Strategies for the total asymmetric synthesis of heliannuols K and L: Scope and limitations

Article abstract of DOI:10.1002/ejoc.200400908

Kulinkovich reactions of oxa-esters bearing terminal double bonds afford cyclopropanols by intramolecular cyclization. These can undergo Saegusa oxidation to provide β-chlorooxacycloalkanones and can then be then dehydrohalogenated into oxacycloalkenones.

Full text of DOI:10.1002/ejoc.200400908

FULL PAPER
Strategies for the Total Asymmetric Synthesis of Heliannuols K and L:
Scope and Limitations
Frédéric Lecornué,[a] Renée Paugam,[a] and Jean Ollivier*[a]
Keywords: Asymmetric synthesis / Oxygen heterocycles / Natural products / Titanium
Kulinkovich reactions of oxa-esters bearing terminal double
bonds afford cyclopropanols by intramolecular cyclization.
These can undergo Saegusa oxidation to provide β-chloro-
oxacycloalkanones and can then be then dehydrohaloge-
nated into oxacycloalkenones. Through a judicious choice of
starting esters, diverse aryl-fused benzoxocinones possessing
the basic skeleton of sesquiterpenes, such as heliannuols,
can be obtained. Although the syntheses of certain com-
pounds in racemic form seem accessible, however, improve-
ments through new strategies are still required for the total
asymmetric synthesis. This article describes the first synthe-
sis of enantiomerically enriched OMe-heliannuol K and the
first stereo- and enantioselective synthesis of heliannuol L,
and new approaches and studies of their limitations in the
preparation of these products are detailed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The preparation of natural and environmentally friendly
bioactive products constitutes a synthetic challenge involv-
ing control over chemoselectivity, regioselectivity, and
stereoselectivity. In this area, heliannuols,[1] isolated from
sunflowers, represent a group of aryl derivatives showing
allelopathic activities. Heliannuols K (1) and L (2) (Fig-
ure 1) appeared to us to be particularly attractive natural
products in relation to our previous work on the construc-
tion of benzo-fused cyclic ethers.[2]
Figure 2. Synthesis of potential precursor 5.
stereoselective synthesis of heliannuol A, whilst no total
synthesis, racemic or asymmetric, of heliannuols K or L has
been reported in the literature. In this article we report the
scope and limitations of our procedure for the application
of the asymmetric synthesis of heliannuols K (1) and L (2).
Results and Discussion
Figure 1. Heliannuols (+)-K (1) and (–)-L (2) from Helianthus an-
nuus.
On the Synthesis of Heliannuol K
In order to preserve the integrity of the stereogenic car-
bon in the cyclopropanols 4a/4b, it would be important to
avoid dehydrohalogenation and rather to proceed by deha-
logenation. To achieve this, it proved essential to determine
experimental conditions to allow the radical 6 to be gener-
ated and trapped in situ by an appropriate reducing agent
to furnish the benzoxocinone 8 (Scheme 1).
As shown in Table 1, oxidants such as ferric or cupric
acetylacetonate[6] (Entries 1 and 2), manganese picolinate[7]
(Entry 3), and vanadyl acetylacetonate[8] (Entry 4) in the
presence of triethylsilane as hydrogen donor left the starting
material unchanged. On the other hand, the Saegusa oxi-
dation procedure[9] with one equivalent of ferric chloride
and pyridine (Entry 5) gave a diastereomeric mixture
(77:23) of the chlorides 7a and 7b (trans-7a as the major
The intramolecular titanium-mediated cyclopropanation
reaction[3] of the oxa-ω-alkenoic ester 3 gave a dia-
stereomeric mixture of the cyclopropanols 4a and 4b,
which, after oxidation and dehydrochlorination, yielded the
benzoxocinone 5 (Figure 2).[4]
However, any asymmetric center present in the oxacycle
would inevitably undergo racemization during the dehydro-
chlorination step.
To the best of our knowledge, the racemic synthesis of
an O-Me heliannuol K precursor has previously been re-
ported by Venkateswaran[5] as an intermediate in the formal
[a] Laboratoire des Carbocycles, UMR 8615, Institut de Chimie
Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Eur. J. Org. Chem. 2005, 2589–2598
DOI: 10.1002/ejoc.200400908
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F. Lecornué, R. Paugam, J. Ollivier
FULL PAPER
Scheme 2. a) ClCH2OCH3, iPr2Net, CH2Cl2, room temp. b) (EtO)2-
P(O)CH2CO2Et, NaH, THF, reflux.
The ester (E)-13, separated from its (Z) isomer by silica
gel chromatography, was readily reduced to the correspond-
ing alcohol 14. In order to test the feasibility of our pro-
cedure, nonasymmetric dihydroxylation of the double bond
was then carried out to give the expected racemic triol 10
(Scheme 3).
Scheme 1. Dechlorination without racemization.
isomer) even when ten equivalents of triethylsilane were
used. However, treatment of these chlorides 7a and 7b with
tris(trimethylsilyl)silane[10] afforded the expected oxacy-
clooctanone 8 (Entry 6).
The first strategy explored for the asymmetric synthesis
of (+)-heliannuol K (1) involved the preparation of the
enantiopure precursor 3. This compound could in turn be
derived from olefin 11, which could be prepared by dehy-
dration and reduction of triol 10. Ketone 9 would therefore
be an appropriate precursor in this retrosynthetic scheme
(Figure 3).
Scheme 3. a) DIBAH, THF, 0 °C. b) OsO4, NMO, tBuOH, H2O,
THF, 0 °C.
While conversion of vic-diols into olefins has been suc-
cessfully reported by Garegg and Samuelson,[12] and by
Lowary,[13] dehydration of the triol 10 did not give the ex-
pected alcohol 15. Likewise, regioselective benzylic hydro-
genolysis with Pearlman’s catalyst[14] did not succeed in pro-
viding diol 16 (Scheme 4).
Figure 3. Retrosynthetic scheme for the synthesis of enantiopure
oxa-ω-alkenoic ester 3.
Scheme 4. a) I2, PPh3, imidazole, THF, reflux. b) H2, Pd(OH)2/C,
EtOH, 20 °C.
Ketone 9, prepared from the commercially available 2-
methylhydroquinone,[11] was thus protected as a MOM
ether under classical conditions (protection as TBDMS
Nevertheless, both enantiopure alcohol (S)-15 and diol
ether was also effective, although in lower yield, indubitably (S)-16 could be considered as potential precursors in the
due to large steric hindrance). Wittig–Horner treatment of asymmetric synthesis of intermediate 3. Indeed, the chiral
the ketone 12 then yielded an (E/Z) mixture of the corre- carbonate deriving from the alcohol (S)-15 could undergo
sponding esters 13, the configurations of which were attrib- a palladium-catalyzed enantioselective reduction according
uted by observation of an nOe effect between the ethylenic to the Tsuji procedure[15] while dehydration[12,13] of the chi-
hydrogen and the 6-hydrogen on the aryl moiety in the (E) ral diol (S)-16 should afford the enantiopure olefin 3 (Fig-
isomer (Scheme 2).
ure 4).
Table 1. Attempts of synthesis of benzoxocinone 8 from cyclopropanols 4a,b.
Entry
Oxidant (eq.)
Solvent
Reducing agent (equiv.)
Time
Temperature
Product (yield)
1
2
3
4
5
6
Fe(acac)3 (0.1)
Cu(acac)2 (0.04)
Mn(pic)3 (2.5)
VO(acac)2 (0.3)
Et2O
EtOH
DMF or Et2O
EtOH
DMF
Et3SiH (1.3)
Et3SiH (1.3)
Et3SiH (2)
Et3SiH (2)
Et3SiH (10)
(TMS)3SiH (1.2)
100 h
72 h
24 h
24 h
24 h
2 h
20 °C
20 °C
0 Ǟ 20 °C
20 °C
0 °C
no reaction
no reaction
no reaction
no reaction
7a, 7b[b] (73%)
8[b] (52%[c])
[a]
FeCl3[a] (2.2)
FeCl3 (2.2)
PhCH3
80 °C
[a] One equivalent of pyridine was added. [b] As a diastereomeric mixture (77:23). [c] Overall yield over the two steps: chlorides 7a and
7b were isolated before reduction.
