Evidence against the structure proposed for a natural phenylethanol isolated from mangrove Avicennia marina

Article abstract of DOI:10.1080/00397911.2016.1198813

In an effort to establish the absolute configuration of a previously reported natural triol, the proposed structure was synthesized in an enantiomerically enriched form. The synthetic sample showed NMR and specific rotation completely incompatible with th

Full text of DOI:10.1080/00397911.2016.1198813

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Evidence against the structure proposed for a
natural phenylethanol isolated from mangrove
Avicennia marina
Yong-Qing Yang
To cite this article: Yong-Qing Yang (2016): Evidence against the structure proposed for a
natural phenylethanol isolated from mangrove Avicennia marina, Synthetic Communications,
DOI: 10.1080/00397911.2016.1198813
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1198813
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Date: 23 July 2016, At: 07:08

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1198813
Evidence against the structure proposed for a natural
phenylethanol isolated from mangrove Avicennia marina
a,b
Yong-Qing Yang
a
b
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China; State Key Laboratory of Bioorganic and
Natural Products Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 20 March 2016
In an effort to establish the absolute configuration of a previously
reported natural triol, the proposed structure was synthesized in an
enantiomerically enriched form. The synthetic sample showed NMR
and specific rotation completely incompatible with those reported in
the literature and thus disproved the previously assigned structure.
KEYWORDS
Configuration; natural
products; structural
determination; triol
GRAPHICAL ABSTRACT
Introduction
Avicennia marina, a mangrove-derived fungus, has been shown to be a rich source of
[
1–10]
bioactive chemical compounds.
Another two with antiproliferative activity were
[
11]
recently disclosed,
one of which was assigned the structure 1 (Fig. 1) without defining
the absolute configuration, although the optical rotation was determined.
To acquire the missing stereochemical information for 1, an enantioselective synthesis
was carried out. However, the synthetic 1 unexpectedly showed NMR as well as optical
rotation data completely incompatible with those for the natural product. The previously
assigned planar structure therefore must be incorrect. Because the structure for 1 is so
simple, no one would ever question about the correctness of the assignment in the previous
report, especially when one notices that the conclusion was reached through using such
advanced NMR experiments on a modern instrument with an impeccable line of reasoning.
To clear any confusions and misunderstanding caused by the previous report, it is
necessary to disclose the present results.
CONTACT Yong-Qing Yang
12013, China.
Supplemental data (Full experimental details, IR, H NMR, C NMR, 2-D NMR, ESI-MS, and HRESI-MS data) can be
accessed on the publisher's website.
2016 Taylor & Francis
yqy@ujs.edu.cn
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu
2
1
13
©

2
Y.-Q. YANG
Figure 1. Structure 1 previously proposed for the natural product.
Results and discussion
The synthesis of (S)-1 was performed as shown in Scheme 1. Initial attempt of the simple
[
12]
etherification between bromide 2 and phenol 3 afforded ether 4 (also a natural product
)
[
13]
using literature
conditions suffered very low yields. However, significantly improved
results (59% yield) were later obtained using Cs CO /n-Bu NI/dimethylformamide
2
3
4
(
DMF) to replace K CO /acetone. HMBC (Heteronuclear Multiple Bond Correlation)
2 3
0
correlation of H-1 /C-4 of 4 conformed that the allylation was chemoselectively carried
out on phenolic hydroxyl group (cf. Supplementary Material, S18). An asymmetric dihy-
[
14]
droxylation was then carried out using Sharpless AD-mix-α, which is known to generate
(
S)-diols. As a reference for the ee measurement, racemic 1 was also prepared under the
[
15]
NaIO /LiBr/AcOH conditions followed by hydrolysis.
4
1
The H NMR (in CD OD) for the synthetic 1 showed chemical shifts consistent with
those for the natural product. However, significant differences were found in line-splitting
3
0
0
0
patterns for H-1 and H-2 the two H-1 protons for the natural product appeared as two
doublets at δ 4.23 and 3.89 ppm with the coupling constant J ¼ 9.3 Hz, while the corre-
sponding signals for the synthetic 1 were found as δ 4.21 (dd, J ¼ 10.0, 2.8 Hz, 1H) and
3
.88 (dd, J ¼ 10.0, 8.0 Hz, 1H), respectively. To be on the safe side, the spectrum was also
Scheme 1. Synthesis of triol 1.

