Biomimetic Total synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6 H -dibenzo-[ b, d ]pyran and its diastereoisomer

Article abstract of DOI:10.1055/s-0034-1380122

The first total synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran and its diastereoisomer via tandem pericyclic reactions were achieved in one step. Our biomimetic strategy features a sequential Aldol-type addition, 6π electrocyclization, and hetero-Diels-Alder cycloaddition, where three rings, two C-C bonds, and two C-O bonds were spontaneously constructed in a highly efficient way.

Full text of DOI:10.1055/s-0034-1380122

SYNLETT
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4
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© Georg Thieme Verlag Stuttgart · New York
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Biomimetic Total Synthesis of 6a,7,8,9,10,10a-Hexahydro-3,6,9-
trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-dibenzo-
[b,d]pyran and Its Diastereoisomer
Huiying Zeng*
Daiping Duan
Boxiao Tang
O
O
O
pyridine
The Key Laboratory of Coordination Chemistry of Jiangxi,
Province and College of Chemistry and Chemical
Engineering, Jinggangshan University, Ji’an, Jiangxi
343009, P. R. of China
+
160 °C, 73%
HO
OH
H
2E, 6E
zenghuiying2005@163.com
Received: 30.11.2014
Accepted after revision: 27.12.2014
Published online: 10.02.2015
ed into confluentin via an Aldol-type reaction followed by
an oxa 6π-electrocyclization, which was reported by Lee.6
We envisioned that it is possible to form 6a,7,8,9,10,10a-
hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-
1,9-epoxy-6H-dibenzo[b,d]pyran (1) and its diastereoiso-
mer 2 via a sequential Aldol-type reaction, oxa-6π electro-
cyclization, and [4+2] cycloaddition. Those natural products
were isolated by Kitanaka in 2002,7 they were also isolated
by Liu in 2013.8 These biosynthetic considerations add at-
tractiveness of those compounds as synthetic targets.
Apart from the structural features, their biological ac-
tivities offer the impetus for them as the synthetic targets.
They have good bioactivities, such as compound 1 and its
diastereoisomer 2 have been tested as antiallergy, with IC50
values of 5.8 and 18.1 μg/mL against enzymatic activity of
histidine decarboxylase, respectively.7 This activity suggests
that those molecules might be valuable leading compounds
for treatment of histamine liberators. Combined the struc-
ture features and biological activities, herein we would like
to report our endeavors which resulted in the first total
synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-
(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-diben-
DOI: 10.1055/s-0034-1380122; Art ID: st-2014-w0988-l
Abstract The first total synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-
trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran
and its diastereoisomer via tandem pericyclic reactions were achieved
in one step. Our biomimetic strategy features a sequential Aldol-type
addition, 6π electrocyclization, and hetero-Diels–Alder cycloaddition,
where three rings, two C–C bonds, and two C–O bonds were sponta-
neously constructed in a highly efficient way.
Key words biomimetic, total synthesis, tandem pericyclic reactions,
6π electrocyclization, hetero-Diels–Alder cycloaddition
Pericyclic cascade reactions have been recognized to
play essential roles in the biosynthesis of natural products.
They are crucial and efficient in building up structural com-
plexity from simple precursors. Many canonical syntheses
have been achieved by ingenious combinations of electro-
cyclizations, sigmatropic rearrangements, and cycloaddi-
tions, such as 8π–6π electrocyclization cascades,1 electrocy-
clizations followed by cycloadditions,2 oxa 6π electrocy-
clization followed by [4+2] cycloadditions.3 As the most
powerful catalyst in nature, enzymes have miraculous abili-
ties to control reaction pathways by converting the same
simple starting materials into diverse products. Inspired by
abilities of enzymes, synthetic organic chemists have de-
signed tremendous amount of biomimetic strategies to
control reaction pathways.4
5-Methylbenzene-1,3-diol and farnesal are ubiquitous
and fundamental natural products. They are important pre-
cursors for constructing various complex natural products
via divergent biogenerative ways (Scheme 1). For instance,
it can produce Bisabosqual’s family core 3 via an Aldol-type
reaction and a subsequent intramolecular [4+2] cycloaddi-
tion, which was achieved by Snider.5 It can also be convert-
zo[b,d]pyran (1) and its diastereoisomer 2 in one step via
biomimetic-controlling reaction pathway.
5-Methylbenzene-1,3-diol and Z/E-citral were used as
starting materials for investigating the tandem-cyclization
conditions (Scheme 2). In this model reaction, to our de-
light, the desired fused ring product 4 was obtained in 80%
yield when the mixture was refluxed in pyridine at 160 °C
under argon for 16 hours. Encouraged by this reaction, 5-
methylbenzene-1,3-diol with Z/E mixture of farnesal was
refluxed under the identical conditions, 6a,7,8,9,10,10a-
hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-
1,9-epoxy-6H-dibenzo[b,d]pyran (1) and its diastereoiso-
mer 2 were obtained in 38% and 29% yields, respectively
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 927–930