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Strategies for the Total Asymmetric Synthesis of Heliannuols K and L
FULL PAPER
Figure 4. a) ClCO2Me, pyridine. b) Pd(acac)2, HCO2 H, NEt3,
nBu3P. c) I2, PPh3, imidazole, THF, reflux. d) 6 n HCl, THF.
e) NaH, DMPU, Br(CH3)2CCO2Et, toluene, reflux.
Scheme 6. a) AD-mix-β, tBuOH, H2O, 0 °C. b*) H2, Pd(OH)2/C,
EtOH, 20 °C (* reaction performed on the racemic mesylate).
Another approach toward enantiopure (R)-3 would re-
quire oxidation and subsequent Wittig condensation of
alcohol 18, which might be derivable from diol 17 by stereo-
selective Raney nickel reduction as recently reported for the
parent compound by Pan[16] (Figure 5).
On the other hand, treatment of racemic mesylate 17a
with Pearlman’s catalyst[14] gave the expected alcohol 18a
and the dehydroxylated sulfonate 25, but in yields too low
for this route to be viable (Scheme 7).
Figure 5. Alternative retrosynthetic scheme for the synthesis of
enantiopure oxa-ω-alkenoic ester 3.
Scheme 7. a) H2, Pd(OH)2/C, EtOH, 20 °C.
In this regard, we were unable to reproduce the synthesis
of the styrenol 21 either from 4,7-dimethyl-6-methoxycou-
marin (19)[17] or by dehydration[18] of phenol 20 (prepared
from the corresponding ketone 9[19]), which only allowed
the benzopyranyl derivative 22[18a] to be isolated. Finally,
treatment of phenol 20 with methanesulfonyl chloride un-
der basic conditions[20] resulted in both dehydration of the
tertiary alcohol function and esterification of the phenol to
yield the mesylate 23 (Scheme 5).
Finally, to overcome these difficulties for the formation
of an exploitable intermediate, the direct asymmetric hydro-
genation of the benzoxocinone 5 was explored. This com-
pound was prepared as outlined in Figure 2, as in our pre-
vious work.[4]
However, when the oxidation of the cyclopropanols 4a
and 4b was carried out in ether, the benzofuran 26 was iso-
lated in addition to the chlorides 7a and 7b. Its formation,
not observed in DMF, follows a radical process, proceeding
first by a classic homolytic scission of an internal cyclopro-
pane bond (the chlorides 7a and 7b are formed by halogen
trapping at this stage[25]). Homolytic rupture involving a
new ring closure then occurs, with formation of enone 26
by base-induced proton elimination (Scheme 8).
Scheme 5. a) KOH, ethane-1,2-diol, reflux. b) I2, C6H6, reflux, or
MgSO4, C6H6, reflux or p-toluenesulfonic acid, CH2Cl2, reflux.
c) MeSO2Cl, NEt3, DMAP.
Subsequent Sharpless asymmetric dihydroxylation[21] of
mesylate 21 furnished the optically active diol (R)-17a, de- Scheme 8. a) FeCl3, pyridine, Et2O, 0 °C. b) FeCl3, pyridine, DMF,
0 °C.
termination of the enantiomeric excess of which failed by
HPLC, but was accomplished through the Mosher ester de-
rivatives[22] (racemic diol 17a was prepared by a sodium
periodate/ruthenium chloride procedure[23]). However, ap-
In the light of research into the asymmetric hydrogena-
plication of the Pan procedure[16] to racemic mesylate 17a tion of unactivated arylalkenes, the optically active iridium
only furnished the diol 24, resulting from removal of the complexes [mainly the borate 27 (Figure 6)] proposed by
methanesulfonic group, a reaction already reported in the Burgess[26] appeared to be the best candidates for chiral in-
literature[24] (Scheme 6).
ductors for this type of compound.
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F. Lecornué, R. Paugam, J. Ollivier
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Scheme 10. a) (S,S)-Jacobsen manganese complex, p-phenylpyri-
dine N-oxide, NaOCl, CH2Cl2, 4 °C. b) Shi procedure: d-fructose
derivative, nBu4NHSO4, oxone, K2CO3, CH3CN-DMM, 0 °C.
c) H2, Pd/C, MeOH, EtOAc, 20 °C.
Figure 6. Iridium complex 27 used for asymmetric hydrogenation.
Hydrogenation of alkene 5 in the presence of catalyst 27
under atmospheric pressure achieved no reduction of the
ethylenic carbon–carbon bond. After three hours at 50 bar,
however, reduction had occurred to yield benzoxocinone 8.
Rotational analysis showed that only a weak asymmetric
induction had been achieved. Moreover, a negative rota-
tional value clearly indicated the unexpected (S) configura-
tion for the major enantiomer, contrary to Burgess’s predic-
tion[26] (Scheme 9). In addition, demethylation effected un-
der standard conditions (vide supra)[27] gave an inextricable
mixture in which the presence of heliannuol K (1) was un-
detectable.
Minimized molecular modeling calculation geometries[31]
performed on the more stable conformation predicted a di-
hedral angle of 85° between 5-H and 6-H for the cis rela-
tionship, while an angle of 165°, with a 3J coupling constant
of 7 or 8 Hz, was predicted for the corresponding trans rela-
tionship (Figure 7). Moreover, cross correlation peaks be-
tween 5-H (δ = 4.08 ppm) and 6-H (δ = 3.41 ppm) in the
NMR NOESY experiment clearly confirmed the cis rela-
tionship between these two hydrogens.
Scheme 9. a) H2, Pd/C, 0.1 equiv. 27, 50 bar, CH2Cl2, 20 °C.
b) EtSNa, DMF, 140 °C.
Further exploration to improve this synthesis will there-
fore be necessary. Finally, the best method to achieve an
efficient total enantioselective synthesis of heliannuol K
should be the oxidation of the alcohol function of the oxa-
cycle of heliannuol A (heliannuol A differs from helian-
nuol K only in the presence of a hydroxy function instead
of the ketone). The asymmetric synthesis of both enantio-
mers of heliannuol A has been previously reported in the
literature by Shishido.[28]
Figure 7. PM3-minimized geometries of (5S,6R)- and (5S,6S)-29.
Reduction of the ketone function of the oxacyclooc-
tanone 29 with DIBAH at –78 °C furnished the diol 30 with
total and expected stereoselectivity, while a weaker selectiv-
ity (77:23) occurred with sodium borohydride. Finally, de-
methylation[27] of ether 30 afforded (–)-heliannuol L (2)
with retention of the integrity of all stereogenic centers
(Scheme 11).
On the Synthesis of Heliannuol L
The asymmetric epoxidation of the benzoxocinone 5 was
performed by both the Jacobsen[29] and the Shi[30] pro-
cedures and furnished the epoxide 28 in 19% and 43%
yields, respectively. Ees of 91% were determined by HPLC
for both procedures, however. As reported in our previous
work,[4] regioselective hydrogenolysis yielded the homoben-
Scheme 11. a) DIBAH, THF, –78 °C. b) EtSNa, DMF, 140 °C.
Conclusions
1
zylic alcohol 29 as a single isomer, as observed by H and
We report in this article on our studies on some novel
13C NMR spectroscopy. Surprisingly, a 0.3 Hz coupling approaches in the total enantiomerically enriched synthesis
constant between the protons in position C-5 and C-6 of of heliannuols K and L. The major difficulties encountered
the oxacycle suggests a dihedral angle close to 90° during this work are also reported. In the case of helian-
(Scheme 10).
nuol K, a number of problems were encountered; firstly, es-
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Strategies for the Total Asymmetric Synthesis of Heliannuols K and L
FULL PAPER
6-Methoxy-2,2,5,8-tetramethyl-8,8a-dihydro-1H-benzo[b]cyclopropa-
[e]oxepin-1a(2H)-ol (4a and 4b): BrTi(OiPr)4 (0.3 mL, 0.98 mmol)
and then, over a period of 4 h, a ethereal solution of cyclohex-
ylmagnesium chloride (1.57 m, 2.5 mL, 3.9 mmol) were added suc-
cessively to a solution of oxaester 3 (300 mg, 0.98 mmol) in THF
(25 mL). After additional stirring for 1 h, the mixture was diluted
with diethyl ether (25 mL), hydrolyzed at 0 °C with saturated aque-
ous NH4Cl solution (3 mL), and vigorously stirred for 1 h. After
filtration through Celite, drying over magnesium sulfate, and con-
centration, the residue was chromatographed on silica gel (toluene/
tablishing the stereogenic center early did allow an accept-
able yield of an enantiomerically enriched precursor of heli-
annuol K to be obtained, but the direct asymmetric hydro-
genation of a potential precursor by use of chiral metallic
complexes as would be predicted proved disappointing.
