Synthesis of multiply 13C-labeled furofuran lignans using 13C-labeled cinnamyl alcohols as building blocks

Article abstract of DOI:10.1016/j.steroids.2005.10.005

Plant lignans are currently being widely studied for their potential benefits for human health as their consumption has been correlated with lower risks for developing chronic diseases, such as breast cancer and coronary heart disease. However, studies of

Full text of DOI:10.1016/j.steroids.2005.10.005

steroids 7 1 ( 2 0 0 6 ) 231–239
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
Synthesis of multiply 13C-labeled furofuran lignans using
13C-labeled cinnamyl alcohols as building blocks
Kati Haajanen, Nigel P. Botting∗
School of Chemistry, University of St. Andrews, St. Andrews, Fife, KY16 9ST, Scotland, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Plant lignans are currently being widely studied for their potential benefits for human health
as their consumption has been correlated with lower risks for developing chronic diseases,
such as breast cancer and coronary heart disease. However, studies of some classes of lig-
nans, in particular the furofurans, are hampered by the lack of suitable standards to allow
accurate analysis. Herein, we report the syntheses of two racemic 13C-labeled furofuran
lignans [7,8,9-13C3]medioresinol and [7,8,9-13C3]sesamin as internal standards for LC–MS
analysis. The labeled furofuran lignans were constructed from triply labeled cinnamyl alco-
hols, using a radical cyclization method.
Received 19 August 2005
Received in revised form 20 October
2005
Accepted 26 October 2005
Available online 19 December 2005
Keywords:
© 2005 Elsevier Inc. All rights reserved.
Lignan
Furofuran
Phytoestrogen
Isotopic labeling
Synthesis
Analysis
1.
Introduction
Two classes of lignans being investigated for their specific
health effects are the sesamin derivatives present in sesame
Lignans [1] and other dietary phytoestrogens are currently
being widely studied for their potential benefits for human
health. The plant lignans are metabolized in humans to the
so-called mammalian lignans, enterolactone 1 and enterodiol
2 (Fig. 1) [2,3]. Studies have shown that these compounds
produce estrogenic, antiestrogenic and antiproliferative
responses in different animal models [4,5]. They appear to
regulate hormone production in adults by inhibiting the
hormone biosynthetic enzymes, thus lowering the risk of
developing hormone-dependent cancers [6]. They also have
anti-oxidant activity [7,8]. A combination of these effects
has been used to explain the reported correlations between
high levels of enterolactone in the body and lower risks
for developing chronic diseases, such as breast cancer and
coronary heart disease [9,10].
seeds and the rye lignans, both of which are known to be
metabolized to enterolactone [11]. In this work, we have syn-
thesized the two racemic 13C-labeled lignans shown in Fig. 1.
[7,8,9-13C3]Sesamin 3a is an isotopomer of sesamin contain-
ing three 13C atoms in positions 7, 8 and 9, according to the
IUPAC numbering of lignan atoms. [7,8,9-13C3]Medioresinol 3b
is similarly an analogue of the rye lignan medioresinol. The
synthetic challenge was to make lignan derivatives contain-
ing three 13C atoms to be employed as internal standards in
the quantification of lignans in human plasma by a new and
accurate LC–MS method that is being developed. The size of
the lignan molecules means that a minimum of three extra
mass units is required to produce an optimum internal stan-
dard which has a large enough mass difference to nullify the
effect of natural abundance heavy isotopes in the analyte [12].
∗
Corresponding author. Tel.: +44 1334 463856;
fax: +44 1334 433808.
E-mail address: npb@st-andrews.ac.uk (N.P. Botting).
0039-128X/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2005.10.005

232
steroids 7 1 ( 2 0 0 6 ) 231–239
Fig. 1 – Lignan structures.
In previous studies [13] a similar approach was employed for
the mammalian lignans, enterodiol and enterolactone and the
plant lignans, matairesinol and secoisolariciresinol and the
13C-labeled compounds were successfully employed as stan-
dards in both GC–MS [14] and LC–MS [15] analysis. However,
13C-labeling of the furofuran lignans presented a different
synthetic challenge and required the development of new
methodology.
TLC analyses were performed using silica plates
and laboratory reagent grade EtOAc (5–20%) and light
petroleum:CH2Cl2 (1:1). Light petroleum of bp 40–60 ◦C and
silica gel of 35–70 ␮m particle size were used for column
chromatography. For preparative TLC, Merck 250 ␮m and
Analtech 1000 ␮m TLC plates, purchased from Sigma–Aldrich,
were used.
The alternative to labeling with 13C atoms in the lignan
framework is to employ deuterium labeling which can be car-
ried out using a simple aromatic proton/deuterium exchange
procedure and is less expensive [16]. Indeed, a number of
deuterium-labeled lignans, including enterodiol, enterolac-
tone, matairesinol and secoisolariciresinol, have been pre-
pared in this way and successfully used as internal standards
for GC–MS analysis [16]. Unfortunately, this methodology
is not suitable for furofuran lignans, which are acid-labile
compounds and do not survive the acidic deuteration con-
ditions (for example, heating under reflux in CF3COOD)
[17].
2.2.
synthesis of
Representative Grignard reaction procedure:
3-(3,4-methylenedioxyphenyl)-3-hydroxypropene [18]
Piperonal (5.00 g, 0.033 mol) in THF (60 cm3) was added drop-
wise to an ice-cooled solution of vinyl magnesium bromide
(33 cm3, 1.0 M in THF) under N2 and the mixture was stirred
for 2 h at room temperature. The reaction was quenched
by the addition of saturated aqueous NH4Cl (25 cm3) and
water (15 cm3). The organic phase was separated, dried
over MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography (sil-
ica, 9:9:1 light petroleum:CH2Cl2:EtOAc), affording 3-(3,4-
methylenedioxyphenyl)-3-hydroxypropene (5.27 g, 89%) as a
yellow oil, whose spectral data were identical to those pre-
viously reported [19].
2.
Experimental
2.1.
General
2.3.
3-(4-Benzyloxy-3,5-dimethoxyphenyl)-3-
Melting points were determined in open capillary tubes and
are uncorrected. All 1H and 13C NMR spectra were recorded in
CDCl3 at 300 and 75.46 MHz, respectively, using Bruker Avance
500 and Varian Gemini 2000 spectrometers. The chloroform
peaks (7.27 ppm for 1H, 77.00 ppm for 13C) were used as ref-
erences. The EI and CI mass spectra were obtained on a VG
Autospec mass spectrometer and the ESI and APCI mass spec-
tra on a Micromass LCT mass spectrometer. IR spectra were
obtained on a Perkin-Elmer series 1420 spectrometer.
