Domino Strategy for the Stereoselective Construction of Angularly Fused Tricyclic Ethers

Article abstract of DOI:10.1021/acs.joc.5b02241

A stereoselective synthesis of decahydrofuro[3,2-d]isochromene derivatives has been achieved by the condensation of 2-cyclohexenylbutane-1,4-diol with aldehydes in the presence of a stochiometric amount of BF₃·OEt₂ in dichloromethane at -78 °C. Similarly, the condensation of 2-cyclopentenylbutan-1,4-diol with aldehydes provides the corresponding octahydro-2H-cyclopenta[c]furo[2,3-d]pyran derivatives in good yields with high diastereoselectivity. It is an elegant strategy for the quick construction of tricyclic architectures with four contiguous stereogenic centers in a single step. These tricyclic frameworks are the integral part of numerous natural products.

Full text of DOI:10.1021/acs.joc.5b02241

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Note
Domino strategy for the stereoselective
construction of angularly fused tricyclic ethers
B.V Subba Reddy, Durgaprasad Medaboina, S. Gopal Reddy, V.
Hanuman Reddy, Kiran Kumar Singarapu, and Balasubramanian Sridhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02241 • Publication Date (Web): 12 Nov 2015
Downloaded from http://pubs.acs.org on November 15, 2015
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Domino strategy for the stereoselective construction of
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angularly fused tricyclic ethers
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B. V. Subba Reddy,*,† Durgaprasad Medaboina,† S. Gopal Reddy,†V. Hanuman Reddy,†
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Kiran Kumar Singarapu,# Balasubramanian Sridhar.‡
†Natural Product Chemistry, #Centre for Nuclear Magnetic Resonance, ‡Laboratory of Xꢀray
Crystallography , CSIRꢀIndian
Institute of Chemical Technology, Hyderabad –500 007, India.
Eꢀmail:basireddy@iict.res.in; Fax: 0091ꢀ40ꢀ27160512
Abstract
:
A stereoselective synthesis of decahydrofuro[3,2-d]isochromene derivatives has
been achieved by the condensation of 2-cyclohexenylbutane-1,4-diol with
aldehydes in the presence of a stochiometric amount of BF3.OEt2 in
dichloromethane at -78 °C. Similarly, the condensation of 2-cyclopentenylbutan-
1,4-diol with aldehydes provides the corresponding octahydro-2H-
cyclopenta[c]furo[2,3-d]pyran derivatives in good yields with high
diastereoselectivity. It is an elegant strategy for the quick construction of tricyclic
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architectures with four contiguous stereogenic centers in a single-step. These
tricyclic frameworks are the integral part of numerous natural products.
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Polyheterocyclic frameworks are privileged scaffolds in medicinal chemistry. These structures
are important synthetic targets for organic chemists due to their prevalence in numerous
synthetic and naturally occurring molecules.1 In particular, angularly fused polyheterocyles have
become interesting targets among synthetic community.2 Moreover, oxygen containing fused
structures having characteristic [6ꢀ6ꢀ5] tricyclic system comprise the core of various naturally
occurring molecules that possess a variety of biological activities. For example, Phomactin A is a
specific platelet activating factor (PAF) antagonist, which inhibits the PAFꢀinduced platelet
aggregation and Neovibsanins are found to display neurite outgrowth activity in PC12 cells
(Figure 1).3 As a result, a few approaches have been described in the literature to construct the
relevant scaffolds.4 However, most of these approaches involve multistep reaction sequence,
therefore, it is highly desirable to pursue efficient approaches for the stereoselective construction
such skeletons
.
FIGURE 1. Natural products containing tricyclic structures.
The ‘Prins cyclization’ is a direct and efficient route for the stereoselective construction of
tetrahydropyran ring system, which is a backbone of many natural products.5 In particular, its
intramolecular version has become very popular for the stereoselective synthesis of fused and
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bridged oxacycles.6,7 Furthermore, it has been successfully applied in the total synthesis of
biologically active natural products.8
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Following our interests on domino cyclization,9 we report a novel and efficient strategy for the
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stereoselective
synthesis
of
decahydrofuro[3,2ꢀd]isochromene
and
octahydroꢀ2Hꢀ
cyclopenta[c]furo[2,3ꢀd]pyran derivatives. The required enediols (3) and (4) were prepared by
the condensation of diethyl succinate with cyclic ketone under basic conditions. The resulting
diesters10 were reduced under LAH conditions to produce the corresponding enediols (3) and (4)
(Scheme 1).
SCHEME 1. Preparation of starting materials 3 and 4
OEt
OH
O
O
O
EtO
+
LAH, 0 oC , 1h
THF
a) NaH, THF, rt 12h
OEt
OH
OEt
( )n
= 1 or 2
b) conc H2SO4,
EtOH, reflux, 12h
( )n
( )n
O
O
n
1: n = 1
2: n = 2
3: n = 1; 72 %
4: n = 2; 68 %
TABLE 1. Optimization of the reaction conditions
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At the outset, we attempted the coupling of enediol (4) (1.0 equiv) with pꢀtolualdehyde (1.2
equiv) in the presence of BF3.OEt2 (1.2 equiv). The reaction proceeded smoothly at ꢀ78 °C with
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high stereocontrol (entry a, Table 1). However, the reaction was found to be sluggish at 0 C
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resulting in the decomposition of starting material (entry b, Table 1). Other Lewis acids such as
SnCl4, TiCl4 and In(OTf)3 gave the product relatively in lower yields (entries cꢀe, Table 1),
whereas TMSOTf gave the mixture of products (entry f, Table 1). Bronsted acids such as pꢀTSA
and CSA failed to initiate the reaction even after long reaction time at elevated temperature
(entries g,h, Table 1). Though the reaction was successful with 1.2 equiv of TfOH, the required
product was isolated in low yield (entry i, Table 1). We further performed the reaction in
different solvents such as THF, benzene and CH3CN (entries jꢀl, Table 1). Among them, DCM
gave the best results in terms of yield. The structure and relative stereochemistry of 6a were
established by 1D and 2D NMR experiments (Supporting information).
TABLE 2. Synthesis of decahydrofuro[3,2ꢀd]isochromene/octahydroꢀ2Hꢀcyclopenta[c]furo[2,3ꢀ
d]pyran derivatives
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The scope of the reaction is further exemplified with diverse aldehydes bearing different
substitution pattern on aromatic ring (Table 2). In all the cases, the products were obtained in
good yields with high selectivity. It is noteworthy to mention that a wide range of functional
groups are well tolerated under the reaction conditions. The functional groups present on
aromatic ring had shown some effect on the conversion. It was observed that alkyl substituted
aromatic aldehydes gave the products relatively in higher yields than the corresponding halide or
methoxyꢀsubstituted aldehydes. The reaction is further extended to aliphatic aldehydes (Table 2,
6g and 6h) and heterocyclic aldehyde (Table 2, 6n). This method also works well with sterically
hindered substrates such as pꢀtertꢀbutylbenzaldehyde and pivalaldehyde (Table 2, 6f and 6h).
Therefore, this method is successful with aromatic, aliphatic and heteroaromatic aldehydes to
generate the products with diverse substitution pattern. However, the reactions were not
successful with ketones like cyclohexanone and acetone.
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In order to broaden the scope of this methodology, we studied the effect of substituents on
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enediol precursor. Accordingly,
we prepared a series of substituted enediols adopting the
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synthetic sequence as outlined in Scheme 2. The intermediate, cyclohexenyl butyrolactone (7)
was prepared by reacting cyclohexanone with ϒꢀbutyrolactone.11 Reduction of lactone 7 with
DIBALꢀH afforded the lactol 8 in 90% yield, which was then treated with Grignard reagents to
produce the substituted enediols 9 with good diastereoselectivity, which was confirmed by NMR.
