Confirmation of the stereochemistry of two naturally occurring epimeric phenylpropanoids via synthesis: Elucidation of hitherto unknown full stereostructures

Article abstract of DOI:10.1016/j.tetlet.2019.05.022

Herein we report our efforts toward unequivocal assignment of the hitherto unknown absolute configurations of two naturally occurring phenylpropanoids from Abies delavayi and Abies fabri via a combination of chiral pool synthesis and single crystal X-ray

Full text of DOI:10.1016/j.tetlet.2019.05.022

Accepted Manuscript
Confirmation of the stereochemistry of two naturally occurring epimeric phe-
nylpropanoids via synthesis: elucidation of hitherto unknown full stereostruc-
tures
Ipsita Chakraborty, Sandip Chatterjee, Avrajit Manna, Tanurima Bhaumik
PII:
S0040-4039(19)30460-5
https://doi.org/10.1016/j.tetlet.2019.05.022
TETL 50794
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 April 2019
6 May 2019
10 May 2019
Please cite this article as: Chakraborty, I., Chatterjee, S., Manna, A., Bhaumik, T., Confirmation of the
stereochemistry of two naturally occurring epimeric phenylpropanoids via synthesis: elucidation of hitherto
unknown full stereostructures, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.022
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Confirmation of the stereochemistry of two naturally occurring
epimeric phenylpropanoids via synthesis: elucidation of hitherto
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unknown full stereostructures
Ipsita Chakraborty, Sandip Chatterjee, Avrajit Manna and Tanurima Bhaumik*
OH
OH
OBn
OBn
OH
OH
OH
OH
HO
HO
HO
HO
OMe
OMe
OMe
OMe
5 steps
5 steps
OH OH
HO
OH
OH OH
D-Mannitol