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OH
CHO
O
H
O
O
O
HO
OH
H
H
+
OH
H
O
1
bisabosqual B
CHO
O
OH
H
O
OH
H
CHO
O
H
O
O
O
3
H
confluentin
H
H
OH
2
bisabosqual A
Scheme 1 Biogenerative relationship of complex natural products from 5-methylbenzene-1,3-diol and 3,7,11-trimethyldodeca-2,6,10-trienal
The intermediate 7, derived from a 6π electrocyclization
of 6, tautomerized to ortho-quinone methide 8, which un-
dergoes an intramolecular hetero-Diels–Alder reaction to
furnish the desired product 1 [only from (6E)-farnesal] and
HO
OH
pyridine
O
O
its diastereoisomer 2 [only from (6Z)-farnesal].
+
A pure (2E,6E)-farnesal10 was also subjected to the iden-
tical conditions (Scheme 5), and we were pleased to find
that compound 1 can be synthesized in a diastereoselective
fashion in 73% yield.11
160 °C, 80%
O
H
4
Scheme 2 Model reaction
In conclusion, the first total synthesis of (±)-
6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methyl-
pent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran (1) and
its diastereoisomer 2 have been accomplished in one step
with 38% and 29% yields, respectively (67% overall yield).
When a pure (2E,6E)-farnesal was used as the starting ma-
terial, diastereoselective total synthesis of (±)-
6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methyl-
pent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran (1) was
achieved in 73% yield. The transformation involves a 6π
(67% overall yield, Scheme 3). The spectroscopic data of our
synthetic products are in agreement with those reported in
the literature.9 The plausible mechanism of those transfor-
mations has been outlined in Scheme 4. Initially, farnesal is
treated with diphenol to generate intermediate 5 via an
aldol-type or a Friedel–Crafts-type reaction, followed by de-
hydration to form vinyl-ortho-quinone methide 6.
pyridine
160 °C, 16 h
O
O
O
+
+
O
O
HO
OH
H
H
Z/E mixture
1, 38%
2, 29%
Scheme 3 Total synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran (1) and its dia-
stereoisomer 2 in one step
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aldol-type
Friedel-Crafts
O
HO
HO
OH
HO
O
+
dehydrogenation
HO
OH
Z/E mixture
5
6
O
O
O
O
6π
hetero-Diels–Alder
tautomerization
O
O
O
OH
H
H
8
7
from 6Z
from 6E
Scheme 4 Possible mechanism of the total synthesis of those natural products from 5-methylbenzene-1,3-diol and farnesal
O
O
pyridine
O
+
160 °C, 73%
HO
OH
H
1
Scheme 5 Diastereoselective total synthesis of 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-diben-
zo[b,d]pyran (1)
electrocyclization, followed by [4+2] cycloaddition to
simultaneously construct three rings. Two C–C bonds, two
C–O bonds, and two quaternary carbon centers were gener-
ated. The simplicity of this biomimetic synthesis highly re-
sembles the enzymatic process to generate natural prod-
ucts via pericyclic cascade reactions. Further expansion of
this protocol to synthesize other natural products is in
progress in our group.
References and Notes
(1) Selective representive examples, see: (a) Classics in Total Synthe-
sis; Nicolaou, K. C.; Sorensen, E. J., Eds.; VCH: Weinheim, 1996.
(b) Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221.
(c) Moses, J. E.; Baldwin, J. E.; Bruckner, S.; Eade, S. J.;