The relative stereochemistry of compound 9 was established as syn with respect to ꢀOH and ꢀ
CH2CH2OH groups based on stereochemistry of 10a which was confirmed by Xꢀray
crystallography. The observed stereochemistry is consistent with a known method,12 in which
antiꢀCram's stereoselection was explained based on a chelate model A (Scheme 2).
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SCHEME 2. Preparation of compounds 9a-e.
TABLE 3. Synthesis of substituted decahydrofuro[3,2ꢀd]isochromene.
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Treatment of various substituted enediols 9 with different aldehydes under optimised conditions
gave the corresponding decahydrofuro[3,2ꢀd]isochromene derivatives (10) in excellent yields
(10a-h, Table 3). There was no effect of the substituents on stereochemical outcome of the
reaction, which was confirmed by a single crystal Xꢀray diffraction of 10a (Supporting
information). The reaction was quite successful with different aldehydes bearing olefin (10b,
Table 3), ester (10c, Table 3), N,Nꢀdiphenylamino functionality (10d, Table 3). Furthermore,
aliphatic aldehyde bearing benzyloxy group also participated effectively (10f and 10g Table 3).
However, the aliphatic aldehyde having amide functionality (Nꢀ(3ꢀoxopropyl)benzamide) failed
to give the product under similar conditions.
Based on our previous observations,9 we proposed a plausible reaction mechanism in Scheme 3.
The reaction is expected to proceed through the formation of oxocarbenium ion I from the
condensation of aldehyde with enediol under acidic conditions. The resulting oxocarbenium ion
is trapped by an internal olefin leading to the formation of a cyclic carbocation II, which is
simultaneously neutralized by a tethered hydroxyl group to generate the tricyclic III ether as
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depicted in Scheme 3. The exceptional diastereoselectivity observed in this process can be
explained by a favourable trapping of the more stable carbocation from a less hindered equatorial
side to overcome unfavourable 1,3ꢀdiaxial interactions.13
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SCHEME 3. A plausible reaction path way
In conclusion, we have developed a novel strategy for the efficient synthesis of angularly fused
tricyclic ethers from aldehydes and enediols using a stoichiometric amount of BF3.Et2O. It is an
elegant approach for the stereoselective synthesis of decahydrofuro[3,2ꢀd]isochromene and
octahydroꢀ2Hꢀcyclopenta[c]furo[2,3ꢀd]pyran derivatives. This method offers numerous
advantages such as good yields, excellent diastereoselectivity, diverse functional group tolerance,
and a wide substrate scope, which make it an attractive strategy for the synthesis of biologically
relevant structural scaffolds with four contiguous stereogenic centres.
Experimental Section
General. All solvents were dried according to standard literature procedures. The reactions were
performed in ovenꢀdried round bottom flasks and the flasks were fitted with rubber septa and the
reactions were conducted under a nitrogen atmosphere. Glass syringes were used to transfer
solvents. Crude products were purified by column chromatography on silica gel of 60–120 or
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100ꢀ200 mesh. Thin layer chromatography plates were visualized by exposure to ultraviolet light
and/or by exposure to iodine vapors and/or by exposure to methanolic acidic solution of pꢀ
anisaldehyde followed by heating (<1 min) on a hot plate (~250 °C). Organic solutions were
concentrated on rotary evaporator at 35–40 °C. IR spectra were recorded on FTꢀIR spectrometer.
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1H and C NMR (protonꢀdecoupled) spectra were recorded in CDCl3 solvent on 200, 300, 400
or 500 MHz NMR spectrometer. Chemical shifts (δ) were reported in parts per million (ppm)
with respect to TMS as an internal standard. Coupling constants (J) are quoted in hertz (Hz).
Mass spectra were recorded on mass spectrometer by Electrospray ionization (ESI) or
Atmospheric pressure chemical ionization (APCI) technique.
X-ray Crystallography.
Xꢀray data for the compounds were collected at room temperature using Smart Apex CCD
diffractometer with graphite monochromated MoKα radiation (λ=0.71073Å) with ωꢀscan
method. Preliminary lattice parameters and orientation matrices were obtained from four sets of
frames.
Integration and scaling of intensity data was accomplished using SAINT program14. The
structure was solved by direct methods using SHELXSꢀ201415 and refinement was carried out by
fullꢀmatrix leastꢀsquares technique using SHELXLꢀ201415. Anisotropic displacement parameters
were included for all nonꢀhydrogen atoms. All H atoms were positioned geometrically and
treated as riding on their parent C atoms [CꢀH = 0.93ꢀ0.97 Å and Uiso(H) = 1.5Ueq(C) for methyl
H or 1.2Ueq(c) for other H atoms]. The methyl groups were allowed to rotate but not to tip.
Typical procedure for domino cyclization
To a mixture of 2ꢀcyclohexenylbutanꢀ1,4ꢀdiol (0.5 mmol) and pꢀtolualdehyde (0.6 mmol) in
o
anhydrous DCM (5 mL) was added BF3.OEt2 (1.2 equiv) at ꢀ78 C. The resulting mixture was
allowed to stir at the same temperature for 1h . After completion, the reaction was quenched with
sat. NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with
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dichloromethane (2x5 mL). The organic phases were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. The resulting crude product was purified by silica gel column
chromatography (100ꢀ200 mesh) using ethyl acetate/hexane gradient mixture to afford the pure
product 6a (Table 2, entry a).
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6-p-Tolyldecahydrofuro[3,2-d]isochromene (6a):
1
Viscous liquid; Yield 130 mg, 96% ; H NMR (500 MHz, CDCl3): δ 7.20 (d, J = 8.0 Hz, 2H),
7.14 (d, J = 7.9 Hz, 2H), 4.31 (d, J = 11.1 Hz, 1H), 4.08 (dd, J = 12.3, 0.9 Hz, 1H), 4.0 (td, J =
3.2, 8.6 Hz, 1H), 3.91 (q, J = 8.3 Hz, 1H), 3.85 (dd, J = 3.2, 12.2 Hz, 1H), 2.50ꢀ2.42 (m, 1H),
2.33 (s, 3H), 2.10ꢀ2.01 (m, 2H), 1.90 (dd, J = 5.1, 10.9 Hz, 1H), 1.77ꢀ1.71 (m, 1H), 1.69ꢀ1.52
(m, 3H), 1.42ꢀ1.36 (m, 1H), 1.34ꢀ1.24 (m, 2H), 1.05 (d, J = 14.0 Hz, 1H);
13C NMR (126 MHz,
CDCl3) δ 137.8, 137.4, 129.0, 126.7, 80.8, 79.8, 66.4, 64.8, 45.3, 41.8, 32.2, 28.1, 23.0, 22.4,
21.1, 21.0; IR (KBr): υ 3019, 2925, 2855, 1216, 1110, 771, 667; HRMS (Orbitrap ESI) calcd for
C18H25O2 [M+H]+: 273.1849. Found: 273.1844.
