An efficient total synthesis of (+)-heliannuol D

Article abstract of DOI:10.1016/j.tetasy.2010.08.018

An efficient total synthesis of (+)-heliannuol D was accomplished in 14 steps and in 12% overall yield by employing a diastereoselective conjugate addition reaction to create a tertiary benzylic stereogenic center and simple assembly of the functionalized oxepane framework by an efficient one-pot transformation procedure as the key steps.

Full text of DOI:10.1016/j.tetasy.2010.08.018

Tetrahedron: Asymmetry 21 (2010) 2319–2320
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An efficient total synthesis of (+)-heliannuol D
⇑
Mayu Osaka, Makoto Kanematsu, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient total synthesis of (+)-heliannuol D was accomplished in 14 steps and in 12% overall yield by
employing a diastereoselective conjugate addition reaction to create a tertiary benzylic stereogenic cen-
ter and simple assembly of the functionalized oxepane framework by an efficient one-pot transformation
procedure as the key steps.
Received 10 August 2010
Accepted 27 August 2010
Available online 20 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
produce oxepane 2, the penultimate intermediate for 1, via a one-
pot epoxidation/desilylation/7-exo-trig heterocyclization of the
Heliannuol D 1, a representative heliannane type sesquiterpenoid
isolated from the fresh leaf aqueous extracts of Helianthus annuus L.
SH-222 and YPP by Macías et al.,1 was discovered to have phytotoxic
allelopathic activity. The structural features of this natural product
are a characteristic bicyclic core, an oxepane fused to the aryl ring,
and two syn-oriented tertiary stereogenic centers at C7 and C10 on
the oxepane ring. The absolute configuration has been established
to be (7R,10R) by our enantioselective total synthesis of (ꢀ)-1.2a
Although three enantioselective2 and seven racemic3 total synthe-
ses have been reported so far, the development of more efficient
and reliable methodologies for the enantioselective synthesis of
heliannuol D would be particularly valuable for various biological
evaluations. Herein we report an efficient total synthesis of the
natural enantiomer (+)-heliannuol D (1), by employing a diastereo-
selective conjugate addition reaction for the construction of the C7
stereogenic center and a concise assembly of the functionalized
oxepane framework of the natural product as the key steps. (Fig. 1)
phenoxide onto the epoxide. There are two important issues for
the preparation of 3. The first one is the discrimination of the two
phenolic hydroxyls on the phenyl ring. We thought that this could
be achieved by the selective formation of the six-membered lactone
4,4 which can be derived from 5. The second consideration was how
to construct the two stereogenic centers at the future C7 and C10
positions; the former would be assembled by a diastereoselective
1
MOMO
Me
MOMO
Me
OH
OMs
OTBS
O
O
2
3
OH
O
O
HO
Me
MeO
Me
N
HO
7
O
O
OMe
MeO
Me
10
Ph
Me
O
4
5
OH
Figure 1. (+)-Heliannuol D (1).
Br
O
O
O
OMe
7
MeO
Me
N
Ph
2. Results and discussion
+
O
O
OMe
Our retrosynthetic analysis of heliannuol D is shown in Scheme 1.
6
We envisaged that basic treatment of hydroxymesylate 3 that would
N
O
Ph
Scheme 1. Reterosynthetic analysis of 1.
8
⇑
Corresponding author. Tel.: +81 88 633 7287; fax: +81 88 633 9575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.018

