Asymmetric synthesis of (-)-pterosin N from a chiral 1,3-dioxolanone

Article abstract of DOI:10.1002/ejoc.201402234

The first asymmetric total synthesis of (-)-pterosin N from the N,N-diisopropyl-10-camphorsulfonamide-derived chiral 1,3-dioxolanone 11 has been accomplished in 9 steps with 8% overall yield. The key steps in this synthesis were the highly stereoselective propargylation of 1,3-dioxolanone 11 to construct the chiral tertiary alcohol moiety, construction of a diene-ynone by Stille coupling, and an intramolecular Diels-Alder reaction followed by aromatization to finish the synthesis. Copyright

Full text of DOI:10.1002/ejoc.201402234

FULL PAPER
DOI: 10.1002/ejoc.201402234
Asymmetric Synthesis of (–)-Pterosin N from a Chiral 1,3-Dioxolanone
Hsiu-Han Wu,[a] Shao-Chien Hsu,[a] Feng-Lin Hsu,[b] and Biing-Jiun Uang*[a]
Keywords: Natural products / Total synthesis / Asymmetric synthesis / Diels–Alder reactions / Synthetic methods
The first asymmetric total synthesis of (–)-pterosin N from the
N,N-diisopropyl-10-camphorsulfonamide-derived chiral 1,3-
dioxolanone 11 has been accomplished in 9 steps with 8%
overall yield. The key steps in this synthesis were the highly
stereoselective propargylation of 1,3-dioxolanone 11 to con-
struct the chiral tertiary alcohol moiety, construction of a diene-
ynone by Stille coupling, and an intramolecular Diels–Alder
reaction followed by aromatization to finish the synthesis.
increase the complexity during synthesis.[5i] It can also be
problematic to build a stereogenic center and functional
group at the same time.[5h] Although there have been some
reports on the synthesis of pterosins,[5] to the our best
knowledge, there is no report dealing with the synthesis of
chiral pterosins. Here, we report our findings on the synthe-
sis of (–)-pterosin N (1).
Introduction
Pterosins are sesquiterpenes that contain a polysubsti-
tuted 1-indanone in the main skeleton (some examples are
shown in Figure 1) and exist in bracken fern (Pteridium
aquilinum).[1] Some pterosins have been shown to possess
biological activity[2–4] including antibacterial[2,3] and cytoto-
xicity.[3] Recently, pterosins were found to effectively allevi-
ate hyperglycemia, glucose intolerance, insulin resistance,
dyslipidemia, and islet hypertrophy in diabetic mouse mod-
els.[4] The isolation of the active ingredients was limited by
the natural resources.[1,4] The versatile bioactivities attracted
us to develop a synthetic method for the preparation of
chiral pterosins.
Results and Discussion
The retrosynthetic analysis of the (–)-pterosin N (1) is
outlined in Scheme 1. The formation of (–)-pterosin N (1)
could be achieved through an intramolecular Diels–Alder
reaction of diene-ynone 6 followed by aromatization.
Diene-ynone 6 should be available through the removal of
Figure 1. (–)-Pterosin N (1), pterosin Z (2), pterosin A (3), ptero-
side D (4) and palmitylpterosin A (5).
Most syntheses of pterosin natural products use 2,6-di-
methylbenzene analogues as starting materials.[5a,5b,5f–5j]
These syntheses usually start from the construction of the
indanone core followed by introduction of the required
functional groups. The challenge of synthesizing pterosins is
usually restricted by the contiguous functional groups that
[a] Department of Chemistry, National Tsing Hua University,
Hsinchu 30013, Taiwan
E-mail: bjuang@mx.nthu.edu.tw
[b] Graduate Institute of Pharmacognosy, School of Pharmacy,
Taipei Medical University,
Taipei 110, Taiwan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402234.
Scheme 1. Retrosynthetic analysis of (–)-pterosin N (1). IMDA =
intramolecular Diels–Alder reaction.
Eur. J. Org. Chem. 2014, 4351–4355
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H.-H. Wu, S.-C. Hsu, F.-L. Hsu, B.-J. Uang
FULL PAPER
the chiral auxiliary in 7 followed by the construction of the 4-methoxybenzyl chloride (PMBCl) under basic conditions
ynone group. The preparation of diene 7 should be available (Scheme 3).[16]
from a Stille coupling of vinyltin compound 9 and vinyl
iodide 8.