6-Phenyldecahydrofuro[3,2-d]isochromene (6b):
Pale yellow liquid ; Yield 122 mg, 95% ; 1H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.27 (m, 5H), 4.35
(d, J = 10.9 Hz, 1H), 4.10 (dd, J = 1.0, 12.3 Hz, 1H), 4.01 (td, J = 3.6, 8.6 Hz, 1H), 3.91 (q, J =
8.6 Hz, 1H), 3.87 (dd, J = 3.2, 12.2 Hz, 1H), 2.52ꢀ2.43 (m, 1H), 2.11ꢀ2.02 (m, 2H), 1.91 (dd, J =
5.1, 10.9 Hz, 1H), 1.78ꢀ1.73 (m, 1H), 1.69ꢀ1.53 (m, 3H), 1.43ꢀ1.38 (m, 1H), 1.35ꢀ1.27 (m, 2H),
1.04 (d, J = 14.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 140.8, 128.3, 127.8, 126.8, 81.0, 79.8,
66.4, 64.8, 45.3, 41.9, 32.2, 28.1, 23.0, 22.4, 21.0; IR (KBr): υ 3029, 2925, 2855, 1453, 1218,
1110, 1030, 771, 700; HRMS (Orbitrap ESI) calcd for C17H23O2 [M+H]+: 259.1692. Found:
259.1688.
6-(4-Chlorophenyl)decahydrofuro[3,2-d]isochromene (6c):
1
Viscous liquid; Yield 141 mg, 96% ; H NMR (500 MHz, CDCl3): δ 7.33ꢀ7.30 (m, 2H), 7.27ꢀ
7.25 (m, 2H), 4.32 (d, J = 11.1 Hz, 1H), 4.09 (dd, J = 0.7, 12.3 Hz, 1H), 4.00 (td, J = 3.2, 9.0 Hz,
1H), 3.91 (q, J = 8.5 Hz, 1H), 3.85 (dd, J = 3.2, 12.2 Hz, 1H), 2.49ꢀ2.39 (m, 1H), 2.11ꢀ1.98 (m,
2H), 1.84 (dd, J = 5.0, 10.3 Hz, 1H), 1.78ꢀ1.72 (m, 1H), 1.70ꢀ1.52 (m, 3H), 1.44ꢀ1.38 (m, 1H),
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1.31ꢀ1.21 (m, 2H), 1.01 (d, J = 14.1 Hz, 1H); C NMR (75 MHz, CDCl3) 139.4, 133.4, 128.5,
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128.2, 80.2, 79.6, 66.6, 64.8, 45.2, 42.2, 32.2, 28.1, 22.9, 22.3, 21.0. IR (KBr): υ 3005, 2929,
2856, 1491, 1217, 1108, 1029, 771, 747, 665; HRMS (Orbitrap ESI) calcd for C17H22ClO2
[M+H]+: 293.1302. Found: 293.1297.
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6-(4-Fluorophenyl)decahydrofuro[3,2-d]isochromene (6d):
1
Viscous liquid; Yield 124 mg, 90%; H NMR (500 MHz, CDCl3): δ 7.31ꢀ7.25 (m, 2H), 7.06ꢀ
7.00 (m, 2H), 4.33 (d, J = 10.9 Hz, 1H), 4.08 (dd, J = 0.9, 12.2 Hz, 1H), 4.00 (td, J = 3.2, 8.6
Hz, 1H), 3.91 (q, J = 8.6 Hz, 1H), 3.85 (dd, J = 3.2, 12.2 Hz, 1H), 2.49ꢀ2.40 (m, 1H), 2.11ꢀ1.99
(m, 2H), 1.86 (dd, J = 5.1, 10.9 Hz, 1H), 1.78ꢀ1.72 (m, 1H), 1.70ꢀ1.53 (m, 3H), 1.44ꢀ1.38 (m,
1H), 1.32ꢀ1.21 (m, 2H), 1.02 (d, J = 14.1 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 163.8, 160.6,
136.6, 128.4, 128.3, 115.0, 114.5, 80.2, 79.6, 66.4, 64.8, 45.2, 42.1, 32.1, 28.0, 22.9, 22.3, 20.9;
IR (KBr): υ 3019, 2933, 2857, 1512, 1215, 742, 667; HRMS (Orbitrap ESI) calcd for C17H22FO2
[M+H]+: 277.1598. Found: 277.1591.
6-(4-Isopropylphenyl)decahydrofuro[3,2-d]isochromene (6e):
Pale yellow liquid ; Yield 141 mg, 94%; 1H NMR (500 MHz, CDCl3): δ 7.24ꢀ7.18 (m, 4H), 4.32
(d, J = 10.9 Hz, 1H), 4.08 (dd, J = 1.0, 12.3 Hz, 1H), 4.01 (td, J = 3.2, 8.6 Hz, 1H), 3.91 (q, J =
8.5 Hz, 1H), 3.85 (dd, J = 3.2, 12.2 Hz, 1H), 2.89 (hep, J = 6.8 Hz, 1H), 2.52ꢀ2.42 (m, 1H),
2.10ꢀ2.01 (m, 2H), 1.93 (d, J = 5.3, 11.1 Hz, 1H), 1.77ꢀ1.71 (m, 1H), 1.70ꢀ1.52 (m, 3H), 1.43ꢀ
1.36 (m, 1H), 1.35ꢀ1.25 (m, 2H), 1.23 (d, J = 7.0 Hz, 6H), 1.09 (d, J = 13.8 Hz, 1H);
13C NMR
(126 MHz, CDCl3) δ 148.4, 138.1, 126.8, 126.4, 80.8, 79.8, 66.4, 64.8, 45.3, 41.7, 33.8, 32.2,
28.1, 24.0, 23.9, 23.0, 22.5, 21.0; IR (KBr): υ 3007, 2930, 2859, 1459, 1216, 1108, 771, 745,
665; HRMS (Orbitrap ESI) calcd for C20H29O2 [M+H]+: 301.2162. Found: 301.2155.
6-(4-tert-Butylphenyl)decahydrofuro[3,2-d]isochromene (6f):
Pale yellow liquid; Yield 144 mg, 92% ; 1H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.34 (m, 2H), 7.25ꢀ
7.22 (m, 2H), 4.32 (d, J = 11.1 Hz, 1H), 4.08 (dd, J = 1.0, 12.2 Hz, 1H), 4.01 (td, J = 3.0, 8.6
Hz, 1H), 3.91 (q, J = 8.5 Hz, 1H), 3.85 (dd, J = 3.2, 12.2 Hz, 1H), 2.51ꢀ2.42 (m, 1H), 2.10ꢀ2.01
(m, 2H), 1.93 (dd, J = 5.1, 10.9 Hz, 1H), 1.77ꢀ1.71 (m, 1H), 1.69ꢀ1.52 (m, 3H), 1.43ꢀ1.37 (m,
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1H), 1.35ꢀ1.25 (m, 2H), 1.10 (d, J = 14.0 Hz, 1H), 1.30 (s, 9H); C NMR (75 MHz, CDCl3) δ
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150.7, 137.7, 126.5, 125.2, 80.7, 79.8, , 66.3, 64.8, 45., 41.6, 34.5, 32.2, 31.3, 28.1, 23.0, 22.5,
21.1; IR (KBr): υ 3018, 2924, 2853, 1462, 1216, 771; HRMS (Orbitrap ESI) calcd for
C21H31O2[M+H]+: 315.2318. Found: 315.2310.
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6-Isopropyldecahydrofuro[3,2-d]isochromene (6g):
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Pale yellow liquid; Yield 91 mg, 82%; H NMR (500 MHz, CDCl3): δ 3.96ꢀ3.90 (m, 2H), 3.84
(q, J = 8.3 Hz, 1H), 3.63 (dd, J = 3.5, 12.0 Hz, 1H), 3.23 (dd, J = 2.7, 10.0 Hz, 1H), 2.24ꢀ2.15
(m, 1H), 2.00ꢀ1.86 (m, 3H), 1.74ꢀ1.53 (m, 6H), 1.47ꢀ1.40 (m, 2H), 1.23ꢀ1.11 (m, 1H), 1.00 (d, J
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= 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); C NMR (126 MHz, CDCl3) δ 81.1, 80.2, 66.1, 64.6,
44.9, 37.7, 32.3, 28.2, 28.1, 23.2, 22.4, 21.1, 20.5, 14.1; IR (KBr): υ 2926, 2855, 1456, 1369,
1222, 1079, 1031, 771, 668; HRMS (APCI) calcd for C14H25O2[M+H]+: 225.1849. Found:
225.1848.
