Synthesis of tetrahydropyranyl diarylheptanoids from Dioscorea villosa

Article abstract of DOI:10.1016/j.tetlet.2016.06.102

Concise syntheses of four tetrahydropyranyl diarylheptanoids isolated from Dioscorea villosa have been described. The key features include Prins cyclization to construct the tetrahydropyran cores, Keck asymmetric allylation, and Mitsunobu inversion. Optimization of the Prins cyclization conditions in order to minimize racemization has been described. Our syntheses also confirmed the absolute stereochemistry of the natural products.

Full text of DOI:10.1016/j.tetlet.2016.06.102

Accepted Manuscript
Synthesis of tetrahydropyranyl diarylheptanoids from Dioscorea villosa
Kawalee Kantee, Vatcharin Rukachaisirikul, Kwanruthai Tadpetch
PII:
S0040-4039(16)30781-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.102
TETL 47829
Reference:
Tetrahedron Letters
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24 May 2016
13 June 2016
22 June 2016
Please cite this article as: Kantee, K., Rukachaisirikul, V., Tadpetch, K., Synthesis of tetrahydropyranyl
diarylheptanoids from Dioscorea villosa, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.102
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Synthesis of tetrahydropyranyl diarylheptanoids from Dioscorea
villosa
Kawalee Kantee, Vatcharin Rukachaisirikul, Kwanruthai Tadpetch*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of
Songkla University, Hat Yai, Songkhla 90112, Thailand
ABSTRACT
Concise syntheses of four tetrahydropyranyl diarylheptanoids isolated from Disocorea villosa
have been described. The key features include Prins cyclization to construct the
tetrahydropyran cores, Keck asymmetric allylation and Mitsunobu inversion. Optimization of
the Prins cyclization conditions in order to minimize racemization has been described. Our
syntheses also confirmed the absolute stereochemistry of the natural products.
Keywords:
Diarylheptanoids
Tetrahydropyran
Dioscorea villosa
Prins cyclization
* Corresponding author. Tel.: +66 74 288437; fax: +66 74 558841.
Email address: kwanruthai.t@psu.ac.th (K. Tadpetch).
1

The diarylheptanoids are a group of plant secondary metabolites possessing the 1,7-
diphenylheptane skeleton, which exhibit a wide range of biological properties such as anti-
inflammatory, antioxidant, anticancer, antibacterial and antiosteoporotic activities.1 A
subgroup of these diarylheptanoids are those possessing tetrahydropyran (THP) rings which
have been shown to display interesting biological activities. Selected examples of this
subgroup of diarylheptanoids are illustrated in Figure 1. Diospongin B (1), isolated from the
rhizomes of Dioscorea spongiosa, shows promising inhibitory activity on bone resorption
and could potentially be used as an antiosteoporotic drug.2 Centrolobine (2), which was
isolated from the heartwood of Centrolobium robustum and from the stem of Brosimum
potabile,3 exhibits anti-inflammatory, antibacterial and anti-leishmanial activities.4
Additionally, rhoiptelol B (3), isolated from the fruits of Rhoiptelea chiliantha5 and the bark
of Alnus hirsuta,6 possesses inhibitory activity against lipopolysaccharide (LPS)-induced
nuclear factor-B (NF-B) activation, nitric oxide (NO) and tumor necrosis factor alpha
(TNF- production7 and hypoxia-inducible factor-1 (HIF-1) in AGS cells.6
Figure 1. Selected biologically active tetrahydropyranyl diarylheptanoid natural products
In 2012, Chen and co-workers reported the isolation of five new cyclic
diarylheptanoids containing THP cores (4-8) from the methanol extracts of the roots and
rhizomes of Dioscorea villosa (wild yam) (Figure 2).8 The absolute configurations of 4-8
were proposed based on the Mosher’s ester analysis. In 2013, Lee and co-workers disclosed
the isolation of tetrahydropyranyl diarylheptanoids 4, 6 and 8 from the rhizomes of Dioscorea
nipponica along with two new tetrahydropyranyl diarylheptanoids, diosniponols A and B.9 In
Lee’s study, compounds 4, 6 and 8 displayed anti-neuroinflammatory activity (inhibitory
effect on NO production in LPS-activated murine microglia BV-2 cells) with low cell
toxicity. Further investigation on this group of compounds could be beneficial for drug
discovery in neurodegenerative diseases such as Alzheimer’s disease as well as other related
diseases.
2

