Systematic Asymmetric Synthesis of All Diastereomers of (-)-Talaumidin and Their Neurotrophic Activity

Article abstract of DOI:10.1021/acs.joc.5b00945

(-)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, shows significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells

Full text of DOI:10.1021/acs.joc.5b00945

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Article
Systematic Asymmetric Synthesis of All Diastereomers
of (–)-Talaumidin and Their Neurotrophic Activity
Kenichi Harada, Miwa Kubo, Hiroki Horiuchi, Akiko Ishii,
Tomoyuki Esumi, Hideaki Hioki, and Yoshiyasu Fukuyama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00945 • Publication Date (Web): 25 Jun 2015
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Systematic Asymmetric Synthesis of All Diastereomers of (–)-Talaumidin
and Their Neurotrophic Activity
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Kenichi Harada,† Miwa Kubo,† Hiroki Horiuchi,† Akiko Ishii,† Tomoyuki Esumi,† Hideaki Hioki,‡
Yoshiyasu Fukuyama†,*
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†Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiroꢀcho, Tokushima
770ꢀ8514, Japan
‡Faculty of Education, Gunma University, Maebashi, Gunma 371ꢀ8510, Japan
*fukuyama@ph.bunriꢀu.ac.jp
ABSTRACT
(–)ꢀTalaumidin (1), a 2,5ꢀbiarylꢀ3,4ꢀdimethyltetrahydrofuran lignan isolated from Aristolochia
arcuata Masters, shows significant neuriteꢀoutgrowth promotion and neuroprotection in primary
cultured rat cortical neurons and in NGFꢀdifferentiated PC12 cells. The four stereogenic centers on
the tetrahydrofuran moiety in 1 result in the presence of seven diastereomers except for their
enantiomers. In order to investigate the stereochemistry–activity relationships of the stereoisomers,
the systematic synthesis of all stereoisomers of 1 was accomplished by employing Evans aldol,
diastereoselective hydroboration, reductive deoxygenation, and Mitsunobu reactions as key steps.
The ability of all of synthesized stereoisomers to promote neuriteꢀoutgrowth in PC12 and neuronal
cells was evaluated. All stereoisomers exhibited moderate to potent neurotrophic activities in
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NGFꢀdifferentiated PC12 cells at 30 ꢁM and in primary cultured rat cortical neuronal cells at 0.01
ꢁM. In particular, 1e bearing all cis substituents resulted in the most potent neuriteꢀoutgrowth
promotion.
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INTRODUCTION
Neurotrophic factors have been recognized to play important roles in the life of neuron, namely in
regard to differentiation of nerve stem cells, neuriteꢀoutgrowth, and survival of neurons.1–4 Their
activities are postulated to beneficial in the treatment of neurodegenerative diseases, such as
Alzheimer’s and Parkinson’s diseases. However, their high molecular weight and peptidyl
properties restrict their clinical applications owing to their decreased bioavailability and
unfavorable pharmacokinetics.5 Therefore, research on small neurotrophic molecules has garnered
significant scientific attention. As part of our ongoing research in this area, we have continued to
search for neurotrophic molecules from plants.6–10 In the course of our studies on neurotrophic
compounds, we isolated a tetrahydrofuranꢀtype lignan, (–)ꢀ(2S,3S,4S,5S)ꢀtalaumidin (1) from
Aristolochia arcuata Masters. (Figure 1) Remarkably, 1 exhibits not only significant
neuriteꢀoutgrowth promotion in primary cultured rat cortical neurons and in NGFꢀdifferentiated
PC12 cells, but also exhibits protective effects against cell death induced by several insults.11 In
addition to its neurotrophic activity, talaumidin possesses an interesting structure consisting of a
2,5ꢀbiarylꢀ3,4ꢀdimethyltetrahydrofuran skeleton with four continuous stereogenic centers. Thus, its
intriguing structure and biological activity have stimulated considerable efforts in regard to its
synthesis. In 2006, we accomplished the first synthesis of (–)ꢀtalaumidin (1)12,13 by employing
Evans asymmetric antiꢀselective aldol reaction, diastereoselective hydroboration, and FriedelꢀCrafts
arylation as key steps. Subsequently, several groups reported the synthesis of talaumidin and its
analogues. Specifically, Hanessian et al. synthesized 1 together with four related compounds using
stereoselective cyclizations.14 Hong et al. reported a BF3·OEt2 promoted reductive deoxygenation
reaction in the synthesis of talaumidin analogues.15 Moreover, Ghosh and Matcha16 used a
diastereoselective aldol reaction, and Liang et al.17 and Barker et al.18 also achieved the synthesis of
talaumidin. After our inaugural report on the synthesis of 1, we focused on the stereochemistry–
activity relationships imparted by the four continuous stereogenic centers. From a synthetic point of
view, it is attractive not only to synthesize all seven diastereomers, but also to prepare a library of
stereoisomers, which would provide useful information on the structure–activity relationships of 1.
Herein, we report the synthesis of all stereoisomers of talaumidin and their neurotropic activities.
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Figure 1. The structures of talaumidin (1) and stereoisomers 1a–1g.
RESULTS AND DISCUSSION
We envisioned that the systematic synthesis of all stereoisomers could be accomplished using the
same
starting
materials,
4ꢀbenzyloxyꢀ3ꢀmethoxybenzaldehyde
(2)
and
(+)ꢀ4ꢀbenzylꢀ3ꢀpropionyloxazolidinone (3). (Scheme 1) The Evans aldol reaction between 2 and 3
would be a key step for the construction of the desired absolute configurations at C2 and C3 in all
isomers. The antiꢀselective Evans aldol reaction could form (2R,3S)ꢀ4a, which would be converted
to (2S,3S)ꢀisomers 1a–1c, whereas the synꢀselective Evans aldol reaction would be employed for
the synthesis of (2S,3S)ꢀ4b, which would generate the (2S,3R)ꢀconfiguration of 1d–1g. The
neighboring C4 stereochemistry could be controlled by the diastereoselective
hydroboration/epimerization procedure, which was utilized for the previously reported synthesis of
talaumidin.12,13 The methylenedioxybenzene moiety would be introduced via nucleophilic addition
of a Grignard reagent or aryl lithium reagent. In the final stage, the stereoselective cyclization of the
core THF ring would be attained by an intramolecular cyclization under Mitsunobu conditions or an
acetalization/reduction procedure.
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Scheme 1. Systematic strategy used to synthesize all stereoisomers of 1
Our synthetic study commenced with the Evans aldol reaction between 2 and 3. (Scheme 2) In
accordance with Evans procedure, the antiꢀselective aldol reaction was carried out with MgCl2,
TMSCl, and Et3N in EtOAc.19 The obtained TMS ether was treated with HF/pyridine to afford
(2R,3S)ꢀaldol 4a in 68% yield with 98%de. On the other hand, the synꢀselective aldol reaction was
performed using Bu2BOTf and iꢀPr2NEt in DCM, giving rise to (2S,3S)ꢀaldol 4b in 80% yield with
>99%de.20,21 The relative configurations of the compounds were confirmed by comparison of the
coupling constants between HC2 and HC3. Referring to Cha’s report,22 the antiꢀ and
synꢀconfigurations were determined by the J2,3 values of 4a (7.4 Hz) and 4b (4.7 Hz).
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Scheme 2. Evans syn- and anti-selective aldol reactions of 2 and 3
Next, key intermediates (2R,3S,4S)ꢀ9a and (2S,3R,4S)ꢀ9b were prepared from 4a and 4b by the
same procedures.23 (Scheme 3) Protection of the secondary alcohols in 4a and 4b as TBS ethers,
followed by reductive removal of the oxazolidinone auxiliaries with a metal hydride afforded 5a
and 5b. Alcohols 5a and 5b were oxidized to aldehydes 6a and 6b, respectively. The Grignard
reaction of 6a and 6b with methyl magnesium bromide, followed by subsequent oxidation of the
generated secondary alcohols, gave ketones 7a and 7b in 98% and 83% yields. Treatment of the
ketones with Tebbe reagent afforded 8a and 8b. The absolute configurations of C1 in 8a and 8b
were confirmed by Kusumi’s method24 after removal of the TBS group and esterification with
MTPA.13,25 Diastereoselective hydroboration of 8a and 8b proceeded smoothly, giving 9a and 9b
with >99%de.26,27
Scheme 3. Preparation of 9a and 9b
With (2R,3S,4S)ꢀ9a in hand, the synthesis of (2S,3S)ꢀisomers 1a–1c was investigated.13,28 (Scheme
4) A series of oxidation/Grignard reaction/reꢀoxidation reactions of 9a gave a ketone 10 in 71%
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yield over 3 steps. Compound 10 was treated with TBAF, and then a diluted HCl solution, giving
rise to a dihydrofuran 11a in 70% yield. The reduction of dihydrofuran 11a and removal of the
benzyl group was carried out with Pd(OH)2/C in EtOH under a hydrogen atmosphere, giving
(2S,3S,4S,5R)ꢀ1a in 53% yield. Notably, NaBH3CN reduction of cyclic hemiꢀacetal 12a, which was
derived from 10 via treatment with TBAF followed by removal of the benzyl group, produced a 1:2
diastereomeric mixture of (2S,3S,4R,5S)ꢀ1b and talaumidin (1). Furthermore, the synthesis of 1c
was achieved by the intramolecular cyclization under Mitsunobu conditions. Hydride reduction of
10 proceeded stereoselectively according to the Felkin–Anh model;29–31 subsequent deprotection of
the TBS group yielded diol 13a. Intramolecular cyclization under Mitsunobu conditions28 of 13a
surprisingly gave rise to 14 as a single product, and then hydrogenolysis of the benzyl group
furnished (2S,3S,4R,5R)ꢀ1c in 87% yield. It should be noted that the intramolecular addition of
hydroxy anion to the quinone methide species can account for the formation of 14.
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Scheme 4. Synthesis of 1a, 1b, and 1c
After the completion of synthesis of (2S,3S)ꢀisomers, we focused on the synthesis of
(2S,3R)ꢀisomers 1d–1g. First, the synthesis of 1e was examined. (Scheme 5) The primary alcohol
moiety in (2S,3R,4S)ꢀ9b was oxidized by Dess–Martin periodinane to give aldehyde 15 in 87%
yield. After the Pinnick oxidation of 15, removal of the TBS group by HF/pyridine brought about
concomitant cyclization, which afforded lactone 16 in a good yield. Nucleophilic addition of 16
with methylenedioxyphenyl lithium and subsequent dehydration of the generated alcohol under
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acidic conditions produced dihydrofuran 11b. The hydrogenation of the dihydrofuran under
Pdꢀcatalytic conditions gave rise to cisꢀsubstituted (2S,3R,4S,5R)ꢀ1e, following the removal of the
benzyl group.
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Scheme 5. Synthesis of 1e
Subsequently, we prepared acetal 19 and sulfone 20, which are intermediates in the synthesis of 1f.
