Efficient enantioselective total synthesis of (+)-helianane

Article abstract of DOI:10.1055/s-0030-1260532

The enantiocontrolled total synthesis of (+)-helianane, a marine-derived heterocyclic sesquiterpene, has been accomplished with an efficient chirality transfer during the Me³Al-mediated aromatic Claisen rearrangement and a ring-closing metathesis as the key steps. The absolute structure of the natural product has been firmly established by total synthesis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260532

LETTER
1171
Efficient Enantioselective Total Synthesis of (+)-Helianane
Total
S
ynthesis of
a
(+)-Heliana
n
ne a Soga, Makoto Kanematsu, Masahiro Yoshida, Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337287; E-mail: shishido@ph.tokushima-u.ac.jp
Received 1 February 2011
Our strategies for the synthesis of helianane (1) are illus-
trated in Scheme 1. For the synthesis of 1 we chose the di-
hydrobenzoxocine 5 with a stereogenic center at C5 as the
penultimate intermediate, which can be converted into 1
Abstract: The enantiocontrolled total synthesis of (+)-helianane, a
marine-derived heterocyclic sesquiterpene, has been accomplished
with an efficient chirality transfer during the Me3Al-mediated aro-
matic Claisen rearrangement and a ring-closing metathesis as the
key steps. The absolute structure of the natural product has been by hydrogenation. The eight-membered heterocycle fused
firmly established by total synthesis.
to the aryl ring would be assembled by ring-closing met-
athesis of the diene 6, which would be prepared from the
phenol 7 by Pd-catalyzed dimethylallyl etherification.6,7
For the key construction of the tertiary stereogenic center
at the benzylic position, we planned to use a substrate-
controlled chirality transfer in the Claisen re-
arrangement8,9 of the allyl aryl ether 8 prepared from m-
cresol and R-(E)-1-(benzyloxy)pent-3-en-2-ol (9)10 by the
Mitsunobu coupling11 (Scheme 1).
Key words: metathesis, total synthesis, terpenoids, Claisen rear-
rangement, helianane
The sesquiterpene helianane (1)1 was isolated from the
sponge Haliclona fascigera by Crews et al. Its structure,
which was elucidated by extensive NMR studies, revealed
that helianane possesses a tetrahydrobenzoxocine skele-
ton with a tertiary stereogenic center at the benzylic posi-
tion. The absolute configuration at the C5 stereogenic
center was deduced to be S by a preliminary assignment
based on an approximate relationship between the abso-
lute stereochemistry of the C–CH3 group and the d/l opti-
cal rotation in aromatic bisabolene derivatives.2 Although
there have been no reports on possible biological activity
of the natural product, the related chlorinated congener 2,
isolated from the sponge Spirastrella hartmani along with
the bromo analogue 3, has been shown to exhibit in vitro
cytotoxic activity.3 Because of its simple and interesting
structural features, the racemic 1 has been the subject of
five reported total syntheses;4 however, no enantioselec-
tive synthesis has ever been accomplished. During the
course of our synthetic studies on the sunflower-derived
helianane sesquiterpenes,5 we published the enantioselec-
tive total synthesis of heliannuol A (4), which has a struc-
ture similar to that of 1, and we established its absolute
structure by total synthesis.6 Here we describe the first
enantioselective total synthesis of helianane (1), which
allowed the confirmation of the absolute structure
(Figure 1).
1
O
O
5
6
OBn
OBn
OH
O
H
7
8
9
m-cresol
+
OBn
OH
Scheme 1 Retrosynthetic analysis
The Mitsunobu reaction between m-cresol and the alcohol
9, derived from R-(–)-benzyl glycidyl ether in two steps,
in the presence of 1,1-(azodicarbonyl)dipiperidine
(ADDP)12 and n-Bu3P proceeded in 64% yield to give the
ether 8 (>99% ee; by HPLC analysis using a Chiralcel AD
column).13 The key Claisen rearrangement of 8 was exam-
ined, and the results are shown in Table 1. On heating a
solution of 8 in N,N-dimethylaniline at 210 °C for 1.5
hours,9a a chromatographically separable mixture of the
desired phenol (S)-7 was obtained in 50% yield in enanti-
omerically pure form (determined by HPLC analysis us-
ing a Chiralcel AD column), along with the regioisomer
10 (26%, entry 1) Treatment of a solution of 8 in dichlo-
roethane with 10 mol% of Eu(fod)39b at 90 °C for 40 hours
gave a mixture of 7 (>99% ee) and 10 in 71% and 21%
yield, respectively (entry 2). The optimized reaction con-
ditions call for 3 equivalents of Me3Al14 in hexane at room
temperature for 0.5 hours; the requisite 7 was obtained in
R
HO
5
OH
O
O
helianane (1) R = H
2 R = Cl
heliannuol A (4)
3 R = Br
Figure 1 Structures of helianane and heliannuol A
SYNLETT 2011, No. 8, pp 1171–1173
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260532; Art ID: U01311ST
© Georg Thieme Verlag Stuttgart · New York