Moreover, the impossibility of generating the phenolic func-
tion by removal of the methoxy group under classical meth-
ods requires that new procedures with other protecting
groups have to be explored. In contrario, the first total race-
mic and enantiomeric synthesis of (–)-heliannuol L was diethyl ether, 98:2, then petroleum ether/diethyl ether, 80:20 then
50:50) to give the cyclopropanol 4a (56 mg, 22%) and the cyclopro-
panol 4b (54 mg, 21%) as colorless oils.
fruitfully achieved from the same precursor as used in the
first optically active synthesis of (–)-OMe-heliannuol K.
1
Isomer 4a: H NMR (250 MHz, CDCl3): δ = 6.74 (s, 1 H), 6.59 (s,
3
3
1 H), 3.82 (s, 3 H), 2.79 (dq, J = 7.3, J = 6.7 Hz, 1 H), 2,16 (s, 3
3
H), 1.80 (s, 1 H), 1.50 (s, 3 H), 1.47 (d, J = 7.3 Hz, 3 H), 1.35 (s,
3 H), 1.31–1.14 (m, 1 H), 0.99 (dd, cisJ = 10.7 Hz, gemJ = 5.2 Hz,
1 H), 0.74 (dd, transJ = 6.1 Hz, gemJ = 5.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 154.1, 146.8, 137.6, 123.8, 126.3, 107.2, 77.5,
Experimental Section
General Remarks: Melting points (uncorrected) were determined
with a Büchi B-545 apparatus. Polarimetric measurements were
performed on a Perkin–Elmer 241 polarimeter. FT-IR: Perkin–El-
mer spectrophotometer (Spectrum One). 1H NMR: Bruker
AM 250 (250 MHz), AM 360 (360 MHz), AC 250 (250 MHz),
AC 200 (200 MHz), or DRX 400 (400 MHz): δ = 7.27 ppm for
CHCl3 as internal standard. 13C NMR: Bruker AM 250 (63 MHz),
AM 360 (90 MHz), AC 250 (63 MHz), AC 200 (50.3 MHz): δ =
77 ppm relative to the resonance of the solvent (CDCl3). The
DEPT-135 pulse was used for the determination of signal types.
MS (Electronic Impact or Chemical Ionization): Nermag R-10 cou-
pled with a OK1 DP 125 gas chromatograph. Relative percentages
are shown in brackets; High Resolution Mass Spectra were re-
corded with a Finningan MAT 95S instrument (Electronic Impact
or ElectroSpray). Elemental analysis were performed with a Per-
kin–Elmer 240C analyzer by the Service de Microanalyse, Institut
de Chimie des Substances Naturelles, Gif-sur-Yvette (France). The
enantiomeric excesses were determined by GPC (Cydex-B) or by
HPLC (Chiracel OD-H column) or by 19F NMR of Mosher esters
62.3, 55.6, 36.0, 34.2, 27.4, 25.4, 18.3, 15.7, 21.0 ppm. IR (neat): ν
˜
= 3391, 2960, 2934, 1505 cm–1. MS EI, m/z = 262 [M]+· (41), 260
(13), 229 (13), 206 (28), 191 (74), 178 (29), 177 (100); 165 (83), 164
(54), 163 (19), 149 (26), 149 (16), 91 (10). HRMS EI: found
262.1564; C16H22O3 requires 262.1568.
1
Isomer 4b: H NMR (250 MHz, CDCl3): δ = 6.66 (s, 1 H), 6.49 (s,
3
3
1 H), 3.79 (s, 3 H), 3.44 (dq, J = 7.9, J = 7.3 Hz, 1 H), 2.14 (s, 3
H), 1.94 (s, 1 H), 1.60 (m, 1 H), 1.48 (s, 3 H), 1.26 (s, 3 H), 1.22
(d, 3J = 7.9 Hz, 3 H), 0.83 (dd, transJ = 7.3 Hz, gemJ = 5.5 Hz, 1 H),
0.69 (dd, cisJ = 11.0 Hz, gemJ = 5.5 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 154.1, 145.9, 136.1, 124.5, 126.5, 110.1, 77.9,
64.7, 55.6, 33.1, 30.1, 26.6, 24.2, 22.7, 15.6, 13.3 ppm. IR (neat): ν
˜
= 3392, 2975, 2932, 1505 cm–1. MS EI, m/z = 262 [M]+· (46), 191
(23), 178 (18), 177 (100), 176 (36), 165 (32), 164 (17), 149 (22), 91
(7). HRMS EI: found 262.1576; C16H22O3 requires 262.1568.
8-Methoxy-2,2,6,9-tetramethyl-2H-1-benzoxocin-3(4H)-one (5): Cy-
clopropanols 4a/4b (71 mg, 0.27 mmol) in dimethylformamide
(1 mL) were added dropwise under argon at 0 °C to a solution of
anhydrous ferric(iii) chloride (97 mg, 0,6 mmol) and pyridine
(0.22 mL, 0.27 mmol) in dimethylformamide (3 ml). After stirring
for 4 h at this temperature, the mixture was diluted with ethyl ace-
tate (5 mL), H2O (1 mL), and aqueous HCl solution (1 n, 1 mL).
The aqueous phase was separated and extracted with ethyl acetate
(3×15 mL). The combined organic layers were washed with H2O
(10 mL), dried over magnesium sulfate, and concentrated. DBU
(0.085 mL, 0.54 mmol) was added dropwise at –10 °C to the crude
residue dissolved in diethyl ether (10 ml), and the mixture was left
to warm to room temperature and stirred overnight. After it had
again been cooled to 0 °C, diethyl ether (5 mL) and H2O (3 mL)
was added. The aqueous phase was extracted with diethyl ether
(3×10 mL), and the combined organic layers were washed with
brine (5 mL), dried over magnesium sulfate, concentrated, and
chromatographed on silica gel (eluent: petroleum ether/diethyl
ether, 98:2) to give the expected ketone 5 (38.5 mg, 55%) as a white
solid.[4]
1
or by H NMR with the chiral shift reagent: (+)-europium tris[3-
(heptafluoropropylhydroxymethylene)camphorate]. Solvents were
dried by standard procedures. All reactions requiring anhydrous
conditions were performed under argon.
Ethyl 2-[4-Methoxy-5-methyl-2-(1-methylprop-2-enyl)phenoxy]-2-
methylpropanoate (3): DMPU (2.4 mL, 19.8 mmol) and 4-methoxy-
5-methyl-2-(1-methylprop-2-enyl)phenol (prepared from the 2-
methylanisole[32]) (1.9 g, 9.9 mmol) were successively added under
argon at 20 °C to a solution of 60% sodium hydride suspension
(514 mg, 12.8 mmol) in anhydrous toluene (105 mL). After the mix-
ture had been stirred for 15 min, ethyl bromoisobutyrate (2.18 mL,
14.8 mmol) was added and the mixture was heated at reflux for
60 h. After cooling, filtration, and washing with toluene, the resi-
due was concentrated and chromatographed on silica gel (eluent:
petroleum ether/diethyl ether, 95:5 then 70:30) to furnish the oxa-
ester 3 (2.4 g, 80%) as a pale yellow oil. 1H NMR (250 MHz,
CDCl3): δ = 6.60 (s, 1 H), 6.56 (s, 1 H), 6.02 (ddd, transJ = 17.0 Hz,
3
3
cisJ = 11.0, J = 5.5 Hz, 1 H), 5.06 (m, 2 H), 4.28 (q, J = 7.1 Hz,
3
3
2 H), 3.95 (dq, J = 6.8, J = 5.5 Hz, 1 H), 3.77 (s, 3 H), 2.12 (s, 3
H), 1.56 (s, 3 H), 1.52 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.30 (d,
trans- and cis-5-Chloro-8-methoxy-2,2,6,9-tetramethyl-5,6-dihydro-
2H-1-benzoxocin-3(4H)-one (7): The cyclopropanols 4a/4b (74 mg,
3
3J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 174.7, 0.28 mmol) in dimethylformamide (1 mL) were added dropwise un-
152.8, 145.7, 142.9, 135.0, 124.2, 120.5, 112.7, 109.3, 79.2, 61.2,
55.4, 35.5, 25.6, 24.9, 19.0, 16.0, 14.0 ppm. IR (neat): ν = 3082,
der argon at 0 °C to a solution of ferric(iii) chloride (100 mg,
0.62 mmol) and pyridine (0.024 mL, 0.28 mmol) in dimethylform-
˜
2981, 2936, 1735, 1501 cm–1. MS EI, m/z = 306 [M]+· (45), 193 (11), amide (3 mL). After stirring for 3 h at the same temperature, the
192 (98), 191 (57), 178 (11), 177 (100), 159 (7). HRMS EI: found
306.1821; C18H26O4 requires 306.1830.
