Titanocene(III) chloride mediated radical induced addition-elimination route to the synthesis of racemic and optically active trisubstituted tetrahydrofurans: Formal synthesis of magnofargesin and 7’-epimagnofargesin

Article abstract of DOI:10.1007/s12039-016-1106-0

Titanocene(III) Chloride mediated radical induced synthesis of 4-benzylidene substituted tetrahydrofuran, a typical lignan skeleton, has been accomplished in good yield through addition-elimination route in racemic as well as in optically active forms. The method has been applied to the synthesis of furano lignans, magnofargesin (1) and 7’-epimagnofargesin (2) in optically active forms.

Full text of DOI:10.1007/s12039-016-1106-0

c
J. Chem. Sci. Vol. 128, No. 7, July 2016, pp. 1067–1079. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1106-0
Titanocene(III) chloride mediated radical induced addition-elimination
route to the synthesis of racemic and optically active trisubstituted
tetrahydrofurans: Formal synthesis of magnofargesin and
7ꢁ-epimagnofargesin
P CHAKRABORTYa, S K MANDALb and S C ROYa,∗
aDepartment of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700 032, India
bDepartment of Chemistry, Saldiha College, Saldiha, Bankura 722 173, India
e-mail: ocscr@iacs.res.in
MS received 25 February 2016; revised 19 April 2016; accepted 26 April 2016
Abstract. Titanocene(III) Chloride mediated radical induced synthesis of 4-benzylidene substituted tetrahy-
drofuran, a typical lignan skeleton, has been accomplished in good yield through addition-elimination route in
racemic as well as in optically active forms. The method has been applied to the synthesis of furano lignans,
magnofargesin (1) and 7ꢁ-epimagnofargesin (2) in optically active forms.
Keywords. Titanocene(III) chloride; radical; tetrahydrofurans; synthesis; furano lignans.
spirocyclic imines8b were also prepared using this tech-
nique. Banwell used this technique as a key step for
the synthesis of aromatic erythrina alkaloids9a and
chemoenzymatic approach towards the total synthesis
of (+)-Brunsvigine.9b Such a useful technique in the
field of radical chemistry has neither been cultivated nor
used extensively10 by using titanocene(III) species as
a radical initiator specially for the synthesis of natural
products.11a,b Herein, we depict a novel methodology
for the synthesis of benzylidene substituted tetrahydro-
furans using Cp2TiCl induced radical based addition-
elimination strategy that has been implemented to the
total synthesis of two furano lignans, magnofargesin
(1) and its isomer 7ꢁ-epimagnofargesin (2).11c The radi-
cal initiator titanocene(III) chloride (Cp2TiCl) was pre-
pared from commercially available Cp2TiCl2 and Zn
dust in THF under argon atmosphere.12
1. Introduction
Radical induced addition-elimination process has been
used as a tool for the synthesis of bioactive natural
products due to mild and simple reaction conditions
along with a vast substrate tolerance. The early report1
by Kharasch et al., has further been developed2 by
Heiba and Dessau describing an unexpected cascade
radical cyclization initiated by intermolecular addition
of carbon-centered trichloromethyl radical to alkynes.
Interestingly, Baldwin et al., synthesized3 the cyclopen-
tanoid isonitrile, the core skeleton of antibiotic metabo-
lites of fungi in the genus trichoderma, via a novel
radical addition-elimination method. Harris and Weiler4
prepared stereospecific exocyclic alkene by a consec-
utive radical cyclization-elimination process in 1987.
In the same year, Pattenden and his group developed5
a cobalt-mediated addition-elimination protocol for the
synthesis of carbon-carbon double bond. Baichi and
Bosch6 used the identical protocol for the synthe-
sis of bicyclic β-lactams. Naito et al., successfully
applied the addition-elimination process for asymmet-
ric synthesis of (-)-α-Kainic acid7a and a concise for-
mal synthesis of (–)-martinellic acid.7b Some strained
functionalized alkylidene-cyclobutanes8a and fused
OMe
MeO
OMe
OMe
HO
HO
MeO
MeO
O
MeO
MeO
O
OMe
OMe
Magnofargesin (1)
∗For correspondence
7'-Epimagnofargesin (2)
1067

1068
P Chakraborty et al.
55.0, 55.2, 57.1, 79.4, 81.9, 84.8, 84.9, 86.5, 86.7,
2. Experimental
122.6, 122.7, 127.2, 127.4, 127.7, 128.2, 128.3, 128.5,
128.6, 128.8, 129.1, 131.8, 137.4; HRMS: calcd. for
C18H17BrO2 [M+Na]+ 367.0304; found: 367.0300.
Compounds 6b-6g were prepared following the simi-
lar procedure used for the preparation of 6a.
1H NMR were recorded in CDCl3 on 300, 400 and 500
MHz and 13C NMR were recorded on 75, 100 and 125
MHz spectrometer respectively using TMS as an inter-
nal standard. IR spectra were recorded on a Shimadzu
FTIR-8300 instrument. High-resolution mass spectra
(HRMS) were obtained using a Qtof Micro YA263
instrument. Ethyl acetate was dried over anhydrous cal-
cium chloride. Petroleum ether of boiling range 60-
80◦C and diethyl ether were dried over sodium. Silica
gel of 60-120 mesh was used for column chromatogra-
phy. THF used for radical cyclisation was super dried
by distilling twice with sodium. DCM solvent was used
after freshly distilling over P2O5. All the reactions were
carried out either in argon or nitrogen atmosphere with
oven-dried glass apparatus. Most of the compounds
described are already reported in the literature and are
characterized by NMR, IR and MASS spectral studies
and have been compared with authentic samples.
Allylic alcohols 4a-g13 and the epoxides 5a-g14c,15–17
were prepared following the standard literature
procedures.
2.2 2-(-2-Bromo-3-phenylallyloxy)(4-chlorophenyl)
methyl)oxirane (6b)
Viscous liquid as an inseparable mixture of two iso-
mers in approx. 1.5:1 ratio. Yield 88%. IR (Neat):
3055, 1596, 1488, 1257, 1078, 1014, 756, 690 cm−1;
1H NMR (400 MHz, CDCl3): δ 2.62-2.65 (m, 0.60H),
2.72-2.78 (m, 1H), 2.81-2.84 (m, 0.40H), 3.18-3.26 (m,
1H), 4.20-4.52 (complex multiplets, 2.60H), 4.60 (d,
J = 6 Hz, 0.40H), 7.28-7.44 (m, 9H (aromatic hydro-
gens) + 1H (olefinic hydrogen); 13C NMR (75 MHz,
CDCl3): δ 44.28, 45.3, 54.0, 54.8, 57.2, 57.3, 78.9, 81.0,
84.5, 84.6, 86.8, 87.0, 122.5, 122.6, 128.4, 128.6, 128.8,
128.9, 129.0, 129.1, 131.8, 131.9, 134.5, 135.9; HRMS:
calcd. for C18H16BrClO2 [M+Na]+ 400.9914; found,
400.9912.
2.3 2-(-2-Bromo-3-phenylallyloxy)(p-tolyl)methyl)
oxirane (6c)
2.1 Preparation of the epoxy ether 6a
To a stirred suspension of NaH (53 mg, 50% disper-
sion, 1.1 mmol) in dry THF (1 mL) was added dropwise
a solution of epoxy alcohol 5a (75 mg, 0.50 mmol) in
dry THF (5 mL) at 0◦C under nitrogen. After the liber-
ation of hydrogen gas ceased (approx. 25 min), a solu-
tion of dibromo compound 12 (166 mg, 0.60 mmol)
in dry THF (7.5 mL) was added dropwise at 0◦C over
10 min. The reaction mixture was stirred at RT for
3h and then carefully quenched with ice water. After
removal of most of the solvent under reduced pres-
sure, the resulting residue was extracted with diethyl
ether (4 × 25 mL). The combined ether extract was
successively washed with water (2 × 10 mL) and
brine (1 × 10 mL) and finally dried (Na2SO4). Sol-
vent was removed under reduced pressure and the
crude mass obtained was purified by column chro-
matography over silica gel to furnish 2-(-2-bromo-
3-phenylallyloxy)(phenyl)methyl)oxirane (6a, 146 mg,
Viscous liquid as an inseparable mixture of two iso-
mers in approx. 2:1 ratio. Yield 84%. IR (Neat): 2921,
1514, 1490, 1263, 1076, 756, 692 cm−1; 1H NMR (500
MHz, CDCl3): δ 2.36 (2s merged, 3H), 2.63-2.65 (m,
0.67H), 2.74-2.82 (m, 1.33H), 3.21-3.23 (m, 0.33H),
3.26-3.29 (m, 0.67H), 4.14-4.48 (complex multiplets,
2.67H), 4.61 (d, J = 4.5Hz, 0.33H), 7.10-7.63 (m,
9H (aromatic hydrogens) + 1H (olefinic hydrogen);
13C NMR (125 MHz, CDCl3): δ 21.3, 44.4, 44.5, 45.1,
74.4, 74.6, 79.7, 82.5, 121.9, 127.2, 127.4, 127.6, 127.8,
128.2, 128.3, 128.4, 128.5, 128.6, 129.1, 129.2, 129.3,
129.4, 129.5, 131.9, 134.6, 135.2, 138.5; HRMS: calcd.
for C19H19BrO2 [M + Na]+ 381.0466; found, 381.0465.
2.4 2-(-2-Bromo-3-phenylallyloxy)(4-methoxyphenyl)
methyl)oxirane (6d)
85%) as a viscous liquid and as an inseparable mix- Viscous liquid as an inseparable mixture of two iso-
ture of two isomers in approx. 3:1 ratio. IR (Neat): mers in approx. 1:1 ratio. Yield 85%. IR (Neat): 2997,
3058, 2854, 1598, 1490, 1257, 1068, 756, 694 cm−1; 1610, 1512, 1249, 1074, 757, 692 cm−1; 1H NMR (500
1H NMR (400 MHz, CDCl3): δ 2.66 (dd, J = 2.4, MHz, CDCl3): δ 2.63 (dd, J = 2.5, 5.0 Hz, 0.50H),
4.8 Hz, 0.75H), 2.75-2.83 (m, 1.25H), 3.23-3.24 (m, 2.74-2.76 (m, 1H), 2.82 (dd, J = 4.0, 5.0 Hz 0.50H),
0.25H), 3.27-3.30 (m, 0.75H), 4.21-4.52 (complex mul- 3.22-3.24 (m, 0.50H), 3.26-3.28 (m, 0.50H), 3.81 (s,
tiplets, 2.75H), 4.64 (d, J = 4.4 Hz, 0.25H), 7.29-7.43 3H), 4.18-4.48 (complex multiplets, 2.50H), 4.60 (d,
(m, 10H (aromatic hydrogens) + 1H (olefinic hydro- J = 4.0 Hz, 0.50H), 6.92 (d, J = 8.0 Hz, 2H), 7.29-
gen); 13C NMR (75 MHz, CDCl3): δ 44.3, 45.2, 54.2, 7.34 (m, 6H), 7.41-7.43 (m, 2H); 13C NMR (100 MHz,