Vinyl iodide 8 should be easily derived from 10 through
propargylation of 1,3-dioxolanone 11 with propargyl brom-
ide.[6]
The propargylation of 1,3-dioxolanone 11 was achieved
to give 10 in 79% yield with high diastereoselectivity (dr Ͼ
99:1) by using the method we had developed (Scheme 2).[6]
The hydrostannation of 10 was conducted by treating with
tributyltin hydride and azobis(isobutyronitrile) (AIBN) to
give vinyltin compound 12 in exclusive yield. This was fol-
lowed by the treatment of 12 with iodine to give the corre-
sponding vinyl iodide 8 in almost quantitative yield.[7]
Scheme 3. Synthesis of vinyltin compound 9. TBAI = tetrabut-
ylammonium iodide.
An initial attempt of the Stille coupling of vinyl iodide 8
and vinyltin compound 9 under standard Stille conditions[9]
by using 10 mol-% of PdCl2(CH3CN)2 (Table 1, Entry 1)
catalyst was less effective and gave the desired diene in 35%
yield. After screening CuI salts [CuI, CuCl and copper thio-
phene-2-carboxylate (CuTC)] as additives in the coupling
reaction,[10,11] it was found that CuTC gave a better yield
(Table 1, Entry 2). The yield could be increased to 68%
when 2 equiv. of CuTC were used (Table 1, Entry 3). It was
found that the reaction time was dramatically decreased
when PdCl2(CH3CN)2 was replaced by either PdCl2-
(PPh3)2 or Pd(PPh3)4 for the coupling reaction (Table 1, En-
tries 3–5).[11] It had been reported that the coupling reac-
tion could be achieved in N-methyl-2-pyrrolidone (NMP)
by using a stoichiometric amount of CuTC without Pd cat-
alyst.[10c,11b] However, it did not work in our case (Table 1,
Entry 6). The addition of CsF[10b,11c] in the reaction mix-
ture could increase the yield to 76% (Table 1, Entry 7). The
coupling yield was decreased to 70% if the palladium cata-
lyst loading was reduced to 5 mol-%, (Table 1, Entry 8).
Scheme 2. Synthesis of vinyl iodide 8.
Vinyltin compound 9 was prepared from 2,3-dihy- With advanced intermediate 7 (Table 1, Entry 7; operated
drofuran by using a known dyotropic rearrangement,[8] fol- on a gram scale) in hand, we continued our effort to finish
lowed by protection of the hydroxy group in alcohol 13 with the synthesis of (–)-pterosin N (Scheme 4).
Table 1. Optimization of the Stille coupling reaction between iodide 8 and vinyltin compound 9. PMB = 4-methoxybenzyl.
Entry
Catalyst
CuTC[a]
[equiv.]
t
[h]
Additional additive
Yield[e]
[%]
1
2
3
4
5
6
7
8
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
Pd(PPh3)4
–
1
2
2
2
1.5
2
2
20
12
12
2
1.5
15
1.5
1.5
–
–
–
–
–
35
46
68
68
68
4
–
NMP[b]
CsF[d]
CsF[d]
Pd(PPh3)4
76
70
[c]
Pd(PPh3)4
[a] CuTC was prepared according to ref.[13] [b] NMP was used as solvent. [c] 5 mol-% of Pd(PPh3)4 was used. [d] 2 equiv. of CsF were
used. [e] Isolated yield. The NOE study of 7 confirmed the (E)/(E) form as the major product, see the Supporting Information.
4352
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Eur. J. Org. Chem. 2014, 4351–4355

Asymmetric Synthesis of (–)-Pterosin N
to CDCl3 (δ = 7.24 ppm), multiplicity (br. = broad, s = singlet, d
= doublet, t = triplet, q = quadruplet, sept = septuplet, m = mul-
tiplet) and integration. 13C NMR spectra were recorded with a Var-
ian Mercury-400 (100 MHz) spectrometer. Chemical shift values
are referenced to CDCl3 (δ = 77.00 ppm). HRMS data were re-
corded with mass spectrometers at the NSC Instrumentation Cen-
ter at NTHU. IR spectra were obtained with a Bomen MB 100FT
spectrometer. Thin-layer chromatography was performed with silica
gel G60 F254 (Merck) with short-wavelength UV light for visual-
ization. Silica Gel 60 (particle size 63–200 um, purchased from
Merck) was used for column chromatography.
