Asymmetric synthesis of ent-fragransin C1

Article abstract of DOI:10.1039/c7ob00749c

The first asymmetric synthesis of ent-fragransin C₁ was reported. The key step involves an intramolecular C-O bond formation (furan ring formation) via chemoselective generation of the benzylic carbocation leading to the 2,3-anti-3,4-syn-4,5-anti-tetrahydrofuran moiety as a single diastereomer in good yield. Our synthesis confirms that ent-fragransin C₁ possesses 2R,3R,4S,5S configurations.

Full text of DOI:10.1039/c7ob00749c

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Asymmetric Synthesis of ent-Fragransin C1
Santikorn Chaimanee, Manat Pohmakotr, Chutima Kuhakarn, Vichai Reutrakul, and Darunee
Soorukram*
Received 00th January 20xx,
Accepted 00th January 20xx
The first asymmetric synthesis of ent-fragransin C1 was reported. The key step involves an intramolecular CO bond
formation (furan ring formation) via chemoselective generation of the benzylic carbocation leading to the 2,3-anti-3,4-syn-
4,5-anti-tetrahydrofuran moiety as a single diastereomer in good yield. Our synthesis confirms that ent-fragransin C1
possesses 2R,3R,4S,5S configurations.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
the structureactivity relationship (SAR) observed for 2,5-
diaryltetrahydrofurans7 into account, we aim to develop an
Lignans are a large group of natural products formed by the
dimerization of two phenylpropanoid (C6–C3) units with a broad
structural diversity.1 These secondary plant metabolites have been
found to possess a wide range of important biological activities
including antioxidant, anti-inflammatory, antitumor, antifungal, and
antiviral properties.2 In recent years, new lignans and neolignans
bearing unprecedented carbon skeletons and stereochemistries
have been actively isolated and identified.3
Fragransin C1 (1) and its enantiomer, ent-1, are naturally
occurring 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans (Figure 1).
The chemical structure of 1 was first reported in 1987 by Namba
and co-workers4a and was proposed to possess 2S,3S,4R,5R
configurations. In 2011, ent-1 was isolated by Zhu and Shi and was
reported to contain a similar relative configuration of 2,3-anti-3,4-
syn-4,5-anti as observed in 1. It was assigned to have 2R,3R,4S,5S
configurations according to the CD spectral data.5 Having focused
on asymmetric synthesis of lignans6 and taken the significance of
asymmetric synthesis of ent-1. Our study will benefit the
confirmation of its absolute configuration prior to further
evaluation of its biological activity. Notably, despite numerous
reports
on
asymmetric
synthesis
of
2,5-diaryl-3,4-
dimethyltetrahydrofurans,8 stereoselective synthesis of 1 or ent-1
has never been reported.
On the basis of our recent report on the formal synthesis of (+)-
3-epi-eupomatilone-6 and its 3,5-bis-epimer, primary synthetic plan
to ent-1 will utilize stereoselective construction of chiral
trisubstituted -butyrolactone cores bearing the syn-dimethyl
stereocenters as a key step.6c As depicted in Scheme 1, it was
envisioned that ent-1 should be obtained through the nucleophilic
addition8h of arylmagnesium halide (Ar1MgX) to a trisubstituted -
lactol 2, which in turn would be readily prepared from (3R,4S,5S)--
butyrolactone 3 possessing the 3,4-syn-4,5-anti stereochemistries.
The (3R,4S,5S)--butyrolactone 3 should be obtained with high
stereoselectivity from (1S,2S,3R)-alcohol
4
via oxidative
lactonization reaction. Finally, using our previous synthetic strategy,
(1S,2S,3R)-4 should be stereoselectively synthesized from the
substrate-controlled addition of aryllithium (Ar2Li) to an aldehyde
derived from (2R,3R)-alkene 5.
Figure 1. Structures of naturally occurring fragransin C1 (1) and its
enantiomer, ent-1.
Department of Chemistry and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok
10400, Thailand. E-mail: darunee.soo@mahidol.ac.th; Fax: +662 354 7151; Tel:
+662 201 5148.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Primary synthetic plan to ent-1 via chiral -butyrolactone 3.
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Results and discussion
The observed chemoselective formation of VtiehweArtibcleenOznylilnice
carbocation under mildly acidic reaction conditions leading to the
DOI: 10.1039/C7OB00749C
As outlined in Scheme 2, the (2R,3R)-alkene 5 [diastereomeric ratio
1
formation of furan 8 with high stereoselectivity encouraged us to
revise our synthetic plan to ent-1. As shown in Scheme 4, we
anticipated that an intramolecular cyclization of an intermediate
oxonium ion IV would lead to ent-1 after debenzylation. The
oxonium ion IV would be generated from an alcohol 9, which in
turn should be readily prepared from (2R,3R)-10 and (2R,3R)-11,
respectively.
(dr) = 9 : 1, H NMR analysis] was subjected to oxidative cleavage
using OsO4, N-methylmorpholine-N-oxide (NMO) followed by NaIO4
to provide the corresponding aldehyde 6.6c After purification, 6 was
further treated with [4-(benzyloxy)-3-methoxyphenyl]lithium (1.5
equiv.) [freshly prepared from bromine-lithium exchange between
1-(benzyloxy)-4-bromo-2-methoxybenzene and n-BuLi] in THF at
o
78 C for 4 h to give the corresponding lithium alkoxide 7. Similar
to the previously reported results,6c when 7 was quenched with a
saturated aqueous NH4Cl solution, a trisubstituted tetrahydrofuran
8, containing 2,3-anti-3,4-syn stereochemistries, was obtained in
1
59% yield (from 5) (dr = 89 : 8 : 3, H NMR analysis). The chemical
structure of 8 and its stereochemistry were established on the basis
of mass spectrometry, NMR analyses, and NOESY experiments (see
ESI). Interestingly, when 7, derived from 5 (dr = 9 : 1), was
quenched with
a saturated aqueous NaHCO3 solution, the
corresponding alcohol adducts 4A and 4B were obtained in 55%
yield as a mixture of diastereomers (dr = 67 : 33) after column
chromatography without the formation of furan 8. The mechanism
for the formation of 8 was proposed to proceed via the formation
of an intermediate oxonium ion I followed by an intramolecular
cyclization (Scheme 3). The observed stereochemical outcome of 8
(2,3-anti-3,4-syn) can be explained by the more favorable transition
state III possessing a minimal steric interaction between the aryl
ring and the adjacent methyl group (II vs. III).
Scheme 4. Synthetic plan to ent-1 via the chemoselective formation of the
benzylic carbocation.