(Scheme 6) The 3Rꢀconfiguration of 1f was formed by the epimerization of 16 under basic
conditions. After Dibal reduction of 17, 18 was converted to acetal 19 and sulfone 20 by Hong’s
procedure.32
Scheme 6. Preparation of acetal 19 and sulfone 20
With 19 and 20 in hand, we investigated the stereoselective introduction of methylenedioxybenzene.
(Table 1) At first, Friedel–Crafts reaction was attempted under SnCl4ꢀcatalyzed conditions, which
were used previously.12,13 (Table 1, entry 1) Disappointingly, undesired epimerization occurred to
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give (2R,3R,4R,5R)ꢀisomer 22 in 49% yield, which was converted to (+)ꢀtalaumidin (entꢀ1) by
removal of the benzyl group.14,15 This epimerization would be attributed to the low reactivity of the
methylenedioxybenzene. In order to improve the nucleophilicity and prevent the epimerization, we
applied Ley’s procedure33 by treating the sulfone acetal with a Grignard reagent in the presence of
ZnBr2. (Table 1, entries 2–4) Although the Grignard reaction of methyl acetal 19 did not give the
desired product, the reaction of sulfone 20 at room temperature afforded 21 in 37% yield, in
addition to small amounts of stereoisomers 22 and 23. Finally, removal of the benzyl group afforded
(2S,3R,4R,5S)ꢀ1f in 64% yield. In order to understand the outcome of the Grignard reaction, 20a
and 20b, which were easily separated by silica gel column chromatography, were subjected to the
same reaction conditions. The Grignard reaction of 20a smoothly proceeded to give 21 in 50% yield,
whereas the reaction of 20b yielded only 16% of 21 along with unreacted starting material. (Table 1,
entries 5 and 6)
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Table 1. Stereoselective arylation of 19 and 20
entry substrate
M
additive
SnCl4
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
solvent temp (°C)
21 (%)
22 (%)
23 (%)
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H
DCM
THF
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THF
−78
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trace
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rt
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20b
rt
The difference in the reactivity between 20a and 20b is caused by the rate of sulfone elimination,
which is the rateꢀdetermining step in this reaction. (Figure 2) In each isomer, the phenyl sulfone is
oriented in two kinds of conformations: pseudoꢀaxial or pseudoꢀequatorial. Considering the
anomeric effect,34 the elimination of pseudoꢀaxial oriented sulfones B and C is faster than that of
pseudoꢀequatorial A and D. In the case of 20a, the less hindered conformer B is favored over A,
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whereas conformer D is superior to C due to steric repulsion between the aryl and sulfone groups. It
should be noted that less reactive 20b can be readily converted to 20a in CHCl3 in 1 day.
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Figure 2. Difference in reactivity between 20a and 20b.
Next, the synthesis of (2S,3R,4R,5R)ꢀ1g was carried out. (Scheme 7) Aldehyde 15 was reacted with
methylenedioxyphenyl magnesium bromide, and afforded 24 stereoselectively, in accordance with
the Felkin–Anh model (1Rꢀ24:1Sꢀisomer = 5:1). The obtained alcohol 24 was oxidized by Dess–
Martin periodinane to give ketone 25 in 98% yield. After removal of the TBS group, treatment of
cyclic hemiꢀacetal 12b with BF3·OEt2 led to the oxonium ion, which induced epimerization at C4;
subsequent reduction with NaBH3CN gave rise to 23.15 Epimerization is caused by the steric
repulsion between the adjacent methyl and aryl groups. The synthesis of (2S,3R,4R,5R)ꢀ1g was
attained by the hydrogenolysis of the benzyl ether moiety in 23.
Scheme 7. Synthesis of 1g
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Finally, (2S,3R,4S,5S)ꢀ1d was synthesized by the intramolecular cyclization under Mitsunobu
conditions of diol 13b.25 (Scheme 8) In order to facilitate the selective elimination of the
C4ꢀhydroxy group, the benzyl group in 24 was converted to a tosyl group in 2 steps. After removal
of the TBS group, diol 13b was subjected to the intramolecular cyclization under Mitsunobu
conditions using Tsunoda reagent, CMMP,35 which resulted in the formation of 26 with high
stereoselectivity. The synthesis of 1d was completed by the hydrolysis of the tosyl group under
basic conditions.
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Scheme 8. Synthesis of 1d
The systematic synthesis of talaumidin isomers 1a–1g was successfully accomplished and
facilitated the evaluation of the neurotrophic activities of the synthesized stereoisomers. According
to a previously reported experimental procedure,36 compounds 1 and 1a–1g were evaluated for their
ability to induce neuriteꢀoutgrowth in NGFꢀdifferentiated PC12 cells at 10 ꢁM and 30 ꢁM, together
with entꢀtalaumidin (entꢀ1). (Figure 3) Entꢀtalaumidin showed similar neurotrophic activity as (−)ꢀ1,
and all stereoisomers resulted in moderate to potent neuriteꢀoutgrowth promotion. In particular, 1e,
bearing all cis substituents, was found to exhibit higher activity than natural product (−)ꢀ1. In
addition, we also evaluated the ability of the compounds to promote neuriteꢀoutgrowth in primary
cultured rat cortical neurons at 0.01 ꢁM.37 (Figure 4) Notably, all of the compounds exhibited potent
neuriteꢀoutgrowth activity. Further, 1e also resulted in significant promotion of neuriteꢀoutgrowth.
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Figure 3. Comparison of neurite length of NGFꢀdifferentiated PC12 cells promoted by 1 and 1a–1g
at 10 and 30 ꢁM. PC12 cells were cultured in a 24ꢀwell plate in DMEM/10% HS + 5%FBS for
1day at a cell density of 2000 cells cm−2; the medium was changed to DMEM/2% HS + 1% FBS
with control (0.5% EtOH), NGF 2 ng mL−1, NGF 2 ng mL−1 + samples (10 ꢁM and 30 ꢁM). After
96 h, PC12 cells were fixed and stained with methylene blue, and the neurite length was quantified.
At least 100 cells were used to calculate the neurite length. Data were expressed as mean as ± SE. *,
P<0.05; **, P<0.01 compared with NGF by Dunnett's tꢀtest.
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Figure 4. Comparison of neurite length of neuronal cells promoted by 1 and 1a–1g at 0.01 ꢁM. The
neuronal cells (5000 cell cm−2) were cultured for 7 days in the presence of 0.5% EtOH, bFGF, 1a,
1b, 1c, 1d, 1e, 1f, 1g, talaumidin, and entꢀtalaumidin and were fixed with 4% paraformaldehyde.
Morphometric analysis was carried out on these neurons according to the described criteria. The
data are expressed ± S.E. (n = 60); Dunnett’s tꢀtest vs. control, *, P<0.05, **, P<0.01.
CONCLUSION
We accomplished the systematic synthesis of all stereoisomers of (−)ꢀtalaumidin. The (2S,3S)ꢀ and
(2S,3R)ꢀconfigurations were constructed by Evans synꢀ and antiꢀselective aldol reactions with 2 and
3, and the configuration at C4 was controlled by diastereoselective hydroboration and epimerization.
(2S,3S,4S,5R)ꢀ1a was synthesized from dehydrofuran 11 by stereoselective hydrogenation.
Reduction of hemiꢀacetal 12 with NaBH3CN in the presence of BF3·OEt2 gave rise to
(2S,3S,4R,5S)ꢀ1b. Furthermore, diol 13 was subjected to the intramolecular cyclization under
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Mitsunobu conditions, resulting in the formation of (2S,3S,4R,5R)ꢀ1c. (2S,3R,4S,5S)ꢀ1d was
synthesized by the intramolecular cyclization of tosylate 25 using Tsunoda reagent, CMMP;
(2S,3R,4S,5R)ꢀ1e was prepared by the catalytic reduction of dihydrofuran 21. The synthesis of
(2S,3R,4R,5S)ꢀ1f was achieved according to Ley’s and Hong’s procedures, which is the Grignard
reaction of sulfone 22 in the presence of ZnBr2. In addition, treatment of 26 with BF3·OEt2 and
NaBH3CN furnished (2S,3R,4R,5R)ꢀ1g via the epimerization at C4. The ability of all synthesized
stereoisomers to promote neuriteꢀoutgrowth promotion was evaluated. Among the talaumidin
isomers, cisꢀsubstituted 1e exhibited the most significant neurotrophic activity in PC12 cells as well
as in neuronal cells.
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EXPERIMENTAL SECTION
General Method.
The melting points were measured with a melting point apparatus and were uncorrected. IR spectra
were recorded on an infrared. Highꢀresolution mass spectra were obtained using a magnetic sector
analyzer with electron ionization (EI), chemical ionization (CI), and fast atom bombardment (FAB)
1
13
mass spectrometry. H and C NMR spectra were referenced relative to peaks of TMS (0 ppm for
1H NMR) and CDCl3 (77.03 ppm for 13C NMR). Column chromatography was carried out with
silica gel (70–230 and 230–400 mesh). Specific rotations were measured with 3.5×10 mm, 3.5×100
mm, and 10×100 mm cells.
(2S,3S,4S,5R)-1a: To a solution of 11a (4.0 mg, 9.30 ꢁmol) in benzene (1.00 mL) was added
Pd(OH)2/C (1.5 mg). This mixture was stirred vigorously under hydrogen atmosphere at rt for 16 h.
After being filtered, removal of solvent afforded the residue, which was purified by prep. TLC
1
(hexane:EtOAc = 2:1) to yield 1a (1.7 mg, 53%) as a colorless oil; H NMR (300 MHz, CDCl3) δ
0.67 (3H, d, J = 7.0 Hz), 1.04 (3H, d, J = 6.6 Hz), 1.75 (1H, ddq, J = 9.6, 9.3, 6.6 Hz), 2.23 (1H,
ddq, J = 9.6, 8.8, 7.0 Hz), 3.93 (3H, s), 4.36 (1H, d, J = 9.3 Hz), 5.09 (1H, d, J = 8.8 Hz), 5.59 (1H,
s), 5.96 (2H, s), 6.78 (2H, brꢀs), 6.88 (1H, brꢀs), 6.92 (1H, d, J = 8.1 Hz), 6.97 (1H, dd, J = 8.1, 1.5
Hz), 7.04 (1H, d, J = 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 14.9, 15.1, 46.0, 48.1, 55.9, 83.0, 87.5,
100.9, 107.6, 107.8, 109.2, 114.2, 119.5, 120.3, 132.6, 135.2, 145.2, 146.5, 146.5, 147.4; IR (ATR)
3463 cm−1; HRMS (EI) m/z: [M]+ Calcd for C20H22O5 342.1467; Found 342.1465; [α]26 +29.0 (c
D
0.43, CHCl3).