(5R)-6-({[Bis(1-methylethyl)amino]sulfonyl}methyl)-5,12,12-tri-
methyl-5-prop-2-ynylspiro[1,3-dioxolane-2,6Ј-bicyclo[2.2.1]heptan]-
4-one (10): To a solution of dry tetrahydrofuran (THF; 4.00 mL)
containing dry diisopropylamine (1.10 mL, 7.85 mmol) was added
n-butyllithium (3.10 mL, 2.34 m in hexane, 7.25 mmol) at 0 °C un-
der argon and stirred for 30 min. To the mixture was then added
dropwise 1,3-dioxolan-5-one 11 (2.37 g, 6.12 mmol in 8.00 mL of
THF) at –100 °C and stirred for 30 min at the same temperature.
After slow addition of propargyl bromide (80 % in toluene,
0.80 mL, 8.96 mmol) at –100 °C, the mixture was warmed to
–78 °C and stirred for 3 h. The reaction was quenched by the ad-
dition of ice-cold water (20 mL), and the resulting mixture was ex-
tracted with ethyl acetate (3ϫ 10 mL). The combined extracts were
dried (anhydrous Na2SO4) and concentrated in vacuo. The crude
residue was purified by silica gel column chromatography (EtOAc/
hexanes, 1:6) to give 10 (2.05 g, 79%) as a white solid. Rf = 0.3
Scheme 4. Completion of the synthesis of (–)-pterosin N (1). BHT
= 2,6-bis(1,1-dimethylethyl)-4-methylphenol.
An attempt to convert diene 7 to the corresponding
diene-ynone 6 by reaction with 1-propynylmagnesium
bromide was unsuccessful. Therefore, diene 7 was reduced
to the corresponding diol by lithium aluminum hydride
(LAH) followed by Parikh–Doering oxidation[12] to give al-
dehyde 14. Treatment of 14 with 1-propynylmagnesium
bromide gave 15 as diastereomers in 70% yield. Oxidation
of 15 by Parikh–Doering oxidation gave diene-ynone 6 in
77% yield. Diene-ynone 6 was subsequently heated in tolu-
ene at 180–200 °C for 2 d to undergo intramolecular Diels–
Alder (IMDA)[14] cyclization. The crude cyclization product
was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquin-
one (DDQ) to remove the PMB group and followed by aro-
matization in one pot. (–)-Pterosin N (1) was obtained in
41% yield from 6 after purification of the reaction product.
Both 1H and 13C NMR spectra and other physical data
of synthetic (–)-pterosin N (1) were in agreement with the
reported data.[5h,15]
1
(EtOAc/hexanes, 1:6). M.p. 145 °C. H NMR: δ = 3.69 (sept, J =
6.8 Hz, 2 H), 3.30 (d, J = 13.7 Hz, 1 H), 2.65–2.52 (m, 3 H), 2.44–
2.31 (m, 2 H), 2.08 (t, J = 2.6 Hz, 1 H), 2.03–1.93 (m, 1 H), 1.83–
1.76 (m, 3 H), 1.65 (s, 3 H), 1.38–1.32 (m, 1 H), 1.28 (d, J = 6.8 Hz,
12 H), 1.05 (s, 3 H), 0.9 (s, 3 H) ppm. 13C NMR: δ = 173.2, 115.8,
79.0, 71.7, 54.4, 52.1, 50.8, 48.3 (2 C), 46.4, 44.4, 28.7, 26.6, 26.1,
22.7 (2 C), 21.9 (2 C), 21.1, 20.6, 20.2 ppm. IR: ν = 3002, 2970,
˜
2360, 2342, 1793, 1738, 1372, 1328, 1229, 1205, 983 cm–1. HRMS
(ESI): calcd. for C22H35NO5S [M + H]+ 426.2314; found 426.2316.
[α]2D5 = +26.4 (c = 1.00, CH2Cl2).