Based on the revised synthetic plan, the requisite (2R,3R)-aryl
ketone 10 was readily prepared starting from (2R,3R)-11 (Scheme
5). Removal of the chiral auxiliary moiety of (2R,3R)-116c (dr = 96 : 4)
yielded (2R,3R)-2,3-dimethyl-4-pentenoic acid 129 (92% yield, dr =
96 : 4) which was then converted to the corresponding Weinreb
amide 13 in 74% yield. Treatment of 13 with [4-(benzyloxy)-3,5-
dimethoxyphenyl]lithium (1.5 equiv.) [freshly prepared from the
bromine-lithium exchange between 2-(benzyloxy)-5-bromo-1,3-
dimethoxybenzene with n-BuLi] in THF at −78 °C and the reaction
mixture was allowed to stir at room temperature for 2 h gave the
expected (2R,3R)-ketone 10 in 75% yield (dr = 96 : 4). The (2R,3R)-
ketone 10 was subjected to stereoselective reduction using NaBH4
in MeOH at −78 to 0 °C for 4 h to give the desired alcohol
(1R,2R,3R)-14 in 87% yield as an inseparable mixture of
diastereoisomers (dr = 84 : 11 : 5). Similar results were observed
when DIBALH was employed as a reducing agent in THF at −78 °C.10
The stereochemical outcome of the hydride reduction of (2R,3R)-10
to give (1R,2R,3R)-14 as a major diastereomer could be explained
on the basis of the Felkin–Ahn model.11 The relative
stereochemistry at the C-1 and C-2 of (1R,2R,3R)-14 was assigned
by the analysis of the coupling constant between H-1 and H-2; H-1
appeared as a doublet at  4.27 (d, 3J = 9.2 Hz) ppm.12 Next,
treatment of alcohol 14 (as a mixture of diastereomers, dr = 84 : 11
: 5) with TBSCl gave TBS-ether 15, containing (1R,2R,3R)-15 as a
major isomer, in 82% yield. The second aromatic ring was installed
via dihydroxylation of the terminal alkene of (1R,2R,3R)-15 by using
OsO4 and NMO followed by oxidative cleavage using NaIO4 to
provide the corresponding aldehyde. Without isolation, the
Scheme 2. The selective formation of alcohols 4 and furan 8.
Scheme 3. Proposed mechanism for the formation of furan 8.
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Scheme 5. Synthesis of chiral alcohols 9.
aldehyde formed was further reacted with [4-(benzyloxy)-3-
methoxyphenyl]lithium (1.5 equiv.) in THF at 78 oC for 4 h to yield,
after column chromatography, the corresponding alcohols
(1R,2S,3R,4R)-9A (47% yield, single isomer) and (1S,2S,3R,4R)-9B
(12% yield, single isomer) along with a mixture of 9A and 9B (10%
yield).13 The stereochemical outcome of the addition of aryllithium
to aldehyde derived from (1R,2R,3R)-15 to give (1R,2S,3R,4R)-9A as
a major diastereomer14 could be explained by the Felkin–Ahn
model.11
(route a). Thus, (1R,2S,3R,4R)-9A was subjected to TBS deprotection
using TBAF to give diol (1R,2R,3S,4R)-19A in 87% yield (Scheme 6).
To our delight, it was found that diol (1R,2R,3S,4R)-19A underwent
stereoselective intramolecular cyclization via the CO bond
formation (furan formation) to form the desired furan
(2R,3R,4S,5S)-20 in 92% yield as a single diastereomer by simply
treatment with a catalytic amount of p-TsOH in dry CH2Cl2 at room
temperature for 1.5 h. The NOESY experiments confirmed that
(2R,3R,4S,5S)-20
possessed
2,3-anti-3,4-syn-4,5-anti
The chemoselective generation of the oxonium ion
intermediate IV was then planned to be generated via a methane
sulfonate derivative 16 (Scheme 6).15 Unexpectedly, upon
treatment of (1R,2S,3R,4R)-9A with methane sulfonyl chloride and
dry Et3N in THF at room temperature for 1 h, the aryltetralin 17 was
obtained in 54% yield as a single diastereomer without the
formation of the desired furan 18. The chemical structure of 17 and
its stereochemistry were established based on mass spectrometry,
the NMR analyses, and the NOESY experiments (see ESI). The
relative stereochemistry at the 3,4-position was assigned by the
analysis of the coupling constant between H-3 and H-4; H-4
appeared as a doublet at  3.55 (d, 3J = 9.8 Hz) ppm.16 The reaction
mechanism for the formation of 17 was proposed (Scheme 6).
Indeed, the chemoselective generation of the oxonium ion
intermediate IV via methane sulfonate derivative 16 was achieved
as expected. However, IV rapidly underwent an intramolecular
Friedel–Crafts reaction (route a vs. route b) to form an intermediate
V leading to 17 after re-aromatization process. It is also worth
mentioning here that the observed stereoselective formation of
aryltetralin 17 could be useful for the synthesis of a variety of
biologically active aryltetralin lignans.17
stereochemistries (see ESI).
At this stage, the observed stereoselective formation of
(2R,3R,4S,5S)-20 from (1R,2R,3S,4R)-19A should be discussed
(Scheme 7). According to the experimental results described above,
it was proposed that the chemoselective formation of benzylic
carbocation is governed by the substitution pattern in the aromatic
rings. Upon treatment of (1R,2R,3S,4R)-19A with p-TsOH, the
oxonium ion VI was chemoselectively generated. Intramolecular
cyclization of VI via the more favorable transition state VIII led to
the formation of furan (2R,3R,4S,5S)-20 as a single isomer. On the
1
contrary, furan 21 was not detected in the H NMR analysis of the
crude mixture18 implying that the oxonium IX was not formed under
our reaction conditions presumably due to the developing steric
interaction between the adjacent methoxy and benzyloxy
substituents on the aromatic ring of IX. Alternatively, the formation
of 20 from 21 via an acid-catalyzed ring opening of the furan ring of
21 followed by cyclization via the more favorable transition state
VIII should not be excluded.10 The chemoselective formation of the
oxonium ion VI and stereoselective cyclization were further
confirmed when (1S,2S,3R,4R)-9B was readily converted to
(2R,3R,4S,5S)-20 as a single isomer in 89% yield (Scheme 6).
To circumvent the formation of aryltetralin 17, it was
anticipated that the increase in the nucleophilicity of the oxygen
atom at the C-1 would both facilitate the CO bond formation
(route b) and suppress the competitive Friedel–Crafts reaction
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DOI: 10.1039/C7OB00749C
Scheme 6. Synthesis of aryltetralin 17 and furan 20.
With (2R,3R,4S,5S)-20 in hand, it was converted to ent-1 (99%
yield) by hydrogenation using Pd/C in dry ethyl acetate. The
spectroscopic data of the synthesized ent-1 are in good agreement
with those reported (see ESI).
Conclusions
The first asymmetric synthesis of ent-fragransin C1 was described
using an intramolecular CO bond formation via the
chemoselective formation of the benzylic carbocation as a key step.
On this basis, ent-fragransin C1 bearing the 2,3-anti-3,4-syn-4,5-anti
stereochemistires was synthesized in good yield as a single
diastereomer. Our synthesis confirms the 2R,3R,4S,5S
configurations assigned for the natural ent-fragransin C1. The
biological activity evaluation is currently under investigation.
Moreover, aryltetralin derivative was also synthesized with high
stereoselectivity via an intramolecular CC bond formation. This
approach could be useful for asymmetric synthesis of various
biologically active aryltetralin derivatives.
Experimental
General information
The 1H NMR spectra were recorded on a Bruker-400 (400 MHz)
spectrometer in acetone-d6 or CDCl3 using tetramethylsilane as an
internal standard. The 13C NMR spectra were recorded on a Bruker-
400 (100 MHz) spectrometer in acetone-d6 or CDCl3 using residual
non-deuterated solvent peaks as an internal standard.
Tetrahydrofuran (THF) was distilled from sodium-benzophenone
ketyl. Dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and ethanol
(EtOH) were distilled over calcium hydride and stored over
Scheme 7. Proposed mechanism for the formation of 20.