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S,3
S,4
R,5
S)-1b: To a solution of 10 (9.30 mg, 16.6 ꢁmol) in THF (500 ꢁL) was added TBAF
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(20.0 ꢁL, 1.0 M solution in THF). This mixture was stirred for 11 h, and quenched with H2O. The
aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, and concentrated in vacuo. The residue was dissolved in DCM (1.00
mL) and the resulting solution was cooled to −78 °C. To this solution was added NaBH3CN (1.8 mg,
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28.6 ꢁmol) and BF3 OEt2 (2.0 ꢁL, 34.4 ꢁmol). The reaction mixture was stirred at the same
⋅
temperature for 20 min. After saturated aqueous NaHCO3 was added, the aqueous layer was
extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by prep. TLC (hexane:EtOAc = 3:1) to yield a
diastereomeric mixture (6.2 mg, 63% in two steps). To a solution of this mixture (6.20 mg, 14.4
ꢁmol) in benzene (1.0 mL) was added 20% Pd(OH)2/C (3.10 mg). The reaction mixture was stirred
vigorously under hydrogen atmosphere at rt for 10 h. After being filtered, removal of solvent
afforded the residue, which was purified by prep. TLC (benzene:ether = 5:1) to yield 1b (1.5 mg,
30%) and 1 (2.9 mg, 59%). 1b as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.62 (3H, d, J = 7.3
Hz), 0.99 (3H, d, J = 6.2 Hz), 2.37–2.48 (2H, m), 3.91 (3H, s), 4.63 (1H, d, J = 9.5 Hz), 5.43 (1H, d,
J = 4.0 Hz), 5.56 (1H, s), 5.95 (2H, s), 6.78 (1H, d, J = 8.1 Hz), 6.81 (1H, dd, J = 8.1, 1.1 Hz), 6.84
(1H, dd, J = 8.1, 1.5 Hz), 6.86 (1H, d, J = 1.1 Hz), 6.89 (1H, d, J = 8.1 Hz), 6.93 (1H, d, J = 1.5
Hz); 13C NMR (100 MHz, CDCl3) δ 9.6, 11.9, 43.5, 47.5, 56.0, 84.8, 85.8, 100.9, 106.9, 108.0,
108.5, 114.1, 119.1, 119.3, 134.7, 134.9, 145.1, 146.3, 146.7, 147.5; IR (ATR) 3493, 1513 cm−1;
HRMS (EI) m/z: [M]+ Calcd for C20H22O5 342.1467; Found 342.1476; [α]22D −46.5 (c 0.32, CHCl3).
(2S,3S,4R,5R)-1c: To a solution of 14 (12.8 mg, 29.6 ꢁmol) in benzene (1.50 mL) was added
Pd(OH)2/C (2.90 mg). The mixture was stirred vigorously under hydrogen atmosphere at rt for 75 h.
After being filtrated, the solution was concentrated in vacuo. The residue was purified by column
chromatography (hexane:EtOAc = 3:1) to yield 1c (8.8 mg, 87%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.02 (6H, d, J = 6.6 Hz), 2.22–2.34 (2H, m), 3.91 (3H, s), 4.45 (1H, d, J = 6.4 Hz),
4.46 (1H, d, J = 6.7 Hz), 5.57 (1H, s), 5.96 (2H, s), 6.79 (1H, d, J = 7.8 Hz), 6.88 (1H, dd, J = 7.8,
1.6 Hz), 6.90 (1H, s), 6.94 (1H, d, J = 1.6 Hz), 6.97 (1H, s), 6.97 (1H, s); 13C NMR (100 MHz,
CDCl3) δ 12.9, 44.5, 44.5, 55.9, 77.3, 87.4, 87.5, 101.0, 106.8, 108.0, 109.0, 114.1, 119.4, 119.9,
134.0, 136.2, 145.0, 146.5, 147.0, 147.8; IR (ATR) 3482 cm−1; HRMS (EI) m/z: [M]+ Calcd for
C20H22O5 342.1467, Found 342.1470; [α]20D +8.4 (c 0.65, CHCl3).
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(2
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R
,4
S,5
S)-1d: To a solution of 27 (6.30 mg, 12.7 ꢁmol) in ethanol (100 ꢁL) was added aq
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NaOH (0.5 g/mL, 200 ꢁL). After being stirred rt for 15 h, the reaction mixture was added brine
(1.00 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4,
concentrated in vacuo. The residue was purified by prep. TLC (benzene:EtOAc = 20:1) to afford 1d
(3.31 mg, 77%) as colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.61 (3H, d, J = 7.1 Hz), 1.00 (3H, d,
J = 6.6 Hz), 2.37–2.46 (2H, m), 3.89 (3H, s), 4.62 (1H, d, J = 9.3 Hz), 5.43 (1H, d, J = 4.4 Hz), 5.52
(1H, s), 5.94 (1H, d, J = 1.5 Hz), 5.95 (1H, d, J = 1.5 Hz), 6.77 (1H, dd, J = 8.1, 1.7 Hz), 6.78 (1H,
d, J = 7.9 Hz), 6.83 (1H, dd, J = 8.1, 1.7 Hz), 6.88 (1H, d, J = 7.9 Hz), 6.92 (1H, d, J = 1.7 Hz),
6.93 (1H, d, J = 1.7 Hz); 13C NMR (125 MHz, CDCl3) δ 9.4, 11.8, 43.5, 47.7, 56.0, 84.8, 85.7,
100.9, 106.5, 108.0, 108.7, 113.9, 118.8, 119.6, 132.5, 137.2, 144.3, 146.2, 146.9, 147.8; IR (ATR)
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3464 cm−1; HRMS (CI) m/z: [M + H]+ Calcd for C20H23O5 343.1546, Found 343.1540; [α]20
D
−134.3 (c 1.01, CHCl3).
(2S,3R,4S,5R)-1e: To a solution of 16 (58.9 mg, 181 ꢁmol) in THF was added a solution of
3,4ꢀmethylenedioxyphenyl lithium (in THF, 1.80 mL, 397 ꢁmol). After being stirred for 23 h, the
reaction was worked up with saturated aqueous NH4Cl and extracted with ether. The combined
organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography (hexane:EtOAc = 5:1) to afford a dihydrofuran (56.4 mg)
as colorless oil. The solution of the dihydrofuran (12.6 mg, 30.3 ꢁmol) in benzene (1.00 mL) was
added Pd(OH)2/C (1.30 mg). The mixture was stirred vigorously under hydrogen atmosphere at rt
for 17 h. After being filtrated, the solution was concentrated in vacuo. The residue was purified by
1
column chromatography (hexane:CHCl3 = 1:5) to yield 1e (7.70 mg, 56%) as a colorless oil: H
NMR (400 MHz, CDCl3)
δ 0.59 (3H, d, J = 6.1 Hz), 0.61 (3H, d, J = 6.1 Hz), 2.61–2.68 (2H, m),
3.91 (3H, s), 5.09 (2H, d, J = 6.4 Hz), 5.97 (2H, s), 6.81 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 8.1,
1.5 Hz), 6.88 (1H, dd, J = 8.0, 1.4 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.94 (1H, d, J = 1.4 Hz), 6.96 (1H,
d, J = 1.5 Hz); 13C NMR (100 MHz, CDCl3)
δ 11.8, 11.8, 41.5, 41.5, 56.0, 82.7, 82.8, 100.9, 107.1,
107.9, 109.0, 114.0, 118.0, 119.3, 119.5, 132.4, 134.5, 144.3, 146.2, 147.4; IR (ATR) 3472, 2969,
1516, 1236, 1038, 455 cm−1; HRMS (EI) m/z: [M]+ Calcd for C20H22O5 342.1467, Found 342.1476;
[α]20D −121.2 (c 0.10, CHCl3).
(2S,3R,4R,5S)-1f: To a solution of 21 (35.5 mg, 82.0 ꢁmol) in benzene (3.00 mL) was added
Pd(OH)2/C (6.00 mg). The mixture was stirred vigorously under hydrogen atmosphere at rt for 75 h.
After being filtrated, the solution was concentrated in vacuo. The residue was purified by column
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chromatography (hexane:EtOAc = 6:1) to yield 1f (17.9 mg, 64%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.68 (3H, d, J = 6.5 Hz), 0.69 (3H, d, J = 6.5 Hz), 2.20–2.29 (2H, m), 3.91 (3H, s),
5.40 (2H, d, J = 6.0 Hz), 5.53 (1H, s), 5.96 (2H, s), 6.81 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 8.1,
1.5 Hz), 6.88 (1H, dd, J = 8.0, 1.5 Hz), 6.91 (1H, d, J = 8.0 Hz), 6.94 (1H, d, J = 1.5 Hz), 6.96 (1H,
d, J = 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 14.6, 14.7, 43.8, 43.9, 56.0, 83.7, 100.9, 107.0, 107.8,
108.9, 113.9, 119.2, 119.4, 133.4, 135.5, 144.5, 146.2, 146.4, 147.5; IR (ATR) 3490 cm−1; HRMS
(CI) m/z: [M + H]+ Calcd for C20H23O5 343.1546, Found 343.1540; [α]20D −13.3 (c 1.04, CHCl3).
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(2S,3R,4R,5R)-1g: To a solution of 23 (2.0 mg, 4.63 ꢁmol) in benzene (1.00 mL) was added
Pd(OH)2/C (0.5 mg). The mixture was stirred vigorously under hydrogen atmosphere at rt for 75 h.
After being filtrated, the solution was concentrated in vacuo. The residue was purified by column
chromatography (hexane:EtOAc = 6:1) to yield 1g (1.3 mg, 82%) as a colorless oil: 1H NMR (500
MHz, CDCl3) δ 0.65 (3H, d, J = 6.8 Hz), 1.04 (3H, d, J = 6.6 Hz), 1.71–1.77 (1H, m), 2.18–2.24
(1H, m), 3.89 (3H, s), 4.36 (1H, d, J = 9.3 Hz), 5.10 (1H, d, J = 8.5 Hz), 5.54 (1H, s), 5.98 (2H, s),
6.82 (1H, d, J = 8.1 Hz), 6.82 (1H, dd, J = 8.1, 1.9 Hz), 6.87 (1H, d, J = 1.9 Hz), 6.90 (1H, d, J =
8.1 Hz), 6.94 (1H, d, J = 8.1, 1.7 Hz), 7.04 (1H, d, J = 1.7 Hz); 13C NMR (125 MHz, CDCl3) δ 15.0,
15.1, 45.9, 48.3, 55.9, 83.1, 87.4, 101.0, 106.9, 108.1, 109.5, 113.9, 119.9, 120.1, 133.1, 134.8,
144.6, 146.2, 147.1, 147.8; IR (ATR) 3470 cm−1; HRMS (EI) m/z: [M]+ Calcd for C20H22O5
342.1467, Found 342.1476; [α]20D −8.65 (c 0.17, CHCl3).
