An Alternative Total Synthesis of (-)-Heliannuol E1

Article abstract of DOI:10.1055/s-2003-42097

An efficient, enantiocontrolled total synthesis of (-)-heliannuol E has been accomplished using a palladium-catalyzed cyclization of the six-membered oxygen containing heterocycle as the key reaction step.

Full text of DOI:10.1055/s-2003-42097

LETTER
2395
An Alternative Total Synthesis of (–)-Heliannuol E1
An
Alternative
o
T
otal Synthe
m
sis of (–)-Heliannuo
o
l
E
yo Kamei, Mitsuru Shindo, Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6339575; E-mail: shishido@ph2.tokushima-u.ac.jp
Received 16 September 2003
OH
OR'
Abstract: An efficient, enantiocontrolled total synthesis of (–)-
RO
Me
RO
Me
heliannuol E has been accomplished using a palladium-catalyzed
cyclization of the six-membered oxygen containing heterocycle as
the key reaction step.
1
Br
HO
4
O
OH
OH
3
Key words: sesquiterpene, allelopathic activity, asymmetric syn-
thesis, palladium-catalyzed cyclization
OR'
OH
lipase mediated
desymmetrization
RO
Me
RO
Me
Heliannuol E (1),2 a naturally occurring irregular sesquit-
erpenoid exhibiting allelopathic activity, has been isolated
by Macias and coworkers from the extracts of Helianthus
annuus L. cv. SH-222® and is thought to be biogenetically
related to the seven-membered congener heliannuol C
(2)3. Its biological activity coupled with its intriguing
structural features made this natural product a fascinating
synthetic target. To date, two total syntheses4,5 of 1 have
been accomplished, and its absolute stereochemistry was
established by the second total synthesis of Nishiyama5 as
illustrated in Figure 1. We report herein an alternative, ef-
ficient total synthesis of the enantiomerically pure (–)-he-
liannuol E (1) with the natural configuration (Figure 1).
OH
OH
6
5
Scheme 1 Retrosynthetic analysis.
The prochiral diol 11, the substrate for the chemoenzy-
matic transformation, was prepared from a commercially
available 3-hydroxy-4-methyliodobenzene (7). Sequen-
tial methoxymethyl (MOM) protection and Sonogashira
coupling8 with propargyl alcohol provided 8, which was
subjected to reduction with LiAlH4 followed by vinyl
ether formation, to give 9. Reductive Claisen rearrange-
ment,9 followed by hydroboration of the resulting alkenyl
alcohol 10, produced the diol 11 in good overall yield
(Scheme 2).
HO
Me
HO
Me
4
OH
2
O
O
OH
heliannuol E (1)
heliannuol C (2)
Figure 1
As shown in Scheme 1, we anticipated that (–)-heliannuol
E (1) would be prepared from the bicyclic diol 3 with the
requisite carbon skeleton and 2R,4S absolute stereochem-
istries at the stereogenic centers by sequential dehydration
and deprotection. The diol 3 would be constructed by a
palladium-catalyzed intramolecular aryl ether forming
cyclization6 of the bromo diol 4, which could be prepared
from the optically active alcohol 5 via Wittig olefination,
followed by asymmetric dihydroxylation for the construc-
tion of the future C-2 stereogenic center. Introduction of
the desired chirality at the benzylic position of 5 would
be realized by lipase-mediated desymmetrization7 of the
s-symmetrical prochiral 3-aryl-1,5-pentanediol 6.
Scheme 2 Reagents and conditions a) NaH, MOMCl, DMF, 25 °C,
10 min, 88%; b) propargyl alcohol, (Ph3P)4PdCl2, Et3N, CuI, benzene,
25 °C, 1 h, 97%; c) LiAlH4, THF, 25 °C, 1 h, 91%; d) ethyl vinyl
ether, Hg(OCOCF3)2, reflux, 19 h, quant.; e) i-Bu3Al, CH2Cl2, 25 °C,
0.5 h, 87%; f) BH3·SMe2, THF, 25 °C then NaOH (aq), H2O2, 25 °C,
2 h, 91%.
With the substrate for the desymmetrization in hand, we
then searched for the optimum conditions for the lipase-
mediated asymmetric acetylation of 11. Of these, lipase
AK-catalyzed conditions,4,10 using vinyl acetate as an acyl
donor in benzene, proved to be the best choice. Thus, the
enantiomerically pure (>99% ee, HPLC on a Chiralcel
OD-H column) monoacetate 12 was obtained in 53%
yield, accompanied by 38% yield of the corresponding di-
acetate, which could be converted back into 11 quantita-
SYNLETT 2003, No. 15, pp 2395–2397
0
1
.1
2
.2
0
0
3
Advanced online publication: 15.10.2003
DOI: 10.1055/s-2003-42097; Art ID: U18403ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2396
T. Kamei et al.
LETTER
tively by alkaline hydrolysis (K2CO3 in aq MeOH). The and 19% yield, respectively. The remaining steps in the
