Synthesis and disproof of the structure proposed for the tetrahydrofuranol isolated from Michelia compressa var. lanyuensis (Magnoliaceae)

Article abstract of DOI:10.1080/14786419.2015.1129331

The previously proposed structure for a tetrahydrofuranol isolated from the leaves of Michelia compressa var. lanyuensis (Magnoliaceae) was synthesised in an enantiopure form using diethyl D-tartarate as the starting material. The synthetic sample showed spectroscopic data incompatible with those for the natural product and thus unequivocally disproved the previously assigned structure.

Full text of DOI:10.1080/14786419.2015.1129331

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis and disproof of the structure proposed
for the tetrahydrofuranol isolated from Michelia
compressa var. lanyuensis (Magnoliaceae)
Yong-Qing Yang
To cite this article: Yong-Qing Yang (2016): Synthesis and disproof of the structure proposed
for the tetrahydrofuranol isolated from Michelia compressa var. lanyuensis (Magnoliaceae),
Natural Product Research, DOI: 10.1080/14786419.2015.1129331
To link to this article: http://dx.doi.org/10.1080/14786419.2015.1129331
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Date: 01 April 2016, At: 21:02

Natural Product research, 2016
http://dx.doi.org/10.1080/14786419.2015.1129331
Synthesis and disproof of the structure proposed for the
tetrahydrofuranol isolated from Michelia compressa var.
lanyuensis (Magnoliaceae)
Yong-Qing Yanga,b
b
aschool of Pharmacy, Jiangsu university, Zhenjiang, china; state Key laboratory of Bioorganic and Natural
Products chemistry, shanghai Institute of organic chemistry, chinese academy of sciences, shanghai, china
ARTICLE HISTORY
ABSTRACT
received 16 July 2015
accepted 2 November 2015
The previously proposed structure for a tetrahydrofuranol isolated
from the leaves of Michelia compressa var. lanyuensis (Magnoliaceae)
was synthesised in an enantiopure form using diethyl D-tartarate as
the starting material. The synthetic sample showed spectroscopic
data incompatible with those for the natural product and thus
unequivocally disproved the previously assigned structure.
KEYWORDS
Michelia compressa var.
lanyuensis; pressalanin a;
Magnoliaceae; chiral pool;
configuration
1. Introduction
In their study of a new taxon of Michelia, Michelia compressa var. lanyuensis S. Y. Lu (Magnolia
compressa Maxim.), Chen and co-workers isolated and characterised several new compounds
(Chen 2010; Cheng et al. 2010; Lo et al. 2010; Wang et al. 2010), one of which was assigned
a tetrahydrofuranol structure (1) through extensive spectroscopic analyses (Chen 2010).
Given the very simple molecular architecture of 1 and the seemingly very convincing line of
reasoning, the conclusion about the deduced structure appeared impeccable. However, the
absolute configuration of 1 remained unelucidated. To gain this final missing piece of struc-
tural information, the absolute configuration, a chiral pool-based synthesis was carried out.
2. Results and discussion
The synthesis of 1 was performed according to the route shown in Scheme 1. Following
the literature (Somfai & Olsson 1993) the commercially available diethyl D-tartrate was
CONTACT Yong-Qing Yang
yqy@ujs.edu.cn; yangyq1@sioc.ac.cn
supplemental data for this article can be accessed at http://dx.doi.org/10.1080/14786419.2015.1129331.
© 2016 taylor & Francis