6-tert-Butyldecahydrofuro[3,2-d]isochromene (6h):
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Pale yellow liquid; Yield 95 mg, 80%; H NMR (500 MHz, CDCl3): δ 3.90 (q, J = 7.7 Hz, 1H),
3.84ꢀ3.78 (m, 2H), 3.58 (dd, J = 4.7, 12.0 Hz, 1H), 2.82 (d, J = 6.4 Hz, 1H), 2.20ꢀ2.11 (m, 1H),
2.00ꢀ1.92 (m, 1H), 1.93ꢀ1.86 (m, 1H), 1.83ꢀ1.76 (m, 2H), 1.73ꢀ1.65 (m, 2H), 1.50ꢀ1.24 (m, 5H),
0.95 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 88.6 , 81.8, 69.0, 64.9, 40.4, 39.3, 36.6, 34.9, 32.5,
30.6, 26.5, 24.5, 23.6; IR (KBr): υ 2927, 2855, 1453, 1362, 1218, 1076, 1029, 771, 669; HRMS
(Orbitrap ESI) calcd for C15H27O2[M+H]+: 239.2005. Found: 239.2001.
6-(4-Bromophenyl)decahydrofuro[3,2-d]isochromene (6i):
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Viscous liquid; Yield 161 mg, 96%; H NMR (500 MHz, CDCl3): δ 7.47 (d, J = 8.3 Hz, 2H),
7.19 (d, J = 8.3 Hz, 2H), 4.31 (d, J = 10.9 Hz, 1H), 4.08 (dd, J = 0.9, 12.2, 1H), 3.99 (td, J = 3.5,
8.8, 1H), 3.90 (q, J = 8.5 Hz, 1H), 3.85 (dd, J = 3.2, 12.2, 1H), 2.48ꢀ2.39 (m, 1H), 2.11ꢀ1.98 (m,
2H), 1.83 (dd, J = 5.1, 10.9 Hz, 1H), 1.78ꢀ1.72 (m, 1H), 1.70ꢀ1.53 (m, 3H), 1.44ꢀ1.38 (m, 1H),
1.30ꢀ1.23 (m, 2H), 1.01 (d, J = 14.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 139.8, 131.4,
128.5, 121.5, 80.2, 79.6, 66.4, 64.8, 45.1, 42.1, 32.1, 28.0, 22.9, 22.3, 21.0. IR (KBr): υ 2929,
2857, 1487, 1456, 1218, 1109, 1009, 771; HRMS (APCI) calcd for C17H22BrO2[M+H]+:
337.0797. Found: 337.0784
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6-(3-Methoxyphenyl)decahydrofuro[3,2-d]isochromene (6j):
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Pale yellow liquid; Yield 100 mg, 70%; H NMR (500 MHz, CDCl3): δ 7.27ꢀ7.25 (m, 1H), 6.90
(d, J = 7.4 Hz, 1H), 6.88ꢀ6.86 (m, 1H), 6.82 (ddd, J = 0.8, 2.5, 8.0 Hz, 1H), 4.31 (d, J = 10.9
Hz, 1H), 4.09 (dd, J = 1.0, 12.3 Hz, 1H), 4.00 (td, J = 3.2, 8.8 Hz, 1H), 3.91 (q, J = 8.6 Hz, 1H),
3.85 (dd, J = 3.2, 12.2 Hz, 1H), 3.81 (s, 3H), 2.50ꢀ2.41 (m, 1H), 2.10ꢀ2.00 (m, 2H), 1.89 (dd, J =
5.1, 10.9 Hz, 1H), 1.78ꢀ1.71 (m, 1H), 1.69ꢀ1.52 (m, 3H), 1.44ꢀ1.38 (m, 1H), 1.34ꢀ1.24 (m, 2H),
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1.07 (d, J = 14.1 Hz, 1H);
13C NMR (126 MHz, CDCl3) δ 159.6, 142.3, 129.3, 119.3, 113.0,
112.6, 80.9, 79.7, 66.4, 64.8, 55.1, 45.2, 41.9, 32.2, 28.1, 23.0, 22.4, 21.0. IR (KBr): υ 2925,
2854, 1586, 1455, 1256, 1109, 1029, 772; HRMS (EI) calcd for C18H24O3[M]+: 288.1725 Found:
288.1730
6-m-Tolyldecahydrofuro[3,2-d]isochromene (6k):
Pale yellow liquid; Yield 133 mg, 98%; 1H NMR (300 MHz, CDCl3): δ 7.25ꢀ7.18 (m, 1H), 7.15ꢀ
7.06 (m, 3H), 4.31 (d, J = 11.1 Hz, 1H), 4.09 (d, J = 12.2 Hz, 1H), 4.02 (td, J = 3.2, 9.0 Hz, 1H),
3.91 (q, J = 8.3 Hz, 1H), 3.85 (dd, J = 3.0, 12.4 Hz, 1H), 2.56ꢀ2.40 (m, 1H), 2.35 (s, 3H), 2.13ꢀ
1.99 (m, 2H), 1.92 (dd, J = 5.0, 10.9 Hz, 1H), 1.80ꢀ1.50 (m, 4H), 1.45ꢀ1.23 (m, 3H), 1.06 (d, J =
13.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 140.6, 138.0, 128.6, 128.1, 127.3, 124.1, 81.1,
79.8, 66.4, 64.8, 45.3, 41.8, 32.2, 28.1, 23.0, 22.4, 21.4, 21.0; IR (KBr): υ 2924, 2854, 1456,
1219, 1111, 1031, 773; HRMS (Orbitrap ESI) calcd for C18H25O2[M+H]+: 273.1849. Found:
273.1842.
