Enantioselective syntheses of diarylheptanoids (2R,4S,6R)-2-(4-hydroxyphenethyl)-6-(4-hydroxyphenyl) tetrahydro-2H-pyran-4-ol and (3R,5R)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol

Article abstract of DOI:10.1016/j.tetlet.2014.12.144

The first total syntheses of diarylheptanoid natural products (2R,4S,6R)-2-(4-hydroxyphenethyl)-6-(4-hydroxyphenyl) tetrahydro-2H-pyran-4-ol (4) and (3R,5R)-1,7-bis (4-hydroxyphenyl)heptane-3,5-diol (12) were accomplished using substrate selective hydroge

Full text of DOI:10.1016/j.tetlet.2014.12.144

Accepted Manuscript
Enantioselective Syntheses of Diarylheptanoids (2R,4S,6R)-2-(4-hydroxyphe-
neth yl)-6-(4-hydroxy phe nyl) tetrahydro-2H-pyran-4-ol and (3R,5R)-1,7-
bis(4-hydroxy phen yl)heptane-3,5-diol
Jhillu Singh Yadav, Eppa Gyanchander, Sheshurao Bujaranipalli, Saibal Das
PII:
S0040-4039(15)00003-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.144
TETL 45669
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2014
29 December 2014
30 December 2014
Please cite this article as: Singh Yadav, J., Gyanchander, E., Bujaranipalli, S., Das, S., Enantioselective Syntheses
of Diarylheptanoids (2R,4S,6R)-2-(4-hydroxypheneth yl)-6-(4-hydroxy phe nyl) tetrahydro-2H-pyran-4-ol and (3R,
5R)-1,7-bis(4-hydroxy phen yl)heptane-3,5-diol, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.12.144
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Enantioselective Syntheses of Diarylheptanoids (2R,4S,6R)-2-(4-hydroxyphenethyl)-6-(4-hydroxy
phe nyl)tetrahydro-2H-pyran-4-ol and (3R,5R)-1,7-bis(4-hydroxyphen yl)heptane-3,5-diol
Jhillu Singh Yadav,* Eppa Gyanchander, Sheshurao Bujaranipalli, Saibal Das

1
Tetrahedron Letters
journal homepage: www.els evier.com
Enantioselective Syntheses of Diarylheptanoids (2R,4S,6R)-2-(4-hydroxypheneth
yl)-6-(4-hydroxy phe nyl) tetrahydro-2H-pyran-4-ol and (3R,5R)-1,7-bis(4-hydroxy
phen yl)heptane-3,5-diol
Jhillu Singh Yadav,* Eppa Gyanchander, Sheshurao Bujaranipalli, and Saibal Das
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
The first total syntheses diarylheptanoid natural products (2R,4S,6R)-2-(4-hydroxyphenethyl)-6-
(4-hydroxyphenyl) tetrahydro-2H-pyran-4-ol (4) and (3R,5R)-1,7-bis (4-hydroxy
Received in revised form
Accepted
phenyl)heptane-3,5-diol (12) were accomplished using substrate selective hydrogenation, ring
cleavage of tetrahydropyran ring and Keck-Maruoka allylation as the key synthetic steps
Available online
Keywords:
Diarylheptanoids
2014 Elsevier Ltd. All rights reserved.
THP ring
Substrate selective hydrogenation
Dihydropyranone
Keck-Maruoka allylation
Diarylheptanoids1 are a family of natural plant metabolites
which possess characteristic aromatic rings at C-1, C-7 positions
and posses various biological activities such as anti-oxidative,2
anti-cancer,3hepatoprotective,4 antibacterial,5 antiosteoporotic6
and melanogenesis inhibitory activities.7
Diarylheptanoids containing tetrahydropyran (THP) ring such
as centrolobine, 8 calyxins, 9 diospongins10 and others11 has been
found substantial interest for synthetic community due to their
bioactivities. Recently, Chen12 et al. reported the isolation of five
new diarylheptanoids (1-5) having THP ring along with 9 (6-14)
known diarylheptanoids13 from Dioscorea villosa L in 2012
(Figure 1). The roots and rhizomes of Dioscorea villosa L are
known as wild yam. The rhizomes and roots of this plant are used
for their phyto-estrogenic properties, such as the treatment of
menstrual complaints and rheumatoid arthritis.14 Many reports
have indicated that diosgenin could be used as a precursor for the
partial synthesis of steroid-based drugs, like progesterone and
testosterone.15
A variety of novel approaches has been used to synthesize
THP ring towards diaryl heptanoids. Specially using different
sequence of reactions like Prins reaction,16 oxa-Michael
reaction,17 reductive etherification,18 Diels-Alder reaction,19
palladium mediated cyclization,20 radical cyclization,21a
Maitland-Jaap reaction ,21b ,21c olefin metathesis,21d etc. Owing to
the growing importance of this family of compounds, continuity
of our interest in natural product synthesis, herein, we report the
first total synthesis of 4 and 12 by employing substrate selective
hydrogenation, palladium catalyzed ring cleavage of THP and
Keck-Maruoka allylation as the key steps.
Results and Discussion
The retro synthetic analysis of 4 and 12 is depicted above
(Scheme 1). Accordingly both compound 4 and 12 could be
obtained from a common key intermediate 15 by substrate
selective hydrogenation and palladium catalyzed THP ring
cleavage respectively. The key compounds may be obtained by
treating 16 and 17 under aldol conditions. Further, compound 16
Figure 1: Selective Diarylheptanoids
____________________________
* Corresponding author. Tel.: +91-40- 2719 -3737; fax: +91-40-
2716-0512. E-mail address: yadavpub@iict.res.in

