Acetal-initiated Prins bicyclization for the synthesis of hexahydrofuro-[3,4-c]furan lignans and octahydropyrano[3,4-c]pyran derivatives

Article abstract of DOI:10.1039/c4ob00305e

An acetal-initiated Prins bicyclization approach has been developed for the stereoselective synthesis of hexahydrofuro[3,4-c]furan lignans. This also provides a direct way to generate a new series of octahydropyrano[3,4-c]pyran derivatives in a single-ste

Full text of DOI:10.1039/c4ob00305e

Organic &
Biomolecular Chemistry
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Acetal-initiated Prins bicyclization for the
synthesis of hexahydrofuro-[3,4-c]furan lignans
and octahydropyrano[3,4-c]pyran derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 4754
B. V. Subba Reddy,*a M. Ramana Reddy,a B. Sridharb and Kiran Kumar Singarapuc
Received 10th February 2014,
Accepted 8th April 2014
An acetal-initiated Prins bicyclization approach has been developed for the stereoselective synthesis of
hexahydrofuro[3,4-c]furan lignans. This also provides a direct way to generate a new series of octahydro-
pyrano[3,4-c]pyran derivatives in a single-step process.
DOI: 10.1039/c4ob00305e
www.rsc.org/obc
Introduction
The tetrahydrofuran core is frequently found in various biolo-
gically active natural products.1,2 In particular, furofuran lignans
have attracted considerable interest over the years due to their
promising biological activity.3 Sesamin, a furofuran lignan, was
isolated from Fagara plants and from sesame oil (Fig. 1).4
Sesamin is used as a dietary supplement for fat-reduction
and is also known to induce apoptosis in human lymphoid
leukemia Molt 4B cells.5 It contains a substituted 3,7-dioxa-
bicyclooctane core, the synthesis of which is a challenging task.6
Among various approaches, Prins cyclization is a powerful
method for the stereoselective construction of oxygen-contain-
ing heterocycles7 and has been employed successfully for the
synthesis of several natural products.8 In particular, intramole-
cular Prins cyclization is an attractive strategy for the stereo-
selective construction of fused heterobicycles and tricycles.9
However, few methods are reported for the synthesis of tetra-
hydrofuran derivatives through a Prins cyclization10 wherein a
five-membered oxocarbenium ion is trapped with an external
nucleophile.11 Furthermore, Prins cascade cyclization has not
yet been explored for the stereoselective synthesis of furo[3,4-c]-
furan scaffolds.
Fig. 1 Biologically active furo[3,4-c]furan lignans.
herein report a versatile method for the synthesis of 1,6-diaryl-
hexahydrofuro[3,4-c]furan and 1,8-diaryloctahydropyrano-[3,4-c]-
pyran derivatives through a Prins bicyclization strategy.
Results and discussion
Initially, we performed a reaction of (E)-2-styrylpropane-1,3-
diol (1) with 2-bromobenzaldehyde in the presence of 10 mol%
p-TSA. To our surprise, no cyclization was observed under
these conditions (Table 1, entry a).
In continuation of our interest in Prins cyclization and its
application in the total synthesis of natural products,12 we
Therefore, the next reaction was performed using 10 mol%
Sc(OTf)3. Though the reaction proceeded under these con-
ditions, the desired product was obtained in only a 40% yield
after a long reaction time (Table 1, entry b). Similarly, 10 mol%
In(OTf)3 also gave the product in poor yield (Table 1, entry c).
In fact, no significant improvement either in yield or in
reaction time was observed even when increasing the amount
of Sc(OTf)3 from 10 mol% to 30 mol% (Table 1, entry d).
Remarkably, a combination of Sc(OTf)3 and p-TSA gave the
product in a high yield in a short reaction time (Table 1, entry e).
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India. E-mail: basireddy@iict.res.in; Fax: +91-40-27160512;
Tel: +91-40-27193535
bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
cCentre for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data, nOe experiments, X-ray crystal co-ordinates and CIF file
formats of 2a and 7a. CCDC 943366 and 943367. For ESI and crystallographic
data in CIF or other electronic formats see DOI: 10.1039/c4ob00305e
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Table 1 Screening of acid catalysts in the formation of 2a/3aa
aliphatic aldehydes. In the case of n-propionaldehyde, the
respective ethyl-substituted cis-fused hexahydrofuro[3,4-c]furan
was obtained in a slightly lower yield than its aromatic
counterparts (Table 2, entry h). On the other hand, the α,β-un-
saturated aldehyde afforded styryl substituted furo[3,2-c]furan
in an excellent yield (Table 2, entry i). In addition, the reaction
was also successful with heterocyclic aldehydes. For example,
furfural gave the corresponding bicyclic ethers 2 and 3 in a
76% yield with 7 : 3 selectivity (Table 2, entry j). This is an
entirely new process for the direct conversion of homoallylic
diol, 1, into cis-fused furo[3,2-c]furan derivatives.
The reaction proceeds via the formation of an oxocarbe-
nium ion generated from the acetal. This is formed in situ
from the aldehyde and the homoallylic diol, most likely after
activation with p-TSA. The oxocarbenium ion is then attacked
by an internal olefin, resulting in the formation of a more
stable benzylic carbocation which is simultaneously trapped
by a tethered hydroxyl group, leading to the formation of 2 and
3. The intermediate has flexibility in terms of C–C bond
rotation, which can result in the formation of 2 and 3.
However, the thermodynamically more stable diastereomer 2
is predominantly formed. The formation of 4 due to the elim-
ination of the proton was not observed (Scheme 1).14
Entry Catalyst
Time (h) Yieldb (%) 2a : 3a ratioc
a
b
c
d
e
10 mol% p-TSA
4
6
6
6
2
0
0
10 mol% Sc(OTf)3
10 mol% In(OTf)3
30 mol% Sc(OTf)3
10 mol% Sc(OTf)3/p-TSA
40
30
55
86
6 : 4
6 : 4
6 : 4
6 : 4
a The reaction was performed on a 0.5 mmol scale. b Isolated yield.
c The ratios were determined from 1H NMR spectra of the crude
products.
To confirm the reaction mechanism, we carried out the
cyclization of (E)-2-(4-methoxyphenyl)-5-styryl-1,3-dioxane (1a)
in the presence of 10 mol% Sc(OTf)3 in DCE at 70 °C. Under
the above conditions, the corresponding 1-(4-methoxyphenyl)-
6-phenylhexahydrofuro[3,4-c]furan was obtained in a 95% yield
with 6 : 4 diastereoselectivity. This indicates that acetal
formation is a highly likely mechanism for this reaction
(Scheme 2).
Fig. 2 ORTEP diagram of 2a.
Inspired by the results obtained with homoallylic diol (1),
From the above results, it was obvious that binary acid we extended this process to γ,δ-unsaturated alcohols. Accord-
(Sc(OTf)3/p-TSA) is essential for performing the reaction
ingly, treatment of (E)-3-styrylpentane-1,5-diol (5) with 2-bromo-
successfully. These results are consistent with our earlier benzaldehyde in the presence of 10 mol% Sc(OTf)3 in
observation that binary acid exhibits remarkable synergistic dichloroethane at room temperature afforded the respective
effects.13 Therefore, the cooperative effect between the Sc-
trans-fused octahydropyrano[3,4-c]pyran 7a as the sole product,
(OTf)3 and the p-TSA provides high conversions and enhanced in a 90% yield (Table 3). The structure and stereochemistry of
rates in a tandem process. Under optimized conditions, the 1-(2-bromophenyl)-8-phenyloctahydropyrano[3,4-c]pyran (7a)
expected product 2a/3a was obtained in an 86% yield with 6 : 4
were assigned based on single crystal X-ray analysis (Fig. 3).