6-o-Tolyldecahydrofuro[3,2-d]isochromene (6l):
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Pale yellow liquid; Yield 129 mg, 105ꢀ107 °C; H NMR (300 MHz, CDCl3): δ 7.36 (d, J = 7.3
Hz, 1H), 7.23ꢀ7.19 (m, 1H), 7.18ꢀ7.13 (m, 2H), 4.60 (d, J = 11.1 Hz, 1H), 4.08 (dd, J = 0.9, 12.2
Hz, 1H), 4.04 (td, J = 3.0, 8.8 Hz, 1H), 3.93 (q, J = 8.5 Hz, 1H), 3.85 (dd, J = 3.2, 12.3 Hz, 1H),
2.55ꢀ2.44 (m, 1H), 2.42 (s, 3H), 2.13ꢀ2.00 (m, 3H), 1.79ꢀ1.73 (m, 1H), 1.69ꢀ1.55 (m, 3H), 1.44
(d, J = 14.4 Hz, 1H), 1.32ꢀ1.19 (m, 2H), 1.06 (d, J = 14.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
138.9, 135.9, 130.4, 127.5, 126.8, 126.3, 79.9, 66.5, 65.0, 45.5, 40.9, 32.6, 29.7, 28.2, 23.0, 22.5,
22.1, 19.7; . IR (KBr): υ 3006, 2932, 2859, 1458, 1217, 1107, 1029, 745, 666 ; HRMS (Orbitrap
ESI) calcd for C18H25O2[M+H]+: 273.1849. Found: 273.1844
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6-(3-Bromophenyl)decahydrofuro[3,2-d]isochromene (6m):
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Pale yellow liquid; Yield 154 mg, 92% ; 1H NMR (500 MHz, CDCl3): δ 7.49ꢀ7.47 (m, 1H), 7.44ꢀ
7.40 (m, 1H), 7.24ꢀ7.19 (m, 2H), 4.31 (d, J = 10.9 Hz, 1H), 4.09 (dd, J = 1.0, 12.3 Hz, 1H), 4.01
(td, J = 3.2, 8.6 Hz, 1H), 3.91 (q, J = 8.5 Hz, 1H), 3.85 (dd, J = 3.3, 12.3 Hz, 1H), 2.49ꢀ2.40 (m,
1H), 2.11ꢀ1.98 (m, 2H), 1.85 (dd, J = 5.1, 10.9 Hz, 1H), 1.79ꢀ1.73 (m, 1H), 1.71ꢀ1.52 (m, 3H),
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1.47ꢀ1.40 (m, 1H), 1.33ꢀ1.21 (m, 2H), 1.04 (d, J = 14.0 Hz, 1H). C NMR (126 MHz, CDCl3) δ
143.1, 130.9, 129.8, 125.7, 122.6, 79.6, 66.4, 64.9, 45.2, 42.0, 32.1, 28.0, 22.9, 22.3, 21.1. IR
(KBr): υ 3015, 2931, 2858, 1569, 1216, 1109, 1216, 1109, 1028, 747, 667; HRMS (APCI) calcd
for C17H22BrO2[M+H]+: 337.0797. Found: 337.0788
6-(4-Bromothiophen-2-yl)decahydrofuro[3,2-d]isochromene (6n):
Pale yellow liquid; Yield 143 mg, 84% ; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J = 1.3 Hz, 1H),
6.90 (d, J = 1.2 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 4.06 (dd, J = 1.5, 12.3 Hz, 1H), 3.99 (td, J =
3.2, 8.8 Hz, 1H), 3.89 (q, J = 8.6 Hz, 1H), 3.85 (dd, J = 3.3, 12.3 Hz, 1H), 2.41ꢀ2.31 (m, 1H),
2.09ꢀ2.01 (m, 1H), 1.96 (td, J = 5.1, 13.4 Hz, 1H), 1.85 (dd, J = 5.0, 10.9 Hz, 1H), 1.79ꢀ1.73 (m,
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1H), 1.72ꢀ1.60 (m, 3H), 1.48ꢀ1.42 (m, 1H), 1.30ꢀ1.18 (m, 3H); C NMR (126 MHz, CDCl3) δ
145.2, 127.6, 122.2, 108.8, 79.5, 75.8, 66.5, 64.9, 45.0, 42.8, 32.2, 28.0, 22.8, 22.6, 20.9. IR
(KBr): υ 2920, 2851, 1458, 1219, 1106, 1029, 772, 600; HRMS(EI) calcd for C15H19BrO2S
[M]+: 342.0289. Found: 342.0280.
6-Phenyloctahydro-2H-cyclopenta[c]furo[2,3-d]pyran (6o):
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Pale yellow liquid; Yield 97 mg, 80%; H NMR (300 MHz, CDCl3): δ 7.36ꢀ7.26 (m, 5H), 4.13
(d, J = 12.2 Hz, 1H), 3.97ꢀ3.86 (m, 2H), 3.79ꢀ3.34 (m, 2H), 2.39ꢀ2.30 (m, 1H), 2.18ꢀ2.08 (m,
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3H), 2.06ꢀ1.98 (m, 1H), 1.87ꢀ1.64 (m, 4H), 1.29ꢀ1.20 (m, 1H); C NMR (126 MHz, CDCl3) δ
140.8, 128.3, 127.8, 127.3, 89.7, 83.4, 66.9, 64.9, 47.3, 40.1, 34.3, 29.4, 25.9, 21.7; IR (KBr): υ
2921, 2850, 1453, 1218, 1112, 1029, 771, 749, 605; HRMS(EI) calcd for C16H20O2 [M]+:
244.1463 Found: 244.1460.
6-p-Tolyloctahydro-2H-cyclopenta[c]furo[2,3-d]pyran (6p):
Pale yellow liquid; Yield 105 mg, 82%; 1H NMR (300 MHz, CDCl3): δ 7.22 (d, J = 7.9 Hz, 2H),
7.14 (d, J = 7.7 Hz, 2H), 4.11 (d, J = 12.0 Hz, 1H), 3.96ꢀ3.86 (m, 2H), 3.75 (dd, J = 2.7, 12.2 Hz,
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1H), 3.72 (d, J = 11.2 Hz, 1H), 2.40ꢀ2.28 (m, 1H), 2.33 (s, 3H), 2.17ꢀ2.07 (m, 3H), 2.05ꢀ1.97 (m,
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1H), 1.87ꢀ1.68 (m, 3H), 1.27ꢀ1.19 (m, 2H); C NMR (126 MHz, CDCl3) δ 137.9, 137.5, 129.0,
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127.3, 89.8, 83.3, 66.9, 64.9, 47.1, 40.2, 34.4, 29.4, 26.0, 21.8, 21.0. IR (KBr): υ 2952, 2921,
1515, 1453, 1218, 1111, 1031, 809, 771 HRMS (Orbitrap ESI) calcd for C17H23O2 [M+H]+:
259.1692. Found: 259.1689.
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6-(4-Bromophenyl)octahydro-2H-cyclopenta[c]furo[2,3-d]pyran (6q):
Pale yellow liquid; Yield 135 mg, 84%; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 8.3 Hz, 2H),
7.21 (d, J = 8.3 Hz, 2H), 4.11 (d, J = 12.2 Hz, 1H), 3.95ꢀ3.86 (m, 2H), 3.74 (dd, J = 2.7, 12.3 Hz,
1H), 3.72 (d, J = 10.9 Hz, 1H), 2.36ꢀ2.26 (m, 1H), 2.18ꢀ2.08 (m, 2H), 2.05ꢀ1.95 (m, 2H), 1.87ꢀ
1.68 (m, 4H), 1.22ꢀ1.15 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 140.0, 131.4, 129.0, 121.7,
89.5, 82.7, 66.9, 64.9, 47.2, 40.0, 34.3, 29.4, 25.6, 21.8. IR (KBr): υ 2952, 2870, 1591, 1488,
1218, 1112,1006, 815, 772; HRMS(EI) calcd for C16H19BrO2 [M]+: 322.05684 Found:
322.05680.
6-(4-Chlorophenyl)octahydro-2H-cyclopenta[c]furo[2,3-d]pyran (6r):
Pale yellow liquid; Yield 118 mg, 86%; 1H NMR (300 MHz, CDCl3): δ7.33ꢀ7.30 (m, 2H), 7.28ꢀ
7.25 (m, 2H), 4.11 (d, J = 12.2 Hz, 1H), 3.95ꢀ3.86 (m, 2H), 3.77ꢀ3.71 (m, 2H), 2.36ꢀ2.26 (m,
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1H), 2.18ꢀ2.08 (m, 2H), 2.06ꢀ1.95 (m, 2H), 1.87ꢀ1.68 (m, 4H), 1.23ꢀ1.15 (m, 1H); C NMR (126
MHz, CDCl3) δ 139.4, 133.5, 128.7, 128.4, 89.5, 82.6, 66.9, 64.9, 47.3, 40.0, 34.3, 29.4, 25.8,
21.9. IR (KBr): υ 2956, 2851, 1491, 1217, 1089, 1011, 819, 748; HRMS(EI) calcd for
C16H19ClO2 [M]+: 278.1073 Found: 278.1070.