Diethyl ether and THF were distilled over Na and CH2Cl2
over CaH2. DMSO was freshly distilled from CaH2. The hex-
ane used for washing NaH was pre-dried over MgSO4, run
through a column of activated basic alumina and stored
over molecular sieves. Reactions were mostly carried out
under N2, excluding benzyl ether protections, which were per-
formed under air and using a CaO seal over the reaction flask.
MgSO4 and Na2SO4 were used for drying organic products in
solution.
hydroxypropene
4-O-Benzylsyringaldehyde 12 (5.00 g, 18.4 mmol) in dry THF
(40 cm3) was added dropwise to an ice-cooled solution of
vinyl magnesium bromide (18.4 cm3, 1.0 M in THF). The
reaction was then carried out according to the repre-
sentative Grignard reaction procedure. The crude prod-
uct was purified by flash chromatography (silica, 4:4:1
light petroleum:CH2Cl2:EtOAc) to afford 3-(4-benzyloxy-3,5-
dimethoxyphenyl)-3-hydroxypropene (4.62 g, 84%) as a pale
yellow oil (found: M+, 300.1372. C18H20O4 requires 300.1362);
ꢀmax (cm−1) 3100–3600br (O–H), 2800–3100 (CH), 1597, 1504,
1457, 1418, 1374, 1328, 1233 and 1127; ıH 1.95–2.0 (1 H, br,
OH), 3.85 (6 H, s, 2× ArOCH3), 5.01 (2 H, s, ArOCH2Ph),
5.15 (1 H, d, J = 5.4 Hz, ArCHOH), 5.23 (1 H, dt, J = 9.9
and 1.5 Hz, ArCHOHCH CH2), 5.38 (1 H, dt, J = 17.4 and
1.5 Hz, ArCHOH–CH CH2), 6.06 (1 H, ddd, J = 17.4, 9.9, 5.7,
ArCHOHCH CH2), 6.61 (2 H, s, 2-H and 6-H) and 7.29–7.52 (5 H,

steroids 7 1 ( 2 0 0 6 ) 231–239
233
m, ArOCH2C6H5); ıC 56.1, 76.0, 75.8, 103.2, 115.3, 127.8, 128.1,
128.5, 137.8, 138.3, 140.0 and 153.6.
M+, 339.9967, C14H13O2I requires 339.9960); ıH 3.88 (3 H, s,
Ar–OCH3), 5.13 (2 H, s, ArOCH2Ph), 6.63 (1 H, d, J = 9.3 Hz, 5-H),
7.14–7.18 (2 H, m, Ar–H) and 7.31–7.44 (5 H, m, benzyl Ar–H);
ıC 56.0 (CH3), 70.9 (CH2), 83.0 (q), 115.8 (CH), 120.7 (CH), 127.1
(2 CH), 127.9 (CH), 128.3 (2 CH), 128.5 (CH), 132.0 (CH), 136.5 (q),
148.1 (q) and 150.4 (q).
2.4.
Representative procedure for epoxidation using
VO(acac)2 and t-BuOOH [20]: synthesis of 3-(3,4-
methylenedioxyphenyl)-3-hydroxy-1,2-epoxypropane
(11a)
2.7.
3,4-Methylenedioxybenzo[13C]nitrile (5a) [22]
3-(3,4-Methylenedioxyphenyl)-3-hydroxypropene (1000 mg,
5.6 mmol), vanadyl acetylacetonate (0.049 g, 0.014 mmol,
adding another 0.049 g after the first 8 h) and finally t-BuOOH
(2.8 cm3, 5 M, pre-dried by diluting with 3 cm3 of CH2Cl2 at
ice-bath temperature and keeping over molecular sieves for
1 h) were dissolved in dry CH2Cl2 (50 cm3). After 24 h the
reaction mixture was diluted with CH2Cl2 (80 cm3), washed
with saturated aqueous NaCl (100 cm3) and dried (Na2SO4).
The solvent was removed at reduced pressure and the product
was purified by flash chromatography using a 12:12:1 mixture
of light petroleum:CH2Cl2:EtOAc on silica gel. The purified
4a (2.00 g, 9.9 mmol) in DMF (75 cm3) was added to a mixture
of K13CN (1.40 g, 21.1 mmol), Pd(OAc)2 (0.722 g, 3.2 mmol), PPh3
(1.68 g, 6.4 mmol) and Ca(OH)2 (0.238 g, 3.2 mmol) under N2.
The mixture was stirred for 40 h at 90 ◦C. Water (50 cm3) was
added and the mixture was extracted with EtOAc (300 cm3).
The organic phase was washed with water (50 cm3) and brine
(50 cm3) and dried (MgSO4). Purification by flash chromatogra-
phy (silica, 1:1:8 EtOAc:CH2Cl2:hexane) gave 5a (0.887 g, 60%)
as a light coloured solid, mp 93 ◦C (literature [23], 90–91 ◦C)
(found: C, 64.8; H, 3.1; N, 9.5; C713CH5NO2 requires C, 64.9;
H, 3.4; N, 9.5%); ꢀmax (cm−1) 3100–2900 (C–H), 2169 (13C≡N),
1856, 1726, 1622, 1482, 1441, 1353, 1259 and 1031; ıH 6.08 (2
H, s, OCH2O), 6.88 (1 H, d, J = 7.8 Hz, 5-H), 7.05 (1 H, dd, J = 5.4
and 1.5 Hz, 2-H) and 7.23 (1 H, ddd, J = 7.8, 5.4 and 1.5 Hz, 6-H);
ıC 102.2 (O–C–O), 104.9 (d, J = 84 Hz, C1), 109.1 (C2), 111.4 (C6),
118.9 (enhanced C≡N), 128.2 (C5), 147.9 (C3) and 151.5 (C4);
m/z (ES+ in MeCN/H2O/HCOOH) 149 (100, M + H) and 190 (16,
M + H + MeCN).
product 11a (727 mg, 67%) was
a viscous liquid, whose
spectral data corresponded to those previously reported
[19].
2.5.