2320
M. Osaka et al. / Tetrahedron: Asymmetry 21 (2010) 2319–2320
conjugate addition5 of a methyl group onto 6 with a chiral auxiliary
providing 5 and the latter by an asymmetric dihydroxylation of the
corresponding trisubstituted alkene, which would be derived from
4, respectively. The unsaturated enone 6 can be prepared by the
Heck reaction of the arylbromide 76 and the (R)-3-acryloyl-4-
phenyloxazolidin-2-one 87 (Scheme 1).
of the secondary alcohol moiety provided the mesylate 3, which was
treated with K2CO3 in methanol at room temperature to give the
oxepane 29 in 58% yield after purification by silica gel column
chromatography.10 Presumably this was generated by a sequential
epoxidation, desilylation, and [7-exo-trig] mode of nucleophilic
epoxide opening with a phenoxide anion as expected. Finally, com-
pound 2 was exposed to acidic conditions to produce heliannuol D
(1) in 81% yield. The spectroscopic properties as well as the specific
The substrate 6 for the key diastereoselective conjugate addition
was synthesized in 81% yield by the Heck reaction of the arylbromide
7 and the enone 8 with catalytic Pd(OAc)2 and (o-Tol)3P in the pres-
ence of Et3N. Treatment of a solution of 6 in THF with MeMgBr and
CuBrꢁSMe2 at ꢀ20 °C produced the methylated product 5 as an
inseparable mixture of diastereoisomers (12:1 from 1H NMR in
C6D6), which was recrystallized immediately from AcOEt and n-
hexane to give diastereomerically pure 5 in 71% yield. After hydro-
lytic removal of the chiral auxiliary, the resulting carboxylic acid 9
was treated with BBr3 in CH2Cl2 at room temperature to give the lac-
tone 4, which without purification was converted to the MOM ether
10 in 92% yieldin twosteps. Thus we could discriminatebetween the
two phenolic hydroxy groups. A DIBAH reduction followed by Wittig
reaction provided the methyl enol ether 11, which was subjected
sequentially to acidic hydrolysis and Wittig reaction to give the phe-
nol 12 in 54% yield from 10. After protection of the hydroxyl function
in 12 as the TBS ether, the resulting 13 was subjected to an asymmet-
ric dihydroxylation reaction employing AD-mix-b and CH3SO2NH2
to give diol 14 in 94% yield as a single product.8 Selective mesylation
rotation ½fa 2D8
ꢂ
¼ þ18 (c 1.01, CHCl3); lit.1 ½a D26
¼ þ16 (c 0.1, CHCl3)}
ꢂ
of the synthetic heliannuol D were identical with those of the natural
product (Scheme 2).
3. Conclusion
In conclusion, we have completed a concise enantioselective
total synthesis of heliannuol D in 14 steps and in 12% overall
yield,11 which has enabled us to obtain not only the natural prod-
uct but also the related compounds for various biological evalua-
tions. The key steps include a diastereoselective construction of a
tertiary benzylic stereogenic center (C7) employing a conjugate
addition of a methyl group onto the enone system with a chiral
auxiliary and a simple assembly of the functionalized oxepane
framework by an efficient one-pot transformation procedure. The
synthetic route developed herein is general and efficient and
would be applicable to other related natural products.
Acknowledgments
MeO
Me
CO2H
OMe
c
d
a
b
This work was supported financially by a Grant-in-Aid for the
Program for Promotion of Basic and Applied Research for Innova-
tions in the Bio-oriented Industry (BRAIN).
5
+
7
8
6
OMe
9
References
RO
Me
MOMO
Me
f, g
h, i
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O
O
OH
4: R=H
11
e
10: R=MOM
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MOMO
Me
MOMO
k
OH
OR
OTBS
Me
j
OR
12: R=H
14: R=H
3: R=Ms
l
13: R=TBS
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MOMO
Me
m
n
1
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8. The absolute configuration of
a newly generated stereogenic center was
O
determined by the Kusumi–Mosher method. The stereochemical homogeneity
of 14 was confirmed by the 1H NMR of the MTPA ester and the 13C NMR.
9. Since the 10-epi-isomer of 2 was not involved in the crude product, the reaction
proceeded via epoxide intermediate.
2
OH
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, (o-Tol)3P, Et3N, rt, 81%; (b)
MeMgBr, CuBrꢁSMe2, THF, ꢀ20 °C, then recrystallization from AcOEt/hexane, 71%;
10. Under the reaction conditions used, the eight-membered cyclized product2a
was not obtained at all.
i
(c) 30% H2O2 (aq), LiOHꢁH2O, 97%; (d) BBr3, CH2Cl2, rt; (e) MOMCl, Pr2NEt, CH2Cl2,
60 °C, 92% (two steps); (f) DIBAH, CH2Cl2, ꢀ78 °C; (g) (Ph3P+CH2OCH3)Clꢀ, NaHMDS,
THF, rt, 81% (two steps); (h) 2 N HCl, acetone, 0 °C; (i) [Ph3P+CH(CH3)2]Iꢀ, tBuOK,
THF, rt, 67% (two steps); (j) TBSCl, imidazole, 4-DMAP, CH2Cl2, rt, quant.; (k) AD-
mix-b, CH3SO2NH2, tBuOH/H2O, rt, 94%; (l) MsCl, pyridine, 4-DMAP, CH2Cl2, rt; (m)
K2CO3, MeOH, rt, 58% (two steps); (n) 6 N HCl, THF, rt, 81%.
11. Comparison of the overall yield and steps for the previous enantioselective total
syntheses:for Ref.2a, 3.8%for 20 steps from4-methyl-2,5-dimethoxyiodobenzene;
for Ref.2b, 2.8% for 15 steps from 4-methyl-3-methoxyiodobenzene; for Ref.2c, 9.4%
for 15 steps from 1,4-dimethoxy-2-methyl-5-(prop-1-en-2-yl)benzene, the
preparation and yield of which have not been mentioned in the literature.