(2R,3R,4R,5R)-talaumidin (ent-1): To a solution of 22 (6.55 mg, 14.7 ꢁmol) in benzene (2.00 mL)
was added Pd(OH)2/C (5.60 mg). The mixture was stirred vigorously under hydrogen atmosphere at
rt for 75 h. After being filtrated, the solution was concentrated in vacuo. The residue was purified
by column chromatography (hexane:EtOAc = 6:1) to yield entꢀ1 (4.21 mg, 84%) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 1.02 (3H, d, J = 5.8 Hz), 1.04 (3H, d, J = 5.8 Hz), 1.73–1.78 (2H, m),
3.92 (3H, s), 4.61 (2H, d, J = 9.1 Hz), 5.57 (1H, s), 5.95 (2H, s), 6.77 (1H, d, J = 8.0 Hz), 6.84 (1H,
dd, J = 8.0, 1.6 Hz), 6.84 (1H, dd, J = 8.0, 1.6 Hz), 6.89 (1H, d, J = 8.0 Hz), 6.93 (1H, d, J = 1.6
Hz), 6.94 (1H, d, J = 1.6 Hz); 13C NMR (75 MHz, CDCl3) δ 13.8 ,50.9, 51.2, 56.0, 88.2, 88.4, 101.0,
106.6, 107.9, 108.5, 114.0, 119.4, 119.7, 134.1, 136.6, 147.0, 147.8; IR (ATR) 3459 cm−1; HRMS
(EI) m/z: [M]+ Calcd for C20H22O5 342.1467, Found 342.1471; [α]20D +88.3 (c 2.10, CHCl3).
(S)-4-benzyl-3-((2R,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-hydroxy-2-methylpropanoyl)ox
azolidin-2-one (4a): To a solution of (S)ꢀ(+)ꢀ4ꢀbenzylꢀ3ꢀpropionylꢀ2ꢀoxazolidinone (1.01 g, 4.33
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mmol) in EtOAc (8.60 mL) was successively added 4ꢀbenzyloxyꢀ3ꢀmethoxybenzaldehyde (1.23 g,
5.45 mmol), magnesium chloride (84.2 mg, 866 ꢁmol), triethylamine (800 ꢁL, 8.66 mmol), and
trimethylsilyl chloride (830 ꢁL, 6.50 mmol). The resulting mixture was stirred at rt for 14 h. The
reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was stirred for
10 min. The aqueous layer was extracted with Et2O and the combined organic layers were washed
with brine, dried over anhydrous MgSO4 and concentrated in vacuo. To the residue was added
HF/pyridine/MeCN (1:3:5; 70.0 mL) at 0 °C and the mixture was stirred overnight. To a saturated
aqueous NaHCO3 was added the reaction mixture. The aqueous layer was extracted with EtOAc
and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography (hexane:ether = 3:2 to 2:1) to afford 4a (1.39 g,
68%) as colorless solids: 1H NMR (300 MHz, CDCl3) δ 1.10 (3H, d, J = 6.9 Hz), 2.68 (1H, dd, J =
13.7, 9.3 Hz), 3.00 (1H, d, J = 7.1 Hz), 3.21 (1H, dd, J = 13.7, 3.3 Hz), 3.93 (3H, s), 4.14 (1H, dd, J
= 9.1, 3.2 Hz), 4.21 (1H, d, J = 9.1 Hz), 4.34 (1H, dq, J = 6.9, 7.4 Hz), 4.71 (1H, ddd, J = 9.3, 3.3,
3.2 Hz), 4.76 (1H, dd, J = 7.4, 7.1 Hz), 5.14 (2H, s), 6.87 (1H, dd, J = 8.1, 1.6 Hz), 7.02 (1H, d, J =
1.6 Hz), 7.16 (1H, d, J = 8.1 Hz), 7.28–7.43 (10H, m); 13C NMR (75 MHz, CDCl3) δ 14.9, 37.6,
44.2, 55.5, 56.0, 66.0, 71.1, 76.6, 110.0, 113.7, 118.9, 127.3, 127.4, 127.8, 128.6, 129.0, 129.5,
135.2, 135.3, 137.1, 147.9, 149.9, 153.6, 176.7; IR (ATR) 3482, 1771, 1695 cm−1; HRMS (EI) m/z:
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[M]+ Calcd for C28H29O6N 475.1994; Found 475.2000; [α]20 −118.9 (c 1.09, CHCl3); m.p. 91–
D
92 °C.
(S)-4-benzyl-3-((2S,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-hydroxy-2-methylpropanoyl)oxa
zolidin-2-one (4b): To a solution of (+)ꢀ(S)ꢀ4ꢀbenzylꢀ3ꢀpropylꢀ2ꢀoxazolidinone (3.00 g, 12.9 mmol)
in DCM (70.0 mL) was added 1.0 M dibutylboron triflate in DCM (14.2 mL, 14.2 mmol) and Et3N
(2.69 mL, 19.3 mmol) at −78 °C, and then stirring was continued for 30 min at −40 °C. To the
reaction mixture cooled to −78 °C was added a solution of 4ꢀbenzyloxyꢀ3ꢀmethoxybenzaldehyde
(3.40 g, 14.2 mmol) in DCM (60.0 mL). After being stirred for 11 h, the reaction was quenched by
addition of phosphoric buffer (15.4 mL), methanol (51.5 mL), and 30% H2O2 (15.4 mL) at 0 °C.
The mixture was stirred for 1 h. The aqueous layer was extracted with DCM and the combined
organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (hexane:EtOAc = 2:1) to afford 4b (4.88 g, 80%, 99%de)
1
as colorless solid: H NMR (400 MHz, CDCl3) δ 1.25 (3H, d, J = 6.8 Hz), 2.74 (1H, dd, J = 13.3,
9.6 Hz), 3.22 (1H, dd, J = 13.3, 3.4 Hz), 3.86 (3H, s), 3.94 (1H, dd, J = 9.0, 8.4 Hz), 4.08 (1H, dd, J
= 9.0, 2.4 Hz), 4.11 (1H, qd, J = 6.8, 4.7 Hz), 4.49 (1H, dddd, J = 9.6, 8.4, 3.4, 2.4 Hz), 4.97 (1H, d,
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J = 4.7 Hz), 5.14 (2H, s), 6.80 (1H, dd, J = 8.0, 1.7 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.92 (1H, d, J =
1.7 Hz), 7.17–7.19 (2H, m), 7.24–7.35 (6H, m), 7.40–7.43 (2H, m); 13C NMR (100 MHz, CDCl3) δ
11.4, 37.8, 44.6, 55.3, 56.0, 66.1, 70.9, 74.0, 109.7, 113.5, 118.3, 127.3, 127.4, 127.8, 128.5, 129.0,
129.4, 134.5, 135.0, 137.1, 147.4, 149.5, 152.9, 176.5; IR (ATR) 3509, 1775, 1695 cm−1; HRMS
(EI) m/z: [M]+ Calcd for C28H29O6N 475.1995, Found 475.1979; [α]20D +58.9 (c 1.00, CHCl3); m.p.
116–117 °C.
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(2S,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1
-ol (5a): To a solution of 4 (1.13 g, 2.39 mmol) and 2,6ꢀlutidine (560 ꢁL, 4.78 mmol) in DCM (2.40
mL) was added tꢀbutyldimethylsilyl trifluorometanesulfonate (830 ꢁL, 3.59 mmol). After being
stirred for 5 min, the reaction mixture was cooled to 0 °C followed by quenched with water. The
aqueous layer was extracted with EtOAc and the combined organic layers were washed with water
and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (hexane:EtOAc = 5:1 to 3:1) to yield TBSꢀprotected compound (1.40 g,
99%) as a yellow oil. To a solution of this compound (101 mg, 4.64 mmol) in MeOH (7.60 ꢁL, 188
ꢁmol) and Et2O (3.20 mL) was added lithium borohydride (4.31 mg, 188 ꢁmol) and THF (86.0 ꢁL)
at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was added
to 3 mol/L aqueous NaOH (150 ꢁL) and the aqueous layer was extracted with EtOAc and the
combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography (hexane:EtOAc = 8:1 to 4:1) to yield 5a (65.4 mg, 92%) as
a colorless oil: 1H NMR (300 MHz, CDCl3) δ −0.24 (3H, s), 0.04 (3H, s), 0.81 (3H, d, J = 6.9 Hz),
0.88 (9H, s), 1.91 (1H, dddq, J = 6.9, 6.0, 3.6, 6.9 Hz), 3.59 (1H, dd, J = 11.0, 6.0 Hz), 3.61 (1H, dd,
J = 11.0, 3.6 Hz), 3.88 (3H, s), 4.48 (1H, d, J = 6.9 Hz), 5.13 (2H, s), 6.70 (1H, dd, J = 8.2, 1.6 Hz),
6.80 (1H, d, J = 8.2 Hz), 6.90 (1H, d, J = 1.6 Hz), 7.28–7.45 (5H, m); 13C NMR (75 MHz, CDCl3) δ
−5.2, −4.5, 14.3, 18.0, 25.8, 43.1, 55.9, 66.5, 71.1, 80.9, 110.1, 113.4, 119.0, 127.4, 127.8, 128.5,
136.9, 137.2, 147.4, 149.5; IR (neat) 3437 cm−1; HRMS (EI) m/z: [M]+ Calcd for C24H36O4Si
416.2383 for; found 416.2393; Anal. Cacld for C24H36O4Si: C, 68.19; H, 8.71. Found: C, 68.74; H,
8.58; [α]26D −83.8 (c 1.00, CHCl3).
(2R,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1
-ol (5b): To a solution of 4b (7.80 g, 16.3 mmol) in DMF (163 mL) was added imidazole (3.30 g,
49.0 mmol) and TBSCl (4.90 g, 32.6 mmol). After being stirred for 13 h, the reaction mixture was
cooled to 0 °C, the reaction was quenched with saturated aqueous NaHCO3 (163 mL). The aqueous
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layer was extracted with ether and the combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography
(hexane:EtOAc = 3:1) to afford a TBS ether (9.60 g, 99%) as colorless oil: To a solution of the TBS
ether (7.60 g, 12.8 mmol) in THF:methanol = 30:1 (205 mL) was added NaBH4 (4.60 g, 123 mmol)
and water (66.0 mL). After the reaction mixture was stirred for 3 h, the solution was extracted with
EtOAc and the combined organic layers were washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc = 4:1)
to afford 5b (5.27 g, 99%) as colorless oil: 1H NMR (500 MHz, CDCl3) δ −0.17 (3H, s), 0.05 (3H,
s), 0.78 (3H, d, J = 6.6 Hz), 0.90 (9H, s), 1.99–2.00 (1H, qddd, J = 6.6, 8.1, 4.7, 4.4 Hz), 3.44 (1H,
dd, J = 10.5, 4.7 Hz), 3.57 (1H, dd, J = 10.5, 8.1 Hz), 3.88 (3H, s), 4.74 (1H, d, J = 4.4 Hz), 5.13
(2H, s), 6.72 (1H, dd, J = 8.3, 1.2 Hz), 6.83 (1H, d, J = 8.3 Hz), 6.91 (1H, d, J = 1.2 Hz), 7.31 (1H,
brꢀt, J = 7.1 Hz), 7.37 (2H, brꢀdd, J = 7.3, 7.1 Hz), 7.45 (2H, brꢀd, J = 7.3 Hz); 13C NMR (125 MHz,
CDCl3) δ −5.3, −4.6, 12.1, 18.1, 25.8, 43.0, 55.9, 65.6, 71.1, 110.3, 113.2, 118.8, 127.4, 127.8,
128.5, 135.7, 137.2, 147.2, 149.2; IR (ATR) 3437 cm−1; HRMS (EI) m/z: [M]+ Calcd for
C24H36O4Si 416.2382, Found 416.2387; [α]20D −47.7 (c 1.00, CHCl3).
