Enantioselective total synthesis of (-)-heliannuol A

Article abstract of DOI:10.1039/b211227b

An efficient and enantiocontrolled total synthesis of (-)-heliannuol A has been accomplished by employing ring closing metathesis and sequential diastereoselective epoxidation and regioselective reductive cleavage of the epoxide ring.

Full text of DOI:10.1039/b211227b

Enantioselective total synthesis of (2)-heliannuol A
Hidetoshi Kishuku, Mitsuru Shindo and Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan.
E-mail: shishido@ph2.tokushima-u.ac.jp
Received (in Cambridge, UK) 14th November 2002, Accepted 16th December 2002
First published as an Advance Article on the web 9th January 2003
An efficient and enantiocontrolled total synthesis of (2)-hel-
iannuol A has been accomplished by employing ring closing
metathesis and sequential diastereoselective epoxidation
and regioselective reductive cleavage of the epoxide ring.
which, fortunately, was obtained as a crystalline solid. Re-
crystallization from hexane gave the optically pure 7 in 67%
yield from 6.
Mesylation followed by cyanation produced the cyanide (8)
which was hydrolyzed to provide the carboxylic acid (9). To
differentiate between the two methoxy moieties on the aryl ring,
compound 9 was then treated with boron tribromide in
methylene chloride (CH2Cl2) to give the lactone (10), whose
phenolic hydroxy group was protected as the methoxymethyl
(MOM) ether to furnish 11. Sequential reduction with diisobu-
tylaluminium hydride (DIBAL-H) and Wittig reaction pro-
duced the phenolic alkene (4) in good overall yield.
(2)-Heliannuol A (1)1is a naturally occurring sesquiterpenoid
exhibiting strong allelopathic activity. Isolated by Macías and
coworkers from aqueous extracts of fresh sunflower leaves
(Helianthus annuus L. var. SH-222) (Fig. 1), this intriguing
natural product has a unique carbon skeleton made up of an
oxygen containing eight-membered heterocycle fused to the
aryl ring and two tertiary stereogenic centres (C-7 and 10)
whose absolute configurations were determined to be R and S,
respectively, by our enantioselective total synthesis of (+)-heli-
annuols D and A,2 the unnatural enantiomers. Here we report an
efficient enantiocontrolled total synthesis of the natural enantio-
mer (2)-heliannuol A (1).
Although the conversion4,5 of 4 into the diene (3) proved very
difficult, we were finally able to obtain the substrate for the key
RCM reaction cleanly by employing the p-allyl palladium
species generated from the mixed carbonate.6 Thus, reaction of
4 with i-butyl-2-methyl-3-buten-2-yl carbonate in the presence
of tetrakis(triphenylphosphine)palladium in THF gave the diene
(3) in 82% yield as a single product. We were then able to begin
construction of the eight-membered heterocycle via the RCM
reaction. Treatment of 3 with 10 mol% of (tricyclohexyl)-
phosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidaz-
ol-2-ylidene][benzylidene]ruthenium(IV) dichloride in CH2Cl2
at room temperature furnished the desired cyclized product (2)
in 88% yield. To evaluate the substrate-controlled diaster-
Our basic strategy is shown in Scheme 1. We envisaged a
pivotal construction of the eight-membered heterocycle in 1
employing the ring closing metathesis (RCM)3,4 of the diene
(3), in which the benzylic tertiary stereogenic centre (C-7)
would be generated via a lipase mediated asymmetric acetyla-
tion of the prochiral diol (5).2 The second stereogenic centre at
C-10 would be created by diastereoselective epoxidation of the
double bond in 2 followed by regioselective hydride reduc-
tion.
Porcin pancreatic lipase (PPL) mediated transesterification of
the prochiral diol (5) in diethyl ether using vinyl acetate as an
acetyl donor provided the (R)-monoacetate (6) in 41% yield
(94% yield based on the consumed 5) with 78% ee (HPLC on a
Chiralcel OJ column).
Removal of the hydroxy moety in 6 by tosylation and