Synthesis of trisubstituted tetrahydrofurans
1069
CDCl3): δ 44.3, 45.2, 54.1, 55.0, 55.3, 56.7, 56.8, 78.9, 0.20H), 4.48 (ABq, J = 15.5 Hz, 0.80H), 7.18-7.23 (m,
81.4, 84.9, 85.0, 86.4, 86.6, 113.7, 114.0, 114.1, 122.6, 4H), 7.33-7.37 (m, 2H); 13C NMR (75 MHz, CDCl3): δ
122.7, 128.3, 128.4, 128.5, 128.7, 129.1, 129.2, 129.3, 14.1, 22.7, 24.9, 25.2, 31.9, 32.0, 32.3, 32.8, 43.3, 45.7,
131.8, 159.9; HRMS: calcd. for C19H19BrO3 [M+Na]+ 53.3, 54.8, 58.1, 58.2, 80.2, 85.6, 85.8, 122.9, 128.3,
397.0415; found: 397.0417.
128.4, 128.5, 131.8; HRMS: calcd. for C16H21BrO2
[M+Na]+ 347.0623; found: 347.0627.
2.5 2-(-2-Bromo-3-phenylallyloxy)(naphthalen-6-yl)
methyl)oxirane (6e)
2.8 Typical Cp2TiCl mediated addition-elimination
procedure for the synthesis of benzylidene substituted
furan derivative 7a
Viscous liquid as an inseparable mixture of two iso-
mers in approx. 2:1 ratio. Yield 89%. IR (Neat): 3056,
1598, 1488, 1078, 910, 757 cm−1; 1H NMR (500 MHz,
CDCl3): δ 2.72-2.73 (m, 0.66H), 2.74-2.80 (m, 0.67H),
2.84-2.88 (m, 0.67H), 3.34-3.36 (m, 0.33H), 3.39-3.41
(m, 0.67H), 4.27-4.61 (complex multiplets, 2.67H),
4.84 (d, J = 4.0 Hz, 0.33H), 7.31-7.33 (m, 3H), 7.43-
7.48 (m, 2H), 7.52-7.62 (m, 3H), 7.82-7.87 (m, 5H); 13C
NMR (125 MHz, CDCl3): δ 44.4, 45.3, 54.2, 55.0, 57.1,
57.2, 79.7, 82.0, 84.9, 122.6, 124.9, 125.1, 126.3, 126.4,
126.8, 127.3, 127.8, 128.1, 128.3, 128.5, 128.6, 131.8,
133.3, 134.8; HRMS: calcd. for C22H19BrO2 [M+Na]+
417.0461; found: 417.0464.
A solution of titanocene dichloride (564 mg, 2.28
mmol) in dry THF (10 mL, strictly deoxygenated) was
stirred with activated zinc dust (360 mg, 5.5 mmol)
for 1h under argon (activated zinc dust was prepared
by washing 20g of commercially available zinc dust
with 60 mL of 4M HCl and thorough washing with
water and finally with dry acetone and then dried in
vacuum). The resulting green solution was then added
dropwise to a stirred solution of the epoxy ether 6a
(345 mg, 1.0 mmol) in dry THF (20 mL) at RT under
argon during 1h. The reaction mixture was stirred for
6 hours and was quenched with a saturated solution
of sodium dihydrogen phosphate (5 mL). Most of the
solvent was removed under reduced pressure and the
residue was extracted with diethyl ether (4 × 30 mL).
The combined ether layer was washed with saturated
NaHCO3 (2 × 25 mL) and finally dried over Na2SO4.
After removal of the solvent under reduced pressure the
crude residue obtained was purified by column chro-
matography over silica gel to afford the substituted
furan compound (2S,3R)-4-benzylidene-tetrahydro-2-
phenylfuran-3-yl)methanol (E:Z =1:2) (7a, 192 mg,
72%) as a mixture of two isomers in 1:2 ratio. IR (Neat):
2.6 2-(-2-Bromo-3-phenylallyloxy)(oxiran-2-yl)
methyl)-3a,7a-dihydrobenzo[d][1,3]dioxole (6f)
Viscous liquid as an inseparable mixture of two iso-
mers in approx. 2:1 ratio. Yield 85%. IR (Neat): 2995,
1614, 1519, 1249, 1080, 768, 690 cm−1; 1H NMR (500
MHz, CDCl3): δ 2.54-2.56 (m, 0.67H), 2.64-2.74 (m,
1.33H), 3.10-3.16 (m, 1H), 4.09-4.47 (complex multi-
plets, 2H), 5.10-5.12 (m, 0.67H), 5.25-5.29 (m, 0.33H),
5.88 (2s merged, 2H), 6.70-6.79 (m, 2H), 6.83-6.84 (m,
1H), 7.16-7.35 (m, 6H), 13C NMR (125 MHz, CDCl3): δ
44.4, 45.3, 54.2, 55.1, 56.8, 75.4, 79.2, 81.5, 84.8, 84.9,
86.6, 86.7, 107.9, 108.0, 108.3, 108.4, 115.1, 115.4,
121.1, 121.6, 122.6, 122.7, 126.4, 127.8, 128.2, 128.3,
128.4, 128.5, 128.6, 129.1, 129.2, 131.1, 131.3, 131.8,
131.9, 140.4, 142.7, 147.9, 148.1; HRMS: calcd. for
C19H17BrO4 [M+Na]+ 411.0208; found: 411.0206.
1
3330, 1598, 1488, 1078, 910, 757 cm−1; H NMR
(500 MHz, CDCl3): δ 3.00-3.01 (m, 0.33H), 3.45-3.49
(m, 0.67H), 3.76-3.79 (m, 1H), 3.81-3.85 (m, 0.50H)
3.93-3.97 (m, 0.50H), 4.61-4.95 (complex multiplets,
2.33H), 5.22 (d, J = 3.6 Hz, 0.67H), 6.45 (q, J = 2.0
Hz, 0.33H), 6.49 (d,J = 2.0 Hz, 0.67H), 7.16-7.45 (m,
10H); 13C NMR (125 MHz, CDCl3): δ 52.1, 55.9, 61.9,
63.1, 70.3, 73.2, 82.3, 84.6, 122.1, 126.1, 126.3, 127.1,
127.2, 127.7, 127.9, 128.1, 128.2, 128.6, 128.7, 136.6,
136.9, 140.6, 141.4, 141.6; HRMS: calcd. for C18H18O2
[M+Na]+ 289.1204; found: 289.1205.
2.7 2-(1-(-2-bromo-3-phenylallyloxy)pentyl)oxirane
(6g)
Compounds 7b-7g were prepared following the simi-
lar procedure used for the preparation of 7a.
Viscous liquid as an inseparable mixture of two isomers
in approx. 4:1 ratio. Yield 84%. IR (Neat): 2929, 1507,
1490, 1255, 1083, 756, 691 cm−1; 1H NMR (500 MHz,
CDCl3): δ 0.80 (t, J = 7.0 Hz , 3H), 1.17-1.62 (m, 6H),
2.45 (dd, J = 3.0, 4.5 Hz, 0.80H), 2.70 (t, J = 4.5 Hz,
0.80H), 2.74 (d, J = 3.5 Hz, 0.40H), 2.84-2.87
2.9 (2S,3R)-4-Benzylidene-2-(4-chlorophenyl)
tetrahydrofuran-3-yl)methanol (E:Z=1:1) (7b)
(m, 0.20H), 2.92-2.94 (m, 0.80H), 3.12-3.16 (m, IR (Neat): 3363, 2871, 1596, 1490, 1213, 1062, 825,
0.80H), 3.36-3.40 (m, 0.20H), 4.37 (d, J = 4.0 Hz, 756 cm−1; 1H NMR (500 MHz, CDCl3): δ 2.87 (d, J =

