Asymmetric synthesis of polyfunctionalized allenic esters: Toward the synthesis of an iphionane sesquiterpene

Article abstract of DOI:10.1055/s-2006-942463

Tetrabutylammonium fluoride (TBAF) reacts smoothly with optically active acetylenic ω-keto esters to afford optically active allenic esters (ee >95%) in high yield. After protection of the hydroxyl group, the addition of morpholine followed by an acidic h

Full text of DOI:10.1055/s-2006-942463

PAPER
2613
Asymmetric Synthesis of Polyfunctionalized Allenic Esters: Toward the
Synthesis of an Iphionane Sesquiterpene
A
symmetric Synth
u
esis of Polyf
r
unctiona
é
lized Allen
l
ic Este
i
rs e Klein, Michel Miesch*
Laboratoire de Chimie Organique Synthétique (LCOS), Université Louis Pasteur - Institut de Chimie, LC 3 UMR 7177 CNRS/ULP
, rue Blaise Pascal, 67008 Strasbourg, France
1
Fax +33(3)90241754; E-mail: miesch@chimie.u-strasbg.fr
Received 28 March 2006; revised 10 April 2006
Dedicated to Professor Guy Ourisson on the occasion of his 80 birthday
th
Abstract: Tetrabutylammonium fluoride (TBAF) reacts smoothly
with optically active acetylenic w-keto esters to afford optically ac-
tive allenic esters (ee >95%) in high yield. After protection of the
hydroxyl group, the addition of morpholine followed by an acidic
hydrolysis, quantitatively led to optically active bicyclic a,b-unsat-
urated ketones (ee >95%). By using this methodology, the formal
N
C6H5
O
methyl acrylate, p-TsOH
toluene, reflux
CO2Me
1
2 (90%, 95% ee)
synthesis of an iphionane sesquiterpene was achieved.
1
) ethylene glycol, p-TsOH cat., C6H6, reflux
O
Key words: alkynes, fluorine, domino reactions, nucleophilic addi-
2) LiAlH4, THF, 25 °C
tion, fused rings
3
4
5
) TsCl, Et3N, DMAP, CH2Cl2, 25 °C
) Li acetylide ethylenediamine, DMSO, 0 °C
) n-BuLi, THF, ClCO2Et
CO2Et
3 (67%, 95% ee)
6
) HCl (10%), 25 °C
Electrophilic optically active allenes (especially esters)
are important building blocks for the total synthesis of
Scheme 1
bioactive compounds. However, synthetic routes for opti-
1
cally active allenic esters are rare. Recently, we have de-
in 98% yield (ee >95% for this determination, see below;
dr = 90:10) (Scheme 2).
veloped
a
new cascade reaction that produces
electrophilic allenic esters starting from acetylenic w-keto
2
For further synthetic purposes, allene 4 had to be convert-
ed into the hydroxy ketone 6. Indeed, the latter represents
an important substructure of bioactive iphionane sesqui-
terpenes (Figure 1).4
esters. To further extend the utility of our methodology,
we present herein a new, multigram scale synthesis of op-
tically active allenic esters so that the latter can be consid-
ered as appropriate synthons for further synthetic
applications.
Thus, an allenic ester can be transformed into the corre-
sponding b-keto ester 5 by addition of an amine (for
example morpholine) followed by hydrolysis of the corre-
For that purpose, we had to develop a new reaction se-
quence because our former route was inefficient to get ef-
fectively optically active allenic esters. We started from
the chiral imine 1 that was obtained by addition of (R)-(+)-
methylbenzylamine to 2-methylcyclohexanone as previ-
ously described. The Michael addition of methyl acrylate
to 1 proceeded smoothly to afford compound 2. Protection
CO2Et
O
C
HO
TBAF, THF, 25 °C, 30 min
3
9
8%, dr >90:10
3
CO2Et
4
of the carbonyl group as a dioxolane, reduction with
LiAlH , and subsequent addition of tosyl chloride afford-
4
Scheme 2
ed the tosyl derivative. Addition of the acetylide as an eth-
ylenediamine complex led to the acetylenic derivative
which was readily transformed into the desired acetylenic
w-keto ester 3 after addition of ethyl chloroformate to the
corresponding acetylide and acidic deprotection of the di-
oxolane group (Scheme 1).