2
can be achieved by using Keck-Maruoka allylation of known
aldehyde 18.
Under the normal hydrogenation conditions (H2, Pd/C,
EtOAc) interestingly we ended up with pyran opened as well as
keto reduced product 23 as a single product. The compound 23
was confirmed by matching with previous report.13f Similar type
of ring cleavage was reported by Jennings25et al. where the
cleavage of pyran ring was attributed to acidic character of the
Pd/C at benzylic C1-position. In order to reduce the acidic
character of the Pd/C catalyst Et3N26 was added. Under such
condition the reduction at α face of the enone gave desired
alcohol 24 and keto compound 25 in 10:1 diastereo selective
ratios in acceptable 70% yield. The pyrone 25 was converted into
the desired pyranol 24 in 86% yield by using the Luche reduction
condition (Scheme 3).
Scheme 1: Retrosynthetic analysis
Accordingly, the synthesis of 4 and 12 started from known
aldehyde 1822 which upon Keck-Muroka allylation23gave the
desired homo allylic alcohol 19 in 90% yield with 92%ee based
on chiral HPLC. The hydroxyl group in 19 was protected as its
TBS ether to obtain 20 in 90% yields. Then 20 was subjected to
Upjhon dihydroxylation to obtain desired diol compound,
followed by oxidative cleavage of diol to aldehyde 16 in 85%
yield for two steps. The aldol reaction between compound 17
with 16 obtained dia-stereomeric ratio (1:1.2 by 1H NMR)
containing alcohol 21 in 75% yield. The secondary alcohol thus
produced was treated with DMP oxidation to get β-diketone 22 in
90% yield. The β-diketone was easily converted into the key
intermediate dihydropyranone24 15 by treating with
trifluoroacetic acid in methylene chloride with 89% yield
(Scheme 2).
Scheme 3: Reagents and conditions a) Pd/C, H2, EtOAc, 74% b) Pd/C, H2,
°
Et3N, EtOH, 70% 10:1 ratio of 24/25. c) CeCl3, NaBH4, MeOH, -78 C, 30
min, 83%. d) BBr3, CH2Cl2, -78 °C for 1 h then 1 h at r t, 78% for 4 and 80%
for 12.
Finally methoxy deprotection27,28 of compound 23 and 24
under BBr3 condition afforded diarylheptanoids 12 and 4 in good
yields. The analytical data of target natural products completly
matched with reported values. The optical rotation of
diarylheptanoid 412 showed +31.25 (C=0.10, MeOH) compared
to reported value +37.5 (C=0.22, MeOH) and for compound 1213f
optical rotation showed +5.5 (C=0.25, MeOH) compared to
reported value +4.0 (C=0.10, MeOH).
Conclusion
In conclusion short and convergent first total syntheses of
diarylheptanoids were achieved successfully. Usages of
hydrogenation in different condition were advantageous in
obtaining different desired products. For the first time ring
cleavage was applied for the desired natural product synthesis of
4 and 12 from compound 18 in 8 steps with an overall yield of
20% and 15.8% respectively.
Acknowledgments
E.G.C thank the Council of Scientific and Industrial Research
(CSIR), New Delhi for research fellowship. B.S.R thank the
UGC. Authors also thank CSIR and DST, New Delhi for
Bhatnagar and J. C. Bose Fellowships respectively. This work is
partly funded by CSC-0108, origin under XII five year plan
programme.
Scheme 2: Reagents and conditions a) TiCl4, Ti(iOPr)4, Ag2O, (S)-BINOL,
°
Allyl tri n-butyl stannane, CH2Cl2, -20 °C to 0 C, 12 h, 90% (92% ee). b)
TBS-Cl, imidazole, DMAP, CH2Cl2, 90%. c) OsO4, NMO, acetone: H2O (8:2)
followed by NaIO4, NaHCO3, THF: H2O (6:4), 85% for two steps. d) 17,
LHMDS, THF, -78°C, 30 min, then 16, 60 min, 75%. e) Dess-Martin
periodinanae, NaHCO3, CH2Cl2, 90%. f) TFA, CH2Cl2, 4h, 89%.