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P Chakraborty et al.
5.5 Hz, 0.50H), 3.33 (s, 0.50H), 3.64-3.76 (m, 1.50H), 3.98-4.02 (m, 0.50H), 4.67-4.79 (m, 1.33H), 4.82-5.03
3.86-3.89 (m, 0.50H), 4.56 (q, J = 7.5 Hz, 1H), 4.68- (m, 0.67H), 5.12 (d, J = 6.4 Hz, 0.33H), 5.39 (d, J =
4.86 (complex multiplets, 1.50H), 5.12 (d, J = 3.5 Hz, 3.6 Hz, 0.67H), 6.47(d, J = 2.4 Hz, 0.33H), 6.52 (d,
0.50H), 6.37 (d,J = 1.5 Hz, 0.50H), 6.42 (d, J = 1.0 J = 1.6 Hz, 0.67H), 7.17-7.52 (m, 8H), 7.80-7.86 (m,
Hz, 0.50H), 7.07-7.31 (m, 9H); 13C NMR (125 MHz, 4H); 13C NMR (75 MHz, CDCl3): δ 52.1, 55.9, 61.9,
CDCl3): δ 52.1, 56.0, 61.8, 63.0, 70.3, 73.1, 81.6, 83.9, 63.1, 70.4, 73.3, 82.4, 84.7, 122.2, 122.3, 124.2, 124.8,
116.3, 122.4, 122.5, 127.2, 127.4, 127.5, 127.7, 128.0, 125.3, 126.0, 126.1, 126.2, 126.3, 127.1, 127.3, 127.7,
128.2, 128.7, 128.8, 133.4, 133.6, 136.4, 136.8, 140.0, 127.8, 128.1, 128.3, 128.5, 128.6, 128.7, 133.0, 133.4,
140.8, 141.0; HRMS: calcd. for C18H17ClO2 [M+Na]+ 136.5, 137.0, 138.8, 139.5, 140.5, 141.5; HRMS: calcd.
323.0815; found: 323.0815.
for C22H20O2 [M+Na]+ 339.1356; found: 339.1361.
2.13 (2S,3R)-2-(Benzo[d][1,3]dioxol-6-yl)
(4-benzylidene-tetrahydrofuran-3-yl)methanol
(E:Z=1:2) (7f)
2.10 (2S,3R)-4-Benzylidene-tetrahydro-2-p-tolylfuran-
3-yl)methanol (E:Z=1:1) (7c)
IR (Neat): 3360, 2921, 1598, 1512, 1269, 1176, 813,
IR (Neat): 3411, 2885, 1488, 1444, 1247, 1037, 933,
1
696 cm−1; H NMR (500 MHz, CDCl3): δ 2.33 and
1
756, 694 cm−1; H NMR (500 MHz, CDCl3): δ 2.86-
2.34 (2 s, 3H), 2.99 (d, J = 6.0 Hz, 0.50H), 3.45
(d, J = 3.5 Hz, 0.50H), 3.76 (d, J = 6.0 Hz, 0.5H),
3.82 (dd, J = 5.0, 11.0 Hz, 0.50H), 3.91-3.97 (m,
1H), 4.64 (ABq, J = 13.0 Hz, 1H), 4.74-4.93 (com-
plex multiplets, 1.50H), 5.17 (d, J = 3.5 Hz, 0.50H),
6.45 (brs, 0.5H), 6.49 (brs, 0.50H), 7.05-7.47 (m, 9H);
13C NMR (75 MHz, CDCl3): δ 21.2, 52.0, 55.8, 56.1,
56.3, 61.8, 63.0, 70.2, 73.1, 82.2, 84.5, 109.1, 110.5,
122.0, 126.1, 126.4, 127.1, 127.2, 128.1, 128.2, 128.7,
129.3, 129.6, 136.6, 137.0, 137.4, 137.7, 138.2, 139.0,
140.8, 141.8; HRMS: calcd. for C19H20O2 [M+Na]+
303.1361; found: 303.1362.
2.87 (m, 0.33H), 3.32-3.33 (m, 0.67H), 3.63-3.68 (m,
1H), 3.71-3.74 (m, 0.50H), 3.83-3.87 (m, 0.50H), 4.54
(ABq, J = 13.0 Hz, 1H), 4.64-4.83 (complex mul-
tiplets, 1.33H), 5.03 (d, J = 3.5 Hz, 0.67H), 5.85
and 5.86 (two singlets, 2H), 6.36 (brs, 0.33H), 6.41
(brs, 0.67H), 6.67-6.82 (m, 3H), 7.08-7.30 (m, 5H);
13C NMR (75 MHz, CDCl3): δ 52.1, 55.7, 61.7, 62.9,
70.2, 73.1, 82.2, 84.5, 101.1, 106.7, 106.8, 108.2, 119.6,
120.0, 122.1,122.2, 127.1, 127.3, 128.1, 128.2, 128.7,
136.1, 136.5, 136.9, 140.5, 141.5, 147.1, 147.4, 148.0;
HRMS: calcd. for C19H18O4 [M+Na]+ 333.1103;
found: 333.1106.
2.11 (2S,3R)-4-Benzylidene-tetrahydro-2-(4-methoxy-
phenyl)(furan3-yl)methanol (E:Z=1:2) (7d)
2.14 (2R,3R)-4-Benzylidene-2-butyl-tetrahydrofuran-
3-yl)methanol (E:Z=1:2) (7g)
IR (Neat): 3417, 2934, 1612, 1513, 1248, 1175, 1033,
IR (Neat): 3414, 2930, 1723, 1449, 1038, 913, 754,
1
756, 695 cm−1; H NMR (500 MHz, CDCl3): δ 2.96-
1
695 cm−1; H NMR (500 MHz, CDCl3): δ 0.87-0.89
3.00 (m, 0.33H), 3.42-3.45 (m, 0.67 H), 3.74 (d, J =
6.0 Hz, 1H), 3.79-3.82 (m, 3.67H), 3.92-3.95 (m,
0.33H), 4.60 (ABq, J = 13.5 Hz, 1H), 4.75-4.89 (com-
plex multiplets, 1.33H), 5.14 (d, J = 4.0 Hz, 0.67H),
6.45(d, J = 2.5 Hz, 0.33H), 6.49 (d, J = 2.5 Hz,
0.67H), 6.86-6.89 (m, 2H), 7.16-7.38 (m, 7H); 13C
NMR (75 MHz, CDCl3): δ 51.9, 55.4, 55.6, 61.8, 63.0,
70.2, 72.9, 82.1, 84.3, 114.0, 114.1, 121.9, 122.0, 127.1,
127.2, 127.5, 127.8, 128.1. 128.2, 128.7, 133.2, 134.1,
136.6, 137.0, 140.9, 141.9, 159.3, 159.5; HRMS: calcd.
for C19H20O3 [M+Na]+ 319.1305; found: 319.1310.
(m, 3H), 1.22-1.62 (m, 6H), 2.67-2.68 (m, 0.33H), 3.11
(m, 0.67H), 3.61-3.82 (complex multiplets, 2H), 3.92
(q, J = 5.5 Hz, 0.33H), 4.16-4.17 (m, 0.67H), 4.43-
4.45 (m, 1.33H), 4.64 (ABq, J = 14.5 Hz, 0.67H),
6.44 (s, 1H), 7.13-7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3): δ 14.1, 20.6, 22.7, 25.7, 31.9, 34.4, 34.6,
49.5, 53.3, 62.3, 64.0, 69.0, 71.8, 80.8, 83.3, 122.3,
126.9, 127.1, 128.0, 128.1, 128.6, 128.7, 136.8, 137.1,
141.2, 142.4; HRMS: calcd. for C16H22O2 [M+Na]+
269.1517; found: 269.1520.
2.15 Preparation of 1-((Z)-3-(1-(4-methoxyphenyl)
2.12 (2S,3R)-4-Benzylidene-tetrahydro-2-(naphthalene- allyloxy)-2-bromoprop-1-enyl)benzene (18)
2-yl)furan-3-yl)methanol (E:Z=1:2) (7e)
The compound 18 (316 mg, 88%) was prepared from
IR (Neat): 3421, 2939, 1598, 1508, 1062, 819, 752, 696 compound 17 (164 mg, 1.0 mmol) following the sim-
1
cm−1; H NMR (400 MHz, CDCl3): δ 3.09-3.11 (m, ilar procedure used for the preparation of compounds
0.33H), 3.54-3.58 (m, 0.67H), 3.81-3.89 (m, 1.50H), 6a. IR (neat): 2993, 1610, 1512, 1247, 1068, 750, 692