HO
O
O
O
O
RO
HO
HO
HO
HO
R1
The next stage called for our TBAF reaction with the acet-
ylenic w-keto ester 3. The reaction proceeded smoothly
and the desired optically active allenic ester 4 was isolated
Iphionane A
Lucinone
Iphionane B
R =
O
HO
R1
O
OH
AcO
OH
R1 = COOH
SYNTHESIS 2006, No. 15, pp 2613–2617
x
x.
x
x
.
2
0
0
6
Iphionane C
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942463; Art ID: Z05506SS
Georg Thieme Verlag Stuttgart · New York
Figure 1 Bioactive iphionane sesquiterpenes
©

2
614
A. Klein, M. Miesch
PAPER
5
sponding enamine. A saponification–decarboxylation re-
action should then afford ketone 6. When morpholine was
added to 4, the quantitative formation of enamine 7 was
observed. Unfortunately, during the purification stage by
silica gel column chromatography, the enamine 7 led to
the corresponding 1,6-diketone 8, which was isolated in
CO2Et
C
1) TBDMSOTf, Et3N, CH2Cl2, reflux
O
HO
2
) Morpholine, Et2O, reflux
3
) HCl (10%), Et2O, 35 °C
4) LiI, DMF, 100 °C
4
10 (75%, 95% ee)
3
5% yield along with degradation products. The desired
Scheme 5
hydroxy b-keto ester 5 was not detected (Scheme 3).
To further extend the utility of this methodology, we en-
visioned the enantioselective synthesis of iphionane C
isolated from Jasonia candicans. Based on our previous
E = CO2Et
HO
E
O
E
C
O
HO
HO
7
results, the latter could be prepared from the acetylenic w-
keto ester 11 which could result from (+)-dihydrocarvone,
a readily available, optically active, starting material
(Scheme 6).8
5
6
4
SiO2
O
N
H
E
R = CO2H, E = CO2Et
C
N
O
O
O
O
HO
H
O
E
O
O
E
O
R
SiO2
E
8
(35%)
7
(quant.)
5
Iphionane C
1
1
Scheme 3
Scheme 6
On the other hand, treatment of the crude enamine 7 with
formic acid afforded a mixture of two compounds: the
Indeed, the synthesis of the acetylenic w-keto ester 11 was
readily achieved starting from the chiral imine 12 which
was prepared by reaction of (R)-(+)-methylbenzylamine
with (+)-dihydrocarvone. The allenic ester 13 was ob-
tained as a mixture of isomers (dr = 90:10) by using the
route described in Scheme 1 (Scheme 7).
1
,6-diketone 8 as above and the a,b-unsaturated b-keto es-
ter 9 were isolated respectively in 34 and 32% yield. Once
again, the formation of the hydroxy b-keto ester 5 was not
observed (Scheme 4).
E = CO2Et E
After protection of the hydroxyl group as a tert-butyldi-
methylsilyl ether, the addition of morpholine to the corre-
sponding allenic ester led quantitatively to the enamine
14. The latter was hydrolyzed under acidic conditions to
give the b-keto ester 15 in 88% yield. This compound was
readily transformed into the desired a,b-unsaturated ke-
tone 15, isolated in 96% yield; this compound being a po-
tential precursor of iphionane C (Scheme 8). As before,
we can estimate that compound 16 was obtained with 95%
E
C
N
O
HO
O
O
O
HCOOH
+
E
Et2O, 25 °C
7
8 (32%)
9 (34%)
Scheme 4
Finally, after protection of the hydroxyl group as a tert-
butyldimethylsilyl ether followed by addition of morpho-
line, acidic hydrolysis, and a saponification–decarboxyla-
tion sequence, the a,b-unsaturated ketone 10 was isolated
in 75% overall yield with no trace of the hydroxy b-keto
ester 5 (Scheme 5). The enantiomeric excess (ee) of ke-
tone 10 was determined by chiral GC analysis and is in ac-6
cord with the data recently reported in the literature.