(5R)-6-({[Bis(1-methylethyl)amino]sulfonyl}methyl)-5-[(2E)-4,4-di-
butyl-4-stannaoct-2-enyl]-5,12,12-trimethylspiro[1,3-dioxolane-2,6Ј-
bicyclo[2.2.1]heptan]-4-one (12): A mixture of compound 10 (2.58 g,
6.06 mmol), tributyltin hydride (2.5 mL, 9.29 mmol) and AIBN
(0.26 g, 1.58 mmol) in benzene (50 mL) was stirred at reflux tem-
perature for 2 h. The mixture was directly concentrated in vacuo,
and the residue was purified by silica gel column chromatography
(EtOAc/hexanes, 1:6) to give vinyltin compound 12 (4.32 g, 99%)
1
as a pale yellow gum. Rf = 0.5 (EtOAc/hexanes, 1:7). H NMR: δ
= 6.08 (d, J = 18.8 Hz, 1 H), 5.92 (dt, J = 18.8, 6.5 Hz, 1 H), 3.69
(sept, J = 6.8 Hz, 2 H), 3.27 (d, J = 13.7 Hz, 1 H), 2.54–2.61 (m,
2 H), 2.42–2.48 (m, 1 H), 2.29–2.37 (m, 2 H), 1.96–2.03 (m, 1 H),
1.79 (s, 3 H), 1.52–1.62 (m, 4 H), 1.32–1.35 (m, 18 H), 1.00 (s, 3
H), 0.91 (s, 3 H), 0.86 (t, J = 8.4 Hz, 15 H) ppm. 13C NMR: δ =
174.2 141.0, 134.8, 115.5, 80.3, 54.3, 52.0, 50.6, 48.2 (2 C), 46.7,
45.7, 44.4, 29.0 (3 C), 27.2 (3 C), 26.5, 25.8, 22.7 (2 C), 21.9 (2 C),
Conclusions
We have accomplished the first asymmetric synthesis of
(–)-pterosin N (1) in 9 steps with 8% overall yield from 1,3-
dioxolanone 11. This synthetic strategy provided an alterna-
tive pathway for the synthesis of indanone-containing natu-
ral products and other pterosins in enantiomerically pure
form.
20.8, 20.6, 20.1, 13.7 (3 C), 9.4 (3 C) ppm. IR: ν = 2954, 2929,
˜
1797, 1458, 1338, 1140, 977 cm–1. HRMS (ESI): calcd. for
C34H63NO5SSn [M + H]+ 718.3527; found 718.3525. [α]2D5 = +23.0
(c = 1.00, CH2Cl2).
(5R)-6-({[Bis(1-methylethyl)amino]sulfonyl}methyl)-5-[(2E)-3-iodo-
prop-2-enyl]-5,12,12-trimethylspiro[1,3-dioxolane-2,6Ј-bicyclo[2.2.1]-
heptan]-4-one (8): To a solution of vinyl tin compound 12 (1.1 g,
1.53 mmol) in CH2Cl2 (15 mL) was added iodine (0.4 g,
1.58 mmol), and the mixture was stirred at room temperature for
Experimental Section
General Method: 1H NMR spectra were recorded with a Bruker
AV-400 (400 MHz) or a Varian Mercury-400 (400 MHz) spectrom-
eter. Data are reported as follows: chemical shift values referenced
Eur. J. Org. Chem. 2014, 4351–4355
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4353

H.-H. Wu, S.-C. Hsu, F.-L. Hsu, B.-J. Uang
FULL PAPER
1 h. To the mixture was added a saturated Na2S2O3 solution, and
vigorous stirring was continued until the color had disappeared.
The organic layer was separated, and the aqueous layer was ex-
tion was quenched with saturated NaHCO3 solution, and the mix-
ture was extracted with CH2Cl2 (3ϫ 50 mL). The combined or-
ganic layers were washed with brine, dried (anhydrous Na2SO4),
tracted with CH2Cl2 (3 ϫ 15 mL). The combined organic layers concentrated in vacuo, and the residue was purified by silica gel
were dried (anhydrous Na2SO4), concentrated in vacuo, and the
residue was purified by silica gel column chromatography (EtOAc/
hexanes, 1:5) to give 8 (0.86 g, 99%) as a white solid. Rf = 0.3
(EtOAc/hexanes, 1:5). M.p. 144.9–145.9 °C. 1H NMR: δ = 6.47–
6.54 (m, 1 H), 6.22 (d, J = 14.5 Hz, 1 H), 3.69 (sept, J = 6.8 Hz, 2
H), 3.26 (d, J = 13.6 Hz, 1 H), 2.57 (d, J = 13.6 Hz, 1 H) 2.24–
2.49 (m, 4 H), 1.98–2.05 (m, 1 H), 1.76–1.86 (m, 3 H), 1.55 (s, 3
H), 1.30–1.33 (m, 1 H), 1.28 (d, J = 6.8 Hz, 12 H), 1.01 (s, 3 H),
column chromatography (EtOAc/hexanes, 1:3) to give 14 (1.23 g,
78% in 2 steps) as a pale yellow oil. Rf = 0.2 (EtOAc/hexane, 1:3).
