An efficient ruthenium-catalyzed formal synthesis of (-)-isoavenaciolide

Article abstract of DOI:10.1002/ejoc.200400047

A formal synthesis of (-)-isoavenaciolide (1) by two different routes is reported. The first approach, leading to a key precursor 2 of (-)-isoavenaciolide (1), features the stereoselective construction of the three contiguous stereogenic centers by Evans

Full text of DOI:10.1002/ejoc.200400047

FULL PAPER
An Efficient Ruthenium-Catalyzed Formal Synthesis of (؊)-Isoavenaciolide
Olivier Labeeuw,[a] Delphine Blanc,[a] Phannarath Phansavath,*[a]
[a]
[a]
ˆ
Virginie Ratovelomanana-Vidal,* and Jean-Pierre Genet
Keywords: Antifungal agents / Asymmetric synthesis / Hydrogenation / (Ϫ)-Isoavenaciolide / Ruthenium / Natural products
A formal synthesis of (−)-isoavenaciolide (1) by two different
routes is reported. The first approach, leading to a key pre-
sequential ruthenium-catalyzed hydrogenation reactions of
β-keto ester 4 and β-hydroxy ketone 14 to form the two hy-
cursor 2 of (−)-isoavenaciolide (1), features the stereoselec- droxyl groups with an excellent control of the anti stereo-
tive construction of the three contiguous stereogenic centers
by Evans diastereoselective reduction (d.e. = 80%) of β-hy-
droxy ketone 8. In the more efficient second approach, the
nine-step sequence leading to the key precursor 2 involves
chemistry (d.e. = 99%).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
synthesis of the known acetonide 2 (Scheme 1), which is an
advanced precursor[7] of (Ϫ)-isoavenaciolide.
(Ϫ)-Isoavenaciolide (1; Scheme 1), a naturally occurring
Retrosynthetically, the target compound 2 was envisioned
secondary metabolite isolated from the fermentation broth to be available from 9 by protection of the diol moiety and
of Aspergillus and Penicillium species,[1] has been found to subsequent oxidation of the double bond (Scheme 2). The
exhibit antifungal activity and, more recently, to irreversibly anti-diol 9 would result from enantiopure β-hydroxy ester 5
inhibit vaccinia H1 related (VHR) phosphatase activity.[2] by diastereoselective alkylation and conversion of the ester
Due to its interesting α-methylene-bis(butyrolactone) skel- function into the corresponding ketone, followed by stereo-
eton and biological properties, numerous total syntheses of selective reduction of the keto group either with Evans’ re-
(Ϫ)-isoavenaciolide have been reported. Many of these ap- agent[25] or by catalytic asymmetric hydrogenation. Asym-
proaches involve optically active natural products as the metric hydrogenation of β-keto ester 4 would set the first
chiral sources,[3Ϫ6] while the other syntheses rely on stereo- hydroxyl group with high enantioselectivity.
selective reactions.[7Ϫ10] Several formal syntheses of (Ϫ)-
isoavenaciolide have also been described.[11Ϫ15] In connec-
tion with our ongoing program towards the preparation of
biologically relevant natural products or pharmaceutical
compounds,[16Ϫ22] we were interested in a synthesis of (Ϫ)-
isoavenaciolide using ruthenium-mediated asymmetric
hydrogenation[23,24] for the construction of two of the three
contiguous stereogenic centers. We report herein an efficient
Scheme 1. Structures of (Ϫ)-isoavenaciolide (1) and advanced pre-
cursor 2
Scheme 2. Retrosynthetic analysis for (Ϫ)-isoavenaciolide (1)
[a]
`
´
Laboratoire de Synthese Selective Organique et Produits
´
Naturels, UMR 7573, Ecole Nationale Superieure de Chimie Results and Discussion
de Paris,
11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France
The synthesis of the desired acetonide 2 began with ru-
thenium-mediated asymmetric hydrogenation of β-keto es-
Fax: ϩ33-1-44071062
E-mail: phansava@ext.jussieu.fr; gvidal@ext.jussieu.fr
2352
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DOI: 10.1002/ejoc.200400047
Eur. J. Org. Chem. 2004, 2352Ϫ2358

An Efficient Ruthenium-Catalyzed Formal Synthesis of (Ϫ)-Isoavenaciolide
FULL PAPER
was achieved by ozonolysis in dichloromethane in the pres-
ence of a 2.5  ethanolic sodium hydroxide solution.[32] The
spectroscopic data of 2 were found to be in agreement with
reported literature data.[7,8] Since this advanced intermedi-
ate is used for the total synthesis of (Ϫ)-isoavenaciolide (1),
our seven-step sequence leading to 2 in 37% overall yield
represents a formal total synthesis of this natural product
and compares favorably with Suzuki’s twelve-step approach
(30% overall yield) to 2.[7,8]
However, a major drawback in the above synthesis of 2
is the use of tetramethylammonium triacetoxyborohydride
for the stereoselective reduction of 8, especially when
working on large scale, since at least six equivalents of this
expensive reagent are needed for complete conversion.
Moreover, the diastereomeric excess obtained for the re-
duction step (d.e. ϭ 80%) is quite unsatisfactory and could
be improved. Thus, we were interested in a catalytic prep-
aration of 2 by ruthenium-mediated asymmetric hydrogen-
ation of 8, which would avoid the use of a large excess of
expensive tetramethylammonium triacetoxyborohydride
and should allow a higher diastereomeric excess. Unfortu-
nately, the presence of an allyl moiety on β-hydroxy ketone
8 is inconsistent with the hydrogenation reaction because of
the expected competitive reduction of the monosubstituted
alkene function. However, the asymmetric hydrogenation of
Scheme 3. Reagents and conditions: (a) 0.03 mol % [(S)-(MeO-
BIPHEP)RuBr2], H2 (10 bar), EtOH, 80 °C, 48 h, 94%, e.e. ϭ 98%;
(b) LDA (2 equiv.), THF, Ϫ78 °C, 1 h; allyl bromide (2.5 equiv.),
HMPA (1.2 equiv.), Ϫ78 °C for 1 h then Ϫ20 °C for 1 h, 81%,
d.e. ϭ 97%; (c) MeNHOMe·HCl (4.7 equiv.), iPrMgCl (9 equiv.),
THF, Ϫ20 °C, 80%; (d) nC8H17Li (2.3 equiv.), Et2O/THF, Ϫ10 °C,
5 h, 85%; (e) Me4NHB(OAc)3 (6 equiv.), CH3CN/AcOH (1:1), Ϫ20
°C, 21 h, 94%, d.e. ϭ 80%; (f) 2,2-dimethoxypropane, acetone,
PTSA cat., room temp., 1 h, 94%; (g) O3, 2.5  ethanolic NaOH, β-keto esters bearing a remote di- or trisubstituted alkene
moiety has been reported[33,34] and under controlled reac-
tion conditions, chemoselective reduction of the keto group
CH2Cl2, Ϫ78 °C, 3 h, 80%
ter 4[26] (Scheme 3). The reaction was carried out in ethanol over the alkene function can be achieved in high yield and
at 80 °C under 10 bar of hydrogen, using 0.03 mol % of the with excellent enantiomeric excess. Thus, we designed a new
complex [(S)-(MeO-BIPHEP)RuBr2] prepared in situ ac- pathway to 2 via the anti-diol 17 which would result from
cording to our convenient procedure[27] from commercially asymmetric hydrogenation of β-hydroxy ketone 14 bearing
available [(COD)Ru(2-methylallyl)2]. Under these con- a trisubstituted alkene moiety (Scheme 4).