SYNTHETIC COMMUNICATIONS®
3
13
Table 1. Comparison of C NMR data for the natural product and the synthetic (S)-1.
a
b
b
3
Nat. (125 MHz, CD OD)
Synth. (100 MHz, CD
3
OD)
3
Synth. (125 MHz, CDCl )
1
1
1
1
7
7
7
6
3
2
2
58.4 (C-4)
159.0
132.4
130.9
115.6
77.7
157.1
131.3
130.1
114.8
75.6
35.1 (C-1)
33.4 (C-2 and C-6)
17.2 (C-3 and C-5)
0
8.3 (C-2 )
0
4.2 (C-3 )
72.8
71.6
0
2.3 (C-1 )
70.5
69.3
6.1 (C-8)
8.5 (C-7)
64.4
63.7
39.4
38.2
0
7.6 (C-4 )
26.7
26.6
0
6.7 (C-5 )
25.0
25.0
a
b
Taken with assignments from Ref. [11].
This work.
recorded in CDCl , the more commonly employed NMR solvent. However, in CDCl the
3
3
discrepancies were even more significant, not only found in the signal splitting patterns but
also in chemical shifts (cf. Supplementary Material, Table S-1).
Distinct discrepancies between the synthetic 1 and the natural product also occurred in
1
3
C NMR, almost for every signal (Table 1). The specific rotations were also totally differ-
2
5
25
ent (½a� À 27.3 (c 0.6, MeOH) for the synthetic (S)-1 vs. ½a� þ 2.08 (c 0.11, MeOH) for the
D
D
natural product). All these differences unmistakably show that the synthetic 1 and the
natural product are not identical.
To further confirm the structure of synthetic 1, 2-D NMR of it has been carried out (cf.
1
1
Supplementary Material, S12–14). H- H COSY correlation of H-2,6/H-3,5 indicates1,4-
1
1
disubstituted benzene moiety, H- H COSY correlation of H-7/H-8 and HMBC correla-
tions of H-7/C-1 and H-8/C-1 indicate [ArCH CH OH] moiety, and HMBC correlation
2
2
0
of H-1 /C-4 indicates [-CH CH(OH)C(CH ) OH] is attached to C-4.
2
3 2
Since the molecular identity of the synthetic 1 is unequivocal, the same planar structure
cannot possibly be shared by the natural product isolated by Shi and coworkers.[ From
now on, the physical as well as spectroscopic data for that natural product in the previous
report should be completely dissociated with the proposed structure (1); the data presented
in this work should be used instead.
14]
Experimental
The NMR spectra were recorded on either an Agilent 500/54 NMR spectrometer
1
1
(
operating at 500 MHz for H) or a Bruker Advance 400 (operating at 400 MHz for H).
Infrared (IR) spectra were measured on a Nicolet 380 IR spectrophotometer. Electrospray
ionization–mass spectrometric (ESI-MS) data were acquired on a Shimadzu LCMS-
2
010EV mass spectrometer. ESI-HRMS data were obtained with a Fisher Scientific LTQFT
Ultra mass spectrometer. Optical rotations were measured on a Jasco P-1030 polarimeter.
The melting point for (S)-1 (uncorrected) was determined on a hot-stage melting-point
apparatus equipped with a microscope. Dry dimethylformamide (DMF) was dried over
CaH and distilled. All chemicals were reagent grade and used as purchased. Column
2
chromatography was performed on silica gel (300–400 mesh) under slightly positive
pressure. PE denotes petroleum ether (bp 60–90 °C).

