Practical Synthesis of (±)-Nyasol

Article abstract of DOI:10.1080/00397911.2014.954729

A practical total synthesis of racemic nyasol (7) was explored. The α-hydroxyketo compound 3 was prepared from commercially available starting materials in two steps. Chelation-controlled reduction of the α-hydroxyketo compound 3 with Zn(BH₄)

Full text of DOI:10.1080/00397911.2014.954729

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Practical Synthesis of (±)-Nyasol
Yuanying Fang a & Haeil Park a
a College of Pharmacy , Kangwon National University , Chuncheon ,
South Korea
Accepted author version posted online: 25 Sep 2014.Published
online: 19 Nov 2014.
To cite this article: Yuanying Fang & Haeil Park (2015) Practical Synthesis of (±)-Nyasol, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
45:1, 137-142, DOI: 10.1080/00397911.2014.954729
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Synthetic Communications1, 45: 137–142, 2015
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.954729
PRACTICAL SYNTHESIS OF (ꢀ)-NYASOL
Yuanying Fang and Haeil Park
College of Pharmacy, Kangwon National University, Chuncheon,
South Korea
GRAPHICAL ABSTRACT
Abstract A practical total synthesis of racemic nyasol (7) was explored. The a-hydroxy-
keto compound 3 was prepared from commercially available starting materials in two steps.
Chelation-controlled reduction of the a-hydroxyketo compound 3 with Zn(BH4)2 gave the
anti-1,2-diol compound 4 as the major product (anti=syn ¼ 11.5:1). Stereospecific elimin-
ation reaction of a 1,3-cyclic thionocarbonate intermediate (5) exclusively yielded the
Z-alkene compound 6. Our total synthesis is very concise (seven steps), uses commercially
available starting materials, and offers good overall yield (40%).
Keywords Anti-diol; chelation-controlled reduction; 1,3-cyclic thionocarbonate inter-
mediate; (ꢀ)-nyasol; stereospecific cis-elimination
INTRODUCTION
Norlignans are naturally occurring pharmaceutically important compounds
that possess diphenylpentane backbone structures. Nyasol and hinokiresiol (Fig. 1)
are two typical compounds in this family. Two compounds have stereoisomeric
relationships in their structures. Nyasol, the Z-stereoisomer of hinokiresinol, is an
important norlignan compound isolated from many medicinal plants[1a–1f] and
possesses diverse clinically valuable bioactivities such as anti-oomycete,[1a] anti-
allergic,[1f] anti-atherogenic,[1g] antileishmanic,[2a] estrogen-like,[2b] anti-angiogenic,[2c]
anti-oxidant,[2d] and anti-ischemic[2e] activities.
(ꢀ)-Nyasol was isolated from the methanol extract of Anemarrhena asphodeloides
rhizomes.[1a] Nyasol effectively inhibited mycelial growth of Colletotrichum orbiculare,
Received May 27, 2014.
Address correspondence to Haeil Park, College of Pharmacy, Kangwon National University,
Chuncheon 200-701, South Korea. E-mail: haeilp@kangwon.ac.kr
137