3
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28 General procedure for deprotection of methoxy group): In a 50 ml,
round-bottomed flask was placed a solution of methoxy diaryl heptanoid
(10 mmol) in anhydrous methylene chloride under N2. The reaction
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methoxy groups) was added by syringe. Then the reaction mixture was
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by column chromatography on silica gel using petroleum/ethyl acetate
(1:1) as an eluent to give diaryl heptanoids with 75-80% yield.
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(2R,4S,6R)-2-(4-hydroxyphenethyl)-6-(4-hydroxyphenyl) tetrahydro-
25
2H-pyran-4-ol (4): White solid, Mp 132-136 °C; [α]D (+) 31.25 (c
0.10, MeOH), reported value +37.5 (C=0.22, MeOH)12
; Rf = 0.2 (50%
EtOAc–hexane). IR (neat, cm-1): 3336 (bs), 3019, 2934, 1611, 1513,
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1
1449, 1372, 1235, 1172, 1058, 830, 755. H NMR (300 MHz, CD3OD): δ
7.2 (dd (dt-like), J = 8.50, 2.13Hz, 2H), 6.99 (dd (dt-like), J = 8.30, 2.40
Hz, 2H), 6.76 (dd (dt-like), J = 8.50, 2.74 Hz, 2H), 6.67 (dd (dt-like), J =
8.39, 2.74 Hz, 2H), 4.26 (dd, J = 11.33, 1.13 Hz, 1H), 3.82 (dddd, J =
11.13, 10.93, 4.72, 4.57 Hz, 1H), 3.44 (m, 1H), 2.62 (m, 2H), 2.07 (dddd,
J = 12.27, 3.77, 1.88, 1.70 Hz, 1H), 1.95 (m, 1H), 1.85 (dddd, J = 13.97,
8.31, 7.36, 5.65 Hz, 1H), 1.73 (dddd, J = 13.78, 9.06, 7.74, 4.72 Hz, 1H),
1.42 (ddd, J = 12.08, 11.33, 10.97 Hz, 1H), 1.22 (ddd, J = 12.0, 11.44,
11.1 Hz, 1H) 13C NMR (75 MHz, CD3OD ): δ 157.94, 156.39, 134.69,
134.27, 130.38, 128.56, 116.12, 116.0, 78.76, 76.39, 69.09, 43.63, 41.89,
39.29, 31.88. HRMS (ESIMS) calcd for C19H22O4Na [M+Na]+ 337.1410,
found 337.1427. (3R, 5R)-1, 7-bis(4-hydroxyphenyl) heptane-3, 5-diol
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25
(12): White solid, Mp 146-152 °C; [α]D (+) 5.5 (c 0.25, MeOH),
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; Rf = 0.2 (50% EtOAc–
hexane).IR (neat, cm-1): 3440 (bs), 3172, 2931, 2854, 1595, 1514, 1461,
1356, 1232, 1167, 1101, 1055, 916, 814. 1H NMR (300 MHz, CD3OD):
7.00 (d, J = 8.3 Hz, 4H), 6.70 (d, J = 8.3 Hz, 4H), 3.81 (m, 2H), 2.72-
2.58 (m, 2H), 2.57-2.47 (m, 2H), 1.72-1.62 (m, 4H), 1.53 (dd, J = 6.2, 5.8
Hz, 2H). 13C NMR (125 MHz, CD3OD): δ 156.3, 134.5, 130.3, 116.1,
68.7, 45.6, 41.4, 32.1. HRMS (ESIMS) calcd for C19H24O4Na [M+Na]+
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