3-(4-Benzyloxy-3,5-methoxyphenyl)-3-hydroxy-
1,2-epoxypropane (11b)
The representative epoxidation procedure was applied to 3-(4-
benzyloxy-3,5-dimethoxyphenyl)-3-hydroxypropene (100 mg,
0.33 mmol), using VO(acac)2 (2.9 mg, 0.83 ␮mol) and t-BuOOH
(0.17 cm3, 5 M in decane) in CH2Cl2 (3.4 cm3). The solution
was stirred for 1 h at 0 ◦C over molecular sieves. Stirring
was then continued for 5 h at room temperature, after which
time additional VO(acac)2 (4 mg) was dissolved in dry CH2Cl2
(1 cm3) and added to the reaction. The reaction was quenched
after 20 h and the work-up was carried out as before. The
crude product was purified by column chromatography (sil-
ica, 9:9:1 light petroleum:CH2Cl2:EtOAc), affording 11b (51 mg,
48%) as a viscous oil which was a 80:20 mixture of cis/trans iso-
mers (found: M+, 316.1319. C18H20O5 requires 316.1311); ꢀmax
(cm−1) 3100–3700 (br, O–H), 2800–3100 (CH), 1593, 1506, 1458,
1420, 1375, 1330, 1233 and 1127; ıH 2.2–2.25 (1 H, br, OH),
2.80–2.83 (1 H, m, one of CH(O)CH2), 2.85–2.91 and 2.96–2.99
(1 H, m, CH(O)CH2 from trans/cis epoxides), 3.22–3.28 (1 H,
m, CH(O)CH2), 3.86 (6 H, s, 2× ArOCH3), 4.87 (1 H, d, J = 3 Hz,
ArCHOH), 5.02 (2 H, s, ArOCH2Ph), 6.04 (2 H, s, Ar–H) and
7.28–7.53 (5 H, m, ArOCH2C6H5); ıC 55.0, 56.1, 71.0, 75.0, 103.3,
127.8, 128.1, 128.5, 135.1 and 153.7.
2.8.
4-Benzyloxy-3-methoxybenzo[13C]nitrile (5b)
The reaction of 4b (1.85 g, 5.4 mmol) with K13CN (540 mg,
8.2 mmol), Pd(OAc)2 (220 mg, 0.98 mmol), PPh3 (513 mg,
1.96 mmol) and Ca(OH)2 (73 mg, 0.735 mmol) in dimethylfor-
mamide (40 cm3) gave 5b as a light coloured solid (869 mg,
67%), mp. 87–88 ◦C (literature [24], 90 ◦C) (found: C, 75.0 H,
5.55 N, 5.65; M+, 240.0985. C1413CH14NO2 requires C, 75.0; H,
5.5; N, 5.8%; M, 240.0980); ꢀmax (cm−1) 2166 (13C≡N), 1593, 1577,
1509, 1264, 1241, 1135, 1026 and 984; ıH 3.92 (s, 3 H, Ar–OCH3),
5.21 (2 H, s, Ar–OCH2Ph), 6.92 (1 H, dd, J = 8.7 and 1.2 Hz, 5-H),
7.11 (1 H, dd, J = 5.4 and 1.8 Hz, 2-H), 7.22 (1 H, ddd, J = 8.7, 5.4
and 1.8 Hz, 6-H) and 7.33–7.45 (5 H, m, Ar–OCH2C6H5), ıC 56.2
(CH3), 70.9 (CH2), 113.2 (CH), 114.3 (CH), 119.2 (enhanced CN),
126.2 (CH), 127.2 (2× CH), 128.3 (CH) and 128.8 (2× CH); m/z
(EI+) 240 (5%, M+), 91 (100, C7H7); (ESI+) 241 (100, M) and 282
(80, M + MeCN).
2.9.
[Carbonyl-13C]piperonal (6a): representative
procedure for the DIBAL-H reduction of aromatic nitriles
into benzaldehydes [25]
2.6.
4-Benzyloxy-3-methoxyiodobenzene (4b) [21]
KOH (0.469 g, 0.00835 mol) was dissolved in ethanol (35 cm3)
under N2. 4-Hydroxy-3-methoxyiodobenzene (1.75 g,
DIBAL-H was added dropwise over 10 min to a solution of 5a
(0.83 g, 5.6 mmol) in diethyl ether (115 cm3) at −78 ◦C under
argon. The mixture was then stirred for 7 h at this temperature,
after which time it was poured into a mixture of 10% aqueous
acetic acid (60 cm3) and ice. The phases were separated and
the aqueous layer was extracted with EtOAc (300 cm3). The
combined organic extracts were washed with brine (100 cm3)
and dried (MgSO4). The solvents were evaporated at reduced
pressure and the crude product was purified by column
chromatography (silica, 2:9:9 EtOAc:light petroleum:CH2Cl2),
0.0076 mol) in dry dimethylformamide (35 cm3) was added
dropwise, followed by benzyl bromide (0.99 cm3, 0.00835 mol).
The reaction mixture was stirred overnight and then poured to
water. The product was extracted with diethyl ether (150 cm3).
The organic phase was washed with brine (2 × 50 cm3) and
dried over MgSO4. The solvents were then evaporated at
reduced pressure. Column chromatography (silica, 10% EtOAc
in hexane) gave 4b (2.19 g, 89%) as a colourless oil (found

234
steroids 7 1 ( 2 0 0 6 ) 231–239
affording 6a (0.729 g, 86%) as a light yellow solid, mp 37 ◦C (lit-
erature [26], 37 ◦C) (found: C, 63.75; H, 3.8; M + H+, 152.0429.
C713CH6O3 requires C, 63.6; H, 4.0%; M + H, 152.0429); ꢀmax
(cm−1) 1867, 1726, 1642, 1634, 1597, 1456, 1274, 1094 and 929;
ıH 6.09 (2 H, s, OCH2O), 6.94 (1 H, d, J = 8.4 Hz, 5-H), 7.35 (1 H,
dd, J = 4.5 and 1.5 Hz, 2-H), 7.43 (1 H, ddd, J = 8.4, 4.5 and 1.5 Hz,
6-H) and 9.82 (1 H, d, J = 173 Hz, 13CHO); ıC 107.0 (C2), 108.7 (C6),
128.7 (C5) and 190.3 (enhanced CHO); m/z (CI+) 152 (100, M + H)
and 151 (35, M).
erature [31], 63–66 ◦C) (found: C, 64.9; H, 5.3; M + H+, 224.0911.