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activated molecular sieves (4 Å). Methanol (MeOH) was distilled
ARTICLE
(1R,2S,3R)-1-[4-(Benzyloxy)-3-methoxyphenyl]-4-V[i(etwerAtr-ticle Online
over Mg powder. Other common solvents [CH2Cl2, hexanes, and butyldimethylsilyl)oxy]-2,3-dimethylbutan-D1O-oI:l1(04.A10)3a9n/Cd7OB00749C
EtOAc] were distilled before use. All glassware including needles (1S,2S,3R)-1-[4-(Benzyloxy)-3-methoxyphenyl]-4-[(tert-
and syringes were oven-dried and kept in a desiccator before use. butyldimethylsilyl)oxy]-2,3-dimethylbutan-1-ol (4B). According to
Purification of the reaction products was carried out by column the same procedure as for 8, oxidative cleavage of 5 (dr = 90 : 10)
chromatography on silica gel.
(89.5 mg, 0.4 mmol) provided 6, which was further reacted with [4-
tert-Butyl{[(2R,3R)-2,3-dimethylpent-4-en-1-
(benzyloxy)-3-methoxyphenyl]lithium
[prepared
from
1-
yl]oxy}dimethylsilane (5).6c [α]24 +21.2 (c 1.10, CHCl3). 1H NMR (benzyloxy)-4-bromo-2-methoxybenzene (176 mg, 0.6 mmol) and n-
D
(400 MHz, CDCl3): δ 5.755.66 (m, 1H, CH), 5.004.91 (m, 2H, CH2), BuLi (1.6 M in hexane, 0.4 mL, 0.6 mmol)]. After stirring at −78 °C
3.49 (dd, J = 9.8, 6.5 Hz, 1H, CHH), 3.39 (dd, J = 9.8, 6.5 Hz, 1H, for 2 h, the reaction mixture was quenched with a saturated
CHH), 2.352.26 (m, 1H, CH), 1.611.52 (m, 1H, CH), 1.00 (d, J = 6.9 aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (3 × 30
Hz, 3H, CH3), 0.89 [s, 9H, SiC(CH3)3], 0.81 (d, J = 6.9 Hz, 3H, CH3), mL). The combined organic phase was washed with brine and dried
0.03 (s, 6H, 2 × SiCH3). 13C NMR (100 MHz, CDCl3): δ 141.8 (CH), over anhydrous Na2SO4. Purification by column chromatography
113.9 (CH2), 66.3 (CH2), 40.5 (CH), 38.8 (CH), 25.9 (3 × CH3), 18.4 (C), (10% EtOAc in hexanes) gave a mixture of 4A (major) and 4B
17.9 (CH3), 12.9 (CH3), −5.4 (2 × CH3). IR (CHCl3): νmax 1472w, 1257m, (minor) (96.6 mg, 55% yield, dr = 67 : 33) as a colorless oil. Rf 0.10
1091m, 838s cm−1. MS: m/z (%) relative intensity 229 [(M + H)+, 2], (10% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, interpreted
220 (100), 204 (53), 190 (85), 148 (76), 98 (32). HRMS (ESI-TOF) equally for both isomers): δ 7.507.20 (m, 10H, ArH of 4A and 4B),
calcd for C13H29OSi [M + H]+: 229.1988, found: 229.1986.
6.98 (d, J = 1.2 Hz, 1H, ArH of 4A), 6.94 (d, J = 1.8 Hz, 1H, ArH of 4B),
6.856.74 (m, 4H, ArH of 4A and 4B), 5.14 (s, 4H CH2 of 4A and 4B),
(2S,3S,4R)-2-[4-(Benzyloxy)-3-methoxyphenyl]-3,4-
dimethyltetrahydrofuran (8). To a solution of 5 (dr = 90 : 10) (63 4.80 (s, 2H, OH of 4A and 4B), 4.44 (s, 2H, CH of 4A and 4B), 3.90 (s,
mg, 0.28 mmol) and NMO (113.7 mg, 0.84 mmol) in CH2Cl2 (11 mL) 6H, 2  OCH3 of 4A and 4B), 3.653.55 (m, 2H, CHH of 4A and 4B),
were added OsO4 (2.5% w/v in t-butanol, 0.14 mL, 0.014 mmol) and 3.553.45 (m, 2H, CHH of 4A and 4B), 2.152.05 (m, CH of 4B),
water (0.14 mL). After stirring for 14 h at room temperature, NaIO4 2.051.98 (m, CH of 4A), 1.981.89 (m, CH of 4B), 1.821.73 (m, CH
(119.3 mg, 0.56 mmol) was added, and stirring of the reaction of 4A), 0.94 [s, 9H, SiC(CH3)3 of 4B], 0.93 [s, 9H, SiC(CH3)3 of 4A],
mixture continued for 1 h. Then it was quenched with a saturated 0.91 (d, J = 7.1 Hz, 3H, CH3 of 4A), 0.85 (d, J = 7.2 Hz, 3H, CH3 of 4B),
aqueous Na2S2O3 solution (10 mL) and extracted with CH2Cl2 (3 × 20 0.80 (d, J = 7.1 Hz, 3H, CH3 of 4B), 0.74 (d, J = 7.2 Hz, 3H, CH3 of 4A),
mL). The combined organic phase was washed with brine and dried 0.13 (s, 6H, 2 × SiCH3 of 4A), 0.12 (s, 6H, 2 × SiCH3 of 4B). 13C NMR
over anhydrous Na2SO4. The crude mixture was filtered through a (100 MHz, CDCl3, 4A marked *): δ 149.5 (C), 149.2 (C*), 147.0 (C),
short column (50% Et2O in pentane) to give 6. A flame-dried round 146.6 (C*), 138.1 (C), 138.0 (C*), 137.6 (C*), 137.4 (C), 128.5 (2  CH
bottom flask equipped with a magnetic stirring bar, an argon inlet, of 4A and 4B), 127.7 (CH of 4A and 4B), 127.3 (2  CH of 4A and 4B),
and a rubber septum was charged with 1-(benzyloxy)-4-bromo-2- 118.9 (CH), 118.1 (CH*), 113.7 (CH of 4A and 4B), 110.0 (CH of 4A
methoxybenzene (123 mg, 0.42 mmol) and dry THF (1 mL). The and 4B), 76.8 (CH*), 76.6 (CH), 71.2 (CH2 of 4A and 4B), 65.5 (CH2),
solution was cooled at −78 °C and then a solution of n-BuLi (1.6 M in 65.0 (CH2*), 56.0 (OCH3 of 4A and 4B), 46.0 (CH*), 44.9 (CH), 40.3
hexane, 0.26 mL, 0.42 mmol) was added dropwise. The resulting (CH*), 35.2 (CH), 29.7 (C of 4A and 4B), 25.9 (3  CH3 of 4A and 4B),
mixture was stirred for 10 min and then a solution of 6 in dry THF 17.5 (CH3*), 15.6 (CH3), 12.6 (CH3), 5.7 (CH3*), 5.4 (CH3), 5.5
(0.7 mL) was added dropwise. After stirring at −78 °C for 2 h, the (CH3*). IR (neat): νmax 3398br, 1593m, 1514s, 1456s, 1258s, 1226s,
reaction mixture was quenched with a saturated aqueous NH4Cl 1138s, 1078s, 1035s cm−1. MS (ISCID): m/z (%) relative intensity 467
solution (10 mL) and extracted with EtOAc (3 × 30 mL). The [(M + Na)+, 100], 413 (2), 376 (9). HRMS (ESI-TOF) calcd for
combined organic phase was washed with brine and dried over C26H40NaO4Si [M + Na]+: 467.2594, found: 467.2609.
