Enantioselective synthesis of the originally proposed usneoidone structure: Evidence for a structural revision

Article abstract of DOI:10.1002/ejoc.200300767

The enantioselective synthesis of the initially proposed structure of usneoidone has been completed according to a convergent strategy in which the key steps were an enantioselective Michael addition involving chiral imines to set up the C12 quaternary center, and the final assembly of the chiral pyran moiety with the aromatic subunit through a cyanohydrin anion alkylation step. The obtained product displays spectroscopic data that significantly differ from the reported values. A putative revised structure in which the pyran ring is opened is proposed for usneoidones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300767

FULL PAPER
Enantioselective Synthesis of the Originally Proposed Usneoidone Structure:
Evidence for a Structural Revision
[a]
[a]
[a]
[a]
`
Michele Danet, Marie Normand-Bayle, Jacqueline Mahuteau, Jean d’Angelo,
[b]
[a]
¨
Georges Morgant, and Didier Desmaele*
Keywords: Terpenoids / Structure revision / Heterocycles / Michael addition / Enantioselectivity
The enantioselective synthesis of the initially proposed struc-
rin anion alkylation step. The obtained product displays
ture of usneoidone has been completed according to a con- spectroscopic data that significantly differ from the reported
vergent strategy in which the key steps were an enantiose-
lective Michael addition involving chiral imines to set up the
C12 quaternary center, and the final assembly of the chiral
values. A putative revised structure in which the pyran ring
is opened is proposed for usneoidones.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
pyran moiety with the aromatic subunit through a cyanohyd- Germany, 2004)
Introduction
A few years ago, Urones and co-workers reported the
isolation and the structure determination of four new mero-
terpenes — (E)- and (Z)-usneoidones (1a and 1b, Figure 1)
and (E)- and (Z)-usneoidols (2a and 2b) — from the brown
seaweed Cystoseira usneoides found off the West Coast of
the Iberian Peninsula. These compounds displayed signifi-
cant antiherpes and antitumoral activities, but also showed
some cytotoxicity against normal cells.[1a,1b] The most strik-
ing feature of usneoidones is the 2,2,6,6-tetrasubstituted-
6H-pyran-3-one moiety, which is found in only a few mar-
ine natural products. Following the isolation, Urones et al.
Figure 1. Structures of usneoidones and usneoidols, as proposed
described a synthetic approach of the crucial pyran core,
based on phenylselenium-mediated cyclization of geranyl
acetate.[2] Later on the same group reported the total syn-
thesis of an analogue of (E)-usneoidol devoid of the C12
carbonyl.[3] The structural novelty and the relevant biologi-
cal activities of usneoidones present an exciting challenge
for chemical synthesis. Our aim was to develop a convergent
synthesis whose strategy was readily amenable to the syn-
thesis of analogues. Furthermore, an enantioselective syn-
thesis should permit the elucidation of the absolute configu-
ration of these compounds. Herein we report the enantiose-
lective synthesis of compounds 1a,b, providing evidence
that the structure of usneoidones was wrongly assigned.
by Urones et al.
Results and Discussion
Our plan for preparing 1a,b, arbitrarily targeting the
(11R)-enantiomer, was based on the convergent coupling of
the anion of the silylated cyanohydrin 3 with the aromatic
subunit 5. The chiral cyanohydrin 3 can be obtained from
the alkyne 4 by zirconocene-catalyzed carboalumination
and cyanohydrin formation. Compound 4, in turn, could
be assembled from keto ester (R)-7b through side-chain
homologation and introduction of the C13ϪC14 double
bond. In such an approach, the key synthetic issue was the
stereoselective elaboration of the densely functionalized py-
ran nucleus. We have established in earlier studies that the
asymmetric Michael addition of chiral imine 8a with methyl
acrylate afforded the Michael adduct 7a regio- and stereose-
lectively.[4] Assuming that the C6 gem-dimethyl group
[a]
´
´
Unite de Chimie Organique Associee au CNRS, Centre
´
d’Etudes Pharmaceutiques, Universite Paris Sud,
´
ˆ
5 rue J.-B. Clement, 92296 Chatenay-Malabry, France
Fax: (internat.) ϩ 33-1-46835752
E-mail: didier.desmaele@cep.u-psud.fr
[b]
Laboratoire de Cristallographie Bioinorganique, Centre
´
d’Etudes Pharmaceutiques, Universite Paris Sud,
´
ˆ
5 rue J.-B. Clement, 92296 Chatenay-Malabry, France
Eur. J. Org. Chem. 2004, 1911Ϫ1922
DOI: 10.1002/ejoc.200300767
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1911

D. Desmae¨le et al.
FULL PAPER
should not interfere with the Michael addition step, we lowed by ring opening of the putative radical intermediate
chose to prepare the keto ester 7b from the chiral imine 8b, 13. Careful deoxygenation of the reaction medium reduced
derived from pyranone 9b and (S)-1-phenylethylamine. The the formation of 14, but did not completely suppress it. The
aromatic subunit 5 could be prepared from the known mechanistic aspects of the Michael addition involving chiral
bromohydroquinone 6, in a sequence involving chemoselec- imines have been extensively studied on the basis of both
tive protection, prenylation, and allylic functionalization experimental and theoretical investigations. Both the un-
(Scheme 1).
usual regioselectivity and the high stereoselectivity were ex-
plained by invoking a cyclic transition state and a concerted
proton transfer from the nitrogen atom of the secondary
enamine to the electrophilic alkene.[7,4a] In the present case,
it must be emphasized that the intrinsic regioselectivity of
the Michael addition toward the formation of the more
substituted adduct 7b overcomes the steric hindrance due
to the additional quaternary carbon center lodged in the
proximity of the reactive enamine carbon. The direct evalu-
ation of the enantiomeric excess of keto ester 7b by 1H
NMR shift experiments failed. However, the enantiomeric
excess was finally evaluated to be 95% by studying the cor-
responding alcohol 15 with an equatiorial OH group[8] in
the presence of Eu(hfc)3 (Scheme 2). The (2R) absolute con-
figuration of 7b was not demonstrated but was assigned ac-
cording to the general empirical rule governing this type of
enantioselective Michael addition.[7]
Scheme 1. Retrosynthetic analysis of usneoidones
To implement this synthetic plan, we required a viable,
large-scale preparation of 2,6,6-trimethyl-pyran-3-one (9b).
This was secured by a hydroboration-Swern oxidation reac-
tion sequence of 2,2,6-trimethyl-3,4-dihydro-2H-pyran (11),
easily accessible by acid-catalyzed cyclization of 6-meth-
ylhept-5-en-2-one (10).[5] This sequence routinely furnished
pyranone 9b in a 53% overall yield from 10 on a twenty
five-gram scale. When 9b was subjected to standard imin-
ation conditions [(S)-PhCH(Me)NH2, TsOH, toluene, azeo-
tropic removal of water] none of the desired imine was ob-
tained due to competitive rearrangements, as previously ob-
served with other α-alkoxy-substituted imines.[6] However,
Scheme 2. Enantioselective synthesis of the chiral pyran 7b: a) i:
40% H2SO4, 20 °C, 45 min, ii: distillation, 85%; b) i: BH3.SMe2,
cyclohexane, 0 °C, 3 h ii: NaOH, H2O2, EtOH, 80 °C, 2 h, 93%;
(c) i: DMSO, ClCOCOCl, CH2Cl2, Ϫ78 °C ii: Et3N, 68%; d) (S)-
˚
PhCH(Me)NH2, 5-A molecular sieves-SiO2ϪAl2O3, cyclohexane,
48 h, 20 °C; e) H2CϭCHCO2Me, 48 h, 50 °C, 62% overall from 9b
With the key pyran 7b in hand, we turned to the intro-
upon treatment with a catalyst made by mixing 5-A molec- duction of the ∆4,5 double bond. In the event, bromination
ular sieves, silica and basic alumina, the desired imine 8b of the trimethylsilyl enol ether derived from racemic 7b, fol-
was obtained smoothly. Subsequent Michael addition with lowed by dehydrobromination by treatment with lithium
methyl acrylate delivered, after acidic work up, the Michael bromide and lithium carbonate in DMF, gave enone 16 in
adduct (R)-7b in 62% overall yield from 9b, along with sev- 54% overall yield. Unfortunately, all attempts to protect the
eral minor components. One of them (ca. 8Ϫ10%) was highly hindered ketonic group of 16 as a dioxolane or 1,3-
identified as nitrile 14, the formation of which might be dithiolane failed. Assuming that the carbonyl group in 7b
tentatively explained by oxidation of the imine at C2, fol- should be more reactive we decided to protect the C3 car-
˚
1912
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Eur. J. Org. Chem. 2004, 1911Ϫ1922

Enantioselective Synthesis of an Usneoidone Structure
FULL PAPER
bonyl group before introducing the double bond. To our but a mixture of iodoolefin 25 (ca. 5%) and alkyne 26
delight, treatment with ethylene glycol under the standard (25Ϫ30%) resulting from an apparent 1,4-type addition of
conditions of 7b afforded the corresponding ketal 18 in 84% a methyl group to the unsaturated ketal moiety,[12] along
yield,[9] which was then brominated (Br2, CCl4, 40 °C, with several other unidentified products (Scheme 4).
quantitative). Attempts to perform the elimination with
various bases, including DBU, failed repeatedly. Finally,
saponification of the ester group of 18, followed by treat-
ment with an excess of tBuOK in DMSO at 110 °C,
smoothly delivered the desired enone 20 in 75% overall
yield from 18. The structure of this compound was secured
by means of an X-ray diffraction analysis (Scheme 3).
Scheme 4. Attempted functionalization of the side chain through
zirconocene-catalyzed carboalumination: a) LAH, Et2O, 20 °C,
30 min, 84%; b) CBr4, PPh3, pyridine, Et2O, 4 h, 20 °C, 80%; c)
TMSCCLi, THF, DMPU, 12 h, 20 °C, 76%; d) nBu4NF, THF,
20 °C, 1 h, 92%
To overcome this problem, an alternative strategy was in-
vestigated to set up the C5ϪC6 fragment based on a
Scheme 3. Elaboration of the pyran core and ORTEP drawing of
the crystal structure of 20: a) TMSCl, Et3N, DMF, 12 h, 100 °C,
87%, b) Br2, CCl4, 0 °C, 77%; c) LiBr, Li2CO3, DMF, 100 °C, 12 h,
81%; d) (CH2OH)2, TsOH, toluene, reflux, 8 h, 84%; e) Br2, CCl4,
40 °C, 45 min; f) 2  NaOH, MeOH, 20 °C, 18 h; g) tBuOK,
DMSO, 110 °C, 4 h, 75% from 18
HornerϪEmmons olefination. Thus, treatment of bromide
23 with tBuLi, followed by reaction of the intermediate li-
thio derivative with the Weinreb amide 28,[13] afforded the
desired ketone 27 in 46% yield. Condensation of the latter
with triethyl phosphonoacetate in THF using nBuLi as base
furnished the unsaturated ester 29 in 83% yield as a 4:1
(E)/(Z) mixture.[14,15] The major isomer exhibited an NOE
Once we had developed an efficient access to the chiral between the vinylic proton (δ ϭ 5.65 ppm) and the allylic
pyranone subunit, we turned our attention to the side-chain methylene (δ ϭ 2.09 ppm), thus supporting the (E)-ge-
elongation. We first envisaged a two-carbon homologation ometry of its double bond. Attempts to improve this selec-
via alkyne 4, followed by Negishi-type carboalumination[10] tivity by using NaH as base in various solvents were unsuc-
to form 21 (Scheme 4). Thus, reduction of the acid group cessful. Since the separation of the two isomers turned out
of 20 with LiAlH4 gave alcohol 22 with a 84% yield, which to be quite difficult, the following steps were therefore con-
was converted into bromide 23 upon treatment with CBr4/ ducted on the mixture. Thus, DIBAL-H reduction of the
PPh3. Nucleophilic substitution with the lithium derivative ester group of 29, followed by manganese dioxide oxidation
of trimethylsilylacetylene, followed by desilylation with of the allylic alcohol 30, uneventfully afforded the desired
nBu4NF provided the requisite alkyne 4 in 70% overall yield aldehyde 31 in 85% overall yield. Due to the presence of
from 22. Next, the stereocontrolled formation of the trisub- the acetal group, we preferred to avoid the use of a Lewis
stituted double bond C6ϪC7 was investigated. However, acid for the formation of the silylated cyanohydrin 3. Thus,
the zirconium-catalyzed carboalumination of 22 (i: AlMe3, heating 31 with tert-butyldimethylsilyl cyanide in aceto-
Cp2ZrCl2, 1.5 equiv. H2O, CH2Cl2, Ϫ20 °C, 10 min, ii: I2, nitrile without the use of any catalyst[16] delivered the ex-
THF, 20 °C)[11] afforded none of the desired iodoalkene 21, pected silylated cyanohydrin 3 in 80% yield (Scheme 5).