reaction mixture was diluted with H2O (3 mL), aqueous HCl solu-
tion (1 n, 0.5 mL), and diethyl ether (5 mL). The organic phase was
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F. Lecornué, R. Paugam, J. Ollivier
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washed with H2O (3×1 mL) and dried over anhydrous sulfate, and
the solvents were evaporated. The crude residue was then purified
by chromatography on silica gel (eluent: pentane/diethyl ether, 96:4
then 93:7) to furnish the trans-chloride 7a (14 mg, 17%) and the
cis-chloride 7b (47 mg, (56%) as colorless oils.
solution (6 n, 2×10 mL) and brine (10 mL). The organic layer was
dried over magnesium sulfate, evaporated, and flash chromato-
graphed on silica gel (petroleum ether/diethyl ether, 92:8 then
70:30) to give pure MOM-ether 12 (0.87 g, 70%) as a yellow solid,
m.p. 39–40 °C. 1H NMR (250 MHz, CDCl3): δ = 7.24 (s, 1 H), 7.00
(s, 1 H), 5.22 (s, 2 H), 3.83 (s, 3 H), 3.52 (s, 3 H), 2.65 (s, 3 H),
2.24 (s, 3 H) ppm. 13C NMR (CDCl3, 90 MHz): δ = 198.6, 152.3,
150.8, 133.5, 126.2, 117.8, 110.3, 94.9, 56.2, 55.5, 31.8, 16.5 ppm.
C12H16O4 requires 224.1048; calcd. C 64.27, H 7.19; found 64.05,
H 7.24.
1
trans-7a: H NMR (250 MHz, CDCl3): δ = 6.78 (s, 1 H), 6.66 (s, 1
3
3
H), 4.41 (dt, J = 4.0, J = 11.1 Hz, 1 H), 3.83 (s, 3 H), 3.60–3.42
(m, 1 H), 2.97 (broad s, 1 H), 2.65 (dd, gemJ = 11.5, J = 4.0 Hz, 1
3
H), 2.18 (s, 3 H), 1.53 (d, 3J = 9.5 Hz, 3 H), 1.50 (broad s, 6
H) ppm. 13C NMR (CDCl3, 90 MHz): δ = 207.4, 162.1, 145.8,
131.7, 125.9, 127.3, 110.9, 85.2, 62.9, 55.6, 44.2, 30.3, 23.7, 23.0,
Ethyl (2E)- and (2Z)-3-[5-Methoxy-2-(methoxymethoxy)-4-methyl-
phenyl]but-2-enoate (13): Triethyl phosphonoacetate (0.22 mL,
1.12 mmol) was added dropwise under argon at 0 °C to a solution
of sodium hydride suspension (60%, 42 mg, 1.03 mmol) in tetra-
hydrofuran (1.5 mL). After the mixture had been stirred for 10 min,
the ketone 12 (193 mg, 0.86 mmol) in tetrahydrofuran (1 mL) was
added dropwise at the same temperature. After having been heated
for 3 h, the mixture was cooled to 0 °C and diethyl ether (10 mL)
and H2O (3 mL) were added. The aqueous phase was extracted
with diethyl ether (3 × 20 mL) and the combined organic layers
were washed with brine (5 mL), dried over magnesium sulfate, con-
centrated, and purified by flash chromatography on silica gel (elu-
ent: petroleum ether/diethyl ether, 93:7 then 70:30) to give ester (E)-
13 (200 mg, 79%) as a white solid and ester (Z)-13 (27 mg, 11%)
as a colorless oil.
15.9 ppm. IR (neat): ν = 2982, 2936, 1714, 1503 cm–1. MS EI, m/z
˜
= 298 [M]+· (9), 296 [M]+· (30), 260 (26), 191 (47), 177 (25), 176
(27), 165 (100), 91 (5), 69 (7). HRMS EI: found 296.1170;
C16H21ClO3 requires 296.1179.
cis-7b: 1H NMR (250 MHz, CDCl3): δ = 6.75 (s, 1 H), 6.51 (s, 1
H), 4.95 (t, 3J = 8.5 Hz, 1 H), 3.78 (s, 3 H), 3.32–3.08 (m, 2 H),
3
2.82 (dd, gemJ = 15.5, J = 10.3 Hz, 1 H), 2.14 (s, 3 H), 1.55 (s, 3
H), 1.49 (d, 3J = 6.9 Hz, 3 H), 1.46 (s, 3 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 207.8, 155.1, 145.3, 133.9, 125.8, 127.5,
110.9, 86.0, 61.9, 55.5, 47.6, 46.9, 25.1, 23.6, 21.7, 15.9 ppm. IR
(neat): ν = 2977, 2934, 1714, 1504 cm–1. MS EI, m/z = 298 [M]+·
˜
(7), 296 [M]+. (25), 260 (19), 191 (32), 177 (31), 176 (100), 165
(71), 161 (18). HRMS EI: found 296.1173; C16H21ClO3 requires
296.1179.
1
Isomer (2E)-13: M.p. 35–36 °C. H NMR (250 MHz, CDCl3): δ =
8-Methoxy-2,2,6,9-tetramethyl-5,6-dihydro-2H-1-benzoxocin-3(4H)-
one (8)
3
6.94 (s, 1 H), 6.62 (s, 1 H), 5.91 (s, 1 H), 5.09 (s, 2 H), 4.22 (q, J
= 7.1 Hz, 2 H), 3.80 (s, 3 H), 3.48 (s, 3 H), 2.52 (s, 3 H), 2.21 (s, 3
a) From the Chlorides 7a/7b: AIBN (5 mg, 0.026 mmol) and tris(tri-
methylsilyl)silane (0.1 mL, 0.31 mmol) were added successively at
20 °C to a solution of the chloro ketones 7a/7b (78 mg, 0.26 mmol)
in anhydrous toluene (1 mL). The mixture was heated at 80 °C for
2 h, and then cooled. The residue was concentrated and chromato-
graphed on neutral alumina (eluent: petroleum ether/diethyl ether,
98:2 then 95:5) to give the expected ketone 8 (44 mg, 80%) as a
white solid.[4]
3
H), 1,32 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz):
δ = 166.5, 156.4, 152.4, 147.2, 131.7, 127.6, 119.0, 118.5, 110.4,
95.3, 59.5, 55.8, 55.5, 19.9, 16.0, 14.1 ppm. IR (neat): ν = 2979,
˜
2829, 1714, 1634, 1505 cm–1. MS EI, m/z = 294 [M]+· (26), 262 (16),
233 (50), 219 (21), 216 (37), 204 (100), 189 (40), 176 (68), 161 (59),
45 (86). HRMS EI: found 294.1471, C16H22O5 requires 294.1467;
calcd. C 65.29, H 7.53; found 64.76, H 7.57.
Isomer (2Z)-13: 1H NMR (250 MHz, CDCl3): δ = 6.94 (s, 1 H),
6.50 (s, 1 H), 5.96 (s, 1 H), 5.05 (s, 2 H), 4.00 (q, 3J = 7.1 Hz, 2
H), 3.77 (s, 3 H), 3.46 (s, 3 H), 2.20 (s, 3 H), 2.17 (s, 3 H), 1.08 (t,
3J = 7.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 165.5,
153.0, 152.9, 146.3, 129.2, 126.7, 118.9, 118.5, 109.8, 95.7, 59.5,
b) From the Benzoxocinone 5: Pd/C (10%, 5 mg) was added to a
solution of enone 5 (20 mg, 0.07 mmol) in ethyl acetate (1 mL) and
the mixture was stirred at 20 °C for 3 days under hydrogen atmo-
sphere. After filtration through Celite and concentration, the resi-
due was chromatographed on silica gel (eluent: petroleum ether/
diethyl ether, 93:7) to furnish the expected ketone 8 (20 mg, 98%).
