Synthesis of racemic and enantiomerically pure acetylenic -keto esters derived from 2-methyl-1,3-cycloalkanediones and 2-methylcycloalkanones respectively

Article abstract of DOI:10.1055/s-0029-1217043

Racemic and enantiomerically pure alkynyl esters tethered, respectively, to 2-methyl-1,3-cycloalkanediones and 2-methylcycloalkanones were readily obtained starting from common intermediates, which were available on large scale.

Full text of DOI:10.1055/s-0029-1217043

PRACTICAL SYNTHETIC PROCEDURES
171
Synthesis of Racemic and Enantiomerically Pure Acetylenic w-Keto Esters
Derived from 2-Methyl-1,3-cycloalkanediones and 2-Methylcycloalkanones
Respectively
S
ynthesis of
R
h
a
cemic and
E
i
nantio
l
meric
a
i
lly
P
ur
p
e
A
cetylenic
p
w
-Keto
E
ste
e
r
s
Geoffroy,a Marie-Paule Ballet,a Sidonie Finck,a,1 Eric Marchioni,b Christophe Marcic,b Michel Miesch*a
a
Université de Strasbourg, Institut de Chimie, UMR 7177, Laboratoire de Chimie Organique Synthétique,
1 rue Blaise Pascal, BP296/R8, 67008 Strasbourg, France
Fax +33(3)90241754; E-mail: m.miesch@chimie.u-strasbg.fr
Université de Strasbourg, Faculté de Pharmacie, IPCH, UMR 7178, Laboratoire de Chimie
b
PSP
Analytique et Sciences de l’Aliment-74, route du Rhin, 67400 Illkirch, France
Received 6 July 2009; revised 17 July 2009
No175
Abstract: Racemic and enantiomerically pure alkynyl esters tethered, respectively, to 2-methyl-1,3-cycloalkanediones and 2-methyl-
cycloalkanones were readily obtained starting from common intermediates, which were available on large scale.
Key words: alkynyl ester, enantiomer-chain, elongation, trimethylsilylpropyne, Corey–Fuchs reaction
O
1) ref. 11, 12
TsO
(CH2)n
2) TsCl, Et3N, DMAP (cat.),
CH2Cl2, 20 °C, 18 h
O
O
O
O
O
1 (n = 1)
2 (n = 2)
CO2Et
O
(CH2)n
O
(CH2)n
O
CO2Et
(CH2)n
O
O
20 (n = 1, 67%)
21 (n = 2, 47%)
16 (n = 1, 59%)
17 (n = 2, 49%)
1) NaI, acetone, 20 °C, 15 h
O
1) Li(en)2acetylide, DMSO, 0 °C, 4 h
2) n-BuLi, TMS-propyne, 0 °C, 1 h
9 (n = 1, 60%)
28 (n = 2, 54%)
2) n-BuLi, ClCO2Et, THF, –78 °C, 3 h
3) p-TsOH on SiO2, THF, 20 °C, 5 h
3) NaOH, EtOH, 20 °C, 1 h
4) n-BuLi, ClCO2Et, THF, –78 °C, 2 h
5) (COOH)2, SiO2, 20 °C, 5 h
TsO
O
O
CO2Et
O
O
(CH2)n
(CH2)n
CO2Et
O
(CH2)n
39 (n = 1, 48%)
40 (n = 2, 61%)
1) ref. 2, 13
37 (n = 1, 73%)
38 (n = 2, 64%)
29 (n = 1, 30%)
30 (n = 2, 60%)
(CH2)n
2) TsCl, Et3N, DMAP (cat.),
CH2Cl2, 20 °C, 18 h
n = 1 or 2
Scheme 1
2-Substituted 2-methyl-1,3-cycloalkanediones and 2,2- through which to gain access to these types of compound,
disubstituted cycloalkanones derived from optically ac- the final goal being to define the most efficient reaction
tive imines are useful starting materials for the elaboration pathway and to use these reaction conditions for the syn-
of new methodologies.2,3 For example, compounds de- thesis of enantiomerically pure acetylenic w-keto esters
rived from non-activated alkynes tethered to 2-methyl- (Scheme 1).