Synthesis of trisubstituted tetrahydrofurans
1071
1
cm−1; H NMR (500 MHz, CDCl3): δ 3.81 (d, J =
obtained was purified by column chromatography over
silica gel (40% ethyl acetate- petroleum ether) to fur-
3.0 Hz, 3H), 4.27-4.39 (m, 2H), 5.05 (d, J = 6.5 Hz,
1H), 5.23-5.33 (m, 2H), 5.96-6.03 (m, 1H), 6.90 (d, J =
9.0 Hz, 2H), 7.30-7.36 (m, 6H), 7.43-7.45 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 55.4, 56.1, 73.9, 81.0, 81.6,
85.5, 86.2, 114.0, 116.7, 116.9, 122.6, 122.9, 128.2,
128.5, 128.7, 129.1, 131.9, 132.3, 132.5, 135.3, 138.4,
138.6, 159.5; HRMS: calcd. for C19H19BrO2 [M+Na]+
381.0466; found: 381.0465.
25
nish 25 (385 mg, 91%) as a viscous liquid. [α]D
=
−133.84 (c = 9.2, CHCl3); IR (neat): 3350, 1522, 1250,
1069, 750, 697 cm−1; H NMR (400 MHz, CDCl3):
1
δ 3.37 (dd, J = 4.8, 11.6 Hz, 1H), 3.55 (dd, J = 3.2,
11.6 Hz, 1H), 3.81-3.91 (m, 7H), 4.13 (d, J = 16 Hz,
1H), 4.36 (d, J = 16 Hz, 1H), 4.57 (d, J = 8.0 Hz,
1H), 6.83-6.92 (m, 3H), 7.29-7.30 (m, 4H), 7.40-7.42
(m, 2H) ; 13C NMR (100 MHz, CDCl3): δ 56.0, 56.7,
62.6, 75.5, 81.6, 84.8, 86.7, 110.3, 111.2, 120.6, 122.5,
128.4, 128.6, 129.5, 131.8, 149.4; HRMS: calcd. for
C20H23BrO5 [M+Na]+ 445.0627; found: 445.0627.
2.16 Preparation of the bromo ether 24
To a stirred suspension of NaH (53 mg, 50% disper-
sion, 1.1 mmol) in dry THF (1 mL) was added drop-
wise a solution of alcohol 22a (124 mg, 0.50 mmol)
in dry THF (5 mL) at 0◦C under nitrogen. After the
evolution of hydrogen ceased (approx. 25 min), a solu-
tion of dibromo compound 12 (166 mg, 0.60 mmol)
in dry THF (7.5 mL) was added dropwise at 0◦C over
10 min. The reaction mixture was stirred at RT for
3h and then carefully quenched with ice water. After
removal of most of the solvent under reduced pressure,
the resulting residue was extracted with diethyl ether
(4 × 25 mL). The combined ether extract was succes-
sively washed with water (2 × 10 mL) and brine (1 × 10
mL) and finally dried (Na2SO4). Solvent was removed
under reduced pressure and the crude mass obtained
was purified by column chromatography over silica gel
(30% ethyl acetate-petroleum ether) to furnish 24 (209
2.18 Preparation of compound 26
A solution of compound 25 (423 mg, 1.0 mmol) in
DCM (20 mL) was treated with pyridine (0.64 mL, 8.0
mmol) and TsCl (248 mg, 1.3 mmol) was added to it
at 0◦C and then stirred for overnight at RT. The mix-
ture was poured into ice water, the organic layer was
separated and the aqueous portion was extracted with
DCM (3 × 50 mL). The combined organic layers were
washed successively with 2M HCl solution (10 mL),
water (10 mL) and brine (10 mL) and finally dried over
Na2SO4.The solvent was removed under reduced pres-
sure followed by column chromatography over silica
gel (25% ethyl acetate-petroleum ether) to afford the
monotosylated derivative 26 (514 mg, 89%) as a vis-
25
cous oil. [α]D = −86.49 (c = 3.4, CHCl3); IR (Neat):
25
mg, 83%) as a viscous liquid. [α]D = −156.24 (c =
3344, 2937, 1595, 1356, 1240, 1069, 754, 698 cm−1;
1H NMR (500 MHz, CDCl3): δ 2.32 (s, 3H), 3.72-3.87
(m, 8H), 3.94 (dd, J = 3.0, 10.5 Hz, 1H), 4.03-4.08
(m, 1H), 4.28 (d, J = 15.5 Hz, 1H), 4.50 (d, J =
7.0 Hz, 1H), 6.75-6.81 (m, 3H), 7.19-7.25 (m, 6H),
7.33-7.35 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ 21.7, 55.9, 56.0, 56.9, 70.0,
73.3, 80.4, 84.5, 86.9, 110.3, 111.3, 120.4, 122.4, 128.0,
128.4, 128.7, 129.9, 131.7, 131.8, 132.8, 144.9, 149.5;
HRMS: calcd. for C27H29BrO7S [M+Na]+ 599.0715;
found: 599.0715.
5.0, CHCl3); IR (Neat): 2990, 1522, 1250, 1069, 750,
697 cm−1; H NMR (500 MHz, CDCl3): δ 1.24-1.70
1
(m, 10H), 3.58 (dd, J = 7.0, 9.0 Hz, 1H), 3.68 (dd,
J = 6.5, 8.5 Hz, 1H), 3.87-3.88 (m, 6H), 4.16 (d, J =
16 Hz, 1H), 4.36-4.45 (m, 2H), 4.55 (d, J = 8.0 Hz,
1H), 6.83-6.91 (m, 3H), 7.25-7.30 (m, 4H), 7.39-7.41
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 23.9, 24.1,
25.2, 35.2, 35.3, 36.4, 55.8, 56.0, 56.6, 65.6, 65.9, 78.6,
78.7, 82.0, 85.3, 86.4, 110.6, 110.7, 110.8, 111.1, 120.5,
120.7, 122.9, 128.1, 128.2, 128.3, 128.4, 128.8, 129.1,
129.8, 130.0, 131.7, 131.8, 149.3, 149.4; HRMS: calcd.
for C26H31BrO5 [M+Na]+ 525.1253; found: 525.1255.
2.19 Preparation of compound 27
To a stirred suspension of sodium hydride (53 mg, 50%
dispersion, 4.0 mmol) in dry THF (10 mL) at 0◦C was
2.17 Preparation of compound 25
Compound 24 (503 mg, 1.0 mmol) was stirred with added dropwise a solution of mono tosylate derivative
80% aqueous acetic acid (2 mL) for 6 h at 40◦C (mon- 26 (865 mg, 1.50 mmol) in dry THF (10 mL) under
itored by TLC). After completion of the reaction, the N2 for 30 min. The reaction mixture was stirred for 1
reaction mixture was extracted with ethyl acetate (3 × h at 0◦C at RT for 3 h. It was then carefully quenched
30 mL) and the combined organic layer was washed with ice-water. After removal of most of THF under
with brine (5 mL) then dried over Na2SO4. Solvent reduced pressure, the resulting residue was extracted
was removed under reduced pressure and the residue with diethyl ether (3 × 50 mL). The combined ether