C913C3H12O4 requires C, 64.6; H, 5.4%; M + H, 224.0914); ꢀmax
(cm−1) 1851, 1652, 1576, 1505, 1451, 1394, 1259, 1228 and 1031;
ıH 1.34 (3 H, t, J = 7 Hz, CO2CH2CH3), 4.26 (2 H, dq, J = 7 and 3 Hz,
CO2CH2CH3), 6.02 (2 H, s, OCH2O), 6.26 (1 H, dddd, JC–H = 161 Hz,
JH–H 16, JH–C–C 3 and 1.2 Hz, CH CHCO2Et), 6.82 (1 H, d, J 8.1 Hz,
Ar–H), 6.98–7.06 (2 H, m, Ar–H) and 7.60 (1 H, dddd, JC–H = 156 Hz,
JH–H 16 Hz, JH–C–C and JH–C–C–C 6.6 and 3 Hz, CH CHCO2Et); ıC
14.3 (CO2CH2CH3), 60.4 (CO2CH2CH3), 106.5 (C5), 108.5 (C2),
116.2 (enhanced t, JC–C = 75 Hz, Ar–CH CH–CO2Et), 124.4 (C6),
144.3 (enhanced d, JC–C = 75 Hz, Ar–CH CH–CO2Et) and 167.2
(enhanced d, JC–C = 75 Hz, CO2Et); m/z (CI+) 224 (85, M + H), 223
(100, M) and 178 (75).
2.10. O-Benzyl [carbonyl-13C]vanillin (6b)
The reduction of 5b (0.30 g, 1.25 mmol) with DIBAL-H (1.87 cm3,
1 M in hexanes) in diethyl ether (25 cm3) according to the rep-
resentative procedure gave 6b (0.225 g, 74%) as a white solid,
mp 62–63 ◦C (literature [27], 63–64 ◦C) (found: C, 74.1; H, 5.75;
C1413CH14O3 requires C, 74.0; H, 5.8); ꢀmax (cm−1) 2361, 1644
2.13. Ethyl O-benzyl [˛,ˇ,ꢀ-13C3]feruloate (8b)
The Wittig reaction of 6b (0.15 g, 0.62 mmol) and 7 (0.217 g,
0.62 mmol) in dry toluene (6.2 cm3) gave 8b (0.192 g, 98%) as
a white solid, mp 69 ◦C (literature [32], 64 ◦C) (found: C, 72.3; H,
6.5; C1613C3H20O4: requires C, 72.4; H, 6.4%); ꢀmax (cm−1) 2349,
1665, 1593, 1569, 1507, 1465, 1256, 1151 and 1139; ıH 1.34 (3
H, t, J = 7.2 Hz, OCH2CH3), 3.93 (3 H, s, Ar–OCH3), 4.27 (2 H, dq,
JH,C = 3 Hz, JH,H = 7.2 Hz, 13CO2CH2CH3), 5.20 (2 H, s, Ar–OCH2Ph),
6.63 (1 H, ddd, JH–C = 161 Hz, JH–C–CO = 2.1 Hz, JH–C=C–H = 16.2 Hz,
Ar–13CH 13CH–13COOEt), 6.88 (1 H, d, J = 8.1 Hz, 5-H), 6.98–7.10
(2 H, m, 6-H and 2-H), 7.29–7.46 (5 H, m, Ar–OCH2C6H5)
and 7.62 (1 H, dddd, JH–C = 154.5 Hz, JH–C=C–H/JH–C=C–CO = 6.9
and 3 Hz, JH–C=C–H = 16.2 Hz, Ar–13CH 13CH–13COOEt); ıC 56.0
(CH3), 70.8 (CH2), 116.0 (enhanced td, JC–C = 73 Hz, JC–H = 3.8 Hz,
Ar–CH CH–CO2Et), 127.2 (2× CH), 128.0 (CH), 128.6 (2× CH),
144.5 (enhanced dd, JC–C = 73 Hz, JC–H 3.8 Hz, Ar–CH CH–CO2Et)
and 167.2 (enhanced d, JC,C = 73 Hz, 13CO2Et); m/z (CI+) 316 (70,
M + H) 270 (100, M + H, −CH3CH2OH), 192 (25) and 91 (48, C7H7).
(
13C O), 1638, 1596, 1582, 1506, 1267, 1131; ıH 3.95 (3 H, s,
Ar–OCH3), 5.26 (2 H, s, Ar–OCH2Ph), 6.99 (1 H, d, J = 8.1 Hz, 5-
H), 7.33–7.47 (7 H, m, 2-H, 6-H and Ar–OCH2C6H5) and 9.84 (1
H, d, JH,C = 172.8 Hz, 13CHO); ıC 56.0 (CH3), 70.8 (CH2), 109.2 (d,
J = 3.2 Hz), 112.3 (d, J = 6 Hz), 126.1 (CH, d, J = 6 Hz), 127.1 (2× CH),
128.2 (CH), 128.7 (2× CH) and 191.0 (enhanced CHO); m/z (CI+)
244 (100, M + H) and 91 (83, C7H7).