The above results provide a gateway to extend this process
diastereoselectivity (Table 1, entry e). The ratio of the products
1
(2 : 3) was confirmed from the H NMR spectrum of the crude to other substrates such as (E)-3(2-bromostyryl)pentane-1,5-
mixture. The diastereomers were easily separated by flash
diol (6). The scope of the reaction was investigated with
chromatography. The structure and stereochemistry of 1-(2- various aldehydes, and the results are presented in Table 3.
bromophenyl)-6-phenylhexahydrofuro[3,4-c]furan (2a) were A variety of aromatic, heteroaromatic and aliphatic aldehydes
established by detailed 1D and 2D NMR experiments (see
ESI†). Furthermore, the stereochemistries of 2a and 3a were pyrano[3,4-c]pyrans in good to high yields (80–92%). Similarly,
were treated with (E)-3-styrylpentane-1,5-diol to give octahydro-
confirmed by X-ray crystallography (Fig. 2).
α,β-unsaturated aldehydes also worked well in this reaction to
produce styryl substituted pyrano[3,4-c]pyran (8f) in an excel-
The scope of this process is further illustrated with respect
to various aldehydes (Table 2). Both electron-rich and electron- lent yield. The structure and stereochemistry of 8d were estab-
deficient aromatic aldehydes, such as 4-methoxy-, 3,4-methyl- lished by detailed 1D and 2D NMR experiments (see ESI†). In
enedioxy-, 4-chloro-, 4-bromo-, 4-cyano-, and 4-nitro-benzal-
all cases, the corresponding trans-fused octahydropyrano[3,4-c]-
dehydes, reacted well with (E)-homoallylic diol (1) to furnish pyrans were obtained in good yields with a high selectivity
the corresponding cis-fused 1,6-diarylhexahydrofuro[3,4-c]- (Table 3). Therefore, this method provides a direct approach
furan derivatives in good yields (Table 2, entries b–g). The reac-
for the conversion of γ,δ-unsaturated diols into trans-fused
tion worked not only with aromatic aldehydes but also with pyranopyrans.
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Table 2 Synthesis of hexahydrofuro[3,4-c]furan derivativesa
Products
Entry
a
Aldehyde
2
3
Time (h)
4
Yieldb (%)
86
2 : 3 ratioc
60 : 40
b
4
75
60 : 40
c
d
e
f
3
3
4
4
3
90
80
82
78
90
56 : 44
55 : 45
62 : 38
60 : 40
58 : 42
g
h
i
4
3
70
85
60 : 40
65 : 35
j
2
76
70 : 30
a The reactions were performed on a 0.5 mmol scale. b Yield refers to pure products after column chromatography. c Diastereomeric ratios were
determined from the 1H NMR spectra of the crude products.
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Scheme 1 A plausible reaction pathway.
Fig. 3 ORTEP diagram of 7a.
Scheme 2 Acetal-initiated cyclization of 1a.
Table 3 Synthesis of octahydropyrano[3,4-c]pyran derivativesab
Scheme 3 Heck reaction of 7a for the construction of the biaryl deriva-
tive 9a.
(10 mol%), and K2CO3 (2 equiv.), in DMA at 130 °C
(Scheme 3). The 6-7-6-carbocyclic framework is a common
structural core in allocolchicine (A) and N-acetyl colchinol-O-
methyl ether (NCME) (B). The allocolchicines are seven-mem-
bered biaryl derivatives of naturally occurring colchicines,
which are potent tubulin inhibitors.16
Conclusions
In summary, we have developed an acetal-initiated Prins
cascade reaction for the synthesis of cis-fused hexahydrofuro-
[3,4-c]furan derivatives. This reaction provides direct access to
furofuran lignan analogues, which are reported to be potent
antitumor, antimitotic, and antiviral agents. The method gene-
rates two heterocyclic rings with four new stereogenic centers,
in a one-pot operation.
Experimental
General remarks
a The reactions were performed on a 0.5 mmol scale. b Yield refers to
pure products after column chromatography.
IR spectra were recorded on an FT-IR spectrometer (KBr) and
1
are reported in reciprocal centimeters (cm−1). H NMR spectra
were recorded at 500 MHz and 300 MHz, and 13C NMR at
125 MHz and 75 MHz. For H NMR, tetramethylsilane (TMS)
was used as the internal standard (δ = 0) and values are
reported as follows: chemical shift, integration, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
To demonstrate the synthetic utility of this method, we
applied the protocol to the generation of allocolchicine ana-
logues. Accordingly, compound 7a was transformed into a
polycyclic compound, 9a, in a 76% yield via aryl–aryl bond
formation15 using Pd(OAc)2 (10 mol%), triphenylphosphine
1
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br = broad), and the coupling constants in Hz. For 13C NMR,
(1R,4aS,8S,8aS)-1-(Furan-2-yl)-8-phenyloctahydropyrano[3,4-c]-
CDCl3 (δ = 77.27) was used as the internal standard and pyran (7c). White solid, m.p. 85–87 °C; 1H NMR (300 MHz,
spectra were obtained with complete proton decoupling. Low- CDCl3): δ 7.10–6.95 (m, 5H), 6.86 (brs, 1H), 5.74–5.69 (m, 1H),
resolution MS and HRMS data were obtained using ESI and EI 5.61 (d, J = 3.7 Hz, 1H), 4.20–3.99 (m, 4H), 3.76–3.62 (m, 2H),
ionization. Melting points were measured on micro melting 2.29 (q, J = 9.8 Hz, 1H), 1.89–1.53 (m, 5H) ppm; 13C NMR
point apparatus. Commercially available salicylaldehyde, aceto- (75 MHz, CDCl3): δ 150.5, 140.6, 139.1, 127.1, 126.8, 126.4,
phenone, and TMSOTf were used without further purification. 109.4, 108.3, 82.9, 74.2, 68.6, 68.4, 48.6, 40.6, 33.4, 31.2 ppm;
DCE was distilled from CaH under a N2 atmosphere.
IR (KBr): ν 3034, 2835, 2717, 1731, 1455, 1149, 1081, 818,
Typical procedure for Prins cascade cyclization. To a stirred 766 cm−1; MS (EI): m/z ([M]+): 284; HRMS (EI): m/z calcd for
solution of alcohol (1 or 5 or 6) (0.5 mmol) and aldehyde C18H20O3: 284.1412; found: 284.1425.
(0.6 mmol) in dry dichloromethane (5 mL) at 0 °C was added
(1R,4aS,8S,8aS)-1,8-Diphenyloctahydropyrano[3,4-c]pyran
the catalyst, as specified in Tables 2 and 3. The resulting (7d). White solid, m.p. 104–106 °C; 1H NMR (300 MHz,
mixture was stirred at the temperature specified in Tables 2 CDCl3): δ 6.86–6.79 (m, 10H), 4.15–4.04 (m, 4H), 3.77–3.66 (m,
and 3 under a nitrogen atmosphere. After completion, as indi- 2H), 2.21 (q, J = 9.8 Hz, 1H), 1.97–1.64 (m, 5H) ppm; 13C NMR
cated by thin-layer chromatography (TLC), the reaction mixture (75 MHz, CDCl3): δ 139.3, 127.3, 126.9, 126.4, 82.9, 68.5, 50.6,
was quenched with saturated NaHCO3 solution (1.0 mL) and 40.9, 33.6 ppm; IR (KBr): ν 3033, 2924, 2852, 1729, 1454, 1147,
extracted with dichloromethane (2 × 5 mL). The combined 1088, 979, 754 cm−1; MS (EI): m/z ([M]+): 294; HRMS (EI): m/z
organic layers were washed with brine (5 mL), dried over anhy- calcd for C20H22O2: 294.1619; found: 294.1623.
drous Na2SO4, and concentrated in vacuo. The resulting crude
(1R,4aS,8S,8aS)-1-(4-Chlorophenyl)-8-phenyloctahydropyrano-
product was purified by silica gel column chromatography, [3,4-c]pyran (7e). White solid, m.p. 124–126 °C; 1H NMR
using ethyl acetate–hexane as the eluent, to afford the pure (300 MHz, CDCl3): δ 7.01–6.70 (m, 9H), 4.16–4.01 (m, 4H),
product.