ditions, β-hydroxy ester 5 was obtained in 94% yield and
with excellent enantiomeric excess (e.e. ϭ 98%, determined
by chiral HPLC, Chiralcel OD-H column; flow rate:
0.8 mL/min; eluent: hexane/propan-2-ol (9:1); detection at
215 nm). Under optimized conditions, alkylation of enanti-
omerically enriched 5 with allyl bromide following the
[28,29]
´
FraterϪSeebach procedure
afforded hydroxy ester 6 in
81% yield with high diastereoselectivity (d.e. ϭ 97%, deter-
mined by chiral HPLC, Chiralcel OD-H column; flow rate:
0.5 mL/min; eluent: hexane/propan-2-ol (95:5); detection at
215 nm). The resulting ester 6 was then converted into the
corresponding Weinreb amide 7[30] upon reaction with N,O-
Scheme 4. New pathway to compound 2 by asymmetric hydrogen-
ation of β-hydroxy ketone 14
The preparation of compound 17 followed a similar syn-
dimethylhydroxylamine hydrochloride in the presence of thetic route as for 8, and started with alkylation of the en-
isopropylmagnesium chloride.[31] Subsequent treatment of antiomerically enriched β-hydroxy ester 5 with 4-bromo-2-
7 with n-octylmagnesium bromide or chloride afforded β- methylbut-2-ene (Scheme 5), which afforded 11 in 78% yield
hydroxy ketone 8 in only 20Ϫ25% yield. However, the use as a single diastereomer after separation by flash chroma-
of the more reactive n-octyllithium allowed the formation tography (d.e. ϭ 99%, determined by chiral HPLC, Chiral-
of 8 in a good 85% yield. Reduction of the ketone moiety cel OD-H column; flow rate: 0.5 mL/min; eluent: hexane/
with tetramethylammonium triacetoxyborohydride in acetic propan-2-ol (95:5); detection at 215 nm). After conversion
acid[25] then afforded the expected anti-diol 9 with 80% dia- of 11 into the corresponding Weinreb amide 12 by reaction
stereomeric excess (determined by chiral HPLC, Chiralcel with N,O-dimethylhydroxylamine hydrochloride and n-bu-
OD-H column; flow rate: 1 mL/min; eluent: hexane/pro- tyllithium,[35] subsequent treatment with n-octyllithium un-
pan-2-ol (95:5); detection at 215 nm). The 90:10 mixture of der various conditions furnished ketone 14 in only 5Ϫ24%
anti/syn diols 9 was converted into the corresponding ace- yield. Indeed, in contrast with compound 7, direct addition
tonides 10 and direct conversion of olefin 10 into ester 2 of n-octyllithium to 12 led to competitive decomposition
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O. Labeeuw, D. Blanc, P. Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
The asymmetric hydrogenation reaction was first at-
tempted under a low pressure of hydrogen to avoid the re-
duction of the alkene function (Scheme 7, Table 1). Thus,
in the presence of 2 mol % of [(S)-(MeO-BIPHEP)RuBr2]
at 50 °C in methanol under either 1 or 15 bar of hydrogen,
low conversions were observed (20 or 50%, entries 1 and
2). Increasing the temperature to 80 °C afforded complete
conversion, but only the saturated diol 18 was isolated (en-
try 3). When the reaction was carried out at 50 °C under
50 bar of hydrogen, complete conversion was observed after
72 h and the desired diol 17 was obtained in 86% yield with
excellent diastereoselectivity (d.e. ϭ 99%), accompanied by
Scheme 5. Reagents and conditions: (a) LDA (2.5 equiv.), THF,
Ϫ78 °C, 1 h; 4-bromo-2-methylbut-2-ene (2.5 equiv.), HMPA (1.2
equiv.), Ϫ78 °C for 3 h then Ϫ20 °C for 1 h, 78%, d.e. ϭ 99%; (b)
MeNHOMe·HCl (3 equiv.), nBuLi (6 equiv.), THF, Ϫ78 °C, 2 h,
92%; (c) nC8H17Li (2.7 to 4 equiv.), THF or Et2O, Ϫ40 °C, 3 h,
36Ϫ63% of 13 and 5Ϫ24% of 14
14% of the saturated product 18 (entry 4).
of the amide function[36] to yield hydroxy amide 13 with
liberation of formaldehyde, probably due to the more de-
manding steric hindrance of the gem-dimethylallyl moiety
compared to the allyl function.
Scheme 7
However, this side-reaction could be circumvented by
protecting the hydroxyl group as its tert-butyldimethylsilyl
ether 15. Treatment with n-octyllithium furnished the corre-
sponding ketone 16 in a satisfactory 73% yield (Scheme 6).
Finally, deprotection of the hydroxyl function with tetrabu-
tylammonium fluoride afforded β-hydroxy ketone 14, re-
quired for the asymmetric hydrogenation.
Upon reducing the reaction time to 6 h a high conversion
(95%) was still observed and the 17/18 ratio increased in
favour of the desired anti-diol 17 (from 86:14 to 97:3, en-
tries 4 and 5), again with high diastereoselectivity (d.e. ϭ
99%). The asymmetric hydrogenation reaction was also per-
formed using (S)-SYNPHOS, a new atropisomeric ligand
bearing
a
benzodioxane core synthesized in our
group.[37Ϫ39] Thus, in the presence of 2 mol % of [(S)-(SYN-
PHOS)RuBr2] at 50 °C under 50 bar of hydrogen, anti-diol
17 was obtained with high diastereomeric excess (d.e. ϭ
99%, entry 6) and the 17/18 ratio was improved slightly to
98:2. Under the same reaction conditions but with 4 mol %
of [(S)-(MeO-BIPHEP)RuBr2] instead of 2 mol %, similar
results were observed but this time complete conversion was
obtained (entry 7). As observed previously with the parent
compound 8, reduction of β-hydroxy ketone 14 with tetra-
methylammonium triacetoxyborohydride afforded a lower
diastereomeric excess (d.e. ϭ 83%) than for the ruthenium-
mediated hydrogenation (d.e. ϭ 99%), thus validating our
Scheme 6. Reagents and conditions: (a) 2,6-lutidine, TBSOTf,
CH2Cl2, 0 °C, 1 h, 99%; (b) nC8H17Li (2 equiv.), THF, Ϫ50 °C,
2 h, 73%; (c) nBu4NF, THF, 0 °C, 2 h, 96%
Table 1. Catalytic asymmetric hydrogenation of β-hydroxy ketone 14 in the presence of [(S)-(MeOϪBiPHEP)RuBr2] or [(S)-(SYNPHOS)-
RuBr2]
Entry
ligand
% cat.