Figure 2. Tetrahydropyranyl diarylheptanoids isolated from D. villosa and D. nipponica and
inhibitory effects on NO production in LPS-activated murine microglia BV-2 cells of
diarylheptanoids 4, 6 and 8.
To date, there has been only one report regarding the synthesis of diarylheptanoid 5
by Yadav and co-workers (Scheme 1).10 Their strategy to construct the 4-
hydroxytetrahydropyran (4-OH THP) core relied on the selective hydrogenation and
reduction of dihydropyrone 13, which could be prepared from the aldol reaction between
aldehyde 10 and acetophenone 11. Diarylheptanoid 5 could be synthesized in 9 steps from
aldehyde 9 in 20% overall yield.
Scheme 1. Yadav’s synthesis of diarylheptanoid 5.
The Prins cyclization reaction is a powerful synthetic transformation for
constructing substituted THP rings11 and has been utilized in a number of syntheses of
natural products containing the 4-OH THP motif.12 Typically, Prins cyclization reactions
involve the acid-promoted coupling of aldehydes and homoallylic alcohols and proceed with
high level of stereoselectivity favoring 2,4,6-cis THP rings.13 Typical acids used include
3

trifluoroacetic acid (TFA)14 or a combination of BF3·OEt2 and acetic acid.15 In 2008,
Tadpetch and Rychnovsky reported a variation of the Prins cyclization reaction which was
catalyzed by O3ReOSiPh3 or O3ReOH as a convenient method to construct 4-OH THPs.16
This protocol was highly effective with electron-rich aromatic aldehydes. In addition, both
equatorial 4-OH and axial 4-OH products are possible using this catalytic system depending
on the electronic nature of both the aldehyde and homoallylic alcohol. Thus, it was
envisioned that the desired natural products 4-7 could be prepared with this methodology
from benzaldehyde derivative 15 and chiral homoallylic alcohol 16 utilizing the
commercially available and easy-to-handle perrhenic acid (Scheme 2). Notably, the desired
axial hydroxyl stereochemistry of compounds 6 and 7 would be directly accessed rather than
the 2,4,6-cis stereoisomer typically obtained from the Prins reactions.
Scheme 2. Retrosynthetic analysis of compounds 4-7.
Our synthesis commenced with optimization of the reaction conditions using a racemic
homoallylic alcohol precursor. Effects of the electronic properties of both substrates on the
diastereoselectivity of the reaction were also investigated. It has been demonstrated by
Rychnovsky and co-workers that the axial selectivity of nucleophilic trapping at the 4-
position of the THP ring is a function of the lifetime and reactivity of the tetrahydropyranyl
cation and the nucleophile, and could be tuned by altering the electronic properties of the
substrates.17 We thus investigated the effect of electron-donating and electron-withdrawing
substituents (R1 and R2) on the reaction outcome. Benzyl (Bn) and benzenesulfonyl (SO2Ph)
protecting groups were chosen as representative electron-donating and electron-withdrawing
groups, respectively.
The synthesis of aldehyde and racemic homoallylic alcohol precursors for reaction
optimization is described in Scheme 3. The benzaldehyde precursors were prepared by
protection of the hydroxyl group of 4-hydroxybenzaldehyde (18) with a benzyl or a
4

benzenesulfonyl group. Treatment of 18 with BnBr in the presence of K2CO3 in DMF at
room temperature yielded 4-benzyloxybenzaldehyde (19) in quantitative yield, while 4-
benzenesulfonyloxybenzaldehyde (20) was prepared in 83% yield by treating 18 with
benzenesulfonyl chloride and Et3N in CH2Cl2 at rt. Horner-Wadsworth-Emmons (HWE)
reactions of aldehydes 19 and 20 using triethylphosphonoacetate and NaH gave ,-
unsaturated esters 21 and 22 in good yields. Hydrogenation of the alkene moiety in 21 and 22
using Pd/C in EtOAc furnished esters 23 and 24, which after subjection to LiAlH4 reduction
delivered alcohols 25 and 26 in excellent yields. Oxidation of 25 and 26 with iodoxybenzoic
acid (IBX) in DMSO-CH2Cl2 resulted in the formation of the corresponding aldehydes 27
and 28. Treatment of 27 and 28 with allylmagnesium bromide yielded the desired racemic
homoallylic alcohols 29 and 30 in 57% and 65% yield, respectively.
Scheme 3. Preparation of the aldehyde and racemic homoallylic alcohol precursors.
With the aldehyde and racemic homoallylic alcohol precursors in hand, we began
investigating the effect of both substrates’ protecting groups on product yields and
stereoselectivity (Table 1). Reaction conditions using 10 mol% of the O3ReOH catalyst in
CH2Cl2 (0.1M) at room temperature were initially chosen. When both R1 and R2 were
electron-withdrawing groups (SO2Ph), the reaction was very slow and low yields of the
desired products were obtained; however, the axial 4-OH THP product (31ax) was observed
as a minor product, while the expected equatorial 4-OH THP 31eq was obtained as a major
5

