), 3.91 (s, 3H), 3.85 (dd, J = 9.5, 6.5 Hz,
1H). 13C NMR (CDCl3, 125 MHz): δ 170.5, 168.5, 147.9, 143.1, 134.9,
129.1, 128.6, 126.7, 126.4, 124.2, 85.6, 80.4, 66.22, 66.20, 53.9,
50.8. HRMS (ESI-TOF) calcd for C20H18NO7 ([M + H]+) 384.1083,
found 384.1076.
= 254 nm; tR = 23.7 (major), 15.0 (minor) min). [α]20 = –24.9 (c =
D
1
0.59, CHCl3). H NMR (CDCl3, 500 MHz): δ 7.15–7.09 (m, 2H), 7.08–
7.02 (m, 1H), 6.97–6.86 (m, 3H), 5.71 (s, 1H), 5.27 (d, J = 5.0 Hz, 1H),
4.17 (t, J = 9.4 Hz, 1H), 3.99 (dd, J = 9.6, 6.2 Hz, 1H), 3.96–3.86 (m,
10H), 3.84 (s, 3H), 2.30 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.0,
168.9, 151.0, 149.4, 148.9, 140.0, 134.4, 128.3, 122.8, 118.8, 117.8,
111.5, 111.0, 108.8, 84.7, 81.0, 66.7, 66.2, 56.0. 55.9, 53.7, 51.2,
20.7. HRMS (ESI-TOF) calcd for C25H30NO10 ([M + NH4]+) 504.1870,
found 504.1872.
(3aR,4R,6S,6aR)-6-(Benzo[d][1,3]dioxol-5-yl)-4-(3,4-dimethoxy
phenyl)tetrahydrofuro[3,4-c]furan-1(3H)-one (4dn). A mixture of
compound 3dn (141 mg, 0.32 mmol) and NaCl (150 mg, 2.57 mmol)
in DMSO (10 mL) and water (1 mL) was heated at 100 °C under an
argon atmosphere. After completion of the reaction, the mixture
was cooled to room temp, diluted with water (50 mL) and extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (30 mL), dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure, and the residue was purified
by column chromatography (petroleum ether/CH2Cl2 = 2/1) to
afford a white solid in 89% yield (109 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (2/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm; tR = 26.8 (major),
19.1 (minor) min). [α]20D = –175.3 (c = 0.21, CHCl3). Mp: 164–165 °C
(petroleum ether/CH2Cl2). 1H NMR (CDCl3, 500 MHz): δ 6.98–6.87
(m, 5H), 6.83 (d, J = 8.4 Hz, 1H), 6.02–5.95 (m, 2H), 5.22 (d, J = 8.6
Hz, 1H), 5.19 (d, J = 5.0 Hz, 1H), 4.09 (t, J = 9.5 Hz, 1H), 3.96 (dd, J =
9.8, 6.7 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.68–3.57 (m, 1H), 3.51 (t,
J = 8.8 Hz, 1H). 13C NMR (CDCl3, 125 MHz): δ 175.1, 149.2, 148.7,
147.9, 147.7, 130.0, 129.1, 120.0, 117.8, 111.3, 108.9, 108.4, 106.7,
101.2, 82.7, 81.6, 67.9, 56.1, 56.0, 50.9, 45.3. HRMS (ESI-TOF) calcd
for C21H24NO7 ([M + NH4]+) 402.1553, found 402.1551.