T (°C)
P (bar)
t (h)
Conv. (%)[a]
17/18[b]
d.e. (%)[c]
1
2
3
4
5
6
7
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-SYNPHOS
(S)-MeO-BIPHEP
2
2
2
2
2
2
4
50
50
80
50
50
50
50
1
15
15
50
50
50
50
24
72
72
72
6
6
6
20
50
100
100
95
95
100
100:0
97:3
0:100
86:14
97:3
98:2
97:3
99
99
Ϫ
99
99
99
99
[a] Conversions were determined by 1H NMR analysis of the crude reaction mixture. [b] The 17/18 ratio was measured by HPLC: column,
Chiralcel OD-H; flow rate: 1.0 mL/min; eluent: hexane/propan-2-ol (95:5); detection at 215 nm; tR 13.8 min, anti-18 isomer; tR 11.5 min,
[c]
syn-18 isomer; tR 15.7 min, anti-17 (2R,3R,4S) isomer; tR 12.7 min, syn-17 (2R,3R,4R) isomer. Diastereomeric excess of 17 was deter-
mined by chiral HPLC: column, Chiralcel OD-H; flow rate: 1.0 mL/min; eluent: hexane/propan-2-ol (95:5); detection at 215 nm; tR
15.7 min, anti-17 (2R,3R,4S) isomer; tR 12.7 min, syn-17 (2R,3R,4R) isomer.
2354
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An Efficient Ruthenium-Catalyzed Formal Synthesis of (Ϫ)-Isoavenaciolide
FULL PAPER
Coupling constants (J) are given in Hertz (Hz). Infrared spectra
(IR) were recorded on either a PerkinϪElmer 783G spectrometer
or an IRFT Nicolet 205 spectrometer. Mass spectra (MS) were
measured on a HewlettϪPackard 5989A (70 eV) mass spec-
trometer. Flash column chromatography was performed on Merck
silica gel (0.040Ϫ0.063 mesh). Thin layer chromatography (TLC)
analysis was performed on Merck silica gel 60 PF 254 and revealed
with either a ultra-violet lamp (λ ϭ 254 nm) or a potassium per-
manganate solution. Specific rotation values were recorded on a
PerkinϪElmer 241 polarimeter.
new approach to the anti-diol 17. Synthesis of compound 2
was then achieved by converting anti-diol 17 into the corre-
sponding acetonide 19 by ozonolysis in dichloromethane
with
a 2.5  ethanolic sodium hydroxide solution
(Scheme 8). Thus, the advanced precursor 2 of (Ϫ)-isoaven-
aciolide (1) was obtained in 86% overall yield from 17 and
its spectroscopic data were found to be in agreement with
those reported previously for this compound.[7,8]
β-Hydroxy Ester 5: Asymmetric hydrogenation of β-keto ester 4
was performed as follows: (S)-MeO-BIPHEP (16.4 mg,
0.028 mmol) and [(COD)Ru(2-methylallyl)2] (7.5 mg, 0.023 mmol,
commercially available from Acros) were placed in a round-bot-
tomed flask and dissolved in 2 mL of acetone (degassed by three
cycles of vacuum/argon at room temperature). A 0.15  methanolic
HBr solution (343 µL, 0.05 mmol) was added to this suspension
and the solution was stirred at room temperature for 30 min. After
evaporation of the solvent under vacuum, a solution of β-keto ester
4 (18.4 g, 78 mmol) in ethanol (1.4 mL) was added to the ru-
thenium catalyst. The resulting mixture was heated at 80 °C under
10 bar of hydrogen for 48 h. After removal of the solvent, purifi-
cation of the residual oil by flash chromatography (silica gel, 10%
EtOAc in cyclohexane) afforded β-hydroxy ester 5 (17.5 g, 94%) as
a colorless oil. [α]2D5 ϭ ϩ10.9 (c ϭ 1.1, EtOH). IR (film): ν˜ ϭ 3453
Scheme 8. Reagents and conditions: (a) 2,2-dimethoxypropane,
acetone, PPTS cat., room temp., 20 min, 98%; (b) O3, 2.5  etha-
nolic NaOH, CH2Cl2, Ϫ78 °C, 1 h, 88%
Conclusion
In summary, a formal synthesis of (Ϫ)-isoavenaciolide (1)
has been achieved following two routes. In a first approach,
a seven-step sequence leading to the key intermediate 2 in
37% overall yield allowed the stereoselective construction
of the three contiguous stereogenic centers with reasonable
diastereoselectivity for the 1,3 anti-diol moiety (d.e. ϭ 80%).
In the more efficient second route, the key precursor 2 was
synthesized in a highly stereoselective manner in nine steps
and 38% overall yield, which compares favorably with other
reported approaches. The two hydroxyl groups of the natu-
ral product were successfully formed by sequential catalytic
asymmetric hydrogenation reactions of β-keto ester 4 and
β-hydroxy ketone 14 with an excellent control of the anti
stereochemistry (d.e. ϭ 99%) and high chemoselectivity.
This efficient preparation of enantiomerically pure 1,3-anti
diols by asymmetric hydrogenation of β-hydroxy ketones
has been extended to various other substrates and will be
reported in a forthcoming paper.
(broad), 3031, 2981, 2925, 2860, 1734, 739, 699 cmϪ1 1H NMR
.
(300 MHz, CDCl3): δ ϭ 7.32 (m, 5 H), 4.56 (s, 2 H), 4.24 (m, 1 H),
4.16 (q, J ϭ 7.2 Hz, 2 H), 3.52 (dd, J ϭ 9.6, 4.7 Hz, 1 H), 3.47 (dd,
J ϭ 9.6, 5.9 Hz, 1 H), 3.00 (d, J ϭ 4.3 Hz, 1 H, OH), 2.54 (d, J ϭ
6.2 Hz, 2 H), 1.26 (t, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 172.2, 137.9, 128.5, 127.8 (2 C), 73.4, 73.2, 67.2, 60.7,
38.3, 14.2 ppm. MS (EI): m/z ϭ 239 [M ϩ H]ϩ. C13H18O4 (238.3):
calcd. C 65.53, H 7.61; found C 65.49, H 7.65. HPLC analysis:
Chiralcel OD-H column; flow rate: 0.8 mL/min; eluent: hexane/
propan-2-ol (9:1); detection at 215 nm; tR ϭ 12.5 min, (R)-5 isomer;
tR ϭ 14.1 min, (S)-5 isomer; e.e. ϭ 98%.