product (entry 1). Increasing the catalyst loading to 20 mol% only slightly improved the
product yield but the stereoselectivity for the formation of the axial 4-OH product decreased
(entry 2). Changing the phenol protecting group on the homoallylic alcohol to an electron-
donating group (Bn) led to trace amounts of the desired products and the major products
observed were 4-OH THPs resulting from oxonia-Cope induced side-chain exchanges
(entries 3-4) which was consistent with previous observations.14a,18 When using an electron-
rich aldehyde and an electron-withdrawing substituent on the homoallylic alcohol, the desired
4-OH THP product was obtained in 43% yield with complete equatorial stereoselectivity for
nucleophilic trapping at the 4-position (entry 5). Increasing the catalyst loadings to 15, 30 and
40 mol% led to moderately higher yields (entries 6-8). It was found that 50 mol% catalyst
gave the highest yield of 64% (entry 9). Higher catalyst loadings of 60, 80 and 100 mol%
seemed to diminish the yields (entries 10-12). We then chose benzaldehyde 19 and
homoallylic alcohol 30 as the optimized substrates for further studies and decided that the
stereochemistry of the alcohol stereogenic center at the 4-position would be inverted via a
Mitsunobu reaction.
Table 1. Screening O3ReOH-catalyzed Prins cyclization conditions
entry
R1
R2
cat. loading (mol%) yield (%)
eq:ax
1
2
3
4
5
6
7
8
SO2Ph
SO2Ph
SO2Ph
Bn
SO2Ph
SO2Ph
Bn
10
20
10
10
10
15
30
40
18
28
6.7:1
7.7:1
-
trace
trace
43
Bn
-
Bn
SO2Ph
SO2Ph
SO2Ph
SO2Ph
eq only
eq only
eq only
eq only
Bn
56
Bn
50
Bn
51
6

9
Bn
Bn
Bn
Bn
SO2Ph
SO2Ph
SO2Ph
SO2Ph
50
60
64
58
53
48
eq only
eq only
eq only
eq only
10
11
12
80
1 equiv
With optimized substrates and reaction conditions in hand, we proceeded to complete
the natural product synthesis by using enantiopure homoallylic alcohols (Scheme 4). Keck
asymmetric allylation19 of aldehyde 28 using (S)-BINOL and Ti(Oi-Pr)4 catalysts gave the
(R)-homoallylic alcohol precursor 30 in 76% yield and 98% ee as determined by chiral
HPLC. The absolute configuration of the newly generated stereogenic center was confirmed
by Mosher’s method.20 Prins cyclization of (R)-30 and 4-benzyloxybenzaldehyde (19) using
50 mol% O3ReOH catalyst in CH2Cl2 at room temperature smoothly provided the desired
(2S,4R,6S)-THP product 31 in 64% yield. The enantiopurity of 31 was determined by chiral
HPLC analysis of its acetate derivative (32) to be 51% ee which indicated the significant loss
of enantiopurity resulting from racemization which is a very common side-reaction of Prins
cyclization reactions. Next, different Prins cyclization conditions utilizing TFA and BF3·OEt2
as acid promoters were investigated. Prins cyclization of (R)-30 and benzaldehyde 19 in the
presence of TFA resulted in a messy reaction and a number of side-products were observed.
However, the Prins cyclization reaction of (R)-30 and benzaldehyde 19 using a combination
of BF3·OEt2, AcOH and TMSOAc as a fluoride trap in CH2Cl221 led to much cleaner reaction
compared to that using TFA and the all-cis THP product 32 was obtained in 36% yield (48%
yield based on recovered (R)-30). To our delight, the optical purity of THP product 32 was
observed to be 88% ee. Although the BF3·OEt2-mediated conditions gave good
enantiointegrity, the product yield was diminished compared to that of the O3ReOH-catalyzed
conditions. Additionally, three different protecting groups had to be removed in order to
complete the natural product. Thus, use of the same protecting group for the phenol moieties
of both substrates would be advantageous to reduce the synthetic steps. We decided to use the
acetate protecting groups on both substrates as Willis and co-workers had successfully
utilized this protecting group in the synthesis of a novel tetrahydropyranyl diarylheptanoid
isolated from Zingiber offiinale.21
7