2.11. Ethyl (triphenylphosphoranylidene)[13C2]acetate
(7) [28]
Ethyl [13C2]bromoacetate (1.18 g, 7.0 mmol) was added drop-
wise over 20 min to a solution of triphenylphosphine (1.84 g,
7.0 mmol) in dry toluene (14 cm3) under Ar at room tem-
perature. The temperature was then raised to 90 ◦C and
the stirring was continued for 19 h. The mixture was fil-
tered and the toluene was evaporated off. The solid, ethyl
2-triphenylphosphinyl-[13C2]acetate bromide, was dried in
vacuo and dissolved in water. The pH was raised to 12
by the addition of 2 M NaOH stirring continuously. The
insoluble product was extracted using CH2Cl2 (70 cm3). The
organic phase was washed with brine (20 cm3) and dried
over MgSO4. The solvents were removed at reduced pres-
sure and the pure product 7 (2.114 g, 86%) was obtained as
2.14. The representative DIBAL-H reduction of ethyl
cinnamates: 3,4-methylenedioxy[˛,ˇ,ꢀ-13C3]cinnamyl
alcohol (9a) [33]
DIBAL-H (11.8 cm3, 1 M in hexanes, 11.8 mmol) was added
dropwise to a solution of 8a (1.16 g, 4.9 mmol) in dry CH2Cl2
(25 cm3) under N2 at −78 ◦C. The mixture was stirred at this
temperature for 1 h. The reaction was quenched by pouring the
solution on a mixture of saturated aqueous NH4Cl and ice. The
phases were separated and the aqueous phase was extracted
with CH2Cl2 (150 cm3). The combined organic extracts were
washed with brine (100 cm3) and dried (MgSO4). The evapora-
tion of solvents gave 9a (0.94 g, 99%), pure without chromato-
graphic purification, as a white solid, mp 79 ◦C (literature [34],
75–76 ◦C) (found: C, 66.6; H, 5.4; M + H+, 182.0809. C713C3H10O3:
C, 66.3; H, 5.6%; M + H, 182.0809); ꢀmax (cm−1) 3300 (br, O–H),
1503, 1441, 1239, 1093, 1062, 1036, 990, 965 and 924; ıH 1.38
(1 H, ddd, J = 9, 6 and 3 Hz, O–H), 4.30 (2 H, dddd, JC–H = 142,
JH–H 11.4, 10.5 and 5.7 Hz, CH2OH), 5.97 (2 H, s, OCH2O), 6.22 (1
H, md, JH–C = 147 Hz, Ar–13CH 13CH–13CH2OH), 6.55 (1 H, ddd,
JH–C = 159 Hz, JH–H = 17.4 and 7.8 Hz, Ar–13CH 13CH–13CH2OH),
6.75–6.85 (2 H, m, Ar–H) and 6.94 (1 H, d, J = 4 Hz, Ar–H); ıC
63.8 (enhanced d, JC–C = 45 Hz, CH2OH), 105.7, 108.3, 121.2, 126.6
(enhanced dd, JC–C = 75 and 45 Hz, Ar–CH CH–CH2OH) and
131.1 (enhanced d, JC–C = 75 Hz, Ar–CH CH–CH2OH); m/z (CI+)
182 (40, M + H), 181 (75, M), 164 (100) and 136 (32).
a white solid, mp 123–124 ◦C (literature [29], 128 ◦C) (found
12
M + H+, 351.1426.
C
13C2H22O2P requires M + H, 351.1425);
20
ıH 1.1 (3 H, br, CO2CH2CH3), 2.9 (1 H, br, d, JH,P ≈ 120 Hz,
Ph3P CHCO2CH2CH3), 4.0 (2 H, br, CO2CH2CH3) and 7.43–7.70
(15 H, m, P(C6H5)3); ıC 128.6, 128.8, 131.9, 132.9, 133.1 (the 15
aromatic C–H) and 171.3 (d, JC,C = 106 Hz, CO2Et); m/z (ES+) 413
(40), 351 (100, M), 333 (30) and 279 (20).
2.12. Representative Wittig reaction procedure for the
synthesis of [˛,ˇ, ꢀ-13 C3]cinnamic acids: ethyl
3,4-methylenedioxy- [˛,ˇ, ꢀ-13 C3]cinnamate (8a) [30]
A solution of 6a (0,70 g, 4.6 mmol) and the ylide 7 (1.62 g,
4.6 mmol) in toluene (46 cm3) was heated under reflux for 3 h
under an Ar atmosphere and then left to stir overnight at room
temperature. The solvent was evaporated and the product was
purified by flash chromatography (silica, 2:1 CH2Cl2:hexane)
to afford 8a (1.175 g, 80%) as a white solid, mp 62–67 ◦C (lit-

steroids 7 1 ( 2 0 0 6 ) 231–239
235
6.46 (1 H, dm, JH–C = 154 Hz, Ar–13CH 13CH) and 6.67–6.98 (6
H, m, Ar–H); ıC 54.38 (OCH2O), 54.43 (OCH2O), 69.5 (enhanced
d, JC–C = 48 Hz, Ar–13CH 13CH–CH2OR), 79.4, 105.7, 107.6,
108.2, 121.1 (arom. C6 and C6ꢀ), 123.9 (enhanced dd, JC–C = 48
and 73 Hz, Ar–13CH 13CH–CH2OR) and 132.4 (enhanced d,
JC–C = 73 Hz, Ar–13CH 13CH–CH2OR); m/z (CI+) 358 (95, M + H),
357 (100, M) and 164 (55).
2.15. O-Benzyl [˛,ˇ,ꢀ-13C3]coniferyl alcohol (9b)
8b (0.18 g, 0.57 mmol) was reacted with DIBAL-H (1.40 cm3,
1.0 M in hexanes, 1.40 mmol) in CH2Cl2 (3 cm3) according to
the representative procedure. The crude product contained
aluminium salts, which were removed by passing the prod-
uct through a short silica gel column (1:5 diethyl ether:CH2Cl2).
This afforded 9b (0.148 g, 96%) as a white solid, mp 87 ◦C (litera-
ture [35], 86–88 ◦C) (found: C, 74.4; H, 6.4; C1413C3H18O3 requires
C, 74.7; H, 6.6%); ıH 1.48 (1 H, br, O–H), 3.91 (3 H, s, Ar–OCH3), 4.30
(2 H, dqu, JH–C = 142.5 Hz, JH–C–C–H ≈ JH–C–C ≈ JH–C–C=C = 5.4 Hz,
13CH 13CH–13CH2OH), 5.17 (2 H, s, Ar–OCH2Ph), 6.24 (1 H, d
m, JH–C = 147 Hz, Ar–CH CH), 6.54 (1 H, ddd, JH–C = 151.2 Hz,
JH–C=C–H = 16.5 Hz, JH–C=C–C = 7.5 Hz, Ar–CH CH), 6.82–6.90 (2 H,
2.17. O-Benzyl[˛,ˇ,ꢀ-13C3]coniferyl bromide 10b:
1-(3,5-dimethoxy-4-benzyloxy-phenyl)-1-(3-(3-methoxy-
4-benzyloxyphenyl)-[13C3]prop-2-enyloxy)-2,3-
epoxypropane (12b)
9b (0.76 g, 2.78 mmol) was reacted with pyridine (0.045 cm3,
0.56 mmol) and PBr3 (0.26 cm3, 2.78 mmol) in diethyl ether
(30 cm3) as described above. The crude product 10b was
used directly in the synthesis of the ether intermediate.