(1R,3R,3aR,6aR)-Methyl 3-(4-(benzyloxy)-3-methoxyphenyl)-1-
(3,4-dimethoxyphenyl)-4-oxohexahydrofuro[3,4-c]furan-3a-carbo
xylate (3dp). Purified by column chromatography (petroleum
ether/ethyl acetate = 2/1) to afford a colorless oil in 95% yield (254
mg) and 99% ee. The ee was determined by HPLC analysis using a
Chiralcel AD-H column (1/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ
= 254 nm; tR = 12.3 (major), 7.3 (minor) min). [α]20D = –2.7 (c = 0.59,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ 7.43 (d, J = 7.3 Hz, 2H), 7.36 (t, J
= 7.5 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.08–6.99 (m, 2H), 6.97–6.86
(m, 4H), 5.67 (s, 1H), 5.25 (d, J = 5.0 Hz, 1H), 5.15 (s, 2H), 4.16 (t, J =
9.4 Hz, 1H), 4.00 (dd, J = 9.6, 6.4 Hz, 1H), 3.97–3.82 (m, 13H). 13C
NMR (CDCl3, 125 MHz): δ 171.2, 169.0, 149.5, 149.3, 148.8, 148.6,
137.2, 128.6, 128.42, 128.39, 127.8, 127.3, 118.9, 117.8, 113.6,
111.4, 110.5, 108.8, 85.1, 80.8, 71.0, 66.7, 66.2, 56.0, 53.6, 51.2.
HRMS (ESI-TOF) calcd for C30H34NO9 ([M + NH4]+) 552.2234, found
552.2243.
(1R,3R,3aR,6aR)-Methyl 1-(3,4-dimethoxyphenyl)-4-oxo-3-(3,4,5
-trimethoxyphenyl)hexahydrofuro[3,4-c]furan-3a-carboxylate
(3dq). Purified by column chromatography (petroleum ether/ethyl
acetate = 2/1) to afford a colorless oil in 95% yield (232 mg) and
99% ee. The ee was determined by HPLC analysis using a Chiralcel
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8OB00455B
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ARTICLE
((2S,3S,4R,5R)-2-(Benzo[d][1,3]dioxol-5-yl)-5-(3,4-dimethoxy
phenyl)tetrahydrofuran-3,4-diyl)dimethanol (5dn). LiAlH4 (74 mg,
1.95 mmol) was added slowly to a solution of compound 4dn (189
mg, 0.49 mmol) in THF (10 mL) at 0 °C under an argon atmosphere.
After completion of the reaction, the mixture was diluted with
water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed with brine (30 mL), dried
with anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(petroleum ether/ethyl acetate = 1/1) to afford a colorless oil in
98% yield (187 mg) and 99% ee. The ee was determined by HPLC
analysis using a Chiralcel IA column (2/1 hexane/i-PrOH; flow rate
= 254 nm; tR = 25.4 (major), 28.6 (minor) min). [α]20 = +28.6 (c =
D
0.52, CHCl3). Mp: 175–176 °C (petroleum ether/ethyl acetate). 1H
NMR (CDCl3, 500 MHz): δ 6.96 (s, 3H), 6.87 (d, J = 8.6 Hz, 2H), 6.82
(d, J = 8.0 Hz, 1H), 5.97 (s, 2H), 5.11–5.00 (m, 2H), 3.92 (s, 3H), 3.89
(s, 3H), 3.53–3.44 (m, 2H), 3.44–3.35 (m, 2H), 3.26–3.14 (m, 2H). 13
C
NMR (CDCl3, 125 MHz): δ 148.9, 148.2, 147.7, 146.7, 132.7, 131.3,
119.2, 118.3, 111.1, 109.5, 108.2, 106.9, 101.0, 82.0, 81.9, 70.3,
70.2, 56.00, 55.96, 49.89, 49.87. HRMS (ESI-TOF) calcd for
C21H26NO6 ([M + NH4]+) 388.1760, found 388.1762.
((2S,3S,4R,5R)-2-(Benzo[d][1,3]dioxol-5-yl)-5-(3,4-dimethoxy
phenyl)tetrahydrofuran-3,4-diyl)bis(methylene) dimethanesulfon
ate (8dn). Under an argon atmosphere, to an ice-cooled solution of
diol 5dn (430 mg, 1.11 mmol) and Et3N (0.32 mL, 2.3 mmol) in
CH2Cl2 (10 mL) was added MsCl (0.18 mL, 2.3 mmol). The reaction
mixture was stirred at room temperature for 30 min before the
addition of H2O (20 mL) and CH2Cl2 (20 mL). The organic phase was
separated, dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate = 3/1) to afford a
red oil in 98% yield (592 mg) and 98% ee. The ee was determined by
HPLC analysis using a Chiralcel IC column (2/1 hexane/i-PrOH; flow
rate 1.0 mL/min; λ = 254 nm; tR = 11.6 (major), 8.7 (minor) min).