1072
P Chakraborty et al.
148.4, 149.0; HRMS: calcd, for C11H13BrO3 [M+Na]+
extract was washed with water (10 mL) and brine (10
mL) and finally dried (Na2SO4). Removal of the solvent
under reduced pressure afforded a viscous liquid which
was purified by column chromatography over silica gel
(25% ethyl acetate-petroleum ether) to furnish 27 (510
294.9946; found: 294.9946.
2.22 Preparation of 1-((Z)-2,3-dibromoprop-1-enyl)-
4-methoxybenzene (36a)
25
mg, 84%) as a viscous liquid. [α]D = −125.34 (c =
2.6, CHCl3); IR (Neat): 2967, 1545, 1389, 1276, 1023, A solution of PBr3 (0.12 mL, 1.3 mmol) in diethyl
1
759, 688 cm−1; H NMR (500 MHz, CDCl3): δ 2.66 ether (10 mL) was added dropwise to the compound
(dd, J = 3.0, 5.0 Hz, 1H), 2.74-2.84 (m, 1H), 3.23- 35az (243 mg, 1.0 mmol) at 0◦C and the solution was
3.29 (m, 1H), 3.86-3.92 (m, 6H), 4.28-4.32 (m, 2H), stirred for 1h. After completion of the reaction (mon-
4.44-4.50 (m, 1H), 6.86-6.98 (m, 3H), 7.28-7.36 (m, itored by TLC) the solution was then neutralized by
4H), 7.41-7.43 (m, 2H); 13C NMR (100 MHz, CDCl3): aqueous saturated NaHCO3 solution and extracted with
δ 44.4, 54.2, 55.1, 56.0, 56.1, 56.9, 81.5, 85.0, 86.5, dihloromethane (3 × 10 mL). The combined organic
110.2, 111.2, 120.1, 120.5, 122.7, 128.2, 128.3, 128.4, extract was washed with brine (10 mL) and dried
128.5, 129.1, 129.9, 131.9, 149.4; HRMS: calcd. for over anhydrous Na2SO4. Removal of the solvent under
C20H21BrO4 [M+Na]+ 427.0521; found: 427.0520.
reduced pressure afforded the dibromo compound 36a
(70%) which was directly used in the next step without
any further purification.
2.20 Preparation of compound 28
2.23 Preparation of 4-((Z)-2,3-dibromoprop-1-enyl)-
1,2-dimethoxybenzene (36b)
The compound 28 (246 mg, 73%) was prepared from
compound 27 (400 mg, 0.98 mmol) by radical cycliza-
tion reaction following the similar procedure used for
the preparation of compound 7a. The isolated com-
pound was found to be an inseparable mixture of two
isomers in a ratio of 1:1. IR (neat): 3440, 2958, 1560,
The compound 36b (72%) was prepared from 35bz fol-
lowing the same protocol which was used for the prepa-
ration of compound 36a and was directly used in the
next step without any further purification.
1
1299, 1276, 1033, 750, 678 cm−1; H NMR (500
MHz, CDCl3): δ 3.00-3.01 (m, 0.50H), 3.45-3.46 (m,
0.50H), 3.77-3.95 (complex multiplex including sev-
eral singlets, 8H), 4.64 (q, J = 13 Hz, 1H), 4.75-
5.08 (complex multiplets, 1.50H), 5.13 (d, J = 4.0 Hz,
0.50H), 6.47 (brs, 0.50H), 6.53 (d, J = 1.5 Hz, 0.50H),
6.84-6.90 (m, 1H), 6.93-6.97 (m, 2H), 7.18-7.40 (m,
5H); 13C NMR (100 MHz, CDCl3): δ 51.9, 55.6,
56.0, 56.1, 61.7, 62.8, 70.36, 73.0, 82.3, 84.5, 109.5,
111.2, 118.6, 118.9, 122.0, 122.1, 127.1, 127.3, 128.1,
128.2, 128.7, 133.2, 134.1, 136.6, 137.0, 140.9, 141.9,
159.3, 159.5; HRMS: calcd. for C20H22O4 [M+Na]+
349.1416; found: 349.1417.
2.24 Preparation of 2-(((Z)-2-bromo-3-(4-methoxy-
phenyl)allyloxy)(phenyl)methyl)oxirane (37a)
The compound 37a (292 mg, 78%) was prepared from
5a (150 mg, 1.0 mmol) and 36a (366 mg, 1.2 mmol)
following the similar procedure used for the preparation
of compounds 6a-g. IR (neat): 3001, 1606, 1510, 1249,
1
1178, 910, 732 cm−1; H NMR (500 MHz, CDCl3):
δ 2.89 (dd, J = 3.0, 5.0 Hz, 0.50H), 2.98-3.03 (m,
1H), 3.06 (dd, J = 3.5, 6.0 Hz, 0.50H), 3.46-3.47
(m, 0.40H), 3.51-3.53 (m, 0.60H), 4.03-4.06 (m, 3H),
4.41-4.73 (m, 2.70H), 4.87 (d, J = 4.5 Hz, 0.30H),
7.06-7.08 (m, 1H), 7.13-7.17 (m, 1H), 7.57-7.67 (m,
7H), 7.84-7.88 (m, 1H); 13C NMR (125 MHz, CDCl3):
δ 44.3, 44.4, 45.1, 45.3, 54.2, 55.1, 55.2, 55.3, 57.2,
74.9, 79.4, 81.8, 82.3, 83.4, 113.6, 114.0, 119.7, 127.2,
127.3, 127.4, 127.6, 127.7, 128.6, 128.7, 128.8, 129.0,
129.8, 130.6. 133.3, 133.4, 137.5, 137.7, 159.6, 159.9;
HRMS: calcd. for C19H19BrO3 [M+Na]+ 397.0415;
found: 397.0417.
2.21 Preparation of (Z)-2-bromo-3-(4-methoxyphenyl)
prop-2-en-1-ol (35az) and (Z)-2-bromo-3-(3,4-dime-
thoxyphenyl)prop-2-en-1-ol (35bz)
Dibromo compounds 35az and 35bz were prepared
following the standard literature procedure.18c,d
Spectral data of 35bz: IR (neat): 3492, 2933, 1515,
1465, 1271, 1143, 1024, 873 cm−1; 1H NMR (500 MHz,
CDCl3): δ 3.86 (s, 6H), 4.39 (s, 2H), 6.84 (d, J =
8.5 Hz, 1H), 6.99 (s, 1H), 7.15 (dd, J = 1.0, 7.5 Hz,
2.25 Preparation of (4-(4-methoxybenzylidene)-tetra-
hydro-2-phenylfuran-3-yl) (38a)
1H), 7.30-7.32 (m, 1H); 13C NMR (100 MHz, CDCl3): The compound 38a (107 mg, 68%) was prepared from
δ 55.9, 69.6, 110.7, 110.8, 122.5, 123.4, 127.5, 127.6, 37a (200 mg, 0.53 mmol) as a mixture of two isomers in