1,3-cyclopentanedione (or -cyclohexanedione) have been
The alkylation reaction of 2-methyl-1,3-cyclopentanedi-
one 1 (or -cyclohexanedione 2) with 1-iodopentyne (or
-hexyne) followed by the introduction of the carbethoxy
group proved to be a priori the most efficient route to the
desired acetylenic w-keto esters. However, it is known
that the alkylation reaction of 2-methyl-1,3-cyclopen-
tanedione (or -cyclohexanedione) can be readily achieved
used in radical chemistry4 and organometallic chemistry5
to set up new cyclisation reactions. Surprisingly, to the
best of our knowledge, alkynyl esters tethered to 2-meth-
yl-1,3-cyclopentanedione (or -cyclohexanedione) have
not been described in the literature. Being involved in
studies on the reactivity of acetylenic w-keto esters bear-
ing a three- or four-carbon tether toward bases and Lewis
with activated halides such as allyl bromide, propargyl
acids,6 we wish to report here different synthetic routes
bromide and benzyl bromide.7 Nevertheless, there are few
reports concerning the use of non-activated halides. More-
over, when the latter were involved, chemoselectivity
problems (C-alkylation versus O-alkylation) always oc-
SYNTHESIS 2010, No. 1, pp 0171–0179
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1217043; Art ID: Z14609SS
x
x
.
x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

172
P. Geoffroy et al.
PRACTICAL SYNTHETIC PROCEDURES
O
O
Table 1 C- and O-Alkylation of Diones 1 and 2
n
1
2
2
2
Base/Solvent
TBAF/THF
t-BuOK/DMF
NaH/DMF
Ratio C/O-alkylation Yield (%)
4
0:1
quant
70
i
i
O
O
+
O
1:1.33
1:1.66
1:1.22
n = 1
n = 2
(CH2)n
1 (n = 1)
2 (n = 2)
O
O
48
3
TBAF/THF
89
O
i: 1-iodohexyne, solvent (see Table 1)
5
halide, i.e. allyl bromide. Indeed, the alkylation reaction
of 2-methyl-1,3-cyclopentanedione (1) with allyl bromide
took place readily to yield, after ozonolysis of the double
bond, the aldehyde 6 (Scheme 3).9 A Wittig reaction, fol-
lowed by a catalytic hydrogenation of the electrophilic
double bond, di-protection of the dione and reduction of
the carbethoxy group with LiAlH4 afforded the hydroxy
Scheme 2
HO
O
O
O
O
O
ref. 8, 9a
i
O
derivative 7. After oxidation of the hydroxy group,10
a
O
Corey–Fuchs reaction,11 along with the concomitant in-
troduction of the carbethoxy group delivered, after mono-
deprotection of the bis-dioxolane 8, the desired acetylenic
w-keto ester 9 (10 steps, 13% overall yield from 1)
(Scheme 3).
O
O
1
6
7
CO2Et
CO2Et
O
iii
O
ii
O
O
In order to increase the length of the tether, the same strat-
egy was utilized except for the first step, i. e. the alkyla-
tion reaction with allyl bromide, which was replaced by a
Michael addition of acrolein to 2-methyl-1,3-cyclopen-
tanedione 1 (or -cyclohexane dione 2) leading respective-
ly to the aldehyde derivatives 10/11 and 12/13.12 Using
the same reaction sequence described for obtaining the
hydroxy derivative 7, compounds 12/13 were isolated in
72% and 66% overall yields, respectively. After oxidation
of the latter into the corresponding aldehydes, a Corey–
Fuchs reaction followed by the introduction of the carbe-
thoxy group gave the di-protected diones 14/15. Mono-
deprotection of these diones afforded the acetylenic w-
keto esters 16/17 (9 steps, 43% overall yield from 1 and
39% overall yield from 2) (Scheme 4).
O
O
8
9
O
Scheme 3
Reagents and conditions: i: (a) Ph3P=CHCO2Me,
CH2Cl2, 0 °C to 20 °C, 12 h (93%); (b) H2, Pd/C, AcOEt, 20 °C, 7 h
(98%); (c) ethylene glycol, CH(OMe)3, p-TsOH, CH2Cl2, 40 °C, 20 h
(87%); (d) LiAlH4, THF, 20 °C, 10 min (98%); ii: (a) SO3, Py, Et3N,
DMSO, CH2Cl2, 0 °C to 20 °C, 1 h (81%); (b) Ph3P, CBr4, Et3N,
CH2Cl2, 0 °C to 20 °C, 2 h (70%); (b) n-BuLi, ClCO2Et, THF, –78 °C
to 20 °C, 4 h (78%); iii: p-TsOH, SiO2, THF, 20 °C, 5 h (81%).