Eur. J. Org. Chem. 2004, 1911Ϫ1922
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D. Desmae¨le et al.
FULL PAPER
Scheme 5. Elaboration of the side chain of cyanohydrin 3: a) i:
tBuLi, Et2O, Ϫ78 °C, 15 min, ii: 28, THF, 3 h, 20 °C, 46%; b)
EtO2CCH2PO(OEt)2, nBuLi, THF, 20 °C, 24 h, 83%, (E)/(Z) ϭ
4:1; c) DIBAL-H, THF, Ϫ70 °C, 2 h, 95%; d) MnO2, CH2Cl2,
20 °C, 8 h, 90%; e) tBuMe2SiCN, CH3CN, 80 °C, 10 h, 80%
With the desired chiral cyanohydrin 3 in hand, the next
task was to develop a suitable strategy for the preparation
of the aromatic fragment 5. The sequence was initiated with
the selective protection of the less-hindered phenol group
of bromo-hydroquinone 6, which is easily available from o-
cresol (32) in a three-step sequence.[17] Thus, monosilylation
of 6 with triisopropylsilyl chloride and methylation of the
remaining phenol group afforded almost exclusively the aryl
bromide 35 in 70% overall yield. Metalation of 35 with
nBuLi, followed by transmetalation of the intermediate ar-
yllithium derivative with copper cyanide, and addition of 2-
methyl-2-vinyloxirane 36, gave the desired allylic alcohol 37
in 67% yield, but with a disappointing 2.5:1 E/Z ratio.[18]
To solve this problem selenium dioxide allylic oxidation was
chosen as the key step to control the stereochemistry of the
double bond. Thus, the aryllithium reagent derived from 35
was alkylated with prenyl bromide to yield 38 (91%). Sel-
enium dioxide allylic oxidation of 38 turned out to be some-
what capricious. When the reaction was conducted with a
Scheme 6. Synthesis of the aromatic subunit 5: a) Br2, AcOH, 20
°C, 96%; b) CrO3, AcOH, 0 °C, 5 h, 95%; c) Na2S2O4, EtOH, 20
°C, 2 h, 52%;%; d) TIPSCl, Imidazole, DMF, 18 h; e) CH3I,
K2CO3, acetone, reflux, 4 h, 70% from 6; f) i: nBuLi, Et2O, Ϫ78
°C ii: CuCN, LiCl, Ϫ30 °C, 30 min iii: 36, Ϫ78 °C to 20 °C, 1 h,
67%; g) i: PhLi, Et2O, 0 °C, ii: BrCH2CHϭC(CH3)2, DMPU, 20
°C, 18 h, 91%; h) i: SeO2, dioxane, water, 100 °C, 1 h, ii: NaBH4,
EtOH, 15 min, 20 °C, 60%; i) Br2, Ph2PCH2CH2PPh2, CH2Cl2,
20 °C, 2 h, 88%
catalytic amount of SeO2 in the presence of tBuO2H[19] the metric isomers at ∆6,7 and diastereomers at the C5 cyanohy-
desired alcohol (E)-37 was obtained in 44% yield but was drin center. Treatment with nBu4NF smoothly cleaved the
unexpectedly accompanied by diol 39 (25%). The formation phenolic protecting group and caused the reversion of the
of the latter was suppressed, and the yield of 37 was im- cyanohydrin to the parent carbonyl compound. Finally,
proved to 60%, upon using a stoichiometric amount of acidic hydrolysis of the ketal group afforded 1a,b [3:1 (E)/
1
SeO2 in refluxing dioxane, followed by reduction with (Z) ratio] in 51% overall yield from 3. Surprisingly, the H,
NaBH4.[20] The relative position of the butenol side-chain 13C NMR and MS data of our sample did not match the
with respect to the methoxy group on the aromatic ring, reported values for 1a,b.[1a] Although most of the signals of
as well as the double bond geometry, were unequivocally both the aromatic nucleus and the linker are very close to
established as given by NOESY analysis. Alcohol (E)-37 the ones described for the natural product, large discrepanc-
was finally transformed into bromide 5 upon treatment ies existed for the two vinylic protons 13-H and 14-H of the
with
1,1,2,2,-tetrabromo-1,2-bis(diphenylphosphanyl)e- pyran core (see Table 1). Since the structure of this moiety
thane[21] (Scheme 6).
in our sample has been unambiguously established, the as-
The critical coupling of the subunits 3 and 5 was achieved signed structure of the usneoidones came into doubt. The
by condensation of the lithio derivative of 3, prepared by misattribution of the pyran system of usneoidones was re-
1
reaction with LDA, with 5 in the presence of DMPU.[22] inforced by the H NMR spectroscopic data reported for
The resulting adduct 40 was obtained as a mixture of geo- the pyranone 41,[2] which are very close to our own values
1914
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Enantioselective Synthesis of an Usneoidone Structure
FULL PAPER
Table 1. Selected spectroscopic data of usneoidones and derivatives
Entry
δ, 13-H (ppm)
δ, 14-H (ppm)
J13-H,14-H (Hz)
δ, C13 (ppm)
δ, C14 (ppm)
δ, C12 (ppm)
(E)-Usneoidone[a]
6.60
6.86
5.94
5.90
5.90
5.91
5.96
6.64
6.91
7.20
7.16
6.85
6.83
6.82
6.82
6.72
7.13
7.04
15.1
15.6
10.4
10.5
10.2
10.5
10.5
17.1
15.5
118.4
119.3
122.2
123.5
122.2
122.1
123.5
118.3
156.3
155.7
155.5
155.4
154.9
154.7
153.0
156.2
202.9
203.3
199.6
199.5
197.4
197.7
198.8
200.0
(Z)-Usneoidone[a]
1a
1b
16
41
42
46
47 (in [D6]acetone)
[a]
Data reported for the natural product in ref.[1a]
for 1a,b. To assess the origin of this discrepancy, our first
feeling was to consider a 5-oxo-tetrahydropyranyl system as
a possible alternative structure for the pyran core of usneo-
idone. To explore this point we decided to prepare the py-
ranone 42 as a model of this putative structure. Thus acetal
(Ϯ)-20 was hydrolyzed and the resulting unsaturated ketone
43 was epoxidized by treatment with hydrogen peroxide in
the presence of sodium hydroxide providing α,β-epoxy ke-
tone 44 as a mixture of diastereomers in 77% yield. Whar-
ton rearrangement[23] of 44 delivered the expected allylic
alcohols 45, which were subsequently oxidized by using
DessϪMartin periodinane and esterified with diazometh-
ane into enone 42. Once again, however, the two vinylic
protons of 42 were found to resonate upfield from those in
the natural product (Scheme 7).[1a]
This result led us to reconsider the structure of the chiral
part of usneoidones. Indeed, we became quite suspicious of
the abnormally downfield chemical shift of 14-H, and the
15.1 Hz coupling constant between 13-H and 14-H, featur-
ing a cis-enone reported for the natural product. However
such values are commonly found for acyclic trans-enones.
For example, compound 46, which has been extracted as
a minor polar component together with usneoidones from
1
Cystoseira usneoides,[1c] displays H NMR spectra that are
remarkably similar to the values reported for the usneo-
idones, as did the synthetic diol 47[24] (See Table 1). These
striking similarities led us to propose the putative structures
48a,b for usneoidones. Such a structure, however, should
show a molecular ion at m/z ϭ 472 in the MS, while the
reported value is m/z ϭ 454. This apparent contradiction
can easily be solved considering that the molecular ion in
the MS of 46 at m/z ϭ 458 is of very low abundance (0.2%).
Indeed the exact mass was measured on the Mϩ Ϫ H2O ion
at m/z ϭ 440. Accordingly, the mass spectra of 48a,b might
display a very weak molecular ion peak at m/z ϭ 472, which
was not observed and a higher Mϩ Ϫ H2O peak at m/z ϭ
454 as reported (Figure 2).
Scheme 7. Completion of the synthesis of 1a,b and Wharton re-
arrangement of 44: a) i: LDA, Ϫ78 °C, THF, 15 min, ii: 2 equiv. 5,
DMPU, 4 h, 20 °C, 80%; b) 1  nBu4NF, THF, 2 h, 20 °C; c) 0.5
 HCl, THF, 2 h, 20 °C, 64% overall from 40; d) 1  HCl, THF,
1 h, 20 °C, 85%; e) H2O2, 1  NaOH, MeOH, 30 min, 0 °C, 77%;
f) H2NNH2, MeOH, AcOH, 60 °C, 2 h, 40%; g) DessϪMartin per-
iodinane, CH2Cl2, 1 h, h) CH2N2, Et2O, 0 °C, 52% from 45
of usneoidones. These observations and a careful scrutiny
of the reported spectroscopic data led us to surmise that
usneoidones do not possess a pyran ring in their structure.
The open-chain structure 48a,b was thus proposed. Vali-
dation of this proposal through synthesis is required.
In summary, we have achieved a stereocontrolled and
convergent synthesis of the structures 1a,b originally as-
signed to usneoidones. We have found that the spectro-
scopic data of the pyran moiety are different from those of
the natural product. In addition, we have outlined a syn-
thesis of the alternative pyran 42, but once again the spec-
Experimental Section
General: Melting points were recorded with a Büchi capillary tube
melting point apparatus, and are uncorrected. IR spectra were ob-
tained as solids or neat liquids with a Fourier Transform Bruker
tral characteristics were completely at variance with those Vector 22 spectrometer. Only significant absorptions are listed. Op-
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D. Desmae¨le et al.
FULL PAPER
1
°C). H NMR (200 MHz, [D6]benzene): δ ϭ 4.39 (t, J ϭ 1.8 Hz, 1
H, HCϭ), 1.95Ϫ1.80 (m, 2 H, ϭCHCH2), 1.71 (s, 3 H, CH3Cϭ
CH), 1.55 (t, J ϭ 6.6 Hz, 2 H, HCϭCCH2CH2), 1.15 [s, 6 H,
OC(CH3)2] ppm. 13C NMR (50 MHz, [D6]benzene): δ ϭ 150.2 (C,
CH3CϭCH), 93.9 (CH, CH3CϭCH), 73.7 [C, OC(CH3)2], 33.6
(CH2, C5), 27.2 (2 CH3, OC(CH3)2], 21.4 (CH3, CH3CϭCH), 19.5
(CH2, C4) ppm.