Synthesis of trisubstituted tetrahydrofurans
1073
1
1130, 756 cm−1; H NMR (400 MHz, CDCl3): δ 2.79
(t, J = 4.8 Hz, 1H), 2.95 (dd, J = 2.8, 4.8 Hz, 1H),
3.22 (d, J = 3.2 Hz, 1H), 3.84 (s, 3H), 3.87 (s, 6H),
4.83 (d, J = 2.8 Hz, 1H), 6.62 (s, 2H); 13C NMR (125
MHz, CDCl3): δ 43.9, 55.2, 56.3, 61.0, 71.1, 103.4,
135.3, 153.6; HRMS: calcd. for C12H16O5 (M+Na+)
263.0895; found: 263.0892.
1:1.5 ratio following the similar procedure used for the
preparation of compounds 7a-g. IR (neat): 3477, 2956,
1
1606, 1510, 1251, 1178, 1031, 702 cm−1; H NMR
(500 MHz, CDCl3): δ 2.97-2.98 (m, 0.40H), 3.44 (m,
0.60H), 3.75-3.82 (m, 4H), 3.93 (dd, J = 6.0, 11.0 Hz,
1H), 4.59-4.67 (m, 1H), 4.73-4.94 (complex multiplets,
1.40H), 5.20 (d, J = 3.5 Hz, 0.60H), 6.38 (d, J = 2.0
Hz, 0.40H), 6.43 (d, J = 1.0 Hz, 0.60H), 6.84 (d, J =
8.5 Hz, 2H), 6.91 (d, J = 11.5 Hz, 1H), 7.10 (d, J =
9 Hz, 1H), 7.24-7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 52.0, 55.3, 55.4, 55.9, 61.9, 63.1, 70.3, 73.2,
82.3, 84.6, 114.1, 114.2, 121.5, 121.7, 126.1, 126.3,
127.6, 127.9, 128.6, 129.2, 129.3, 129.5, 129.8, 138.4,
139.0, 141.5, 142.2, 158.7; HRMS: calcd. for C19H20O3
[M+Na]+ 319.1310; found: 319.1312.
2.27 Preparation of (R)-2-((R)-((Z)-2-bromo-3-(3,4-
dimethoxyphenyl)allyloxy)(3,4,5-trimethoxyphenyl)
methyl)oxirane (42a)
Compound 42a (386 mg, 78%) was prepared from
41a (240 mg, 1.0 mmol) and 36b (403 mg, 1.2 mmol)
using the similar procedure used for the preparation of
25
compound 6a. [α]D = −59.2 (c = 2.81, CHCl3);
IR (Neat): 3018, 1593, 1463, 1215, 1130, 756, 667
2.26 Preparation of (R)-(3,4,5-trimethoxyphenyl)
((R)-oxiran-2-yl)methanol (41a)
cm−1; H NMR (400 MHz, CDCl3): δ 2.83 (dd, J =
1
2.8, 12.4 Hz, 2H), 3.19 (m, 1H), 3.81-3.92 (m, 15H),
Activated powdered 4-Å molecular sieves (150 mg, 4.24-4.45 (m, 3H), 6.59-6.63 (m, 2H), 6.76-6.80 (m,
25 wt %) in dry CH2Cl2 (5 mL) were placed in a flame- 2H), 6.85-6.92 (m, 1H), 7.17 (t, J = 3.2 Hz, 1H); 13
C
dried two-necked round-bottom flask under an argon NMR (125 MHz, CDCl3): δ 45.3, 45.9, 54.1, 54.3, 54.4,
atmosphere. It was cooled to –20◦C and a solution of 55.1, 55.8, 55.9, 56.1, 57.1, 60.4, 60.8, 69.6, 73.6, 75.1,
(-)-DET (104 mg, 0.505 mmol) in dry CH2Cl2 (2 mL) 80.1, 80.4, 80.5, 83.2, 86.7, 104.1, 104.2, 104.4, 110.7,
[previously stirred with 4-Å molecular sieves (50 mg) 110.9, 111.5, 111.7, 111.7, 112.0, 114.4, 114.6, 121.2,
for 20 min] and a solution of Ti(i-PrO)4 (0.1 mL, 121.3, 122.4, 122.6, 122.7, 125.1, 126.7, 126.8, 127.4,
127.5, 128.2, 129.5, 133.0, 133.1, 133.3, 137.0, 137.2,
137.9, 148.5, 148.6, 148.8, 149.0, 149.1, 149.7, 153.3,
153.4, 153.5; HRMS: calcd for C23H27BrO7 [M+Na]+
0.337 mmol) in dry CH2Cl2 (2 mL) [previously stirred
with 4-Å molecular sieves (50 mg) for 20 min] were
cannulated sequentially into the reaction flask with stir-
ring. After 20 min, 5.5 M t-BuOOH in decane (0.61 517.0838; found: 517.0840.
mL) was added to the mixture and it was stirred at
–20◦C for another 0.5 h. Then, a solution of allylic alco-
2.28 Synthesis of a mixture of magnofargesin (1) and
7ꢁ-epimagnofargesin (2)
hol 40 (760 mg, 3.37 mmol) in dry CH2Cl2 (4 mL) [pre-
viously stirred with 4-Å molecular sieves (75 mg) for
20 min] was cannulated into the mixture and the stir- A solution of titanocene dichloride (564 mg, 2.28
ring was continued for further 4 h. Finally, an aque- mmol) in dry and deoxygenated THF (10 mL) was
ous solution of 30% tartaric acid (3.4 mL) was added, stirred with activated zinc dust (360 mg, 5.5 mmol) for
the mixture was stirred for 0.5 h, and the temperature 1h under argon (activated zinc dust was prepared by
was allowed to warm to 0◦C. Most of the CH2Cl2 was washing 20g of commercially available zinc dust with
removed under reduced pressure and the residue was 60mL of 4 M HCl and thorough washing with water
stirred at 0◦C for 0.5 h with 30% aq NaOH (3.5 mL) and finally with dry acetone and then dried in vacuum).
saturated with NaCl. The resulting mixture was filtered The resulting green solution was then added dropwise
through celite using Et2O and the filtrate was placed to a stirred solution of the epoxy ether 42a (495 mg, 1
in a separatory funnel and the organic layer was sep- mmol) in dry THF (20 mL) at room temperature under
arated. The aqueous layer was extracted with Et2O argon during 1h. The reaction mixture was stirred for 6
(1 × 30 mL) and the combined ethereal extracts were h and was quenched with a saturated solution of sodium
washed with brine (30 mL) and dried (Na2SO4). The dihydrogen phosphate (5 mL). Most of the solvent was
solvent was removed under reduced pressure and the removed under reduced pressure and the residue was
residue obtained was purified by column chromatogra- extracted with diethyl ether (4 × 30 mL). The combined
phy over silica gel (30% ethyl acetate–light petroleum) ether layer was washed with saturated NaHCO3 (2 ×
to give pure chiral epoxide 41a (347 mg, 43%). as 25 mL) and finally dried over Na2SO4. After removal
25
a colorless viscous liquid. [α]D = −22.8 (c = 1, of the solvent under reduced pressure the crude residue
CHCl3); IR (Neat): 3447, 3016, 1541, 1458, 1217, obtained was purified by column chromatography