2
Y.-Q. YanG
O
O
O
OH
OH
LiBH4
THF
Anisaldehyde
OH
O
O
dimethyl acetal
EtO
EtO
EtO
EtO
O
O
OMe
OMe
p-TsOH/DMF
96%
OH
100%
O
2
3
4
BH3/THF
O
OH
O
O
OMe
Dess-Martin
OH
OH
Ph3P/DIAD
periodinane
O
O
O
CH2Cl2
87%
92% from 4
OH
7
OMe
5
6
OMe
TMSCHN2
(PPh3)3RhCl
2,4-dioxane
44%
PPh3/i-PrOH
OH
"Nat. 1" [α]D25 +1.48 (c 0.55, CHCl3)
[α]D26 −6.3 (c 0.25, CHCl3) cf. text
DDQ/CH2Cl2
80%
O
MeO
O
O
(S)-1
8
Scheme 1. synthesis of (S)-1.
transformed into triol 5 via the three-step sequence: (1) protection with anisaldehyde
dimethylacetal in the presence of p-TsOH to afford 3, (2) reduction of the ester groups with
LiBH4 and (3) reductive cleavage of the acetal group in diol 4 with BH3 to afford 5.
The known triol (5) was then treated with Ph3P/DIaD (diisopropyl azodicarboxylate) to
provide tetrahydrofuranol 6 in 92% yield over two steps (from 4). The free hydroxyl group in
6 was oxidised with Dess–Martin periodinane. Subsequent conversion of the cyclopentanone
was achieved smoothly using the (Ph3P)3RuCl/Ph3P/TMSCHn2/i-PrOH/2,4-dioxane conditions,
an effective protocol developed by Lebel and co-workers (Lebel et al. 2004) for conversion
of ketones of low reactivity into alkenes. Finally, the PMB protecting group was cleaved with
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to provide the desired (S)-1 in 80% yield.
In the previous study (Chen 2010), it was already concluded that natural 1 and a (racemic)
synthetic 1 were identical by comparison of spectral data.Therefore, the only missing information
for establishment of the absolute configuration for natural 1 appeared to be the optical rotation
data for either (R)- or (S)-1. Thus, once the (S)-1 was in hand, the optical rotation was measured.
The result was somewhat unexpected; the specific rotation turned out to be −6.3 (c 0.25,
CHCl3), seemingly substantially different from the corresponding data for natural 1 (+1.48 (c
0.55, CHCl3)). Besides, contrary to what was claimed by the previous investigator, significant
discrepancies existed between both the 1H and 13C nMR data for natural 1 and the synthetic
samples (cf. Tables S1 & S2). Thus, it can be safely concluded that the planar structure previ-
ously assigned for the natural product must be incorrect.
3. Experimental
3.1. General
The nMR spectra were recorded on either an agilent 500/54 nMR spectrometer (operating
at 500 MHz for 1H) or a Bruker advance 400 (operating at 400 MHz for 1H) nMR spectrometer.

naTuRaL PRODuCT ReSeaRCH
3
IR spectra were measured on a nicolet 380 Infrared spectrophotometer. eSI-MS data were
recorded on a Shimadzu LCMS-2010eV mass spectrometer. eI-MS data were acquired on
an agilent Technologies 5973 n mass spectrometer. eSI-HRMS data were obtained with a
Fisher Scientific LTQFT ultra mass spectrometer. eI-HRMS data were collected on a Waters
Micromass GCY Premier instrument. Optical rotations were measured on a Jasco P-1030
polarimeter. CH2Cl2 was dried with activated 4 Å MS (molecular sieves). DryTHF and 2,4-diox
-
ane were obtained by distillation over Ph2CO/na under argon prior to use. Dry i-PrOH was
commercially available and used as received. all chemicals were reagent grade and used
as purchased. Column chromatography was performed on silica gel (300–400 mesh) under
slightly positive pressure. Pe = petroleum ether (b.p. 60–90 °C).
3.2. Synthesis
3.2.1. Synthesis of 4
a solution of ester 3 (324 mg, 1.0 mmol) in dry THF (2 mL) was added slowly to a suspension
of powdered LiBH4 (174 mg, 8.0 mmol) in dry THF (3 mL) stirred in an ice-water bath. after
completion of the addition, stirring was continued in the ice-water bath for 10 min and at
ambient temperature for 2 h. When TLC showed completion of the reduction, etOH (4.7 mL,
80 mmol) was added slowly. The solids were filtered off with suction through a sintered
glass funnel. The filtrate was concentrated on a rotary evaporator to give a sticky oil, which
was purified by column chromatography (10:1 CH2Cl2/MeOH) on silica gel to afford the
known diol 4 as a colourless oil (247 mg, 1.0 mmol, 100%):[ꢀ]2D5 −10.4 (c 1.90, CHCl3). 1H nMR
(500 MHz, CD3OD): δ 7.42 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 4.10–4.06 (m,
1H), 4.04–4.01 (m, 1H), 3.79 (s, 3H), 3.76–3.72 (m, 4H); 13C nMR (125 MHz, CD3OD): δ 161.9,
131.1, 129.4, 114.5, 105.0, 80.6, 80.2, 63.5, 63.2, 55.7; FT-IR (film): vmax 3259 (br), 2926, 2853,
1517, 1248, 1062, 808 cm−1; eSI-MS m/z 241.3 ([M + H]+).
3.2.2. Synthesis of 6
BH3 (1.0 M, in THF, 1.8 mL, 1.8 mmol) was added slowly to a solution of diol 4 (120 mg,
0.5 mmol) in dry THF (0.2 mL) stirred in a −20 °C bath (ice-naCl) under n2 (balloon). after
completion of the addition, the mixture was heated to reflux under argon (balloon) for
2 h (when TLC showed completion of the reduction). The heating bath was removed. To
the mixture already cooled to ambient temperature, MeOH (1 mL) was added very slowly.
The mixture was concentrated on a rotary evaporator. The residue was purified by column
chromatography (20:1 etOac/MeOH) on silica gel to afford triol 5 as a colourless oil, from
1
which the following data were collected: H nMR (500 MHz, CDCl3): δ 7.26 (d, J = 9.0 Hz,
2H), 6.89 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 3.88–3.79 (m,
2H), 3.80 (s, 3H), 3.75–3.62 (m, 3H), 3.60–3.51 (m, 1H), 2.75 (br s, 3H); FT-IR (film) vmax 3375
(br), 2939, 1612, 1586, 1513, 1425, 1250, 1032, 822 cm−1; eSI-MS m/z 265.2 ([M + na]+). all
the above-mentioned 5 was then directly dissolved in dry THF (4 mL). To this solution was
added Ph3P (158 mg, 0.6 mmol), followed by a solution of DIaD (122 mg, 0.6 mmol) in dry
THF (2 mL). The mixture was stirred at ambient temperature for 12 h. When TLC showed
completion of the reaction, the mixture was concentrated on a rotary evaporator. The residue
was purified by column chromatography (1:1 etOac/Pe) on silica gel to afford alcohol 6 as
a colourless oil (88 mg, 0.4 mmol, 80% overall from 4). Data for 6: [ꢀ]2D7 −6.4 (c 0.46, CHCl3);
1H nMR (500 MHz, CDCl3): δ 7.26 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.51 (s, 2H), 4.32
(d, J = 4.1 Hz, 1H), 4.06 (dd, J = 10.1, 4.9 Hz, 1H), 3.972 (d, J = 5.9 Hz, 1H), 3.971 (dd, J = 10.0,

