Chiron Approaches to the Antitumor Natural Product Fuzanin D

Article abstract of DOI:10.1055/s-0036-1588343

Fuzanin D, a pyridine-containing natural product, which exhibits cytotoxic activity against DLD-1 cells, is synthesized in a concise manner using l-arabinose or ethyl l-lactate as chiral pool substrates in nine steps (14.4% overall yield) and six steps (30.8% overall yield), respectively. The key steps involve Wittig olefination and olefin cross--metathesis.

Full text of DOI:10.1055/s-0036-1588343

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
Y. Gao et al.
Paper
Synthesis
Chiron Approaches to the Antitumor Natural Product Fuzanin D
Yangguang Gao*a,b
Zhou Caob
Chengzhong Sub
O
O
Zefeng Chenc
Xianran Hea,b
Fei Dinga,b
Hang Lia,b
Yongmin Zhang*a,d
OH
L-arabinose
or ethyl L-lactate
Br
N
+
OH
fuzanin D
9 steps, 14.4% overall from
6 steps, 30.8% overall from ethyl L-lactate
OHC
L-arabinose
a Institute for Interdisciplinary Research, Jianghan University,
Wuhan Economic and Technological Development Zone,
Wuhan 430056, P. R. of China
N
sunlt413@jhun.edu.cn
b Key Laboratory of Optoelectronic Chemical Materials and
Devices of Ministry of Education, Jianghan University,
Wuhan Economic and Technological Development Zone,
Wuhan 430056, P. R. of China
c Chimie, IUT d’Orsay, Université Paris Sud, Plateau de Moulon,
91400 Orsay, France
d Institut Parisien de Chimie Moléculaire, CNRS UMR 8232,
Université Pierre et Marie Curie-Paris 6, 4 place Jussieu,
75005 Paris, France
yongmin.zhang@upmc.fr
Received: 10.08.2016
Accepted after revision: 17.10.2016
Published online: 18.11.2016
1).9 On the basis of synthesis, the original absolute configu-
ration of fuzanin D was suggested to be reassigned. In the
synthesis of fuzanin D, Sharpless epoxidation was utilized
to set the chiral centers, and a Julia olefination was utilized
to construct the carbon–carbon double bond. Herein, we
describe an alternative syntheses of fuzanin D using L-arab-
inose or ethyl L-lactate as chiral pool substrates.
DOI: 10.1055/s-0036-1588343; Art ID: ss-2016-h0561-op
Abstract Fuzanin D, a pyridine-containing natural product, which ex-
hibits cytotoxic activity against DLD-1 cells, is synthesized in a concise
manner using L-arabinose or ethyl L-lactate as chiral pool substrates in
nine steps (14.4% overall yield) and six steps (30.8% overall yield), re-
spectively. The key steps involve Wittig olefination and olefin cross-
metathesis.
OH
OH
Key words synthesis, chiral pool, antitumor, cross-metathesis, olefi-
nation
N
N
OH
OH
fuzanin D
proposed structure
fuzanin C
Pyridine-containing natural products, which mainly
originate from animals, plants, eukaryotes and prokaryotes,
fascinate the chemical community due to their wide spec-
trum of biological activity,1 such as cytotoxic,2 antimicrobi-
al,3 antifungal,4 anti-HIV,5 neurotoxic,6 and anti-inflamma-
tory.7 Fuzanin D, a disubstituted pyridine-containing natu-
ral product, incorporating a long chain with an E,E-
conjugated diene moiety and adjacent hydroxy groups was
isolated from the culture supernatant of Kitasatospora sp.
IFM10917 by Ishibashi and co-workers in 2009.8 The in vi-
tro determination of the biological activity of fuzanin D re-
vealed inhibitory activity against DLD-1 cells with an IC50
value of 41.2 μM. Besides, it also displayed moderate inhibi-
tion of Wnt signal transcription at 25 mM.