1
Tetrahedron Letters
Confirmation of the stereochemistry of two naturally occurring
epimeric phenylpropanoids via synthesis: elucidation of hitherto
unknown full stereostructures
Ipsita Chakraborty, Sandip Chatterjee, Avrajit Manna and Tanurima Bhaumik*
Department of Chemistry, Jadavpur University, Jadavpur, Kolkata 700032, West Bengal, India
*Corresponding author. e-mail: tanurimabhaumik@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report our efforts toward unequivocal assignment of the hitherto unknown absolute
configurations of two naturally occurring phenylpropanoids from Abies delavayi and Abies fabri
via a combination of chiral pool synthesis and single crystal X-ray analysis which also
confirmed their previously reported gross structures with relative stereochemistry. Toward this
end we have achieved the first stereodivergent syntheses of threo-(1R,2R)-(−)- and erythro-
(1S,2R)-(+)-1-(4-hydroxyphenyl)-1-methoxy-2,3-propanediol. The synthetic threo-isomer was
found to be identical to the naturally occurring threo-isomer, while the natural erythro-isomer
was postulated to be the enantiomer of the synthetic erythro-isomer.
Available online
Keywords:
Absolute configuration
Natural products
Chiral pool synthesis
Single crystal X-ray analysis
2009 Elsevier Ltd. All rights reserved.
Both Abies delavayi and Abies fabri are trees found
exclusively in China. Systematic phytochemical investigations of
Abies delavayi by Yang and co-workers in 20141 and those of
Abies fabri by Li and co-workers in 20152 resulted in the
isolation of two new isomeric phenylpropanoids, 1-(4-
hydroxyphenyl)-1-methoxy-2,3-propanediol (Fig. 1). The relative
configuration of the two chiral centers were assigned by
comparing the coupling constants with those of the analogous
phenylpropanoids, syringoylglycerols and guaiacylglycerol (Fig.
2) derivatives (ca. 5 Hz for the erythro-isomer and 7 Hz for the
threo-isomer).3 The coupling constant between the two vicinal
protons at C-1 and C-2 for the stereoisomer isolated from Abies
delavayi was determined as 6.6 Hz by Yang and co-workers and
phenylpropanoids 1 and 2 important substrates for biological
evaluation.
OMe
OMe
OH
OH
OH
OH
HO
HO
OMe
OH
4: Guaiacylglycerol
OH
3: Syringylglycerol
Figure 2. Analogous phenylpropanoids.
To the best of our knowledge, no research group has reported
the determination of the full stereostructures of these two natural
products. Our plan was to sequentially arrange classical reactions
to achieve the stereodivergent syntheses of one threo- and one
erythro-stereoisomer with known absolute stereochemistry at one
of the two stereogenic centers (Fig. 1). Unambiguous
stereochemistry at the two chiral centers would then be assigned
by X-ray crystallographic analysis of any two of the synthesized
compounds, one from each series (i.e. threo- and erythro-series).
1
they proposed it to be the threo-isomer (Fig. 1). The H and 13C
NMR spectroscopic data of the stereoisomer isolated from Abies
fabri were similar to those of the threo-isomer except for one
proton signal which was shifted upfield by 0.9 ppm. Hence, Li
and co-workers suggested it to be the erythro-isomer (Fig. 1)
despite a 6.3 Hz coupling constant between the two vicinal
protons at C-1 and C-2.
Our continued interest in the chiral pool synthesis of
potentially bioactive chiral natural products and their synthetic
analogues,5 made us interested in the asymmetric synthesis of
these molecules.
OH
HO
OH
OH
HO
OH
HO
OH
OH
OH
OH
HO
or
or
OMe
OMe
ent-1
Proposed threo -(-)-isomer (Yang)
OMe
2
OMe
ent-2
Proposed erythro -(-)-isomer (Li)
We initiated the project by transforming D-(+)-mannitol 5
into R-(+)-glyceraldehyde derivative 6 (Scheme 1) following a
two-step literature procedure.6 The reaction of aldehyde 6 and the
Grignard reagent prepared from 4-benzyloxybromobenzene,7 for
6 h at reflux gave a mixture of epimeric alcohols 7 in ca. 1:1 ratio
(determined by 1H NMR spectroscopy) in moderate yield (58%).
Chelation controlled or oxidation-reduction reactions to modulate
the diastereoselectivity were not attempted as our aim was the
stereodivergent syntheses of both the threo- and erythro-
compounds. Since, at this stage the isomeric alcohols could not
be separated by column chromatography, the mixture was treated
1
Figure 1. Stereoisomers of 1-(4-hydroxyphenyl)-1-methoxy-2,3-propanediol.
A mixture of phenylpropanetriols, threo- and erythro-1-C-
syringyl-glycerol, which are structurally related to the two above
mentioned natural products, was reported to inhibit the
production of pro-inflammatory cytokines interleukin (IL)-12
p40, IL-6, and tumor necrosis factor-α in lipopolysaccharide
stimulated bone marrow-derived dendritic cells.4 The interesting
biological profile of similar phenylpropanoids make