2,6,6-Trimethyltetrahydropyran-3-ol (12): BoraneϪdimethyl sulfide
complex (10 , 10 mL 0.10 mol) was added dropwise to an ice-
cooled solution of the dihydropyran 11 (34.0 g, 0.27 mol) in cyclo-
hexane (140 mL). The mixture was stirred at 20 °C for 3 h and
200 mL of 95% ethanol was carefully added. A condenser was ad-
apted and 3  sodium hydroxide (100 mL, 0.3 mol), and 35% hy-
drogen peroxide (27 mL, 0.3 mol) were sequentially added drop-
wise. A vigorous reaction took place and the mixture was refluxed
for a further 2 h. The mixture was cooled to 20 °C and partially
concentrated under reduced pressure. The residue was extracted
with CH2Cl2 (5 ϫ 50 mL). The combined organic phases were
washed with aqueous sodium bisulfite and brine, dried with
MgSO4, filtered and concentrated. The residue was distilled under
reduced pressure to give the alcohol 12 as a colorless oil 36.3 g,
93% yield; b.p. 105Ϫ110 °C/22 Torr (oil-bath temperature). IR
Figure 2. Structure of meroterpene 51 and putative structures of us-
neoidones
tical rotations were measured with a PerkinϪElmer 241 Polar-
imeter at 589 nm. The 1H and 13C NMR spectra were recorded
with Bruker AC 200 P (200 MHz and 50 MHz, for 1H and 13C,
(film): ν˜ ϭ 3600Ϫ3200 (OH), 1448, 1380, 1366, 1233, 1051 cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ 3.50Ϫ3.35 (m, 1 H, 2-H),
3.25Ϫ3.10 (m, 1 H, 3-H), 1.95Ϫ1.60 (m, 1 H, 4-H), 1.80 (s, 1 H,
OH), 1.75Ϫ1.45 (m, 3 H, 4-H and 5-H), 1.25Ϫ1.20 (m, 9 H, 3 ϫ
CH3) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 72.7 (CH, C3), 71.4
(C, C6), 71.0 (CH, C2), 36.0 (CH2, C5), 31.0 [CH3, OC(CH3)2],
29.3 (CH2, C4), 21.7 [CH3, OC(CH3)2], 18.7 (CH3, CH3CHOC)
ppm. MS (EI): m/z (%) ϭ 144 (1.8) [Mϩ], 130 (1.2), 129 (19), 116
(5.6), 111 (5.2), 99 (8.2), 88 (73.5), 71 (20.3), 59 (25.7), 57 (64.2), 56
(100). 3,5-Dinitrobenzoate of 12: M.p. 161Ϫ162 °C. C15H18N2O7
(338.3): calcd. C 53.25, H 5.36, N 8.28; found C 53.24, H 5.40,
N 8.19.
1
respectively) or Bruker ARX 400 (400 MHz and 100 MHz, for H
and 13C, respectively) spectrometers. Assignment of methyl, methyl-
ene, methine, and quaternary carbon nuclei in the 13C NMR spec-
tra rests on the J-modulated spin-echo sequence. Mass spectra were
recorded with a HewlettϪPackard G 1019 A (70 eV). Analytical
thin-layer chromatography was performed on Merck silica gel
60F254 glass precoated plates (0.25 mm layer). Column chromatog-
raphy was performed with Merck silica gel 60 (230Ϫ400 mesh
ASTM). Diethyl ether and tetrahydrofuran (THF) were distilled
from sodium/benzophenone ketyl. Methanol and ethanol were
dried with magnesium and distilled. Benzene, toluene, DMF, and
CH2Cl2 were distilled from calcium hydride, under nitrogen. All
reactions involving air- or water-sensitive compounds were rou-
tinely conducted in glassware which was flame-dried under a posi-
tive pressure of nitrogen. Chemicals obtained from commercial
suppliers were used without further purification. Elemental analy-
ses were performed by the Service de microanalyse, Centre dЈE-
2,6,6-Trimethyldihydropyran-3-one (9b): Anhydrous DMSO
(36 mL, 0.50 mol) in CH2Cl2 (60 mL) was added dropwise at Ϫ78
°C to a solution of oxalyl chloride (40 g, 0.315 mol) in CH2Cl2
(100 mL). After stirring for five minutes, a solution of the alcohol
12 (30.0 g, 0.208 mol) in CH2Cl2 (60 mL) was added dropwise.
After stirring at Ϫ78 °C for a further 30 min, Et3N (200 mL, 1.40
mol) was added. The reaction mixture was then slowly raised to
room temperature over a 3 h period. Water (250 mL) was added,
the organic layer was separated and the aqueous phase was ex-
ˆ
tudes Pharmaceutiques, Chatenay-Malabry, France, with
a
PerkinϪElmer 2400 analyzer.
2,6,6-Trimethyl-3,4-dihydro-2H-pyran (11): Sulfuric acid (40% w/w, tracted with CH2Cl2 (4 ϫ 100 mL). The combined organic phases
400 g) was placed in an ice-chilled 1 L flask. 6-Methylhept-5-en-2- were washed with 3  HCl (3 ϫ 20 mL) and brine, dried with
one (10; 40 g, 0.317 mol) was added dropwise at 0 °C with vigorous MgSO4, filtered and concentrated under reduced pressure (below
stirring. The temperature was then raised to 20 °C and the mixture 30 °C). The residue was taken up in diethyl ether and filtered
was stirred until a homogeneous solution was obtained (ca. through a pad of silica. The filtrate was concentrated and distilled
45 min). The mixture was cooled to 0 °C and 50% aqueous sodium to give the pyranone 9b (21 g, 68%) as a pale yellow oil; b.p. 56Ϫ58
1
hydroxide was added until neutrality. Diethyl ether was added °C/20 Torr. IR (film): ν˜ ϭ 1731 (CO), 1448, 1370 cmϪ1. H NMR
(500 mL) and the mixture was filtered. The solid was washed thor- (200 MHz, CDCl3): δ ϭ 4.05 [q, J ϭ 7.0 Hz, 1 H, OCH(CH3)Cϭ
oughly with diethyl ether. The ethereal layer was separated and the O], 2.54 (ddd, J ϭ 16.5, 9.5, 5.7 Hz, 1 H, 4-H), 2.37 (ddd, J ϭ 16.5,
aqueous phase was extracted with diethyl ether (5 ϫ 200 mL). The 5.7, 5.1 Hz, 1 H, 4-H), 1.99 (dt, J ϭ 14.2, 5.7 Hz, 1 H, 5-H), 1.83
combined organic phases were dried with MgSO4, filtered and con- (ddd, J ϭ 14.2, 10.1, 5.1 Hz, 1 H, 5-H), 1.34 [s, 3 H, OC(CH3)2],
centrated at atmospheric pressure until the volume of the solution 1.31 [s, 3 H, OC(CH3)2], 1.26 (d, J ϭ 7.0 Hz, 3 H, OCH(CH3)Cϭ
was reduced to ca 100 mL. Amberlite IR 120 (2 g) was then added O) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 212.1 (CO), 72.1 (CH,
and the mixture was stirred for 8 h at room temperature. The acidic C2), 71.9 (C, C6), 34.4 [CH3, OC(CH3)2], 34.3 [CH3, OC(CH3)2],
resin was filtered off and the mixture was slowly distilled to give a 29.1 (CH2, C4), 24.4 (CH2, C5), 15.5 [CH3, OCH(CH3)CϭO)]
two-phase distillate. Pentane (50 mL) was added and the organic ppm. MS (EI): m/z (%) ϭ 142 (32.0) [Mϩ], 127 (4.4), 109 (2.5), 99
phase was separated, dried with Na2CO3, filtered and concentrated (5.7), 98 (26.4), 81 (4.3), 70 (91.4), 56 (100). Semicarbazone of 9b:
at atmospheric pressure. Distillation afforded the dihydropyran 11 M.p. 208Ϫ209 °C. C9H17N3O2 (199.2): calcd. C 54.25, H 8.60, N
(34 g, 85%) as a colorless oil; b.p. 125Ϫ130 °C (Ref.[5] b.p. 127Ϫ129 21.09; found C 54.31, H 8.30, N 21.09.
1916
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1911Ϫ1922

Enantioselective Synthesis of an Usneoidone Structure
FULL PAPER
Methyl (R)-3-(2,6,6-Trimethyl-3-oxo-tetrahydro-2H-pyran-2-yl)pro-
panoate (7b): A mixture of 44 g of 5-A molecular sieves, 11 g of CO2CH3), 2.50Ϫ2.10 (m, 3 H, CH2CH2CO2CH3), 1.98Ϫ1.80 (m,
CHCO), 5.90 (d, J ϭ 10.2 Hz, 1 H, HCϭCHCO), 3.64 (s, 3 H,
˚
basic alumina and 6 g of silica was activated by heating for a few
minutes at 0.05 Torr with a Bunsen burner. After cooling, 100 mL
of cyclohexane was added followed by optically pure (S)-(ϩ)-1-
phenylethylamine (24.0 g, 0.198 mol) and the ketone 9b (21.1 g,
0.148 mol) in 20 mL of cyclohexane. The suspension was stirred
vigorously at 20 °C for 18 h. The reaction mixture was then filtered
and the solid residue was washed repeatedly with dry diethyl ether.
The filtrate was concentrated under reduced pressure (0.05 Torr, 40
°C) to give the crude imine 8b (1:1 diastereomeric mixture, 37.0 g,
1 H, CH2CH2CO2CH3), 1.45 (s, 3 H, HCϭCHCOCH3), 1.35 [s, 6
H, OC(CH3)2] ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 197.4 (CO),
173.9 (CO2CH3), 154.9 (CH, HCϭCHCO), 122.2 (CH, HCϭ
CHCO), 79.6 (C, C2), 71.7 [C, OC(CH3)2], 51.4 (CH3, OCH3), 34.5
(CH2, CH2CH2CO2CH3), 30.3 (CH2, CH2CH2CO2CH3), 28.9 [2
CH3, OC(CH3)2], 26.2 [CH3, CH2C(CH3)O] ppm. C12H18O4·1/
4H2O (230.8): calcd. C 62.45, H 8.08; found C 62.21, H 8.30.
Methyl
(R)-3-(6,8,8-Trimethyl-1,4,7-trioxaspiro[4.5]dec-6-yl)pro-
quantitative) as a pale-yellow oil. IR (film): ν˜ ϭ 1666 (CϭN) cmϪ1
.
pionoate (18): Keto ester 7b (3.20 g, 14.0 mmol), ethylene glycol
(8.70 g, 140 mmol), p-toluenesulfonic acid (0.1 g, 0.58 mmol) and
150 mL of toluene were placed into a round-bottomed flask
equipped with a DeanϪStark apparatus. The reaction mixture was
heated at reflux for 9 h, and two additional portions of p-tolu-
enesulfonic acid (0.1 g, 0.58 mmol) were added. The reaction mix-
ture was taken up in EtOAc (250 mL), washed with saturated aque-
ous sodium hydrogencarbonate and brine and dried with MgSO4.
After concentration under reduced pressure the residue was taken
up in anhydrous methanol (10 mL) and added dropwise to a solu-
tion of sodium methoxide in methanol (from 0.25 g of sodium in
100 mL of MeOH). The reaction mixture was stirred at 20 °C for
1 h, and most of the methanol was removed in vacuo. A saturated
aqueous ammonium chloride solution was added to the residue and
the mixture was extracted with EtOAc (4 ϫ 50 mL). The collected
organic phases were washed with brine, dried with MgSO4 and
concentrated. Chromatography (cyclohexane/EtOAc, 5:1 ϩ 0.5%
Et3N) gave the acetal 18 (3.2 g, 84%); colorless oil. [α]2D0 ϭ ϩ4.9
(c ϭ 5, EtOH). IR (film): ν˜ ϭ 1734 (CO2Me), 1436, 1369, 1256,
1206 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 3.85 (s, 4 H, OCH2-
CH2O), 3.55 (s, 3 H, CO2CH3), 2.55 (m, 2 H, CH2CO2CH3), 2.00
(m, 1 H, 10-H), 1.88Ϫ1.55 (m, 5 H, CH2CH2CO2CH3, 9-H, 10-H),
1.12 [s, 3 H, CH2C(CH3)O], 1.08 [s, 6 H, OC(CH3)2] ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ 174.7 (CO2CH3), 108.8 (C, C5), 77.2
(C, C6) 71.1 (C, C8), 64.7 (CH2, OCH2CH2O), 64.5 (CH2, OCH2-
CH2O), 51.1 (CH3, OCH3), 34.9 (CH2), 31.7 (CH2), 30.5 [CH3,
OC(CH3)2], 29.1 [CH3, OC(CH3)2], 28.4 (CH2), 25.8 (CH2), 22.5
[CH3, CH2C(CH3)O] ppm. C14H24O5 (272.3): calcd. C 61.76, H
8.82; found C 61.86, H 8.99.