1074
P Chakraborty et al.
over silica gel (30% ethyl acetate-petroleum ether) to bromo epoxide afforded only the 2,3-trans products as
afford magnofargesin (1) and 7ꢁ-epimagnofargesin (2) revealed from our earlier studies.11
as a mixture of two isomers in 1: 1 ratio (324 mg, 78%).
The dibromo compound 12 was prepared from cin-
IR (neat): 3442, 3020, 1595, 1494, 1217, 1128, 767, namaldehyde 8 following standard chemical transfor-
1
669 cm−1; H NMR (400 MHz, CDCl3): δ 2.98 (m, mations (scheme 2). Thus, a solution of cinnamalde-
0.50H, C8-H for 1), 3.41 (m, 0.50H, C8-H for 2), 3.79- hyde 8 in DCM was stirred for 15 min with Br2 at 0ꢁC
3.89 (m, 16H, 5 × OCH3 and C9-H), 3.97 (dd, J = followed by the addition of Et3N and stirred for 15 min
5.6, 11.2 Hz, 1H, C9-H), 4.63 (dd, J = 1.6, 14.0 Hz, to yield a 1:10 mixture of E/Z isomers 9 as an yellow
1H, C9ꢁ-H for 2), 4.73-4.77 (m, 0.50H, C9ꢁ-H for 1), oil. After keeping for 3 days at room temperature the
4.85 (d, J = 6.4 Hz, 0.50H, C7-H for 1), 4.93 (dd, mixture of isomers in 9 completely converted to Z-α-
J = 1.6, 14.0 Hz, 0.50H, C9ꢁ-H for 1), 5.07 (d, J = bromocinnamaldehyde 10 in the form of a bright yellow
3.6 Hz, 0.50H, C7-H for 2), 6.39 (d, J = 2.0 Hz, solid. Reduction of the aldehyde 10 with sodium boro-
0.50H, C7ꢁ-H for 1), 6.47 (d, J = 1.6 Hz, 0.50H, C7ꢁ- hydride in the presence of CeCl3.7H2O furnished the
H for 2), 6.61 (s, 1H, C2-H and C6-Hfor 2), 6.63 alcohol 11 which was finally brominated using PBr3 to
(s, 1H, C2-H and C6-Hfor 1), 6.70-6.74 (m, 1H, ArH), yield the dibromo compound 12.13
6.81-6.93 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
Thus, a series of bromoepoxides were prepared and
δ 52.0, 55.7, 56.0, 56.3, 60.9, 61.8, 62.8, 70.3, 73.1, subjected to radical cyclization using titanocene(III)
82.4, 84.6, 103.1, 103.2, 111.3, 111.6, 120.6, 120.8, chloride and the results are summarized in table 1.
121.8, 122.1, 129.4, 130.0, 136.9, 137.8, 138.8, 139.4, The methodology worked well for aromatic (Entry 1-6,
148.3, 148.4, 149.0, 153.4, 153.5; HRMS: calcd. for table 1) as well as aliphatic substrate (Entry 7, table 1)
C23H28O7 [M+Na]+ 439.1733; found: 439.1735.
with comparable yield.
The two isomers could not be separated by usual
Two possible pathways may be predicted for the for-
chromatographic methods. But, the spectral and ana- mation of the cyclized product 7 as shown in scheme 3.
lytical data of the mixture of two isomers were in Path A involves the radical 13 that undergoes cycliza-
agreement with the reported values.12,19
tion to furnish the intermediate 14. Then, the expulsion
of the bromine radical from 14 yielded the intermedi-
ate 15 which on acidic work up provided the desired
product 7 as an inseparable mixture of two isomers
(E/Z). In path B, a diradical species 16 may be formed
which undergoes radical coupling to form the interme-
diate 15 and finally to the product 7. But, formation
of aryl/vinyl radical in path B may be discarded as
observed20 by Campaña and Cuerva in a control exper-
iment of intramolecular conjugate addition using aryl
iodide and Cp2TiCl.
In support of path A, a separate experiment was car-
ried out where the bromo compound 18 was treated
with Cp2TiCl in THF under identical reaction condi-
tions (scheme 4). It was observed that only the unre-
acted starting bromide 18 was isolated without a trace
of the cyclized product 19 ensuring the inability of
Cp2TiCl to form a vinyl radical from vinyl bromide.
3. Results and Discussion
Thus, the bromo epoxide 6 was prepared as an insep-
arable mixture of two isomers in different ratio from
the corresponding aldehyde 3 following standard chem-
ical transformations as shown in scheme 1. The bromo
epoxide 6 on treatment with Cp2TiCl in THF under
argon afforded the tetrahydrofuran 7 via radical induced
cyclization-elimination pathway as an inseparable mix-
ture of cis-trans isomers in different ratio. In some
cases, the ratio was found to be 1:1 depending on
the substrate. In all cases, radical cyclization of the
OH
OH
MgBr
mCPBA
R
CHO
R
THF, 0oC
3h
75-88%
R
DCM, 0oC
3h
69-76%
O
R= Aryl/Alkyl
5
(1:1)
4
3
Standing at rt
for 3 days
CHO
CHO
1. Br2
CHO
Br
2. Et3N
DCM
Br
90%
E : Z= 1:10
10
HO
3
Br
8
O
Br
9
Z-isomer
Cp2TiCl
Br
only
12
NaBH4
CeCl3. 7H2O
R
2 O
PBr3
OH
Br
THF
R
O
NaH,THF
0oC, 3h
7
Br
12
Br
11
6
67-78%
Ether
70%
mixture (E and Z)
MeOH
95%
(two isomeric mixture)
84-89%
Scheme 1. Radical induced synthesis of tetrahydrofurans.
Scheme 2. Synthesis of dibromo compound.

Synthesis of trisubstituted tetrahydrofurans
1075
Table 1. Synthesis of various benzylidene substituted furan moieties.
Sl. No. Substrate
Product (E:Z)
Yield (%)a
HO
O
Br
O
O
6a
7a (1:2)
1
72
HO
O
Br
O
O
Cl
6b
Cl
7b (1:1)
2
3
70
67
HO
O
Br
O
O
6c
7c (1:1)
HO
O
Br
O
O
MeO
MeO
6d
7d (1:2)
4
5
68
78
HO
O
Br
O
O
6e
7e (1:2)
HO
O
Br
O
O
O
O
O
O
6f
7f (1:2)
6
76
67
HO
O
Br
O
O
6g
7g (1:2)
7
aYield refers to pure isolated product.

1076
P Chakraborty et al.
Radical
addition Ti(iv)O
OTi(iv)
Ph
.
Br
Br
.
Ph
Ph
Path A
R
O
Br
O
R
O
14
Cp2TiCl
13
R
O
6
Path B
Cp2TiClBr
Ph
OH
OTi(iv)
Ph
Ph
Ti(iv)O
H3O+
R = alkyl/aryl
Ph = Pheny
.
.
Cp2TiClBr
R
O
R
Radical
O
R
O
coupling
7
16
15
Scheme 3. Probable Mechanism for radical cyclization.
Me
Br
Br
O
Br
12
Cp2TiCl
THF
O
OH
MeO
MeO
NaH/THF
0oC, 3h
MeO
19
18
17
88%
Scheme 4. Experimental support in favour of path A.
For asymmetric synthesis of tetrahydrofurans, eas- in good yield. The ketone 23 was reduced by LiAlH4
ily accessible R-2,3-O-cyclohexylidine glyceraldehyde in THF at -78◦C to afford the known alcohol 22a as
20 was used as a source of chiral pool. Freshly pre- the sole product.21c The high selectivity of the nucle-
pared 3,4-dimethoxyphenyl magnesium bromide 21 ophilic addition of hydride to carbonyl moiety in 23
was added to the aldehyde 20 to obtain an insepara- may be explained with the analogy as reported earlier.21
ble mixture of two isomeric alcohols 22a and 22b in a The alcohol 22a was then alkylated with dibromo com-
ratio of 1:1 (scheme 5). The crude mixture of 22 was pound 12 in the presence of NaH in THF under argon
subjected to PCC oxidation to produce the ketone 23 to furnish 24. The aryl ether 24 on treatment with 80%
MgBr
O
O
O
O
O
O
THF
60%
PCC, DCM
+
+
MS 4Ao
85%
O
O
OH
O
OH
OMe
OMe
CHO
MeO
1:1
MeO
MeO
20
21
OMe
22b
OMe
23
OMe
22a
Br
OH
HO
Br
Br
Br
O
O
Aq. acetic acid
40oC
LAH, THF
O
12
O
NaH, THF, 00 C
83%
-78oC
80%
O
O
OH
MeO
91%
MeO
OMe
MeO
OMe
OMe
TsO
22a
25
24
HO
Cp2TiCl
OH
O
TsCl, Py
DCM
Br
Br
O
O
NaH, THF
THF
73%
MeO
89%
0oC
84%
OMe
O
28
MeO
MeO
E : Z = 1 : 1
27
OMe
OMe
26
Scheme 5. Asymmetric synthesis of tetrahydrofurans.