Scheme 4. Prins cyclizations of (R)-homoallylic alcohol 30 and aldehyde 19 under O3ReOH-
catalyzed and BF3·OEt2-mediated conditions.
Synthesis of (R)-homoallylic alcohol 36 was achieved in a similar fashion to that of
(R)-30 with slight modification (Scheme 5). Wittig olefination of 4-hydroxybenzaldehyde
(18) with (carbethoxymethylene)triphenylphosphorane, followed by hydrogenation of the
resulting ,-unsaturated ester gave ester 33 in excellent yields. Reduction of the ester
functional group of 33 using LiAlH4 furnished diol 34 in 95% yield. Selective protection of
the phenol group of 34 using 0.5 equiv of Ac2O in the presence of Et3N and catalytic DMAP
delivered the monoacetylated product in 60% yield, which upon subjection to IBX oxidation
gave aldehyde 35 in 91% yield. Keck allylation of 35 using (S)-BINOL and Ti(Oi-Pr)4
catalysts gave (R)-homoallylic alcohol precursor 36 in 54% yield and 96% ee. Prins
cyclization of (R)-36 and 4-acetoxybenzaldehyde (37) under the established BF3·OEt2-
mediated conditions gave the THP product 38 in 53% yield and 85% ee. Although the
enantiopurity of the THP product obtained from these acetate-protected substrates was
slightly lower than that of 32, the product yield was significantly higher and we selected these
optimized substrates and reaction conditions to complete the synthesis of diarylheptanoid
natural products 4-7. Methanolysis of the three acetate groups of 38 using K2CO3 in methanol
smoothly gave diarylheptanoid 5 in 80% yield. The spectroscopic data of 5 were identical to
those of the natural product. The specific rotation of 5 was determined to be []24 +36.5 (c
D
0.22, MeOH) which was nearly identical to the specific rotation of the natural product ([]22
D
+32.9 (c 0.22, MeOH)) and thus confirmed the absolute configurations of (1R,3S,5R)
assigned to the natural product by Lee and co-workers. Diarylheptanoid 5 was subjected to
Mitsunobu inversion, followed by methanolysis to give diarylheptanoid 7. The specific
8

rotation of 7 was determined to be []24 +180.6 (c 0.02, MeOH) which was in accordance
D
with that of the natural product ([]22 +190.2 (c 0.02, MeOH)) and thus confirmed the
D
absolute configurations of (1R,3R,5R) assigned to the natural product.
Scheme 5. Preparation of (R)-homoallylic alcohol 36 and syntheses of 5 and 7.
Syntheses of diarylheptanoids 4 and 6 were completed using the same synthetic
sequence starting from (S)-homoallylic alcohol 36 (Scheme 6). Keck allylation of 35 using
(R)-BINOL and Ti(Oi-Pr)4 catalysts gave (S)-homoallylic alcohol precursor 36 in 44% yield
and 96% ee. Prins cyclization of (S)-36 and 4-acetoxybenzaldehyde (37) under the same
BF3·OEt2-mediated conditions gave the THP product 39 in 45% yield and 96% ee. Notably,
the key Prins cyclization of (S)-36 resulted in no loss of optical purity of the product.
Following the same synthetic operations for 5 and 7, methanolysis of 39 afforded
diarylheptanoid 4 in 87% yield. Mitsunobu inversion of 4 and subsequent methanolysis
smoothly furnished diarylheptanoid 6. Spectroscopic data of both 4 and 6 were
indistinguishable to those reported for the natural products. In addition, synthetic compounds
4 and 6 displayed nearly identical specific rotations to those of the natural products which
confirmed their absolute configurations.
9

Scheme 6. Synthesis of the natural products 4 and 6.
In conclusion, we report concise syntheses of four diarylheptanoids containing THP
cores which were previously isolated from Disocorea villosa and Dioscorea nipponica. The
key features of the syntheses include Prins cyclization to construct the THP cores as well as
Keck asymmetric allylation and Mitsunobu inversion. Investigation of the Prins cyclization
conditions in order to minimize racemization has been described. Our syntheses also
confirmed the absolute stereochemistry of the natural products 4-7.
Acknowledgements
This work was supported by Prince of Songkla University (Grant No. SCI581192S).
K. Kantee thanks the Faculty of Science Research Fund, Prince of Songkla University for
research assistantship (Contract No. 1-2557-02-002). The Graduate School, Prince of
Songkla University and the Center of Excellence for Innovation in Chemistry (PERCH-CIC)
are acknowledged for partial support. We thank Dr.Thitima Rujiralai for assistance in HPLC
experiments.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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12

Synthesis of tetrahydropyranyl diarylheptanoids from Dioscorea
villosa
Kawalee Kantee, Vatcharin Rukachaisirikul, Kwanruthai Tadpetch*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of
Songkla University, Hat Yai, Songkhla 90112, Thailand
Highlights
 Synthesis of four tetrahydropyranyl diarylheptanoids which were previously isolated
from Dioscorea villosa.
 Prins cyclization reaction as a key strategy to construct the tetrahydropyran cores.
 Investigation of Prins cyclization conditions to minimize racemization.
13

Graphical Abstract
Synthesis of tetrahydropyranyl diarylheptanoids from
Leave this area blank for abstract info.
Dioscorea villosa
Kawalee Kantee, Vatcharin Rukachaisirikul, Kwanruthai Tadpetch*