3.77–3.65 (m, 2H), 2.12 (q, J = 9.8 Hz, 1H), 1.94–1.64 (m, 5H)
(3aS,3a1S,11bR,14aS)-1,2,3a,3a1,11b,13,14,14a-Octahydro- ppm; 13C NMR (75 MHz, CDCl3): δ 139.2, 137.9, 131.9, 128.5,
3,12-dioxadibenzo[4,5:6,7]cyclohepta[1,2,3-de]naphthalene 127.3, 127.1, 126.9, 126.4, 82.7, 81.9, 68.5, 51.1, 40.8,
(9a). To a stirred solution of compound (7a) (372 mg, 1 mmol) 33.6 ppm; IR (KBr): ν 3064, 2924, 2837, 1731, 1492, 1149, 1091,
in DMA (3 mL) were added triphenylphosphine (26 mg, 980, 756 cm−1; MS (EI): m/z ([M]+): 328; HRMS (EI): m/z calcd
10 mmol), Pd(OAc)2 (22 mg, 10 mmol) and K2CO3 (276 mg, for C20H21ClO2: 328.1230; found: 328.1234.
2 equiv.) at room temperature under a nitrogen atmosphere.
(1R,4aS,8S,8aS)-1-(4-Nitrophenyl)-8-phenyloctahydropyrano-
The resulting mixture was heated at 140 °C under vigorous [3,4-c]pyran (7f). White solid, m.p. 218–220 °C; 1H NMR
stirring for 48 h. After completion, the reaction was diluted (300 MHz, CDCl3): δ 7.70–7.61 (d, J = 9.0 Hz, 2H), 7.01 (d, J =
with water and extracted with EtOAc. The combined 8.3 Hz, 2H), 6.90–6.77 (m, 6H), 4.21–4.04 (m, 4H), 3.77–3.67
organic layers were dried over MgSO4. The solvent was (m, 2H), 2.17 (q, J = 9.0 Hz, 1H), 2.01–1.86 (m, 1H), 1.84–1.67
removed under vacuum and the residue was purified by silica (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): δ 146.7, 145.6, 138.9,
gel chromatography to give the compound 9a in a 75% yield as 128.1, 127.4, 127.1, 126.8, 121.9, 82.4, 81.3, 68.5, 68.5, 51.2,
a solid.
40.5, 32.5, 32.5 ppm; IR (KBr): ν 3078, 2925, 2846, 1517, 1346,
(1R,4aS,8S,8aS)-1-(2-Bromophenyl)-8-phenyloctahydropyrano- 1084, 982, 755 cm−1; MS (EI): m/z ([M]+): 339; HRMS (EI): m/z
[3,4-c]pyran (7a). White solid, m.p. 110–112 °C; 1H NMR calcd for C20H21NO4: 339.1470; found: 339.1472.
(300 MHz, CDCl3): δ 7.06–6.96 (m, 4H), 6.90–6.80 (m, 4H),
(1S,4aR,8S,8aR)-1-Pentyl-8-phenyloctahydropyrano[3,4-c]-
6.71–6.63 (m, 1H), 4.71 (d, J = 9.6 Hz, 1H), 4.19–4.05 (m, 3H), pyran (7g). Semi solid; 1H NMR (500 MHz, CDCl3): δ 7.32–7.26
3.81–3.67 (m, 2H), 2.18 (q, J = 9.8 Hz, 1H), 2.05–1.89 (m, 1H), (m, 5H), 4.11–4.07 (m, 1H), 4.02–3.96 (m, 2H), 3.70–3.64 (m,
1.82–1.63 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3): δ 139.1, 1H), 3.54–3.48 (m, 1H), 3.09 (dt, J = 3.6, 8.5 Hz, 1H), 1.74–1.55
138.8, 131.3, 129.1, 128.1, 127.1, 127.0, 126.9, 126.6, 123.6, (m, 5H), 1.16–1.08 (m, 1H), 1.08–0.93 (m, 1H), 0.73 (t, J =
81.7, 80.2, 68.8, 68.4, 50.8, 40.4, 33.5, 33.3 ppm; IR (KBr): 7.3 Hz, 1H), 0.60–0.55 (m, 1H) ppm; 13C NMR (125 MHz,
ν 3034, 2835, 2717, 1731, 1455, 1149, 1081, 818, 766 cm−1; MS CDCl3): δ 141.7, 128.0, 127.7, 127.3, 83.0, 78.9, 68.5, 67.8, 50.1,
(EI): m/z ([M]+): 372; HRMS (EI): m/z calcd for C20H21BrO2: 40.4, 34.4, 33.6, 33.5, 31.8, 25.0, 22.7, 14.4 ppm; IR (KBr):
372.0725; found: 372.0732.
ν 3365, 2993, 2795, 1697, 1654, 1056, 872, 755, 732 cm−1; MS
4-((1R,4aS,8S,8aS)-8-Phenyloctahydropyrano[3,4-c]pyran-1-yl)- (EI): m/z ([M]+): 288; HRMS (EI): m/z calcd for C19H28O2:
benzonitrile (7b). White solid, m.p. 186–188 °C; 1H NMR 288.2089; found: 288.2093.
(300 MHz, CDCl3): δ 7.12 (d, J = 8.3 Hz, 2H), 6.98–6.77 (m, 7H),
(1S,4aR,8S,8aR)-1-Ethyl-8-phenyloctahydropyrano[3,4-c]pyran
1
4.15–4.03 (m, 4H), 3.77–3.65 (m, 2H), 2.13 (q, J = 9.8 Hz, 1H), (7h). Semi solid; H NMR (500 MHz, CDCl3): δ 7.32–7.25 (m,
1.97–1.66 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3): δ 144.6, 5H), 4.10–4.06 (m, 1H), 4.03–3.98 (m, 2H), 3.69–3.64 (m, 1H),
138.8, 130.6, 128.0, 127.4, 127.2, 127.0, 118.3, 110.1, 82.5, 81.7, 3.55–3.49 (m, 1H), 3.05–3.00 (m, 1H), 1.75–1.55 (m, 5H),
68.6, 68.5, 50.9, 40.6, 33.5, 33.4 ppm; IR (KBr): ν 2925, 2890, 0.70–0.64 (m, 1H), 0.56 (t, J = 3.3 Hz, 1H) ppm; 13C NMR
2851, 2221, 1453, 1092, 983, 833, 764 cm−1; MS (EI): m/z ([M]+): (125 MHz, CDCl3): δ 141.7, 128.0, 127.7, 127.3, 82.8, 80.1, 68.5,
319; HRMS (EI): m/z calcd for C21H21NO2: 319.1572; found: 67.8, 49.8, 40.3, 33.6, 33.4, 27.4, 10.2 ppm; IR (KBr): ν 3088,
319.1577.
2920, 2843, 1717, 1646, 1184, 791, 768 cm−1; MS (EI): m/z
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([M]+): 246; HRMS (EI): m/z calcd for C16H22O2: 246.1620; 6.80–6.69 (m, 2H), 6.15 (d, J = 15.8 Hz, 1H), 5.25 (dd, J = 7.5,
found: 246.1626.