β-Hydroxy Ester 6: A solution of β-hydroxy ester 5 (5.0 g,
21.0 mmol) in THF (50 mL) was added to a solution of LDA
(51.0 mmol) in THF at Ϫ78 °C. After stirring at Ϫ78 °C for 1 h,
HMPA (4.5 mL, 25.1 mmol) and allyl bromide (4.6 mL,
52.7 mmol) were added. The reaction mixture was stirred at Ϫ78 °C
for 1 h, then at Ϫ20 °C for 1 h before more allyl bromide (1.5 mL,
17.1 mmol) was added. After stirring at Ϫ20 °C and at 0 °C for
1 h each, the mixture was quenched with saturated aqueous NH4Cl
and extracted with Et2O. The combined organic layers were washed
with water and brine, dried over MgSO4 and concentrated. Purifi-
cation of the residue by flash chromatography (silica gel, 1 to 10%
EtOAc in cyclohexane) afforded 6 (4.7 g, 81%) as a colorless oil.
[α]2D5 ϭ ϩ9.4 (c ϭ 1.2, CHCl3). IR (film): ν˜ ϭ 3480 (broad), 3040,
2990, 2940, 2870, 1730, 1455, 740, 700 cmϪ1. 1H NMR (200 MHz,
CDCl3): δ ϭ 7.36 (m, 5 H), 5.78 (ddt, J ϭ 17.0, 10.1, 7.0 Hz, 1 H),
5.03Ϫ5.15 (m, 2 H), 4.60 (d, J ϭ 12.0 Hz, 1 H), 4.53 (d, J ϭ
12.0 Hz, 1 H), 4.07Ϫ4.22 (m, 2 H), 3.94 (m, 1 H), 3.59 (dd, J ϭ
9.8, 4.4 Hz, 1 H), 3.54 (dd, J ϭ 9.8, 5.3 Hz, 1 H), 3.16 (d, J ϭ
7.4 Hz, 1 H, OH), 2.74 (m, 1 H), 2.39 (m, 2 H), 1.25 (t, J ϭ 7.1 Hz,
Experimental Section
General Remarks: All solvents were reagent grade and were distilled
under argon prior to use. Amines were distilled from potassium
hydroxide and CH2Cl2 from calcium hydride. THF and Et2O were
distilled from sodium-benzophenone. Unless stated otherwise, all
reactions were carried out under an argon atmosphere. All com-
mercially available reagents were used without further purification
unless otherwise indicated. Nuclear magnetic resonance: 1H and
13C NMR spectra were recorded either at 200 MHz and 50 MHz,
respectively, on an AC200 Bruker spectrometer, at 300 MHz and 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 174.4, 137.9, 134.8,
75 MHz, respectively, on an AC300 Bruker spectrometer, or at
400 MHz and 100 MHz, respectively, on an ARX400 Bruker spec-
trometer. Chemical shifts are given in ppm referenced to the re-
sidual proton resonance of the solvent (δ ϭ 7.26 ppm for CDCl3)
for 1H NMR spectroscopy. For 13C NMR, chemical shifts are refer-
128.5, 127.9, 127.8, 117.4, 73.5, 72.3, 71.0, 60.7, 47.7, 33.6, 14.3
ppm. MS (EI): m/z ϭ 278 [M]ϩ. C16H22O4 (278.3): calcd. C 69.04,
H 7.96; found C 69.01, H 8.12. HPLC analysis: Chiralcel OD-H
column; flow rate: 0.5 mL/min; eluent: hexane/propan-2-ol (95:5);
detection at 215 nm; tR ϭ 19.6 min, (2S,3R)-6 isomer; tR
ϭ
enced to the central peak of the solvent (δ ϭ 77.1 ppm for CDCl3). 22.1 min, (2R,3R)-6 isomer; d.e. ϭ 97%.
Eur. J. Org. Chem. 2004, 2352Ϫ2358
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O. Labeeuw, D. Blanc, P. Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
Amide 7: A 2  solution of isopropylmagnesium chloride in THF
(5.4 mL, 10.8 mmol) was added to a solution of N,O-dimethylhy-
δ ϭ 137.9, 137.4, 128.6, 128.0, 127.9, 116.6, 73.5, 73.2, 72.1, 72.0,
43.5, 34.0, 32.0, 30.0, 29.8, 29.7, 29.4, 26.5, 22.8, 14.2 ppm. MS
droxylamine hydrochloride (943 mg, 5.6 mmol) and β-hydroxy ester (EI): m/z ϭ 349 [M ϩ H]ϩ. C22H36O3 (348.52): calcd. C 75.82, H
6 (1.0 g, 3.6 mmol) in THF (7 mL) at Ϫ20 °C. After stirring for 2 h 10.41; found C 75.69, H 10.52. HPLC analysis: Chiralcel OD-H
at Ϫ20 °C, more N,O-dimethylhydroxylamine hydrochloride
(943 mg, 5.6 mmol) and isopropylmagnesium chloride (5.4 mL,
column; flow rate: 1.0 mL/min; eluent: hexane/propan-2-ol (95:5);
detection at 215 nm; tR ϭ 14.1 min, syn-9 isomer; tR ϭ 16.5 min,
10.8 mmol) were added and the reaction mixture was stirred for 2 h anti-9 isomer; d.e. ϭ 80%.
at Ϫ10 °C. A third addition of N,O-dimethylhydroxylamine hydro-
Acetonide 10: 2,2-Dimethoxypropane (1.0 mL, 8.2 mmol) and p-
chloride (943 mg, 5.6 mmol) and isopropylmagnesium chloride
(5.4 mL, 10.8 mmol) allowed complete conversion after stirring at
Ϫ10 °C for 2 h. The reaction mixture was quenched with a satu-
rated aqueous solution of NH4Cl, followed by 1  HCl, and then
extracted with Et2O. The combined organic layers were dried over
MgSO4 and concentrated. Purification of the residue by flash chro-
matography (silica gel, 10 to 40% EtOAc in cyclohexane) afforded
7 (844 mg, 80%) as a colorless oil. [α]2D5 ϭ Ϫ12.0 (c ϭ 1.0, CHCl3).
IR (film): ν˜ ϭ 3400 (broad), 3030, 2930, 2860, 1640, 1450, 740, 700
toluenesulfonic acid (7.1 mg, 4.1 10Ϫ2 mmol) were added to a solu-
tion of diol 9 (287 mg, 0.82 mmol) in acetone (2 mL) at room tem-
perature. The reaction mixture was stirred for 1 h then concentrated
and the residual oil was washed with saturated aqueous NaHCO3.
After extraction with Et2O, the combined organic layers were
washed with brine, dried over Na2SO4 and concentrated. Purifi-
cation of the residue by flash chromatography (silica gel, 5 to 20%
EtOAc in cyclohexane) afforded 10 (299 mg, 94%) as a colorless
oil. [α]2D5 ϭ ϩ15.1 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 3040, 3000,
1
cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 7.35 (m, 5 H), 5.81 (ddt,
2940, 2860, 1455, 735, 700 cmϪ1 1H NMR (400 MHz, CDCl3):
.