Synthesis of trisubstituted tetrahydrofurans
1077
aqueous acetic acid at 40◦C afforded the diol 25. The and 34b was separately treated with DIBAL-H in THF
diol 25 was selectively mono-tosylated using tosyl chlo- at -78◦C to produce the corresponding isomeric mixture
ride with excess of pyridine in DCM to furnish the of bromo alcohols 35a and 35b in 1:10 ratio (E/Z).
mono-tosylated alcohol 26 which on treatment with The major Z-isomer in 35az (76%) and 35bz (75%)
NaH in THF produced the chiral epoxide 27 in 84% was separated by column chromatography over silica
yield. The chiral radical precursor 27 on treatment with gel.18d Alcohols 35az and 35bz were brominated sepa-
Cp2TiCl in THF under argon produced the cyclized rately with PBr3 to produce the corresponding methoxy
product 28 as an inseparable mixture of two isomers in substituted dibromo compounds 36a (64%) and 36b
equal ratio (E:Z = 1:1).
(62%). Alkylation of 5a with the dibromo compound
To study the scope of the method an attempt to pre- 36a furnished the epoxy ether 37a. The epoxy ether 37a
pare substituted dibromo compound 36a,b following was then treated with Cp2TiCl in THF under argon to
the procedure as stated in scheme 2 was unsuccessful furnish the furan moiety 38a in 68% yield (scheme 7).
as it produced only a mixture of unidentified products. The result showed no significant change in the diastere-
Finally, the aromatic substituted dibromo compounds omeric ratio (E/Z =1:1.5) which implied that the elec-
36a and 36b were prepared following the procedure as tronic effect of the methoxy group in the aromatic
depicted in scheme 6.
moiety failed to incorporate much selectivity.
Thus, phosphonium ylide 3118a,b prepared from bro-
We then turned our attention to the synthesis of
mophoshphonium salt 30 which was selectively bromi- furano lignans using the similar protocol. Lignans have
nated following standard literature method18c to form attracted much interest over last few decades on account
bromo carbethoxymethylenetriphenylphosphorane 32. of their widespread occurrence in nature22 and broad
The bromide 32 was refluxed separately with aldehyde range of biological activities.19,23–27 Magnofargesin,
33a and 33b to furnish the isomeric unsaturated bro- an antagonist of platelet-activity factor (PAF)28 is a
moesters 34a and 34b respectively (E/Z = 1:10). With- class of lignan and has been a long standing inter-
out further purification, the mixture of esters in 34a est for synthetic chemists. Although plentiful synthetic
Ph
P
Ph
PPh3
Br2, DCM
Ph
4N NaOH, 2h
67%
Ph
O
O
Ph
O
Br
PH
+
0oC, 3h
63%
Ph
Br-
O
O
31
THF, addition at
0oC, then rt,
overnight
O
29
30
O
78%
O
OH
DIBAL-H, THF, 3h
-78oC
THF, reflux, 6h
CHO
Br
Br
Br
Ph
R2
O
R2
P
R1
Ph
R1
Ph
O
E:Z=1:10
34a R1 = H, R2 = OMe
34b R1 = OMe, R2 = OMe
32
R2
35a R1 = H, R2 = OMe
35b R1 = OMe, R2 = OMe
R1
33a R1 = H, R2 = OMe
33b R1 = OMe, R2 = OMe
OH
Br
PBr3, 1h
Br
Br
Major isomer
separated
R2
R2
Diethyl ether
R1
R1
(Z)
36a R1 = H, R2 = OMe; 64%
36b R1 = OMe, R2 = OMe; 62%
35az R1 = H, R2 = OMe; 76%
35bz R1 = OMe, R2 = OMe; 75%
Scheme 6. Synthesis of aromatic substituted dibromides.
OMe
Br
Br
HO
OMe
O
O
MeO
Br
36a
Cp2TiCl, THF
rt, 68%
O
NaH, THF, 0o
3h, 78%
C
O
OH
38a
E:Z=1:1.5
37a
5a
Scheme 7. Synthesis of tetrahydrofurans.

1078
P Chakraborty et al.
O
(R)
MeO
MeO
CHO
MeO
MeO
(R)
MeO
MeO
(-)-Diethyl D-tartrate
MgBr
OH
MeO
MeO
OH
OH
+
Ti(OiPr)4, TBHP
-20oC, 4h, 43%
THF, 0oC, 3h
80%
OMe
39
OMe
40
OMe
OMe
41a
(Kinetic Resolution)
41b
NaH, THF
o C, 3h
78%
Br
0
Br
MeO
OMe
36b
OMe
OMe
OMe
OMe
6'
5'
4'
9
7' 1'
8'
O
HO
Cp2TiCl
Br
(R)
OMe
8
HO
3'
OMe
(R)
MeO
MeO
2'
1
MeO
MeO
+
9'
O
O
THF, 6h
78%
MeO
MeO
7
O
4
OMe
OMe
(E:Z= 1:1)
OMe
2
42a
1
Scheme 8. Formal synthesis of magnofargesin and 7ꢁ-epimagnofargesin.
strategies leading to benzyledene substituted tetrahy- 4. Conclusions
drofurans have been reported in the literature, the
In conclusion, we have successfully developed a sim-
ple and efficient Cp2TiCl mediated radical induced
synthetic protocol for the synthesis of benzylidene
substituted tetrahydrofurans following the addition-
elimination strategy. The technique has been applied
to the total synthesis of a mixture of naturally occur-
ring furano lignans, magnofargesin and its epimer
7ꢁ-epimagnofargesin, through addition-elimination pro-
cess. Since, magnofargesin and its epimer 7ꢁ-epimag-
nofargesin have already been separated earlier from
the mixture by Wardrop using special technique, we
acomplished the formal synthesis of two naturally
occurring furano lignans, magnofargesin (1) and 7ꢁ-
epimagnofargesin (2) in optically active forms.
major drawbacks are tedious reaction procedures, low
yield and tedious separation technique.29 In continua-
tion of our study on Cp2TiCl mediated radical induced
synthesis of natural product, we demonstrated the
formal synthesis of magnofargesin (1) and its stereoiso-
mer epi-magnofargesin (2)11 in optically active forms
using addition-elimination methodology. Thus, 3,4,5-
trimethoxybenzaldehyde 39 was treated with vinyl
magnesium bromide to furnish the allyl alcohol 40
which on Sharpless kinetic resolution,14 using (-)-
diethyl tartrate, titanium(IV) isopropoxide [Ti(iPrO)4],
tert-butyl hydroperoxide and 4-Å molecular sieves
in DCM at -20◦C afforded the chiral epoxy alcohol
41a in 43% isolated yield (95% ee, determined from
the corresponding Mosher ester)14c (scheme 8). The
other enantiomer of the allylic alcohol 41b was isolated
as such.
The pure epoxy alcohol 41a was then alkylated using
the dibromo compound 36b in the presence of NaH in
THF to furnish the chiral epoxy ether 42a in good yield.
Finally, the chiral radical precursor 42a when treated
with Cp2TiCl in THF under argon afforded a mixture
of 1 and 2 in a ratio of 1:1. The ratio of the two iso-
mers was determined from the 1H NMR spectrum of the
crude cyclized product and compared with the values
reported in the literature.11,29 Since, the total synthesis
of 1 and 2 has been reported by Wardrop29 by separating
two isomers using special technique, we accomplished
the formal synthesis of two naturally occurring furano
lignans, magnofargesin (1) and 7ꢁ-epimagnofargesin (2)
in optically active forms through Cp2TiCl mediated
radical induced addition-elimination pathway.
Supplementary Information (SI)
Copies of NMR spectra of unknown compounds are
available in Supplementary Information at www.ias.ac.
in/chemsci.
Acknowledgements
P. C. thanks CSIR, New Delhi for awarding research
fellowship (No. 9/80(677)2009-EMR-I).
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