55.8, 55.7, 26.3, 16.2, 13.9 ppm. IR (neat): ν = 2953, 2854, 1728,
˜
1715, 1646, 1505 cm–1. MS EI, m/z = 294 [M]+· (47), 262 (13, 233
(41), 219 (21), 216 (31), 205 (42), 204 (100), 189 (28), 176 (68),
161 (59), 45 (44). HRMS EI: found 294.1471, C16H22O5 requires
294.1467.
c) Asymmetric Route: Iridium complex 27 (1.1 mg, 0.077 μmol) was
added to a solution of enone 5 (20 mg, 0.07 mmol) in chloroform
(2 mL), and the test tube was placed in a bomb, which was pressur-
ized to 50 bar with hydrogen. After its contents had been stirred at
20 °C for 3 h, the bomb was vented and the mixture was evaporated
and chromatographed on silica gel as previously reported to give
the enantiomerically enriched benzoxocinone (S)-8 (19 mg, 95%)
with an enantiomeric excess of 14% as determined by use of euro-
pium chiral reagent. The enantiomeric purity determination was
carried out by 1H NMR in the presence of increasing amounts
(from 10 mol% to 100 mol%) of the shift reagent [(+)-Eu(hfc)3].
The singlet of the methoxy protons gave a double set of signals in
the racemic benzoxocinone 8. [α]2D0 = –5.2 (c = 0.95, CHCl3).
(2E)-3-[5-Methoxy-2-(methoxymethoxy)-4-methylphenyl]but-2-en-1-
ol (14): A DIBAH solution in toluene (1 m, 1.75 mL, 1.75 mmol)
was added dropwise at 0 °C under argon to a solution of ester
(E)-13 (223 mg, 0.76 mmol) in anhydrous tetrahydrofuran (1 mL).
After stirring for 2 h at the same temperature, the mixture was
quenched by addition of an aqueous HCl solution (2 n, 1 mL) and
diluted with ethyl acetate (15 mL). The aqueous phase was ex-
tracted with ethyl acetate (3×10 mL), and the combined organic
layers were washed with brine (3 mL), dried over magnesium sul-
fate, evaporated, and flash chromatographed on silica gel (eluent:
petroleum ether/diethyl ether, 80:20 then 70:30) to yield the ex-
pected allylic alcohol 14 (181 mg, 95%) as a colorless oil. 1H NMR
1-[5-Methoxy-2-(methoxymethoxy)-4-methylphenyl]ethanone (12):
N,N-Diisopropylethylamine (1.94 mL, 11.1 mmol) and chlorometh-
oxymethane (0.85 mL, 11.1 mmol) were added dropwise and suc-
cessively under argon at 0 °C to a solution of 2-hydroxy-5-methoxy-
4-methylacetophenone (9, 1 g, 5.55 mmol) in dichloromethane
(15 mL). After stirring for 5 d at 20 °C, the mixture was diluted
with dichloromethane (20 mL) and treated with aqueous NaOH
3
(250 MHz, CDCl3): δ = 6.91 (s, 1 H), 6.63 (s, 1 H), 5.70 (dt, J =
6.8, 4J = 1.5 Hz, 1 H), 5.09 (s, 2 H), 4.35 (d, 3J = 6.8 Hz, 2 H),
3.80 (s, 3 H), 3.48 (s, 3 H), 2.20 (s, 3 H), 2.06 (s, 3 H), 1.57 (s, 1
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 152.5, 147.3, 137.8,
132.7, 126.2, 128.2, 118.5, 111.4, 95.5, 60.0, 55.9, 55.6, 17.4,
2594
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2589–2598

Strategies for the Total Asymmetric Synthesis of Heliannuols K and L
FULL PAPER
16.0 ppm. IR (neat): ν = 3418, 2952, 1652, 1505 cm–1. MS EI, m/z
1.17 mmol) in tetrahydrofuran (4 mL). The resulting solution was
allowed to stir at 20 °C for two hours and was then cooled to 0 °C,
diethyl ether (10 mL) was added, and the mixture was quenched by
addition of a saturated aqueous NH4Cl solution (2 mL). The aque-
ous phase was then extracted with ethyl acetate (3×5 mL), and the
combined organic layers were washed with brine (7 mL), dried over
magnesium sulfate, and concentrated. Triethylamine (0.98 mL,
7 mmol) and DMAP (11.5 mg, 0.09 mmol) were added at 20 °C
under argon to the crude residue, diluted with 6 mL of diethyl
ether. Methanesulfonyl chloride (0.4 mL, 3.5 mmol) was then
added dropwise at 0 °C, and the solution was allowed to stir at
20 °C for one hour. After extraction of the aqueous phase with
ethyl acetate (3 × 10 mL), the combined organic phases were
washed with brine (5 m), dried over magnesium sulfate, concen-
trated, and chromatographed on silica gel (eluent: petroleum ether/
ethyl acetate, 92:8 then 85:15) to give the expected mesylate 23
˜
= 252 [M]+· (7), 234 (25), 202 (35), 201 (25), 190 (54), 189 (100),
176 (23), 175 (84), 115 (11), 45 (28). HRMS EI: found 252.1356,
C14H20O4 requires 252.1361.
3-[5-Methoxy-2-(methoxymethoxy)-4-methylphenyl]butane-1,2,3-
triol (10): NMO (151 mg, 1.28 mmol) and an aqueous OsO4 solu-
tion (4%, 0.054 mL, 0.22 mmol) were successively added at 20 °C
to a solution of allylic alcohol (E)-14 (108 mg, 0.43 mmol) in a tert-
butanol/THF/H2O mixture (7:2:1, 4.2 mL). After this mixture had
been stirred for 3 days at the same temperature, a saturated aque-
ous Na2S2O3 solution (5 mL) was added. The aqueous phase was
then extracted with AcOEt (3×15 mL), and the combined organic
layers were successively washed with an aqueous Na2S2O3 solution
(0.1 m, 10 mL), an aqueous HCl solution (0.1 m, 10 mL), and H2O
(10 mL). After drying over magnesium sulfate and concentration
the residue was purified by flash chromatography on silica gel (elu-
ent: petroleum ether /ethyl acetate, 20:80 then 0:100) to give the
1
(198 mg, 66%) as a pale yellow oil. H NMR (250 MHz, CDCl3):
δ = 7.14 (s, 1 H), 6.70 (s, 1 H), 5.27 (broad s, 1 H), 5.16 (broad s,
1 H), 3.84 (s, 3 H), 3.05 (s, 3 H), 2.21 (s, 3 H), 2.14 (s, 3 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 156.1, 141.9, 138.8, 134.6, 127.0,
1
triol 10 (73 mg, 55%) as a yellow solid, m.p. 72–73 °C. H NMR
3
(250 MHz, CDCl3): δ = 6. 92 (s, 1 H), 6.65 (s, 1 H), 5.72 (t, J =
4.2 Hz, 1 H), 5.13 (s, 2 H), 4.38 (d, 3J = 4.2 Hz, 2 H), 3.85 (s, 3
H), 3.51 (s, 3 H), 2.27 (s, 3 H), 2.08 (s, 3 H), 1.61 (broad s, 3
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 152.4, 146.6, 130.9,
126.3, 117.0, 108.9, 94.6, 77.1, 73.7, 63.8, 56.0, 55.8, 25.3,
124.7, 116.9, 116.4, 54.4, 37.5, 23.1, 15.7 ppm. IR (neat): ν = 3084,
˜
2938, 1501 cm–1. MS EI, m/z = 256 [M]+· (42), 177 (100), 149 (56),
119 (14), 91 (13). HRMS EI: found 256.0761; C22H28O4 requires
256.0769.