4-Phenyl-6-p-tolyldecahydrofuro[3,2-d]isochromene (10a):
White solid; m.p. 140ꢀ142 °C. Yield 165 mg, 95%; 1H NMR (500 MHz, CDCl3): δ 7.38ꢀ7.34 (m,
2H), 7.32ꢀ7.27 (m, 4H), 7.23ꢀ7.16 (m, 3H), 4.93 (d, J = 3.0 Hz, 1H), 4.56 (d, J = 11.1 Hz, 1H),
3.94 (td, J = 2.8, 9.4 Hz, 1H), 3.80 (dd, J = 8.5, 17.2 Hz, 1H), 2.35 (s, 3H), 2.27ꢀ2.17 (m, 2H),
2.07ꢀ2.01 (m, 1H), 1.93ꢀ1.88 (m, 1H), 1.78ꢀ1.57 (m, 4H), 1.51ꢀ1.31 (m, 3H), 1.13 (d, J = 13.8
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Hz, 1H); C NMR (126 MHz, CDCl3) δ 141.6, 138.0, 137.3, 128.9, 128.0, 126.9, 126.7, 125.1,
80.7, 80.4, 76.3, 64.8, 50.8, 41.7, 32.4, 25.3, 23.1, 22.3, 21.1, 21.1; IR (neat): υ 2932, 2860,
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348.2079.
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Crystal Data for 10a: C24H28O2 (M =348.46): monoclinic, space group P21/c (no. 14), a =
18.4384(16) Å, b = 8.3568(7) Å, c = 13.1820(11) Å, β = 108.980(1)°, V = 1920.7(3) Å3, Z = 4,
T = 294.15 K, ꢁ(MoKα) = 0.075 mmꢀ1, Dcalc = 1.205 g/mm3, 21823 reflections measured (4.672
≤ 2Θ ≤ 56.656), 4619 unique (Rint = 0.0244) which were used in all calculations. The final R1
was 0.0532 (I > 2σ(I)) and wR2 was 0.1466 (all data) CCDC 1423578 contains supplementary
Crystallographic data for the structure. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033; email:
deposit@ccdc.cam.ac.uk].
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4-Phenyl-6-styryldecahydrofuro[3,2-d]isochromene (10b):
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White solid; m.p. 145ꢀ147 °C. Yield 162 mg, 90% ; H NMR (500 MHz, CDCl3): δ 7.44ꢀ7.41
(m, 2H), 7.38ꢀ7.29 (m, 6H), 7.26ꢀ7.20 (m, 2H), 6.67 (d, J = 15.8 Hz, 1H), 6.25 (dd, J = 7.4 Hz,
15.8, 1H), 4.87 (d, J = 3.0 Hz, 1H), 4.25 (dd, J = 7.7, 9.9 Hz, 1H), 3.91 (td, J = 2.8, 9.4 Hz, 1H),
3.78 (dd, J = 8.5, 16.7 Hz, 1H), 2.18ꢀ2.08 (m, 2H), 2.02ꢀ1.96 (m, 1H), 1.82ꢀ1.06 (m, 6H), 1.53ꢀ
1.40 (m, 2H), 1.34ꢀ1.24 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 141.5, 136.7, 132.5, 128.6,
128.4, 128.09, 127.6, 126.8, 126.5, 125.1, 80.0, 79.8, 76.0, 64.7, 50.7, 40.2, 32.5, 25.2, 23.0,
22.5, 20.9; IR (neat): υ 3026, 2930, 2860, 1494, 1449, 1214, 1138, 1066, 1028, 964, 843, 748,
694; HRMS(EI) calcd for C25H28O2 [M]+: 360.2089 Found: 360.2075.
Methyl 4-(4-phenyldecahydrofuro[3,2-d]isochromen-6-yl)benzoate (10c):
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White solid; m.p. 148ꢀ150 °C. Yield 137 mg, 70% ; H NMR (500 MHz, CDCl3): δ 8.07ꢀ8.04
(m, 2H), 7.50ꢀ7.47 (m, 2H), 7.38ꢀ7.30( m, 4H), 7.25ꢀ7.21 (m, 1H), 4.95 (d, J = 3.0 Hz, 1H), 4.66
(d, J = 10.9 Hz, 1H), 3.94 (td, J = 2.7, 9.3 Hz, 1H), 3.92 (s, 3H), 3.81 (dd, J =8.6, 16.9 Hz, 1H),
2.29ꢀ2.17 (m, 2H), 2.10ꢀ2.04 (m, 1H), 1.89 (dd, J = 4.8, 10.8 Hz, 1H), 1.8ꢀ1.59 (m, 4H), 1.54ꢀ
1.46 (m, 2H), 1.43ꢀ1.34 (m, 1H), 1.07(d, J =14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
166.8, 146.1, 141.2, 129.65, 128.1, 126.9, 125.0, 80.4, 80.2, 76.5, 64.9, 52.0, 50.8, 41.9, 32.4,
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25.3, 23.0, 22.2, 21.1; IR (neat): υ 2931, 2861, 1719, 1611, 1437, 1275, 1107, 1069, 1028, 751,
704; HRMS(EI) calcd for C25H28O4 [M]+: 392.1987 Found: 392.1977.
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4-(4-(4-Methoxyphenyl)decahydrofuro[3,2-d]isochromen-6-yl)-N,N-diphenylaniline (10d):
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Pale yellow solid; m.p. 220ꢀ222 °C. Yield 199 mg, 75% ; H NMR (400 MHz, CDCl3): δ 7.31ꢀ
7.21 (m, 8H), 7.12ꢀ7.04 (m, 6H), 7.03ꢀ6.97 (m, 2H), 6.88ꢀ6.83 (m, 2H), 4.88 (d, J = 2.93 Hz,
1H), 4.55 (d, J = 11.0 Hz, 1H), 3.94 (td, J = 2.4, 9.2 Hz, 1H), 3.80 (dd, J = 8.4, 14.9 Hz, 1H),
3.78 (s, 3H), 2.3ꢀ2.13 (m, 2H), 2.03ꢀ1.95 (m, 1H), 1.93ꢀ1.86 (m, 1H), 1.8ꢀ1.43 (m, 6H), 1.43ꢀ
1.18 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 158.4, 147.7, 147.2, 135.3, 133.8, 129.1, 127.8,
126.34, 124.1, 123.9, 122.6, 113.4, 80.5, 80.4, 76.2, 64.8, 55.2, 51.0, 41.7, 32.4, 29.6, 25.4, 23.1,
22.4, 21.1; IR (neat): υ 2928, 2857, 1589, 1510, 1490, 1276, 1246, 1174, 1069, 1032, 832, 753,
696; HRMS(EI) calcd for C36H37NO3 [M]+: 531.2773 Found: 531.2770.
6-(Biphenyl-4-yl)-4-p-tolyldecahydrofuro[3,2-d]isochromene (10e):
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White solid; m.p. 155ꢀ157 °C. Yield 192 mg, 91% ; H NMR (300 MHz, CDCl3): δ 7.64ꢀ7.56
(m, 4H), 7.50ꢀ7.40 (m, 4H), 7.38ꢀ7.33 (m, 1H), 7.30ꢀ7.24 (m, 2H), 7.16ꢀ7.10 (m, 2H), 4.93 (d, J
= 2.4 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 3.96 (td, J = 2.6, 9.2 Hz, 1H), 3.82 (dd, J = 8.3, 16.8
Hz, 1H), 2.32 (s, 3H), 2.29ꢀ2.19 (m, 2H), 2.09ꢀ2.00 (m, 1H), 1.95 ( dd, J = 4.3, 10.5 Hz, 1H),
1.81ꢀ1.33 (m, 7H), 1.20 (d, J = 13.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 140.9, 140.6,
140.1, 138.5, 136.32, 128.7, 128.7, 127.4, 127.1, 127.0, 125.0, 80.6, 80.4, 76.3, 64.8, 50.9, 41.8,
32.5, 25.4, 23.1, 22.4, 21.19, 21.0; IR (neat): υ 2930, 2860, 1514, 1486, 1451, 1140, 1099, 1070,
1032, 968, 833, 752, 696; HRMS(EI) calcd for C30H32O2 [M]+: 424.24023 Found: 424.24020.