1H NMR: δ = 9.48 (d, J = 3.2 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H),
6.86 (d, J = 8.4 Hz, 2 H), 6.11 (d, J = 15.6 Hz, 1 H), 5.39–5.47 (m,
2 H), 4.42 (s, 2 H), 3.78 (s, 3 H), 3.44 (t, J = 6.8 Hz, 2 H), 2.36–
2.61 (m, 4 H), 1.68 (s, 3 H), 1.30 (s, 3 H) ppm. 13C NMR: δ =
203.8, 159.0, 139.2, 136.4, 130.4, 129.1 (2 C), 119.3, 113.6 (2 C),
72.3, 69.3, 55.1, 40.6, 28.7, 21.9, 16.7, 12.4 ppm. IR: ν = 2938,
˜
0.9 (s, 3 H) ppm. 13C NMR: δ = 173.8, 138.9, 134.5, 115.9, 79.6, 2866, 1734, 1613, 1586, 1363, 1216, 1088, 1035, 969, 818 cm–1
.
54.4, 51.9, 50.7, 48.2 (2 C), 46.8, 44.3, 43.9, 26.5, 25.9, 22.7 (2 C),
HRMS (ESI): calcd. for C19H26O4 [M + H]+ 319.1909; found
21.9 (2 C), 21.0, 20.6, 20.3 ppm. IR: ν = 2991, 2968, 2947, 2933,
319.1907. [α]2D6 = –2.7 (c = 1.00, CH2Cl2).
˜
1786, 1334, 1144, 1125, 1040 cm–1. HRMS (ESI): calcd. for
C22H36INO5S [M + H]+ 553.1359; found 553.1360. [α]2D5 = +19.2
(c = 1.00, CH2Cl2).
(5R,7E,9E)-12-[(4-Methoxyphenyl)methoxy]-5,9-dimethyldodeca-
7,9-dien-2-yne-4,5-diol (15): To a solution of aldehyde 14 (1.22 g,
3.83 mmol) in Et2O at –30 °C was added 1-propynlmagnesium
bromide (26.2 mL, 0.5 m in THF, 13.1 mmol), and the mixture was
stirred at the same temperature for 1 h. The reaction was quenched
by the addition of saturated NH4Cl solution (80 mL), and the mix-
ture was extracted with EtOAc (3ϫ 50 mL). The combined extracts
were dried (anhydrous Na2SO4) and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography
(EtOAc/hexanes, 1:3) to give diastereomers 15 (0.96 g, 70%) as a
(5R)-6-({[Bis(1-methylethyl)amino]sulfonyl}methyl)-5-{(2E,4E)-7-
[(4-Methoxyphenyl)methoxy]-4-methylhepta-2,4-dienyl}-5,12-12-
trimethylspiro[1,3-dioxolane-2,6Ј-bicyclo[2.2.1]heptan]-4-one (7): To
a solution of N,N-dimethylformamide (3.4 mL) were added vinyl
iodide 8 (0.2 g, 0.37 mmol), vinyl tin compound 9 (0.22 g,
0.44 mmol), Pd[(PPh3)]4 (44 mg, 0.038 mmol), CuTC (140 mg,
0.73 mmol) and CsF (114 mg, 0.75 mmol). The mixture was stirred
at room temperature for 1.5 h. The reaction was quenched by the
addition of a saturated NH4Cl solution (10 mL), and the mixture
was extracted with EtOAc (3 ϫ 10 mL). The combined extracts
were dried (anhydrous Na2SO4) and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography
(EtOAc/hexanes, 1:6) to give 7 (0.15 g, 76%) as a pale yellow oil.
