E
Y. Gao et al.
Paper
Synthesis
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
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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.
(1) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in Natural
Product Synthesis; Wiley-VCH: Weinheim, 2011, 267.
(2) (a) Takekawa, Y.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N.
J. Nat. Prod. 2006, 69, 1503. (b) Tsukamoto, S.; Takahashi, M.;
Matsunaga, S.; Fusetani, N.; van Soest, R. W. M. J. Nat. Prod.
2000, 63, 682. (c) Schmidt, G.; Timm, C.; Köck, M. Org. Biomol.
Chem. 2009, 7, 3061.
(3) Arai, M.; Ishida, S.; Setiawan, A.; Kobayashi, M. Chem. Pharm.
Bull. 2009, 57, 1136.
(4) (a) Musiol, R.; Serda, M.; Hensel-Bielowka, S.; Polanski, J. Curr.
Med. Chem. 2010, 17, 1960. (b) Nicholas, G. M.; Molinski, T. F.
Tetrahedron 2000, 56, 2921.
(5) (a) Cheng, X.-F.; Meng, Z.-M.; Chen, Z.-L. Phytochemistry 1998,
49, 2193. (b) Eun, J. S.; Seo, S.-Y. Arch. Pharm. Res. 2009, 32,
1673.
(6) Kem, W. R.; Scott, K. N.; Duncan, J. H. Experientia 1976, 32, 684.
(7) (a) Mukherjee, S.; Pal, M. Drug Discovery Today 2013, 18, 389.
(b) De Marino, S.; Iorizzi, M.; Zollo, F.; Debitus, C.; Menou, J. L.;
Ospina, L. F.; Alcaraz, M. J.; Payá, M. J. Nat. Prod. 2000, 63, 322.
(8) Aida, W.; Ohtsuki, T.; Li, X.; Ishibashi, M. Tetrahedron 2009, 65,
369.
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
Hz, 1 H), 4.60 (t, J = 8.0 Hz, 1 H), 4.36–4.30 (m, 1 H), 2.30 (s, 3 H),
1.70–1.56 (m, 8 H), 1.40–1.36 (m, 2 H), 1.16 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.87, 146.49, 137.73, 133.88,
132.88, 131.83, 130.84, 126.25, 121.76, 108.74, 79.08, 74.03, 38.15,
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
(4 mL) was added p-toluenethiol (62 mg, 0.50 mmol) and AIBN (82
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%).
(9) Kumar, S. N.; Sai Pavan Kumar, C. H. N. S.; Srihari, E.; Kancharla,
S.; Srinivas, K.; Shrivastava, S.; Naidu, V. G. M.; Rao, V. J. RSC Adv.
2014, 4, 8365.
(10) Dunn, A. D. Org. Prep. Proced. Int. 1999, 31, 120.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F