Consequently, we can estimate that the ee of the allene de-
rivative 4 is at least 95%. This is in good agreement not
only with the value determined for ketone 10, but also
with the ee value (95% determined by chiral GC analysis)
of the Michael adduct 2. Thus, our new reaction sequence
can readily afford optically active allenic esters in high
yield and high ee. Moreover, it is possible to run our reac-
tion sequence on a multigram scale.
E = CO2Et
N
C6H5
O
cf. scheme 1
1
2
E
11
E
C
HO
TBAF, THF, 25 °C, 30 min
13 (91%, dr = 90:10)
Scheme 7
Synthesis 2006, No. 15, 2613–2617 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Polyfunctionalized Allenic Esters
2615
H O : C, 71.97; H, 8.86. Found: C, 72.20; H,
22 3
ee, since the reaction sequence is identical to that in de- Anal. Calcd for C15
.09.
9
scribed in Scheme 5.
Acetylenic w-Keto Ester 11
CO2Et
N
2
a,2c
Compound 11 was prepared according to literature procedures.
CO2Et
2
0
C
1) TBDMSOTf, Et N,
CH2Cl2, reflux
O
Colorless oil; [a]D +37.1 (c = 0.98, CHCl3).
HO
3
RO
–1
IR (CCl ): 1644, 1715, 2239 cm .
4
1
2
) morpholine, Et2O,
reflux
H NMR (CDCl , 300 MHz): d = 1.12 (s, 3 H), 1.28 (t, J = 7.1 Hz,
3
3 H), 1.45–1.70 (m, 6 H), 1.72 (s, 3 H), 1.73–1.90 (m, 2 H), 2.25–
2
2
13
14 (100%)
.40 (m, 4 H), 2.49 (dd, J = 12.8, 14.8 Hz, 1 H), 4.19 (q, J = 7.1 Hz,
H), 4.73 (d, J = 16.8 Hz, 2 H).
R = TBDMS
HCl (10%),
Et2O, 25 °C
1
3
C NMR (CDCl , 75 MHz): d = 14.0, 13.4, 20.7, 22.4, 23.1, 26.0,
3
CO2Et
O
3
2
6.4, 37.2, 43.2, 45.7, 47.3, 61.7, 73.3, 89.0, 110.0, 147.3, 153.8,
14.8.
O
Anal. Calcd for C H O : C, 74.45; H, 9.02. Found: C, 74.35; H,
1
8
26
3
LiI, DMF, 100 °C
9.19.
Allene 4
16 (96%, 95% ee)
15 (88%)
At 20 °C, to a solution of acetylenic w-keto ester 3 (3.90 g, 15.6
mmol) in THF (75 mL) was added TBAF as a 1.0 M solution in
THF (18.70 mL). After 30 min of gentle stirring at 20 °C, the mix-
ture was quenched with a sat. aq NH Cl solution (20 mL), H O
Scheme 8
4
2
(
3 × 20 mL) and then extracted with Et O (3 × 10 mL). The com-
In summary, we presented here a new and efficient meth-
odology for the synthesis of not only optically active
polyfunctionalized allenic esters, but also of poly-
functionalized hexahydroindene fused rings. Further in-
vestigations of this chemistry are currently under way in
our laboratory.
2
bined organic layers were washed with brine, dried (MgSO ) and
filtered before solvents were removed under reduced pressure (15
mm Hg/30 °C). The crude product was purified on a silica gel col-
umn (75 g SiO , EtOAc–hexane, 5:95) to afford compound 4 as a
9
tography on a silica gel column, it was not possible to get an analyt-
ical sample of each isomer. Nevertheless, we obtained an [a]D
4
2
:1 mixture of isomers; yield: 3.824 g (98%). By additional chroma-
2
0
value, but this value corresponded to a mixture of the two isomers.
The IR and microanalysis were also performed on the mixture of the
two isomers. The mixture of the two isomers was a white powder;
mp 57–58 °C.
Melting points were measured on a Stuart Scientific melting point
apparatus (SMP 3) and are uncorrected. Reactions were carried out
under argon with magnetic stirring and degassed solvents. Et O and
2
THF were distilled from Na/benzophenone. TLC was carried out on
silica gel plates (Merck 60F254) and the spots were visualized under
UV lamp (254 or 365 nm) and/or sprayed with a solution of vanillin
Allene 4a
20
[
a]D –112.3 (mixture of isomers, c = 1.01, CHCl3).