15.8 Hz, 1H), 4.16–4.04 (m, 3H), 3.77–3.60 (m, 4H), 1.91 (q, J =
(1S,4aS,8R,8aS)-1-(2-Bromophenyl)-8-(thiophen-2-yl)octahydro- 9.8 Hz, 1H), 1.73–1.54 (m, 6H) ppm; 13C NMR (125 MHz,
1
pyrano[3,4-c]pyran (8a). White solid, m.p. 78–80 °C; H NMR CDCl3): δ 140.7, 136.1, 131.1, 129.2, 128.1, 127.8, 127.5, 127.3,
(300 MHz, CDCl3): δ 6.96–6.93 (m, 5H), 6.84 (d, J = 5.2 Hz, 1H), 126.7, 126.0, 82.5, 80.2, 68.5, 68.1, 51.2, 40.1, 33.3, 33.2 ppm;
6.35–6.26 (m, 2H), 4.42 (d, J = 9.8 Hz, 1H), 4.16–4.06 (m, 3H), IR (KBr): ν 3062, 3028, 2924, 1739, 1370, 1147, 1083, 1020, 983,
3.76–3.66 (m, 2H), 2.14 (q, J = 9.8 Hz, 1H), 1.93–1.57 (m, 6H) 756 cm−1; MS (EI): m/z ([M]+): 398; HRMS (EI): m/z calcd for
ppm; 13C NMR (125 MHz, CDCl3): δ 143.0, 139.6, 127.3 127.1, C22H23BrO2: 398.0880; found: 398.0883.
126.6, 125.8, 125.4, 124.2, 83.1, 77.1, 68.5, 68.4, 52.0, 40.7,
(3aS,3a1S,11bR,14aS)-1,2,3a,3a1,11b,13,14,14a-Octahydro-
33.3, 33.1 ppm; IR (KBr): ν 3035, 2838, 2707, 1701, 1475, 1159, 3,12
dioxadibenzo[4,5:6,7]cyclohepta[1,2,3-de]naphthalene
1
1081, 811, 700 cm−1; MS (EI): m/z ([M]+): 378; HRMS (EI): m/z (9a). White solid, m.p. 68–70 °C; H NMR (300 MHz, CDCl3):
calcd for C18H19BrO2S: 378.0289; found: 378.0297.
δ 7.64–7.58 (m, 2H), 7.51–7.44 (m, 2H), 7.38–7.31 (m, 5H), 4.62
(1S,4aS,8R,8aS)-1-(2-Bromophenyl)-8-(furan-2-yl)octa hydro- (d, J = 9.0 Hz, 2H), 4.21–4.12 (m, 2H), 3.91–3.81 (m, 2H),
1
pyrano[3,4-c]pyran (8b). White solid, m.p. 85–87 °C; H NMR 1.88–1.70 (m, 4H), 1.50–1.36 (m, 2H) ppm; 13C NMR (75 MHz,
(300 MHz, CDCl3): δ 7.07–6.94 (m, 5H), 6.84 (brs, 1H), CDCl3): δ 138.6, 135.5, 131.1, 127.0, 126.9, 126.6, 78.6, 67.3,
5.72–5.69 (m, 1H), 5.61 (d, J = 3.0 Hz, 1H), 4.18–4.00 (m, 5H), 49.8, 40.5, 32.5 ppm; IR (KBr): ν 2924, 1726, 1447, 1379, 1259,
3.75–3.64 (m, 2H), 2.35 (q, J = 9.8 Hz, 1H), 1.89–1.55 (m, 7H) 1121, 1070, 983, 755 cm−1; MS (EI): m/z ([M]+): 292; HRMS (EI):
ppm; 13C NMR (75 MHz, CDCl3): δ 150.5, 140.6, 139.1, 127.1, m/z calcd for C20H20O2: 292.1463; found: 292.1462.
126.8, 126.4, 109.5, 108.3, 83.0, 74.2, 68.7, 68.4, 48.7, 40.7,
33.5, 33.1 ppm; IR (KBr): ν 3028, 2924, 2844, 1739, 1436, 1370, [3,4-c]furan (2a). Solid, m.p. 102–104 °C; H NMR (300 MHz,
1248, 1147, 1083, 756 cm−1; MS (EI): m/z ([M]+): 362; HRMS CDCl3): δ 7.79–7.68 (m, 1H), 7.43–7.30 (m, 2H), 7.18–7.06 (s,
(1R,3aR,6R,6aS)-1-(2-Bromophenyl)-6-phenylhexahydrofuro-
1
(EI): m/z calcd for C18H19BrO3: 362.0518; found: 362.0513.
(1S,4aR,8R,8aR)-1-(2-Bromophenyl)-8-(3,4,5-trimethoxy phenyl)- 8.3 Hz, 1H), 4.20–4.01 (m, 2H), 3.86 (q, J = 6.0 Hz, 1H),
octahydropyrano[3,4-c]pyran (8c). White solid, m.p. 3.65–3.57 (m, 1H), 3.49–3.39 (m, 1H), 3.30–3.17 (m, 1H), ppm;
4H), 6.70–6.63 (m, 2H), 5.01 (d, J = 5.2 Hz, 1H), 4.38 (d, J =
1
102–104 °C; H NMR (300 MHz, CDCl3): δ 6.97–6.84 (m, 4H), 13C NMR (125 MHz, CDCl3): δ 140.1, 137.2, 131.7, 128.4, 127.8,
6.08 (s, 1H), 4.15–3.97 (m, 3H), 3.72 (s, 6H), 3.66 (s, 3H), 2.14 127.5, 126.9, 126.6, 125.8, 121.6, 82.5, 81.6, 74.2, 71.4, 55.0,
(q, J = 9.8 Hz, 1H), 1.92–1.53 (m, 4H) ppm; 13C NMR (75 MHz, 47.0 ppm; IR (KBr): ν 3035, 2954, 2862, 1494, 1253, 1048, 1023,
CDCl3): δ 151.4, 139.6, 135.9, 134.9, 127.2, 126.6, 126.5, 105.3, 758 cm−1; MS (EI): m/z ([M]+): 344; HRMS (EI): m/z calcd for
83.2, 82.5, 68.6, 68.4, 60.3, 55.9, 50.9, 40.8, 33.6, 33.5 ppm; C18H17BrO2: 344.0411; found: 344.0426.
IR (KBr): ν 2924, 2717, 1436, 1370, 1248, 1083, 756, 697 cm−1
MS (EI): m/z ([M]+): 462; HRMS (EI): m/z calcd for C23H27BrO5: [3,4-c]furan (3a). Liquid; 1H NMR (500 MHz, CDCl3):
462.1042; found: 462.1051. δ 7.53–7.42 (m, 2H), 7.37–7.22 (m, 7H), 7.15–7.07 (m, 1H), 5.31
(1R,4aR,8S,8aR)-1-(3-Bromo-4-fluorophenyl)-8-(2-bromophenyl)- (d, J = 4.5 Hz, 1H), 5.01 (d, J = 4.5 Hz, 1H), 4.35 (m, 1H), 4.19
octahydropyrano[3,4-c]pyran (8d). White solid, m.p. (q, J = 6.7 Hz, 1H), 3.91–3.83 (m, 2H), 3.23–3.11 (m, 1H),
;
(1S,3aS,6R,6aR)-1-(2-Bromophenyl)-6-phenylhexahydrofuro-
1
128–130 °C; H NMR (500 MHz, CDCl3): δ 6.97–6.90 (m, 4H), 3.05–2.96 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 140.7,
6.85–6.77 (m, 3H), 6.57 (t, J = 8.3 Hz, 1H), 4.12–3.98 (m, 4H), 140.4, 132.5, 128.5, 127.9, 127.1, 127.1, 126.8, 125.8, 121.5,
3.72–3.65 (m, 2H), 2.07 (q, J = 9.9 Hz, 1H), 1.90–1.81 (m, 1H), 85.3, 84.3, 73.4, 72.1, 61.0, 46.6 ppm; IR (KBr): ν 2954, 2860,
1.78–1.64 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): δ 158.2, 1466, 1252, 1040, 750, 699, 574 cm−1; MS (EI): m/z ([M]+): 344;
155.0, 139.0, 136.9, 132.5, 127.7, 127.6, 127.1, 126.9, 126.8, HRMS (EI): m/z calcd for C18H17BrO2: 344.0411; found:
114.9, 114.6, 82.4, 81.2, 68.5, 68.5, 51.1, 40.5, 33.5, 33.4 ppm; 344.0415.