curred. Indeed, it was shown that the addition of 1-io-
dohexyne to 2-methyl-1,3-cyclopentanedione 1, in the
presence of TBAF as a base,8 afforded the O-alkylation
product 3 exclusively. Amazingly, when the same reac-
tion was carried out starting from 2-methyl-1,3-cyclohex-
anedione 2, a mixture of O-alkylated product 4 and C-
alkylated product 5 was obtained (Scheme 2). The ratio of
O-alkylated product 4 increased when other base/solvent
sytems (t-BuOK/THF, NaH/DMF, n-BuLi/THF) were
utilized (Table 1).
The Corey–Fuchs reaction, which allows the introduction
of the alkynyl moiety, represents the key step in the above
synthetic route. Nevertheless, these routes are quite long
and six chromatographic separations on silica gel were
necessary in order to obtain the final products. To improve
these time-consuming purifications as well as the overall
yields, the alkynyl moiety was directly introduced using
acetylides such as lithium acetylide and 3-trimethylsilyl-
These results prompted us to set up another synthetic
route involving an alkylation reaction with an activated
CO2Et
CO2Et
O
OH
ii
O
O
O
O
O
O
O
O
O
iii
i
ref. 12a
(CH2)n
(CH2)n
(CH2)n
(CH2)n
(CH2)n
O
O
O
O
16 (n = 1)
17 (n = 2)
O
14 (n = 1)
15 (n = 2)
O
1 (n = 1)
2 (n = 2)
10 (n = 1)
11 (n = 2)
12 (n = 1)
13 (n = 2)
Scheme 4 Reagents and conditions: i: (a) Ph3P=CHCO2Me, CH2Cl2, 0 °C to 20 °C, 4 h (n = 1: 95%; n = 2: 93%); (b) H2, Pd/C, AcOEt, 20
°C, 5 h (n = 1: quant; n = 2: quant); (c) ethylene glycol, CH(OMe)3, p-TsOH, CH2Cl2, 45 °C, 25 h ( n = 1: 85%; n = 2: 79%); (d) LiAlH4, THF,
20 °C, 10 min (n = 1: quant; n = 2: quant); ii: (a) SO3, Py, Et3N, DMSO, CH2Cl2, 0 °C to 20 °C, 1 h (n = 1: 91%; n = 2: 70%); (b) Ph3P, CBr4,
Et3N, CH2Cl2, 0° C to 20 °C, 12 h (n = 1: 77%; n = 2: 95%); (c) n-BuLi, ClCO2Et, THF, –78 °C to 20 °C, 20 h (n = 1: 86%; n = 2: 89%), iii:
(COOH)2, SiO2, CH2Cl2, 20 °C, 5 h (n = 1: quant; n = 2: quant).
Synthesis 2010, No. 1, 171–179 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Racemic and Enantiomerically Pure Acetylenic w-Keto Esters
173
2-propynyllithium. However, it was desirable to start overall yield from 1 and 25% overall yield from 2) and 16/
from a common intermediate that would allow the intro- 17 (9 steps, 39% overall yield from 1 and 23% overall
duction of three or four methylene units. For this purpose, yield from 2) (Scheme 1). At this stage, it should be noted
methyl acrylate was added to 2-methyl-1,3-cyclopen- that the tosylates 20/21 are readily available on a large
tanedione 1 (or -cyclohexanedione 2) to yield, after pro- scale (60 mmol) and that they represent common interme-
tection of the diones, compounds 18/19.13 After reduction diates for the synthesis of the desired acetylenic w-keto es-
of the carbethoxy groups, the resulting hydroxy deriva- ters (Scheme 1).
tives were transformed into the tosylates 20/21
(Scheme 5).
The above synthetic route was also followed using the
chiral tosylates 29/30 together with the iodo derivatives
31/32. Thus, the enantiomerically pure alkynyl deriva-
E = CO2Me
O
OTs
ii
I
tives 33/36 were readily obtained and could be easily
transformed into the corresponding enantiomerically pure
acetylenic w-keto esters 37–40.3,15 Only one purification
by silica gel chromatography was necessary for the trans-
formation of the tosylates 29/30 or of the iodo derivatives
31/32 into the desired acetylenic w-keto esters 37–40.