Rf = 0.15 (EtOAc/hexanes, 1:6). 1H NMR: δ = 7.24 (d, J = 8.6 Hz,
2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.13 (d, J = 15.6 Hz, 1 H), 5.50
(m, 1 H), 5.43 (t, J = 6.9 Hz, 1 H), 4.43 (s, 2 H), 3.78 (s, 3 H), 3.69
(sept, J = 6.8 Hz, 2 H), 3.45 (t, J = 7.0 Hz, 2 H), 3.25 (d, J =
14.0 Hz, 1 H), 2.26–2.60 (m, 6 H), 2.00–2.04 (m, 1 H), 1.49–1.80
(m, 4 H), 1.73 (s, 3 H), 1.48 (s, 3 H), 1.25–1.30 (m, 1 H), 1.27 (d,
J = 12.0 Hz, 12 H), 1.00 (s, 3 H), 0.88–0.92 (m, 3 H) ppm. 13C
NMR: δ = 174.4 159.0, 139.3, 134.5, 129.0 (2 C), 128.0, 119.3,
115.5, 113.6 (2 C), 80.5, 72.4, 69.1, 55.1, 54.2, 51.8, 50.5, 48.0 (2
C), 46.6, 44.2, 28.7, 51.9, 26.4, 25.7, 22.6 (2 C), 21.7 (2 C), 21.0,
1
pale yellow oil. Rf = 0.3 (EtOAc/hexanes, 1:1). H NMR: δ = 7.24
(d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.11–6.13 (d, J =
16 Hz, 1 H), 5.55–5.66 (m, 1 H), 5.41 (t, J = 6.8 Hz, 1 H), 4.43 (s,
2 H), 3.78 (s, 3 H), 3.44 (t, J = 6.8 Hz, 2 H), 2.23–2.54 (m, 4
H), 1.87 (s, CϵC–CH3, major isomer), 1.86 (s, CϵC–CH3, minor
isomer), 1.73 (s, 3 H), 1.21 (s, HO–C–CH3, major isomer), 1.22 (s,
HO–C–CH3, minor isomer) ppm. 13C NMR: δ = 159.1, 138.6,
134.9, 130.4, 129.2 (2 C), 121.9, 113.7 (2 C), 82.8, 77.3, 69.3, 69.0,
68.8, 55.2, 41.4, 40.7, 36.3, 35.7, 28.7, 22.4, 22.1, 12.6, 3.6 ppm. IR:
ν = 3408, 2934, 2859, 1612, 1513, 1247, 1095, 1034, 968, 820 cm–1.
˜
HRMS (ESI): calcd. for C22H30O4 [M + H]+ 359.2222; found
359.2221. [α]2D5 = +17.6 (c = 0.40, CH2Cl2).
(5R,7E,9E)-5-Hydroxy-12-[(4-methoxyphenyl)methoxy]-5,9-dimeth-
yldodeca-7,9-dien-2-yn-4-one (6): A mixture of SO3·py (0.87 g,
5.47 mmol), pyridine (0.46 mL, 5.40 mmol) and DMSO (2.40 mL,
33.8 mmol) in a flask was stirred at room temperature for 30 min,
then the mixture was added to a stirred solution containing diol
15 (0.13 g, 0.36 mmol) and Et3N (1.10 mL, 7.88 mmol) in CH2Cl2
(3.6 mL) at 0 °C. The resulting mixture was stirred at room tem-
perature for 1 h. The reaction was quenched with saturated
NaHCO3 solution, and the mixture was extracted CH2Cl2 (3ϫ
10 mL). The combined organic layers were washed with brine, dried
(anhydrous Na2SO4), concentrated (rotary evaporator), and the res-
idue was purified by silica gel column chromatography (EtOAc/
hexanes, 1:4) to give 6 (0.10 g, 77%) as a pale yellow oil. Rf = 0.5
(EtOAc/hexanes, 1:2). 1H NMR: δ = 7.24 (d, J = 8.6 Hz, 2 H), 6.86
(d, J = 8.6 Hz, 2 H), 6.11 (d, J = 15.3 Hz, 1 H), 5.34–5.47 (m, 2
H), 4.42 (s, 2 H), 3.78 (s, 3 H), 3.42–3.53 (m, 2 H), 2.27–2.66 (m,
4 H), 2.1 (s, 3 H), 1.60 (s, 3 H), 1.41 (s, 3 H) ppm. 13C NMR: δ =
190.2, 159.1, 139.0, 134.8, 131.8, 130.4, 129.1 (2 C), 127.8, 125.5,
120.0, 113.7 (2 C), 79.6, 72.5, 69.3, 55.2, 42.9, 28.8, 24.7, 12.5,
20.5, 20.1, 12.4 ppm. IR: ν = 2960, 2938, 1795, 1613, 1513, 1393,
˜
1337, 1247, 1138, 977 cm–1. HRMS (ESI): calcd. for C35H53NO7S
[M + H]+ 632.3621; found 632.3624. [α]2D6 = +10.4 (c = 1.00,
CH2Cl2).