11b (0.98 g, 3.1 mmol) in THF (25 cm3) was reacted with NaH
(0.37 g, 9.3 mmol in 22 cm3 10:1 THF/DMSO) and 10b in THF
(25 cm3), according to the representative procedure. The
m, 5-H, 6-H), 6.98 (1 H, dd, JH–C–C–C–H = 1.8 Hz, JH−C−C−
=
13
C
4.2 Hz, 2-H) and 7.3–7.46 (5 H, m, Ar–OCH2C6H5); ıC 56.0, 71.0,
63.8 (enhanced d, JC,C = 46 Hz, 13CH2OH) 126.6 (enhanced dd,
JC,C = 46 and 75.5 Hz, 13C 13C–13C) and 131.1 (enhanced dt,
JC,C = 75.5 Hz, Ar–13CH), m/z (ES+) 296 (100, M + Na) and 569 (10,
2× M + Na).
pure product 12b (0.983 g, 58% from the coniferyl alcohol)
+
was a viscous yellow oil (found: C, 73.1; H, 6.6; M + NH4
,
2.16. 3,4-Methylenedioxy [˛,ˇ,ꢀ-13C3]cinnamyl bromide
(10a): 1(3,4-methylenedioxyphenyl)-1-(3-(3,4-
methylenedioxyphenyl)-[13C3]prop-2-enyloxy)-2,3-
epoxypropane (12a)— representative procedure for the
bromination-etherification reaction sequence [36,37]
589.2928. C3213C3H36O7 requires C, 73.5; H, 6.35%; M + NH4,
589.2907); ıH; 2.63–2.66 and 2.73–2.86 (2 H, m, CH(O)CH2 from
cis/trans epoxides), 3.16–3.21 and 3.23–3.27 (1 H, m, CH(O)CH2
from cis/trans epoxides), 3.85 (6 H, s, 2 Ar–OCH3), 3.92 (3 H,
s, Ar–OCH3), 4.33 (1 H, t, JH−C−C−H = JH−C−O−
= 3.9 Hz;
13
C
Ar–CH(O13CH213CH 13CHAr)CH(O)CH2
dominant syn epoxide), 4.16 (2 H,
from
the
pre-
The bromination reaction and all the stages involving cin-
namyl bromides were carried at 0–10 ◦C and protected from
light. 9a (0.80 g, 5.0 mmol) was dissolved in diethyl ether
(55 cm3) under Ar at 0 ◦C. Pyridine (0.08 cm3, 1.0 mmol) and
PBr3 (0.47 cm3, 5.0 mmol) were added dropwise and the mix-
ture was stirred for 1 h at 0 ◦C. The reaction was quenched
by the addition of ice and water (ca. 40 cm3). The mixture
was extracted with diethyl ether (300 cm3) and the organic
extracts were washed with brine (80 cm3). The organic solu-
tion was dried (MgSO4) and concentrated. The crude bromide
10a, a white solid, was used directly in the etherification
reaction. NaH (0.636 g, 60%, 15.9 mmol) was washed with
dry hexane and dissolved in 10:1 THF/DMSO (33 cm3) under
argon. 11a (1.03 g, 5.3 mmol) was dissolved in THF (40 cm3)
and added dropwise at 0 ◦C. The reaction mixture was stirred
at 0 ◦C for 40 min, after which time 10a in THF (40 cm3)
was added. The temperature was allowed to rise to room
temperature and stirring was allowed to continue for 48 h.
The reaction was quenched with ice and the mixture was
extracted with EtOAc (250 cm3). The organic solution was
washed with brine (100 cm3) and dried (MgSO4). The solvents
were removed under reduced pressure and the pure product
12a (1.146 g, 73% from the cinnamyl alcohol) was obtained by
flash chromatography (silica, 1:10:10 EtOAc:CH2Cl2:hexane)
as a pale yellow oil, whose spectral data were compared to
the reported unlabeled compound [37] (found: C, 65.5; H, 5.1;
M + H+, 358.1282. C1713C3H18O6·0.5H2O requires C, 65.6; H,
5.2%; C1713C3H19O6 requires M + H, 358.1282); ıH 2.58–2.62 and
2.75–2.84 (2 H, m, CH(O)CH2 from trans/cis epoxides), 3.13–3.17
and 3.18–3.24 (1 H, m, CH(O)CH2 from cis/trans epoxides), 4.08
(2 H, dm, JH–C 142 Hz, 13CH2OR), 5.96 (2 H, s, OCH2O), 5.98
(2 H, s, OCH2O), 6.08 (1 H, dm, JH–C = 153 Hz, Ar–13CH 13CH),
m
d, JH–C = 150 Hz,
13CH2–OR) 5.03 and 5.17 (4 H,
(1 H,
d, JH–C = 158.1 Hz, Ar–13CH 13CHOR), 6.60 (2 H, d,
JH−C− = 4.8 Hz, 2-H and 6-H), 6.80–6.85 (2 H, m, Ar–H),
2
s,
2
Ar–OCH2Ph), 6.18
m
d, JH–C = 154.5 Hz, Ar–13CH 13CHOR), 6.47 (1 H,
m
13
C
6.97 (1 H, d, J = 3.9 Hz, Ar–H) and 7.30–7.45 (10 H, m, 2
Ar–OCH2C6H5); ıC 55.9 (Ar–OMe), 56.2 (Ar–OMe), 70.1
(enhanced m, Ar–13CH 13CH–CH2OR), 75.0 (Ar–OCH2Ph),
104.2, 123.9 (enhanced m, Ar–13CH 13CH–CH2OR) 127.2 (3×
CH), 127.8 (CH), 128.1 (2× CH), 128.4 (CH), 128.6 (3× CH) and
132.7 (enhanced m, Ar–13CH 13CH–CH2OR); m/z (APCI+) 589
(100, M + NH4+), 561 (40) and 255 (30).
2.18. [7,8,9-13C3]Sesamin (3a) [37]
Cp2TiCl2 (1.77 g, 7.1 mmol) and activated, flame-dried Zn dust
(2.83 g, 43.2 mmol), were stirred in THF (120 cm3) for 1 h at room
temperature. The resulting green Cp2TiCl solution was added
via a cannula to 12a (1.10 g, 3.1 mmol) in THF (100 cm3) at 60 ◦C
over 20 min. The reaction was allowed to continue for an addi-
tional 20 min, after which time I2 (1.02 g, 4.0 mmol) in THF
(25 cm3) was added. Stirring was continued at 60 ◦C for another
1 h and the mixture was cooled to room temperature. A satu-
rated aqueous solution of NaHCO3 and Na2S2O3 (100 cm3) was
added and the mixture was extracted with EtOAc (400 cm3).
The organic phase was washed with brine and dried (MgSO4).