15.9 ppm. IR (KBr): ν = 3419, 2936, 1505 cm–1. MS ES, m/z =
˜
309.1 [M + Na]+. HMRS ES+: found 309.13098; C14H22O6Na re-
(2R)-2-{5-Methoxy-4-methyl-2-[(methylsulfonyl)oxy]phenyl}-
quires 309.13140; calcd. C 58.73, H 7.74; found 58.55, H 7.44.
propane-1,2-diol (17a)
a) Racemic Procedure: A solution of sodium periodate (150 mg,
0.7 mmol) and ruthenium chloride hydrate (6.8 mg, 0.03 mmol) in
water (1 mL) was added at 0 °C to a solution of sulfonate 23
(120 mg, 0.47 mmol) in an ethyl acetate/acetonitrile mixture (1:1,
5.5 mL). After the mixture had been stirred at this temperature for
1 h, a saturated aqueous Na2S2O3 solution (7 mL) was added and
the aqueous phase was extracted with ethyl acetate (3×10 mL).
The combined organic layers were dried over magnesium sulfate,
concentrated, and chromatographed on silica gel (eluent: pentane/
ethyl acetate, 5:95) to furnish the expected racemic diol 17a (87 mg,
64%) as a white solid.
4-Methoxy-2-(6-methoxy-2,4,4,7-tetramethyl-3,4-dihydro-2H-1-
benzopyran-2-yl)-5-methylphenol (22)
a) I2/C6H6: A solution of phenol 20 (330 mg, 1.68 mmol) and iod-
ine (5 mg, 0.2 mmol) in benzene (7 mL) was heated at reflux for
5 h. After cooling, the organic phase was successively washed with
a saturated aqueous Na2S2O3 solution (2×5 mL), H2O (5 mL), and
brine (5 mL), and then dried over magnesium sulfate and concen-
trated. After flash chromatography on silica gel (eluent: pentane
ether/diethyl ether, 92:8 then 80:20), dimer 22 (140 mg, 47%) was
obtained as a white solid.
Magnesium Sulfate/C6H6: A solution of phenol 20 (330 mg,
1.68 mmol) and magnesium sulfate (1.51 g, 12.6 mmol) in benzene
(10 mL) was heated at reflux for 24 h. After cooling, the organic
phase was filtered, evaporated, and flash chromatographed as pre-
viously to give dimer 22 (143 mg, 48%).
b) Asymmetric Procedure: A solution of AD-mix-β (1.076 g) in a
H2O/tBuOH mixture (1:1, 7.7 mL) was allowed to stir at 20 °C for
two hours. After the mixture had been cooled to 0 °C, the sulfonate
23 (197 mg, 0.77 mmol) was added and the solution was stirred at
this temperature for 48 h. Sodium sulfite (1.15 g, 0.92 mmol) and
ethyl acetate (5 mL) were then added and the aqueous phase was
extracted with ethyl acetate (3×10 mL). The combined organic lay-
ers were dried over magnesium sulfate, concentrated, and chro-
matographed on silica gel (eluent: pentane/ethyl acetate, 35:65) to
give the diol 17a (194 mg, 87%) as a white solid with an enantio-
meric excess of 88% as determined by 19F NMR on the Mosher
ester derivatives; m.p. 107–108 °C. [α]2D0 = +1.8 (c = 1.01, CHCl3).
1H NMR (200 MHz, CDCl3): δ = 7.20 (s, 1 H), 7.16 (s, 1 H), 4.10
(d, gemJ = 11.5 Hz, 1 H), 3.85 (s, 3 H), 3.70 (d, gemJ = 11.5 Hz, 1
H), 3.27 (s, 3 H), 3.13 (broad s, 2 H), 2.20 (s, 3 H), 1.54 (s, 3
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 155.9, 138.9, 134.6,
127.3, 123.5, 109.8, 74.5, 69.3, 55.5, 38.7, 25.0, 15.7 ppm. IR (KBr):
p-Toluenesulfonic Acid/CH2Cl2: A solution of phenol 20 (98 mg,
0.5 mmol) and TsOH (60 mg, 0.5 mmol) in CH2Cl2 (5 mL) was
heated at reflux for 2 h. After filtration, the organic phase was
washed with H2O (5 mL) and brine (5 mL), dried over magnesium
sulfate, and concentrated. The residue was then flash chromato-
graphed as previously to give dimer 22 (36 mg, 40%), m.p. 102–
103 °C (ref.[18a] 105–106 °C). 1H NMR (360 MHz, CDCl3): δ = 7.71
(s, 1 H), 6.74 (s, 1 H), 6.69 (s, 1 H), 6,64 (s, 1 H), 6,62 (s, 1 H),
2
3.79 (s, 3 H), 3.75 (s, 3 H), 2.56 (d, J = 14.5 Hz, 1 H), 2.17 (s, 3
2
H), 2.15 (s, 3 H), 2.04 (d, J = 14.5 Hz, 1 H), 1.69 (s, 3 H), 1.43 (s,
3 H), 1.22 (s, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 152.7,
150.8, 147.4, 143.9, 129.1, 127.2, 127.0, 126.1, 119.5, 119.4, 109.3,
107.9, 80.2, 55.9, 55.7, 47.1, 32.4, 32.3, 31.1, 28.1, 15.7, 15.5 ppm.
ν = 3521, 2939, 1505, 1499 cm–1. MS EI, m/z = 290 [M]+· (1), 259
˜
IR (KBr): ν = 3399, 2956, 2925, 2832, 2864, 1499 cm–1. MS EI,
˜
(33), 181 (11), 180 (100), 165 (47), 151 (11). HRMS EI: found
290.0821; C12H18O6S requires 290.0824; calcd. C 49.64, H 6.25;
found C 49.69, H 6.28.
m/z = 356 [M]+· (32), 203 (8), 179 (86), 178 (100), 163 (18). HRMS
EI: found 356.1978, C22H28O4 requires 356.1987.
2-Isoproprenyl-4-methoxy-5-methylphenylmethanesulfonate (23): A 2-(3-Methoxy-4-methylphenyl)propane-1,2-diol (24): Raney nickel
methylmagnesium bromide solution in tetrahydrofuran (3 m, 0.980
mol, 2.93 mmol) was added dropwise at 0 °C under argon to a solu-
tion of 2-hydroxy-5-methoxy-4-methylacetophenone[11] (211 mg,
(400 mg), previously washed with ethanol, was added at 20 °C to a
solution of diol 17a (167 mg, 0.57 mmol) in ethanol (7 mL). After
having been heated at reflux for 48 h, the cooled mixture was con-
Eur. J. Org. Chem. 2005, 2589–2598
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2595

F. Lecornué, R. Paugam, J. Ollivier
FULL PAPER
centrated and then chromatographed on silica gel (eluent: petro-
leum ether/ethyl acetate, 1:1 then 20:80) to furnish the starting ma-
terial (40 mg, 36%) and the diol 24 (39 mg, 35%) as a white solid,
m.p. 81–82 °C. 1H NMR (360 MHz, CDCl3): δ = 7.12 (d, 3J =
7.9 Hz, 1 H), 7.02 (s, 1 H), 6.87 (d, 3J = 7.9 Hz, 1 H), 3.86 (s, 3
H), 3.82 (d, gemJ = 11.0 Hz, 1 H), 3.64 (d, gemJ = 11,0 Hz, 1 H),
2.58 (s, 2 H), 2.21 (s, 3 H), 1.53 (s, 3 H) ppm. 13C NMR (CDCl3,
90 MHz): δ = 157.8, 143.9, 130.4, 125.5, 116.6, 107.1, 74.9, 71.1,
91 (4), 77 (13). HRMS EI: found 260.1401, C16H20O3 requires
260.1412.
Racemic and (–)-(1aR,9bS)-8-Methoxy-4,4,7,9b-tetramethyl-1a,9b-
dihydro-2H-oxireno[e][1]benzoxocin-3(4H)one (28)
a) Racemic Route: m-Chloroperbenzoic acid (70 %, 52 mg,
0.2 mmol) was added at 0 °C to a solution of the ketone 5 (36 mg,
0.14 mmol) in dichloromethane (0.4 mL). After stirring at this tem-
perature for 4 h, the resulting solution was diluted with dichloro-
methane (5 mL) and washed with an aqueous NaOH solution (2 n,
2 ×2 mL) and then with a saturated aqueous Na2S2O3 solution
(2 mL). After drying over magnesium sulfate, the organic phase
was chromatographed on silica gel (eluent: pentane/diethyl ether,
90:10 then 87:13) to give the epoxide 28 (34 mg, 89%) as a white
solid.[4]
55.3, 26.1, 15.8 ppm. IR (KBr): ν = 3393, 2974, 2932, 1505 cm–1.