Freshly distilled methyl acrylate (26.0 g, 0.3 mol) and hydroquinone
(0.05 g) were added to the crude imine 8b (37.0 g, 0.148 mol). The
stirred mixture was heated at 50 °C for 4 days. After cooling to 20
°C, 20% aqueous acetic acid (100 mL) and THF (300 mL) were
added, and the mixture was stirred at 20 °C for 3 h. Solvents were
removed under reduced pressure and 1  hydrochloric acid
(100 mL) was added. The mixture was extracted with diethyl ether
(4 ϫ 50 mL) and the collected organic phases were washed with
brine, dried with MgSO4 and concentrated. Chromatography
(cyclohexane/EtOAc, 4:1) gave the keto ester 7b (20.9 g, 62% overall
yield from 9b). Distillation afforded an analytical sample as a color-
less oil: b.p. 110 °C/0.05 Torr. [α]2D0 ϭ ϩ50.6 (c ϭ 7, EtOH). IR
1
(film): ν˜ ϭ 1740 (CO2Me), 1720 (CO), 1439, 1370, 1297 cmϪ1. H
NMR (400 MHz, CDCl3): δ ϭ 3.66 (s, 3 H, OCH3), 2.48 (t, J ϭ
6.7 Hz, 2 H, CH3O2CCH2CH2), 2.39 (ddd, J ϭ 15.7, 9.6, 6.2 Hz,
1 H, 4-H), 2.27 (ddd, J ϭ 15.7, 9.8, 5.6 Hz, 1 H, 4-H), 2.12Ϫ1.94
(m, 3 H, CH3O2CCH2CH2 and 5-H), 1.87 (ddd, J ϭ 13.9, 9.8,
6.2 Hz, 1 H, 5-H), 1.33 [s, 3 H, OC(CH3)2], 1.32 [s, 3 H,
CH2C(CH3)O], 1.28 [s, 3 H, OC(CH3)2] ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 214.1 (CO), 173.8 (CO2Me), 81.0 (C, C2), 71.8 (C,
C6), 51.4 (CH3, OCH3), 35.0 (CH2, C5), 33.8 (CH2, CH2CO2CH3),
33.4 (CH2, CH2CH2CO2CH3), 29.5 [CH3, OC(CH3)2], 29.2 [CH3,
OC(CH3)2], 28.8 (CH2, C4), 26.0 [CH3, OϭCC(CH3)CH2] ppm.
C12H20O4 (228.3): calcd. C 63.14, H 8.83; found C 62.95, H 8.99.
Methyl (؎)-3-(2,6,6-Trimethyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)-
propanoate (16): Chlorotrimethylsilane (1.47 g, 13.5 mmol) and
Et3N (2.75 g, 27.2 mmol) were added to a solution of the keto ester
(Ϯ)-7b [prepared as (R)-7b using racemic 1-phenylethylamine,
1.03 g, 4.51 mmol] in dry DMF (5 mL). The mixture was stirred at
100 °C for 16 h. After cooling the mixture was diluted with pentane
(50 mL), and washed with water (2 ϫ 5 mL), dried with MgSO4
and concentrated under reduced pressure to leave a yellow oil
(6R,10 R)- and (6R,10S)-3-(10-Bromo-6,8,8-trimethyl-1,4,7-trioxa-
spiro[4.5]dec-6-yl)propionic Acid (19):
A solution of bromine
(1.55 g, 9.8 mmol) in CCl4 (5 mL) was added dropwise to a solution
of the acetal 18 (2.4 g, 8.8 mmol) in CCl4 (20 mL) at 40 °C. The
(1.18 g, 87%). The crude silyl enol ether (1.18 g, 3.92 mmol) was resulting dark-red solution was heated at 40 °C for 45 min, while
taken up in CCl4 (20 mL) and a solution of bromine (640 mg,
4.0 mmol) in 2 mL of CCl4 was added dropwise at Ϫ78 °C. When
the addition was complete, aqueous sodium thiosulfate was added
the color progressively faded. After cooling, aqueous sodium thio-
sulfate was added, the phases were separated and the aqueous layer
was extracted with CH2Cl2 (4 ϫ 20 mL). The combined organic
and the mixture was extracted with CH2Cl2 (4 ϫ 10 mL). The com- layers were sequentially washed with sodium hydrogencarbonate
bined organic phases were washed with brine, dried with MgSO4 and brine, dried with MgSO4 and concentrated in vacuo to give a
and concentrated under reduced pressure to give a yellow oil which yellow oil (3.1 g) which was taken up in methanol (20 mL). 2 
was used directly in the next step. The crude mixture of bromoke-
tones obtained above (1.16 g) was taken up in dry DMF (17 mL).
Sodium hydroxide (15 mL, 30 mmol) was added and the reaction
mixture was stirred at 20 °C for 18 h. Most of the methanol was
Lithium carbonate (558 mg, 7.55 mmol) and lithium bromide removed under reduced pressure and 3  hydrochloric acid was
(656 mg, 7.55 mmol) were added and the resulting mixture was
heated at 80 °C for 16 h. After cooling to 20 °C the reaction mix-
added at 0 °C until pH 3. The mixture was extracted with CH2Cl2
(4 ϫ 30 mL). The combined organic layers were dried with MgSO4
ture was poured into 1  hydrochloric acid, and extracted with and concentrated in vacuo to give the crude acid 19 (2.8 g, 94%)
diethyl ether. The organic layer was dried with MgSO4 and concen-
trated under reduced pressure to leave an oil which was purified by
chromatography over silica gel (cyclohexane/EtOAc, 4:1) to give
the enone 16 as a colorless oil 550 mg, 54% overall yield from 7b.
as a yellow oil which was used in the next step without further
purification. IR (film): ν˜ ϭ 3500Ϫ2500 (OH), 1705 (CO2H), 1446,
1415, 1367, 1339, 1312, 1209, 1098 cmϪ1 1H NMR (200 MHz,
.
CDCl3) the presence of a 2:1 mixture of diastereomers induced the
splitting of some signals, δ ϭ 4.78Ϫ4.74 (m, 1 H, CHBr),
4.37Ϫ4.33 (m, 2 H, OCH2CH2O), 4.10Ϫ4.01 (m, 2 H, OCH2-
IR (film): ν˜ ϭ 1740 (CO2Me), 1683 (CO), 1438, 1373, 1260 cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ 6.82 (d, J ϭ 10.2 Hz, 1 H, HCϭ
Eur. J. Org. Chem. 2004, 1911Ϫ1922
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1917

D. Desmae¨le et al.
CH2O), 2.57Ϫ1.30 (m, 6 H), 1.34 and 1.32 (2 s, 3 H), 1.30 and 1.24 H, OH), 1.90Ϫ1.50 (m, 4 H, CH2CH2CH2OH), 1.25 [s, 3 H,
FULL PAPER
(2 s, 3 H), 1.21 and 1.07 (2 s, 3 H) ppm. 13C NMR (50 MHz,
OC(CH3)2], 1.22 [s, 3 H, OC(CH3)2], 1.20 [s, 3 H, CH2C(CH3)O]
CDCl3) only the major isomer is described δ ϭ 180.1 (CO2CH3), ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 136.4 (CH, C9), 123.1 (CH,
109.4 (C, C5), 80.1 (C, C6) 73.6 (C, C8), 67.7 (CH2, OCH2CH2O), C10), 104.9 (C, C5), 77.5 (C, C6), 71.8 (C, C8), 65.1 (CH2, OCH2-
67.0 (CH2, OCH2CH2O), 52.5 (CH, CHBr), 47.1 (CH2, C9), 32.8
(CH2, CH2CH2CO2H), 32.2 [CH3, OC(CH3)2], 28.6 (CH2,
CH2O), 64.8 (CH2, OCH2CH2O), 63.1 (CH2, CH2OH), 31.5 (CH2,
CH2CH2CH2OH), 30.7 [CH3, OC(CH3)2], 28.8 [CH3, OC(CH3)2],
CH2CH2CO2H),
27.6
[CH3,
OC(CH3)2],
23.4
(CH3, 26.2 (CH2, CH2CH2CH2OH), 21.2 [CH3, CH2C(CH3)O] ppm.
CH2C(CH3)O] ppm.
C13H22O4 (242.3): calcd. C 64.44, H 9.15; found C 64.23, H 9.24.
(R)-3-(6,8,8-Trimethyl-1,4,7-trioxaspiro[4.5]dec-9-en-6-yl)propionic
Acid (20): A solution of the bromoacetal 19 (3.37 g, 10 mmol) in
DMSO (30 mL) was added dropwise to a solution of potassium
tert-butoxide (5.2 g, 46.4 mmol) in dry DMSO (25 mL). The re-
(R)-6-(3-Bromopropyl)-6,8,8-trimethyl-1,4,7-trioxaspiro[4.5]dec-9-
ene (23): Pyridine (1.58 g, 20 mmol), CBr4 (3.0 g, 9.0 mmol) and a
solution of PPh3 (2.4 g, 9.1 mmol) in diethyl ether (12 mL) were
added sequentially to a solution of the alcohol 22 (1.10 g,
sulting mixture was heated at 110 °C for 4 h. After cooling to 0 °C, 4.5 mmol) in dry diethyl ether (16 mL) at 0 °C. The reaction mix-
1  oxalic acid was added until pH 3. The mixture was extracted
with CH2Cl2 (4 ϫ 50 mL). The combined organic layers were
washed with brine, dried with MgSO4, filtered and concentrated.
Chromatographic purification (cyclohexane/EtOAc, 1:1) gave the
ture was stirred at 20 °C for 4 h and was then filtered through a
sintered glass funnel containing a large pad of silica. The solid was
washed with diethyl ether, the filtrate was concentrated and the
resulting oil was triturated with a mixture of diethyl ether/pentane
2:1. The solid was filtered and the filtrate concentrated to leave a
acid 20 (2.05 g, 80%) as colorless crystals; m.p. 72Ϫ73 °C. [α]2D0
ϭ
Ϫ18.2 (c ϭ 5, EtOH). IR (film): ν˜ ϭ 2800Ϫ2600 (OH), 1705 colorless oil which was used directly in the next step (1.1 g, 80%).
(CO2H), 1415, 1371, 1252, 1148, 1101, 1080 cmϪ1 1H NMR [α]2D0 ϭ Ϫ19.8 (c ϭ 5, EtOH). IR (film): ν˜ ϭ 1467, 1437, 1370,
(200 MHz, CDCl3): δ ϭ 5.80 (d, J ϭ 10.4 Hz, 1 H, 9-H), 5.61 (d,
1259, 1168, 1146 cmϪ1 1H NMR (200 MHz, [D6]benzene): δ ϭ
J ϭ 10.4 Hz, 1 H, 10-H), 4.04Ϫ3.85 (m, 4 H, OCH2CH2O), 5.51 (d, J ϭ 10.4 Hz, 1 H, 9-H), 5.44 (d, J ϭ 10.4 Hz, 1 H, 10-H),
2.70Ϫ2.40 (m, H, CH2CH2CO2H), 2.20Ϫ2.05 (m, H, 3.50Ϫ3.30 (m, 4 H, OCH2CH2O), 3.18Ϫ2.98 (m, 2 H, CH2Br),
.
.
2
1
CH2CH2CO2H), 1.90Ϫ1.70 (m, 1 H, CH2CH2CO2H), 1.25 [s, 6 H, 2.30Ϫ1.45 (m, 4 H, CH2CH2CH2Br), 1.22 (s, 3 H), 1.20 (s, 3 H),
OC(CH3)2], 1.20 [s, 3 H, CH2C(CH3)O] ppm. 13C NMR (50 MHz, 1.18 (s, 3 H) ppm. 13C NMR (50 MHz, [D6]benzene): δ ϭ 137.1
CDCl3): δ ϭ 179.8 (CO2H), 136.7 (CH, C9), 123.0 (CH, C10), (CH, C9), 124.4 (CH, C10), 105.8 (C, C5), 77.9 (C, C6), 72.2 (C,
104.8 (C, C5), 77.0 (C, C6), 71.8 (C, C8), 65.2 (CH2, OCH2CH2O), C8), 65.6 (CH2, OCH2CH2O), 65.4 (CH2, OCH2CH2O), 35.6
65.0 (CH2, OCH2CH2O), 30.4 [CH3, OC(CH3)2], 30.2 (CH2, (CH2, CH2Br or CH2CH2CH2Br), 35.4 (CH2, CH2Br or
CH2CH2CO2H),
29.2
[CH3,
OC(CH3)2],
28.6
(CH2, CH2CH2CH2Br), 31.4 [CH3, OC(CH3)2], 30.1 [CH3, OC(CH3)2],
CH2CH2CO2H), 21.6 [CH3, CH2C(CH3)O] ppm. C13H20O5 28.0 (CH2, CH2CH2 CH2Br), 22.6 [CH3, CH2C(CH3)O] ppm.