138
Y. FANG AND H. PARK
Figure 1. Structures of nyasol and hinokiresinol.
P. capsici, Pythium ultimum, R. solani, and Cladosporium cucumerinum in a range of
1–50mg=ml, but did not affect the growth of bacteria and yeast. Recently (–)-nyasol
has been reported to suppress neuroinflammatory response through the inhibition of
nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-a, and inter-
leukin (IL)-1b. (–)-Nyasol inhibits the production of NO and PGE2 by suppressing the
expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).
Further research on mode of action suggested that (–)-nyasol can modulate neuroin-
flammatory responses induced by microglial activation.[3]
However, because of the rarity of the amount, complicated and time-
consuming isolation and purification procedures, and prohibitive cost to obtain
bioactive substances from natural products, development of a synthetic procedure
is required to support a sizable amount of sample for further biological evaluations.
Therefore, we aimed to develop a practical and efficient total synthesis of hinokire-
sinol and nyasol. Hinokiresinol, the E-stereoisomer of nyasol, is relatively easy to
synthesize from commercial starting materials in comparison with nyasol. Chalcone
formation from 40-methoxyacetophenone and p-anisaldehyde under Claisen–
Schmidt conditions followed by vinyl addition, reduction, and dehydration steps
provided a hinokiresinol precursor with high E-stereoselectivity.[4]
Several synthetic procedures for nyasol have been published.[5–8] Hoveyda’s
group[6] reported a methodology for synthesis of Z=E alkenes using vinyl alumi-
num reagents and a copper catalyst. Carreira’s group[7] developed a more con-
cise synthetic procedure via iridium-catalyzed substitution reactions between
vinyl trifluoroborates and allyl alcohols. However, costly catalysts needed for
these procedures are not suitable for practical large-scale nyasol synthesis.
Recently Choi’s group[8] reported a scalable synthesis of racemic nyasol; how-
ever, long reaction steps were required and the yield of (ꢀ)-nyasol was poor.
We explored more concise and practical synthetic procedures to obtain a sizable
amount of (ꢀ)-nyasol.
RESULTS AND DISCUSSION
Our strategy for (ꢀ)-nyasol synthesis was as follows (Scheme 1): stereospecific
cis-elimination reaction of the 1,3-cyclic thionocarbonate intermediate yields
exclusively a Z-alkene via Corey–Winter olefin synthesis. An anti-1,2-diol could be
prepared via chelation-controlled reduction of an a-hydroxyketo compound. An a,b-
unsaturated ketone compound would be generated from 40-methoxyacetophenone
and p-anisaldehyde and converted to an a-hydroxyketo compound via Michael
addition and Rubottom oxidation reaction.[9–11]

PRACTICAL SYNTHESIS OF (ꢀ)-NYASOL
139
Scheme 1. Retrosynthetic analysis of (ꢀ)-nyasol.
The overall procedure for (ꢀ)-nyasol preparation is outlined in Scheme 2. A
reaction between 40-methoxyacetophenone and p-anisaldehyde (Claisen–Schmidt
condensation) gave chalcone 1 as a yellow solid in 95% yield. Vinyl addition and
in situ silylation with (tert-butyldimethyl)silyl chloride (TBSCl) produced compound
2, which was used for the subsequent reaction without further purification.
Rubottom oxidation of the compound 2 with m-chloroperoxybenzoic acid (mCPBA)
followed by desilylation with 48% aqueous HF solution produced a-hydroxyketo
intermediate 3 as a colorless oil in 90% yield (three steps). Chelation-controlled
reduction of compound 3 with Zn(BH4)2 gave the anti-1,2-diol compound 4 as the
major product (anti=syn ¼ 11.5:1) in 92% yield.[11] Using NaB(OAc)3H or NaBH4
for reduction decreased the anti=syn ratios (Table 1).
Corey–Winter olefin synthesis of compound 4 using thiocarbodiimidazole
(TCDI) and diisopropylethylamine (DIPEA) in dichloromethane afforded 1,3-cyclic
thionocarbonate 5 in 72% yield. Elimination reactions of 1,3-cyclic thionocarbonates
were reported to produce cis-alkenes almost stereospecifically.[9] The elimination
reaction of compound 5 with trimethylphosphite produced compound 6 (84%) and
its E-isomer (8%). By comparing the coupling constants of olefinic protons of the
product 6 and its isomer, the Z (J ¼ 11.4 Hz)=E (J ¼ 16.0 Hz) ratio was identified
Scheme 2. Reagents and conditions: (a) KOH, EtOH, 95%; (b) vinylmagnesium bromide, CuBr-Me2S,
HMPA, TBSCl, THF, 3 h; (c) mCPBA, NaHCO3, CH2Cl2, then HF, MeOH, 90% (3 steps); (d) Zn(BH4)2,
Et2O, 92%; (e) TCDI, DIPEA, CH2Cl2, reflux, 2 h, 72%; (f) P(OMe)3, reflux, 1 d, 84%, Z=E ¼ 11.5; (g)
MeMgI, 160 ꢁC, 150 mbar, 1 h, 82%.