OH
N
OH
fuzanin D
revised structure
Figure 1 Structures of fuzanin C and fuzanin D
As shown in Scheme 1, the synthesis of fuzanin D (1)
could be achieved by Wittig olefination between building
block 2 and 3-methylpicolinaldehyde (3), followed by re-
moval of the cyclohexylidene group. Compound 2 can be
prepared from commercially available L-arabinose through
several conventional manipulations, while aldehyde 3 can
be easily obtained by selective oxidation of 2,3-dimeth-
ylpyridine according to a literature procedure.10
Recently, Rao’s group achieved the syntheses of fuza-
nins C and D and their derivatives, and performed an in vi-
tro biological evaluation of their anticancer activity (Figure
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
Y. Gao et al.
Paper
Synthesis
compound 7 in a high yield (90%). Reduction of iodide 8 was
carried out smoothly with an excess amount of LiAlH4 (10
equiv) to give terminal-methyl-containing compound 9 in
82% yield. In consideration of the low boiling point of the
direct reduction product of iodide 7 by LiAlH4, the isopro-
pylidene group was replaced by a bulky cyclohexylidene
group via a two-step conversion in a yield of 88%. Olefin
cross-metathesis (OCM) between compound 9 and allyl
bromide using a catalytic amount of Grubbs’ second-gener-
ation catalyst (Grubbs II) exclusively generated trans-olefin
2 (J = 15.2 Hz) in 81% yield.
OH
N
OH
fuzanin D (1)
+
O
OHC
O
N
3
2
An alternative synthesis of building block 2 is summa-
rized in Scheme 3. The required secondary allylic alcohol 10
was obtained as a 20:1 mixture of diastereoisomers from
ethyl L-lactate over three steps, being superior to the litera-
ture procedure15 when using CH2Cl2 as the solvent instead
of Et2O. Next, compound 10 and allyl bromide were subject-
ed to a similar OCM as described for 2 (see Scheme 2) to
give trans-olefin 11 in 75% yield. Compound 11 was con-
verted into compound 2 in a high yield (89%) through un-
blocking of the silyl ether under acidic conditions followed
by protection with a cyclohexylidene group.
Br
OH
O
OH
HO
N
OH
L-arabinose
2,3-dimethylpyridine
Scheme 1 Retrosynthetic analysis of fuzanin D
The synthesis of building block 2 was commenced from
the known compound 3,4-O-isopropylidene-L-arabinopyra-
nose (4) (Scheme 2).11 Oxidative cleavage of compound 4
with NaIO4 followed by treatment of the crude product
with Na2CO3 gave protected L-erythrose 5.12 Without fur-
ther purification, compound 5 was subjected to Wittig ole-
fination13 with an in situ generated methyl Wittig reagent
in toluene at reflux to provide enol 6 in 52% yield over two
steps. It should be noted that the ring-opening reaction
with the Wittig reagent gave a low yield of 6 when using
THF as the solvent at 0 °C to room temperature. Iodination
of enol 6 using standard Appel reaction conditions14 gave
OTBS
OTBS
OH
a
b
OEt
Br
OH
OH
O
10
11
O
O
c
2
Br
Scheme 3 An alternative synthesis of compound 2. Reagents and condi-
tions: (a) (i) TBSCl, imidazole, CH2Cl2, 96%; (ii) DIBAL-H, CH2Cl2, –98 °C,
then vinylmagnesium chloride (1.9 M), –98 °C to r.t., 83%; (b) allyl bro-
mide, Grubbs II, CH2Cl2, 75%; (c) PTSA, MeOH, then MeCN, cyclohexa-
none, 89%.
O
OH
OH
O
a
ref. 11
O
O
OH
OH
HO
O
O
O
OH
OH
With building block 2 and 3-methylpicolinaldehyde (3)
in hand, their assembly into fuzanin D became our next
goal. As shown in Scheme 4, treatment of compound 2 with
PPh3 in MeCN at reflux temperature gave the corresponding
alkyltriphenylphosphonium salt 12. Without purification,
the alkyltriphenylphosphonium salt 12 was deprotonated
by n-BuLi at –78 °C in THF to provide the in situ Wittig re-
agent, which reacted with 3-methylpicolinaldehyde (3) in
the presence of LiBr16 to give a separable E/Z-mixture in a
ratio of 3:1. Fortunately, the Z-isomer (J = 11.2 Hz) could be
converted into the desired compound 13a in 67% yield via a
radical-induced isomerization using a slightly modified lit-
erature procedure.17 Finally, deprotection of compound 13a
gave the natural product fuzanin D (1) in 92% yield. The val-
ue of the optical rotation and the spectral data were in good
accordance with those previously reported in the litera-
ture.9
4
5
I
I
HO
d
b
c
O
O
O
O
O
O
6
7
8
f
e
O
O
O
O
Br
9
2
Scheme 2 Synthesis of compound 2. Reagents and conditions: (a)
NaIO4, MeOH–H2O, then Na2CO3; (b) Ph3P+CH3Br–, n-BuLi, toluene, 0 °C
to reflux, 52% over 2 steps; (c) I2, PPh3, imidazole, THF, reflux, 90%; (d)
PTSA, MeOH, then MeCN, cyclohexanone, 88%; (e) LiAlH4, THF, 82%; (f)
allyl bromide, Grubbs II, CH2Cl2, 81%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