anhydrous Na2SO4. Purification by column chromatography (10%
(2R,3R)-2,3-Dimethylpent-4-enoic acid (12).9 A solution of 11
EtOAc in hexanes) gave 8 as a colorless oil (51.4 mg, 59% yield) as a (dr = 96 : 4, 533 mg, 1.95 mmol) in a mixture of THF (9 mL) and
1
mixture of diasteromers (dr = 89 : 8 : 3, 400 MHz H NMR analysis). water (3 mL) cooled at 0 °C was treated with a 30% (v/v) aqueous
Rf 0.31 (20% EtOAc in hexanes); [α]24D +14.8 (c 0.99, CHCl3). 1H NMR solution of H2O2 (0.9 mL, 7.8 mmol) followed by dropwise addition
(400 MHz, CDCl3): δ 7.507.25 (m, 5H, ArH), 6.90 (d, J = 1.8 Hz, 1H, of a solution of LiOH·H2O (131 mg, 3.1 mmol) in water (4 mL). After
ArH), 6.83 (d, J = 8.2 Hz, 1H, ArH), 6.77 (dd, J = 1.8, 8.2 Hz, 1H, ArH), stirring at 0 °C for 2 h, two phases of the reaction mixture were
5.14 (s, 2H, CH2), 4.36 (d, J = 8.2 Hz, 1H, CH), 4.24 (dd, J = 6.4, 8.3 separated. The organic phase was washed with brine, dried over
Hz, 1H, CHH), 3.90 (s, 3H, OCH3), 3.61 (dd, J = 4.6, 8.3 Hz, 1H, CHH), anhydrous Na2SO4, and concentrated in vacuo to give the recovered
2.502.30 (m, 1H, CH), 2.202.00 (m, 1H, CH), 1.00 (d, J = 7.2 Hz, chiral auxiliary. The aqueous phase was acidified (pH 1) by using
3H, CH3), 0.95 (d, J = 7.0 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 10% HCl aqueous solution and extracted with CH2Cl2 (3 × 15 mL).
149.7 (C), 147.5 (C), 137.3 (C), 135.9 (C), 128.5 (2  CH), 127.8 (CH), The combined organic phase was washed with brine and dried over
127.3 (2  CH), 118.3 (CH), 113.8 (CH), 109.6 (CH), 86.4 (CH), 75.3 anhydrous Na2SO4. Purification by column chromatography (20%
(CH2), 71.1 (CH2), 56.0 (OCH3), 45.2 (CH), 36.8 (CH), 13.5 (CH3), 11.9 EtOAc in hexanes) gave 12 (230.4 mg, 92% yield, dr = 96 : 4, 400
1
(CH3). IR (neat): νmax 1513s, 1454m, 1383m, 1264s, 1226m, 1139m, MHz H NMR analysis) as a colorless liquid. Rf 0.33 (30% EtOAc in
1
1012m cm−1. MS (ISCID): m/z (%) relative intensity 335 [(M + Na)+, hexanes); [α]24 +37.8 (c 1.19, CHCl3). H NMR (400 MHz, CDCl3): δ
D
48], 276 (3), 244 (100), 229 (7). HRMS (ESI-TOF) calcd for C20H25O3 5.65 (ddd, J = 17.1, 10.2, 8.2 Hz, 1H, CH), 5.044.93 (m, 2H, CH2),
[M + H]+: 313.1804, found: 313.1792.
2.602.40 (m, 1H, CH), 2.402.30 (m, 1H, CH), 1.13 (d, J = 7.0 Hz,
3H, CH3), 1.07 (d, J = 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ
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182.2 (CO), 140.5 (CH), 115.4 (CH2), 44.8 (CH), 40.8 (CH), 18.4 (CH3), Na)+, 20], 355 [(M + H)+, 5], 306 (49), 286 (100). HRMS (ESI-TOF)
View Article Online
DOI: 10.1039/C7OB00749C
+
14.3 (CH3). MS: m/z (%) relative intensity 129 [(M + H)+, 20], 128 calcd for C22H27O4 [M + H] : 355.1909, found: 355.1906.
(M+, 8), 113 (40), 83 (49), 67 (53).
(1R,2R,3R)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2,3-
dimethylpent-4-en-1-ol (14). A flame-dried round bottom flask
(2R,3R)-N-Methoxy-N,2,3-trimethylpent-4-enamide (13).19
A
flame-dried round bottom flask equipped with a magnetic stirring equipped with a magnetic stirring bar, an argon inlet, and a rubber
bar, an argon inlet, and a rubber septum was charged with 12 (dr = septum was charged with 10 (318.7 mg, 0.9 mmol) and dry MeOH
96 : 4) (228 mg, 1.78 mmol), DMAP (22 mg, 0.18 mmol), and dry (6 mL). The solution was cooled at 78 °C and then NaBH4 (137 mg,
CH2Cl2 (7 mL). The solution was cooled at 0 °C then N,N'- 3.6 mmol) was added. The reaction was slowly warmed up to 0 °C
dicyclohexylcarbodiimide (404 mg, 1.96 mmol) was added. The over 3 h, and the stirring was continued at 0 °C for 1 h. The reaction
mixture was stirred for 15 min and N,O-dimethylhydroxylamine mixture was quenched with H2O (10 mL) and extracted with EtOAc
hydrochloride (208 mg, 2.13 mmol) and NEt3 (0.3 mL, 2.13 mmol) (3 × 15 mL). The combined organic phase was dried over anhydrous
were subsequently added. The reaction was slowly warmed up to Na2SO4. After removal of solvent in vacuo, the crude product was
room temperature, and the stirring was continued at room purified by column chromatography (1% EtOAc in CH2Cl2) to afford
temperature for 15 h. The reaction mixture was quenched with H2O 14 (277.9 mg, 87% yield) as a colorless oil with 84 : 11 : 5
(10 mL) and the suspension was filtered. The filter cake was washed diastereomeric ratio (400 MHz 1H NMR analysis). Rf 0.24 (20% EtOAc
with CH2Cl2 (3 x 10 mL). The layers were separated and the aqueous in hexanes); [α]28D 7.5 (c 0.53, CHCl3). 1H NMR (400 MHz, CDCl3): δ
phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic 7.557.45 (m, 2H, ArH), 7.407.20 (m, 3H, ArH), 6.52 (s, 2H, ArH),
phase was dried over anhydrous Na2SO4. After removal of solvent in 5.955.80 (m, 1H, CH), 5.205.05 (m, 2H, CHH), 5.00 (s, 2H, CH2),
vacuo, the crude product was purified by column chromatography 4.27 (d, J = 9.2 Hz, 1H, CH), 3.82 (s, 6H, 2  OCH3), 2.902.80 (m, 1H,
(20% EtOAc in hexane] to afford 13 (226.5 mg, 74% yield) as a CH), 1.901.80 (m, 1H, CH), 1.09 (d, J = 7.0 Hz, 3H, CH3), 0.57 (d, J =
colorless oil (dr = 96 : 4). Rf 0.40 (20% EtOAc in hexanes); [α]30
7.0 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 153.4 (2  C), 140.6
D
15.0 (c 1.02, CHCl3). 1H NMR (400 MHz, CDCl3): δ 5.725.60 (m, 1H, (CH), 139.8 (C), 137.8 (C), 136.1 (C), 128.5 (2  CH), 128.1 (2  CH),
CH), 5.104.98 (m, 2H, CHH), 3.69 (s, 3H, OCH3), 3.20 (s, 3H, CH3), 127.8 (CH), 115.1 (CH2), 103.7 (2  CH), 77.8 (CH), 74.9 (CH2), 56.1 (2
2.802.66 (m, 1H, CH), 2.502.35 (m, 1H, CH), 1.07 (d, J = 6.9 Hz,  OCH3), 45.1 (CH), 37.3 (CH), 18.4 (CH3), 11.0 (CH3). IR (CHCl3): νmax
3H, CH3), 0.97 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 3602m, 1593s, 1504m, 1464s, 1422m, 1328m, 1237s, 1131s cm−1.