1172
K. Soga et al.
LETTER
Table 1 Results of the Claisen Rearrangement of Compound 8
OH
8 h, quant.
ADDP, n-Bu3P
OBn
7
OH
OH
(S)-16 {[α]D +2.49 (c 1.42, CHCl3)}
9
H2, Pd/C (10%)
EtOH, r.t.
m-cresol
8
benzene, 60 °C
0.5 h, 64%
OH
conditions
11
OBn
3 h, quant.
OH
OH
(R)-16 {[α]D –2.42 (c 0.92, CHCl3)}
OBn
+
7
+
Scheme 3
OH
11
10
OBn
19 (0.5 mol%)
17, Et3N
Entry Conditions
Yield (%), ee (%)a
10 11
7
Me
CH2Cl2, reflux
10 min, quant.
CH2Cl2, 0 °C
1 h, 94%
7
O
Si
Me
1
2
3
N,N-dimethylaniline, 210 °C, 1.5 h
Eu(fod)3 (10 mol%), DCE, 90 °C, 40 h 71 (>99) 21
Me3Al (3 equiv), hexane, r.t., 0.5 h 84 (>99) 11
50 (>99) 26
–
–
5
18
p-TsOH⋅H2O
MeCN, reflux
20 min, 89%
OH
21
O
Si
a HPLC (Chiracel AD column).
Me
Me
20
84% yield (>99% ee), together with 10 (11%) and the Z-
isomer 11 (5%) with the R configuration at the future C5
(entry 3).
O
MesN
NMes
Ph
O
Oi-Bu
Me
Me
Cl
Cl
Si
Ru
22
Cl
6
The absolute configuration of the stereogenic center of 7
was determined to be S by the conversion into curcuphe-
nol (15).2b,c,15 Thus, sequential protection of the phenolic
hydroxyl as the methoxymethyl (MOM) ether and hydro-
genation produced the alcohol 12, which was oxidized un-
der Swern conditions, and the resulting aldehyde was
converted into the alkene 14 by the Julia–Kocienski
olefination.16 Finally, this compound was hydrolyzed with
acidic conditions to give 15, the spectral properties and
optical rotations of which were identical to those of the
natural (+)-curcuphenol (Scheme 2) {[a]D +25.8 (c 0.39,
CHCl3); lit.2b [a]D +24.6 2; lit.15 [a]D +29.1 (c 3.13,
CHCl3)}.
(Ph3P)4Pd (1 mol%)
THF, r.t., 2 h, 88%
PCy3
17
19
Scheme 4
As for the absolute structure of 11, independent hydroge-
nation of 7 and 11 gave the phenolic alcohols (+)-16 and
(–)-16, respectively; thus the absolute configuration at the
future C5 position in 11 was established to be R
(Scheme 3).
The phenol 7 thus prepared was treated with allylchlo-
rodimethylsilane (17) and triethylamine to give the silyl
ether 18, which was subjected to the ring-closing metathe-
sis using the Grubbs second-generation catalyst 19 (0.5
mol%)17 to yield quantitatively the eight-membered silyl
ether 20. Upon exposure to PTSA in refluxing acetoni-
trile, 20 underwent protodesilylation18 to give the phenol
21 in 89% yield. Treatment of 21 with the mixed carbon-
ate 22 in the presence of catalytic (Ph3P)4Pd provided the
diene 6 in 88% yield (Scheme 4).
1) MOMCl, i-Pr2NEt
OH
CH2Cl2, r.t., 9 h, 82%
7
2) H2, Pd/C (10%)
EtOH, r.t., 8 h, 92%
OMOM
12
1) (COCl)2, DMSO, Et3N
CH2Cl2, 0 °C, 0.5 h
Alternatively, the diene 6, the substrate for the ring-clos-
ing metathesis, was prepared starting from (S)-16, which
was derived by hydrogenation of 7, in two steps. Palladi-
um-catalyzed chemoselective allylation of 16 provided
the alcohol 23, which was exposed to the dehydration pro-
tocol of the Nishizawa–Grieco19 to give 6 efficiently
(Scheme 5).
Ph
N
2)
O2
S
OMOM
N
N
14
N
N
13
LHMDS, THF, r.t.
0.5 h, 88% (2 steps)
p-TsOH⋅H2O, MeOH
The requisite diene 6 then was treated with the Grubbs
second-generation catalyst 19 (0.5 mol%) in refluxing
dichloromethane to give the dihydrobenzoxocine 5 in
93% yield. Finally, hydrogenation over 10% Pd/C fur-
r.t., 16 h, 83%
OH
(+)-curcuphenol (15)
Scheme 2
Synlett 2011, No. 8, 1171–1173 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-Helianane
1173
O
(5) For a review, see: Kamei, T.; Morimoto, S.; Shishido, K.
J. Synth. Org. Chem. Jpn. 2006, 64, 1021.
(6) Kishuku, H.; Shindo, M.; Shishido, K. Chem. Commun.
2003, 350.
(7) (a) Kaiho, T.; Yokoyama, T.; Mori, H.; Fujiwara, J.; Nobori,
T.; Okada, H.; Kamiya, J.; Maruyama, M.; Sugawara, T.
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(b) Kaiho, T.; Miyamoto, M.; Nobori, T.; Katakami, T.
J. Synth. Org. Chem. Jpn. 2004, 62, 27. (c) Kamei, T.;
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(d) Morimoto, S.; Shindo, M.; Shishido, K. Heterocycles