Y. Gao et al.
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Synthesis
combined organic layer was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (PE–EtOAc,
3:1) to give compound 5 (6.30 g, 72%) as a syrup. The spectral data
agreed with those reported in the literature.12
O
O
2
Br
[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]methanol (6)
To a suspension of methyltriphenylphosphonium bromide (15 g,
42.13 mmol) in anhydrous toluene (100 mL) was added dropwise n-
BuLi solution (19.3 mL, 2.5 M in hexane, 48.25 mmol) at 0 °C under a
nitrogen atmosphere. The resulting yellow suspension was stirred for
45 min at the same temperature, then a solution of compound 5 (3 g,
18.74 mmol) in toluene (10 mL) was added dropwise. After the addi-
tion was complete, the ice bath was replaced by an oil bath. The mix-
ture was heated at reflux until TLC indicated complete consumption
of the starting material, and was then quenched with sat. aq NH4Cl
(100 mL). The organic layer was separated and the aq phase was ex-
tracted with EtOAc (3 × 100 mL). The combined organic layer was
concentrated in vacuo and column chromatography of the residue on
silica gel (PE–EtOAc, 3:1) afforded compound 6 (1.54 g, 52% over 2
steps) as a yellow oil.
a
N
N
O
O
b
O
O
O
+
O
3:1
Ph3P
Br–
12
13b
13a
c
d
OH
N
[α]D25 –39.2 (c 0.35, CHCl3).
OH
fuzanin D (1)
IR (neat): 3420, 1637, 1376, 1215, 1164, 1039 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.87–5.78 (m, 1 H), 5.35 (dt, J = 17.2,
1.2 Hz, 1 H), 5.29 (dt, J = 10.4, 1.6 Hz, 1 H), 4.61 (t, J = 7.6 Hz, 1 H), 4.23
(q, J = 5.6 Hz, 1 H), 3.54 (t, J = 4.4 Hz, 2 H), 2.23 (br s, 1 H), 1.48 (s, 3 H),
1.36 (s, 3 H).
Scheme 4 Synthesis of fuzanin D (1). Reagents and conditions: (a) PPh3,
MeCN, 80 °C; (b) n-BuLi (2.5 M), LiBr, THF, then 3-methylpicolinalde-
hyde (3), –78 °C, 63% over 2 steps; (c) see ref. 17, 67%; (d) PTSA,
MeOH, 92%.
13C NMR (100 MHz, CDCl3): δ = 133.11, 119.15, 109.02, 78.43, 78.39,
62.21, 27.93, 25.37.
HRMS (ESI): m/z [M – H]– calcd for C8H13O3: 157.0865; found:
157.0842.
In conclusion, the synthesis of fuzanin D (1) has been
achieved starting from either L-arabinose or ethyl L-lactate
in nine steps (14.4 overall yield) and six steps (30.8 overall
yield), respectively. The highlight of the protocol was the
use of the natural chiral pool to set the stereogenic centers,
and adopting Wittig olefination and olefin cross-metathesis
reactions as crucial steps. Our method is flexible and facile,
and can be applied to synthesize homologues or derivatives
of fuzanin D, the results of which will be reported in due
course.
(4R,5R)-4-(Iodomethyl)-2,2-dimethyl-5-vinyl-1,3-dioxolane (7)
To a solution of compound 6 (410 mg, 2.59 mmol) in THF (10 mL)
were added sequentially I2 (1.18 g, 4.65 mmol), PPh3 (1.22 g, 4.65
mmol) and imidazole (530 mg, 8.54 mmol). The mixture was heated
at reflux until the completion of the reaction (monitoring by TLC).
Sat. Na2S2O3 solution (10 mL) was added to quench the reaction, the
organic layer was separated and extracted with EtOAc (3 × 10 mL),
and the combined organic layer was concentrated. The residue was
purified by silica gel column chromatography (PE–EtOAc, 50:1) to fur-
nish compound 7 (625 mg, 90%) as a yellow oil.