4
Y.-Q. YanG
4.1 Hz, 1H), 3.81 (s, 3H), 3.78 (dd, J = 9.5, 1.7 Hz, 1H), 3.74 (d, J = 9.9 Hz, 1H), 1.79 (br s, 1H);
13C nMR (100 MHz, CDCl3): δ 159.4, 129.8, 129.4, 113.9, 84.5, 75.5, 73.8, 71.5, 71.3, 55.3; FT-IR
(film) vmax 3413 (br), 2936, 2871, 1612, 1514, 1249, 1091 cm−1; eSI-MS m/z 247.3 ([M + na]+);
eSI-HRMS calcd for C12H20O4n ([M + nH4]+)242.1387, found 242.1385.
3.2.3. Synthesis of 7
a mixture of Dess–Martin periodinane (585 mg, 1.38 mmol), naHCO3 (773 mg, 9.2 mmol)
and alcohol 6 (103 mg, 0.46 mmol) in dry CH2Cl2 (5 mL) was stirred at ambient temperature
for 8 h. When TLC showed completion of the oxidation, solids were filtered off. The filtrate
was concentrated on a rotary evaporator. The yellowish oily residue was purified by column
chromatography (1:5 eOac/Pe) on silica gel to afford 7 as a colourless oil (89 mg, 0.4 mmol,
87%): [ꢀ]2D7 +19.7 (c 1.07, CHCl3); 1H nMR (500 MHz, CDCl3): δ 7.29 (d, J = 8.9 Hz, 2H), 6.89 (d,
J = 8.6 Hz, 2H), 4.84 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.26 (dd, J = 9.5, 7.5 Hz, 1H),
4.03 (d, J = 17.0 Hz, 1H), 4.02 (t, J = 7.5 Hz, 1H), 3.96 (d, J = 17.5 Hz, 1H), 3.83 (dd, J = 9.5, 7.8 Hz,
1H), 3.81 (s, 3H); 13C nMR (125 MHz, CDCl3): δ 213.0, 159.6, 129.9, 128.9, 113.9, 75.7, 72.3,
70.8, 69.9, 55.2; FT-IR (film) vmax 2933, 2870, 1771, 1612, 1514, 1249, 1110, 1033, 822 cm−1;
eSI-MS m/z 277.2 ([M + MeOH + na]+); eSI-HRMS calcd for C12H18O4n ([M + nH4]+) 240.1230,
found 240.1229.
3.2.4. Synthesis of 8
To a mixture of (Ph3P)3RhCl (8 mg, 0.0085 mmol) and Ph3P (97 mg, 0.37 mmol) in dry 2,4-diox-
ane (1 mL) stirred in a 60 °C bath under argon (balloon) were added dry i-PrOH (0.39 mL),
a solution of 7 (76 mg, 0.34 mmol) in dry 2,4-dioxane (1 mL) and Me3SiCHn2 (2.0 M, in
n-hexane, 0.41 mL, 0.82 mmol). The yellow solution was stirred at 60 °C for 4 h (TLC showed
full consumption of the starting 7). Oxone (209 mg, 0.34 mmol) was added, followed by
naHCO3 (29 mg, 0.34 mmol). The mixture was stirred at 60 °C for 2 h before being cooled
to ambient temperature, diluted with et2O (50 mL), washed with aq. sat. naHCO3 (30 mL),
water (30 mL) and brine (30 mL) and dried over anhydrous na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:10 etOac/Pe) on silica gel gave 8 as
a yellowish oil (33 mg, 0.15 mmol, 44%).[ꢀ]2D5 −11.3 (c 0.4, CHCl3); 1H nMR (400 MHz, CDCl3):
δ 7.27 (d, J = 9.6 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.29 (dt, J = 3.7, 1.3 Hz, 1H), 5.20 (dd, J = 3.7,
2.2 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.48 (dt, J = 12.8, 3.0 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H),
4.30 (ddd, J = 4.4, 3.0, 1.5 Hz, 1H), 4.26 (dt, J = 13.0, 2.4 Hz, 1H), 3.92 (dd, J = 9.7, 3.1 Hz, 1H),
3.88 (dd, J = 9.7, 4.7 Hz, 1H), 3.81 (s, 3H); 13C nMR (125 MHz, CDCl3): δ 159.3, 147.2, 130.1,
129.4, 113.9, 109.3, 78.9, 73.4, 70.2, 70.0, 55.3; FT-IR (film): vmax 3006, 2917, 2850, 1612, 1514,
1248, 1080, 1035, 823 cm−1; eSI-MS m/z 243.2 ([M + na]+); eSI-HRMS calcd for C13H20O3n
([M + nH4]+) 238.1438, found 238.1436.
3.2.5. Synthesis of (S)-1
a mixture of 8 (11 mg, 0.05 mmol) and DDQ (15 mg, 0.065 mmol) in CH2Cl2 (1.5 mL) and
H2O (0.075 mL) was stirred at ambient temperature for 20 min (during which the initial
dark-green solution became a yellow suspension). When TLC showed completion of the
reaction, et2O (50 mL) and H2O (2 mL) were added. The phases were separated. The organic
layer was washed with aq. sat. naHCO3 (10 mL × 8, until the aqueous layer became neutral),
water (20 mL) and brine (20 mL) and dried over anhydrous na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:1 n-pentane/et2O) on silica gel gave