IR (KBr): ν 2967, 2717, 1739, 1436, 1370, 1147, 1083, 756,
690 cm−1; MS (EI): m/z ([M]+): 467; HRMS (EI): m/z calcd for benzo[d][1,3]dioxole (2b). Semi solid; 1H NMR (500 MHz,
C20H19Br2FO2: 467.9738; found: 467.9726. CDCl3): δ 7.37–7.21 (m, 4H), 7.12–7.10 (m, 1H), 6.84–6.73 (m,
(1S,4aR,8R,8aR)-1-(2-Bromophenyl)-8-(3,5-difluorophenyl)- 3H), 5.96–5.88 (m, 2H), 4.93–4.89 (m, 1H), 4.87–4.83 (m, 1H),
octahydropyrano[3,4-c]pyran (8e). White solid, m.p. 4.36–4.33 (m, 1H), 4.20–4.16 (m, 1H), 3.84–3.77 (m, 2H),
5-((1R,3aR,6R,6aS)-6-Phenylhexahydrofuro[3,4-c]furan-1-yl)-
1
104–106 °C; H NMR (300 MHz, CDCl3): δ 6.99–6.87 (m, 5H), 3.23–3.13 (m, 1H), 3.01–2.94 (m, 1H) ppm; 13C NMR (125 MHz,
6.38–6.23 (m, 3H), 4.14–3.98 (m, 4H), 3.75–3.64 (m, 2H), 2.08 CDCl3): δ 146.7, 140.8, 132.5, 127.1, 126.5, 126.1, 120.4, 107.1,
(q, J = 9.6 Hz, 1H), 1.90–1.64 (m, 5H) ppm; 13C NMR (125 MHz, 107.0, 100.4, 83.0, 82.3, 72.4, 67.7, 58.0, 45.1 ppm; IR (KBr):
CDCl3): δ 162.3, 160.3, 143.5, 139.2, 127.5, 127.3, 127.2, 110.7, ν 2875, 1731, 1616, 1494, 1442, 1387, 1245, 1038, 931, 810,
110.5, 102.4, 102.2, 102.0, 82.6, 81.5, 68.5, 68.5, 50.7, 40.4, 770 cm−1; MS (EI): m/z ([M]+): 310; HRMS (EI): m/z calcd for
33.3, 33.2 ppm; IR (KBr): ν 3028, 2967, 1739, 1436, 1370, 1147, C19H18O4: 310.1205; found: 310.1213.
1083, 1020, 983, 756, 697 cm−1; MS (EI): m/z ([M]+): 408; HRMS
(EI): m/z calcd for C20H19BrF2O2: 408.0532; found: 408.0529.
5-((1S,3aS,6R,6aR)-6-Phenylhexahydrofuro[3,4-c]furan-1-yl)-
benzo[d][1,3]dioxole (3b). Semi solid; 1H NMR (300 MHz,
(1S,4aR,8S,8aR)-1-(2-Bromophenyl)-8-styryloctahydropyrano- CDCl3): δ 7.35–7.22 (m, 4H), 7.16–7.12 (m, 1H), 6.82 (s, 1H),
[3,4-c]pyran (8f). White solid, m.p. 94–96 °C; 1H NMR 6.79–6.72 (m, 2H), 5.95–5.90 (m, 2H), 4.93–4.90 (m, 1H),
(300 MHz, CDCl3): δ 7.30–7.06 (m, 7H), 7.05–6.98 (m, 1H), 4.86–4.81 (m, 1H), 4.39–4.34 (m, 1H), 4.23–4.17 (m, 1H),
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4.02–3.98 (m, 1H), 3.85–3.74 (m, 2H), 3.24–3.09 (m, 1H), 3.15–3.01 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 145.4,
3.04–2.95 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 147.3, 140.2, 128.2, 127.8, 127.0, 126.4, 123.3, 82.6, 81.4, 74.2, 71.9,
146.5, 140.5, 134.4, 128.1, 127.7, 127.6, 127.1, 125.8, 125.3, 57.6, 47.0 ppm; IR (KBr): ν 2926, 2855, 1737, 1487, 1238, 1073,
119.0, 107.9, 106.2, 100.8, 85.1, 84.7, 72.7, 72.5, 61.5, 1010, 756, 700 cm−1; MS (EI): m/z ([M]+): 344; HRMS (EI): m/z
46.7 ppm; IR (KBr): ν 2870, 1616, 1494, 1387, 1246, 930, 810, calcd for C18H17BrO2: 344.0411; found: 344.0426.
770 cm−1; MS (EI): m/z ([M]+): 310; HRMS (EI): m/z calcd for
C19H18O4: 310.1205; found: 310.1213.
(1S,3aS,6R,6aR)-1-(4-Bromophenyl)-6-phenylhexahydrofuro-
[3,4-c]furan (3e). Semi solid; 1H NMR (500 MHz, CDCl3):
4-((1R,3aR,6R,6aS)-6-Phenylhexahydrofuro[3,4-c]furan-1-yl)- δ 7.49–7.42 (m, 2H), 7.37–7.24 (m, 6H), 7.19 (d, J = 8.0 Hz, 2H),
benzonitrile (2c). Solid, m.p. 86–88 °C; 1H NMR (500 MHz, 4.94 (d, J = 4.7 Hz, 1H), 4.89 (d, J = 4.8 Hz, 1H), 4.25–4.19 (m,
CDCl3): δ 7.55 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 2H), 3.84–3.79 (m, 2H), 3.22–3.19 (m, 1H), 2.99–2.93 (m, 1H)
7.19–7.09 (m, 3H), 6.68–6.62 (m, 2H), 4.96 (d, J = 5.5 Hz, 1H), ppm; 13C NMR (75 MHz, CDCl3): δ 141.8, 141.1, 132.7, 129.7,
4.41 (t, J = 8.4 Hz, 1H), 4.15–4.04 (m, 2H), 3.91 (dd, J = 6.4, 9.4 128.8, 128.6, 126.9, 122.7, 86.6, 86.2, 74.6, 74.3, 63.5,
Hz, 1H), 3.61 (dd, J = 6.9, 8.8 Hz, 1H), 3.35–3.26 (m, 1H), 48.6 ppm; IR (KBr): ν 3028, 2926, 2855, 1729, 1487, 1221, 1069,
3.20–3.13 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 142.9, 1008, 770 cm−1; MS (EI): m/z ([M]+): 344; HRMS (EI): m/z calcd
139.9, 131.5, 127.8, 127.3, 126.6, 126.1, 118.4, 110.8, 82.6, 81.5, for C18H17BrO2: 344.0411; found: 344.0426.
74.3, 71.9, 57.7, 47.3 ppm; IR (KBr): ν 3055, 2861, 2228, 1735,
(1R,3aS,6R,6aR)-1-(4-Methoxyphenyl)-6-phenylhexahydrofuro-
1604, 1218, 1602, 932, 826 cm−1; MS (EI): m/z ([M]+): 291; [3,4-c]furan (2f). Solid, m.p. 80–82 °C; 1H NMR (500 MHz,
HRMS (EI): m/z calcd for C19H17NO2: 291.1259; found: CDCl3): δ 7.31–7.15 (m, 5H), 6.89–6.81 (m, 3H), 6.68–6.59 (m,
291.1254.