(
25 g) in EtOH–H SO (98:2; 1 L) or with phosphomolybdic acid
2 4
–
1
IR (mixture of isomers, CCl ): 1717, 1961, 3400, 3602 cm .
followed by heating on a hot plate. For column chromatography, sil-
4
1
ica gel (Merck, silica gel 60, 40–60 mm) was used. IR spectra were
H NMR (CDCl , 300 MHz): d = 1.06 (s, 3 H), 1.26 (t, J = 7.1 Hz,
3
1
recorded in CCl on a PerkinElmer IR-881 spectrophotometer. H
3 H), 1.30–1.90 (m, 11 H), 2.50–2.85 (m, 2 H), 4.17 (ABX ,
4
3
1
3
NMR spectra were recorded at 300 MHz (Bruker AC-300) and
C
JAB = 10.8, JBX = 7.1, JAX = 7.1 Hz, Dd = 0.085 ppm, d = 4.21,
A
NMR spectra at 75 MHz (Bruker AC-300) using the signal of the
residual nondeuterated solvent as internal reference. Microanalyses
were performed at the Service Commun de Microanalyse, Institut
de Chimie, Strasbourg. The optical rotations were measured on a
PerkinElmer polarimeter Model 341. The enantiomeric excesses
were measured on a GC-14B Shimadzu equipped with a BPN-b-cy-
clodextrin chiral column. The allene ratio was determined on a GC-
Varian 3400 CX equipped with a Factor Four VF-5ms column
dB = 4.13, 2 H), 5.66 (t, J = 4.2 Hz, 1 H).
1
3
C NMR (CDCl , 75 MHz): d = 14.1, 18.1, 21.5, 23.2, 25.0, 32.4,
3
3
4.9, 36.0, 45.8, 60.6, 84.2, 90.9, 113.5, 166.1, 207.2.
Anal. Calcd for C15H O (mixture of isomers): C, 71.97; H, 8.86.
22 3
Found: C, 72.00; H, 8.87.
Allene 4b
H NMR (CDCl
1
(length: 60 m; internal diameter: 0.25 mm).
3
, 300 MHz): d = 1.06 (s, 3 H), 1.26 (t, J = 7.1 Hz,
3
H), 1.30–1.90 (m, 11 H), 2.50–2.85 (m, 2 H), 4.17 (ABX3,
The acetylenic w-keto esters 3 and 11 were prepared by the reac-
tions outlined in Schemes 1 and 7.
JAB = 10.8, JBX = 7.1, JAX = 7.1 Hz, Dd = 0.085 ppm, d = 4.21,
A
dB = 4.13, 2 H), 5.68 (t, J = 4.2 Hz, 1 H).
13C NMR (CDCl
, 75 MHz): d = 14.1, 19.2, 22.6, 23.6, 24.8, 31.9,
Acetylenic w-Keto Ester 3
Compound 3 was prepared according to literature procedures.
3
2
a,2c
34.6, 35.5, 45.4, 60.8, 83.6, 91.0, 113.5, 166.1, 207.2.
2
0
Colorless oil; [a]D –40.3 (c = 1.01, CHCl3).
Allene 13
–
1
IR (CCl ): 1712, 2239 cm .
Allene 13 was prepared starting from acetylenic w-keto ester 11
(4.96 g, 17.2 mmol) and TBAF (1.0 M THF solution, 13.80 mL) by
using the same procedure as for allene 4. This reaction afforded al-
lene 13 as a mixture of isomers in the ratio 9:1; yield: 4.535 g (91%).
Even by additional chromatography on a silica gel column, it was
not possible to obtain an analytical sample of each isomer. Never-
4
1
H NMR (CDCl , 300 MHz): d = 1.05 (s, 3 H), 1.29 (t, J = 7.1 Hz,
3
3
H), 1.35–1.65 (m, 4 H), 1.66–1.90 (m, 6 H), 2.31 (t, J = 6.7 Hz, 2
H), 2.36 (t, J = 6.4 Hz, 2 H), 4.20 (q, J = 7.1 Hz, 2 H).