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(2R,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanal
(6a): To a solution of 5a (347 mg, 834 ꢁmol) in DCM (8.34 mL) was added PDC (471 mg, 1.25
mmol) and 4Å MS (471 mg) at rt. After being stirred for 12 h, the mixture was added to excess
ether, filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by
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column chromatography (hexane:EtOAc = 10:1) to afford 6a (345 mg, quant.) as colorless oil: H
NMR (500 MHz, CDCl3) δ −0.23 (3H, s), 0.01 (3H, s), 0.85 (9H, s), 0.85 (3H, d, J = 7.4 Hz), 2.66
(1H, ddq, J = 7.7, 2.7, 7.4 Hz), 3.88 (3H, s), 4.69 (1H, d, J = 7.7 Hz), 5.13 (2H, s), 6.72 (1H, dd, J =
8.2, 1.6 Hz), 6.82 (1H, d, J = 8.2 Hz), 6.90 (1H, d, J = 1.6 Hz), 7.27–7.45 (5H, m), 9.78 (1H, d, J =
2.7 Hz): 13C NMR (125 MHz, CDCl3) δ −5.2, −4.5, 11.2, 18.1, 25.7, 54.7, 55.9, 71.1, 76.6, 109.9,
113.3, 119.0, 127.4, 127.9, 128.5, 135.5, 137.1, 147.7, 149.7, 204.7; IR (ATR) 1729 cm−1; HRMS
(EI) m/z: [M]+ Calcd for C24H34O4Si 414.2226, Found 414.2241; [α]20D +83.9 (c 0.26, CHCl3).
(2S,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanal
(6b): To a solution of 5b (6.20 g, 15.0 mmol) in DCM (100 mL) was added Dess–Martin
periodinane (9.50 g, 22.4 mmol). After being stirred at rt for 26 h. the mixture was added to excess
diethyl ether (40.0 mL), filtered through celite and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (hexane:EtOAc = 5:1) to afford 6b (5.40 g, 88%)
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as colorless oil: 1H NMR (500 MHz, CDCl3) δ −0.16 (3H, s), 0.03 (3H, s), 0.88 (9H, s), 1.04 (3H, d,
J = 6.6 Hz), 2.57 (1H, qdd, J = 6.6, 4.2, 1.5 Hz), 3.87 (3H, s), 5.06 (1H, d, J = 4.2 Hz), 5.13 (2H, s),
6.73 (1H, dd, J = 8.2, 1.8 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.88 (1H, d, J = 1.8 Hz), 7.30 (1H, brꢀt, J =
6.5 Hz), 7.35 (2H, brꢀdd, J = 6.5, 7.4 Hz), 7.44 (2H, brꢀd, J = 7.4 Hz), 9.73 (1H, d, J = 1.5 Hz); 13C
NMR (125 MHz, CDCl3) δ −5.2, −4.5, 8.3, 18.1, 25.7, 54.9, 55.9, 71.1, 74.0, 109.9, 113.5, 118.3,
127.4, 127.8, 128.5, 135.6, 137.1, 147.4, 149.4, 204.5; IR (ATR) 1724 cm−1; HRMS (EI) m/z: [M]+
Calcd for C24H34O4Si 414.2226, Found 414.2240; [α]20D −15.2 (c 1.00, CHCl3).
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(3R,4S)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-methylbutan-2-
one (7a): To a solution of 6a (83.2 mg, 201 ꢁmol) in THF (1.00 mL) at rt was added 3.0 M
MeMgBr in THF solution (80.3 ꢁL, 241 ꢁmol). After being stirred 30 min, the reaction was
quenched with sat. NH4Cl (5.00 mL) and extracted with ether. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography (hexane:EtOAc = 3:1) to afford an alcohol (86.0 mg, 100%) as colorless
oil. To a solution of the alcohol (86.0 mg, 200 ꢁmol) in DCM (2.00 mL) was added PDC (376 mg,
1.00 mmol) and powdered 4Å MS (376 mg). After being stirred at rt for 1.5 h. the mixture was
added to excess ether (10.0 mL), filtered through celite and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (hexane:EtOAc = 4:1) to afford 7a (83.6 mg,
98%) as colorless oil: 1H NMR (500 MHz, CDCl3) δ −0.30 (3H, s), −0.05 (3H, s), 0.73 (3H, d, J =
7.1 Hz), 0.80 (9H, s), 2.25 (3H, s), 2.86 (1H, dq, J = 9.3, 7.1 Hz), 3.88 (3H, s), 4.59 (1H, d, J = 9.3
Hz), 5.13 (2H, s), 6.71 (1H, dd, J = 8.2, 1.6 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.88 (1H, d, J = 1.6 Hz),
7.28–7.46 (5H, m); 13C NMR (125 MHz, CDCl3) δ −5.4, −4.6, 13.7, 18.0, 25.7, 31.3, 55.0, 55.9,
71.1, 78.2, 110.0, 113.2, 119.5, 127.4, 127.8, 128.5, 135.9, 137.1, 147.6, 149.6, 212.6; IR (ATR)
836, 1258, 1513, 1715 cm−1; HRMS (CI) m/z: [M]+ Calcd for C25H36O4Si 428.2383, Found
428.2387; [α]20D +84.2 (c 1.47, CHCl3).
(3S,4S)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-methylbutan-2-o
ne (7b): To a solution of 6b (5.44 g, 13.1 mmol) in THF (66.0 mL) at 0 °C was added 3.0 M
MeMgBr in THF solution (6.60 mL, 19.7 mmol). After being stirred 3 h, the reaction was quenched
with sat. NH4Cl (66.0 mL) and extracted with ether. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (hexane:EtOAc = 5:1) to afford an alcohol (4.28 g, 76%) as colorless oil. To a
solution of the alcohol (5.28 g, 12.3 mmol) in DCM (80.0 mL) was added Dess–Martin periodinane
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(DMP, 7.80 g, 18.4 mmol). After being stirred at rt for 15 h. the mixture was added to excess ether
(40.0 mL), filtered through celite and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (hexane:EtOAc = 6:1) to afford 7b (4.40 g, 83%) as colorless
oil: 1H NMR (500 MHz, CDCl3) δ −0.22 (3H, s), 0.01 (3H, s), 0.87 (9H, s), 1.14 (3H, d, J = 6.8 Hz),
1.87 (3H, s), 2.78 (1H, qd, J = 6.8, 6.8 Hz), 3.87 (3H, s), 4.72 (1H, d, J = 6.8 Hz), 5.11 (2H, s), 6.69
(1H, dd, J = 8.0, 1.8 Hz), 6.79 (1H, d, J = 8.0 Hz), 6.87 (1H, d, J = 1.8 Hz), 7.30 (1H, brꢀt, J = 7.1
Hz), 7.36 (2H, brꢀdd, J = 7.3, 7.1 Hz), 7.43 (2H, brꢀd, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ
−5.1, −4.6, 12.9, 18.2, 25.8, 56.0, 56.1, 71.1, 76.1, 110.0, 113.5, 118.7, 127.4, 127.8, 128.5, 136.7,
137.1, 147.3, 149.4, 211.9; IR (ATR) 1714 cm−1; HRMS (EI) m/z: [M]+ Calcd for C25H36O4Si
428.2383, Found 428.2391; [α]20D −22.8 (c 1.00, CHCl3).
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(((1S,2S)-1-(4-(benzyloxy)-3-methoxyphenyl)-2,3-dimethylbut-3-en-1-yl)oxy)(tert-butyl)dimeth
ylsilane (8a): To a solution of 7a (249 mg) in THF (3.70 mL) was added 0.5 M Tebbe reagent (1.28
mL, 640 ꢁmol) at −40 °C. The mixture was stirred at −40 °C for 30 min and then at rt for 15 min.
Saturated aqueous NaHCO3 was added dropwise, and the aqueous layer was extracted with Et2O.
The combined organic layers were dried over anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (hexane:EtOAc = 60:1) to yield 8a (208 mg, 72%
in four steps) as a pale green solid: 1H NMR (300 MHz, CDCl3) δ −0.28 (3H, s), −0.01 (3H, s), 0.78
(3H, d, J = 6.9 Hz), 0.84 (9H, s), 1.72 (3H, brꢀs), 2.39 (1H, dq, J = 7.4, 6.9 Hz), 3.87 (3H, s), 4.41
(1H, d, J = 7.4 Hz), 4.68 (1H, d, J = 1.6 Hz), 4.76 (1H, d, J = 1.6 Hz), 5.12 (2H, s), 6.68 (1H, dd, J
= 8.2, 1.6 Hz), 6.79 (1H, d, J = 8.2 Hz), 6.87 (1H, d, J = 1.6 Hz), 7.30–7.46 (5H, m); 13C NMR (75
MHz, CDCl3) δ −5.3, −4.6, 16.1, 18.2, 20.7, 25.7, 49.7, 55.9, 71.2, 78.1, 110.5, 111.6, 113.2, 119.3,
127.4, 127.8, 128.5, 137.4, 137.5, 147.2, 147.6, 149.3; IR (ATR) 1515 cm–1; HRMS (EI) m/z: [M]+
Calcd for C26H38O3Si 426.2590; Found 426.2545; [α]22D −46.5 (c 0.54, CHCl3); m.p. 135–136 °C.