[α]D25 –1.45 (c 0.76, CHCl3).
IR (neat): 2986, 2931, 1428, 1380, 1215, 1042, 870 cm–1
1H NMR (400 MHz, CDCl3): δ = 5.87–5.80 (m, 1 H), 5.43 (dt, J = 17.2,
1.2 Hz, 1 H), 5.33 (dt, J = 10.4, 1.6 Hz, 1 H), 4.63 (t, J = 6.0 Hz, 1 H),
4.46–4.41 (m, 1 H), 3.14 (dd, J = 10.4, 7.6 Hz, 1 H), 3.06 (dd, J = 10.0,
6.4 Hz, 1 H), 1.51 (s, 3 H), 1.38 (s, 3 H).
All reagents were commercially available and were used directly
without further purification unless otherwise stated. Column chro-
matography was carried out using Haiyang brand silica gel (100–200
mesh). Routine monitoring of reactions was carried out using Huang-
hai brand silica gel 60 F254 TLC plates. Optical rotations were record-
ed with an AUTOPOL IV automatic polarimeter. IR spectra were re-
corded as neat samples with a NICOLET iS 10 infrared spectrometer.
1H and 13C NMR spectra were recorded with a Bruker Avance III spec-
trometer at 400 MHz and 100 MHz, respectively, relative to Me4Si (δ =
0) as an internal standard. HRMS were measured with a Bruker mi-
cro-TOFQ II mass spectrometer.
.
13C NMR (100 MHz, CDCl3): δ = 132.43, 119.49, 109.12, 79.20, 78.56,
28.21, 25.62, 3.91.
HRMS (ESI): m/z [M + Na]+ calcd for C8H13INaO2: 290.9858; found:
290.9862.
2,3-O-Isopropylidene-L-erythrose (5)
To a solution of 3,4-O-isopropylidene-L-arabinopyranose (4) (10.4 g,
54.71 mmol) in MeOH (100 mL) was added a solution of NaIO4 [16 g
dissolved in H2O (90 mL)] via a dropping funnel, and the mixture was
allowed to stir at r.t. After the reaction was complete (monitoring by
TLC), the solution was basified (pH 9) by the addition of Na2CO3 pow-
der, and stirred for another 1 h. The undissolved white solid was fil-
tered and the filtrate was extracted with CH2Cl2 (3 × 150 mL). The
(2R,3R)-2-(Iodomethyl)-3-vinyl-1,4-dioxaspiro[4.5]decane (8)
A mixture of compound 7 (600 mg, 2.24 mmol) in MeOH (10 mL) and
p-toluenesulfonic acid (PTSA) (20 mg, 0.105 mmol) was allowed to
stir at r.t. until the starting material had been completely consumed
(monitoring by TLC). The solution was concentrated in vacuo and the
residue was dissolved in MeCN (20 mL). Cyclohexanone (550 mg, 5.6
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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Synthesis
mmol) was added subsequently and the resulting solution was stirred
for an additional 2 h at r.t., neutralized with Et3N and concentrated.
Column chromatography of the residue on silica gel (PE–EtOAc, 50:1)
provided compound 8 (607 mg, 88%) as a colorless oil.
[α]D25 +6.1 (c 0.41, CHCl3).
IR (neat): 2929, 1608, 1416, 1243, 1025 cm–1
1H NMR (400 MHz, CDCl3): δ = 5.94 (dt, J = 15.2, 7.2 Hz, 1 H), 5.71 (dd,
J = 15.2, 7.2 Hz, 1 H), 4.49 (t, J = 6.4 Hz, 1 H), 4.32 (dt, J = 12.8, 6.4 Hz, 1
H), 3.94 (d, J = 7.6 Hz, 2 H), 1.68–1.61 (m, 4 H), 1.60–1.52 (m, 4 H),
1.39–1.38 (m, 2 H), 1.12 (d, J = 6.4 Hz, 3 H).
.
[α]D25 –1.0 (c 1.08, CHCl3).