1
3
C NMR (CDCl , 75 MHz): d = 14.0, 19.2, 21.0, 22.2, 22.5, 27.4,
3
3
6.7, 38.7, 39.1, 48.3, 61.7, 73.5, 88.7, 153.7, 215.5.
20
theless, we observed an [a]D value, but this value corresponds to a
Synthesis 2006, No. 15, 2613–2617 © Thieme Stuttgart · New York

2
616
A. Klein, M. Miesch
PAPER
mixture of the two isomers. The IR and microanalysis was also per-
formed on the mixture of the two isomers. The mixture of the two
isomers was a white powder; mp 53–54 °C.
bined organic layers were washed with brine, dried (MgSO ) and
filtered before solvents were removed under reduced pressure (15
mm Hg/30 °C). The crude product was purified on a silica gel col-
4
umn (35 g SiO , EtOAc–hexane, 5:95) to afford compound 8 (73
mg, 32% yield) and compound 9 (72 mg, 34% yield).
2
Allene 13a
20
[
a]D –152.2 (mixture of isomers, c = 1.00, CHCl3).
–
1
1,6-Diketone 8
Colorless oil; [a]D –27.9 (c = 0.98, CHCl3).
IR (mixture of isomers, CCl ): 1646, 1717, 1961, 3400, 3602 cm .
4
20
1
H NMR (CDCl , 300 MHz): d = 1.06 (t, J = 7.1 Hz, 3 H), 1.18 (s,
3
–1
IR (CCl ): 1712, 1716 cm .
4
3
2
5
H), 1.30–1.70 (m, 7 H), 1.84 (s, 3 H), 1.95–2.10 (m, 2 H), 2.40–
.85 (m, 2 H), 3.55 (s, 1 H), 4.09 (qd, J = 0.9, 7.1 Hz, 2 H), 4.90–
.05 (m, 2 H), 5.85 (t, J = 4.2 Hz, 1 H).
1
H NMR (CDCl , 300 MHz): d = 1.06 (s, 3 H), 1.27 (t, J = 7.1 Hz,
3
3 H), 1.35–1.90 (m, 10 H), 2.37 (t, J = 5.8 Hz, 2 H), 2.54 (t, J = 6.4
Hz, 2 H), 3.42 (s, 2 H), 4.19 (q, J = 7.1 Hz, 2 H).
1
3
C NMR (CDCl , 75 MHz): d = 13.8, 17.9, 20.5, 25.0, 26.7, 34.8,
3
1
3
3
2
6.5, 36.8, 41.9, 45.1, 60.2, 84.2, 90.6, 108.5, 113.5, 149.3, 165.1,
07.5.
C NMR (CDCl , 75 MHz): d = 14.1, 17.8, 21.0, 22.5, 27.4, 36.7,
3
38.7, 39.0, 43.1, 48.4, 49.3, 61.4, 167.2, 202.5, 215.8.
Anal. Calcd for C H O (mixture of isomers): C, 74.45; H, 9.02.
Anal. Calcd for C H O : C, 67.14; H, 9.01. Found: C, 66.95; H,
18
26
3
15 24
4
Found: C, 74.35; H, 9.25.
9.12.
Allene 13b
b-Keto Ester 9
1
20
H NMR (CDCl , 300 MHz): d = 1.01 (t, J = 7.1 Hz, 3 H), 1.25 (s,
Colorless oil; [a]D +71.1 (c = 1.02, CHCl3).
3
3
2
4
H), 1.30–1.70 (m, 7 H), 1.74 (s, 3 H), 2.10–2.25 (m, 2 H), 2.40–
.85 (m, 2 H), 3.55 (s, 1 H), 4.02 (qd, J = 0.9, 7.1 Hz, 2 H), 4.80–
.90 (m, 2 H), 5.83 (t, J = 4.2 Hz, 1 H).
–1
IR (CCl ): 1644, 1682, 1746 cm .