˜
MS EI, m/z = 196 [M]+· (5), 178 (31), 165 (57), 150 (11), 149 (100),
119 (9), 91 (20), 43 (46). HRMS EI: found 196.1102, C11H16O3
requires 196.1099; calcd. C 67.32, H 8.22; found C 67.51, H 7.99.
2-(2-Hydroxy-1-methylethyl)-4-methoxy-5-methylphenyl Methane-
sulfonate (18a) and 2-Isopropyl-4-methoxy-5-methylphenyl Methane-
sulfonate (25): A mixture of the diol 17a (39 mg, 0.13 mmol) and
palladium hydroxide (39 mg) in ethanol (1 mL) was stirred at 20 °C
under hydrogen atmosphere for 24 h. After filtration through Celite
and concentration, the residue was chromatographed on silica gel
(eluent: pentane/ethyl acetate, 60:40 then 10:90) to give the starting
material (13 mg, 33%), the expected alcohol 18a (10 mg, 27%) as
a colorless oil, and the sulfonate 25 (6.6 mg, 19%) as a colorless
oil.
b) Asymmetric Route by Jacobsen’s Procedure: (S,S)-Jacobsen cata-
lyst[28] (6 mg, 0.009 mmol) and then 4-phenylpyridine N-oxide
(6 mg, 0.03 mmol) were added successively at 0 °C to a solution of
ketone 5 (40 mg, 0.15 mmol) in dichloromethane (0.5 mL). After
the mixture had been stirred for 5 min at this temperature, a
Na2HPO4 buffer solution (0.05 n, 0.5 mL, pH = 11.3) was added,
followed by an aqueous NaOCl solution (0.65 m, 0.5 mL,
0.3 mmol) over a 90 min period. After stirring for 24 h at 0 °C, the
mixture was diluted with dichloromethane (5 mL) and brine
(1 mL). The aqueous phase was extracted with dichloromethane
(3×5 mL) and the combined organic layers were washed with H2O
(5 mL) and dried over magnesium sulfate. The residue was flash
chromatographed (eluent: pentane/diethyl ether, 90:10 then 87:13)
to furnish the expected optically active epoxide 28 (8 mg, 19%) as
a white solid. The enantiomeric excess determined by HPLC was
91%.
Compound 18a: 1H NMR (250 MHz, CDCl3): δ = 7.08 (s, 1 H),
3
3
6.74 (s, 1 H), 3.84 (s, 3 H), 3.75 (d, J = 7.1 Hz, 2 H), 3.39 (qt, J
3
= 7.1, J = 7.0 Hz, 1 H), 3.23 (s, 3 H), 2.19 (s, 3 H), 2.05 (s, 1 H),
1.25 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 90 MHz): δ =
3
156.8, 140.1, 135.0, 126.5, 124.1, 108.3, 67.8, 55.6, 38.0, 35.2, 17.7,
15.9 ppm. IR (neat): ν = 3400, 2966, 2936, 1505 cm–1. MS EI, m/z
˜
= 274 [M]+· (31), 195 (18), 166 (19), 165 (100), 164 (19), 150 (8),
149 (10), 91 (7). HRMS EI: found 274.0879, C12H18O5S requires
274.0874.
c) Asymmetric Route by Shi’s Procedure: A buffer solution of
Na2B4O7·10 H2O (0.005 n) in a Na2EDTA·2 H2O solution
(4×10–4 n, 1.35 mL), nBu4NHSO4 (1.9 mg, 0.005 mmol), and Shi
catalyst (1,2;4,5-di-O-isopropylene-d-erythro-2,3-hexodiulo-2,6-py-
ranose;[29] 10.5 mg, 0.04 mmol) were added successively at 20 °C
to a solution of ketone 5 (35 mg, 0.13 mmol) in an acetonitrile/
dimethoxymethane mixture (1:2, 2 mL). A solution of oxone
(114 mg, 0.18 mmol) in ETDA (4×10–4 n, 0.9 mL) and a solution
of K2CO3 (108 mg, 0.78 mmol) in H2O (0.9 mL) were then added,
at the same time but separately, at 0 °C over a 2 h period. After
stirring for 1 h at this temperature, the mixture was diluted with
H2O (2 mL) and diethyl ether (10 mL). After extraction of the
aqueous phase with diethyl ether (3×10 mL), the combined or-
ganic layers were washed with brine (5 mL), dried over magnesium
sulfate, and concentrated. The residue was isolated as previously to
give optically active epoxide 28 (16 mg, 43%) with an enantiomeric
excess of 91% as determined by HPLC, together with starting ma-
terial (19 mg, 50%). HPLC (Chiralcel OD-H; hexane/EtOH: 99:1;
tR = 5.3 min for (–)-28 and 5.6 min for (+)-28. [α]2D0 = –39 (c = 0.65,
CHCl3).
Compound 25: 1H NMR (360 MHz, CDCl3): δ = 7.06 (s, 1 H), 6.74
3
(s, 1 H), 3.84 (s, 3 H), 3.31 (hp, J = 6.7 Hz, 1 H), 3.18 (s, 3 H),
3
2.18 (s, 3 H), 1.25 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR (CDCl3,
90 MHz): δ = 156.7, 139.6, 139.2, 125.6, 123.7, 108.0, 55.6, 37.9,
27.2, 23.3, 15.8 ppm. IR (neat): ν = 2964, 2930, 1503 cm–1. MS EI,
˜
m/z = 258 [M]+· (52), 180 (25), 179 (100), 151 (21), 139 (37), 136
(13), 119 (11), 91 (13). HRMS EI: found 258.0927; C12H18O4S re-
quires 258.0925.
1-(5-Methoxy-3,6-dimethyl-2,3-dihydro-1-benzofuran-2-yl)-3-meth-
ylbut-3-en-2-one (26): The cyclopropanols 4a/4b (79 mg, 0.3 mmol)
in diethyl ether (1 mL) were added dropwise at 0 °C under argon to
a solution of ferric(iii) chloride (108 mg, 0.66 mmol) and pyridine
(0.025 mL, 0.3 mmol) in diethyl ether (3 mL). After stirring for
three hours at the same temperature, the reaction mixture was
quenched by addition of H2O (1 mL) and diluted with ethyl acetate
(15 mL). The aqueous phase was extracted with ethyl acetate
(3×15 mL) and the combined organic layers were dried over anhy-
drous magnesium sulfate and evaporated under reduced pressure.
The crude residue was chromatographed on silica gel (eluent: pen-
tane/diethyl ether, 96:4 then 93:7) to give chloro ketone 7a (7 mg.
8%), chloro ketone 7b (20 mg, 23%), and the enone 26 (13 mg,
(+)-(5R,6S)-5-Hydroxy-8-methoxy-2,2,6,9-tetramethyl-5,6-dihydro-
2H-1-benzoxocin-3(4H)one (29): Pd/C (10%, 15 mg) was added to a
solution of epoxy ketone (–)-28 (50 mg, 0.18 mmol) in ethyl acetate
(0.6 ml) and anhydrous methanol (0.020 mL) and the mixture was
stirred under H2 at 20 °C for 6 h. After filtration through Celite and
concentration, the residue was purified by flash chromatography on
silica gel (eluent: petroleum ether/diethyl ether, 45:55) to give the
alcohol (5R,6S)-29 (49.3 mg 98%) as a colorless oil.