J ϭ 17.1, 9.9, 7.1 Hz, 1 H), 5.11 (m, 2 H), 4.56 (s, 2 H), 3.95 (m,
1 H), 3.68 (s, 3 H), 3.55 (m, 2 H), 3.27 (m, 1 H), 3.17 (s, 3 H), 2.47
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 176.0, 137.9,
135.1, 128.3, 127.6 (2 C), 117.1, 73.4, 72.8, 71.0, 61.3, 41.3, 33.8,
31.7 ppm. MS (EI): m/z ϭ 294 [M ϩ H]ϩ. C16H23NO4 (293.35):
calcd. C 65.51, H 7.90, N 4.77; found C 65.68, H 7.93, N 4.85.
δ ϭ 7.25 (m, 5 H), 5.66 (ddt, J ϭ 17.0, 10.0, 7.2 Hz, 1 H), 4.94 (d,
J ϭ 17.0 Hz, 1 H), 4.85 (d, J ϭ 10.0 Hz, 1 H), 4.54 (d, J ϭ 12.5 Hz,
1 H), 4.49 (d, J ϭ 12.5 Hz, 1 H), 3.76 (m, 1 H), 3.63 (m, 1 H), 3.41
(m, 2 H), 2.11 (m, 1 H), 2.02 (m, 1 H), 1.57 (m, 1 H), 1.31 (s, 3
H), 1.28 (s, 3 H), 1.30 (m, 14 H), 0.80 (t, J ϭ 6.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 138.9, 137.4, 128.7, 128.0, 127.9,
116.9, 100.9, 73.5, 73.0, 72.6, 69.6, 40.6, 32.5, 32.3, 31.4, 30.1, 30.0,
29.7, 26.6, 25.8, 24.4, 23.1, 14.5 ppm. MS (EI): m/z ϭ 389 [M ϩ
H]ϩ. C25H40O3 (388.59): calcd. C 77.27, H 10.37; found C 77.31,
H 10.40.
β-Hydroxy Ketone 8: Octyllithium (0.58  in Et2O, 13.5 mL,
7.8 mmol) was added dropwise to a solution of 7 (1.0 g, 3.4 mmol)
in THF/Et2O (6.8 mL, 1:1) at Ϫ10 °C. After stirring at Ϫ10 °C for
5 h, the reaction mixture was quenched at 0 °C with saturated aque-
ous NH4Cl, followed by 1  HCl, and then extracted with Et2O.
The combined organic layers were washed with brine, dried over
MgSO4 and concentrated. Purification of the residual oil by flash
chromatography (silica gel, 5 to 20% EtOAc in cyclohexane) af-
forded 8 (1.0 g, 85%) as a colorless oil. [α]2D5 ϭ Ϫ4.7 (c ϭ 0.19,
CHCl3). IR (film): ν˜ ϭ 3400 (broad), 3040, 2940, 2870, 1715, 1650,
1455, 740, 700 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.33 (m, 5
H), 5.70 (ddt, J ϭ 17.1, 10.0, 7.1 Hz, 1 H), 5.06 (m, 2 H), 4.53 (d,
J ϭ 11.9 Hz, 1 H), 4.49 (d, J ϭ 11.9 Hz, 1 H), 3.90 (m, 1 H), 3.50
(d, J ϭ 5.0 Hz, 2 H), 3.24 (d, J ϭ 7.3 Hz, 1 H, OH), 2.84 (ddd,
J ϭ 7.9, 6.4, 5.4 Hz, 1 H), 2.44 (m, 2 H), 2.34 (m, 2 H), 1.49 (m,
2 H), 1.25 (m, 10 H), 0.88 (t, J ϭ 6.9 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 215.4, 137.8, 134.9, 128.5, 127.9, 127.8,
117.6, 73.6, 72.6, 71.6, 52.6, 44.9, 33.6, 31.9, 29.5, 29.2, 29.1, 22.9,
22.7, 14.2 ppm. MS (EI): m/z ϭ 347 [M ϩ H]ϩ. C22H34O3 (346.51):
calcd. C 76.26, H 9.89; found C 75.78, H 10.05.
β-Hydroxy Ester 11: A solution of β-hydroxy ester 5 (1.0 g,
4.2 mmol) in THF (10 mL) was added to a solution of LDA
(10.3 mmol) in THF at Ϫ78 °C. After stirring at Ϫ78 °C for 1 h,
HMPA (0.88 mL, 5.1 mmol) and 4-bromo-2-methylbut-2-ene
(1.23 mL, 10.5 mmol) were added. The reaction mixture was stirred
at Ϫ78 °C for 2 h, then at Ϫ20 °C for 1 h before more 4-bromo-2-
methylbut-2-ene (0.1 mL, 0.8 mmol) was added. After stirring at
Ϫ20 °C and at 0 °C for 1 h each the mixture was quenched with
saturated aqueous NH4Cl and extracted with Et2O. The combined
organic layers were washed with water and brine, dried over MgSO4
and concentrated. Purification of the residue by flash chromatogra-
phy (silica gel, 20% EtOAc in cyclohexane) afforded 11 (999 mg,
78%) as a colorless oil. [α]2D5 ϭ Ϫ1.4 (c ϭ 1.0, CHCl3). IR (film):
ν˜ ϭ 3479 (broad), 3064, 3032, 2979, 2916, 2863, 1725, 1454, 739,
1
699 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.31 (m, 5 H), 5.07
(m, 1 H), 4.56 (d, J ϭ 12.0 Hz, 1 H), 4.52 (d, J ϭ 12.0 Hz, 1 H),
4.12 (dq, J ϭ 10.9, 7.0 Hz, 1 H), 4.06 (dq, J ϭ 10.9, 7.2 Hz, 1 H),
3.90 (m, 1 H), 3.55 (dd, J ϭ 9.7, 4.3 Hz, 1 H), 3.51 (dd, J ϭ 9.7 Hz,
1 H and 5.3 Hz), 3.10 (d, J ϭ 7.5 Hz, 1 H, OH), 2.61 (ddd, J ϭ
7.9, 6.8, 5.5 Hz, 1 H), 2.34 (m, 2 H), 1.68 (s, 3 H), 1.59 (s, 3 H),
1.22 (t, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
174.9, 138.0, 134.3, 128.5, 127.8 (2 C), 120.5, 73.6, 72.6, 71.0, 60.6,
48.2, 28.0, 25.8, 17.8, 14.3 ppm. MS (DCI/NH3): m/z ϭ 307 [M ϩ
H]ϩ, 324 [M ϩ NH4]ϩ. C18H26O4 (306.40): calcd. C 70.56, H 8.55;
found C 70.28, H 8.71. HPLC analysis: Chiralcel OD-H column;
flow rate: 0.5 mL/min; eluent: hexane/propan-2-ol (95:5); detection
at 215 nm; tR ϭ 20.5 min, (2S,3R)-11 isomer; tR ϭ 18.4 min,
(2R,3R)-11 isomer; d.e. ϭ 99%.