177.4 (CO), 141.7 (CH), 114.9 (CH2), 61.4 (OCH3), 41.3 (CH3), 40.1 MS (ISCID): m/z (%) relative intensity 379 [(M + Na)+, 100], 357 [(M
(CH), 32.1 (CH), 19.0 (CH3), 16.0 (CH3). MS (ISCID): m/z (%) relative + H)+, 3], 339 (23). HRMS (ESI-TOF) calcd for C22H28O4Na [M + Na]+:
intensity 194 [(M + Na)+, 100], 172 [(M + H)+, 23], 126 (3), 118 (3). 379.1885, found: 379.1888.
HRMS (ESI-TOF) calcd for C9H18NO2 [M + H]+: 172.1338, found:
172.1346.
{[(1R,2R,3R)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2,3-
dimethylpent-4-en-1-yl]oxy}(tert-butyl)dimethylsilane (15).
A
(2R,3R)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2,3-
flame-dried round bottom flask equipped with a magnetic stirring
dimethylpent-4-en-1-one (10). A flame-dried round bottom flask bar, an argon inlet, and a rubber septum was charged with 14 (270
equipped with a magnetic stirring bar, an argon inlet, and a rubber mg, 0.76 mmol), imidazole (103.5 mg, 1.52 mmol), and dry CH2Cl2
septum
was
charged
with
2-(benzyloxy)-5-bromo-1,3- (2.7 mL). A solution of TBSCl (230 mg, 1.52 mmol) in dry hexane
dimethoxybenzene (521 mg, 1.6 mmol) and dry THF (4.5 mL). The (0.27 mL) was added. The reaction mixture was allowed to stir at
solution was cooled at 78 °C then a solution of n-BuLi (1.6 M in room temperature overnight. After the complete consumption of
hexane, 0.93 mL, 1.5 mmol) was added dropwise. After stirring for 14, the reaction was quenched with a saturated aqueous NaHCO3
10 min, a solution of the amide 13 in dry THF (4.5 mL) was added solution (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The
dropwise at 78 °C. The reaction was slowly warmed up to room combined organic phase was washed with brine (10 mL) and dried
temperature, and the stirring was continued at room temperature over anhydrous Na2SO4. After removal of solvent in vacuo, the
for 2 h. The reaction mixture was quenched with H2O (15 mL) and crude product was purified by column chromatography (10% EtOAc
extracted with EtOAc (3 × 25 mL). The combined organic phase was in hexanes) to afford 15 (160.3 mg, 82% yield) as a colorless oil with
washed with brine (20 mL) and dried over anhydrous Na2SO4. After a 82 : 13 : 5 diastereomeric ratio (400 MHz 1H NMR analysis). Rf 0.54
1
removal of solvent in vacuo, the crude product was purified by (20% EtOAc in hexanes); [α]27 +25.8 (c 1.10, CHCl3). H NMR (400
D
column chromatography (10% Et2O in hexanes) to afford 10 (330.5 MHz, CDCl3): δ 7.507.40 (m, 2H, ArH), 7.357.20 (m, 3H, ArH), 6.45
mg, 75% yield) as a colorless oil with a 96 : 4 diastereomeric ratio (s, 2H, ArH), 5.905.80 (m, 1H, CH), 5.105.00 (m, 2H, CHH), 5.01 (s,
1
(400 MHz H NMR analysis). Rf 0.40 (20% EtOAc in hexanes); [α]24
2H, CH2), 4.20 (d, J = 8.6 Hz, 1H, CH), 3.78 (s, 6H, 2  OCH3),
D
47.4 (c 0.51, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.557.45 (m, 2H, 2.752.90 (m, 1H, CH), 1.651.75 (m, 1H, CH), 1.04 (d, J = 7.0 Hz,
ArH), 7.407.25 (m, 3H, ArH), 7.20 (s, 2H, ArH), 5.805.65 (m, 1H, 3H, CH3), 0.85 [s, 9H, SiC(CH3)3], 0.49 (d, J = 7.0 Hz, 3H, CH3), 0.01 (s,
CH), 5.10 (s, 2H, CH2), 5.105.00 (m, 2H, CHH), 3.89 (s, 6H, 2  3H, SiCH3), 0.34 (s, 3H, SiCH3). 13C NMR (100 MHz, CDCl3): δ 153.1
OCH3), 3.353.25 (m, 1H, CH), 2.702.25 (m, 1H, CH), 1.14 (d, J = 6.9 (2  C), 140.5 (CH), 137.8 (C), 136.4 (C), 135.5 (C), 128.6 (2  CH),
Hz, 3H, CH3), 1.00 (d, J = 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): 128.0 (2  CH), 127.8 (CH), 114.4 (CH2), 104.1 (2  CH), 78.3 (CH),
δ 203.1 (CO), 153.4 (2  C), 141.5 (C), 141.2 (CH), 137.4 (C), 132.7 74.9 (CH2), 56.1 (2  OCH3), 46.7 (CH), 36.4 (CH), 25.9 (3  CH3), 18.9
(C), 128.4 (2  CH), 128.2 (2  CH), 128.0 (CH), 115.0 (CH2), 105.9 (2 (CH3), 18.2 (C), 10.8 (CH3), 4.4 (CH3), 4.9 (CH3). IR (CHCl3): νmax
 CH), 75.1 (CH2), 56.3 (2  OCH3), 45.4 (CH), 41.2 (CH), 19.0 (CH3), 1593m, 1464s, 1129s cm−1. MS (ISCID): m/z (%) relative intensity
15.9 (CH3). IR (CHCl3): νmax 1672m, 1584m, 1501m, 1463m, 1415m, 493 [(M + Na)+, 100], 402 (15), 339 (6), 319 (12). HRMS (ESI-TOF)
1324m, 1131s cm−1. MS (ISCID): m/z (%) relative intensity 377 [(M + calcd for C28H42O4SiNa [M + Na]+: 493.2750, found: 493.2752.