(256.3): calcd. C 60.90, H 7.81; found C 60.93, H 7.92. Crystal
(R)-6,8,8-Trimethyl-6-(pent-4-ynyl)-1,4,7-trioxaspiro[4.5]dec-9-ene
(4): A solution of n-butyllithium (2.5  in hexane, 0.65 mL,
1.6 mmol) was added to a solution of (trimethylsilyl)acetylene
(158 mg, 1.6 mmol) in dry THF (2 mL) at Ϫ78 °C. The mixture
was stirred at Ϫ78 °C for 5 min and the temperature was raised to
20 °C. After stirring for a further 15 min at room temperature the
mixture was cooled to Ϫ50 °C, and a solution of the bromide 23
(250 mg, 0.82 mmol) in THF (1 mL) and DMPU (0.3 mL) was ad-
ded. The reaction mixture was stirred at Ϫ50 °C for 15 min and
the temperature was raised to 20 °C. After 12 h saturated aqueous
ammonium chloride was added and the mixture was extracted with
diethyl ether (4 ϫ 15 mL). The collected organic phases were
washed with brine, dried with MgSO4 and concentrated. The resi-
due was taken up in THF (2 mL) and a THF solution of tetrabu-
tylammonium fluoride (1 , 1 mL, 1 mmol) was added at 0 °C.
After stirring at room temperature for 1 h, saturated aqueous am-
monium chloride was added and the mixture was extracted with
diethyl ether (4 ϫ 10 mL). The collected organic phases were
washed with brine, dried with MgSO4 and concentrated. Chroma-
tography (cyclohexane/EtOAc, 10:1 ϩ 0.5% Et3N) gave compound
data: White crystal of 0.20 ϫ 0.24 ϫ 0.27 mm. C13H20O5, M ϭ
256.30. Orthorhombic, space group P212121, Z ϭ 4, a ϭ 8.618(7),
˚
b ϭ 10.372(4), c ϭ 15.207(6)A, α ϭ β ϭ γ ϭ 90°, V ϭ
3
Ϫ3
˚
˚
1359.3(13)A , d ϭ 1.252 g·cm , F(000) ϭ 552, λ ϭ 0.710693 A
(Mo-Kα), µ ϭ 0.0957 mmϪ1; 3330 reflections measured (0 Յ h Յ
11, 0 Յ k Յ 13, 0 Յ l Յ 20) on a Nonius CAD4 diffractometer.
The structure was solved with SIR92[25] and refined with
CRYSTALS[26] with hydrogen atoms riding. Refinement converged
to R(gt) ϭ 0.0439 for the 1808 reflections having I ϭ 2σ(I), and
wR(gt) ϭ 0.0555, goodness-of-fit S ϭ 1.0873. Residual electron
3
˚
density: Ϫ 0.28 and 0.23 e·A . The crystal cohesion is ensured by
one hydrogen bond involving O37, [for O37ϪH38···O1i: 1.936(3)A,
˚
174.4° (symmetry code i: x Ϫ1/2, Ϫy ϩ1/2, Ϫz)]. CCDC-226013
contains the supplementary crystallographic data for this structure.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB2 1EZ, UK: Fax: (in-
ternat.) ϩ44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk].
(R)-3-(6,8,8-Trimethyl-1,4,7-trioxaspiro[4.5]dec-9-en-6-yl)propan-1-
ol (22): A solution of the acid 20 (2.0 g, 7.8 mmol) in Et2O (10 mL)
was added to an ice-cooled suspension of LiAlH4 (600 mg,
15.8 mmol) in Et2O (20 mL). The resulting mixture was stirred at
0 °C for 30 min, and a further 30 min at 20 °C. Water was added
until most of the salts precipitated. Filtration and concentration
under reduced pressure gave an oil which was chromatographed
over silica gel (cyclohexane/EtOAc, 1:1 ϩ 0.5% Et3N) to provide
the alcohol 22 as a colorless oil (1.6 g, 84%). [α]2D0 ϭ Ϫ11.2 (c ϭ
4 (142 mg, 69% overall yield from 23) as a colorless oil. [α]2D0
ϭ
Ϫ17 (c ϭ 3.7, EtOH). IR (film): ν˜ ϭ 3292 (CϵCϪH), 2116 (weak,
1
CϵC), 1466, 1370, 1251 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ
5.80 (d, J ϭ 10.4 Hz, 1 H, 9-H), 5.68 (d, J ϭ 10.4 Hz, 1 H, 10-H),
4.00Ϫ3.75 (m, 4 H, OCH2CH2O), 2.25Ϫ2.05 (m, 2 H, CH2CϵCH),
1.90 (t,
J
ϭ
2.5 Hz,
1
H, ϵCϪH), 1.80Ϫ1.40 (m,
H, OC(CH3)2], 1.20 [s,
4
3
H,
H,
CH2CH2CH2Cϵ), 1.30 [s,
6
CH2C(CH3)O] ppm. 13C NMR (50 MHz, [D6]benzene): δ ϭ 137.1
5.7, EtOH). IR (film): ν˜ ϭ 3500Ϫ3300 (OH), 1469, 1370, 1251, (CH, C9), 124.5 (CH, C10), 105.9 (C, C5), 84.3 (CϵCH), 78.1 (C,
1
1149, 1118 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 5.75 (d, J ϭ C6), 72.0 (C, C8), 69.4 (CϵCH), 65.6 (CH2, OCH2CH2O), 65.3
10.4 Hz, 1 H, 9-H), 5.55 (d, J ϭ 10.4 Hz, 1 H, 10-H), 4.00Ϫ3.80
(CH2, OCH2CH2O), 35.7 (CH2, CH2CH2CH2Cϵ), 31.2 [CH3,
(m, 4 H, OCH2CH2O), 3.60Ϫ3.40 (m, 2 H, CH2OH), 2.70 (br. s, 1 OC(CH3)2], 30.2 [CH3, OC(CH3)2], 23.4 (CH2, CH2CH2CH2Cϵ
1918
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1911Ϫ1922

Enantioselective Synthesis of an Usneoidone Structure
FULL PAPER
or CH2CH2CH2Cϵ), 22.3 (CH2, CH2CH2CH2Cϵ or OCH2CH3) ppm. C19H30O5 (338.4): calcd. C 67.43, H 8.93; found
CH2CH2CH2Cϵ), 20.0 [CH3, CH2C(CH3)O] ppm. C15H22O3 C 67.37, H 8.79.
(250.3): calcd. C 71.97, H 8.86; found C 71.71, H 9.03.
(R)-(E,Z)-3-Methyl-6-(6,8,8-trimethyl-1,4,7-trioxaspiro[4.5]dec-9-
en-6-yl)hex-2-en-1-ol (30): A toluene solution of DIBAH (1.5 ,
(R)-5-(6,8,8-Trimethyl-1,4,7-trioxaspiro[4.5]dec-9-en-6-yl)pentan-2-
13 mL, 19.5 mmol) was added to a solution of the enoate 29 [4:1
one (27): A solution of tBuLi (1.7  in pentane, 4.3 mL, 7.3 mmol)
(E)/(Z) mixture] (1.68 g, 5.0 mmol) in THF (75 mL) at Ϫ78 °C.
was added dropwise at Ϫ78 °C to a solution of bromide 23 (1.0 g,
3.3 mmol) in a diethyl ether/THF mixture (9:1, 20 mL). The re-
sulting orange solution was stirred for 15 min at Ϫ78 °C, and a
The reaction was stirred for 2 h at Ϫ78 °C. Saturated aqueous am-
monium chloride was then added and the mixture was warmed to
room temperature. The organic layer was separated and the aque-
solution of
N-methoxy-N-methylacetamide (28)
(0.75 g,
ous layer was extracted twice with diethyl ether. The combined or-
ganic layers were washed with an aqueous solution of tartaric acid
sodium potassium salt, dried with MgSO4, evaporated and chroma-
tographed on silica gel (cyclohexane/EtOAc, 2:1 ϩ 0.5% Et3N), to
give alcohol 30 (1.40 g, 95%) as a colorless oil. IR (film): ν˜ ϭ
3600Ϫ3400 (OH), 1667 (CϭC), 1466, 1443, 1370, 1251, 1169, 1148,
1115, 1007 cmϪ1. A 4:1 (E)/(Z) ratio was determined by NMR,
only the main (E) isomer is described. 1H NMR (200 MHz,
CDCl3): δ ϭ 5.76 (d, J ϭ 10.4 Hz, 1 H, 9-H), 5.55 (d, J ϭ 10.4 Hz,
1 H, 10-H), 5.37 (t, J ϭ 6.7 Hz, 1 H, CϭCHCH2OH), 4.09 (d, J ϭ
6.7 Hz, 2 H, CϭCHCH2OH), 4.05Ϫ3.80 (m, 4 H, OCH2CH2O),
1.95 [t, J ϭ 7.2 Hz, 2 H, CH2(CH3)CϭCHCH2OH], 1.70Ϫ1.30 [m,
7.27 mmol) in THF (10 mL) was added. The mixture was stirred
for 15 min at Ϫ78 °C and slowly warmed up to room temperature.
After 3 h, saturated aqueous ammonium chloride was added, the
ethereal layer was separated, and the aqueous phase extracted with
diethyl ether (3 ϫ 20 mL). The combined organic phases were dried
with MgSO4 and concentrated to give an oil which was chromato-
graphed on silica gel (cyclohexane/EtOAc, 8:1 ϩ 0.5% Et3N, then
4:1 ϩ 0.5% Et3N) to give ketone 27 as a yellow oil (0.40 g, 46%).
[α]2D0 ϭ Ϫ18.0 (c ϭ 5.1, EtOH). IR (film): ν˜ ϭ 1714 (CϭO), 1466,
1368, 1251, 1148, 1112 cmϪ1
5.79 (d, J ϭ 10.4 Hz, 1 H, 9-H), 5.58 (d, J ϭ 10.4 Hz, 1 H, 10-H),
4.05Ϫ3.85 (m, H, OCH2CH2O), 2.50Ϫ2.35 (m, H,
.
1H NMR (200 MHz, CDCl3): δ ϭ
4
2
5
H, OH, CH2CH2CH2(CH3)Cϭ], 1.65 [s, 3 H, (CH3)Cϭ
CH3COCH2), 2.12 (s, 3 H, CH3COCH2), 1.84Ϫ1.48 (m, 4 H,
CH3COCH2CH2CH2), 1.27 [s, 3 H, OC(CH3)2], 1.26 [s, 3 H,
OC(CH3)2], 1.22 [s, 3 H, CH2C(CH3)O] ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 208.9 (CO), 136.7 (CH, C9), 122.9 (CH, C10), 104.9
(C, C5), 77.2 (C, C6), 71.3 (C, C8), 65.0 (CH2, OCH2CH2O), 64.8
(CH2, OCH2CH2O), 44.2 (CH2, CH3COCH2), 34.5 (CH2,
CH3COCH2CH2CH2), 30.3 [CH3, OC(CH3)2], 29.6 (CH3,
CH3COCH2), 29.3 [CH3, OC(CH3)2], 21.0 [CH3, CH2C(CH3)O],
17.5 (CH2, CH3COCH2CH2CH2) ppm. C15H24O4 (268.3): calcd. C
67.16, H 8.95; found C 66.83, H 9.18.
CHCH2OH], 1.22 [s, 3 H, OC(CH3)2], 1.20 [s, 3 H, OC(CH3)2],
1.16 [s, 3 H, CH2C(CH3)O] ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 139.6 (C, CϭCHCH2OH), 136.6 (CH, C9), 124.2 (CH, Cϭ
CHCH2OH), 123.3 (CH, C10), 105.1 (C, C5), 77.4 (C, C6), 71.4
(C, C8), 65.1 (CH2, OCH2CH2O), 65.0 (CH2, OCH2CH2O), 59.1
(CH2, CϭCHCH2OH), 40.1 [CH2, CH2(CH3)Cϭ], 34.8 [CH2,
CH2CH2CH2(CH3)CϭC], 29.9 [CH3, OC(CH3)2], 29.5 [CH3,
OC(CH3)2], 21.1 [CH2, CH2CH2(CH3)CϭC], 20.8 [CH3,
CH2C(CH3)O], 16.1 [CH3, CH2(CH3)Cϭ] ppm. C17H28O4 (296.4):
calcd. C 68.89, H 9.52; found C 68.64, H 9.60.