Diol 9: A solution of hydroxy ketone 8 (370 mg, 1.07 mmol) in
acetonitrile (1.1 mL) was added to a solution of tetramethylam-
monium triacetoxyborohydride (1.7 g, 6.4 mmol) in acetonitrile/
acetic acid (8 mL, 1:1) at Ϫ40 °C. The reaction mixture was stirred
at Ϫ20 °C for 21 h then quenched with a 0.5  solution of sodium
potassium tartrate. After addition of CH2Cl2, the mixture was
washed with saturated aqueous NaHCO3 and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated. Purification of the residue by
flash chromatography (silica gel, 5 to 30% EtOAc in cyclohexane)
afforded 9 (350 mg, 94%) as a colorless oil. [α]2D5 ϭ Ϫ13.5 (c ϭ 1.1,
CHCl3). IR (film): ν˜ ϭ 3400 (broad), 3040, 2980, 2910, 1455, 735,
700 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 7.34 (m, 5 H), 5.77 Amide 12: nBuLi (2.40  in hexanes, 26.8 mL, 64.3 mmol) was ad-
1
(ddt, J ϭ 17.1, 10.0, 7.1 Hz, 1 H), 5.05 (m, 2 H), 4.58 (d, J ϭ
ded to a solution of N,O-dimethylhydroxylamine hydrochloride
11.9 Hz, 1 H), 4.54 (d, J ϭ 11.9 Hz, 1 H), 4.03 (m, 1 H), 3.90 (m, (3.1 g, 32.2 mmol) in THF (60 mL) at Ϫ78 °C. After stirring at
1 H), 3.54 (m, 2 H), 3.23 (d, J ϭ 3.5 Hz, 1 H, OH), 3.07 (d, J ϭ room temperature for 10 min, the mixture was cooled to Ϫ78 °C
3.0 Hz, 1 H, OH), 2.21 (m, 3 H), 1.58 (m, 2 H), 1.00Ϫ1.50 (m, 12
and a solution of β-hydroxy ester 11 (3.3 g, 10.7 mmol) in THF
H), 0.89 (t, J ϭ 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): (40 mL) was added. The reaction mixture was stirred at Ϫ78 °C
2356
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2352Ϫ2358

An Efficient Ruthenium-Catalyzed Formal Synthesis of (Ϫ)-Isoavenaciolide
for 2 h, then quenched with a saturated aqueous solution of NH4Cl 6.0 mmol) in THF (50 mL) at 0 °C. After stirring at 0 °C for 4 h,
FULL PAPER
and allowed to warm to room temperature. After extraction with
Et2O, the combined organic layers were dried over MgSO4 and
concentrated. Purification of the residue by flash chromatography
(silica gel, 15% EtOAc in cyclohexane) afforded 12 (3.2 g, 92%) as
a pale-yellow oil. [α]2D5 ϭ ϩ5.2 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ
the reaction mixture was quenched with a saturated aqueous solu-
tion of NH4Cl (15 mL), allowed to warm to room temperature and
extracted with EtOAc. The combined organic layers were dried
over MgSO4 and concentrated. Purification of the residue by flash
chromatography (silica gel, 10 to 15% EtOAc in cyclohexane) af-
forded 14 (2.1 g, 96%) as a pale-yellow oil. [α]2D5 ϭ Ϫ18.8 (c ϭ 1.0,
3417 (broad), 3065, 3031, 2969, 2917, 2861, 1650, 1454, 738, 700
1
cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.31 (m, 5 H), 5.12 (m, 1 CHCl3). IR (film): ν˜ ϭ 3469 (broad), 3030, 2980, 2923, 2853, 1713,
H), 4.55 (d, J ϭ 12.1 Hz, 1 H), 4.51 (d, J ϭ 12.1 Hz, 1 H), 4.12 (d,
J ϭ 8.6 Hz, 1 H, OH), 3.90 (m, 1 H), 3.63 (s, 3 H), 3.56 (dd, J ϭ H), 5.03 (m, 1 H), 4.55 (d, J ϭ 12.2 Hz, 1 H), 4.49 (d, J ϭ 12.2 Hz,
9.7, 5.1 Hz, 1 H), 3.48 (dd, J ϭ 9.7, 6.2 Hz, 1 H), 3.13 (br. s, 4 H), 1 H), 3.88 (m, 1 H), 3.48 (d, J ϭ 5.1 Hz, 2 H), 3.30 (d, J ϭ 7.2 Hz,
2.40 (t, J ϭ 7.3 Hz, 2 H), 1.68 (s, 3 H), 1.62 (s, 3 H) ppm. 13C 2 H, OH), 2.75 (ddd, J ϭ 8.0, 6.6, 5.6 Hz, 1 H), 2.42 (t, J ϭ 7.3 Hz,
1454, 736, 698 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.35 (m, 5
NMR (75 MHz, CDCl3,): δ ϭ 176.8, 138.2, 134.4, 128.4, 127.8,
127.7, 120.9, 73.6, 73.2, 71.1, 61.4, 41.7, 31.9, 28.2, 25.9, 17.8 ppm.
MS (DCI/NH3): m/z ϭ 322 [M ϩ H]ϩ. C18H27NO4 (321.41): calcd.
C 67.26, H 8.47, N 4.36; found C 66.98, H 8.61, N 4.12.
2 H), 2.26 (m, 2 H), 1.67 (s, 3 H), 1.58 (s, 3 H), 1.46 (m, 2 H), 1.24
(br. s, 10 H), 0.88 (t, J ϭ 6.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 216.0, 137.9, 134.4, 128.5, 127.8 (2 C), 120.7, 73.6,
72.9, 71.8, 53.0, 44.8, 31.9, 29.4 (2C), 29.2, 28.0, 25.8, 23.0, 22.7,
17.8, 14.2 ppm. MS (DCI/NH3): m/z ϭ 375 [M ϩ H]ϩ, 392 [M ϩ
NH4]ϩ. C24H38O3 (374.56): calcd. C 76.96, H 10.22; found C 76.83,
H 10.40.
Amide 15: 2,6-Lutidine (4.9 mL, 42.0 mmol) and tert-butyldimeth-
ylsilyl trifluoromethanesulfonate (7.6 mL, 32.4 mmol) were added
to a solution of 12 (6.7 g, 20.8 mmol) in CH2Cl2 (45 mL) at 0 °C.
After stirring at 0 °C for 1 h, the mixture was diluted with water
(20 mL) and extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over MgSO4 and concentrated. Puri-
fication of the residue by flash chromatography (silica gel, 10 to
20% EtOAc in cyclohexane) afforded 15 (8.9 g, 98%) as a colorless
oil. [α]2D5 ϭ ϩ13.3 (c ϭ 1.05, CHCl3). IR (film): ν˜ ϭ 3031, 2955,
Diol 17: (S)-MeO-BIPHEP (7.0 mg, 0.012 mmol) and [(COD)Ru(2-
methylallyl)2] (3.2 mg, 0.01 mmol, commercially available from
Acros), were placed in a round-bottomed flask and dissolved in
1 mL of acetone (degassed by three cycles of vacuum/argon at
room temperature). A 0.175  methanolic HBr solution (126 µL,
0.022 mmol) was added to this suspension and the mixture was
stirred at room temperature for 30 min. After evaporation of the
solvent under vacuum, a solution of β-hydroxy ketone 14 (98.6 mg,
0.25 mmol) in MeOH (2 mL) was added to the ruthenium catalyst.