naTuRaL PRODuCT ReSeaRCH
5
(S)-1 as a colourless oil (4.0 mg, 0.04 mmol, 80%):[ꢀ]2D6 −6.3 (c 0.25, CHCl3); 1H nMR (500 MHz,
CDCl3): δ 5.33 (dd, J = 4.0, 2.0 Hz, 1H), 5.14 (dd, J = 3.5, 2.0 Hz, 1H), 4.58 (m, 1H), 4.50 (dt,
J = 14.0, 3.0 Hz, 1H), 4.27 (dt, J = 14.0, 2.0 Hz, 1H), 3.92 (dd, J = 10.0, 5.0 Hz, 1H), 3.77 (dd,
J = 10.0, 4.0 Hz, 1H), 1.89 (br s, 1H); 13C nMR (125 MHz, CDCl3): δ 150.8, 108.0, 75.3, 73.1, 70.1;
FT-IR (film): vmax 3404 (br), 2857, 1421, 1064, 909 cm−1; eI-MS m/z (%) 100 (M+, 3), 70 (100);
eI-HRMS calcd for C5H8O2 (M+): 100.0524, found 100.0527.
4. Conclusions
In summary, the structure previously proposed for a natural product isolated from the leaves
of Michelia compressa var. lanyuensis (Magnoliaceae) was synthesised in an enantiopure form.
apart from clear-cut 1H and 13C nMR spectra, the relation between absolute configuration
and the optical rotation was also established for the proposed structure for the first time.
However, the synthetic sample showed an optical rotation incompatible with that reported
1
for the natural sample. Significant differences were also found in H and 13C nMR. On the
basis of the newly acquired data, it is concluded that the structure previously assigned to
the title natural product must be incorrect.
Disclosure statement
no potential conflict of interest was reported by the author.
Funding
This work was supported by Jiangsu university under [grant number 14JDG018]; a project funded by
the Priority academic Program Development of Jiangsu Higher education Institutions.
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