(2R,4E,6E)-2-Hydroxy-9-[(4-methoxyphenyl)methoxy]-2,6-dimeth-
ylnona-4,6-dienal (14): To a stirred dry THF (76 mL) solution con-
taining diene 7 (4.80 g, 7.60 mmol) was added dropwise lithium
aluminum hydride (76 mL, 1.0 m in THF, 76 mmol) at room tem-
perature. The reaction mixture was then warmed to 80 °C and
stirred for 30 min. The reaction mixture was quenched by addition
to a mixture of saturated potassium sodium tartrate solution
(200 mL) and Et2O (50 mL). The mixture was stirred at room tem-
perature for 5 h then extracted with Et2O (2ϫ 50 mL). The com-
bined organic layers were dried (anhydrous Na2SO4) and concen-
trated in vacuo. The crude diol was directly used for the next step
without purification. A mixture of SO3·py (14.7 g, 93.3 mmol), pyr-
idine (7.9 mL, 92.7 mmol) and dimethyl sulfoxide (DMSO;
41.2 mL, 580 mmol) in a flask was stirred at room temperature for
30 min, then the mixture was added to a stirred solution containing
4.3 ppm. IR: ν = 2969, 2934, 2862, 2217, 1739, 1670, 1541, 1456,
˜
1247, 1095, 1035, 820 cm–1. HRMS (ESI): calcd. for C22H28O4 [M
+ H]+ 357.2066; found 357.2068. [α]2D5 = +19.0 (c = 1.00, CH2Cl2).
the crude product (1.85 g, 4.93 mmol) and Et3N (19 mL, (–)-Pterosin N (1): A mixture of compound 6 (37.0 mg, 0.10 mmol)
136.13 mmol) in CH2Cl2 (49 mL) at 0 °C. The resulting mixture
was stirred at room temperature for an additional 30 min. The reac-
and 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT; 2.00 mg,
0.01 mmol) in toluene (30 mL) was stirred at 180–200 °C for 2 d.
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Eur. J. Org. Chem. 2014, 4351–4355

Asymmetric Synthesis of (–)-Pterosin N
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The mixture was directly concentrated in vacuo. The residue was
dissolved in CH2Cl2 (10 mL), then DDQ (52.0 mg, 0.23 mmol) and
H2O (0.5 mL) were added. The mixture was stirred at room tem-
perature for 3 h and was quenched with a saturated NaHCO3 solu-
tion. The aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL).
The combined organic layers were concentrated in vacuo and puri-
fied by silica gel column chromatography (EtOAc/hexanes, 1:2) to
afford 1 (10 mg, 41%) as a white solid. Rf = 0.3 (EtOAc/hexanes,
1
1:2). M.p. 150–151 °C (ref.[15] 165–167 °C). H NMR: δ = 7.07 (s,
[6]
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1 H), 3.74 (t, J = 7.4 Hz, 2 H), 3.07 (d, J = 4.6 Hz, 2 H), 2.99 (t,
J = 7.4 Hz, 2 H), 2.64 (s, 3 H), 2.42 (s, 3 H), 1.62 (br., 1 H), 1.36
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ski, B. W. Dymock, J. M. Pons, Synthesis 1998, 1655–1660; c)
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129.4, 126.0, 77.5, 61.5, 41.1, 31.8, 26.0, 14.0 ppm. IR: ν = 3340,
˜
2962, 2924, 1701, 1601, 1451, 1378, 1216, 1093, 1042, 977,
886 cm–1. HRMS (ESI): calcd. for C14H18O3 [M + H]+ 234.1256;
found 234.1249. [α]2D5 = –15.8 (c = 0.10, MeOH) {ref.[15] [α]D = –18
(c = 0.10, MeOH)}.
[8]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all key intermedi-
ates and final products.
[9]
Acknowledgments
[10]
We thank the National Science Council, Taiwan (ROC) for finan-
cial support (NSC 99-2323-B-038-002 and 101N2010E1).
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Received: March 11, 2014
Published Online: June 3, 2014
Eur. J. Org. Chem. 2014, 4351–4355
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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