4
1
H NMR (CDCl , 300 MHz): d = 1.06 (s, 3 H), 1.27 (t, J = 7.1 Hz,
H), 1.30–1.45 (m, 2 H), 1.50–1.65 (m, 4 H), 1.70–2.10 (m, 4 H),
.30–2.70 (m, 2 H), 3.54 (AB, JAB = 15.7 Hz, d = 3.57, d = 3.51,
3
3
1
3
C NMR (CDCl , 75 MHz): d = 13.7, 17.9, 20.5, 25.0, 26.7, 34.9,
3
2
2
A
B
3
2
6.7, 36.8, 43.1, 45.1, 60.7, 83.6, 90.2, 108.6, 114.9, 148.8, 166.9,
07.5.
H), 4.19 (q, J = 7.1 Hz, 2 H).
1
3
C NMR (CDCl , 75 MHz): d = 14.1, 21.9, 22.9, 25.3, 27.0, 30.2,
9.0, 41.5, 48.8, 49.3, 59.9, 130.9, 165.4, 171.7, 192.9.
3
3
Enamine 7
At 40 °C, to a solution of allene 4 (300 mg, 1.20 mmol) in Et O (50
mL), was added morpholine (418 mg, 4.80 mmol). After stirring for
2
Hydrolysis of Enamine 14 to b-Keto Ester 15
At 20 °C, to a solution of enamine 14 (845 mg, 1.72 mmol) in Et O
3
d at 40 °C, the mixture was quenched with H O (20 mL) and then
2
2
(30 mL), was added 10% HCl (10 mL). After 2 h gentle stirring at
extracted with Et O (3 × 10 mL). The combined organic layers were
2
2
0 °C, the mixture was quenched with a sat. aq Na CO solution (20
washed with brine, dried (MgSO ) and filtered before solvents were
2
3
4
mL), H O (3 × 20 mL) and then extracted with Et O (3 × 10 mL).
removed under reduced pressure (15 mm Hg/30 °C) leading to the
crude enamine 7, which was not purified further; yield: 405 mg (ca.
2
2
The combined organic layers were washed with brine, dried
MgSO ) and filtered before solvents were removed under reduced
(
1
00%).
4
pressure (15 mm Hg/30 °C). The crude product was purified on a
1
H NMR (CDCl , 300 MHz): d = 0.88 (s, 3 H), 1.25 (t, J = 7.1 Hz,
3
silica gel column (65 g SiO , EtOAc–hexane, 5:95) to afford b-keto
2
3
H), 1.30–2.35 (m, 13 H), 2.57 (dt, J = 4.0, 3.3 Hz, 1 H), 3.40 (AB,
20
ester 15; yield: 440 mg (88%); colorless oil; [a] +25.22 (c = 1.03,
D
JAB = 15.5 Hz, d = 3.77, d = 3.03, 2 H), 3.66 (t, J = 4.5 Hz, 4 H),
A
B
CHCl ).
3
4
.13 (q, J = 7.1 Hz, 2 H).
–
1
IR (CCl ): 1645, 1644, 1683, 1746 cm .
1
3
4
C NMR (CDCl , 75 MHz): d = 14.0, 21.4, 21.6, 23.7, 24.9, 29.4,
3
1
H NMR (CDCl , 300 MHz): d = 1.08 (s, 3 H), 1.27 (t, J = 7.1 Hz,
3
1
1.2, 32.2, 33.6, 44.0, 49.6, 61.2, 67.4, 67.4, 79.7, 134.5, 143.9,
74.5.
3
3
H), 1.35–1.70 (m, 5 H), 1.73 (s, 3 H), 1.75–1.90 (m, 2 H), 1.91–
2
.05 (m, 2 H), 2.35–2.75 (m, 2 H), 3.54 (AB, JAB = 16.0 Hz,
d = 3.57; d = 3.52, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.70–4.80 (m,
Enamine 14
A
B
2
H).
Enamine 14 was prepared starting from allene 13 (2.0, 4.97 mmol)
and morpholine (1.730 g, 19.90 mmol) by using the same procedure
as for enamine 7; yield: 2.444 g (ca. 100%).