1H), 4.90–4.87 (m, 1H), 4.85 (d, J = 4.7 Hz, 1H), 4.39–4.27 (m,
4-((1S,3aS,6R,6aR)-6-Phenylhexahydrofuro[3,4-c]furan-1-yl)- 1H), 4.22–4.17 (m, 1H), 4.02 (d, J = 9.1 Hz, 1H), 3.79 (s, 3H),
benzonitrile (3c). Solid, m.p. 94–96 °C; 1H NMR (300 MHz, 3.78–3.73 (m, 1H), 3.27–3.15 (m, 1H), 3.04–2.95 (m, 1H) ppm;
CDCl3): δ 7.63 (d, J = 8.3 Hz, 2H), 7.42–7.34 (m, 5H), 7.32–7.29 13C NMR (75 MHz, CDCl3): δ 158.7, 154.4, 132.6, 128.9, 127.7,
(m, 3H), 4.98 (dd, J = 4.7, 13.2 Hz, 2H), 4.26–4.21 (m, 2H), 124.4, 120.6, 116.7, 113.2, 83.0, 81.5, 88.0, 55.1, 47.8,
3.88–3.80 (m, 2H), 3.22–3.15 (m, 1H), 2.98–2.94 (m, 1H) ppm; 38.1 ppm; IR (KBr): ν 2870, 1621, 1490, 1442, 1387, 1245, 1038,
13C NMR (75 MHz, CDCl3): δ 145.9, 139.7, 131.7, 128.1, 127.2, 931, 770 cm−1; MS (EI): m/z ([M]+): 296; HRMS (EI): m/z calcd
125.6, 125.1, 118.1, 85.0, 84.2, 73.0, 72.5, 62.0, 46.8 ppm; IR for C19H20O3: 296.1412; found: 296.1409.
(KBr): ν 3055, 2922, 2228, 1735, 1604, 1218, 1062, 932, 828,
714 cm−1; MS (EI): m/z ([M]+): 291; HRMS (EI): m/z calcd for [3,4-c]furan (3f). Semi solid; 1H NMR (500 MHz, CDCl3):
C19H17NO2: 291.1259; found: 291.1254. δ 7.35–7.23 (m, 5H), 7.13–7.10 (m, 1H), 6.89–6.81 (m, 2H),
(1S,3aS,6R,6aR)-1-(4-Methoxyphenyl)-6-phenylhexahydrofuro-
(1R,3aR,6R,6aS)-1-(4-Chlorophenyl)-6-phenylhexahydrofuro- 4.93–4.87 (m, 2H), 4.40–4.35 (m, 1H), 4.26–4.18 (m, 1H),
1
[3,4-c]furan (2d). Solid, m.p. 106–108 °C; H NMR (500 MHz, 4.04–4.00 (m, 1H), 3.87–3.74 (m, 4H), 3.26–3.15 (m, 1H),
CDCl3): δ 7.29–7.24 (m, 4H), 7.20–7.13 (m, 2H), 7.10 (d, J = 3.06–2.99 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 159.2,
8.5 Hz, 1H), 6.70–6.67 (m, 1H), 6.57 (d, J = 8.3 Hz, 1H), 141.4, 131.1, 129.3, 127.9, 127.5, 127.0, 126.8, 126.3, 113.3,
4.93–4.86 (m, 1H), 4.39 (t, J = 8.3 Hz, 1H), 4.27–4.17 (m, 1H), 83.0, 82.4, 72.3, 67.7, 57.6, 55.2, 45.0 ppm; IR (KBr): ν 2875,
4.11–4.01 (m, 1H), 3.91–3.78 (m, 1H), 3.65–3.56 (m, 1H), 1731, 1616, 1494, 1245, 1308, 931, 810, 770 cm−1; MS (EI): m/z
3.32–3.20 (m, 1H), 3.12–2.95 (m, 1H) ppm; 13C NMR (100 MHz, ([M]+): 296; HRMS (EI): m/z calcd for C19H20O3: 296.1412;
CDCl3): δ 140.8, 140.1, 131.6, 128.6, 127.7, 127.4, 125.8, 125.7, found: 296.1408.
121.4, 84.9, 84.5, 72.8, 72.5, 61.6, 46.5 ppm; IR (KBr): ν 2924,
(1R,3aR,6R,6aS)-1-(4-Nitrophenyl)-6-phenylhexahydrofuro-
2854, 1739, 1636, 1459, 1376, 1071, 1017, 755 cm−1; MS (EI): [3,4-c]furan (2g). Solid, m.p. 78–80 °C; 1H NMR (300 MHz,
m/z ([M]+): 300; HRMS (EI): m/z calcd for C18H17ClO2: CDCl3): δ 8.12 (d, J = 8.3 Hz, 3H), 7.41 (d, J = 8.3 Hz, 2H),
300.0917; found: 300.0919.
7.19–7.08 (m, 3H), 6.70–6.64 (m, 2H), 5.01 (d, J = 6.0 Hz, 1H),
(1S,3aS,6R,6aR)-1-(4-Chlorophenyl)-6-phenylhexahydrofuro- 4.42 (d, J = 8.3 Hz, 1H), 4.16–4.06 (m, 2H), 3.96–3.89 (m, 1H),
[3,4-c]furan (3d). Semi solid; 1H NMR (500 MHz, CDCl3): 3.63 (q, J = 6.7 Hz, 1H), 3.38–3.16 (m, 2H) ppm; 13C NMR
δ 7.39–7.22 (m, 9H), 4.97–4.87 (m, 2H), 4.27–4.17 (m, 2H), (75 MHz, CDCl3): δ 144.6, 139.4, 127.6, 127.1, 126.4, 125.8,
3.85–3.77 (m, 2H), 3.24–3.17 (m, 1H), 3.03–2.89 (m, 1H) ppm; 122.7, 82.5, 81.4, 74.3, 72.0, 57.8, 47.4 ppm; IR (KBr): ν 2926,
13C NMR (75 MHz, CDCl3): δ 128.0, 127.9, 127.6, 127.4, 127.3, 2850, 1720, 1602, 1520, 1345, 1220, 1067, 850, 770 cm−1; MS
127.0, 126.5, 125.1, 84.8, 84.5, 72.7, 72.5, 61.7, 46.8 ppm; IR (EI): m/z ([M]+): 311; HRMS (EI): m/z calcd for C18H17NO4:
(KBr): ν 2924, 2854, 1739, 1636, 1459, 1376, 1071, 821, 311.1157; found: 311.1154.
755 cm−1; MS (EI): m/z ([M]+): 300; HRMS (EI): m/z calcd for
C18H17ClO2: 300.0917; found: 300.0919.
(1S,3aS,6R,6aR)-1-(4-Nitrophenyl)-6-phenylhexahydrofuro-
[3,4-c]furan (3g). Solid, m.p. 82–84 °C; 1H NMR (500 MHz,
(1R,3aR,6R,6aS)-1-(4-Bromophenyl)-6-phenylhexahydrofuro- CDCl3): δ 8.20 (d, J = 8.6 Hz, 3H), 7.46 (d, J = 8.4 Hz, 2H),
[3,4-c]furan (2e). Solid, m.p. 94–96 °C; 1H NMR (300 MHz, 7.40–7.24 (m, 7H), 5.04 (d, J = 4.7 Hz, 1H), 4.99 (d, J = 4.7 Hz,
CDCl3): δ 7.52–7.38 (m, 2H), 7.36–7.24 (m, 2H), 7.1–7.10 (m, 1H), 4.30–4.20 (m, 2H), 3.91–3.80 (m, 2H), 3.26–3.14 (m, 1H),
3H), 6.71–6.66 (m, 1H), 6.51 (d, J = 8.3 Hz, 1H), 4.91–4.84 (m, 3.02–2.93 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 145.9,
1H), 4.39 (t, J = 8.3 Hz, 1H), 4.29–4.16 (m, 1H), 4.08–4.01 (m, 139.7, 131.7, 128.1, 127.2, 125.6, 125.1, 85.0, 84.2, 73.0, 72.5,
1H), 3.90–3.77 (m, 1H), 3.65–3.56 (m, 1H), 3.31–3.21 (m, 1H), 62.0, 46.8 ppm; IR (KBr): ν 2926, 2857, 1729, 1602, 1520, 1345,
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1607, 850, 771 cm−1; MS (EI): m/z ([M]+): 311; HRMS (EI): m/z 4.05–3.88 (m, 2H), 3.74–3.65 (m, 1H), 3.46–3.25 (m, 2H) ppm;
calcd for C18H17NO4: 311.1157; found: 311.1154.