(((1S,2R)-1-(4-(benzyloxy)-3-methoxyphenyl)-2,3-dimethylbut-3-en-1-yl)oxy)(tert-butyl)dimet
hylsilane (8b): To a solution of 7b (1.50 g, 3.50 mmol) in THF (30.0 mL) was added a Tebbe
reagent solution (14.4 mL in toluene, 7.0 mmol) dropwise at −40 °C. After being stirred for 5 h, the
reaction mixture was poured into aq NaHCO3 and exracted with ether. The organic layers were
washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by
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column chromatography (hexane:EtOAc = 9:1) to afford 8b (1.30 g, 87%) as yellow oil: H NMR
(500 MHz, CDCl3) δ −0.24 (3H, s), 0.00 (3H, s), 0.87 (9H, s), 1.07 (3H, d, J = 7.1 Hz), 1.58 (3H, s),
2.31 (1H, qd, J = 7.1, 6.3 Hz), 3.86 (3H, s), 4.46 (1H, d, J = 6.3 Hz), 4.59 (1H, s), 4.67 (1H, s), 5.11
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(2H, s), 6.67 (1H, dd, J = 8.1, 1.7 Hz), 6.77 (1H, d, J = 8.1 Hz), 6.88 (1H, d, J = 1.7 Hz), 7.30 (1H,
brꢀt, J = 7.3 Hz), 7.36 (2H, brꢀdd, J = 7.3, 7.3 Hz), 7.44 (2H, brꢀd, J = 7.3 Hz); 13C NMR (125 MHz,
CDCl3) δ −5.1, −4.6, 15.1, 18.3, 21.7, 25.9, 49.8, 55.9, 71.1, 77.8, 110.4, 111.6, 113.1, 118.9, 127.4,
127.8, 128.5, 137.3, 138.1, 146.9, 147.5, 149.1; IR (ATR) 2954, 1512, 1255 cm–1; HRMS (CI) m/z:
[M + H]+ Calcd for C26H39O3Si 427.2668, Found 427.2662; [α]20D −24.9 (c 1.00, CHCl3).
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(2R,3S,4S)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbu
tan-1-ol (9a): To a solution of 8a (456 mg, 1.07 mmol) in THF (7.1 mL) was added 0.5 mol/L
9ꢀBBN (8.60 mL, 4.28 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then at
rt for 20 h. The reaction mixture was treated with 3 mol/L aqueous NaOH (1.95 mL) and 30% H2O2
(1.95 mL, 4.28 mmol) for 1 h. The aqueous layer was extracted with EtOAc. The combined organic
layers were dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography (hexane:EtOAc = 20:1 to 6:1) to yield 9a (356 mg, 74%, >99% de) as a
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colorless oil: H NMR (300 MHz, CDCl3) δ −0.17 (3H, s), 0.07 (3H, s), 0.78 (3H, d, J = 7.0 Hz),
0.91 (9H, s), 0.91 (3H, d, J = 6.9 Hz), 1.77–1.84 (1H, m), 1.91–1.99 (1H, m), 3.30 (1H, dd, J = 11.0,
4.8 Hz), 3.52 (1H, dd, J = 11.0, 8.9 Hz), 3.88 (3H, s), 4.65 (1H, d, J = 4.8 Hz), 5.13 (2H, s), 6.72
(1H, dd, J = 8.2, 1.9 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.91 (1H, d, J = 1.9 Hz), 7.29–7.46 (5H, m); 13C
NMR (75 MHz, CDCl3) δ −5.1, −4.6, 12.2, 17.2, 18.2, 25.8, 33.9, 45.7, 55.9, 63.9, 71.1, 78.8, 110.5,
113.5, 118.8, 127.4, 127.8, 128.5, 136.7, 137.2, 147.0, 149.2; IR (neat) 3416 cm–1; HRMS (EI) m/z:
[M]+ Calcd for C26H40O4Si 444.2696; Found 444.2698; [α]19D –39.4 (c 1.00, CHCl3).
(2S,3R,4S)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbu
tan-1-ol (9b): To a solution of 8b (1.30 g, 3.05 mmol) in THF (30.0 mL) was added 0.5 M 9ꢀBBN
in THF solution (24.4 mL, 12.2 mmol) at 0 °C. After being stirred at rt for 5 h, a mixture of 3.0 M
aq NaOH (5.10 mL, 15.3 mmol) and 30% H2O2 (5.10 mL) was added to the reaction mixture. After
further 2 h, the reaction mixture was exracted with EtOAc. The organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
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chromatography (hexane:EtOAc = 4:1) to afford 9b (1.26 g, 93%, >99%de) as colorless oil: H
NMR (400 MHz, CDCl3) δ −0.25 (3H, s), 0.02 (3H, s), 0.89 (12H, m), 0.98 (3H, d, J = 6.3 Hz),
1.56–1.66 (2H, m), 3.41 (1H, dd, J = 10.4, 6.3 Hz), 3.61 (1H, dd, J = 10.4, 4.5 Hz), 3.87 (3H, s),
4.66 (1H, d, J = 4.7 Hz), 5.12 (2H, s), 6.70 (1H, dd, J = 8.1, 1.8 Hz), 6.80 (1H, d, J = 8.1 Hz), 6.89
(1H, s), 7.30 (1H, brꢀt, J = 6.6 Hz), 7.36 (2H, brꢀdd, J = 7.5, 6.6 Hz), 7.44 (2H, brꢀd, J = 7.5 Hz);
13C NMR (100 MHz, CDCl3) δ −5.0, −4.3, 10.5, 16.4, 18.2, 25.9, 36.9, 45.4, 56.0, 65.6, 71.2, 76.8,
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110.4, 113.3, 118.9, 127.4, 127.8, 128.5, 137.3, 138.2, 147.0, 149.2; IR (ATR) 3402 cm−1; HRMS
(EI) m/z: [M]+ Calcd for C26H40O4Si 444.2696, Found 444.2690; [α]20D −35.0 (c 1.00, CHCl3).
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(2R,3S,4S)-1-(benzo[d][1,3]dioxol-5-yl)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimet
hylsilyl)oxy)-2,3-dimethylbutan-1-one (10): To a solution of 9a (209 mg, 471 ꢁmol) in DMF
(4.70 mL) was added pyridinium dichromate (509 mg, 1.54 mmol). The mixture was stirred at rt for
2 h. The reaction was taken up with water and 2 mol/L HCl. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with water, and brine, dried over anhydrous
MgSO4, and concentrated in vacuo to give an aldehyde. To a solution of this aldehyde (198 mg, 448
ꢁmol) in THF (4.50 mL) was added anhydrous CeCl3 (276 mg, 1.12 mmol) at 0 °C. After the
mixture was cooled to −78 °C, 3,4ꢀmethylenedioxyphenylmagnesium bromide (1.12 mL, 1.0 mol/L
solution in THF) was added dropwise and the reaction mixture was further stirred at rt for 2 h and
the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with H2O and brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue (340 mg) was dissolved in DCM and to the
resulting solution was added pyridine (57.2 ꢁL, 672 ꢁmol) and Dess–Martin periodinane (228 mg,
538 ꢁmol). The reaction mixture was stirred at rt for 1 h. After being taken up with saturated
aqueous NaHCO3, the aqueous layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane:EOAc = 6:1) to yield 10 (188 mg, 71% in three steps)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ −0.29 (3H, s), −0.10 (3H, s), 0.82 (9H, s), 0.83 (3H,
d, J = 7.2 Hz), 1.23 (3H, d, J = 7.0 Hz), 2.09 (1H, ddq, J = 6.6, 6.0, 7.2 Hz), 3.52 (1H, dq, J = 6.6,
7.0 Hz), 3.86 (3H, s), 4.69 (1H, d, J = 6.0 Hz), 5.15 (2H, s), 6.02 (2H, s), 6.73 (1H, dd, J = 8.3, 2.0
Hz), 6.79 (1H, d, J = 8.0 Hz), 6.83 (1H, d, J = 8.3 Hz), 6.90 (1H, d, J = 2.0 Hz), 7.28–7.47 (7H, m);
13C NMR (100 MHz, CDCl3) δ −5.1, −4.6, 13.0, 17.2, 18.1, 25.8, 40.1, 45.8, 55.9, 71.1, 76.2, 101.7,
107.7, 108.2, 110.7, 113.2, 119.1, 124.4, 127.4, 127.8, 128.5, 132.4, 136.8, 137.2, 147.1, 148.1,
149.2, 151.4, 202.3; IR (ATR) 1673 cm−1; HRMS (EI) m/z: [M]+ Calcd for C33H42O6Si 562.2751;
Found 562.2746; [α]21D −100.0 (c 3.90, CHCl3).
5-((4S,5S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyl-4,5-dihydrofuran-2-yl)benzo[d][1,
3]dioxole (11a): To a solution of 10 (50.2 mg, 893 ꢁmol) in THF (2.00 mL) was added 1.0 mol/L
TBAF solution (1.34 mL, 1.34 mmol) at rt. After being stirred for 1 h, water was added to the
reaction mixture and extracted with ether. The combined organic layers were washed with brine,
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dried over anhydrous MgSO4, and concentrated in vacuo. The residue was dissolved in THF (2.00
mL). 2.0 mol/L HCl (0.5 mL) was added to the solution. After being stirred for 3 h, water was
added to the reaction mixture and extracted with ether. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by
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column chromatography (hexane:EOAc = 10:1) to yield 11a (26.9 mg, 70%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 1.22 (3H, d, J = 6.0 Hz), 1.85 (3H, d, J = 1.4 Hz), 2.93 (1H, dqq, J = 8.5,
6.0, 1.4 Hz), 3.90 (3H, s), 4.85 (1H, d, J = 8.5 Hz), 5.16 (2H, s), 5.97 (2H, s), 6.82 (1H, dd, J = 8.6,
1.7 Hz), 6.86 (2H, brs), 6.98 (1H, brs), 7.08 (1H, d, J = 1.7 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.28–7.46
(5H, m); 13C NMR (100 MHz, CDCl3) δ 11.0, 18.0, 51.7, 56.1, 71.1, 88.0, 101.1, 107.6, 108.1,
108.7, 109.5, 113.8, 118.2, 121.1, 126.2, 127.2, 127.8, 128.5, 135.7, 137.2, 147.0, 147.4, 147.7,
149.7; IR (ATR) 1505 cm−1; HRMS (EI) m/z: [M]+ Calcd for C27H26O5 430.1780; Found 430.1788.
(1
R,2R,3S,4S)-1-(benzo[d][1,3]dioxol-5-yl)-4-(4-(benzyloxy)-3-methoxyphenyl)-2,3-dimethylbu
tane-1,4-diol (13a): To a solution of 10a (45.0 mg, 80.0 ꢁmol) in methanol (800 ꢁL) was added
NaBH4 (6.00 mg, 160 ꢁmol) and CeCl3 7H2O (28.8 mg, 80.0 ꢁmol) at rt. After being stirred for 1 h,
⋅
H2O (2.00 mL) was added to the reaction mixture and extracted with EtOAc. The organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was purified by column
chromatography (hexane:ether = 3:1) to afford a monoꢀalcohol (23.8 mg, 53%). The monoꢀalcohol
(35.5 mg, 62.9 ꢁmol) was dissolved in THF (600 ꢁL). TBAF (THF solution, 75.5 ꢁL, 75.5 ꢁmol)
was added to the mixture at 0 °C. After being stirred for 1 h, H2O was added to the reaction flask
and extracted with EtOAc. The organic layers were washed with brine and dried over MgSO4 and
concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc = 1:1)
to afford 13a (24.2 mg, 85%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.78 (3H, d, J = 6.0
Hz), 0.80 (3H, d, J = 6.6 Hz), 2.04–2.11 (2H, m), 3.90 (3H, s), 4.51 (2H, d, J = 7.4 Hz), 5.14 (2H, s),
5.94 (2H, s), 6.76 (2H, s), 6.76 (1H, dd, J = 7.1, 1.6 Hz), 6.83 (1H, d, J = 7.1 Hz), 6.85 (1H, s), 6.91
(1H, d, J = 1.6 Hz), 7.29–7.44 (5H, m); 13C NMR (75 MHz, CDCl3) δ 14.9, 15.1, 41.9, 42.2, 56.0,
71.1, 100.9, 102.1, 107.0, 107.9, 110.1, 113.7, 118.9, 120.0, 127.3, 127.8, 128.5, 137.7, 138.0,
138.7, 146.7, 147.7, 149.6; IR (ATR) 3221 cm−1; HRMS (EI) m/z: [M]+ Calcd for C27H30O6
450.2043, Found 450.2068; [α]22D +14.6 (c 1.80, CHCl3).