Ethyl (R)-(E,Z)-3-Methyl-6-(6,8,8-trimethyl-1,4,7-trioxaspiro[4.5]-
dec-9-en-6-yl)hex-2-enoate (29): A slight excess of a nBuLi solution
(2.5  in hexane, 0.84 mL, 2.1 mmol) was added dropwise to a solu-
tion of triethyl phosphonoacetate (450 mg, 2.0 mmol) in THF
(2 mL) cooled to Ϫ60 °C. The mixture was warmed up to Ϫ20 °C
and stirred for 20 min at this temperature. A solution of ketone 27
(270 mg, 1.0 mmol) in THF (0.5 mL) was then added in one por-
tion to the clear phosphonoacetate anion solution at Ϫ20 °C, and
the reaction mixture was stirred for 24 h at room temperature. Satu-
rated aqueous ammonium chloride (10 mL) was then added, the
mixture was extracted with diethyl ether (4 ϫ 50 mL) and the col-
lected organic phases were washed with brine, dried with MgSO4
and concentrated. Chromatography (cyclohexane/EtOAc, 6:1 ϩ
0.5% Et3N) gave ester 29 (280 mg, 83%) as an oil. IR (film): ν˜ ϭ
1714 (CO2Et), 1648 (CϭC), 1465, 1369, 1221, 1147 cmϪ1. A 4:1
(E)/(Z) ratio was determined by NMR spectroscopy, only the main
(E) isomer is described. 1H NMR (400 MHz, CDCl3): δ ϭ 5.77 (d,
J ϭ 10.3 Hz, 1 H, 9-H), 5.65 (s, 1 H, ϭCHCO2Et), 5.56 (d, J ϭ
10.3 Hz, 1 H, 10-H), 4.11 (q, J ϭ 7.2 Hz, 2 H, OCH2CH3),
(R)-(E,Z)-3-Methyl-6-(6,8,8-trimethyl-1,4,7-trioxaspiro[4.5]dec-9-
en-6-yl)hex-2-enal (31): A mixture of the alcohol 30 [4:1 (E)/(Z)
mixture] (300 mg, 1.01 mmol) and MnO2 (610 mg, 7.0 mmol) in di-
chloromethane (10 mL) was stirred at 20 °C for 12 h. Filtration
through Celite and concentration afforded a yellow oil. Flash chro-
matography (cyclohexane/ethyl acetate, 4:1) furnished the pure al-
dehyde 31 (270 mg, 90%) as a colorless oil. IR (film): ν˜ ϭ 1672
(CO), 1630 (CϭC), 1466, 1371, 1251, 1169, 1149, 1122, 1082 cmϪ1
.
A 4:1 (E)/(Z) ratio was determined by NMR, only the main (E)
isomer is described. 1H NMR (200 MHz, CDCl3): δ ϭ 9.98 (d, J ϭ
7.9 Hz, 1 H, CHϭO), 5.90 (m, 1 H, CϭCHCHO), 5.79 (d, J ϭ
10.0 Hz, 1 H, 9-H), 5.58 (d, J ϭ 10.0 Hz, 1 H, 10-H), 4.05Ϫ3.80
(m, 4 H, OCH2CH2O), 2.20 [t, J ϭ 7.2 Hz, 2 H, CH2(CH3)Cϭ
CHCHO], 2.16 [s, 3 H, (CH3)CϭCHCHO], 1.90Ϫ1.40 [m, 4 H,
CH2CH2CH2(CH3)Cϭ], 1.22 [s, 3 H, OC(CH3)2], 1.20 [s, 3 H,
OC(CH3)2], 1.16 [s, 3 H, CH2C(CH3)O] ppm. C17H26O4 (294.3):
calcd. C 69.36, H 8.90; found C 69.38, H 8.94.
(6R)-(E,Z)-2-(tert-Butyldimethylsilyloxy)-4-methyl-7-(6,8,8-
4.05Ϫ3.85 (m,
4
H, OCH2CH2O), 2.12 [s,
3
H, (CH3)Cϭ trimethyl-1,4,7-trioxaspiro[4.5]dec-9-en-6-yl)hept-3-enenitrile
(3):
CHCO2Et], 2.15Ϫ2.00 [m,
2
H, CH2(CH3)CϭCHCO2Et], tert-Butyldimethylsilyl cyanide (400 g, 2.88 mmol) was added to a
1.80Ϫ1.40 [m, 4 H, CH2CH2CH2(CH3)Cϭ], 1.22 (t, J ϭ 7.2 Hz, 3 solution of the aldehyde 31 (200 mg, 0.68 mmol) in acetonitrile
H, OCH2CH3), 1.24 [s, 3 H, OC(CH3)2], 1.22 [s, 3 H, OC(CH3)2], (5 mL) and the resulting mixture was heated at reflux for 10 h.
1.17 [s, 3 H, CH2C(CH3)O] ppm. 13C NMR (100 MHz, CDCl3):
Concentration under reduced pressure afforded a crude oil. Chrom-
δ ϭ 166.8 (CO2Et), 160.1 (C, CϭCHCO2Et), 136.8 (CH, C9), 123.0 atographic purification (cyclohexane/EtOAc, 10:1 ϩ 0.5% Et3N)
(CH, C10), 115.4 (CH, CϭCHCO2Et), 105.0 (C, C5), 77.3 (C, C6), gave the cyanohydrin 3 as a colorless oil (235 mg, 80%). IR (film):
71.4 (C, C8), 65.1 (CH2, OCH2CH2O), 64.9 (CH2, OCH2CH2O), ν˜ ϭ 1666 (CϭC), 1472, 1369, 1254, 1149, 1119, 1102, 1083 cmϪ1
59.3 (CH2, OCH2CH3), 41.5 [CH2, CH2(CH3)Cϭ], 34.8 [CH2,
.
1H NMR (200 MHz, CDCl3) the presence of two diastereomers in
CH2CH2CH2(CH3)Cϭ], 30.2 [CH3, OC(CH3)2], 29.6 [CH3, a 1:1 ratio, and a 4:1 ratio of (E)/(Z) geometric isomers induced
OC(CH3)2], 21.0 [CH2, CH2CH2(CH3)Cϭ], 20.9 [CH3, the splitting of some signals δ ϭ 5.80 (d, J ϭ 10.3 Hz, 1 H, 9-H),
CH2C(CH3)O], 18.7 [CH3, CH2(CH3)CϭC], 14.3 (CH3, 5.59 (d,
J
ϭ
10.3 Hz,
1
H, 10-H), 5.33 [m,
1
H, Cϭ
Eur. J. Org. Chem. 2004, 1911Ϫ1922
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1919

D. Desmae¨le et al.
FULL PAPER
CHCH(CN)OSi], 5.08 [d, J ϭ 8.1 Hz, 1 H, CϭCHCH(CN)OSi], (7.3 g, 19.6 mmol) in cyclohexane (40 mL) and the mixture was
4.05Ϫ3.80 (m, 4 H, OCH2CH2O), 2.04 [broad t, J ϭ 7.0 Hz, 2 H, stirred at room temperature for 1 h. The clear solution was then
CH2(CH3)CϭCH(CN)OSi],
1.80Ϫ1.30
[m,
4
H,
cooled to Ϫ78 °C and dry diethyl ether (50 mL) was added, fol-
CH2CH2CH2(CH3)Cϭ], 1.78 and 1.70 [2 s, 3 H, (CH3)Cϭ lowed by 1-bromo-3-methylbut-2-ene (8.7 g, 58.4 mmol) and
CHCH2OH], 1.26 [s, 3 H, OC(CH3)2], 1.24 [s, 3 H, OC(CH3)2], DMPU (7 mL). The temperature was gradually raised to 20 °C
1.19 [s, 3 H, CH2C(CH3)O], 0.90 [s, 9 H, (CH3)3CSi], 0.18 [s, 3 over a 1 h period, and the mixture was stirred at room temperature
H, (CH3)2SiO], 0.12 [s, 3 H, (CH3)2Si]) ppm. 13C NMR (50 MHz,
[D6]benzene) the presence of two diastereomers in a 1:1 ratio, and
(E)/(Z) geometric isomers in a 4:1 ratio induced the splitting of
for 12 h. Saturated aqueous ammonium chloride was added and
the mixture was extracted with diethyl ether (4 ϫ 50 mL). The col-
lected organic phases were washed with brine, dried with MgSO4
some signals δ ϭ 142.9 and 142.8 [C, HCϭC(CH3)CH2], 136.5 and concentrated. Chromatography (cyclohexane ϩ 0.5% Et3N
(CH, C9), 124.0 (CH, C10), 122.2, 122.0 121.5 and 121.4 [CH, Cϭ then cyclohexane/EtOAc, 99:1 ϩ 0.5% Et3N) gave compound 38
CHCH(CN)OSi], 119.5 (C, CN), 105.3 (C, C5), 77.5 (C, C6), 71.4 (6.45 g, 91%) as a colorless oil. IR (film): ν˜ ϭ 1599, 1499, 1466,
1
(C, C8), 65.1 (CH2, OCH2CH2O), 64.8 (CH2, OCH2CH2O), 59.3 1326, 1219 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 6.51 (s, 2 H,
and 59.0 [CH, ϭCHCH(CN)OSi], 40.0 [CH2, CH2(CH3)Cϭ], 35.2 2-H, 6-H), 5.26 (broad t, J ϭ 7.2 Hz, 1 H, ArCH2CHϭC), 3.67 (s,
and 35.1 [CH2, CH2CH2CH2(CH3)Cϭ], 30.8 and 30.7 [CH3, 3 H, OCH3), 3.28 (d, J ϭ 7.2 Hz, 2 H, ArCH2CHϭC), 2.22 (s, 3
OC(CH3)2], 29.7 and 29.6 [CH3, OC(CH3)2], 26.2, 25.7, and 25.5
H, ArCH3), 1.74 [, 3 H, CH2CHϭC(CH3)2], 1.70 [s, 3 H, CH2CHϭ
[3 CH3, (CH3)3CSiO], 21.7 [CH3, CH2C(CH3)O], 21.1 [CH2, C(CH3)2], 1.40Ϫ1.00 [m, 21 H, (CH3)2CHSiO) ppm. 13C NMR
CH2CH2(CH3)Cϭ], 18.2 [C, (CH3)3CSiO], 16.4 and 16.5 (CH3,
CH2(CH3)Cϭ], Ϫ4.8, Ϫ6.3 and Ϫ8.7 [2 CH3, (CH3)2SiO] ppm.
(50 MHz, CDCl3): δ ϭ 151.7 (C, C4), 150.6 (C, C1), 134.9 [C, HCϭ
C(CH3)2], 132.4 (C, C3 or C5), 131.4 (C, C3 or C5), 123.0 (CH,
C24H41NO4Si (435.6): calcd. C 66.16, H 9.49, N 3.21; found C ArCH2CHϭC), 119.7 (CH, C2 or C6), 118.3 (CH, C2 or C6), 60.4
66.16, H 9.68, N 3.06.
(CH3, OCH3), 28.1 (CH2, ArCH2CHϭ), 25.6 [CH3, HCϭ
C(CH3)2], 17.9 [6 CH3, SiCH(CH3)2], 17.7 [CH3, HCϭC(CH3)2],
16.1 (CH3, ArCH3), 12.3 [3 CH, SiCH(CH3)2] ppm. MS (ESI):
m/z (%) ϭ 361.3 (100) [Mϩ Ϫ 1], 291.1(66). C22H38O2Si (362.6):
calcd. C 72.87, H 10.56; found C 72.81, H 10.58.