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Organic & Biomolecular Chemistry
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(1R,2S,3R,4R)-4-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-1-[4-
(benzyloxy)-3-methoxyphenyl]-4-[(tert-butyldimethylsilyl)oxy]-
CH), 128.0 (2  CH), 127.8 (CH), 127.7 (CH), 127.2 (2  CH), 119.6
(CH), 113.8 (CH), 110.7 (CH), 103.7 (2  CH), 79.2 (CH), 75.6 (CH),
View Article Online
DOI: 10.1039/C7OB00749C
2,3-dimethylbutan-1-ol (9A) and (1S,2S,3R,4R)-4-[4-(benzyloxy)- 74.8 (CH2), 71.1 (CH2), 56.1 (2  OCH3), 55.9 (OCH3), 45.7 (CH), 40.0
3,5-dimethoxyphenyl]-1-[4-(benzyloxy)-3-methoxyphenyl]-4-
[(tert-butyldimethylsilyl)oxy]-2,3-dimethylbutan-1-ol (9B). To
(CH), 25.9 (3  CH3), 18.3 (C), 18.1 (CH3), 13.3 (CH3), 4.5 (CH3), 5.0
a
(CH3). IR (CHCl3): νmax 3355br, 1594m, 1507s, 1464s, 1131s cm−1. MS
stirred suspension of 15 (dr = 91 : 5 : 4) (128.6 mg, 0.27 mmol) and (ISCID): m/z (%) relative intensity 709 [(M + Na)+, 100], 669 (3), 618
N-methylmorpholine-N-oxide (110 mg, 0.81 mmol) in CH2Cl2 (12 (2), 537 (4), 446 (2), 319 (4). HRMS (ESI-TOF) calcd for C41H54O7SiNa
mL), osmium tetroxide (2.5% w/v in t-butanol, 0.14 mL, 0.014 [M + Na]+: 709.3537, found: 709.3535.
mmol) and water (0.14 mL) were added. After stirring at room
{[(1R,2R,3R,4S)-6-(Benzyloxy)-4-[4-(benzyloxy)-3-
temperature for 14 h, the NaIO4 (115 mg, 0.54 mmol) was added. methoxyphenyl]-5,7-dimethoxy-2,3-dimethyl-1,2,3,4-
The stirring was continued for 1.5 h then it was quenched with a tetrahydronaphthalen-1-yl]oxy}(tert-butyl)dimethylsilane (17). A
saturated aqueous Na2S2O3 solution (10 mL) and extracted with flame-dried round bottom flask equipped with a magnetic stirring
CH2Cl2 (3 × 15 mL). The combined organic phase was washed with bar, an argon inlet, and a rubber septum was charged with 9A (36.7
brine (10 mL) and dried over anhydrous Na2SO4. After removal of mg, 0.05 mmol) and dry THF (1.5 mL).
A solution of
the solvents in vacuo, the aldehyde crude product was obtained. A methanesulfonyl chloride in dry THF (0.08 mL, 1.03 M, 0.07 mmol)
flame-dried round bottom flask equipped with a magnetic stirring was added at room temperature followed by the addition of Et3N
bar, an argon inlet, and a rubber septum was charged with 1- (0.02 mL, 0.085 mmol). After stirring for 1 h, the reaction mixture
(benzyloxy)-4-bromo-2-methoxybenzene (119 mg, 0.4 mmol) and was quenched with a saturated aqueous NaHCO3 solution (5 mL)
dry THF (2 mL). The solution was cooled at 78 °C then a solution of and extracted with CH2Cl2 (3 × 10 mL). The combined organic phase
n-BuLi (1.6 M in hexane, 0.25 mL, 0.4 mmol) was added dropwise. was dried over anhydrous Na2SO4. After removal of solvent in
After stirring for 10 min, a solution of the above obtained aldehyde vacuo, the crude product was purified by column chromatography
in dry THF (2 mL) was added dropwise. After stirring at 78 °C for 4 (10% EtOAc in hexanes) to afford 17 (19.3 mg, 54% yield) as a single
1
h, the reaction mixture was quenched with a saturated aqueous diastereomer as determined by H NMR (400 MHz) analysis. Rf 0.46
1
NaHCO3 (10 mL) and extracted with EtOAc (3 × 15 mL). The (20% EtOAc in hexanes); [α]26 33.1 (c 1.00, CHCl3). H NMR (400
D
combined organic phase was washed with brine (10 mL) and dried MHz, CDCl3): δ 7.507.40 (m, 4H, ArH), 7.407.25 (m, 6H, ArH), 6.93
over anhydrous Na2SO4. After removal of the solvents in vacuo, the (s, 1H, ArH), 6.76 (d, J = 8.2 Hz, 1H, ArH), 6.68 (d, J = 1.8 Hz, 1H,
crude product was purified by column chromatography (20% EtOAc ArH), 6.53 (dd, J = 8.2, 1.9 Hz, 1H, ArH), 5.11 (s, 2H, CH2), 4.99 (d, J =
in hexanes) to afford 9A (87 mg, 47% yield), 9B (22.1 mg, 12% 4.4 Hz, 1H, CH), 4.954.80 (m, 2H, CH2), 3.84 (s, 3H, OCH3), 3.83 (s,
yield), and a mixture of 9A and 9B (19.1 mg, 10%).
3H, OCH3), 3.55 (d, J = 9.8 Hz, 1H, CH), 2.96 (s, 3H, OCH3), 2.101.98
9A; a colorless oil; Rf 0.16 (20% EtOAc in hexanes); [α]26 +25.6 (m, 1H, CH), 1.981.89 (m, 1H, CH), 1.03 [s, 9H, Si(CH3)3], 1.01 (d, J =
D
(c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.507.20 (m, 10H, 2  7.0 Hz, 3H, CH3), 0.76 (d, J = 6.8 Hz, 3H, CH3), 0.25 (s, 3H, CH3), 0.19
ArH), 6.97 (s, 1H, ArH), 6.84 (s, 2H, ArH), 6.45 (s, 2H, ArH), 5.14 (s, (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 152.2 (C), 151.3 (C), 149.4
2H, CH2), 5.105.00 (m, 1H, CH), 5.01 (s, 2H, CH2), 4.42 (d, J = 8.2 Hz, (C), 145.9 (C), 142.0 (C), 140.1 (C), 137.9 (C), 137.4 (C), 135.3 (C),
1H, CH), 3.89 (s, 3H, OCH3), 3.76 (s, 6H, 2  OCH3), 2.001.90 (m, 128.4 (2  CH), 128.2 (2  CH), 128.1 (2  CH), 127.7 (2  CH), 127.4
1H, CH), 1.901.80 (m, 1H, CH), 0.94 (d, J = 6.9 Hz, 3H, CH3), 0.90 [s, (2  CH), 125.2 (C), 120.4 (CH), 114.5 (CH), 113.2 (CH), 104.4 (CH),
9H, SiC(CH3)3], 0.76 (d, J = 7.0 Hz, 3H, CH3), 0.09 (s, 3H, CH3), 0.27 74.7 (CH2), 73.8 (CH), 71.4 (CH2), 59.5 (OCH3), 56.3 (OCH3), 55.5
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 153.2 (2  C), 149.4 (C), (OCH3), 46.4 (CH), 41.2 (CH), 40.8 (CH), 25.9 (3  CH3), 18.3 (C), 17.5
147.0 (C), 139.9 (C), 138.2 (C), 137.7 (C), 137.4 (C), 135.8 (C), 128.6 (CH3), 6.4 (CH3), 4.2 (CH3), 4.9 (CH3). IR (CHCl3): νmax 1513m,
(2  CH), 128.5 (2  CH), 128.1 (2  CH), 127.8 (CH), 127.7 (CH), 1464m, 1258s, 1125s, 1085m, 1051m cm−1. MS (ISCID): m/z (%)
127.3 (2  CH), 118.4 (CH), 113.7 (CH), 110.2 (CH), 104.5 (2  CH), relative intensity 691 [(M + Na)+, 100], 600 (2), 537 (34), 446 (3),
78.8 (CH), 76.0 (CH), 74.9 (CH2), 71.2 (CH2), 56.1 (2  OCH3), 56.0 413 (3), 355 (2), 323 (4). HRMS (ESI-TOF) calcd for C41H52O6SiNa [M
(OCH3), 44.4 (CH), 44.3 (CH), 26.0 (3  CH3), 18.3 (C), 17.2 (CH3), 9.4 + Na]+: 691.3431, found: 691.3431.