2
Tetrahedron Letters
with methyl iodide and sodium hydride to give the
The specific rotation of synthetic threo-(−)-(1R,2R)-11,
corresponding methyl ethers 8 and 9 in 96% combined yield. To
our delight, the two epimeric methyl ethers could be easily
separated by column chromatography which led to the isolation
of diastereoisomer 8 in 39% yield (Rf = 0.48, 15% ethyl acetate-
hexane) and diastereoisomer 9 in 48% yield (Rf = 0.55, 15%
ethyl acetate-hexane). The more polar methyl ether 8 underwent
acid-induced deketalization to give diol 10 (90%), which upon
hydrogenolysis using 10% Pd-C afforded phenol 11 in almost
quantitative yield. Similarly, the less polar methyl ether 9 was
transformed into diol 12 (96%) and finally phenol 13 (93%).
= −7.95 (c 0.90, MeOH), was also comparable to that reported in
the literature1 for the natural threo-(−)-1-(4-hydroxyphenyl)-1-
methoxy-2,3-propanediol isolated from Abies delavayi,
=
−8.2 (c 0.50, MeOH). Hence, the natural isomer isolated by Yang
and co-workers was unequivocally assigned the absolute
configuration of (1R,2R).
The specific rotation reported2 for the natural erythro-isomer
isolated from Abies fabri by Li and co-workers was = −1.0
(c
0.15,
MeOH).
Synthetic
erythro-(1S,2R)-(+)-1-(4-
hydroxyphenyl)-1-methoxy-2,3-propanediol 13 had a specific
OH OH
rotation of
= +15.45 (c 0.55, MeOH); = 16.3 (c
b
OBn
a
HO
O
O
OH
3.21, MeOH). The magnitude of specific rotation observed for
the natural erythro-isomer is lower compared to that of the
synthetic erythro-(1S,2R)-13 (2). However, as the sign of specific
rotations were opposite, the erythro-isomer isolated from Abies
fabri was proposed to be ent-2 (Fig. 1), the enantiomer of 13.
Hence, the absolute configuration of the natural erythro-isomer
isolated by Li and co-workers was postulated to be (1R,2S). In
the absence of reported data regarding the enantiopurity of the
isolated natural product, it may be assumed that the smaller
magnitude of specific rotation of the natural erythro-sample is
due to the co-existence of two enantiomers, 2 (1S,2R) and ent-2
(1R,2S) (Fig. 1).
O
H
O
OH OH
O
5
OH
6
7
OH
OBn
OH
OH
OBn
d
(1R)
O
O
(3R)
HO
e
HO
HO
O
(2R)
(2R)
OMe
OMe
OMe
c
8
10
11 (1)
OH
OBn
OH
(1S)
OH
OBn
d
HO
e
O
(2R)
OMe
OMe
OMe
13 (2)
9
12
Scheme 1. Reagents and conditions: (a) (i) cyclohexanone, BF3•OEt2,
HC(OEt)3, dry DMSO, rt, 24 h, 65%; (ii) NaIO4, CH3CN-H2O (3:2), rt, 6 h,
95%; (b) 4-benzyloxyphenylmagnesium bromide, dry THF, reflux, 6 h, 58%;
(c) NaH, MeI, dry THF, 0 °C-rt, 24 h, 39% 8, 48% 9; (d) 80% aq. TFA,
MeOH, 50 °C, 4 h, 90% 10, 96% 12; (e) H2/Pd-C, MeOH, 36 h, 99% 11, 93%
13.
In summary, we have reported the short and efficient
stereodivergent syntheses of threo-(1R,2R)-(−)- and erythro-
(1S,2R)-(+)-1-(4-hydroxyphenyl)-1-methoxy-2,3-propanediol for
the first time in six steps from commercially available,
inexpensive D-(+)-mannitol. Our work corroborated the
previously proposed relative stereochemistry of these two natural
products. Furthermore, the naturally isolated threo-isomer was
unequivocally assigned to have the (1R,2R) configuration while
the erythro-isomer was postulated to have the (1R,2S)
configuration. The application of this strategy for the synthesis of
stereoisomers of similar phenylpropanoids, such as the naturally
occurring 4-n-butoxyl-phenylpropanetriol9 and threo-1-(4-
Single crystals of compounds 10 and 13, suitable for X-ray
diffraction, were grown from methanol-hexane and ethyl acetate-
hexane, respectively. X-ray crystallography not only confirmed
their structures but also established the threo- and erythro-
relative configurations of the two chiral centers in 10 and 13,
respectively.8 Compound 10 (Fig. 3) crystallized with
a
hydroxyphenyl)-1-ethoxy-2,3-propanediol,10
together
with
monoclinic space group P21 while compound 13 (Fig. 4)
crystallized with a monoclinic space group C2. Since, chirality at
the C-2 stereogenic centers of compounds 10 and 13 was
translated from the C-2 stereogenic center of C2-symmetric D-
(+)-mannitol 5, the absolute configuration of the two
independent determination of their absolute configurations is
currently being investigated in our laboratory.
Acknowledgments
Financial support from CAS-UGC, India and FIST-DST,
India to the Department of Chemistry, Jadavpur University, India
are acknowledged. I. C., S. C. and A. M. wish to thank UGC,
New Delhi for their Senior Research Fellowships. The authors
also gratefully acknowledge helpful suggestions from Prof. S.
Bhattacharya, Jadavpur University, Dr. D. K. Maity and Dr. A.
Mukherjee in solving the crystal structures.
stereocenters
of
threo-3-(4-(benzyloxy)phenyl)-3-
methoxypropane-1,2-diol 10 and erythro-1-(4-hydroxyphenyl)-1-
methoxy-2,3-propanediol 13 must undoubtedly be (2R,3R) and
(1S,2R), respectively. This also indirectly established the absolute
configuration of threo-1-(4-hydroxyphenyl)-1-methoxy-2,3-
propanediol 11, prepared by the benzyl deprotection of benzyl
ether 10, as (1R,2R).
Appendix A. Supplementary data
Supplementary data associated with this article can be found
in the online version.
References and notes
1. Yang, X.-W.; Li, S.-M.; Li, Y.-L.; Feng, L.; Shen, Y.-H.; Lin, S.;
Tian, J. M.; Zeng, H.-W.; Wang, N.; Steinmetz A.; Liu, Y.;
Zhang, W.-D. Phytochemistry 2014, 105, 164-170.
Figure 3. Crystal structure of 10.
Figure 4. Crystal structure of 13.
2. Li, Y.-L.; Gao, Y.-X.; Jin, H.-Z.; Shan, L.; Chang, W.-L.; Yang,
X.-W.; Zeng, H.-W.; Wang, N.; Steinmetz, A.; Zhang, W.-D.
Phytochemistry 2015, 117, 135-143.
3. (a) Kijima, K.; Otsuka, H.; Ide, T.; Ogimi, C.; Hirata, E.; Takushi,
A.; Takeda, Y. Phytochemistry 1998, 48, 669-676. (b) Yang, X.
W.; Zhao, P. J.; Ma, Y. L.; Xiao, H. T.; Zuo, Y. Q.; He, H. P.; Li,
L.; Hao, X. J. J. Nat. Prod. 2007, 70, 521-525. (c) Miyase, T.;
Ueno, A.; Takizawa, N.; Kobeyashi, H.; Oguchi, H. Chem.
Pharm. Bull. 1987, 35, 3713-3719.
The NMR spectroscopic data of synthetic threo-(1R,2R)-11
(stereostructure as 1, Fig. 1) and erythro-(1S,2R)-13
(stereostructure as 2, Fig. 1) were similar to those reported1,2 for
the natural products threo- and erythro-1-(4-hydroxyphenyl)-1-
methoxy-2,3-propanediol, respectively. This confirmed the
correct assignment of the relative configuration of both natural
products.