[α]20D = –93.3 (c = 0.12, CHCl3). 1H NMR (CDCl3, 500 MHz): δ 7.00 (dd,
J = 8.2, 1.7 Hz, 1H), 6.95 (d, J = 1.1 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H),
6.83 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 5.24–5.14 (m, 2H), 4.13–3.97 (m,
4H), 3.91 (s, 3H), 3.89 (s, 3H), 3.22–3.10 (m, 2H), 2.82 (s, 3H), 2.75 (s,
3H). 13C NMR (CDCl3, 125 MHz): δ 149.0, 148.7, 147.9, 147.3, 130.8,
129.3, 119.6, 118.5, 111.2, 109.6, 108.4, 106.7, 101.2, 80.4, 80.3,
66.9, 66.7, 56.0, 55.9, 44.9, 37.0, 36.8. HRMS (ESI-TOF) calcd for
C23H32NO11S2 ([M + NH4]+) 562.1417, found 562.1419.
1.0 mL/min; λ = 254 nm; tR = 33.0 (major), 27.5 (minor) min). [α]20
D
1
= –88.7 (c = 0.15, CHCl3). H NMR (CDCl3, 500 MHz): δ 6.97 (d, J =
8.2 Hz, 1H), 6.96–6.84 (m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H),
5.13 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.54–3.46 (m, 2H),
3.46–3.36 (m, 2H), 3.02–2.87 (m, 2H), 2.63–2.37 (m, 2H). 13C NMR
(CDCl3, 125 MHz): δ 149.0, 148.4, 147.8, 146.9, 132.8, 131.3, 119.3,
118.2, 111.2, 109.4, 108.3, 106.6, 101.1, 81.0, 61.0, 56.0, 48.20,
48.17, 48.05, 48.01. HRMS (ESI-TOF) calcd for C21H25O7 ([M + H –
H2O]+) 371.1495, found 371.1488.
5-((2S,3S,4R,5R)-5-(3,4-Dimethoxyphenyl)-3,4-bis(methoxy
methyl)tetrahydrofuran-2-yl)benzo[d][1,3]dioxole (6dn). Under an
argon atmosphere, to an ice-cooled solution of diol 5dn (430 mg,
1.11 mmol) in THF (10 mL) was added NaH (440 mg, 60% dispersion
in mineral oil, 11 mmol). The resultant suspension was stirred for 30
min before the addition of CH3I (0.68 mL, 11 mmol). The resulting
reaction solution was stirred at room temperature for 2.5 h before
the addition of H2O. After concentration of the reaction mixture,
the residue was dissolved in 20 mL of CH2Cl2 and 20 mL of H2O and
the queous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine solution (30 mL),
dried with anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate = 5/1) to afford a
colorless oil in 91% yield (421 mg) and 99% ee. The ee was
determined by HPLC analysis using a Chiralcel AD-H column (3/1
hexane/i-PrOH; flow rate 1.0 mL/min; λ = 254 nm; tR = 26.3 (major),
5-((2S,3R,4S,5R)-5-(3,4-Dimethoxyphenyl)-3,4-dimethyltetrahyd
rofuran-2-yl)benzo[d][1,3]dioxole (9dn). Under an argon
atmosphere, to an ice-cooled solution of the mesylate 8dn (272 mg,
0.5 mmoL) in THF (50 mL) was added Super-hydride (12.5 mL, 1.0 M
in THF, 12.5 mmol). The resulting reaction mixture was stirred at
room temperature for 2.5 h before the addition of saturated NH4Cl
solution (15 mL). After evaporation of the volatile organic solvent,
the residue was dissolved in 20 mL of CH2Cl2 and 20 mL of H2O and
the queous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine (30 mL), dried
with anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(petroleum ether/ethyl acetate = 20/1) to afford a colorless oil in
34% yield (62 mg) and 99% ee. The ee was determined by HPLC
analysis using a Chiralcel AD-H column (3/1 hexane/i-PrOH; flow
rate 1.0 mL/min; λ = 254 nm; tR = 32.7 (major), 20.5 (minor) min).