The resulting mixture was placed under hydrogen pressure (50 bar)
at 50 °C for 6 h. After removal of the solvent, the residue was
purified by flash chromatography (silica gel, 15% EtOAc in cyclo-
hexane) to afford a 97:3 mixture of 17/18 (90 mg, 94%) as a pale-
yellow oil. [α]2D5 ϭ Ϫ11.7 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 3406
2929, 2855, 1661, 1471, 1253, 836, 735, 698 cmϪ1 1H NMR
.
(200 MHz, CDCl3,): δ ϭ 7.31 (m, 5 H), 5.05 (m, 1 H), 4.57 (d, J ϭ
12.1 Hz, 1 H), 4.50 (d, J ϭ 12.1 Hz, 1 H,), 4.06 (m, 1 H), 3.67 (s,
3 H), 3.57 (dd, J ϭ 10.4, 2.6 Hz, 1 H), 3.50 (dd, J ϭ 10.4, 4.9 Hz,
1 H), 3.22 (m, 1 H), 3.15 (s, 3 H), 2.25 (m, 2 H), 1.64 (s, 3 H), 1.57
(s, 3 H), 0.86 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H) ppm. 13C NMR
(50 MHz, CDCl3,): δ ϭ 174.8, 138.6, 133.1, 128.3, 127.7, 127.5,
121.5, 73.4, 73.1, 73.0, 61.3, 45.4, 32.0, 26.8, 25.9, 25.8, 18.1, 17.8,
Ϫ4.5, Ϫ4.9 ppm. MS (DCI/NH3): m/z ϭ 436 [M ϩ H]ϩ.
C24H41NO4Si (435.58): calcd. C 66.16, H 9.49, N 3.21; found C
65.88, H 9.68, N 3.12.
(broad), 3031, 2980, 2922, 2852, 1496, 736, 698 cmϪ1 1H NMR
.
(300 MHz, CDCl3): δ ϭ 7.35 (m, 5 H), 5.11 (m, 1 H), 4.50 (d, J ϭ
11.7 Hz, 1 H), 4.45 (d, J ϭ 11.7 Hz, 1 H), 3.99 (m, 1 H), 3.86 (m,
1 H), 3.53 (m, 2 H), 3.16 (d, J ϭ 3.8 Hz, 1 H, OH), 2.85 (d, J ϭ
2.9 Hz, 1 H, OH), 2.24 (m, 1 H), 2.05 (m, 1 H), 1.69 (s, 3 H), 1.61
(s, 3 H), 1.28 (br. s, 10 H), 1.70Ϫ1.10 (m, 5 H), 0.89 (t, J ϭ 6.6 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 137.9, 133.2, 128.6,
128.0, 127.9, 123.0, 73.6, 73.5, 72.4, 72.3, 44.5, 34.0, 32.0, 29.8,
29.7, 29.4, 26.5, 25.9, 24.0, 22.7, 17.9, 14.2 ppm. MS (DCI/NH3):
m/z ϭ 377 [M ϩ H]ϩ, 394 [M ϩ NH4]ϩ. C24H40O3 (376.58): calcd.
C 76.55, H 10.71; found C 76.47, H 10.84. HPLC analysis: column,
Chiralcel OD-H; flow rate: 1.0 mL/min; eluent: hexane/propan-2-
ol (95:5); detection at 215 nm; tR ϭ 15.7 min, anti-17 (2R,3R,4S)
isomer; tR ϭ 12.7 min, syn-17 (2R,3R,4R) isomer; tR ϭ 13.8 min,
anti-18 isomer; tR ϭ 11.5 min, syn-18 isomer; d.e. ϭ 99%.
Ketone 16: n-Octyllithium (0.5  in Et2O, 9.0 mL, 4.5 mmol) was
added dropwise to a solution of 15 (1.96 g, 4.5 mmol) in THF
(40 mL) at Ϫ50 °C. After stirring at Ϫ50 °C for 1 h, n-octyllithium
was added again (9.0 mL, 4.5 mmol) and the solution was stirred
for 1 h. After quenching with methanol and saturated aqueous
NH4Cl, the mixture was allowed to warm to room temperature and
extracted with Et2O. The combined organic layers were dried over
MgSO4 and concentrated. Purification of the residual oil by flash
chromatography (silica gel, 3% EtOAc in cyclohexane) afforded 16
(1.6 g, 73%) as a pale-yellow oil. [α]2D5 ϭ ϩ16.2 (c ϭ 1.02, CHCl3).
IR (film): ν˜ ϭ 3031, 2953, 2927, 2855, 1716, 1471, 1253, 836, 735,
1
697 cmϪ1. H NMR (300 MHz, CDCl3,): δ ϭ 7.31 (m, 5 H), 4.99
(m, 1 H), 4.53 (d, J ϭ 12.1 Hz, 1 H), 4.47 (d, J ϭ 12.1 Hz, 1 H),
3.99 (dt, J ϭ 7.6, 3.8 Hz, 1 H), 3.46 (dd, J ϭ 10.3, 3.8 Hz, 1 H),
3.41 (dd, J ϭ 10.3, 4.3 Hz, 1 H), 2.84 (ddd, J ϭ 10.3, 7.3 Hz and
4.5 Hz, 1 H), 2.42 (t, J ϭ 7.3 Hz, 2 H), 2.26 (m, 1 H), 2.07 (m, 1
H), 1.64 (s, 3 H), 1.55 (s, 3 H), 1.49 (m, 2 H), 1.24 (br. s, 10 H),
0.90 (t, J ϭ 6.3 Hz, 3 H), 0.84 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 213.3, 138.2, 133.4, 128.4,
127.8, 127.7, 121.3, 73.5, 73.3, 72.8, 55.5, 45.5, 31.9, 29.5 (2 C),
29.3, 27.2, 25.9, 25.8, 23.0, 22.7, 18.1, 17.8, 14.2, Ϫ4.4, Ϫ5.0 ppm.
MS (DCI/NH3): m/z ϭ 489 [M ϩ H]ϩ, 506 [M ϩ NH4]ϩ.
C30H52O3Si (488.74): calcd. C 73.71, H 10.72; found C 73.73, H
10.76.
