Convergent formal synthesis of (±)-heliannuols A, K, and L from a common intermediate

Article abstract of DOI:10.1055/s-2004-829064

The intramolecular titanium-mediated cyclopropanation reaction of an oxa-ester bearing a terminal double bond followed by appropriate oxidation and dehydrohalogenation allows easy access to an aryl-fused oxacyclooctenone, an effective precursor of (±)-hel

Full text of DOI:10.1055/s-2004-829064

LETTER
1613
Convergent Formal Synthesis of ( )-Heliannuols A, K, and L from a Common
Intermediate
Convergent
F
o
r
rmal Sy
é
nthesis of
(
d
)-Heliannuo
é
ls
A
,
K
,
an
r
d L ic Lecornué, Jean Ollivier*
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire et des Matériaux d'Orsay, Bât. 420, Université de
Paris-Sud, 91405 ORSAY, France
Fax +33(1)69156278; E-mail: jollivie@icmo.u-psud.fr
Received 31 March 2004
Dedicated to Jacques Salaün on the occasion of his retirement
previously reported to provide the natural products
Abstract: The intramolecular titanium-mediated cyclopropanation
Heliannuol A3a,b and Heliannuol D.3c–e
reaction of an oxa-ester bearing a terminal double bond followed by
appropriate oxidation and dehydrohalogenation allows easy access
to an aryl-fused oxacyclooctenone, an effective precursor of ( )-he-
liannuols A, K and L.
Indeed, simple reduction of the double bond of the hetero-
cycle 6 should lead to the oxacycloctanone 7; double re-
duction of the double bond and the ketone function should
furnish the oxacyclooctanol 8; oxidation of the double
bond would give the epoxide 9, which, by regioselective
ring opening, would provide the benzoxocinone 10.
Deprotection of the methoxy group on the aryl moiety
would then lead directly to the heliannuols K (2), A (1)
and L (3), respectively. The direct reduction of the ketone
7 leads to the oxacyclooctanol 8 and has been previously
reported3b (Scheme 1).
Key words: bicyclic compounds, cyclization, enones, heterocy-
cles, organometallic reagents, radical reactions, titanium
Isolated from Helianthus annus, heliannuols A–L consti-
tute a new class of sesquiterpenes possessing allelopathic
activity.1 Heliannuols A, K and L (1, 2 and 3, respective-
ly) contain the same basic skeleton of an aromatic ring
fused to an eight-membered oxacycle (Figure 1).
OH
HO
HO
OH
HO
O
OH
O
O
O
1
3
2
Figure 1
We recently reported2 a general procedure for the con-
struction of benzo-fused cyclic ethers from oxa-w-alkeno-
ic esters, which allows the benzoxocinone 5 to be obtained
from the acetate 4 (Figure 2).
O
COOEt
O
O
4
5
Scheme 1
Figure 2
Thus, the formylation-oxidation of 2-methylanisole 11 led
after base hydrolysis4 to 4-methoxy-3-methylphenol 12,
which was then alkylated with 1-chloro-2-butene to yield
the allylic ether 13 (Scheme 2).
In order to widen the scope of this approach towards bio-
logically important compounds, we reasoned that the oxa-
cyclooctenone 6 could constitute a particularly efficient
intermediate in the total synthesis of the various helian-
nuols. Demethylation of the methoxy moieties has been
Refluxing in N,N-dimethylaniline for 72 hours achieved
Claisen rearrangement of 13 to give 4-methoxy-5-methyl-
2-(1-methyl-2-propen-1-yl)phenyl (14, 75%) and a small
amount (3%) of the regioisomeric 3-methyl product.
Alkylation of the chromatographically purified major
product 14 with ethyl 2-bromo-2,2-methypropanoate
SYNLETT 2004, No. 9, pp 1613–1615
2
2.
0
7.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829064; Art ID: D08204ST
© Georg Thieme Verlag Stuttgart · New York