140
Y. FANG AND H. PARK
Table 1. Results of chelation-controlled reduction
Entry
Reagent
Yield (%)a
Ratio of anti=syn diolb
1
2
3
NaBH4
NaB(OAc)3H
Zn(BH4)2
85
80
92
2.5:1
6.0:1
11.5:1
aYield after chromatography.
bBased on the ratio between compound 6 and its E-stereoisomer.
as 11.5:1. Demethylation of compound 6 with MeMgI under reduced pressure (150
mbar) gave final product 7 (nyasol) in 82% yield.[12]
The stereochemistry of anti=syn-diol (compound 4) and cyclic thionocarbonate
(compound 5) was difficult to determine, because the diastereoisomers of the com-
pounds 4 and 5 were unable to completely separate and the peaks of hydrogens
1
attached to CꢂO bonds (4: 4.12–4.48 ppm, 5: 4.90–5.13 ppm) on H NMR spectra
were mixed together and the coupling constants could not be measured. The diaster-
eoisomeric ratios of compound 4 and 5 were deduced from the ratio of the com-
pound 6 and its E-stereoisomer, which could be identified by comparing the
1
coupling constants in H NMR as mentioned.
EXPERIMENTAL
All chemicals were obtained from commercial suppliers and used without
further purification. All solvents used for reactions were freshly distilled from proper
dehydrating agent under nitrogen gas. All solvents used for chromatography were
1
purchased and directly applied without further purification. H NMR spectra were
recorded on a Bruker Avance 300 (300-MHz) and Bruker DPX 400 (400-MHz) spec-
trometers. Chemical shifts are reported in parts per million (ppm) downfield relative
to tetramethylsilane as an internal standard. Peak splitting patterns are abbreviated
as m (multiplet), s (singlet), bs (broad singlet), d (doublet), bd (broad doublet), t
(triplet), dd (doublet of doublets), and ddd (doublet of double doublet). 13C NMR
spectra were recorded on a Bruker DPX 400 (100-MHz) spectrometer; fully
decoupled and chemical shifts are reported in parts per million (ppm) downfield rela-
tive to tetramethylsilane as an internal standard. Mass spectra were recorded on a
Voyager DE STR MALDI-TOF mass spectrometer. Analytical thin-layer chromato-
graphy (TLC) was performed using commercial glass plates with silica gel 60F 254
purchased from Merck.
(ꢀ)-(4R,5S)-4-(4-Methoxyphenyl)-5-(1-(4-methoxyphenyl)allyl)-
1,3-dioxolane-2-thione (5)
TCDI (3.4 g, 19.08 mmol) and DIPEA (11.1 mL, 63.61 mmol) were added to a
solution of the compound 4 (2.0 g, 6.36 mmol) in CH2Cl2 (40 mL). The reaction was
refluxed for 2 h, and the product was extracted with CH2Cl2 (150 mL), washed with
saturated brine (100 mL ꢃ 2), and dried with Mg2SO4. The organic layer was evapo-
rated to obtain the crude product, which was purified by column chromatography
(hexane=EtOAc ¼ 4:1) to afford the compound 5 (1.63 g, 72%) as a light yellow