3
4. Dat, L. D.; Thao, N. P.; Tai, B. H.; Luyen, B. T. T.; Kim, S.; Koo,
J. E.; Koh, Y. S.; Cuong, N. T.; Thanh, N. V.; Cuong, N. S.; Nam,
N. H.; Kiem, P. V.; Minh, C. V.; Kim, Y. H. Bioorg. Med. Chem.
Lett. 2015, 25, 1412-1416.
5. (a) Chatterjee, S.; Manna, A.; Bhaumik, T. Tetrahedron:
Asymmetry 2014, 25, 1624-1629. (b) Chatterjee, S.; Manna, A.;
Chakraborty, I.; Bhaumik, T. Carbohydrate Research 2019, 473,
5-11.
8. The X-ray crystallographic data (CIF file) for the structures 10
and 13 reported in this paper have been deposited in the
Cambridge Crystallographic Data Centre (CCDC). The deposition
numbers are CCDC 1585535 for 10 and CCDC 1587447 for 13.
9. Chen, J.; Yang, M. L.; Zeng, J.; Gao, K. Phytochemistry Letters
2013, 6, 41-45.
10. Li, Y.-L.; Gao, Y.-X.; Jin, H.-Z.; Shan, L.; Liang, X.-S.; Xu, X.-
K.; Yang, X.-W.; Wang, N.; Steinmetz, A.; Chen, Z.; Zhang, W.-
D. Phytochemistry 2014, 106, 116-123.
6. Sugiyama, T.; Sugawara, H.; Watanabe, M.; Wamashita, K. Agric.
Biol Chem. 1984, 48, 1841-1844.
7. Zhang, L.-Y.; Zhang, Q.-K.; Zhang, Yu-Dong Liquid Crystals
2013, 40, 1263-1273.
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Tetrahedron Letters
-(+)-1-(4-
Highlights:
 Epimeric
(−)-
and
hydroxyphenyl)-1-methoxy-2,3-propanediol
are prepared.
 Conveyance of stereochemistry from D-
mannitol to C-2 of both the target
molecules.
 Establishment of stereochemistry at C-1 via
single crystal X-ray analysis.
 First assignment of absolute configurations
to two natural phenylpropanoids.