1
13
C NMR (CDCl , 75 MHz): d = 14.1, 20.7, 22.9, 27.4, 30.2, 31.1,
3
3
8.7, 40.8, 46.1, 48.5, 49.3, 61.1, 109.1, 130.9, 149.0, 164.7, 171.5,
192.9.
H NMR (CDCl , 300 MHz): d = 0.00 (s, 3 H), 0.03 (s, 3 H), 0.83
3
(
s, 9 H), 0.98 (s, 3 H), 1.15–1.23 (m, 3 H), 1.24 (t, J = 7.1 Hz, 3 H),
Anal. Calcd for C H O : C, 74.45; H, 9.02. Found: C, 74.54; H,
1
8
26
3
1
2
.40–1.65 (m, 2 H), 1.67 (s, 3 H), 1.70–1.70 (m, 2 H), 1.95–2.15 (m,
H), 2.30–2.60 (m, 2 H), 2.79 (dt, J = 7.1, 4.6, 4 H), 3.34 (AB,
9
.20.
JAB = 17.1 Hz, d = 3.51, d = 3.17, 2 H), 3.65 (t, J = 4.8 Hz, 4 H),
A
B
a,b-Unsaturated Ketone 16
4
.10 (ABX , J = 10.8, J = 7.1, J = 7.1 Hz, Dd = 0.03,
3 AB AX BX
To a solution of b-keto ester 15 (740 mg, 1.62 mmol) in DMF (20
d = 4.12, d = 4.08, 2 H), 4.64 (d, J = 0.9 Hz, 2 H).
A
B
mL), was added LiI (867 mg, 6.48 mmol). The mixture was stirred
1
3
during 2 h at 100 °C. At 25 °C, the mixture was quenched with H O
C NMR (CDCl , 75 MHz): d = –2.1, –2.6, 14.1, 18.7, 19.0, 20.7,
2
3
(
5 mL) and then extracted with Et O (4 × 20 mL). The combined or-
2
8
5.9, 27.2, 27.8, 33.9, 35.6, 35.0, 37.6, 41.8, 48.2, 49.5, 60.6, 67.8,
5.2, 108.3, 135.5, 139.5, 149.7, 171.1.
2
ganic layers were washed with brine, dried (MgSO ) and filtered be-
4
fore solvents were removed under reduced pressure (15 mm Hg/
3
0 °C). The crude product was purified on a silica gel column (65 g
Hydrolysis of Enamine 7 to 1,6-Diketone 8 and b-Keto Ester 9
At 20 °C, to a solution of enamine 7 (285 mg, 0.85 mmol), was add-
ed formic acid (3 mL). After 2 h gentle stirring at 20 °C, the mixture
was hydrolyzed with a sat. aq Na CO solution (20 mL), H O
SiO , EtOAc–hexane, 5:95) to afford 16; yield: 340 mg (96%); col-
orless oil; [a]D +29.35 (c = 0.59, CHCl ,).
2
2
0
3
–1
2
3
2
IR (CCl ): 1657, 1682 cm .
4
(
3 × 20 mL) and then extracted with Et O (3 × 10 mL). The com-
2
Synthesis 2006, No. 15, 2613–2617 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Polyfunctionalized Allenic Esters
2617
1
H NMR (CDCl , 300 MHz): d = 1.08 (s, 3 H), 1.30–1.70 (m, 4 H), References
3
1
2
.75 (t, J = 0.93 Hz, 3 H), 1.76–2.00 (m, 4 H), 2.23 (s, 3 H), 2.50–
(
1) (a) Rossi, R.; Diversi, P. Synthesis 1973, 25. (b) Schuster,
.75 (m, 2 H), 3.30–3.45 (m, 1 H), 4.70–4.80 (m, 2 H).
H.; Coppola, G. Allenes in Organic Synthesis; Wiley: New
York, 1984. (c) The Chemistry of Ketenes, Allenes and
Related Compounds, Part 2; Patai, S., Ed.; Wiley: New
York, 1980. (d) Pasto, D. J. Tetrahedron 1984, 40, 2805.
(e) Hoffmann-Röder, A.; Krause, N. Angew. Chem. Int. Ed.