4
Y.-Q. YANG
Synthesis of 4
To a solution of phenol 3 (138 mg, 1.0 mmol) in dry DMF (5 mL) stirred at ambient
temperature under argon were added in turn Cs CO (652 mg, 2.0 mmol), n-Bu NI
2
3
4
(
18 mg, 0.05 mmol), and prenyl bromide 2 (298 mg, 2.0 mmol). The mixture was stirred
at the same temperature for 12 h. When thin-layer chromatography (TLC) showed
completion of the reaction, the mixture was diluted with Et O (60 mL), washed with water
2
(
3 ꢀ 30 mL) and brine (3 ꢀ 30 mL), and dried over anhydrous Na SO . Removal of the
2
4
drying agent by filtration followed by rotary evaporation and column chromatography
(
1:5 EtOAc/PE) on silica gel afforded 4 as a colorless oil (122 mg, 0.59 mmol, 59%):
1
H NMR (500 MHz, CDCl ): δ 7.13 (d, J ¼ 8.5 Hz, 2H), 6.87 (d, J ¼ 8.5 Hz, 2H), 5.50
3
(
t, J ¼ 6.5 Hz, 1H), 4.49 (d, J ¼ 7.0 Hz, 2H), 3.81 (t, J ¼ 6.5 Hz, 2H), 2.80 (t, J ¼ 6.5 Hz,
1
3
2
1
2
H), 1.80 (s, 3H), 1.74 (s, 3H); C NMR (125 MHz, CDCl ): δ 157.5, 138.1, 130.3,
3
29.9, 119.7, 114.8, 64.7, 63.8, 38.2, 25.8, 18.1; FT-IR (film) v
3395 (br), 3029, 2932,
max
À 1
þ
871, 1612, 1510, 1237, 1176, 1046, 822 cm ; ESI-MS m/z 229.2 ([M þNa] ); ESI-HRMS
þ
calcd. for C H O ([M þH] ) 207.1380, found 207.1380.
1
3
19 2
Synthesis of (S)-1
AD-mix-α (1.40 g, freshly prepared from 7.7 mg of (DHQ) PHAL, 980 mg of K Fe(CN) ,
2
3
6
0
.73 mg of K OsO (OH) , and 412 mg of K CO ) and MeSO NH (95 mg, 1.0 mmol) were
2
2
4
2
3
2
2
added to a mixture of t-BuOH (5 mL) and water (5 mL). After completion of the addition,
the orange mixture was stirred at ambient temperature until a yellow solution was
obtained. The mixture was then cooled in an ice-water bath. A solution of 4 (206 mg,
1
.0 mmol) in t-BuOH (0.5 mL) was added slowly to the yellow solution. Stirring was con-
tinued at the same temperature overnight. When TLC showed completion of the reaction,
Na SO (1.5 g, 12 mmol) was added. The mixture was stirred at ambient temperature for
2
3
4
h (during which the yellow color faded gradually). EtOAc (30 mL) was added. The phases
were separated. The aqueous layer was back extracted with EtOAc (3 ꢀ 30 mL). The com-
bined organic layers were washed with KOH aqueous solution (2 M, 10 mL) and dried over
anhydrous Na SO . Removal of the drying agent by filtration followed by rotary evapor-
2
4
ation and column chromatography (3:1 EtOAc/PE) on silica gel afforded (S)-1 as a white
2
5
solid (164 mg, 0.68 mmol, 68%): Mp 61–62 °C. ½a� À 27.3 (c 0.6, MeOH), of 90.1% ee as
D
determined on a Phenomenex Lux 5 μ Amylose-2 column (4.60 ꢀ 250 mm, particle size
5
µm) eluting with 50:50 of n-hexane/i-PrOH with a flow rate of 0.7 mL/min with the
1
UV detector set to 214 nm. H NMR (400 MHz, CD OD): δ 7.13 (d, J ¼ 8.8 Hz, 2H),
3
6
3
3
4
.88 (d, J ¼ 8.8 Hz, 2H), 4.21 (dd, J ¼ 10.0, 2.8 Hz, 1H), 3.88 (dd, J ¼ 10.0, 8.0 Hz, 1H),
.72–3.68 (m, 1H), 3.70 (t, J ¼ 7.2 Hz, 2H), 2.75 (t, J ¼ 7.2 Hz, 2H), 1.26 (s, 3H), 1.23 (s,
1
H); H NMR (500 MHz, CDCl ): δ 7.15 (d, J ¼ 9.0 Hz, 2H), 6.87 (d, J ¼ 9.0 Hz, 2H),
3
.13 (dd, J ¼ 9.5, 3.0 Hz, 1H), 4.01 (dd, J ¼ 9.5, 7.5 Hz, 1H), 3.82 (t, J ¼ 6.5 Hz, 2H), 3.78
13
(
dd, J ¼ 7.5, 3.0 Hz, 1H), 2.81 (t, J ¼ 6.5 Hz, 2H), 1.32 (s, 3H), 1.27 (s, 3H); C NMR
(100 MHz, CD OD): δ 159.0, 132.4, 130.9, 115.6, 77.7, 72.8, 70.5, 64.4, 39.4, 26.7, 25.0;
3
1
3
C NMR (125 MHz, CDCl ): δ 157.1, 131.3, 130.1, 114.8, 75.6, 71.7, 69.3, 63.7, 38.2,
3
2
1
6.6, 25.0; FT-IR (film of a conc. solution in CH Cl ) v
3380 (br), 2935, 1512, 1243,
2
2
max
À 1
þ
042, 827 cm ; ESI-MS m/z 263.2 ([M þNa] ); ESI-HRMS calcd. for C H O N ([M
13
24 4
þ
þNH ] ) 258.1700, found 258.1701.
4

SYNTHETIC COMMUNICATIONS®
5
Synthesis of racemic 1 (the reference compound for measurement of the ee
value for (S)-1)
A pale yellow mixture of 4 (98 mg, 0.48 mmol), NaIO (30 mg, 0.14 mmol), and LiBr
4
(
12 mg, 0.10 mmol) in AcOH (2 mL) was stirred at 95 °C (oil bath temperature) for 11 h.
The oil bath was removed. The dark mixture was diluted with EtOAc (100 mL), washed
in turn with aqueous saturated Na S O (5 ꢀ 50 mL), water (3 ꢀ 50 mL), and aqueous satu-
2
2 3
rated NaHCO (3 ꢀ 50 mL) and dried over anhydrous Na SO . The drying agent was
3
2
4
removed by filtration. The filtrate was concentrated on a rotary evaporator. The residue
was dissolved in MeOH (5 mL). K CO (100 mg, 0.72 mmol) was added. The mixture
2
3
was stirred at ambient temperature for 12 h, diluted with EtOAc (60 mL), washed with
water (3 ꢀ 30 mL) and brine (30 mL), and dried over anhydrous Na SO . The drying agent
2
4
was removed by filtration. The filtrate was concentrated on a rotary evaporator. The
residue was purified by column chromatography (2:1 EtOAc/PE) on silica gel to furnish
racemic 1 as a yellowish oil (17 mg, 0.071 mmol, 15%).
Acknowledgments
The research is supported by Jiangsu University (No. 14JDG018) and the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
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