(CH3), 4.3 (CH3), 4.7 (CH3). IR (CHCl3): νmax 3358br, 1593s, 1508s,
(1R,2R,3S,4R)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-4-[4-
1464s, 1258s, 1130s cm−1. MS (ISCID): m/z (%) relative intensity 709 (benzyloxy)-3-methoxyphenyl]-2,3-dimethylbutane-1,4-diol (19A).
[(M + Na)+, 100], 669 (2), 618 (2), 537 (6), 525 (11), 446 (3). HRMS A flame-dried round bottom flask equipped with a magnetic stirring
(ESI-TOF) calcd for C41H54O7SiNa [M + Na]+: 709.3537, found: bar, an argon inlet, and a rubber septum was charged with 9A (77
709.3538.
mg, 0.11 mmol) and dry THF (2 mL). A solution of TBAF in dry THF
9B; a colorless oil; Rf 0.20 (20% EtOAc in hexanes). [α]26 +19.4 (0.25 mL, 0.5 M, 0.11 mmol) was added at room temperature. After
D
(c 1.04, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.507.20 (m, 10H, 2  stirring for 3 h, the reaction mixture was quenched with H2O (10
ArH), 6.88 (s, 1H, ArH), 6.82 (d, J = 8.3 Hz, 1H, ArH), 6.75 (d, J = 8.1 mL) and extracted with EtOAc (3 × 10 mL). The combined organic
Hz, 1H, ArH), 6.62 (s, 2H, ArH), 5.16 (s, 2H, CH2), 5.08 (s, 2H, CH2), phase was washed with brine (10 mL) and dried over anhydrous
4.77 (d, J = 5.0 Hz, 1H, CH), 4.31 (d, J = 9.8 Hz, 1H, CH), 3.89 (s, 3H, Na2SO4. After removal of the solvents in vacuo, the crude product
OCH3), 3.85 (s, 6H, 2  OCH3), 2.102.00 (m, 1H, CH), 2.001.90 (m, was purified by column chromatography (50% EtOAc in hexanes) to
1H, CH), 1.10 (d, J = 7.1 Hz, 3H, CH3), 0.98 [s, 9H, SiC(CH3)3], 0.54 (d, afford 19A as a white solid (55.6 mg, 87% yield) as a single
1
J = 6.92 Hz, 3H, CH3), 0.17 (s, 3H, CH3), 0.10 (s, 3H, CH3). 13C NMR diastereomer (400 MHz H NMR analysis). Rf 0.17 (40% EtOAc in
o
(100 MHz, CDCl3): δ 153.2 (2  C), 149.6 (C), 147.3 (C), 139.3 (C), hexanes). Rf 0.17 (40% EtOAc in hexanes); mp 49-52 C (50% EtOAc
1
138.2 (C), 137.7 (C), 137.4 (C), 135.3 (C), 128.6 (2  CH), 128.5 (2  in hexanes). [α]26D 16.5 (c 1.00, CHCl3). H NMR (400 MHz, CDCl3):
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δ 7.507.30 (m, 10H, 2  ArH), 6.97 (d, J = 1.6 Hz, 1H, ArH), 6.83 (d, J 1233s, 1131s cm−1. MS (ISCID): m/z (%) relative intenVsiietwy A5r7tic7le[O(Mnlin+e
+
DOI: 10.1039/C7OB00749C
= 8.3 Hz, 1H, ArH), 6.79 (dd, J = 1.6, 8.3 Hz, 1H, ArH), 6.48 (s, 2H, Na) , 100], 555 (6), 537 (4), 486 (10). HRMS (ESI-TOF) calcd for
ArH), 5.14 (s, 2H, CH2), 4.99 (s, 2H, CH2), 4.85 (d, J = 1.5 Hz, 1H, CH), C35H38O6Na [M + Na]+: 577.2566, found: 577.2563.
4.25 (d, J = 9.9 Hz, 1H, CH), 3.90 (s, 3H, OCH3), 3.80 (s, 6H, 2 
4-[(2R,3R,4S,5S)-5-(4-Hydroxy-3-methoxyphenyl)-3,4-
OCH3), 2.102.00 (m, 1H, CH), 1.901.80 (m, 1H, CH), 0.90 (d, J = 7.2 dimethyltetrahydrofuran-2-yl]-2,6-dimethoxyphenol (ent-1).
A
Hz, 3H, CH3), 0.64 (d, J = 7.0 Hz, 3H, CH3). 13C NMR (100 MHz, flame-dried round bottom flask equipped with a magnetic stirring
CDCl3): δ 153.4 (2  C), 149.2 (C), 146.8 (C), 139.9 (C), 138.0 (C), bar, an argon inlet, and a rubber septum was charged with 20 (22.8
137.8 (C), 137.4 (C), 136.1 (C), 128.6 (2  CH), 128.5 (2  CH), 128.1 mg, 0.04 mmol), Pd/C (10% w/w, 9 mg, 0.08 mmol), and dry EtOAc
(2  CH), 127.9 (CH), 127.8 (CH), 127.3 (2  CH), 118.0 (CH), 113.6 (1 mL). The argon inlet was replaced by a H2 balloon, and the
(CH), 109.9 (CH), 103.8 (2  CH), 77.3 (CH), 76.5 (CH), 75.0 (CH2), reaction mixture was stirred at room temperature for 40 min. The
71.1 (CH2), 56.1 (2  OCH3), 56.0 (OCH3), 47.3 (CH), 45.4 (CH), 18.9 resulting mixture was filtered through a Celite pad and then the
(CH3), 6.0 (CH3). IR (CHCl3): νmax 3383br, 1594s, 1509s, 1464s, 1131s residue was eluted with EtOAc (10 mL). After removal of the
cm−1. MS (ISCID): m/z (%) relative intensity 595 [(M + Na)+, 100], solvents in vacuo, the crude product was purified by column
577 (14), 504 (14), 205 (11). HRMS (ESI-TOF) calcd for C35H40O7Na chromatography (60% EtOAc in hexanes) to afford ent-1 as a sticky
[M + Na]+: 595.2672, found: 595.2674.