IR (neat): 2932, 2854, 1448, 1280, 1108, 928 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.87–5.79 (m, 1 H), 5.41 (d, J = 16.8 Hz,
1 H), 5.31 (d, J = 10.4 Hz, 1 H), 4.61 (t, J = 6.0 Hz, 1 H), 4.41 (q, J = 6.4
Hz, 1 H), 3.14 (dd, J = 10.0, 7.6 Hz, 1 H), 3.03 (dd, J = 10.0, 6.4 Hz, 1 H),
1.69–1.64 (m, 4 H), 1.62–1.56 (m, 4 H), 1.39–1.38 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 131.93, 129.61, 109.05, 78.02, 73.82,
38.12, 35.03, 31.68, 25.22, 24.17, 23.85, 16.24.
HRMS (ESI): m/z [M + H]+ calcd for C12H20BrO2: 275.0647; found:
275.0640.
13C NMR (100 MHz, CDCl3): δ = 132.69, 119.33, 109.76, 78.78, 78.03,
38.09, 35.05, 25.09, 24.08, 23.75, 4.13.
HRMS (ESI): m/z [M + Na]+ calcd for C11H17INaO2: 331.0171; found:
331.0167.
(3R,4S)-4-[(tert-Butyldimethylsilyl)oxy]pent-1-en-3-ol (10)
To a solution of ethyl L-lactate (2.36 g, 20 mmol) in CH2Cl2 (20 mL)
were sequentially added TBSCl (4.50 g, 30 mmol) and imidazole (3.60
g, 60 mmol). The solution was allowed to stir for 2 h at r.t., then
poured into H2O (10 mL) and extracted with CH2Cl2 (2 × 15 mL). The
combined organic layer was concentrated under reduced pressure
and the residue purified by column chromatography on silica gel (PE–
EtOAc, 50:1) to afford TBS-protected ethyl L-lactate (4.46 g, 96%) as a
colorless oil.
(2S,3R)-2-Methyl-3-vinyl-1,4-dioxaspiro[4.5]decane (9)
To a solution of compound 8 (200 mg, 0.649 mmol) in anhyd THF (8
mL) was added LiAlH4 powder (246 mg, 6.49 mmol) under a nitrogen
atmosphere. The suspension was stirred at r.t. for 2 h, then quenched
by the addition of a sat. solution of K/Na tartrate (10 mL) cautiously,
extracted with EtOAc (3 × 10 mL), and the combined organic layer
was concentrated. The residue was purified by silica gel column chro-
matography (PE–EtOAc, 50:1) to furnish compound 9 (96.9 mg, 82%)
as a colorless oil.
[α]D25 +12.3 (c 0.3, CHCl3).
IR (neat): 2927, 2854, 1448, 1366, 1112, 926 cm–1
1H NMR (400 MHz, CDCl3): δ = 5.82–5.75 (m, 1 H), 5.30 (dt, J = 17.2,
1.2 Hz, 1 H), 5.22 (ddd, J = 10.4, 1.6, 0.8 Hz, 1 H), 4.48 (t, J = 7.2 Hz, 1
H), 4.36–4.29 (m, 1 H), 1.69–1.64 (m, 4 H), 1.62–1.58 (m, 4 H), 1.41–
1.39 (m, 2 H), 1.14 (d, J = 6.4 Hz, 3 H).
To a solution of the TBS-protected lactate (7 g, 30.15 mmol) in anhyd
CH2Cl2 (100 mL) was added DIBAL-H (33 mL, 1.1 M in hexane, 36.3
mmol) via a dropping funnel at –98 °C under a nitrogen atmosphere.
After 15 min, vinylmagnesium chloride (30 mL, 1.9 M in toluene, 57
mmol) was added dropwise to the above solution. The solution was
allowed to warm to r.t. and stirred overnight. A sat. solution of K/Na
tartrate (40 mL) was added slowly to quench the reaction and the aq
layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic
layer was concentrated in vacuo. The residue was purified by silica gel
column chromatography (PE–EtOAc, 50:1) to provide compound 10
(5.4 g, 83%) as a yellow oil.
.
13C NMR (100 MHz, CDCl3): δ = 134.91, 118.10, 108.78, 79.74, 73.66,
38.18, 35.13, 25.27, 24.19, 23.88, 16.31.
HRMS (ESI): m/z [M + Na]+ calcd for C11H18NaO2: 205.1204; found:
205.1212.