13C NMR (125 MHz, CDCl3): δ 152.3, 142.3, 129.8, 128.4, 126.8,
(1S,3aR,6R,6aS)-1-Ethyl-6-phenylhexahydrofuro[3,4-c]furan 125.5, 109.9, 107.6, 78.4, 72.7, 68.2, 54.2, 38.9 ppm; IR (KBr):
1
(2h). Semi solid; H NMR (500 MHz, CDCl3): δ 7.41–7.25 (m, ν 2895, 1761, 1642, 1502, 1134, 898, 754 cm−1; MS (EI): m/z
5H), 4.66 (d, J = 7.7 Hz, 1H), 4.35 (t, J = 8.5 Hz, 1H), 4.14–4.10 ([M]+): 256; HRMS (EI): m/z calcd for C16H16O3: 256.1098;
(m, 1H), 3.85–3.81 (m, 1H), 3.67 (dd, J = 6.5, 2.9 Hz, 1H), found: 256.1097.
3.62–3.52 (m, 2H), 3.19–3.11 (m, 1H), 2.90–2.85 (m, 1H),
1.84–1.75 (m, 1H), 1.62–1.53 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 141.2, 128.5, 127.8, 127.1,
83.1, 81.6, 74.3, 71.5, 55.9, 46.8, 23.4, 11.5 ppm; IR (KBr):
Acknowledgements
ν 2922, 2228, 1604, 1218, 1602, 826, 770, 700 cm−1; MS (EI): M.R.R. is thankful to CSIR for the award of a fellowship. B.V.S.
m/z ([M]+): 218; HRMS (EI): m/z calcd for C14H18O2: 218.1306; thanks CSIR, New Delhi for financial support as part of the XII
found: 218.1317.
five year plan program under the title ORIGIN (CSC-0108).
(1R,3aR,6R,6aS)-1-Ethyl-6-phenylhexahydrofuro[3,4-c]furan
1
(3h). Semi solid; H NMR (500 MHz, CDCl3): δ 7.37–7.24 (m,
6H), 4.66 (d, J = 7.7 Hz, 1H), 4.28–4.38 (m, 1H), 4.84–4.81 (m,
1H), 3.69–3.52 (m, 3H), 3.18–3.11 (m, 1H), 2.90–2.74 (m, 1H),
2.34–2.29 (m, 1H), 2.08–1.98 (m, 1H), 1.83–1.76 (m, 1H), 0.85
(t, J = 7.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 141.9,
128.3, 128.0, 127.4, 82.6, 81.2, 72.2, 67.0, 55.0, 44.8, 27.0,
8.9 ppm; IR (KBr): ν 2924, 1729, 1480, 1001, 770, 701 cm−1; MS
(EI): m/z ([M]+): 218; HRMS (EI): m/z calcd for C14H18O2:
218.1306; found: 218.1317.
(1R,3aR,6S,6aS)-1-Phenyl-6-styrylhexahydrofuro[3,4-c]furan
(2i). Semi solid; 1H NMR (500 MHz, CDCl3): δ 7.42–7.21 (m,
10H), 6.63 (d, J = 15.7 Hz, 1H), 6.24 (dd, J = 6.4, 16.0 Hz, 1H),
4.44–4.40 (m, 2H), 4.20–4.16 (m, 2H), 3.72 (dd, J = 4.8, 9.1 Hz,
1H), 3.17–3.11 (m, 1H), 2.73–2.68 (m, 1H) ppm; 13C NMR
(125 MHz, CDCl3): δ 140.6, 130.9, 128.1, 127.7, 127.4, 127.2,
126.1, 125.4, 84.8, 84.1, 72.8, 72.3, 59.7, 46.5 ppm; IR (KBr):
ν 2973, 1815, 1696, 1613, 1075, 832, 787 cm−1; MS (EI): m/z
([M]+): 292; HRMS (EI): m/z calcd for C20H20O2: 292.1463;
found: 292.1471.
Notes and references
1 (a) M. Saleem, H. J. Kim, M. S. Ali and Y. S. Lee, Nat. Prod.
Rep., 2005, 22, 696; (b) M. M. Faul and B. E. Huff, Chem.
Rev., 2000, 100, 2407; (c) E. J. Kang and E. Lee, Chem. Rev.,
2005, 105, 4348.
2 (a) W. D. Macrae and G. H. N. Towers, Phytochemistry, 1984,
23, 1207; (b) A. Huczynski, Bioorg. Med. Chem. Lett., 2012,
22, 7002.
3 (a) Chemistry of Lignans, ed. C. B. S. Rao, Andhra University
Press, 1978; (b) D. A. Whiting, Nat. Prod. Rep., 1985, 2, 191;
(c) D. A. Whiting, Nat. Prod. Rep., 1987, 4, 499;
(d) D. A. Whiting, Nat. Prod. Rep., 1990, 7, 349;
(e) R. S. Ward, Nat. Prod. Rep., 1993, 10, 1; (f) R. S. Ward,
Nat. Prod. Rep., 1995, 12, 183; (g) R. S. Ward, Nat. Prod.
Rep., 1997, 14, 43.
4 E. D. Becker and M. Beroza, Tetrahedron Lett., 1962, 157.
5 Y. Miyahara, T. Komiya, H. Katsuzaki, K. Imai,
M. Nakagawa, Y. Ishi and H. Hibasami, Int. J. Mol. Med.,
2000, 6, 43.
6 (a) C. D. B. Richard, J. R. B. Carole, B. Gordon,
D. H. Jeremy and A. S. Nigel, J. Org. Chem., 2001, 66, 6719;
(b) J. M. Reniguntala, L. C. Le, S. K. Hui, H. C. Chen and
L. R. Shung, J. Am. Chem. Soc., 2001, 123, 7427;
(c) R. Efraim, T. Garazi, L. V. Jose, B. Dolores and C. Luisa,
Angew. Chem., Int. Ed., 2009, 48, 5701.
7 (a) C. Olier, M. Kaafarani, S. S. Gastaldi and M. P. Bertrand,
Tetrahedron, 2010, 66, 413; (b) I. M. Pastor and M. Yus,
Curr. Org. Chem., 2007, 11, 925; (c) E. A. Crane and
K. A. Scheidt, Angew. Chem., Int. Ed., 2010, 49, 8316;
(d) K. Zheng, X. Liu, S. Qin, M. Xie, L. Lin, C. Hu and
X. Feng, J. Am. Chem. Soc., 2012, 134, 17564.
8 (a) E. A. Crane and K. A. Scheidt, Angew. Chem., Int. Ed.,
2010, 49, 8316; (b) M. R. Gesinski, K. Tadpetch and
S. D. Rychnovsky, Org. Lett., 2009, 11, 5342; (c) M. S. Kwon,
S. K. Woo, S. W. Na and E. Lee, Angew. Chem., Int. Ed.,
2008, 47, 1733; (d) S. Manaviazar and K. Hale, Angew.
Chem., Int. Ed., 2011, 50, 8786; (e) P. A. Wender and
A. J. Schrier, J. Am. Chem. Soc., 2011, 133, 9228;
(f) S. K. Woo, M. S. Kwon and E. Lee, Angew. Chem., Int.