Adlington, R. M. Org. Biomol. Chem. 2003, 1, 3670. (d) Parker, K.
A.; Lim, Y.-H. J. Am. Chem. Soc. 2004, 126, 15968.
(2) Selective representative examples, see: (a) Kurdyumov, A. V.;
Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935.
(b) Paduraru, M. P.; Wilson, P. D. Org. Lett. 2003, 5, 4911.
(3) Selective representative examples, see: (a) Lee, J. C.; Strobel, G.
A.; Lobkovsky, E.; Clardy, J. J. Org. Chem. 1996, 61, 3232. (b) Li, C.
M.; Johnson, R. P.; Porco, J. A. Jr. J. Am. Chem. Soc. 2003, 125,
5095.
Acknowledgment
We gratefully acknowledge the National Natural Science Foundation
of China (NSFC) (No. 21302073), Natural Science Foundation of Ji-
angxi Province (No. 20122BAB213005, 2011-32-30), Jinggangshan
University (No. JZB11033, No JZ11014) for financial support.
(4) (a) Breslow, R. Chem. Soc. Rev. 1972, 1, 553. (b) Breslow, R. Acc.
Chem. Res. 1980, 13, 170.
(5) (a) Snider, B. B.; Lobera, M. Tetrahedron Lett. 2004, 45, 5015.
(b) Zhou, J.; Lobera, M.; Neubert-Langille, B. J.; Snider, B. B. Tet-
rahedron 2007, 63, 10018.
Supporting Information
(6) (a) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46,
7539. (b) Lee, Y. R.; Wang, X.; Noh, S. K.; Lyoo, W. S. Synth.
Commun. 2006, 36, 3329.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380122.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(7) Kitanaka, S.; Iwata, N. JP 2002265463 A, 2002.
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(8) Liu, L.-Y.; Li, Z.-H.; Ding, Z.-H.; Dong, Z.-J.; Li, G.-T.; Li, Y.; Liu,
J.-K. J. Nat. Prod. 2013, 76, 79.
(9) See ref. 7 and the Supporting Information for the comparison of
the natural products and our synthesized compounds.
matography on silica gel with the appropriate mixture of
hexane and EtOAc to give 6a,7,8,9,10,10a-hexahydro-3,6,9-
trimethyl-6-(4-methylpent-3-en-1-yl)-1,9-epoxy-6H-
dibenzo[b,d]pyran (1, 476 mg, 73%) as pale yellow liquid. IR
(10) (2E,6E)-Farnesal was oxidized from (2E,6E)-farnesol, see:
(a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616. (b) Ishihara, K.; Ishibashi, H.; Yamamoto, H.
J. Am. Chem. Soc. 2002, 124, 3647.
(11) Diastereoselective Total Synthesis of 3,6,9-Trimethyl-6-(4-
methylpent-3-en-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran (1)
(2E,6E)-Farnesal (440 mg, 2 mmol) and 5-methylbenzene-1,3-
diol (372 mg, 3 mmol) were added to pyridine (15 mL) and the
mixture was refluxed rigorously at 160 °C for 16 h under argon.
The reaction mixture was cooled to r.t., and the solvent was
evaporated in vacuo. The residue was purified by column chro-
(film): νmax = 1621, 1067 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
6.31 (s, 1 H), 6.27 (s, 1 H), 5.17 (t, J = 7.0 Hz, 1 H), 2.85 (s, 1 H),
2.25 (s, 3 H), 2.21–2.19 (m, 1 H), 2.17 (dd, J = 4.5, 3.3 Hz, 1 H),
2.08 (ddd, J = 11.6, 5.3, 2.9 Hz, 2 H), 1.95–1.85 (m, 1 H), 1.82–
1.73 (m, 3 H), 1.71 (s, 3 H), 1.65 (s, 3 H), 1.46–1.38 (m, 1 H), 1.37
(s, 3 H), 0.96 (s, 3 H), 0.87 (dt, J = 6.6, 5.1 Hz, 1 H), 0.63 (ddd, J =
25.0, 13.3, 6.1 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 156.7,
156.5, 137.2, 131.8, 124.3, 114.3, 110.7, 109.6, 85.8, 74.5, 45.3,
42.1, 37.5, 35.3, 29.1, 27.9, 25.7, 22.9, 22.2, 21.7, 20.9, 17.7.
HRMS (APCI): m/z calcd for
C22H31O2: 327.2319; found:
327.2305 [M + H].
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