absolute configuration of the benzylic stereogenic center total synthesis are only the introduction of the benzylic vi-
was established by the following procedure. Silylation nyl moiety and deprotection of the phenolic hydroxyl
and subsequent reduction with LiAlH4 gave the alcohol group. Thus, sequential deprotection of the silyl ether in
13, which was oxidized to the carboxylic acid 15 via the 22 with tetra-n-butylammonium fluoride, dehydration16 of
aldehyde 14. Using standard conditions, we carried out the resulting primary alcohol 24, and acidic hydrolysis
1
condensation of 15 with (R)- and (S)-phenylglycine meth- produced heliannuol E (1), whose H NMR, 13C NMR,
yl ester (PGME) to furnish the diastereomeric amides 16, IR and mass spectral data as well as optical rotation, [a]D
25
the positive and negative Dd values of which are oriented –76.5 (c 0.08, CHCl3) [lit.2 [a]D –68.6 (c 0.1, CHCl3);
27
clearly on the right and left sides of the PGME plane, re- lit.4 [a]D –69.8 (c 0.1, CHCl3); lit.5 [a]D –77.1 (c 0.1,
spectively; thus the absolute configuration was deter- CHCl3)], were identical with those of the natural product
mined to be S11 (Scheme 3).
(Scheme 4).
In summary, an alternative, enantiocontrolled total syn-
thesis of the natural enantiomer (–)-heliannuol E using a
chemoenzymatic desymmetrization of the prochiral s-
symmetrical diol and palladium-catalyzed intramolecular
aryl ether cyclization as the key steps. The synthetic route
developed here is general and efficient and can also be
applied to the synthesis of other heliannuols.
OH
MOMO
b, c
a
11
Me
OAc
12
TBDPSO
OTBDPS
MOMO
d, e
MOMO
Me
f
OTBDPS
OTBDPS
R
MOMO
Me
OH
+0.055
+0.150
14:R=CHO
15:R=CO2H
OMTPA
13
a
14
MOMO
Me
-0.077
Me
H +0.023
TBDPSO
17
b, c
+0.104
+0.018
OH
-0.065
PGME plane
H
+0.001
H
O
-0.032
-0.039
H
N
+0.019
-0.006 Me
OMe
19 ∆δ=δ(S)-δ(R) in CDCl3
OTBDPS
H
Ph
(R)
(S)
-0.098 H
H
O
MOMO
-0.059
(Ph) (H)
MeO
O
H
-0.043
16 ∆δ=δ(R)-δ(S) in CDCl3
-0.069
Me
OMe
PPh2
X
HO
OH
18: X=H
20: X=Br
Scheme 3 Reagents and conditions: a) Lipase AK, vinyl acetate,
benzene, 25 °C, 17 h, 53%; b) TBDPSCl, imidazole, 4-DMAP,
CH2Cl2, 25 °C, 20 min, quant.; c) LiAlH4, THF, 25 °C, 10 min, quant.;
d) Dess–Martin periodinane, CH2Cl2, 25 °C, 20 min, 94%; e) PDC,
DMF, 25 °C, 19 h, quant.; f) (R)- or (S)-phenylglycine methyl ester,
PyBOP®, HOBT, Et3N, CH2Cl2, 25 °C, 1.5 h.
d, e
(R)-MOP (21)
OR
OTBDPS
MOMO
Me
MOMO
+
Wittig olefination of the aldehyde 14 provided 17, which
was submitted to asymmetric dihydroxylation12 using
AD-mix-b in the presence of methanesulfonamide to give
the diol 18 as a separable 8.3:1 mixture of diastereoiso-
mers. The absolute configuration at the future C-2 stereo-
genic center of the major diastereomer was determined to
be the requisite R by the Kusumi–Mosher ester method13
of the MTPA ester 19, as shown in Scheme 4. Bromina-
tion with NBS gave the bromide 20, a substrate for the key
cyclization, which was treated with a catalytic palladium
acetate in the presence of (R)-(+)-2-(diphenylphosphino)-
2¢-methoxy-1,1¢-binaphthyl [(R)-MOP]14 (21) and cesium
carbonate in toluene at 90 °C to furnish the desired cyclic
ether 22 and the ketone 236,15 in 49% and 24% yield, re-
spectively. Attempted conversion using rac-2-(di-tert-bu-
tylphosphino)-1,1¢-binaphthyl6c as the ligand resulted in
the formation of 22 in only 9% yield, accompanied by the
starting material 20 and the corresponding ketone in 49%
O
Me
O
OH
OH
23
22: R=TBDPS
24: R=H
f, g
(–)-1
Scheme 4 Reagents and conditions: a) Ph3PCHMe2I, t-BuOK,
THF, 25 °C, 1 h, 76%; b) AD-mix-b, MeSO2NH2, t-BuOH, H2O, 0
°C, 45 h, 79% (99% based on the consumed 17); c) NBS, DMF, 25
°C, 2 h, 85%; d) Pd(OAc)2, Cs2CO3, 20, toluene, 90 °C, 21 h, 49%;
e) n-Bu4NF, THF, 25 °C, 4 h, quant.; f) o-nitrophenyl selenocyanate,
n-Bu3P, THF, 25 °C then H2O2, THF, 25 °C, 81%; g) 6 N HCl, THF,
25 °C, 21 h, 93%.
Acknowledgment
We are grateful to Dr. Y. Hirose and Mr. T. Mase (the Amano
Enzyme, Co.) for kindly providing us with lipase AK. We also
thank Professor Tamio Hayashi, Kyoto University, for giving us
with the MOP ligand.
Synlett 2003, No. 15, 2395–2397 © Thieme Stuttgart · New York

LETTER
An Alternative Total Synthesis of (–)-Heliannuol E
2397
(9) (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron
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Synlett 2003, No. 15, 2395–2397 © Thieme Stuttgart · New York