6-(3-(Benzyloxy)propyl)-4-p-tolyldecahydrofuro[3,2-d]isochromene (10f):
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Pale yellow liquid; Yield 178 mg, 85% ; H NMR (500 MHz, CDCl3): 7.36ꢀ7.31 (m, 4H), 7.3ꢀ
7.26 (m, 1H), 7.22ꢀ7.18 (m, 2H), 7.14ꢀ7.10 (m, 2H), 4.67 (d, J = 2.2 Hz, 1H), 4.52 (ABq, J =
12.0 Hz, 2H), 3.85 (td, J = 3.0, 9.1 Hz, 1H), 3.74 (dd, J = 5.4, 13.7 Hz, 1H), 3.63ꢀ3.57 (m, 1H),
3.53 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.1ꢀ1.71 (m, 7H), 1.70ꢀ1.60 (m, 4H), 1.60ꢀ1.51 (m, 2H),
1.47 (d, J = 13.2 Hz, 1H), 1.43ꢀ1.37 (m, 1H), 1.24ꢀ1.13 (m, 1H); 13C NMR (101 MHz, CDCl3): δ
139.0, 138.6, 136.1, 128.7, 128.3, 127.6, 127.4, 124.9, 80.4, 76.5, 75.6, 72.8, 70.4, 64.7, 50.6,
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39.8, 32.5, 29.4, 25.2, 25.2, 23.2, 22.3, 21.0, 20.9; IR (neat): υ 2929, 2858, 1514, 1451, 1095,
1067, 1028, 738, 696; HRMS(EI) calcd for C28H36O3 [M]+: 420.2664 Found: 420.2660.
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6-(2-(Benzyloxy)ethyl)-4-propyldecahydrofuro[3,2-d]isochromene (10g):
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Pale yellow liquid; Yield 134 mg, 75% ; H NMR (500 MHz, CDCl3): 7.35ꢀ7.32 (m, 4H), 7.31ꢀ
7.27 (m, 1H), 4.56ꢀ4.47 (m, 2H), 3.91 (td, J =3.0, 8.6 Hz, 1H), 3.83 (dd, J =8.3, 16.7 Hz, 1H),
3.68ꢀ3.59 (m, 2H), 3.56ꢀ3.49 (m, 2H), 2.10ꢀ1.99 (m, 2H), 1.96ꢀ1.89 (m, 1H), 1.86ꢀ1.78 (m, 1H),
1.77ꢀ1.66 (m, 1H), 1.66ꢀ1.39 (m, 10H), 1.36ꢀ1.24 (m, 2H), 1.20ꢀ1.10 (m, 1H), 0.92 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 138.6, 128.2, 127.5, 127.3, 80.4, 74.5, 73.9, 72.9, 67.1,
64.8, 49.1, 40.9, 36.3, 33.2, 32.4, 24.6, 23.1, 22.4, 20.8, 19.2, 14.0; IR (neat): υ 2930, 2862,
1453, 1361, 1091, 1030, 737, 697; HRMS(EI) calcd for C23H34O3 [M]+: 358.2507 Found:
358.2500.
4-Ethyl-6-p-tolyldecahydrofuro[3,2-d]isochromene (10h):
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White solid; m.p. 92ꢀ94 °C. Yield 142 mg, 95% ; H NMR (500 MHz, CDCl3): δ 7.21ꢀ7.17 (m,
2H), 7.16ꢀ7.12 (m, 2H), 4.33 (d, J = 10.9 Hz, 1H), 3.99 (td, J = 2.8, 8.8 Hz, 1H), 3.90 (dd, J =
8.3, 16.9 Hz, 1H), 3.61 (td, J = 2.7, 6.8 Hz, 1H), 2.33 (s, 3H), 2.31ꢀ2.25 (m, 1H), 2.04 (td, J =
5.1, 13.4 Hz, 1H), 1.95ꢀ1.88 (m, 1H), 1.80 (dd, J = 5.1, 10.9 Hz, 1H), 1.74ꢀ1.42 (m, 7H), 1.42ꢀ
1.22 (m, 2H), 1.05 (d, J = 14.2 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ
138.2, 137.1, 128.9, 126.9, 80.5, 80.4, 77.3, 76.6, 64.9, 48.3, 41.7, 32.4, 27.2, 24.4, 23.0, 22.4,
21.0, 10.3; IR (neat): υ 2929, 2860, 1514, 1454, 1368, 1166, 1078, 1032, 996, 963, 863, 813;
HRMS(EI) calcd for C20H28O2 [M]+: 300.20893 Found: 300.20890.
Preparation of compounds 3 and 4.
To the iceꢀcooled solution of NaH (12 mmols) in 20 ml THF was added a solution diethylꢀ
succinate (6 mmols) in THF and stirred for 10 min, 1 drops EtOH was added to initiate the
reaction. After 10 min cyclohexanone or cyclopentanone (6 mmols ) was added dropwise over
1 h and the reaction mixture was stirred for 12 h at rt. The reaction was quenched with 4 M HCl
and extracted with EtOAc (3 × 20 mL). Combined organic layers were dried over Na2SO4,
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filtered, and the solvent was removed under vacuo. The resulting brown syrup was dissolved in
EtOH (20 mL) and acidified with conc H2SO4 and stirred for 1 h at 0 °C. The reaction mixture
was warmed up to rt and refluxed for 12 h. The reaction mixture was quenched with saturated
solution of NaHCO3 and extracted with EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed in vacuo . The crude solution of diester
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was added to the solution of LAH (24 mmol ) at 0 C. Reaction mixture stirred at same temp for
30 min. After consumption of starting material reaction was quenched with sat NH4Cl and
filtered over celite and washed with hot ethyl acetate. Filtrate was dried over Na2SO4 and
evaporated on under vacuum. Residue was purified using column chromatography.
2-cyclopentenylbutane-1,4-diol ( 3):
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Pale yellow liquid; Yield 673 mg, 72 %; H NMR (500 MHz, CDCl3): 5.55 (S, 1H), 3.75ꢀ3.70
(m, 1H), 3.67ꢀ3.55 (m, 3H), 2.62ꢀ2.55 (m, 1H), 2.36ꢀ2.31 (m, 2H), 2.29ꢀ2.23 (m, 2H), 1.91ꢀ1.84
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(m, 2H), 1.75ꢀ1.69 (m, 2H); C NMR (100 MHz, CDCl3): δ 144.32, 126.68, 64.6, 61.2, 41.5,
33.4, 32.3, 32.2, 23.1. IR (KBr): 3312, 2923, 2875, 2857, 1660, 1438, 1218, 1046, 1026, 918,
771; HRMS (ESIꢀOrbitrap) calcd for C9H17O2 [M+H]+: 157.1223 Found: 157.1222.
2-cyclohexenylbutane-1,4-diol (4):
Pale yellow liquid; Yield 693 mg, 68 % ; 1H NMR (500 MHz, CDCl3): δ 5.58 (S, 1H), 3.72ꢀ3.67
(m,1H), 3.65ꢀ3.59 (m, 1H), 3.57 ꢀ3.48 (m, 2H), 2.32ꢀ2.26 (m, 1H), 2.06ꢀ2.01 (m, 2H), 1.98ꢀ1.88
(m, 2H), 1.69ꢀ1.58 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 137.2, 124.6, 64.5, 61.3, 47.4, 32.9,
25.2, 25.2, 22.8, 22.5; IR (neat): υ 3335, 2927, 2884, 2852, 1700, 1676, 1608, 1436, 1218, 1025,
770; HRMS (ESI Orbitrap) calcd for C10H18O2Na [M+Na]+: 193.1190 Found: 193.1202.