brownish oil (15.3 mg, 99% yield) as a single diastereomer (400 MHz
(1R,2R,3S,4S)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-4-[4-
1H NMR analysis). Rf 0.18 (40% EtOAc in hexanes); [α]27 6.97 (c
D
(benzyloxy)-3-methoxyphenyl]-2,3-dimethylbutane-1,4-diol (19B). 0.60, CHCl3) (lit. [α]D +3.8 (c 0.60, CHCl3);4a UV (MeOH) λmax (log ε)
According to the procedure for the synthesis of 19A, 9B (22 mg, 208 (0.85), 233 (0.24), 279 (0.07) nm; CD (MeOH) 226 (Δε 2.23),
1
0.03 mmol) was converted to 19B in 79 % yield (14.5 mg) as a 250 (Δε +0.12). H NMR (400 MHz, acetone-d6): δ 7.51 (s, 1H, OH),
colorless sticky oil. Rf 0.10 (40% EtOAc in hexanes); [α]27 3.0 (c 7.12 (s, 1H, OH), 7.10 (d, J = 1.8 Hz, 1H, ArH), 6.92 (d, J = 8.1, 1.8 Hz,
D
1
0.82, CHCl3). H NMR (400 MHz, CDCl3): δ 7.507.30 (m, 10H, 2  1H, ArH), 6.82 (d, J = 8.1 Hz, 1H, ArH), 6.77 (s, 2H, 2  ArH), 4.43 (d, J
ArH), 6.88 (d, J = 1.8 Hz, 1H, ArH), 6.83 (d, J = 8.2 Hz, 1H, ArH), 6.76 = 5.4 Hz, 1H, 2  CH), 3.86 (s, 3H, OCH3), 3.83 (s, 6H, 2  OCH3),
(dd, J = 1.8, 8.2 Hz, 1H, ArH), 6.54 (s, 2H, ArH), 5.14 (s, 2H, CH2), 4.99 2.202.45 (m, 2H, 2  CH), 1.03 (d, J = 6.7 Hz, 3H, CH3), 1.00 (d, J =
(s, 2H, CH2), 4.52 (d, J = 7.9 Hz, 1H, CH), 4.49 (d, J = 8.5 Hz, 1H, CH), 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, acetone-d6): δ 149.0 (2  C),
3.88 (s, 3H, OCH3), 3.81 (s, 6H, 2  OCH3), 2.152.05 (m, 2H, 2  CH), 148.7 (C), 147.3 (C), 136.6 (C), 135.5 (C), 134.7 (C), 120.4 (CH), 115.9
0.84 (d, J = 7.1 Hz, 3H, CH3), 0.75 (d, J = 7.1 Hz, 3H, CH3). IR (CHCl3): (CH), 111.2 (CH), 105.1 (2  CH), 88.7 (CH), 88.4 (CH), 57.0 (2  CH3),
νmax 3376br, 1594s, 1508s, 1464s, 1421m, 1262m, 1232m, 1131s 56.6 (CH3), 46.1 (CH), 45.7 (CH), 13.7 (CH3), 13.5 (CH3). IR (CHCl3):
cm−1. MS (ISCID): m/z (%) relative intensity 595 [(M + Na)+, 100], νmax 3542s, 1616m, 1517s, 1465s, 1117s cm−1. MS (ISCID): m/z (%)
504 (30), 413 (4), 357 (7). HRMS (ESI-TOF) calcd for C35H40NaO7 [M + relative intensity 397 [(M + Na)+, 100], 357 (1). HRMS (ESI-TOF)
Na]+: 595.2672, found: 595.2676.
calcd for C21H26O6Na [M + Na]+: 397.1627, found: 397.1622.
(2R,3R,4S,5S)-2-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-5-[4-
(benzyloxy)-3-methoxyphenyl]-3,4-dimethyltetrahydrofuran (20).
A flame-dried round bottom flask equipped with a magnetic stirring
bar, an argon inlet, and a rubber septum was charged with 19A
(55.6 mg, 0.1 mmol), p-toluenesulfonic acid monohydrate (3 mg,
0.016 mmol), and dry CH2Cl2 (1.5 mL). The reaction mixture was
stirred at room temperature for 1.5 h. Then it was quenched with a
saturated aqueous NaHCO3 solution (5 mL) and extracted with
CH2Cl2 (3 × 10 mL). The combined organic phase was washed with
brine (10 mL) and dried over anhydrous Na2SO4. After removal of
solvent in vacuo, the crude product was purified by column
chromatography (40% EtOAc in hexanes) to afford 20 as a white
solid (49.5 mg, 92% yield) as a single diastereomer as determined
by 1H NMR (400 MHz) analysis. Rf 0.46 (40% EtOAc in hexanes); mp
Acknowledgements
The authors acknowledge financial support from the Thailand
Research Fund (RSA5880013 and IRN58W0005), the Center of
Excellence for Innovation in Chemistry (PERCH-CIC), the Office
of the Higher Education Commission and Mahidol University
under the National Research Universities Initiative, and
Mahidol University.
Notes and references
1
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2016, 33, 1044; (b) J. Zhang, J. Chen, Z. Liang and C. Zhao,
Chem. Biodivers., 2014, 11, 1, and references cited therein.
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7578 oC (40% EtOAc in hexanes). [α]26 3.8 (c 1.00, CHCl3). 1H
D
2
NMR (400 MHz, CDCl3): δ 7.557.25 (m, 10H, 2  ArH), 7.01 (d, J =
1.8 Hz, 1H, ArH), 6.91 (dd, J = 1.8, 8.3 Hz, 1H, ArH), 6.86 (d, J = 8.3
Hz, 1H, ArH), 6.63 (s, 2H, ArH), 5.16 (s, 2H, CH2), 4.99 (s, 2H, CH2),
4.52 (d, J = 6.4 Hz, 1H, CH), 4.51 (d, J = 5.9 Hz, 1H, CH), 3.88 (s, 3H,
OCH3), 3.80 (s, 6H, 2  OCH3), 2.402.30 (m, 2H, 2  CH), 1.07 (d, J =
6.6 Hz, 3H, CH3), 1.03 (d, J = 6.5 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): δ 153.4 (2  C), 149.6 (C), 147.6 (C), 138.2 (C), 137.9 (C),
137.2 (C), 136.2 (C), 135.1 (C), 128.5 (2  CH), 128.4 (2  CH), 128.1
(2  CH), 127.8 (CH), 127.7 (CH), 127.2 (2  CH), 118.6 (CH), 113.8
(CH), 100.4 (CH), 103.3 (2  CH), 87.5 (CH), 87.1 (CH), 75.0 (CH2),
71.0 (CH2), 56.1 (2  OCH3), 55.9 (OCH3), 44.6 (CH), 43.9 (CH), 13.2
(CH3), 12.8 (CH3). IR (CHCl3): νmax 1593s, 1513s, 1464s, 1262m,
3
4
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Organic & Biomolecular Chemistry
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10 T. Punirun, D. Soorukram, C. Kuhakarn, V. Reutrakul and M.
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12 The coupling constants between H-1 and H-2 of minor
isomers are 8.8 and 6.0 Hz, respectively. See ESI.
13 Attempts to quench the reaction mixture with a saturated
aqueous NH4Cl solution were initially made; however the
reaction did not give rise to the expected furan. A mixture of
products including 17 was obtained. Unlike the cyclization of
7
, these observed results were possibly due to the presence
of the electron-rich aromatic ring at C-4 of which could
9
facilitate Friedel–Crafts reaction when the oxonium ion was
generated.
14 The relative stereochemistries at the C-1 and C-2 of 9A and
9B were assigned by the analysis of the coupling constants
between H-1 and H-2 of their corresponding diols 19A and
19B, respectively. For 19A, H-1 appeared as a doublet at 4.85
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Organic & Biomolecular Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C7OB00749C
Asymmetric Synthesis of ent-Fragransin C1
Santikorn Chaimanee, Manat Pohmakotr, Chutima Kuhakarn, Vichai Reutrakul, and Darunee
Soorukram*
Graphical abstract
The first asymmetric synthesis of ent-fragransin C1 bearing the 2,3-anti-3,4-syn-4,5-anti
stereochemistires is reported.