The solvents were evaporated and the product was purified by
flash chromatography (silica, 1:1:1 EtOAc:petroleum:CH2Cl2)
and preparative TLC (silica, 1:2:2 EtOAc:petroleum:CH2Cl2) to
give 3a (290 mg, 26%) as a white solid, mp 124–125 ◦C (literature
[38], 122 ◦C) (found C, 67.2; H, 4.9; M+, 357.1195. C1713C3H18O6
requires C, 67.2; H, 5.1%; M, 357.1204); ıH 3.06 (1 H, m, 8ꢀ-H), 3.06

236
steroids 7 1 ( 2 0 0 6 ) 231–239
(1 H, m d, JH–C = 130.2 Hz, 8-H), 3.88 (1 H, m, axial 9ꢀ-H), 3.88 (1
H, m d, JH–C = 146 Hz, axial 9-H), 4.24 (1 H, m, equatorial 9ꢀ-H),
4.24 (1 H, m d, JH–C = 149 Hz, equatorial 9-H), 4.73 (1 H, m, 7ꢀ-
H), 4.73 (1 H, m d, JH–C = 141 Hz, 7-H), 5.96 (4 H, s, both OCH2O)
and 6.77–6.86 (6 H, m, Ar–H); ıC 54.3 (enhanced t, J = 33 Hz, C8),
71.7 (enhanced d, J = 33 Hz, C9), 85.8 (enhanced d, J = 33 Hz, C7),
106.5 (C6 and C6ꢀ), 108.19 and 119.3; m/z (EI+) 358 (50, M + H),
357 (100, M), 150 (95) and 149 (80).
2.19. [7,8,9-13C3]Medioresinol dibenzyl ether (13)
The standard cyclization reaction was performed on 12b
(980 mg, 1.58 mmol) according to the representative pro-
cedure, using Cp2TiCl2 (901 mg, 3.62 mmol), Zn (1.44 g,
22.0 mmol) and I2 (520 mg, 0.21 mmol) in THF (122 cm3) to
give 13 (450 mg, 50%) as an oil (found: C, 73.4; H, 6.2; M + H+,
572.2661. C3213C3H37O7 requires C, 73.5; H, 6.4%; M + H,
572.2685); ıH 3.10 (1 H, m, 8ꢀ-H), 3.10 (1 H, m d, JH–C 140 Hz,
8-H), 3.85 (6 H, s, 2 Ar–OCH3), 3.92 (1 H, m, axial 9ꢀ-H), 3.92 (1
H, m d, JH–C 144 Hz, axial 9-H), 3.92 (6 H, s, Ar–OCH3), 4.28 (1
H, m, equatorial 9ꢀ-H), 4.28 (1 H, m d, JH–C = 147 Hz, equatorial
9-H), 4.74 (1 H, m, 7ꢀ-H), 4.74 (1 H, m d, JH–C = 145.5 Hz, 7-H),
5.00 (2 H, s, Ar–OCH2Ph), 5.16 (2 H, s, Ar–OCH2Ph), 6.57 (2 H, s,
2-H and 6-H), 6.81 (ddd, 1 H, JH−C−
= 4 Hz, JH–C–C–C–H = 2 Hz,
13
C
JH–C–C–H = 8.5 Hz, 6ꢀ-H), 6.87 (1 H, d, JH–C–C–H = 8.5 Hz, 5ꢀ-H), 6.94
(1 H, dd, JH−C−
= 4 Hz, JH–C–C–C–H = 2 Hz, 2ꢀ-H) and 7.29–7.51
13
C
(10 H, m, 2 Ar–OCH3C6H5); ıC 54.0 (enhanced t, J = 37 Hz),
56.2, 71.0, 72.0 (enhanced d, J = 37 Hz), 75.0, 85.7 (enhanced d,
J = 38 Hz), 102.9 (CH), 127.2 (4× CH), 128.1 (2× CH), 128.4 (2×
CH) and 128.5 (2× CH); m/z (CI+) 571 (12%, M), 480 (10), 327
(25), 298 (30), 245 (65), 93 (100) and 91 (85).
2.20. [7,8,9-13C3]Medioresinol (3b) [39]
13 (308 mg, 0.54 mmol) was reacted with Raney nickel (6 g)
in ethanol/THF (1:1, 18 cm3) at 75 ◦C for 5 h. The mixture
was filtered hot through celite using acetone. Evaporation of
the solvents gave the crude product, which was subjected
to preparative TLC (silica, 20% acetone in CH2Cl2) to give
3b (150 mg, 71%) as white crystals, mp 157–160 ◦C (literature
[40], 155–160 ◦C) (found: C, 64.7; H, 6.45; M − H−, 390.1531.
C3213C3H36O7 requires C, 64.4; H, 6.2%; M − H, 390.1547); ıH
3.10 (1 H, m, 8ꢀ-H), 3.10 (1 H, m d, JH–C = 138 Hz, 8-H), 3.89
(1 H, m, axial 9ꢀ-H), 3.89 (1 H, m d, JH–C = 147 Hz, axial 9-H),
3.91 (6 H, s, 2 Ar–OCH3), 3.92 (3 H, s, Ar–OCH3), 4.26 (1 H,
dddd, equatorial 9ꢀ-H), 4.26 (1 H, m d, JH–C = 135 Hz, equa-
torial 9-H), 4.72 (1 H, m, 7ꢀ-H), 4.72 (1 H, td, JH–H = 5.7 Hz,
JH–C = 145 Hz, 7-H), 5.50 (1 H, s, Ar–OH), 5.60 (1 H, s, Ar–OH),
6.59 (2 H, s, 2-H and 6-H), 6.83 (1 H, ddd, JH–C–C–H = 8.1 Hz,
Scheme 1 – The synthetic route to labeled cinnamyl
alcohols and lignans.
used this method in the synthesis of pinoresinol, medioresinol
and syringaresinol, which were used as synthetic lignan stan-
dards [41]. The crucial radical cyclization step in the synthe-
sis of these lignans, in our hands, gave low but reproducible
yields (24–51%) of the lignans. Therefore, although we could
not reproduce the reported literature yield, which was 93% in
the case of sesamin [37], the method could still be used in
the synthesis of the labeled analogues. The general synthetic
route for the 13C-labeled lignans is shown in Scheme 1.