PRACTICAL SYNTHESIS OF (ꢀ)-NYASOL
141
oil. 1H NMR (300 MHz, CDCl3) d: 6.81 (m, 4H, C2 and C6 Ar1 and Ar2), 6.74 (m,
=
2H, C3 and C5 Ar2), 6.59 (m, 2H, C3 and C5 Ar1), 5.98–6.11 (m, 1H, CH CH2),
=
=
5.54 (d, 1H, J ¼ 7.4, CH CH2), 5.35 (dd, 1H, J ¼ 7.4, 10.7, CH CH2), 5.13 (m,
1H, CHAr), 4.90 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.27 (m,
=
1H, CHCH CH2); MS (MALDI-TOF): m=z [M] 356.44.
þ
(ꢀ)-(Z)-4,4’-(Penta-1,4-diene-1,3-diyl)bis(methoxybenzene) (6)
A solution of the compound 5 (1.50 g, 4.21 mmol) in P(OMe)3 (2.5 mL) was
refluxed for 24 h. The mixture was evaporated to obtain the crude product, which
was purified by column chromatography (hexane=EtOAc ¼ 10:1) to afford the
compound 6 (994 mg, 85%) and E-stereoisomer (86 mg) as a light colorless oil.
1H NMR (400 MHz, CDCl3) d: 7.21–7.24 (m, 2H, C2 and C6 Ar1), 7.14–7.18 (m,
2H, C2 and C6 Ar2), 6.83–6.88 (m, 4H, C3 and C5 Ar1 and Ar2), 6.53 (d, 1H, J ¼
=
=
11.4, ArCH CH), 5.98–6.07 (m, 1H, CH CH2), 5.69 (dd, 1H, J ¼ 10.0, 11.4,
=
=
ArCH CH), 5.14–5.20 (m, 2H, CH CH2), 4.52 (dd, 1H, J ¼ 6.1, 10.0,
CHCH CH2), 3.79 (s, 3H, OCH3), 3.78 (s, 3H, OCH3); 13C NMR (100 MHz,
=
=
=
CDCl3) d: 159.0 (CHOCH3), 158.6 (CHOCH3), 141.2 (CH CH), 135.9 (CH CH2),
=
=
132.1 (Ar), 130.2 (Ar), 130.1 (Ar), 129.1 (Ar), 129.0 (CH CH), 115.4 (CH CH2),
114.4 (Ar), 114.1 (Ar), 55.7 (OCH3), 55.6 (OCH3), 47.3 (CH); HRMS (MALDI-
TOF): m=z calculated [M]þ 280.1463, observed [M]þ 280.3867. E-Stereoisomer of
1
compound 6: H NMR (300 MHz, CDCl3) d: 7.22–7.24 (m, 2H, C2 and C6 Ar1),
7.08–7.14 (m, 2H, C2 and C6 Ar2), 6.75–6.84 (m, 4H, C3 and C5 Ar1 and Ar2),
=
=
6.29 (d, 1H, J ¼ 16.0, ArCH CH), 6.12–6.20 (dd, 1H, J ¼ 6.6, 16.0, ArCH CH),
=
=
5.96–6.07 (m, 1H, CH CH2), 5.00–5.13 (m, 2H, CH CH2), 4.08 (t, 1H, J ¼ 6.3,
=
CHCH CH2), 3.73 (s, 6H, OCH3).
CONCLUSION
In conclusion, we have established an efficient and practical total synthesis of
(ꢀ)-nyasol via chelation-controlled reduction of an a-hydroxyketo compound with
Zn(BH4)2 and stereospecific cis-elimination of a 1,3-cyclic thionocarbonate inter-
mediate as key reactions. Our total synthesis is very concise (seven steps), uses com-
mercially available chemicals, and offers high overall yield (40%). The reaction of
most reactions are adaptable to scalable processes and are therefore suitable for
large-scale synthesis of (ꢀ)-nyasol. In addition, our method can be easily applied
to synthesize optically active nyasol using chiral inducing agents. Currently we are
investigating asymmetric Michael reaction using chiral ligands to obtain a chiral enol
intermediate, which could allow us to produce optically active nyasol. Also, our syn-
thetic procedure will be applied to prepare nyasol analogs for SAR study in the near
future.
ACKNOWLEDGMENTS
The authors thank to New Drug Development Research Institute and Central
Laboratory of Kangwon National University for use of analytical instruments and
bioassay facilities.

142
Y. FANG AND H. PARK
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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