E
O
O
O
O
O
O
O
O
O
ref. 8,
14
i
(CH2
(CH2)n
(CH2)n
(CH2)n
)
n
O
O
O
O
18 (n = 1)
19 (n = 2)
20 (n = 1)
21 (n = 2)
22 (n = 1)
23 (n = 2)
1 (n = 1)
2 (n = 2)
Other synthetic routes were also tested. For example: 1)
the addition of the dianion derived from tetrolic acid to the
tosylates 20/21 (or iodo derivatives 22/23),16 and 2) the
substitution of the iodo derivatives 22/23 with the dianion
derived from ethyl acetoacetate, followed by the pyra-
zolone formation and subsequent oxidation with hyperva-
lent iodine reagents.17 However, a complex mixture of
compounds was always obtained in the first case and low
yields were observed for the oxidation step in the second
case. Therefore, these routes were abandoned.
Scheme 5 Reagents and conditions: i: (a) LiAlH4, THF, 20 °C, 10
min (n = 1 or 2: quant); (b) TsCl, DMAP (cat), Et3N, CH2Cl2, 0 °C to
20 °C, 12 h (n = 1: 82%; n = 2: 62%); ii: NaI, acetone, 20 °C, 12 h
(n = 1 or 2: quant).
To introduce the three-carbon tether, lithium acetylide
was added to the tosylates 20/21 to give the alkynyl deriv-
atives 24/25 (Table 2). Nevertheless, these reaction condi-
tions did not work well for the introduction of the four-
carbon tether. The alkynyl derivatives 26/27 only formed
from 3-trimethylsilyl-2-propynyllithium if the corre-
sponding iodo derivatives 22/23 were utilized as starting
materials. Finally, the introduction of the carbethoxy
group and mono-deprotection of the bis-dioxolane afford-
ed the desired acetylenic w-keto esters 9/28 (7 steps, 40%
In summary, we have shown that several (enantiomerical-
ly pure) acetylenic w-keto esters can be prepared starting
from common intermediates, i.e. the tosylates 20/21 and
29/30, which are readily available in large scales (60
mmol).
Table 2 Synthesis of Alkynyl Esters Tethered to 2-Methyl-1,3-cycloalkanediones and 2-Methylcycloalkanones
Starting material
Reagent
Product (yield)
Reagent
Product (yield,a [a]D)
CO2Et
OTs
O
O
O
O
O
1) n-BuLi, ClCO2Et
2) p-TsOH/SiO2
Li(en)2acetylide
O
O
O
O
O
O
20
24 (78%)
9 (77%)
CO2Et
OTs
O
O
O
O
O
1) n-BuLi, ClCO2Et
2) p-TsOH/SiO2
Li(en)2acetylide
O
O
O
O
O
O
21
25 (88%)
28 (61%)
I
O
O
O
O
O
O
1) n-BuLi, ClCO2Et
2) (COOH)2/SiO2
1) TMS
CH2Li
O
CO2Et
O
O
2) NaOH
O
O
22
26 (66%)
16 (90%)
Synthesis 2010, No. 1, 171–179 © Thieme Stuttgart · New York

174
P. Geoffroy et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Synthesis of Alkynyl Esters Tethered to 2-Methyl-1,3-cycloalkanediones and 2-Methylcycloalkanones (continued)
Starting material
Reagent
Product (yield)
Reagent
Product (yield,a [a]D)
O
I
O
O
O
O
1) n-BuLi, ClCO2Et
2) (COOH)2/SiO2
1) TMS
CH2Li
O
O
O
2) NaOH
CO2Et
CO2Et
O
O
O
23
27 (57%)
17 (87%)
OTs
O
O
O
O
1) n-BuLi, ClCO2Et
2) HCl (10%), THF
O
Li(en)2acetylide
Li(en)2acetylide
29
33 (80%)
37 (91%)
[a]D20 +1.2 (c 1.00, CHCl3)
[a]D20 +4.6 (c 1.00, CHCl3)
[a]D20 –48.3 (c 1.00, CHCl3)
CO2Et
O
OTs
O
O
O
O
1) n-BuLi, ClCO2Et
2) HCl (10%), THF
30
34 (88%)
38 (73%)
[a]D20 –3.5 (c 1.00, CHCl3)
[a]D20 –7.2 (c 1.00, CHCl3)
[a]D20 –40.3 (c 1.01, CHCl3)
O
I
O
O
O
O
1) n-BuLi, ClCO2Et
2) HCl (10%),THF
1) TMS
CH2Li
2) NaOH
CO2Et
[a]D20 +4.0 (c 1.00, CHCl3)
31
35 (quant)
39
[a]D20 –1.9 (c 1.00, CHCl3)
[a]D20 +4.6 (c 1.00, CHCl3)
(48% from 31)
I
O
O
O
O
O
1) n-BuLi, ClCO2Et
2) HCl (10%),THF
1) TMS
CH2Li
2) NaOH
CO2Et
32
36 (quant)
40 (61% from 32)
[a]D20 –10.6 (c 1.00, CHCl3)
[a]D20 –3.6 (c 1.00, CHCl3)
[a]D20 –36.6 (c 1.00, CHCl3)
a Isolated yield.