2-Bromo-6-methyl-4-(triisopropylsilyloxy)phenol (34): Triisoprop-
ylchlorosilane (8.69 g, 45.0 mmol) was added dropwise at Ϫ10 °C
to a solution of 2-bromo-6-methylbenzene-1,4-diol (6)[17b] (8.36 g,
41.1 mmol) and imidazole (3.1 g, 45.0 mmol) in anhydrous DMF
(125 mL). The temperature was slowly raised to 20 °C and stirring
was continued for 18 h. The mixture was poured into ice-cooled
water and extracted with diethyl ether (3 ϫ 100 mL). The combined
organic phases were dried with MgSO4 and concentrated under
reduced pressure to give a yellowish oil which was used directly in
the next step since substantial isomerization occurred on silica
(14.5 g, quantitative). IR (film): ν˜ ϭ 3535 (OH), 1608, 1577, 1474,
1411, 1183 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 6.82 (m, 1 H,
3-H), 6.62 (m, 1 H, 5-H), 5.10 (broad s, 1 H, OH), 2.24 (s, 3 H,
CH3), 1.35Ϫ1.00 [m, 21 H, (CH3)2CHSiO) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 150.2 (C, C1), 144.8 (C, C4), 125.9 (C, C6),
121.9 (CH, C3 or C5), 119.9 (CH, C3 or C5), 109.3 (C, C2), 18.0
[6 CH3, OSiCH(CH3)2], 16.8 (CH3, ArCH3), 12.6 [3 CH, OS-
iCH(CH3)2] ppm. C16H27O2SiBr·1/4H2O (362.9): calcd. C 52.81, H
7.62; found C 52.68, H 7.61.
(E)-4-[2-Methoxy-3-methyl-5-(triisopropylsilyloxy)phenyl]-2-
methylbut-2-en-1-ol (37): A mixture of 38 (3.1 g, 8.6 mmol) and sel-
enium dioxide (1.14 g, 10.3 mmol) in 1,4-dioxane (33 mL) and
water (2 mL) was refluxed for 1 h. After cooling the selenium was
filtered off and the filtrate was washed with brine, dried and con-
centrated under reduced pressure. The oily residue was taken up in
absolute ethanol (30 mL) and sodium borohydride (380 mg,
10.0 mmol) was added portionwise at 0 °C. When the addition was
complete the mixture was stirred at 20 °C for 30 min. 1  Hydro-
chloric acid was then added until neutrality, and the mixture was
extracted with CH2Cl2 (4 ϫ 50 mL). The organic layer was washed
with brine, dried and concentrated in vacuo. The residue was chro-
matographed on silica gel (cyclohexane/EtOAc, 6:1 ϩ 0.5% Et3N)
to give the allylic alcohol 37 (1.9 g, 60%) as a colorless oil. IR
(film): ν˜ ϭ 3600Ϫ3200 (OH), 1599 (CϭC), 1475, 1327, 1217 cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 6.53 (d, J ϭ 2.9 Hz, 1 H, 4-H),
6.50 (d, J ϭ 2.9 Hz, 1 H, 6-H), 5.55 (t, J ϭ 7.1 Hz, 1 H,
ArCH2CHϭC), 4.02 [br. s, 2 H, HCϭC(CH3)CH2OH], 3.68 (s, 3
H, OCH3), 3.35 (d, J ϭ 7.1 Hz, 2 H, ArCH2CHϭC), 2.23 (s, 3 H,
ArCH3), 1.78 [s, 3 H, HCϭC(CH3)CH2OH], 1.30 (s, 1 H, OH),
1.25Ϫ1.15 [m, 3 H, OSiCH(CH3)2], 1.08 [d, J ϭ 8.5 Hz, 18 H,
OSiCH(CH3)2] ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 151.8 (C,
C2), 150.5 (C, C5), 135.6 [C, HCϭC(CH3)CH2OH], 134.1 (C, C1),
131.5 (C, C3), 124.7 (CH, HCϭC(CH3)CH2OH], 119.9 (CH, C4),
118.3 (CH, C6), 68.8 [CH2, ϭC(CH3)CH2OH], 60.4 (CH3, OCH3),
28.0 (CH2, ArCH2CHϭC), 17.9 [6 CH3, OSiCH(CH3)2], 16.2
(CH3, ArCH3), 13.7 [CH3, HCϭC(CH3)CH2OH], 12.6 [3 CH,
OSiCH(CH3)2] ppm. C22H38O3Si·1/4H2O (382.7): calcd. C 68.97,
H 10.13; found C 68.98, H 9.86.
(3-Bromo-4-methoxy-5-methylphenoxy)triisopropylsilane
(35):
Methyl iodide (11.3 g, 80 mmol) and potassium carbonate (11.3 g,
82 mmol) were added to a solution of the crude phenol 34 (14.5 g,
41 mmol) in acetone (180 mL). The mixture was stirred at reflux
for 4 h. After cooling, saturated aqueous ammonium chloride was
added and the mixture was extracted with diethyl ether (4 ϫ
100 mL). The collected organic phases were washed with brine,
dried with MgSO4 and concentrated. Chromatographic purifi-
cation (cyclohexane ϩ 0.5% Et3N, then cyclohexane/EtOAc, 10:1,
ϩ 0.5% Et3N) gave 35 as a colorless oil (10.7 g, 70% overall from
6). IR (film): ν˜ ϭ 1598, 1561, 1473, 1422, 1308, 1220, 1019 cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ 6.89 (d, J ϭ 3.0 Hz, 1 H, 2-H),
6.63 (d, J ϭ 3.0 Hz, 1 H, 6-H), 3.75 (s, 3 H, OCH3), 2.26 (s, 3
H, ArCH3), 1.35Ϫ1.00 [m, 21 H, (CH3)2CHSiO] ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 152.3 (C, C4), 149.6 (C, C1), 133.1 (C, C5),
121.7 (CH, C2 or C6), 121.3 (CH, C2 or C6), 116.7 (C, C3), 60.2
(CH3, OCH3), 17.8 [6 CH3, SiCH(CH3)2], 16.7 (CH3, ArCH3), 12.3
[3 CH, SiCH(CH3)2] ppm. C17H29BrO2Si (372.9): calcd. C 54.68,
H 7.83; found C 54.31, H 7.88.
(E)-[3-(4-Bromo-3-methylbut-2-enyl)-4-methoxy-5-methylphenoxy]-
triisopropylsilane (5): A solution of bromine (1.74 g, 10.9 mmol) in
CH2Cl2 (5 mL) was added dropwise to an ice-cooled solution of
1,2-bis(diphenylphosphanyl)ethane (2.20 g, 5.45 mmol) in CH2Cl2
(25 mL). The addition was conducted at a rate to maintain the
Triisopropyl[4-methoxy-3-methyl-5-(3-methylbut-2-enyl)phenoxy]- reaction temperature below 10 °C. A solution of alcohol 37 (1.65 g,
silane (38): A dibutyl ether solution of PhLi (2.5 , 11 mL,
27.5 mmol) was added to an ice-cooled solution of aryl bromide 35
1.8 mmol), in CH2Cl2 (5 mL) was added and the resulting mixture
was stirred at 20 °C for 2 h. Et2O (70 mL) followed by n-pentane
1920
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Enantioselective Synthesis of an Usneoidone Structure
FULL PAPER
(140 mL) were added to precipitate the by-products. The mixture C4Ј), 134.6 (C, C2Ј), 134.3 (C, C6Ј), 130.8 (C, C3), 127.9 (CH, C2),
was filtered through a thin pad of silica gel and the solids were 122.2 (2 CH, C6 and C13), 115.7 (CH, C5Ј), 113.8 (CH, C3Ј), 80.4
washed with diethyl ether/pentane (1:2, 2 ϫ 25 mL). The filtrate (C, C11), 71.7 (C, C15), 60.5 (CH3, OCH3), 55.5 (CH2, C4), 41.2
was concentrated under reduced pressure to afford the sensitive
allylic bromide 5 as a colorless oil (1.70 g, 88%) which was used in
the next step without further purification. IR (film): ν˜ ϭ 1600 (Cϭ
(CH2, C8), 39.4 (CH2, C10), 30.4 (CH3, C16), 29.1 (CH3, C17),
28.1 (CH2, C1), 26.6 (CH3, C18), 21.7 (CH2, C9), 19.2 (CH3, C19),
16.5 (CH3, C20), 16.2 (CH3, ArCH3) ppm. MS (70 eV): m/z (%) ϭ
454 (100) [Mϩ], 273 (8), 249 (36), 231 (38), 213 (34), 205 (20), 191
(21), 175 (39), 151 (22), 140 (52), 137 (22), 125 (28), 121 (21), 109
C), 1475, 1327, 1217, 1175 cmϪ1 1H NMR (200 MHz, [D6]ben-
.
zene): δ ϭ 6.74 (d, J ϭ 2.6 Hz, 1 H, 2-H or 6-H), 6.69 (d, J ϭ
2.6 Hz, 1 H, 2-H or 6-H), 5.52 (broad t, J ϭ 7.4 Hz, 1 H, (21), 95 (60). HRMS: calcd. 454.2719; found 454.2724.
ArCH2CHϭC), 3.59 (s, 2 H, CH2Br), 3.39 (s, 3 H, OCH3), 3.24 (d, C28H38O5·H2O (472.6): calcd. C 71.16, H 8.53; found C 71.37, H
J ϭ 7.4 Hz, 2 H, ArCH2CHϭC), 2.15 (s, 3 H, ArCH3), 1.66 [s, 3 8.80.
H, HCϭC(CH3)CH2OH], 1.30Ϫ1.10 [m, 21 H, OSiCH(CH3)2]
ppm. 13C NMR (50 MHz, [D6]benzene): δ ϭ 152.0 (C, C2), 151.0
(C, C5), 133.4 (C, HCϭC(CH3)CH2OH], 132.7 (C, C1), 131.6 (C,
C3), 129.4 [CH, HCϭC(CH3)CH2OH], 121.4 (CH, C4), 120.2 (CH,
C6), 59.7 (CH3, OCH3), 40.6 [CH2, ϭC(CH3)CH2Br], 28.5(CH2,
ArCH2CHϭC), 17.8 [6 CH3, OSiCH(CH3)2], 16.0 (CH3, ArCH3),
14.2 [CH3, HCϭC(CH3)CH2OH], 12.7 [3 CH, OSiCH(CH3)2] ppm.
(؎)-3-(2,6,6-Trimethyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)propionic
Acid (43): 2  Hydrochloric acid (10 mL) was added to a solution
of acetal (Ϯ)-20 (500 mg, 1.95 mmol) in THF (10 mL) and the re-
sulting mixture was stirred at 20 °C for 1 h. The solvent was re-
moved under reduced pressure and the aqueous residue was ex-
tracted with EtOAc (4 ϫ 20 mL). The organic layers were dried
with MgSO4 and concentrated to leave a colorless oil (350 mg,
85%). IR (film): ν˜ ϭ 3600Ϫ2500 (CO2H), 1709 (CO2H), 1682 (CO),
(11R)-(E,Z)-2-[10-(5-Hydroxy-2-methoxy-3-methylphenyl)-4,8-
dimethyl-6-oxodeca-4,8-dienyl]-2,6,6-trimethyl-6H-pyran-3-one
(1a,b): A solution of n-butyllithium (2.5  in hexane, 0.65 mL,
1.6 mmol) was added at Ϫ5 °C to a solution of diisopropylamine
(162 mg, 1.6 mmol) in THF (1 mL). The mixture was stirred at Ϫ5
°C for 15 min and cooled to Ϫ78 °C. A solution of the crude silyl-
ated cyanohydrin 3 (565 mg, 1.3 mmol) in THF (0.75 mL) was ad-
ded dropwise. The resulting mixture was stirred at Ϫ40 °C for
30 min and a solution of bromide 5 (1.41 g, 3.2 mmol) in a mixture
of THF (0.75 mL) and DMPU (2 mL) was then added. The reac-
tion mixture was stirred while the temperature was gradually raised
to room temperature. After 4 h at 20 °C, saturated aqueous am-
1
1439, 1374, 1264, 1183, 1093 cmϪ1. H NMR (200 MHz, CDCl3):
δ ϭ 9.80Ϫ8.80 (m, 1 H, OH), 6.84 (d, J ϭ 10.5 Hz, 1 H, 5-H), 5.92
(d, J ϭ 10.5 Hz, 1 H, 4-H), 2.55Ϫ2.15 (m, 3 H, CH2CH2CO2H),
1.95 (m, 1 H, CH2CH2CO2H), 1.44 [s, 3 H, CH2(CH3)CO], 1.38 [s,
6 H, OC(CH3)2] ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 199.2 (C,
CO), 179.4 (C, CO2H), 155.1 (CH, C5), 122.1 (CH, C4), 79.6 (C,
C2), 71.8 (C, C6), 34.1 (CH2, CH2CH2CO2H), 30.2 [CH3,
CH2(CH3)CO], 28.9 (CH2, CH2CH2CO2H), 28.8 [CH3,
OC(CH3)2], 26.2 [CH3, OC(CH3)2] ppm. C11H16O4 (212.2): calcd.