subsequent reduction with sodium borohydride in DMSO
followed by alkaline hydrolysis furnished the alcohol (7),
Scheme 2
Fig. 1
Scheme 3 Reagents and conditions: i, TsCl, Et3N, 4-DMAP, CH2Cl2, rt; ii,
NaBH4, DMSO, 60 °C then K2CO3, MeOH (aq.), rt, iii, MsCl, Et3N,
CH2Cl2, rt; iv, KCN, KI, 18-crown-6, DMSO, 60 °C; v, NaOH, MeOH
(aq.), reflux; vi, BBr3, CH2Cl2, rt, vii, MOMCl, i-Pr2NEt, CH2Cl2, reflux;
viii, i-Bu2AlH, CH2Cl2, 278 °C; ix, Ph3P+CH3Br2, t-BuOK, toluene, rt.
Scheme 1
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on the sterically less congested carbon (C-9) regioselectively by
treatment with lithium aluminium hydride to give the alcohol
(13) in 83% yield as a single product. Finally, acidic hydrolysis
of the MOM ether produced heliannuol A (1), whose 1H NMR
and 13C NMR,‡ as well as optical rotation, [a]D 278 (c 2.4,
MeOH) {[a]D 255 (c 0.3, MeOH)}, were identical with those
of the natural product.
In summary, we have completed the first enantioselective
total synthesis of the natural enantiomer (2)-heliannuol A. The
synthetic route developed here is general and efficient and can
also be applied to the synthesis of related heliannuols.
We thank Professor Macías (University of Cádiz) for
providing us with spectral data of the natural heliannuol A.
Fig. 2 The most stable conformation calculated for 14.
Notes and references
† Molecular mechanic calculations were carried out using Titan 1.0.5
molecular modeling software (Wavefunction, Inc.), with MMFF as the
force field. The Monte Carlo conformational search was carried out without
imposing any constraints.
‡
Selected spectroscopic data for 12; colorless oil; [a]D 280 (c 0.43,
CHCl3); dH(400 MHz, CDCl3) 1.21 (3H, d, J 6.8 Hz), 1.46 (3H, s), 1.56 (3H,
s), 2.18 (3H, s), 2.33–2.20 (2H, m), 2.55 (1H, d, J 4.0 Hz), 2.96 (1H, dq, J
6.4 and 6.5 Hz), 3. 11 (1H, ddd, J 3.6, 4.0, 11.2 Hz), 3.51 (3H, s), 5.15 (2H,
dd, J 6.4, 10.2 Hz), 6.75 (1H, s), 6.77 (1H, s); dC (100 MHz, CDCl3) 15.9
(CH3), 25.0 (CH3), 27.4 (CH3), 29.4 (CH3), 34.1 (CH2), 37.2 (CH), 56.1
(CH), 57.7 (CH), 59.3 (CH), 79.7 (C), 95.0 (CH2), 116.2 (CH), 125.4 (C),
128.6 (CH), 137.7 (C), 146.3 (C), 152.2 (C); m/z (EI) 292 (M+); HRMS (EI)
calc. for C17H24O4: C, 292.1675. Found: 292.1658.
For 1; dH(400 MHz, CD3OD, 230 °C) 1.15, 1.31 (3H, s), 1.31, 1.44 (3H,
s), 1.36 (2H, m), 1.22, 1.27 (3H, d, J 6.8), 1.65, 1.88 (2H, m), 2.08, 2.10 (3H,
s), 3.23 (1H, m), 3.47, 3.56 (1H, m), 6.46, 6.51 (1H, s), 6.60, 6.65 (1H, s);
dC (100 MHz, CD3OD, 230 °C) 16.1 (CH3), 16.3 (CH3), 18.2 (CH3), 29.7
(CH3), 30.1 (CH), 31.5 (CH2), 38.5 (CH2), 78.9 (CH), 82.9 (C), 114.7 (CH),
122.3 (C), 127.5 (CH), 138.2 (C), 146.3 (C), 153.1 (C); m/z (EI) 250 (M+);
HRMS (EI) calc. for C15H22O3: C, 250.1569. Found: 250.1587.
Scheme
Pd(PH3P)6, THF, rt; ii, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphe-
nyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV dichlo-
ride, CH2Cl2, rt, iii; CF3COCH3, Oxone®, Na2·EDTA·2H2O, NaHCO3,
CH3CN, 0 °C; iv, LiAlH4, THF, rt; v, 6N HCl, THF, rt.
4 Reagents and conditions: i, i-BuOCOOC(Me)2CHNCH2,
)
eoselective epoxidation of 2, we examined a 3D model of the
energy minimum conformation† of 14, which is the methoxy
analog of 2. As shown in Fig. 2, epoxidation would proceed
from the bottom face of the double bond to afford the desired a-
epoxide.
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Oxidation of 2 with methyl(trifluoromethyl)dioxirane7 gen-
erated in situ from methyl trifluoromethyl ketone and Oxone®
in the presence of Na2·EDTA·2H2O and sodium hydrogen
carbonate in acetonitrile provided only the epoxide (12)‡ in
83% yield. The stereochemistry was confirmed by the observa-
tion of a distinct NOE correlation between the Ha (d 3.11) and
Hb (d 2.55) protons. Hydride reduction of the epoxide occurred
7 D. Yang, M. K. Wong and Y. C. Yip, J. Org. Chem., 1995, 60, 3887.
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