1H NMR (400 MHz, CDCl3): δ = 5.83–5.76 (m, 1 H), 5.27 (dt, J = 17.6,
1.6 Hz, 1 H), 5.17 (dt, J = 10.8, 1.6 Hz, 1 H), 4.03–3.86 (m, 1 H), 3.85–
3.81 (m, 1 H), 2.32 (d, J = 4.4 Hz, 1 H), 1.14 (d, J = 6.0 Hz, 3 H), 0.88 (s, 9
H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 136.66, 116.51, 76.73, 71.37, 25.85,
18.11, 17.69, –4.39, –4.80.
(2R,3S)-2-[(E)-3-Bromoprop-1-en-1-yl]-3-methyl-1,4-dioxa-
spiro[4.5]decane (2)
(2S,3R,E)-6-Bromo-2-[(tert-butyldimethylsilyl)oxy]hex-4-en-3-ol
(11)
Method A (Step f, Scheme 2)
To a solution of compound 10 (2.5 g, 11.56 mmol) and allyl bromide
(3.5 g, 28.93 mmol) in CH2Cl2 (10 mL) was added Grubbs II catalyst
(310 mg, 0.365 mmol). The mixture was stirred for 5 h at reflux, and
then concentrated in vacuo. Column chromatography of the residue
on silica gel (PE–EtOAc, 50:1) provided compound 11 (2.67 g, 75%) as
a yellow oil.
To a solution of compound 9 (615 mg, 3.376 mmol) and allyl bromide
(840 mg, 6.94 mmol) in CH2Cl2 (10 mL) was added Grubbs II catalyst
(85.9 mg, 0.101 mmol). The mixture was allowed to stir at reflux until
the completion of the reaction, and then concentrated in vacuo. Col-
umn chromatography of the residue on silica gel (PE–EtOAc, 50:1)
provided compound 2 (749 mg, 81% yield) as a colorless oil.
[α]D25 +10.3 (c 0.92, CHCl3).
Method B (Step c, Scheme 3)
IR (neat): 3306, 1634, 1378, 1253, 970 cm–1
.
To a solution of compound 11 (900 mg, 2.92 mmol) in MeOH (10 mL)
was added p-toluenesulfonic acid (PTSA) (25 mg, 0.131 mmol), and
the mixture was allowed to stir at r.t. until the completion of the reac-
tion (monitoring with TLC). The solution was concentrated under re-
duced pressure and the residue was dissolved in MeCN (20 mL). Next,
cyclohexanone (0.76 g, 7.74 mmol) was added. The resulting solution
was stirred for another 2 h at r.t., then neutralized by the addition of
Et3N and concentrated. Column chromatography of the residue on sil-
ica gel (PE–EtOAc, 50:1) gave compound 2 (0.71 g, 89%) as a colorless
oil.
1H NMR (400 MHz, CDCl3): δ = 5.99–5.91 (m, 1 H), 5.74 (dd, J = 15.2,
6.0 Hz, 1 H), 4.05–4.03 (m, 1 H), 3.95 (d, J = 7.6 Hz, 2 H), 3.87–3.81 (m,
1 H), 2.33 (d, J = 4.0 Hz, 1 H), 1.07 (d, J = 6.4 Hz, 3 H), 0.89 (s, 9 H), 0.07
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 133.59, 128.30, 75.26, 71.25, 32.15,
25.84, 18.09, 17.88, –4.37, –4.81.
HRMS (ESI): m/z [M + Na]+ calcd for C12H25BrNaO2Si: 331.0705; found:
331.0718.
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3-Methyl-2-{(1E,3E)-4-[(2R,3S)-3-methyl-1,4-dioxaspiro[4.5]de-
can-2-yl]buta-1,3-dien-1-yl}pyridine (13a) and 3-Methyl-2-
{(1Z,3E)-4-[(2R,3S)-3-methyl-1,4-dioxaspiro[4.5]decan-2-yl]buta-
1,3-dien-1-yl}pyridine (13b)
Fuzanin D (1)
Compound 13a (100 mg, 0.334 mmol) was dissolved in MeOH (10
mL), then PTSA (19 mg, 0.10 mmol) was added and the mixture
stirred for 3 h. After completion, the reaction was quenched by the
addition of Et3N and then concentrated. Column chromatography of
the residue on silica gel (PE–EtOAc, 1:2) furnished fuzanin D (67.4 mg,
92%) as an amorphous solid.
PPh3 (630 mg, 2.40 mmol) was added to a solution of compound 2
(600 mg, 2.19 mmol) in MeCN (20 mL), and the mixture was heated at
reflux under a nitrogen atmosphere until complete consumption of
the starting material. The solution was concentrated in vacuo to fur-
nish compound 12 as a white powder, which was directly subjected
to the Wittig olefination without further purification.