C 62.25, H 7.60; found C 62.14, H 7.57.
monium chloride was added and the mixture was extracted with (؎)-3-(5-Hydroxy-2,6,6-trimethyl-5,6-dihydro-2H-pyran-2-yl)-
diethyl ether (4 ϫ 15 mL). The collected organic phases were propionic Acid (45): Hydrogen peroxide (35%, 480 mg, 4.9 mmol)
washed with brine, dried with MgSO4 and concentrated. Filtration
through a thin pad of silica (cyclohexane/EtOAc, 9:1 ϩ 0.5% Et3N)
gave the cyanohydrin 40 (830 mg, 80%) as a yellow oil which was
directly used in the next step without further purification.
A THF solution of tetrabutylammonium fluoride (1 , 4 mL,
4 mmol) was added to a solution of the above product (830 mg,
1.04 mmol) in THF (5 mL). The resulting mixture was stirred at 20
°C for 2 h and 0.5  aqueous oxalic acid (6 mL) was added. The
mixture was extracted with diethyl ether (3 ϫ 10 mL). The com-
and 1  sodium hydroxide (2.8 mL, 2.8 mmol) were added sequen-
tially to a solution of enone 43 (350 mg, 1.65 mmol) in methanol
(12 mL). After stirring for 30 min at room temperature, 2  hydro-
chloric acid was added until pH 5. The mixture was extracted with
EtOAc (4 ϫ 15 mL). The combined organic extracts were washed
with sodium hydrogen sulfite, dried with MgSO4 and concentrated
to leave a yellow oil (290 mg, 77%) which was taken up in methanol
(5 mL). Hydrazine monohydrate (206 mg, 4.1 mmol) was added,
followed by acetic acid (12 mg, 0.2 mmol), and the reaction mixture
bined ethereal phases were dried with MgSO4 and concentrated. was heated at reflux for 2 h. After cooling, 2  hydrochloric acid
The residue was taken up in THF (10 mL) and hydrochloric acid
(0.5 , 5 mL) was added. The reaction mixture was stirred at room
temperature for 2 h and the solvent was removed under reduced
pressure. The residue was extracted with CH2Cl2 (3 ϫ 10 mL). The
organic layer was dried with MgSO4 and concentrated. Chromatog-
was added until pH 5. The mixture was extracted with EtOAc (4
ϫ 15 mL). The combined organic extracts were dried with MgSO4
and concentrated. Chromatography on silica gel (cyclohexane/
EtOAc, 2:1) gave the allylic alcohol 45 (as a 2:1 mixture of dia-
stereomers, 110 mg, 40%) as a colorless oil. IR (film): ν˜
ϭ
raphy on silica gel (cyclohexane/EtOAc, 4:1) afforded a 3:1 mixture 3600Ϫ3100 (OH), 1708 (CO2H), 1366, 1286, 1193 cmϪ1. 1H NMR
of (E/Z)-1a,b (380 mg, 64%) as a colorless viscous oil. Attempts at (200 MHz, CDCl3) major isomer δ ϭ 6.80Ϫ6.00 (broad s, 2 H,
separating the two isomers by HPLC failed due to the reconju- OH), 5.99 (dd, J ϭ 10.3, 5.6 Hz, 1 H, 4-H), 5.62 (d, J ϭ 10.3 Hz,
gation of the ∆2,3 double bond. IR (film): ν˜ ϭ 3600Ϫ3300 (OH),
1 H, 3-H), 3.56 (d, J ϭ 5.6 Hz, 1 H, 5-H), 2.41Ϫ2.20 (m, 2 H,
2978 (CH), 2934 (CH), 2826 (CH), 1681 (CϭO), 1601 (CϭC), CH2CH2CO2H), 2.05Ϫ1.85 (m, 1 H, CH2CH2CO2H), 1.80Ϫ1.65
1464, 1374, 1320, 1215, 1175, 1093, 1013 cmϪ1 1H NMR (m, 1 H, CH2CH2CO2H), 1.26Ϫ1.15 [m, 9 H, CH2(CH3)CO and
.
(400 MHz, CDCl3), only the main (E) isomer is described, δ ϭ 6.85
(d, J ϭ 10.4 Hz, 1 H, 14-H), 6.50 (s, 2 H, 3Ј-H and 5Ј-H), 6.20 (br.
OC(CH3)2]; minor isomer δ ϭ 6.80Ϫ6.00 (broad s, 2 H, OH), 5.74
(dd, J ϭ 10.4, 1.8 Hz, 1 H, 4-H), 5.52 (dd, J ϭ 10.4, 2.2 Hz, 1 H,
s, 1 H, OH), 6.10 (s, 1 H, 6-H), 5.94 (d, J ϭ 10.4 Hz, 1 H, 13-H), 3-H), 3.91 (dd, J ϭ 2.2, 1.8 Hz, 1 H, 5-H), 2.41Ϫ2.20 (m, 2 H,
5.41 (t, J ϭ 7.4 Hz, 1 H, 2-H), 3.67 (s, 3 H, OCH3), 3.34 (d, J ϭ CH2CH2CO2H), 2.05Ϫ1.85 (m, 1 H, CH2CH2CO2H), 1.80Ϫ1.65
7.4 Hz, 2 H, 1-H), 3.09 (s, 2 H, 4-H), 2.23 (s, 3 H, ArCH3), 2.10 (m, 1 H, CH2CH2CO2H), 1.26Ϫ1.15 [m, 9 H, CH2(CH3)CO, and
(d, J ϭ 1.2 Hz, 3 H, 19-H), 2.10Ϫ2.00 (m, 2 H, 8-H), 1.70 (s, 3 H, OC(CH3)2] ppm. 13C NMR (50 MHz, CDCl3) major isomer δ ϭ
20-H), 1.70Ϫ1.40 (m, 4 H, 9-H, 10-H), 1.45 (s, 3 H, 16-H), 1.39 (s, 179.5 (CO2H), 134.0 (CH, C3), 125.8 (CH, C4), 74.6 (C, C2), 73.5
3 H, 17-H), 1.37 (s, 3 H, 18-H) ppm. 13C NMR (100 MHz, CDCl3), (C, C6), 67.6 (CH, C5), 37.3 (CH2, CH2CH2CO2H), 29.8 (CH2,
only the main (E) isomer is described, δ ϭ 199.8 (CO, C5), 199.6
CH2CH2CO2H), 27.5 [2 CH3, OC(CH3)2], 25.1 [CH3,
(CO, C12), 159.4 (C, C7), 155.5 (C, C14), 152.1 (C, C1Ј), 150.1 (C, CH2(CH3)CO] ppm; minor isomer δ ϭ 179.2 (CO2H), 132.4 (CH,
Eur. J. Org. Chem. 2004, 1911Ϫ1922
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1921

D. Desmae¨le et al.
FULL PAPER
C3), 128.2 (CH, C4), 73.7 (C, C2), 73.5 (C, C6), 70.6 (CH, C5),
37.3 (CH2, CH2CH2CO2H), 29.0 (CH2, CH2CH2CO2H), 27.5 [2
CH3, OC(CH3)2], 21.6 [CH3, CH2(CH3)CO] ppm.
[7] [7a]
J. dЈAngelo, D. Desmae¨le, F. Dumas, G. Guingant, Tetra-
hedron: Asymmetry 1992, 3, 459Ϫ505. [7b] J. dЈAngelo, C. Cave,
D. Desmae¨le, F. Dumas, Trends in Organic Synthesis (Ed.: S.
G. Pandalai), Trivandrum: India, 1993, Vol. 4, pp. 555Ϫ616.
Equatorial alcohol 15 was obtained by Luche reduction of the
keto ester 7b (NaBH4, CeCl3· 7H2O, MeOH, 1 h, 0 °C). The
2:1 cis/trans mixture of diastereomeric alcohols produced was
separated by saponification and acid-catalyzed lactonisation of
the cis-hydroxy acid, while the trans is recovered unchanged.
Diazomethane reesterification of the latter gave pure 15.
The crude reaction product was treated with MeONa in MeOH
to achieve the transesterification of some 2-hydroxyethyl ester
formed during the acetal formation.
´
[8]
Methyl (؎)-3-(2,6,6-Trimethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl)-
propionoate (42): A mixture of the alcohol 45 (100 mg, 0.48 mmol)
and DessϪMartin periodinane reagent (285 mg, 0.67 mmol) in
CH2Cl2 (5 mL) was stirred at room temperature for 1 h. The reac-
tion mixture was diluted with EtOAc, washed with saturated aque-
ous sodium thiosulfate and 1  hydrochloric acid, dried with
MgSO4 and concentrated. The residue was taken up in dry diethyl
ether (5 mL) and treated at 0 °C with an ethereal solution of diazo-
methane. After being stirred for 5 min the mixture was concen-
trated under reduced pressure. Chromatography on silica gel (cyclo-
hexane/EtOAc, 1:1) afforded the enone 42 (57 mg, 52%) as a color-
less oil. IR (film): ν˜ ϭ 1735 (CO2Me), 1685 (CO), 1437, 1393, 1373,
[9]
[10]
[11]
[12]
E.-i. Negishi, D. E. Van Horn, A. O. King, N. Okukado, Syn-
thesis 1979, 501Ϫ502.
P. Wipf, S. Lim, Angew. Chem. Int. Ed. Engl. 1993, 32,
1068Ϫ1070.
For a similar SN2Ј type process in the course of a carboalumin-
ation reaction, see: G. Hidalgo-Del Vecchio, A. C. Oehlsch-
lager, J. Org. Chem. 1994, 59, 4853Ϫ4857.
1
1292, 1165 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 6.72 (d, J ϭ
10.5 Hz, 1 H, 3-H), 5.96 (d, J ϭ 10.5 Hz, 1 H, 4-H), 3.63 (s, 3 H,
OCH3), 2.50Ϫ2.20 (m, 2 H, CH2CH2CO2H), 2.10Ϫ1.75 (m, 2 H,
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T. A. Oster, T. M. Harris, Tetrahedron Lett. 1983, 24,
CH2CH2CO2H), 1.42 (s, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H) ppm. 13
C
1851Ϫ1854. [13b] R. L. Danheiser, J. M. Morin Jr, E. J. Salaski,
J. Am. Chem. Soc. 1985, 107, 8066Ϫ8073.
NMR (50 MHz, CDCl3): δ ϭ 198.8 (C, C2), 173.9 (CO2Me), 153.0
(CH, C3), 123.5 (CH, C4), 78.2 (C, C2), 73.3 (C, C6), 51.6 (CH3,
OMe), 37.4 (CH2, CH2CH2CO2H), 28.8 (CH2, CH2CH2CO2H),
27.7 (CH3), 27.4 (CH3), 26.3 (CH3) ppm. C12H18O4 (226.3): calcd.
C 63.70, H 8.02; found C 63.53, H 8.08.
[14]
[15]
A. van der Klei, R. L. P. de Jong, J. Lugtenburg, A. G. M.
Tielens, Eur. J. Org. Chem. 2002, 3015Ϫ3023.
The condensation of the cuprate derivatives prepared from bro-
mide 23 with butynoic acid ethyl ester gave pure (E)-29 but in
a very low yield (12%): R. J. Anderson, V. L. Corbin, G. Cot-
terrell, G. R. Cox, C. A. Henrick, F. Schaub, J. B. Siddall, J.
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Acknowledgments
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K. Manju; S. Trehan, J. Chem. Soc., Perkin Trans. 1 1995,
We thank Professor Julio G. Urones (University of Salamanca,
Spain) for kindly providing us with the full spectroscopic data of
natural usneoidones. We gratefully acknowledge Dr. Domingo Go-
mez-Pardo (ESPCI, Paris) for the GC-MS spectra and Mrs. S. Mai-
resse-Lebrun for the elemental analyses.
2383Ϫ2384.
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[17b]
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A. Alexakis, D. Jachiet, J. F. Normant, Tetrahedron 1986,
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´
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Received December 8, 2003
1922
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1911Ϫ1922