1
3
C NMR (CDCl , 75 MHz): d = 20.7, 22.9, 27.5, 30.2, 30.6, 31.4,
3
3
8.6, 40.9, 46.2, 48.3, 109.0, 132.3, 149.3, 161.5, 199.2.
Anal. Calcd for C H O: C, 82.52; H, 10.16. Found: C, 82.33; H,
1
15
22
0.47.
2002, 41, 2933. (f) Miesch, M. Synthesis 2004, 746.
a,b-Unsaturated Ketone 10
Same procedure for a,b-unsaturated ketone 10 was used starting
from b-keto ester 9 (210 mg, 0.84 mmol) and LiI (450 mg, 3.36
mmol); yield: 138 mg (92%); colorless oil; [a]D +81.6 (c = 3.10,
hexane).
(2) (a) Wendling, F.; Miesch, M. Org. Lett. 2001, 3, 2688.
(b) Klein, A.; Miesch, M. Tetrahedron Lett. 2003, 44, 4483.
(c) Mota, A. J.; Klein, A.; Wendling, F.; Dedieu, A.; Miesch,
M. Eur. J. Org. Chem. 2005, 4346.
(3) (a) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am.
Chem. Soc. 1985, 107, 273. (b) d’Angelo, J.; Desmaële, D.;
Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3,
459. (c) Desmaële, D.; Cavé, C.; Dumas, F.; d’Angelo, J.
Enantiomer 2001, 6, 289.
2
0
–
1
IR (CCl ):1657, 1679 cm .
4
1
H NMR (CDCl , 300 MHz): d = 1.05 (s, 3 H), 1.15–1.45 (m, 3 H),
3
1
.46–1.65 (m, 2 H), 1.66–1.90 (m, 3 H), 1.91–2.10 (m, 1 H), 2.21
(
s, 3 H), 2.45–2.70 (m, 2 H), 3.30 (dt, J = 14.3, 3.01 Hz, 1 H).
(
4) The ratio was determined by analytical GC.
1
3
(5) (a) Ahmed, A. J. Nat. Prod. 1990, 53, 1031. (b) El-
Ghazouly, M. G.; El-Sebakhy, A. A.; El-Din, S.; Zdero, C.;
Bohlmann, F. Phytochemistry 1987, 26, 439.
C NMR (CDCl , 75 MHz): d = 22.0, 22.8, 25.2, 27.1, 30.5, 30.9,
3
3
8.9, 41.5, 48.6, 131.9, 162.2, 199.2.
Anal. Calcd for C H O: C, 80.85; H, 10.18. Found: C, 81.01; H,
12
18
(
c) Villaescusa Castillo, L.; Lanza, A. M. D.; Faure, R.;
Debrauwer, L.; Elais, R.; Balansard, G. Phytochemistry
995, 40, 1193. (d) Ahmed, A. A.; Mahmoud, A. A.
9
.95.
1
Tetrahedron 1998, 54, 8141.
6) Bestmann, H.; Graf, G.; Hartung, H.; Kolewa, S.; Vilsmaier,
Acknowledgment
(
We thank Rhodia for a generous gift of TBDMSOTf, ULP and
CNRS for financial support. We also thank Dr. Jennifer Wytko for
her help in preparing the manuscript.
E. Chem. Ber. 1970, 103, 2794.
(7) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044. These authors described the synthesis of optically
active ketone 10, having an [a] +82.91 (c = 3.26, hexane,
D
9
+
8% ee). This value is in good agreement with our data: [a ]
D
81.63 (c = 3.10, hexane, 95% ee).
(
8) (a) See reference 5d. (b) For the synthesis of related
iphionane sesquiterpenes, see: Chiu, P.; Szeto, C. P.; Geng,
Z.; Cheng, K. F. Tetrahedron Lett. 2001, 42, 4091. (c) See
also: Gao, X.; Xiong, Z.; Zhou, G.; Li, Y. Synthesis 2001,
37. (d) For biological activity, see: Benito, P. B.; Abad, M.
J.; Diaz, A. M.; Villaescusa, L.; Gonsalez, M. A.; Silvan, A.
M. Biol. Pharm. Bull. 2002, 25, 1.
Synthesis 2006, No. 15, 2613–2617 © Thieme Stuttgart · New York