Another benefit of this synthetic strategy was that all the
other reaction steps in the route gave generally good yields
and were simple to perform. Additionally, it gave us the oppor-
tunity to prepare and use the triply 13C-labeled cinnamyl
alcohols as building blocks for the lignans. To our knowl-
edge, these multiply 13C-labeled cinnamyl alcohols have not
been previously synthesized although they are the precur-
sors of lignans in plants and could be used to study lignan
biosynthesis. The synthesis of the cinnamyl alcohols is short
and mostly consists of well-known reactions, employing a
key aromatic cyanation using the readily available and rela-
tively inexpensive K13CN. This reaction, which was originally
JH–C–C–C–H = 3.9 Hz, JH−C−
= 2.1 Hz, 6ꢀ-H), 6.91 (1 H, d, J = 8.1 Hz,
13
C
5ꢀ-H) and 6.91 (1 H, dd, JH–C–C–C–H = 3.9 Hz, JH−C−
= 2.1 Hz,
13
C
2ꢀ-H); ıC 54.0 (enhanced t, J = 37 Hz, C8), 55.9 (Ar–OCH3),
56.3 (2 Ar–OCH3), 71.8 (enhanced d, J = 38 Hz, C9) and 85.8
(enhanced d, J = 38 Hz, C7), 102.6; m/z (ES−) 390 (100, M − H) and
406 (67).
3.
Results and discussion
The syntheses were conducted using a key radical cyclization
method as published by Roy et al. [37]. We have previously

steroids 7 1 ( 2 0 0 6 ) 231–239
237
developed by Takagi et al. [42] has been modified and used
extensively in our laboratory in a number of syntheses of 13C-
labeled compounds [12,43]. The other starting materials for
the syntheses were also readily available. For the cyanation
reaction, the aromatic bromide 4a is a commercial compound
and the aromatic iodide 4b was prepared by iodination of 2-
methoxyphenol [44] and subsequent benzylation. To prepare
the epoxy alcohols 11a and 11b, commercial piperonal and
benzyl protected syringaldehyde [45] 14 were reacted with
vinylmagnesium bromide [18] and the resulting allyl alcohols
were epoxidised with t-BuOOH and VO(acac)2 as catalyst [20].
The epoxidation reaction was selective for the cis-isomer, usu-
ally in a 80:20 ratio. However, it was not necessary to separate
the two isomers as both give the same relative stereochemistry
in the furofuran product following the cyclization reaction (see
below).
When the cyanation reaction [22] was performed in the
presence of triphenylphosphine and calcium hydroxide as
base, both the aromatic bromide 4a and iodide 4b reacted
to give benzonitriles 5ab. The reaction was also performed
in our laboratory on 3,4-dimethoxybromobenzene and 4-
benzyloxy-3,5-dimethoxybromobenzene to give the corre-
sponding nitriles in 75 and 78% yields. DIBAL-reduction [25]
then gave the benzaldehydes 6ab without side reactions.
Besides olefin metathesis, the Wittig reaction is undoubtedly
the best double-bond forming reaction available and worked
again very well in the synthesis of the cinnamic acid esters
8ab from the benzaldehydes. The ylide 7 required for the
Wittig reaction was prepared from the commercially avail-
able ethyl bromo[13C2]acetate [28]. Another DIBAL-H reduc-
tion [33] at −78 ◦C gave the cinnamyl alcohols 9ab, which
were usually ready for the next step. Excess aluminium salts
interfere sometimes but can either be removed by column
chromatography or by washing the organic solution with
1 M NaOH.
Fig. 2 – 1H–13C and 13C–13C coupling constants (in Hz) for
the 13C-labeled cinnamic acid esters, cinnamyl alcohols
and furofurans.
All the 13C-labeled compounds were fully characterized by
NMR and IR spectroscopy and mass spectrometry. The 13C
NMR spectra clearly showed the enhanced signals due to the
13C-labeled carbon atoms. Fig. 2 shows the typical coupling
constants in the labeled compounds. Inserting all three 13C
atoms adjacent to each other made it possible to obtain data
of both 1H-13C and 13C-13C couplings. Characteristic changes
in the IR spectra of the labeled compounds were also observed.
For example, the nitrile vibration is shifted due to the effect of
the increase in mass, such that ꢀ13C≡N is observed at 2166 cm−1
in 5b compared with 2222 cm−1 in the corresponding unla-
beled molecule. This comparison between 12CN and 13CN
characteristic IR spectra was first reported by Kagarise et al.
[46]. Similar shifts were also seen for the carbonyl stretches of
the 13C-labeled intermediates.
From now on, the synthetic route followed the original
radical cyclization method described by Roy et al. [37]. The
cinnamyl alcohols 9ab were brominated with PBr3 [36] and
reacted with a suitable epoxy alcohol 11ab to give the ethers
needed for the radical cyclization. As the cinnamyl bromides
10ab, required in the synthesis of the ether intermediates are
very unstable, they were used without purification and the
yields are given over both the bromination and the ether-
ification step. The radical tandem cyclization works on a
500–1000 mg scale, as long as the reaction solvent is degassed
and the starting materials are well-dried. The radical cycliza-
tion gives only the exo,exo-furofurans, which are the naturally
occurring isomers. Initial homolytic cleavage of the epoxide
gives a carbon radical which attacks the alkene in a kinet-
ically favoured 5-exo-cyclization to form the first ring. The
radical intermediate is trapped out by iodine and the sec-
In conclusion it can be seen that a simple and efficient route
has been developed for the synthesis of multiply 13C-labeled
furofuran lignans, which are now being assessed as internal
standards for LC–MS analysis. The key precursors for this syn-
thesis are the [␣,␤,␥-13C3]cinnamic acids. These are also being
employed in studies of the biosynthesis of lignans in plants.
Acknowledgments
We would like to thank the Professor H. Adlercreutz at the
University of Helsinki and the Finnish Cultural Foundation
for funding and Mrs. C. Horsburgh and Mrs. S. Williamson for
mass spectrometric and elemental analyses, respectively.
2
ond ring is then constructed via an SN reaction as the newly
formed alkoxide attacks the alkyl iodide. The reaction goes
via the lowest energy conformation with all the large sub-
stituents in pseudoequatorial positions leading to a single rel-
ative stereochemistry in the product [37]. This chemistry was
thus used to prepare racemic [7,8,9-13C3]sesamin 3a and [7,8,9-
13C3]medioresinol dibenzyl ether 13, which was deprotected
using Raney nickel [39] give the lignan [7,8,9-13C3]medioresinol
3b.
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