[α]D25 –23.7 (c 0.18, CHCl3).
IR (neat): 3227, 2921, 1614, 1583, 1449, 1417, 1372, 1297, 1072, 989
cm–1
.
To a suspension of compound 12 (587 mg, 1.09 mmol) and LiBr (473
mg, 5.45 mmol) in anhyd THF (10 mL) was added n-BuLi (0.5 mL, 2.5
M in THF, 1.25 mmol) via a syringe at –78 °C under a nitrogen atmo-
sphere. After stirring for 45 min at the same temperature, a solution
of 3-methylpicolinaldehyde (3) (110 mg, 0.91 mmol) in anhyd THF (5
mL) was added. The mixture was allowed to warm to r.t. gradually
and quenched with MeOH (8 mL) after completion of the reaction.
The mixture was further stirred overnight and the solvent was re-
moved under reduced pressure. Column chromatography of the resi-
due on silica gel (PE–EtOAc, 25:1) furnished 13a (171.5 mg, 63% over
2 steps) as an amorphous solid, and 13b (57.2 mg, 21% over 2 steps)
as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 3.6 Hz, 1 H), 7.44–7.37 (m, 2
H), 7.04 (dd, J = 7.6, 4.4 Hz, 1 H), 6.80 (d, J = 14.8 Hz, 1 H), 6.55 (dd, J =
15.2, 10.8 Hz, 1 H), 6.00 (dd, J = 15.6, 6.8 Hz, 1 H), 4.24–4.21 (m, 1 H),
3.93–3.91 (m, 1 H), 2.36 (s, 3 H), 1.16 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.15, 146.72, 138.71, 134.82,
133.73, 132.49, 131.10, 127.90, 122.22, 76.03, 70.40, 18.85, 17.72.
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO2: 220.1338; found:
220.1324.
Acknowledgment
Compound 13a
[α]D25 –12.7 (c 0.525, CHCl3).
IR (neat): 2932, 2859, 1735, 1581, 1448, 1367, 1231, 1100, 997 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 4.4 Hz, 1 H), 7.44–7.42 (m, 2
H), 7.06–7.03 (m, 1 H), 6.78 (d, J = 15.2 Hz, 1 H), 6.53–6.47 (m, 1 H),
5.92 (dd, J = 14.8, 7.6 Hz, 1 H), 4.61 (t, J = 7.2 Hz, 1 H), 4.38–4.31 (m, 1
H), 2.35 (s, 3 H), 1.71–1.57 (m, 8 H), 1.41–1.38 (m, 2 H), 1.13 (d, J = 6.4
Hz, 3 H).
We are grateful for financial support from NSFC (No. 21602082), the
Natural Science Foundation of Hubei Province of China (No.
2015CFB333), and Hubei Chenguang Talented Youth Development
Foundation, P. R. of China.
.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588343.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
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f
rmoaitn
13C NMR (100 MHz, CDCl3): δ = 153.28, 146.90, 138.47, 133.45,
133.18, 132.71, 130.92, 128.03, 122.13, 108.91, 78.91, 74.05, 38.21,
35.15, 25.27, 24.20, 23.89, 18.85, 16.48.
References
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NNaO2: 322.1783; found:
322.1780.
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Compound 13b
[α]D25 +9.28 (c 0.28, CHCl3).
IR (neat): 2931, 2859, 1580, 1447, 1365, 1280, 1100, 992 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 4.4 Hz, 1 H), 7.44 (d, J = 8.0
Hz, 1 H), 7.39 (dd, J = 15.6, 10.8 Hz, 1 H), 7.05 (dd, J = 7.6, 4.8 Hz, 1 H),
6.49 (t, J = 11.2 Hz, 1 H), 6.43 (t, J = 11.2 Hz, 1 H), 5.84 (dd, J = 15.2, 8.4
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35.11, 25.21, 24.14, 23.81, 19.13, 16.41.
.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NNaO2: 322.1783; found:
322.1795.
Isomerization of 13b into 13a
To a solution of compound 13b (30 mg, 0.10 mmol) in anhyd toluene
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mg, 0.50 mmol). The mixture was heated at reflux for 3 h, then con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (PE–EtOAc, 10:1) to give compound 13a (20 mg,
67%).
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