Acetonide 19: 2,2-Dimethoxypropane (4.5 mL, 36.6 mmol) and pyr-
idinium p-toluenesulfonate (7.7 mg, 0.031 mmol) were added to a
solution of diol 17 (230 mg, 0.61 mmol) in acetone (3.5 mL) at
room temperature. After stirring at room temperature for 0.5 h, the
reaction mixture was concentrated and the residual oil was washed
with saturated aqueous NaHCO3. After extraction with Et2O, the
combined organic layers were washed with brine, dried over MgSO4
and concentrated. Purification of the residue by flash chromatogra-
phy (silica gel, 5% EtOAc in cyclohexane) afforded 19 (250 mg,
98%) as a pale-yellow oil. [α]2D5 ϭ ϩ16.9 (c ϭ 1.00, CHCl3). IR
(film): ν˜ ϭ 3030, 2984, 2925, 2854, 1454, 736, 698 cmϪ1. 1H NMR
(300 MHz, CDCl3): δ ϭ 7.31 (m, 5 H), 5.01 (m, 1 H), 4.60 (d, J ϭ
12.5 Hz, 1 H), 4.55 (d, J ϭ 12.5 Hz, 1 H), 3.83 (m, 1 H), 3.65 (m,
Hydroxy Ketone 14: Tetrabutylammonium fluoride (1  in THF,
14.3 mL, 14.3 mmol) was added dropwise to a solution of 16 (2.9 g, 1 H), 3.47 (m, 2 H), 2.07 (t, J ϭ 7.0 Hz, 2 H), 1.61 (s, 3 H), 1.58
Eur. J. Org. Chem. 2004, 2352Ϫ2358
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2357

ˆ
O. Labeeuw, D. Blanc, P. Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
[8]
K. Suzuki, M. Miyazawa, M. Shimazaki, G. Tsuchihashi,
Tetrahedron 1988, 44, 4061Ϫ4072.
S. D. Burke, G. J. Pacofsky, A. D. Piscopio, J. Org. Chem. 1992,
57, 2228Ϫ2235.
(s, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.49Ϫ1.14 (m, 5 H), 1.27 (br.
s, 10 H), 0.88 (t, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 138.7, 132.6, 128.4, 127.7, 127.6, 122.7, 100.5, 73.2,
73.0, 72.7, 69.4, 41.0, 31.9, 31.0, 29.7, 29.6, 29.4, 26.3, 25.9 (2 C),
25.6, 24.1, 22.7, 17.9, 14.2 ppm. MS (DCI/NH3): m/z ϭ 417 [M ϩ
H]ϩ, 434 [M ϩ NH4]ϩ. C27H44O3 (416.64): calcd. C 77.83, H 10.64;
found C 77.63, H 10.84.
[9]
[10]
[11]
[12]
[13]
´
´
C. M. Rodriguez, T. Martın, V. S. Martın, J. Org. Chem. 1996,
61, 8448Ϫ8452.
C. E. McDonald, R. W. Dugger, Tetrahedron Lett. 1988, 29,
2413Ϫ2416.
N. Chida, T. Tobe, M. Suwama, M. Ohtsuka, S. Ogawa, J.
Chem. Soc., Chem. Commun. 1990, 994Ϫ995.
N. Chida, T. Tobe, M. Suwama, M. Ohtsuka, S. Ogawa, J.
Chem. Soc., Perkin Trans. 1 1992, 2667Ϫ2673.
K. Ito, T. Fukuda, T. Katsuki, Synlett 1997, 387Ϫ389.
K. Ito, T. Fukuda, T. Katsuki, Heterocycles 1997, 46, 401Ϫ411.
P. Phansavath, S. Duprat de Paule, V. Ratovelomanana-Vidal,
Ester 2 from Acetonide 10: A 2.5  ethanolic NaOH solution
(1 mL) was added to
a solution of acetonide 10 (100 mg,
0.26 mmol) in CH2Cl2 (4 mL). A stream of ozone was bubbled
through the mixture at Ϫ78 °C until a persistent blue color was
achieved (3 h). Water and Et2O were added at Ϫ78 °C and the
mixture was allowed to warm to room temperature. After extrac-
tion with Et2O, the combined organic layers were dried over
Na2SO4 and concentrated. Purification of the residue by flash chro-
matography (silica gel, 5% EtOAc in cyclohexane) afforded 2
(90 mg, 80%) as a colorless oil. [α]2D5 ϭ ϩ2.0 (c ϭ 1.4, CHCl3),
{ref.[7,8] [α]2D0 ϭ 0.0 (c ϭ 1.0, CHCl3)}.
[14]
[15]
[16]
ˆ
J.-P. Genet, Eur. J. Org. Chem. 2000, 3903Ϫ3907.
[17]
[18]
[19]
[20]
[21]
D. Lavergne, C. Mordant, V. Ratovelomanana-Vidal, J.-P.
ˆ
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ˆ
O. Poupardin, F. Ferreira, J.-P. Genet, C. Greck, Tetrahedron
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Ester 2 from Acetonide 19: A 2.5  ethanolic NaOH solution
(2 mL) was added to a solution of acetonide 19 (50 mg, 0.12 mmol)
in CH2Cl2 (8 mL). A stream of ozone was bubbled through the
mixture at Ϫ78 °C for 1 h. Water and Et2O were added at Ϫ78 °C
and the mixture was allowed to warm to room temperature. After
extraction with Et2O, the combined organic layers were dried over
MgSO4 and concentrated. Purification of the residue by flash chro-
matography (silica gel, 5% EtOAc in cyclohexane) afforded 2
(46 mg, 88%) as a colorless oil. [α]2D5 ϭ ϩ4.6 (c ϭ 1.0, CHCl3)
{ref.[7,8] [α]2D0 ϭ 0.0 (c ϭ 1.0, CHCl3)}. IR (film): ν˜ ϭ 3030, 2983,
ˆ
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2405Ϫ2409.
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ˆ
ˆ
(Ed.: A. F. Abdel-Magid), ACS Symposium Series 641, Amer-
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[24]
[25]
2926, 2855, 1735, 1454, 736, 698 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 7.30 (m, 5 H), 4.61 (d, J ϭ 12.3 Hz, 1 H), 4.55 (d,
J ϭ 12.3 Hz, 1 H), 4.05 (m, 2 H), 3.87 (dt, J ϭ 9.1, 3.6 Hz, 1 H),
3.67 (dt, J ϭ 6.4, 3.9 Hz, 1 H), 3.56 (dd, J ϭ 10.6, 6.2 Hz, 1 H),
3.50 (dd, J ϭ 10.6, 3.8 Hz, 1 H), 2.51 (m, 1 H), 1.49Ϫ1.21 (m, 6
H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.26 (br. s, 10 H), 1.21 (t, J ϭ
7.2 Hz, 3 H), 0.88 (t, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 173.2, 138.5, 128.4, 127.7, 127.6, 100.7, 73.4, 72.9,
72.3, 68.8, 60.5, 38.6, 33.1, 31.9, 30.6, 29.6, 29.5, 29.3, 26.1, 25.4,
24.2, 22.7, 14.2, 14.1 ppm. MS (DCI/NH3): m/z ϭ 435 [M ϩ H]ϩ,
452 [M ϩ NH4]ϩ. C26H42O5 (434.61): calcd. C 71.85, H 9.74; found
C 71.93, H 9.92.
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(S)-MeO-BIPHEP and (S)-(Ϫ)-2,2Ј-bis(diphenylphosphanyl)-6,6Ј-
`
dimethoxy-1,1Ј-biphenyl. O. L. is grateful to the Ministere de
l’Education et de la Recherche for a grant (2001Ϫ2004).
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Received January 23, 2004
2358
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2352Ϫ2358