[α]20D = –103.5 (c = 0.09, MeOH). 1H NMR (CDCl3, 500 MHz): δ 7.01–
6.92 (m, 3H), 6.91–6.83 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 5.96 (s, 2H),
5.10 (d, J = 6.6 Hz, 1H), 5.09 (d, J = 6.6 Hz, 1H), 3.90 (s, 3H), 3.88 (s,
3H), 2.71–2.58 (m, 2H), 0.60 (d, J = 7.3 Hz, 3H), 0.59 (d, J = 7.7 Hz,
3H). 13C NMR (CDCl3, 125 MHz): δ 148.6, 147.8, 147.4, 146.3, 134.5,
133.0, 119.5, 118.5, 110.8, 109.8, 107.9, 107.0, 100.9, 82.8, 82.7,
55.9, 41.52, 41.46, 11.8. HRMS (ESI-TOF) calcd for C21H25O5 ([M + H]+)
357.1702, found 357.1705.
19.2 (minor) min). [α]20 = +91.4 (c = 0.65, CHCl3). 1H NMR (CDCl3,
D
500 MHz): δ 7.10–6.99 (m, 3H), 6.93 (d, J = 8.0 Hz, 1H), 6.87 (d, J =
8.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.97 (s, 2H), 5.22–5.11 (m, 2H),
3.91 (s, 3H), 3.90 (s, 3H), 3.30–3.20 (m, 2H), 3.12–2.94 (m, 8H),
2.92–2.79 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 148.4, 148.0, 147.3,
146.5, 133.2, 131.7, 119.8, 118.7, 110.6, 110.1, 107.8, 107.3, 100.8,
81.43, 81.39, 70.1, 70.0, 58.3, 55.82, 55.79, 46.44, 46.39. HRMS
(ESI-TOF) calcd for C23H29O7 ([M + H]+) 417.1913, found 417.1899.
5-((1S,3R,3aR,6aS)-3-(3,4-Dimethoxyphenyl)hexahydrofuro[3,4-
c]furan-1-yl)benzo[d][1,3]dioxole (7dn). Under an argon
atmosphere, to an ice-cooled solution of diol 5dn (430 mg, 1.11
mmol) in THF (10 mL) was added NaH (92 mg, 60% dispersion in
mineral oil, 2.3 mmol). The resultant suspension was stirred for 30
min before the addition of p-TsCl (438 mg, 2.3 mmol). Then the
reaction mixture was stirred at room temperature for 2.5 h before
being quenched by the addition of H2O. The residue was dissolved
in 20 mL of CH2Cl2 and 20 mL of H2O and the queous phase was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine solution (30 mL), dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (petroleum
ether/ethyl acetate = 6/1) to afford a white solid in 74% yield (304
mg) and 97% ee. The ee was determined by HPLC analysis using a
CHIRALPAK IA column (1/1 hexane/i-PrOH; flow rate 1.0 mL/min; λ
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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DOI: 10.1039/C8OB00455B
ARTICLE
Journal Name
Serrano, D. Perrotta and J. Waser, J. Am. Chem. Soc. 2014,
136, 6239–6242.
(a) M. J. Campbell and J. S. Johnson, J. Am. Chem. Soc. 2009,
131, 10370–10371. (b) S. D. Sanders, A. Ruiz-Olalla and J. S.
Johnson, Chem. Commun. 2009, 45, 5135–5137. (c) Y. Kimura,
Y. Sone, T. Saito, T. Mochizuki and Y. Nishii, Asian J. Org.
Financial support of this project from the National Natural
Science Foundation of China (Nos. 21672005, 21472001,
21172002) is gratefully appreciated.
7
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8 | J. Name., 2012, 00, 1-3
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Page 9 of 9
Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00455B
Graphic abstract:
An enantiospecific [3+2] annulation of γꢀbutyrolactone fused cyclopropanes with
aromatic aldehydes was realized to construct chiral furanolignans.