Ed., 2008, 47, 3242; (g) M. R. Gesinski and
(1R,3aR,6R,6aS)-1-Phenyl-6-styrylhexahydrofuro[3,4-c]furan
(3i). Semi solid; 1H NMR (500 MHz, CDCl3): δ 7.39–7.23 (m,
10H), 6.64 (d, J = 15.4 Hz, 1H), 6.23 (dd, J = 6.4, 16.0 Hz, 1H),
4.83 (d, J = 4.7 Hz, 1H), 4.55 (t, J = 5.1 Hz, 1H), 4.26–4.16 (m,
2H), 3.79–3.74 (m, 2H), 3.21–3.14 (m, 1H), 2.89–2.83 (m, 1H)
ppm; 13C NMR (125 MHz, CDCl3): δ 135.9, 130.9, 128.2, 127.8,
127.4, 126.1, 83.7, 72.5, 58.0, 46.1 ppm; IR (KBr): ν 2993, 1834,
1667, 1563, 1016, 875, 735 cm−1; MS (EI): m/z ([M]+): 292;
HRMS (EI): m/z calcd for C20H20O2: 292.1463; found: 292.1471.
(1R,3aS,6R,6aR)-1-(Furan-2-yl)-6-phenylhexahydrofuro[3,4-c]-
1
furan (2j). Semi solid; H NMR (500 MHz, CDCl3): δ 7.73–7.70
(m, 2H), 7.55–7.53 (m, 2H), 7.40–7.33 (m, 2H), 6.34–6.28 (m,
2H), 5.02 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 5.7 Hz, 1H), 4.31–4.16
(m, 3H), 3.85–3.74 (m, 2H), 3.31–3.16 (m, 2H) ppm; 13C NMR
(75 MHz, CDCl3): δ 147.4, 137.8, 130.1, 129.5, 128.1, 127.9,
125.2, 107.2, 78.0, 71.9, 68.2, 62.2, 52.3, 39.2 ppm; IR (KBr):
ν 2982, 1765, 1604, 1542, 1064, 837, 763 cm−1; MS (EI): m/z
([M]+): 256; HRMS (EI): m/z calcd for C16H16O3: 256.1098;
found: 256.1096.
(1S,3aS,6R,6aR)-1-(Furan-2-yl)-6-phenylhexahydrofuro[3,4-c]-
1
furan (3j). Semi solid; H NMR (500 MHz, CDCl3): δ 7.42–7.28
(m, 4H), 6.34 (s, 2H), 5.97 (d, J = 3.1 Hz, 1H), 4.94 (d, J =
5.8 Hz, 1H), 4.66 (d, J = 6.6 Hz, 1H), 4.38–4.30 (m, 1H),
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S. D. Rychnovsky, J. Am. Chem. Soc., 2011, 133, 9727;
2013, 78, 6303; (b) B. V. S. Reddy, D. P. Prasad, B. Sridhar
and S. K. Kumar, J. Org. Chem., 2013, 78, 8161;
(c) B. V. S. Reddy, S. Jalal, P. Borkar, J. S. Yadav, P. P. Reddy,
A. C. Kunwar and B. Sridhar, Org. Biomol. Chem., 2012, 10,
6562; (d) B. V. S. Reddy, P. Borkar, J. S. Yadav, P. P. Reddy,
A. C. Kunwar, B. Sridhar and R. Gree, Org. Biomol. Chem.,
2012, 10, 1349; (e) B. V. S. Reddy, P. Borkar, J. S. Yadav,
B. Sridhar and R. Grée, J. Org. Chem., 2011, 76, 7677;
(f) J. S. Yadav, P. Borkar, P. P. Chakravarthy, B. V. S. Reddy,
A. V. S. Sarma, B. Sridhar and R. Grée, J. Org. Chem., 2010,
75, 2081.
(h) H. Y. Lin and B. B. Snider, Org. Lett., 2011, 13, 1234.
9 (a) M. Suginome, Y. Ohmori and Y. Ito, Chem. Commun.,
2001, 1090; (b) J. D. Elsworth and C. L. Willis, Chem.
Commun., 2008, 1587; (c) X. F. Yang, M. Wang, Y. Zhang
and C. J. Li, Synlett, 2005, 1912; (d) A. C. Spivey, L. Laraia,
A. R. Bayly, H. S. Rzepa and A. J. P. White, Org. Lett., 2010,
12, 900; (e) Z. H. Chen, Y. Q. Tu, S. Y. Zhang and
F. M. Zhang, Org. Lett., 2011, 13, 724; (f) A. J. Bunt,
C. D. Bailey, B. D. Cons, S. J. Edwards, J. D. Elsworth,
T. Pheko and C. L. Willis, Angew. Chem., Int. Ed., 2012, 51,
3901.
13 (a) P. Borkar, P. van de Weghe, B. V. S. Reddy, J. S. Yadav
and R. Gree, Chem. Commun., 2012, 48, 9316;
(b) M. Breugst, R. Grée and K. N. Houk, J. Org. Chem., 2013,
78, 9892.
10 (a) Y. Suzuki, T. Niwa, E. Yasui, M. Mizukami, M. Miyashita
and S. Nagumo, Tetrahedron Lett., 2012, 53, 1337;
(b) A. C. Spivey, L. Laraia, A. R. Bayly, H. S. Rzepa and
A. J. P. White, Org. Lett., 2010, 12, 900; (c) B. V. S. Reddy, 14 F. K. Chio, J. Warne, D. Gough, M. Penny, S. Green,
S. R. Anjum, G. M. Reddy and T. P. Rao, Synlett, 2011, 2951;
(d) S. N. Chavre, H. Choo, J. K. Lee, A. N. Pae and Y. S. Kim
Cho, J. Org. Chem., 2008, 73, 7467; (e) S. N. Chavre,
S. J. Coles, M. B. Hursthouse, P. Jones, L. Hassall,
T. M. McGuire and A. P. Dobbs, Tetrahedron, 2011, 67,
5107.
H. Choo, J. H. Cha, A. N. Pae, K. I. Choi and Y. S. Cho, Org. 15 L. C. Campeau and K. Fagnou, Chem. Commun., 2006,
Lett., 2006, 8, 3617. 1253.
11 (a) S. Unaldi, M. Ozlugedik, R. Frohlich and D. Hoppe, Adv. 16 (a) S. Bergemann, R. Brecht, F. Buttner, D. Guenard,
Synth. Catal., 2005, 347, 1621; (b) T. K. Sarkar, H. A. Haque
and A. Basak, Angew. Chem., Int. Ed., 2004, 43, 1417;
(c) T. P. Loh, Q. Y. Hu, K. P. Tan and H. S. Cheng, Org. Lett.,
2001, 3, 2669; (d) T. P. Loh, Q. Y. Hu, K. P. Tan and
L. T. Ma, J. Am. Chem. Soc., 2001, 123, 2450;
(e) R. J. Linderman and A. Godfrey, J. Am. Chem. Soc., 1988,
110, 6249.
R. Gust, G. Seitz, M. T. Stubbs and S. Thoret, Bioorg. Med.
Chem., 2003, 11, 1269; (b) R. Brecht, G. Seitz, D. Guenard
and S. Thoret, Bioorg. Med. Chem., 2000, 8, 557;
(c) M. Roesner, H. G. Capraro, A. E. Jacobson, L. Atwell,
A. Brossi, M. A. Iorio, T. H. Williams, R. H. Sik and
C. F. Chignell, J. Med. Chem., 1981, 24, 257; (d) A. Brossi,
P. N. Sharma, L. Atwell, A. E. Jacobson, M. A. Iorio,
M. Molinari and C. F. Chignell, Med. Chem., 1983, 26,
1365.
12 (a) B. V. S. Reddy, A. Venkateswarlu, P. Borkar, J. S. Yadav,
M. Kanakaraju, A. C. Kunwar and B. Sridhar, J. Org. Chem.,
4762 | Org. Biomol. Chem., 2014, 12, 4754–4762
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