Preparation of compounds 9a-e.
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To the solution of compound 7 ( 2 mmol ) in DCM was added 1.5 M solution of DIBALꢀH (2
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starting material as evident by TLC reaction was quenched with 20 ml saturated solution of
tartaric acid and stirred at rt for 30 min. Organic layer was separated and aq layer was extracted
with DCM (3 × 10 mL) . Oranic layer was dried over Na2SO4 and evoparated under vaccum.
Crude lactol was taken in 10 ml dry THF and to it was added 4 mmol of RMgBr (R=Ethyl,
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Propyl, Phenyl, pꢀTolyl, pꢀAnisyl) at 0 C and reaction was stirred for 2 h. Reaction was
quenched with saturated NH4Cl and extracted with ethyl acetate. Oranic layer was dried over
Na2SO4 and crude material was purified by colum chromatography.
2-cyclohexenyl-1-phenylbutane-1,4-diol (9a):
Pale yellow liquid; Yield 393 mg, 80 % ; 1H NMR (500 MHz, CDCl3): δ7.32ꢀ7.21 (m, 5H), 5.37
(s, 1H), 4.60 (d, J = 7.6 Hz, 1H), 3.70ꢀ3.65 (m, 1H), 3.59ꢀ3.53 (m, 1H), 2.36ꢀ2.31 (m, 1H), 2.00ꢀ
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1.67 (m, 6H), 1.47ꢀ1.38 (m, 4H); C NMR (126 MHz, CDCl3) δ 143.5, 137.4, 127.9, 127.3,
126.6, 124.5, 76.7, 61.8, 52.6, 32.5, 27.4, 25.2, 22.8, 22.3; IR (neat): υ 3328, 2922, 1661, 1450,
1346, 1012, 917, 756, 698; HRMS (ESI Orbitrap) calcd for C16H22O2Na [M+Na]+: 269.1512
Found: 269.1514.
2-cyclohexenyl-1-p-tolylbutane-1,4-diol (9b)
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Pale yellow liquid; Yield 426 mg, 82 % ; H NMR (300 MHz, CDCl3): δ 7.21 ꢀ7.07 (m, 4H),
5.38 (s, 1H), 4.58 (d, J =7.5 Hz, 1H), 3.73ꢀ3.63 (m, 1H), 3.61ꢀ3.51 (m, 1H), 2.33 (s, 3H), 2.03ꢀ
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1.63 (m, 7H), 1.51ꢀ1.37 (m, 4H); C NMR (101 MHz, CDCl3) δ 140.3, 137.5, 136.7, 128.6,
126.3, 124.3, 76.4, 61.8, 52.4, 32.3, 27.3, 25.1, 22.8, 22.3, 21.1; IR (neat): υ 3328, 2922, 1450,
1346, 1012, 917, 756, 698; HRMS (ESI Orbitrap) calcd for C17H24O2Na [M+Na]+: 283.1674
Found: 283.1671.
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2-cyclohexenyl-1-(4-methoxyphenyl)butane-1,4-diol (9c)
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Pale yellow liquid; Yield 469 mg, 85 % ; H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.6 Hz,
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2H), 6.84 (d, J = 8.6 Hz, 2H), 5.36 (s, 1H), 4.56 (d, J = 7.8 Hz, 1H), 3.80 (s, 3H), 3.76ꢀ3.66 (m,
1H), 3.62ꢀ3.53 (m, 1H), 2.36ꢀ2.28 (m, 1H), 2.03ꢀ1.94 (m, 1H), 1.91ꢀ1.60 (m, 5H), 1.48ꢀ1.36 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 158.7, 137.5, 135.5, 127.6, 124.4, 113.2, 76.3, 61.8, 55.1,
52.65, 32.7, 27.2, 25.1, 22.8, 22.3; IR (neat): υ 3336, 2923, 1611, 1511, 1440, 1242, 1174, 1030,
828, 752; HRMS (ESI Orbitrap) calcd for C17H25O3 [M+H]+: 277.1803 Found: 277.1809.
3-cyclohexenylhexane-1,4-diol (9d)
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Pale yellow liquid; Yield 376 mg, 95 % ; H NMR (500 MHz, CDCl3): δ 5.51ꢀ5.48 (m, 1H),
3.72ꢀ3.65 (m, 1H), 3.61ꢀ3.54 (m, 1H), 3.48ꢀ3.41 (m, 1H), 2.06ꢀ1.89 (m, 5H), 1.83ꢀ1.74 (m, 1H),
1.72ꢀ1.51 (m, 6H), 1.35ꢀ1.25 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
138.1, 123.7, 74.6, 61.7, 51.5, 32.7, 28.1, 25.9, 25.2, 22.9, 22.5, 10.0; IR (neat): υ 3310, 2922,
2876, 1443, 1042, 969, 800; HRMS (ESI Orbitrap) calcd for C12H23O2 [M+H]+: 199.1692
Found: 199.1694.
3-cyclohexenylheptane-1,4-diol (9e)
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Pale yellow liquid; Yield 381 mg, 90 % ; H NMR (500 MHz, CDCl3): δ 5.50 (s, 1H), 3.72ꢀ3.66
(m, 1H), 3.61ꢀ3.50 (m, 2H), 2.06ꢀ1.88 (m, 6H), 1.84ꢀ1.75 (m, 1H), 1.73ꢀ1.43 (m, 6H), 1.38ꢀ1.25
(m, 2H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 138.0, 123.7, 73.0, 61.8, 51.6,
37.4, 32.1, 25.2, 25.0, 22.9, 22.5, 18.9, 14.0; IR (neat): υ 3329, 2926, 2871, 1447, 1216, 1123,
1049, 998, 918, 752; HRMS (ESI Orbitrap) calcd for C13H25O2 [M+H]+: 213.1849 Found:
213.1850.
Acknowledgements
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DP thanks CSIR, New Delhi for the award of a fellowship. B. V. S thanks CSIR, New Delhi for
the financial support as a part of XII five year plan program under title ORIGIN (CSCꢀ0108).
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Supporting Information Available
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NOESY and DQFCOSY study of 6a, ORTEP diagram for compound 10a, copies of 1H and 13C
NMR spectra of products (6a-r,10a-h, 3, 4, and 9a-e) are provided in supporting information.
This material is available free of charge via the internet at http://pubs.acs.org
References and Notes
(1) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2014, 43, 3106. (b)
Shakoori, A.; Bremner, J. B.; Willis, A. C.; Haritakun, R.; Keller. P. A. J. Org. Chem
.
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.
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Caron, P. Y.; Deslongchamps, P. Org. Lett. 2010, 3, 508. (f) Blaszykowski, C.;
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(2) (a) Erguden, J. K.; Moore, H. W. Org. Lett. 1999, 1, 375. (b) Raffa, G.; Rusch, M.;
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Kim, Y. Org. Lett. 2010, 12, 2672. (f) Brummond, K. M.; Chen, D.; Davis, M. M. J.
Org. Chem. 2008, 73, 5064. (g) Patil, N. T.; Kavthe, R. D.; Raut, V. S.; Shinde, V. S.;
Sridhar. B. J. Org. Chem. 2010, 75, 1277.
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Nishizawa, M.; Oda, M.; Kabura, M.; Nagahama, M.; Sakurai, J.; Kubo, M.; Nakai, M.;
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