1614
F. Lecornué, J. Ollivier
LETTER
Scheme 2 Reagents and conditions: a) TiCl4, Cl2CHOMe, CH2Cl2,
r.t.; b) m-CPBA, CH2Cl2, reflux; c) NH4OH, CH3OH, r.t.; d) 1-chloro-
2-butene, K2CO3, acetone, reflux.
Scheme 5 Reagents and conditions: a) H2, Pd/C, EtOAc, r.t., 72 h;
b) (Me3Si)3SiH, AIBN, toluene, 80 °C, 2 h.
Likewise, epoxidation of enone 6 allowed the oxirenone
913 to be obtained in 89% yield, and this was then submit-
ted to ring opening hydrogenation14 to produce the oxacy-
clooctanone 10 as a single cis-diastereomer. Subsequent
stereocontrolled reduction of the ketone function15 fur-
nished the expected diol 18 as a 9:1 mixture of syn- and
anti-isomers (Scheme 6).
furnished in high yield the w-alkenoic ester 15, suitable
for the intramolecular Kulinkovich reaction5 (Scheme 3).
Thus, cyclopropanation was carried out using a titanium
tetraisopropoxide–cyclohexylmagnesium halide couple6
to produce a diastereomeric mixture (1:1) of cyclopro-
panols 16. For structural characterization the mixture was
separated by column chromatography. Ring opening on
cyclopropanols 16 was achieved using the Saegusa
procedure7 to produce a diastereomeric mixture (77:23) of
b-chloroketones 17 also separable by chromatography.
Subsequent base dehydrohalogenation effected on either
or both chlorides 17 delivered the expected oxocinone 68
(Scheme 4).
Scheme 6 Reagents and conditions: a) m-CPBA, CH2Cl2, 0 °C; b)
H2, Pd/C, MeOH, EtOAc, r.t., 48 h; c) DIBALH, THF, 0 °C.
In conclusion, we describe herein access to an intermedi-
ate for the efficient preparation of ( )-heliannuols A, K,
and L. The extension of this pathway to enantioselective
synthesis of these allelopathic agents is under current in-
vestigation.
Scheme 3 Reagents and conditions: a) Dimethylaniline, reflux; b)
NaH, DMPU, (CH3)2CBrCO2Et, toluene, reflux.
Acknowledgment
This work was financially supported by the CNRS and the Univer-
sity of Paris-Sud (XI), by a grant to F. L. from the Ministère de la
Jeunesse, de l’Education Nationale et de la Recherche.
References
Scheme 4 Reagents and conditions: a) C6H11MgCl (4 equiv),
Ti(Oi-Pr)4 (1 equiv), Et2O–THF, r.t., 4 h; b) FeCl3, DMF, pyridine,
0 °C; c) DBU, Et2O, 0 °C to r.t.
(1) (a) Macías, F. A.; Varela, R. M. G.; Varela, R. M.; Torres,
A.; Molinillo, J. M. J. Nat. Prod. 1999, 62, 1636.
(b) Macías, F. A.; Torres, A.; Galindo, J. L. G.; Varela, R.
M.; Álvarez, J. A.; Molinillo, J. M. Phytochemistry 2002, 61,
687.
Subsequent staightforward hydrogenation of the double
bond of the enone 6 gave quantitatively the oxacyclooc-
tanone 79 as the methoxy parent of ( )-heliannuol K (2).
Alternatively, while tris(trimethylsilyl)silane is known as
a hydrosilylating agent for dialkylketones,10 application
of the radical chain process on the b-chlorooctanone 17
entailed only the reduction of the halide group to produce
the required oxacyclooctanone 7 with 80% yield
(Scheme 5).
(2) Lecornué, F.; Ollivier, J. Org. Biomol. Chem. 2003, 1, 3600.
(3) (a) Grimm, E. L.; Levac, S.; Trimble, L. A. Tetrahedron
Lett. 1994, 35, 6847. (b) Tuhina, K.; Bhowmik, D. R.;
Venkateswaran, R. V. Chem. Commun. 2002, 634.
(c) Vyvyan, J. R.; Looper, R. E. Tetrahedron Lett. 2000, 41,
1151. (d) Sabui, S. K.; Venkateswaran, R. V. Tetrahedron
Lett. 2004, 45, 983. (e) Sabui, S. K.; Venkateswaran, R. V.
Tetrahedron Lett. 2004, 45, 2047.
(4) Iyer, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1987, 99, 2759.
(5) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;
Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244.
(b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.
Synthesis 1991, 234. (c) Kulinkovich, O. G.; Sviridov, S. V.;
Vasilevski, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh.
Org. Khim. 1991, 27, 294.
As suggested in Scheme 1, the direct transformation of
enone 6 into the benzoxocinol 811 was performed success-
fully (Raney nickel, H2O, THF, Na2CO3, H2, 94% yield)12
and the product was isolated as a diastereomeric mixture
(82:18) in which the major compound was the cis-isomer.
Synlett 2004, No. 9, 1613–1615 © Thieme Stuttgart · New York