2005, 66, 69.
O
Oi-Bu
OH
22
(S)-16
(Ph3P)4Pd (1 mol%)
THF, r.t., 15 min
83%
O
23
o-O2NC6H4SeCN, n-Bu3P
then H2O2 (aq), NaHCO3
6
THF, r.t., 1 h, 88%
Scheme 5
(8) For examples of the construction of a tertiary stereogenic
center at the benzilic position by chirality transfer during the
aromatic Claisen rearrangement, see: (a) Goerring, H. L.;
Kimoto, W. I. J. Am. Chem. Soc. 1965, 87, 1748.
(b) Borgulya, J.; Madeja, R.; Fahrni, P.; Hansen, H.-J.;
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104, 2939. (b) The Claisen Rearrangement; Hiersemann,
M.; Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007.
(c) Majumdar, K. C.; Almam, S.; Chattopadhyay, B.
Tetrahedron 2008, 64, 597.
(10) Takano, S.; Sekiguchi, Y.; Sato, N.; Ogasawara, K.
Synthesis 1987, 139.
(11) For reviews, see: (a) Mitsunobu, O. Synthesis 1981, 1.
(b) Hughes, D. L. Org. React. 1992, 42, 335. (c) Hughes,
D. L. Org. Prep. Proced. Int. 1996, 28, 127.
(12) (a) Tsunoda, T.; Ito, S. J. Synth. Org. Chem. Jpn. 1997, 55,
631. (b) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron
Lett. 1993, 34, 1639.
(13) The regioisomer generated from the SN2¢ process was
obtained in 14% yield. The stereochemistry and the ee of it
have not been determined.
nished the synthetic helianane (1)20 quantitatively. All
spectral data for the synthetic material were identical to
those published,1,4d including the sign of the optical
rotation1 (Scheme 6).
19 (0.5 mol%)
H2, Pd/C (10%)
6
5
1
EtOH, r.t., 3.5 h
quant.
CH2Cl2, reflux
0.5 h, 93%
Scheme 6
In summary, we have completed the first enantiocon-
trolled total synthesis of helianane using a chirality trans-
fer that occurred with high selectivity during the Me3Al-
mediated Claisen rearrangement for the construction of
the C5 stereogenic center and an efficient ring-closing
metathesis for the construction of the basic carbon frame-
work as the key steps in a longest linear sequence of seven
steps from m-cresol with an overall yield of 34%. In addi-
tion, the absolute configuration at the C5 stereogenic cen-
ter was firmly established by this total synthesis to be S,
which had been proposed by Crews.1 The synthetic route
developed here is general and efficient and could also be
applied to the syntheses of other related natural products.
(14) Chan, T. H.; Osanai, K.; Milacic, V.; Dou, Q. P.
Heterocycles 2008, 76, 485.
(15) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K.
Experientia 1987, 43, 1234.
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Perkin Trans. 1 2002, 2563. (c) Meyers, C.; Carreira, E. M.
Angew. Chem. Int. Ed. 2003, 42, 694. (d) Osaka, M.;
Kanematsu, M.; Yoshida, M.; Shishido, K. Heterocycles
2010, 80, 1003.
Acknowledgment
We thank SANYO FINE Co. Ltd. for providing R-(–)-benzyl glyci-
dyl ether. This work was supported financially by a Grant-in-Aid
for the Program for Promotion of Basic and Applied Research for
Innovation in the Bio-oriented Industry (BRAIN).
(17) For a review, see: Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18.
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(20) Analytical Data for Helianane (1)
References and Notes
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[a]D +24.0 (c 2.28, CH2Cl2) {Lit.1 [a]D +8.0 (c 1.01,
CH2Cl2)}. IR (neat): 2973, 2926, 1456, 1382, 1256, 1138
cm–1. 1H NMR (500 MHz, CDCl3): d = 7.06 (d, J = 8.0 Hz,
1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.71 (d, J = 1.5 Hz, 1 H), 3.19
(br s, 1 H), 2.27 (s, 3 H), 1.78–1.70 (m, 1 H), 1.62–1.56 (m,
1 H), 1.52 (m, 2 H), 1.46–1.32 (m, 2 H), 1.41 (s, 3 H), 1.28
(s, 3 H), 1.25 (d, J = 7.0 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 153.0, 138.8, 135.3, 125.8, 125.8, 124.9, 80.9,
39.7, 38.1, 31.5, 29.2, 26.7, 21.9, 21.2, 20.9. ESI-HRMS:
m/z calcd for C15H22ONa [M+ + Na]+: 241.1568; found:
241.1577.
Synlett 2011, No. 8, 1171–1173 © Thieme Stuttgart · New York

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