1
17%) as a colorless oil. H NMR (250 MHz, CDCl3): δ = 6.65 (s,
1 H), 6.59 (s, 1 H), 5.98 (s, 1 H), 5.84 (s, 1 H), 4.75 (m, 1 H), 3.79
(s, 3 H), 3.30 (dd, gemJ = 16.5, 3J = 6.8 Hz, 1 H), 3.14 (dq, 3J =
6.8, 3J = 6.4 Hz, 1 H), 2.94 (dd, gemJ = 16.5, 3J = 6.0 Hz, 1 H),
2.18 (s, 3 H), 1.91 (s, 3 H), 1.36 (d, 3J = 6.8 Hz, 3 H) ppm. 13C
NMR (CDCl3, 90 MHz): δ = 199.4, 152.3, 152.1, 144.7, 129,1,
126.5, 125.6, 111.7, 106.9, 86.5, 56.3, 43.1, 42.8, 19.6, 17.4,
The enantiomeric purity determination was carried out by 1H
NMR in the presence of increasing amounts (from 10 mol% to 100
mol%) of the shift reagent [(+)-Eu(hfc)3]. The singlets of the aro-
16.5 ppm. IR (neat): ν = 2959, 2926, 1675, 1491 cm–1. MS EI, m/z
˜
= 260 [M]+· (20), 177 (34), 176 (100), 175 (11), 161 (56), 145 (5),
2596
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2589–2598

Strategies for the Total Asymmetric Synthesis of Heliannuols K and L
FULL PAPER
matic protons in the racemic benzoxocinone 29 were already giving
a double set of signals with 10 mol% of Eu(hfc)3. [α]2D0 = +6.4 (c
= 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.79 (s, 1 H),
[1]
a) F. A. Macías, R. M. Varela, A. Torres, J. M. G. Molinillo,
F. R. Fronczek, Tetrahedron Lett. 1993, 34, 1999; b) F. A.
Macías, J. M. G. Molinillo, R. M. Valera, A. Torres, F. R.
Fronczek, J. Org. Chem. 1994, 59, 8261; c) F. A. Macías, RM.
Varela, A. Torres, J. M. G. Molinillo, Tetrahedron Lett. 1999,
40, 4725; d) F. A. Macías, R. M. Varela, A. Torres, J. M. G.
Molinillo, J. Nat. Prod. 1999, 62, 1636; e) F. A. Macías, A.
Torres, J. L. G. Galindo, R. M. Varela, J. A. Álvarez, J. M. G.
Molinillo, Phytochemistry 2002, 61, 687.
3
3
3
6.61 (s, 1 H), 4,08 (ddd, J = 7.6, J = 7.1, J = 0.3, 1 H), 3.81 (s,
3
3
2
3
3 H), 3.41 (dp, J = 6.8, J = 0.3 Hz, 1 H), 2.92 (dd, J = 10.6, J
= 7.6 Hz, 1 H), 2.67 (dd, 2J = 10.6, J = 7.1 Hz, 1 H), 2.17 (s, 3
3
3
H), 1.76 (broad s, 1 H), 1.54 (s, 3 H), 1.42 (d, J = 6.8 Hz, 3 H),
1.41 (s, 3 H) ppm. 13C NMR (CDCl3, 90 MHz): δ = 209.6, 154.8,
146.1, 131.9, 127.4, 125.3, 110.5, 85.7, 72.0, 55.5, 43.9, 39.4, 24.7,
22.6, 16.6, 15.9 ppm. IR (neat): ν = 3445, 2989, 2938, 1709,
[2]
[3]
˜
F. Lecornué, J. Ollivier, Org. Biomol. Chem. 2003, 1, 3600.
a) O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, A. I. Sav-
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asaka, Bull. Chem. Soc. Jpn. 1993, 66, 819; b) K. Yamaguchi,
D. T. Sawyer, Inorg. Chem. 1985, 24, 971.
1505 cm–1. MS EI, m/z = 278 [M]+· (17), 194 (10), 191 (13), 177
(11), 176 (17), 166 (29), 165 (100), 164 (15), 149 (12). HRMS EI:
found 278.1513, C16H22O4 requires 278.1517.
(–)-(3R,5R,6S)-8-Methoxy-2,2,6,9-tetramethyl-3,4,5,6-tetrahydro-
2H-1-benzoxocine-3,5-diol (30): A DIBALH solution in toluene
(1 m, 0.24 mL, 0.53 mmol) was added at –78 °C under argon to a
solution of benzoxocinone (5R,6S)-29 (65 mg, 0.23 mmol) in anhy-
drous tetrahydrofuran, and the mixture was stirred at this tempera-
ture for 1 h. Ethyl acetate (5 mL) was then added, and the mixture
was hydrolyzed at –78 °C with an aqueous HCl solution (3 n,
1 mL) and left to warm to room temperature. The aqueous phase
was extracted with ethyl acetate (3×10 mL), and the combined or-
ganic layers were dried over magnesium sulfate and concentrated.
The residue was purified by flash chromatography on silica gel (elu-
ent: dichloromethane/methanol, 92:8 then 90:10) to furnish diol 30
(60 mg, 92 %) as a white solid.
[4]
[5]
[6]
[7]
[8]
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H. Ishibashi, M. Maeki, J. Yagi, M. Ohba, T. Kanai, Tetrahe-
dron 1999, 55, 6075.
The enantiomeric excesses were determined on a GC chiral column
(Cydex B, 165 °C, 0.8 bar): tR = 113.7 min for (–)-30 and 114.6 min
for (+)-30. [α]2D0 = –44 (c = 0.2, CHCl3), m.p. 156–157 °C. 1H NMR
(400 MHz, CDCl3): δ = 6.76 (s, 1 H), 6.60 (s, 1 H), 4.06–3.90 (m,
1 H), 3.82 (s, 3 H), 3.77–3.62 (m, 1 H), 3.62–3.44 (m, 1 H), 2.17 (s,
[10]
[11]
3
3 H), 1.89–1.69 (m, 2 H), 1.50 (broad s, 2 H), 1,38 (d, J = 7.3 Hz,
[12]
[13]
3 H), 1.27 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 154.1,
146.4, 132.1, 126.8, 124.5, 109.1, 81.7, 74.7, 73.2, 55.5, 39.7, 34.4,
28.8, 18.3, 15,8 ppm. IR (neat): ν = 3418, 2976, 2938, 1505 cm–1.
˜
[14]
[15]
[16]
MS EI, m/z = 280 [M]+. (21), 262 (31), 192 (13), 191 (25), 177 (22);
176 (19), 166 (66), 165 (100), 164 (11), 151 (23), 115 (13), 71 (15).
HRMS EI: found 280.16563; C16H24O4 requires 280.16744; calcd.
C 68.55, H 8.63; found C 68.31, H 8.43.
T. Mandai, T. Matsumoto, M. Kawada, J. Tsuji, J. Org. Chem.
1992, 57, 6090.
A. Li, G. Yue, Y. Li, X. Pan, T. K. Yang, Tetrahedron: Asym-
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[17]
[18]
(–)-Heliannuol L (2): Ethanethiolate (25 mg, 0.4 mmol) and then
diol (3R,5R,6S)-30 (4 mg, 0.014 mmol) were added under argon
at 0 °C to a solution of sodium hydride suspension (60%, 16 mg,
0.4 mmol) in dimethylformamide (2 mL) and the resulting solution
was heated at 140 °C for 16 h. After cooling at 40 °C, the dimethyl-
formamide was directly evaporated under vacuum and the residue
was stirred with ethyl acetate (5 mL) and H2O (0.05 mL). Subse-
quent filtration through magnesium sulfate, evaporation, and
chromatography on silica gel (eluent: ethyl acetate) give 2.6 mg
(69%) of (–)-heliannuol L (2) as a colorless oil.[1e] [α]2D0 = –37 (c =
0.1, CHCl3). 13C NMR (CDCl3, 50 MHz): δ = 150.7, 132.3, 126.9,
125.1, 122.0, 114.1, 81.7, 73.4, 39.8, 34.4, 31.9, 29.6, 18.6, 15.6. MS
ES, m/z = 289 [M + Na]+.
[19]
[20]
[21]
[22]
[23]
[24]
[25]
Acknowledgments
[26]
[27]
[28]
We thank the CNRS and the University of Paris-Sud (XI) for fin-
ancial support and the Ministère de la Jeunesse, de l’Education
Nationale et de la Recherche for a grant to F.L. We are also in-
debted to Mr. J.-P. Baltaze for the NOESY NMR experiments and
to Mr. D. Gori for the HPLC analyses.
a) K. Takabatake, I. Nishi, M. Shindo, K. Shishido, J. Chem.
Soc., Perkin Trans. 1 2000, 1807; b) H. Kishuku, M. Shindo,
K. Shishido, Chem. Commun. 2003, 350.
Eur. J. Org. Chem. 2005, 2589–2598
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2597

F. Lecornué, R. Paugam, J. Ollivier
FULL PAPER
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Received: December 23, 2004
[31] Semiempirical PM3 calculations were performed with the Hy-
perChem. software (version 5.1.).
2598
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2589–2598