4-((1S,2R,3S,4R)-4-(benzo[d][1,3]dioxol-5-yl)-1,4-dihydroxy-2,3-dimethylbutyl)-2-methoxyphe
nyl 4-methylbenzenesulfonate (13b): To a solution of 24 (16.2 mg, 30.0 ꢁmol) in
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benzene:methanol = 4:1 (500 ꢁL) was Pd(OH)2/C (1.60 mg). The reaction mixture was stirred under
H2 for 8 h, and the mixture was filtered through celite and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (hexane:EtOAc = 3:1) to afford a phenol (7.40
mg, 54%) as colorless oil. To a solution of the phenol (15.3 mg, 320 ꢁmol) in DCM (500 ꢁL) was
added Et3N (12.0 ꢁL, 840 ꢁmol) and pꢀtoluenesulfonyl chloride (14.8 mg, 780 ꢁmol). The reaction
mixture was stirred at 45 °C for 2 d, and quenched with sat. NH4Cl, and extracted with EtOAc. The
combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (hexane:EtOAc = 15:1 then 3:1) to afford a
tosylate (16.4 mg, 82%) as colorless oil. To a solution of the tosylate (83.9 mg, 133 ꢁmol) in THF
(1.50 mL) was added 1.0 M TBAF in THF (200 ꢁL, 200 ꢁmol). After being stirred for 10 h, the
reaction mixture was added water (2.00 mL), and extracted ether. The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography (hexane:EtOAc = 2:1 then 1:1) to afford 13b (67.5 mg, 99%) as colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.88 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 1.82–1.89 (4H,
m), 2.44 (3H, brꢀs), 3.55 (3H, s), 4.89 (1H, brꢀs), 4.97 (1H, brꢀs), 5.95 (1H, d, J = 1.4 Hz), 5.96 (1H,
d, J = 1.4 Hz), 6.77–6.83 (5H, m), 7.09 (1H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.74 (2H, brꢀd,
J = 8.0 Hz),; 13C NMR (100 MHz, CDCl3) δ 10.7, 10.7, 21.7, 42.5, 43.0, 55.6, 73.7, 74.6, 101.0,
106.5, 108.0, 110.3, 117.6, 119.0, 123.5, 128.6, 129.3, 133.2, 137.0, 138.3, 144.8, 144.9, 146.5,
147.7, 151.5; IR (ATR) 3545, 3422 cm−1; HRMS (FAB) m/z: [M + Na]+ Calcd for C27H30O8SNa
537.1559, Found 537.1578; [α]20D −3.6 (c 1.10, CHCl3).
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5-((2
R,3R,4S,5S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyltetrahydrofuran-2-yl)benzo
[d
][1,3]dioxole (14): To a solution of 13a (16.3 mg, 36.2 ꢁmol) in DCM (1.00 mL) was added PPh3
(49.4 mg, 188 ꢁmol) and DIAD (30.8 ꢁL, 159 ꢁmol). After being stirred for 12 h, the solution was
concentrated in vacuo. The residue was purified by column chromatography (hexane:ether = 1:1) to
afford 14 (8.80 mg, 56%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.01 (3H, d, J = 4.4 Hz),
1.01 (3H, d, J = 4.4 Hz), 2.22–2.35 (2H, m), 3.90 (3H, s), 4.45 (1H, d, J = 6.6 Hz), 4.46 (1H, d, J =
6.6 Hz), 5.13 (2H, s), 5.94 (2H, s), 6.79–6.98 (5H, m), 7.27–7.58 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 14.9, 15.1, 41.9, 42.2, 56.0, 71.1, 76.7, 77.3, 101.0, 107.0, 107.9, 110.1, 113.8, 119.0,
120.1, 127.3, 127.8, 128.5, 137.2, 137.7, 138.7, 146.7, 147.4, 147.7, 149.7; IR (ATR) 2961, 1506
cm−1; HRMS (EI) m/z: [M]+ Calcd for C27H28O5 432.1936, Found 432.1929.
(2
S,3
R
,4
S)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbu
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tanal (15): To a solution of 9b (5.28 g, 12.3 mmol) in DCM (80.0 mL) was added Dess–Martin
periodinane (7.80 g, 18.4 mmol). After being stirred at rt for 15 h. the mixture was added to excess
ether (40.0 mL), filtered through celite and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (hexane:EtOAc = 6:1) to afford 15 (4.40 g, 83%) as colorless
oil: 1H NMR (400 MHz, CDCl3) δ −0.24 (3H, s), 0.03 (3H, s), 0.89 (9H, s), 1.00 (3H, d, J = 7.0 Hz),
1.11 (3H, d, J = 7.0 Hz), 1.91 (1H, qdd, J = 7.0, 5.9, 5.9 Hz), 2.32 (1H, qdd, J = 7.0, 5.9, 2.4 Hz),
3.87 (3H, s), 4.66 (1H, d, J = 5.9 Hz), 5.12 (2H, s), 6.72 (1H, dd, J = 8.2, 2.0 Hz), 6.81 (1H, d, J =
8.2 Hz), 6.88 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 6.2, 1.3 Hz), 7.34–7.45 (4H, m), 9.54 (1H, d, J =
2.4 Hz); 13C NMR (100 MHz, CDCl3) δ −5.1, −4.4, 12.0, 12.5, 18.2, 25.9, 44.8, 48.2, 55.9, 71.1,
76.2, 110.3, 113.3, 119.0, 127.4, 127.8, 128.5, 136.8, 137.2, 147.4, 149.4, 205.1; IR (ATR) 1722
cm−1; HRMS (EI) m/z: [M]+ Calcd for C26H38O4Si 442.2539, Found 442.2545; [α]20D –25.9 (c 1.22,
CHCl3).
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(3S,4R,5S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyldihydrofuran-2(3H)-one (16): To a
solution of 9b (3.00 g, 6.75 mmol) in DCM (60.0 mL) was added Dess–Martin periodinane (5.70 g,
13.5 mmol). After being stirred at rt for 1 h. the mixture was added to excess ether (120 mL),
filtered through celite and the filtrate was concentrated in vacuo. To a solution of the residue (3.04
g) in tꢀBuOH (14.0 mL) was added a solution of 2ꢀmethylꢀ2ꢀbutene (3.20 mL, 30.4 mmol),
anhydrous NaH2PO4 (891 mg, 7.43 mmol), and NaClO2 (2.44 g, 27.0 mmol) in tꢀBuOH/H2O (3.6:1,
86.0 mL) at rt. After being stirred for 40 min, 5% HCl was added to the reaction mixture, then
extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The
residue (2.90 g) was added to a solution of HF/pyridine/MeCN (1:3:5, 92.0 mL) at 0 °C. After being
stirred for 23 h, saturated NaH2PO4 (100 mL) was added to the reaction mixture, and then extracted
with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (hexane:EtOAc = 3:1) to afford 16 (1.20 g, 55%, over 3
1
steps) as yellow oil: H NMR (200 MHz, CDCl3)
δ 0.56 (3H, d, J = 7.4 Hz), 1.22 (3H, d, J = 7.4
Hz), 2.73 (1H, qdd, J = 7.4, 7.1, 4.9 Hz), 2.98 (1H, qd, J = 7.4, 7.1 Hz), 3.88 (3H, s), 5.15 (2H, s),
5.46 (1H, d, J = 4.9 Hz), 6.72 (1H, dd, J = 8.2, 2.1 Hz), 6.83 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J =
8.2 Hz), 7.25–7.45 (5H, m); 13C NMR (50 MHz, CDCl3)
δ 9.4, 10.1, 40.1, 41.0, 56.1, 71.0, 82.2,
109.1, 114.0, 117.5, 127.8, 128.5, 129.3, 130.2, 137.0, 147.7, 149.7, 180.0; IR (ATR) 1771 cm−1;
HRMS (EI) m/z: [M]+ Calcd for C20H22O4 326.1518, Found 326.1506; [α]20D –53.7 (c 1.00, CHCl3).
(3
R
,4
R,5
S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyldihydrofuran-2(3H)-one (17): To a
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solution of 16 (15.9 mg, 48.7 ꢁmol) in MeOH (200 ꢁL) was added 1.0 mol/L NaOMe solution (in
MeOH, 122 ꢁL, 122 ꢁmol) at rt. After being stirred for 16 h, saturated NaCl solution (2.00 mL) was
added to the reaction mixture and extracted with ether. The organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc =
2:1) to afford 17 (11.0 mg, 69%) as yellow oil: 1H NMR (400 MHz, CDCl3) δ 0.76 (3H, d, J = 7.0
Hz), 1.29 (3H, d, J = 7.0 Hz), 2.31–2.39 (1H, m), 2.42–2.51 (1H, m), 3.88 (3H, s), 5.15 (2H, s),
5.49 (1H, d, J = 7.6 Hz), 6.66 (1H, dd, J = 8.3, 2.0 Hz), 6.67 (1H, d, J = 2.0 Hz), 6.87 (1H, d, J =
8.3 Hz), 7.28–7.44 (5H, m); 13C NMR (100 MHz, CDCl3) δ 13.7, 14.6, 40.0, 42.4, 56.1, 71.1, 82.4,
109.5, 113.8, 118.1, 127.3, 127.9, 128.6, 129.2, 136.9, 148.0, 149.6, 179.8; IR (ATR) 1771 cm−1;
HRMS (CI) m/z: [M + H]+ Calcd for C20H23O4 327.1597, Found 327.1601; [α]20D +27.1 (c 1.00,
CHCl3).