LETTER
Convergent Formal Synthesis of (±)-Heliannuols A, K, and L
1615
(6) (a) U, J. S.; Lee, J.; Cha, J. K. Tetrahedron Lett. 1997, 38,
5233. (b) Lecornué, F.; Ollivier, J. Chem. Commun. 2003,
23, 584.
(7) (a) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41,
2073. (b) Ito, Y.; Fujii, S.; Nakatsuja, F.; Saegusa, T. Org.
Synth., Coll. Vol. VI 1988, 327.
(11) We noted omissions in the reported data of this compound.3
8-Methoxy-2,2,6,9-tetramethyl-3,4,5,6-tetrahydro-2H-1-
benzoxocin-3-ol (8).
1H NMR (250 MHz, CDCl3): d = 6.76 (s, 1 H, cis), 6.72 (s,
1 H, trans), 6.62 (s, 1 H, cis), 6.58 (s, 1 H, trans), 3.81 (s, 6
H), 3.43 (d, J = 9.1 Hz, 2 H), 3.30–3.11 (m, 2 H), 2.16 (s, 6
H), 2.15–1.94 (m, 8 H), 1.62 (br s, 2 H), 1.44 (s, 6 H), 1.38
(s, 6 H), 1.29 (d, J = 7.1 Hz, 6 H). MS (EI, trans isomer):
m/z (%) = 264 (26.4) [M+], 246 (8.7), 178 (16.0), 166 (21.6),
165 (100). MS (EI, cis isomer): m/z (%) = 264 (17.2) [M+],
246 (5.8), 178 (13.1), 166 (17.6), 165 (100). HRMS (trans
isomer): found 264.1735; C16H24O3 requires 264.1725.
HRMS (cis isomer): found 264.1716; C16H24O3 requires
264.1725.
(8) 8-Methoxy-2,2,6,9-tetramethyl-2H-1-benzoxocin-3 (4H)-
one (6).
Mp: 66 °C.1H NMR (250 MHz, CDCl3): d = 6.88 (s, 1 H),
6.64 (s, 1 H), 5.75 (t, J = 7.5 Hz, 1 H), 3.83 (s, 3 H), 2.98 (d,
J = 7.5 Hz, 2 H), 2.21 (s, 3 H), 2.06 (s, 3 H), 1.47 (s, 6 H).
13C NMR (63 MHz, CDCl3): d = 208.65, 154.52, 145.04,
137.10, 132.82, 127.48, 126.38, 119.31, 108.46, 81.63,
55.50, 40.95, 24.59, 23.77, 16.13. IR (neat): 2984, 2938,
1713, 1504, 1464, 1395, 1205, 1152, 1022 cm–1. MS (EI):
m/z (%) = 260 (72.4)[M+], 217 (15.2), 191 (35.5), 190 (49.1),
189 (100), 176 (34.3), 175 (43.8), 159 (8.6), 115 (8.3).
HRMS: found 260.1414; C16H20O3 requires 260.1412.
(9) We noted several omissions in the reported data of this
compound.3
(12) Labib, G. H.; Cordier, P. Compt. Rend. 1957, 245, 1548.
(13) 8-Methoxy-4,4,7,9b-tetramethyl-1a,9b-dihydro-2H-
oxireno[e][1]benzoxocin-3 (4H)-one (9).
Mp: 89 °C. 1H NMR (250 MHz, CDCl3): d = 6.86 (s, 1 H),
6.79 (s, 1 H), 3.85 (s, 3 H), 3.24 (dd, J = 9.6, 4.0 Hz, 1 H),
2.89 (dd, J = 12.4, 4.0 Hz, 1 H), 2.19 (s, 3 H), 2.18–2.11 (m,
1 H), 1.58 (s, 3 H), 1.56 (s, 3 H), 1.37 (s, 3 H). 13C NMR (50
MHz, CDCl3): d = 207.96, 155.26, 144.27, 131.50, 126.82,
126.53, 109.82, 87.09, 61.25, 59.14, 55.60, 42.50, 25.64,
24.17, 23.62, 16.21. IR (neat): 2984, 2936, 1714, 1505,
1464, 1398, 1378, 1205, 1148, 1020 cm–1. MS (EI):
m/z (%) = 276 (94.5) [M+], 247 (25.0), 219 (77.1), 205
(78.0), 192 (28.7), 189 (100), 178 (15.9), 177 (16.7), 176
(28.0), 175 (50.3), 165 (87.6), 164 (39.9), 163 (39.9), 162
(41.9), 149 (32.4), 91 (26.6), 69 (22.9). HRMS: found
276.1352; C16H22O3 requires 276.1361.
8-Methoxy-2,2,6,9-tetramethyl-5,6-dihydro-2H-1-
benzoxocin-3 (4H)-one (7).
Mp: 71 °C. 1H NMR (250 MHz, CDCl3): d = 6.74 (s, 1 H),
6.58 (s, 1 H), 3.80 (s, 3 H), 3.20–3.02 (m, 1 H), 2.61–2.39
(m, 2 H), 2.15 (s, 3 H), 2.07–1.90 (m, 1 H), 1.79–1.61 (m, 1
H), 1.49 (s, 3 H), 1.45 (s, 3 H), 1.34 (d, J = 7.1 Hz, 3 H). 13
NMR (90 MHz, CDCl3): d = 212.98, 154.86, 145.96,
C
136.90, 127.46, 124.37, 108.71, 85.91, 55.45, 36.03, 34.65,
34.46, 24.36, 23.45, 20.43, 15.78. IR (neat): 3038, 2939,
2854, 1713, 1504, 1464, 1397, 1380, 1203, 1144, 1019
cm–1. MS (EI): m/z (%) = 262 (21.9) [M+], 178 (19.3), 165
(100), 163 (4.4), 91 (4.3). HRMS: found 262.1557; C16H22O3
requires 262.1568.
(14) Coogan, M. P.; Haigh, R.; Hall, A.; Harris, L. D.; Hibbs, D.
E.; Jenkins, R. L.; Jones, C. L.; Tomkinson, N. C. O.
Tetrahedron 2003, 59, 7389.
(10) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.;
Giese, B.; Kopping, B. J. Org. Chem. 1991, 56, 678.
(15) Kiyooka, S.-i.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett.
1986, 27, 3009.
Synlett 2004, No. 9, 1613–1615 © Thieme Stuttgart · New York