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(2S,3R,4R)-2-(4-(benzyloxy)-3-methoxyphenyl)-5-methoxy-3,4-dimethyltetrahydrofuran (19):
To a solution of 17 (330 mg, 1.01 mmol) in DCM (10.0 mL) was added 1 mol/L Dibal solution (in
toluene, 1.20 mL, 1.20 mmol) at −78 °C. After being stirred for 30 min, the reaction was worked up
with methanol (600 ꢁL), H2O (2.20 mL), and 2 mol/L aqueous NaOH (2.20 mL) and extracted with
DCM. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue (345 mg)
was dissolved in methanol (10.0 mL). HC(OCH3)3 (409 ꢁL, 3.74 mmol) and pꢀTsOH H2O (652 mg,
⋅
3.43 mmol) was added to the solution. After being stirred for 7 h, the reaction was cooled to 0 °C
and worked up with saturated aqueous NaHCO3 (10.0 mL), then extracted with EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (hexane:EtOAc = 8:1) to afford acetal 19 (328
mg, 95% yield over 2 steps) as colorless oil: 1H NMR (300 MHz, CDCl3)
δ 0.91 (3H, d, J = 6.9 Hz),
1.00 (3H, d, J = 7.4 Hz), 2.24–2.46 (2H, m), 3.48 (3H, s), 3.90 (3H, s), 4.51 (1H, d, J = 9.6 Hz),
4.70 (1H, s), 5.15 (2H, s), 6.76 (1H, dd, J = 8.2, 2.0 Hz), 6.82 (1H, d, J = 8.2 Hz), 6.99 (1H, d, J =
2.0 Hz), 7.27–7.45 (5H, m); 13C NMR (75 MHz, CDCl3)
δ 10.9, 11.4, 42.9, 44.1, 54.9, 55.8, 71.1,
87.7, 110.4, 110.9, 113.4, 119.4, 127.2, 127.8, 128.5, 135.4, 137.3, 147.7, 149.8; IR (ATR) 2960,
1511, 1261 cm−1; HRMS (EI) m/z: [M]+ Calcd for C21H26O4 342.1831, Found 342.1840.
(2S,3R,4R)-2-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyl-5-(phenylsulfonyl)tetrahydrofur
an (20): To a solution of hemiꢀacetal 18 (15.7 mg, 0.05 mmol) in DCM (500 ꢁL) was added
PhSO2H (13.6 mg, 0.10 mmol), CSA (1.20 mg, 0.01 mmol), and CaCl2 (15.4 mg, 0.14 mmol). After
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being stirred for 1 h, the reaction was worked up with saturated aquepus NaHCO3 (2.00 mL) and
extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by column chromatography (hexane: EtOAc =
3:1) to afford 20a (10.9 mg, 51%) and 20b (5.5 mg, 25%) as colorless oils: 20a (major isomer): 1H
NMR (400 MHz, CDCl3) δ 0.60 (3H, d, J = 6.6 Hz), 1.56 (3H, d, J = 7.1 Hz), 2.38–2.48 (1H, m),
2.84–2.95 (1H, m), 3.83 (3H, s), 5.05 (1H, d, J = 7.2 Hz), 5.10 (2H, s), 5.50 (1H, d, J = 9.0 Hz),
6.56 (1H, d, J = 8.2 Hz), 6.60 (1H, s), 6.79 (1H, d, J = 8.2 Hz), 7.15–7.60 (8H, m), 7.92 (2H, d, J =
7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 12.2, 14.4, 42.4, 43.7, 56.1, 71.0, 86.2, 96.3, 110.4, 113.7,
118.8, 127.3, 127.8, 128.5, 128.9, 129.2, 132.7, 133.6, 137.1, 138.5, 147.6, 149.4; IR (ATR) 2965,
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1514, 1146 cm−1; HRMS (CI) m/z: [M]+ Calcd for C26H28O5S 452.1657, Found 452.1658; [α]20
D
+71.6 (c 0.99, CHCl3). 20b (minor isomer): 1H NMR (500 MHz, CDCl3) δ 0.65 (3H, d, J = 6.9 Hz),
1.36 (3H, d, J = 6.6 Hz), 2.19–2.27 (1H, m), 2.61–2.69 (1H, m), 4.00 (3H, s), 4.53 (1H, d, J = 8.8
Hz), 5.10 (1H, d, J = 8.6 Hz), 5.17 (2H, s), 6.71 (1H, dd, J = 8.3, 1.9 Hz), 6.84 (1H, d, J = 8.3 Hz),
13
7.27–7.67 (9H, m), 7.98 (2H, dd, J = 8.1, 1.4 Hz); C NMR (100 MHz, CDCl3) δ 13.8, 16.1, 39.7,
45.7, 56.3, 71.0, 86.4, 98.1, 110.6, 113.2, 119.0, 127.3, 127.8, 128.6, 129.0, 129.2, 132.5, 133.9,
137.2, 137.8, 147.5, 149.7; IR (ATR) 2865, 1591, 1512, 1149 cm−1; HRMS (CI) m/z: [M]+ Calcd for
C26H28O5S 452.1657, Found 452.1659; [α]20D −187.3 (c 1.07, CHCl3).
5-((2
S,3R,4R,5S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyltetrahydrofuran-2-yl)benzo
[d
][1,3]dioxole (21): To a mixture of ZnBr2 (14.6 mg, 64.9 ꢁmol) in THF (250 ꢁL) was added 1.0
mol/L 3,4ꢀmethylenedioxyphenyl magnesium bromide (in toluene/THF, 124 ꢁL, 124 ꢁmol). After
being stirred for 30 min, a solution of 20a (8.00 mg, 17.7 ꢁmol) in THF (180 ꢁL) was added to the
reaction mixture. After being stirred for 1 h at rt, the reaction was cooled to 0 °C and worked up
with saturated aqueous NH4Cl, extracted with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (toluene:EtOAc = 20:1) to afford 21 (3.80 mg, 50%), 22 (0.20 mg, 3%), and 23
(1.60 mg, 21%) as colorless oils: Data of 21 1H NMR (400 MHz, CDCl3) δ 0.67 (3H, d, J = 6.4 Hz),
0.69 (3H, d, J = 6.5 Hz) 2.23–2.26 (2H, m), 3.91 (3H, s), 5.15 (2H, s), 5.40 (2H, d, J = 6.0 Hz), 5.95
(2H, s), 6.74 (1H, dd, J = 8.2, 1.2 Hz), 6.75 (1H, dd, J = 7.8, 1.5 Hz), 6.79 (1H, d, J = 7.8 Hz), 6.81
(1H, d, J = 1.5 Hz), 6.85 (1H, d, J = 1.2 Hz), 6.86 (1H, d, J = 8.2 Hz), 7.31–7.46 (5H, m); 13C NMR
(100 MHz, CDCl3) δ 14.6, 14.7, 43.8, 43.8, 56.1, 71.2, 83.6, 83.7, 100.9, 107.0, 107.8, 110.2, 113.8,
118.4, 119.4, 127.3, 127.8, 128.5, 134.6, 135.5, 137.3, 146.4, 147.1, 147.5, 149.4; IR (ATR) 2950,
1500, 1037 cm−1; HRMS (CI) m/z: [M]+ Calcd for C27H28O5 432.1937, Found 432.1942; [α]20
–
D
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The Journal of Organic Chemistry
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58.4 (c 0.14, CHCl3). Data of 22 1H NMR (300 MHz, CDCl3) δ 1.02 (3H, d, J = 5.8 Hz), 1.03 (3H,
d, J = 5.8 Hz), 1.71–1.83 (2H, m), 3.92 (3H, s), 4.61 (2H, d, J = 8.0 Hz), 5.15 (2H, s), 5.94 (2H, s),
6.77 (1H, d, J = 8.0 Hz), 6.83 (1H, dd, J = 8.0, 1.1 Hz), 6.84 (2H, brꢀs), 6.92 (1H, d, J = 1.1 Hz),
6.97 (1H, brꢀs), 7.28–7.45 (5H, m); 13C NMR (75 MHz, CDCl3) δ 13.8, 13.8, 50.8, 51.2, 56.0, 71.0,
88.3, 88.3, 100.9, 106.5, 107.9, 113.7, 118.6, 119.6, 127.2, 127.7, 128.5, 135.3, 136.5, 137.2, 146.9,
147.6, 147.7, 149.7; IR (ATR) 2961, 1506 cm−1; HRMS (EI) m/z: [M]+ Calcd for C27H28O5
432.1937; Found 432.1942; [α]20D +57.1 (c 3.30, CHCl3)
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5-((2
R,3R,4R,5S)-5-(4-(benzyloxy)-3-methoxyphenyl)-3,4-dimethyltetrahydrofuran-2-yl)benzo
[d
][1,3]dioxole (23): To a solution of 25 (85.0 mg, 151 ꢁmol) in THF (2.00 mL) was added 1.0
mol/L TBAF solution (300 ꢁL, 300 ꢁmol). After being stirred overnight, H2O was added to the
reaction mixture and extracted with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(hexane:EtOAc = 3:1) to afford a diastereomeric mixture of hemiꢀacetal (10.9 mg, 51%). To a
solution of the hemiꢀacetal (185 mg, 413 ꢁmol) in DCM (4.00 mL) was added NaBH3CN (51.9 mg,
826 ꢁmol) and BF3 OEt2 (109 ꢁL, 413 ꢁmol) at −78 °C. After being stirred for 1.5 h, the reaction
⋅
was worked up with saturated aqueous NaHCO3 (4.00 mL) and extracted with EtOAc. The
combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (benzene:ehter = 20:1) to afford 23 (134 mg,
75%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.65 (3H, d, J = 7.1 Hz), 1.05 (3H, d, J = 6.6
Hz), 1.71–1.76 (1H, m), 2.20–2.25 (1H, m), 3.90 (3H, s), 4.37 (1H, d, J = 9.3 Hz), 5.11 (1H, d, J =
8.8 Hz), 5.16 (2H, s), 5.98 (2H, s), 6.81 (1H, dd, J = 8.2, 1.8 Hz), 6.82 (1H, d, J = 8.1 Hz), 6.87 (1H,
d, J = 8.1 Hz), 6.91 (1H, d, J = 1.6 Hz), 6.94 (1H, dd, J = 8.2, 1.8 Hz), 7.04 (1H, d, J = 1.6 Hz),
7.29–7.46 (5H, m); 13C NMR (125 MHz, CDCl3) δ 14.9, 15.1, 45.9, 48.3, 56.0, 71.1, 83.0, 87.4,
101.0, 106.9, 108.1, 110.8, 113.6, 119.2, 120.1, 127.3, 127.8, 128.5, 134.3, 134.8, 137.3, 147.1,
147.2, 147.8, 149.3; IR (ATR) 2925, 1507, 1037 cm−1; HRMS (EI) m/z: [M]+ Calcd for C27H28O5
432.1937; Found 432.1920 for; [α]20D −92.5 (c 0.19, CHCl3).
(1R,2S,3R,4S)-1-(benzo[d][1,3]dioxol-5-yl)-4-(4-(benzyloxy)-3-methoxyphenyl)-4-((tert-butyldi
methylsilyl)oxy)-2,3-dimethylbutan-1-ol (24): To a solution of 15 (366 mg, 826 ꢁmol) in THF
(8.30 mL) was added 1.0 mol/L 3,4ꢀmethylenedioxyphenyl magnesium bromide in ether (1.00 mL,
1.00 mmol) at 0 °C. After being stirred for 1 h, the reaction was quenched with sat. NH4Cl, and
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