Et2O and THF were distilled from Na/benzophenone, CH2Cl2 over
P2O5 and the amines over KOH. Thin-layer chromatography (TLC)
was carried out on silica gel plates (Merck 60F254) and the spots
were visualized under a UV lamp (254 or 365 nm) and/or sprayed
with an acidic alcoholic solution of vanillin or with phosphomolyb-
dic acid followed by heating on a hot plate. For column chromatog-
raphy, silica gel (Merck, Si60, 40–60 mm) was used. Melting points
(mp) were measured on a hot plate Stuart Scientific SMP 3 appara-
tus. 1H NMR spectra were recorded at 300 MHz and 13C NMR spec-
tra at either 75 or 125 MHz on a Bruker AC-300 or ARX-500,
respectively, using the signal of the residual non-deuteriated solvent
Tosylates of Type 20/21 and 29/30; General Procedure (GP1)
A dry vessel equipped with a magnetic stirring bar, a thermometer,
a dropping funnel and drying tubes was charged with the appropri-
ate alcohol (~0.4 M in CH2Cl2). The solution was cooled to 0 °C and
Et3N (1.5 equiv) was added slowly, followed by the TsCl (1.2
equiv) and DMAP (0.1 equiv). The mixture was allowed to warm to
25 °C over 15 h, then the reaction was quenched with sat. aq NH4Cl
(50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were washed with sat. aq NaCl (50 mL) and dried
(Na2SO4). After filtration, the solvent was removed under reduced
pressure. A chromatographic purification afforded the products 20,
21, 29 and 30.
1
as the internal reference. Significant H NMR spectroscopic data
are tabulated in the following order: chemical shift (d) expressed in
ppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; m,
multiplet), coupling constants (J) in Hz, number of protons. The ra-
tios of compounds indicated below were calculated on the basis of
the corresponding NMR integrations. High-resolution mass spectra
(HRMS) were performed on a Agilent 6520 Accurate Mass Q-TOF.
IR spectra were recorded as CCl4 solutions on a Perkin–Elmer IR-
881 and on a Bruker Alpha spectrometer. Microanalysis were car-
ried out by the Service Commun d'Analyses du CNRS, Institut de
Chimie-Strasbourg.
Iodides of Type 22/23 and 31/32; General Procedure (GP2)
A dry vessel equipped with a magnetic stirring bar, a thermometer
and drying tubes was charged with tosylates of type 20, 21, 29 or 30
(~0.12 M in acetone) and NaI (4 equiv). The reaction mixture was
stirred for 15 h at r.t., hydrolyzed with H2O (20 mL) and extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with sat. aq NaCl (50 mL) and dried (Na2SO4). After filtration, the
solvent was removed under reduced pressure. The iodides were
used without purification for the next step.
Synthesis 2010, No. 1, 171–179 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Racemic and Enantiomerically Pure Acetylenic w-Keto Esters
175
Acetylides of Type 24/25 and 33/34; General Procedure (GP3)
A dry, argon-flushed vessel equipped with a magnetic stirring bar,
condenser and dropping funnel was charged with lithium acetylide
ethylenediamine complex (1.5 equiv) and cooled to 0 °C. The tosy-
late (20, 21, 29 or 30) dissolved in a minimum of anhydrous solvent
(DMSO–THF, 2:1, 0.3 M) was added. The reaction mixture was al-
lowed to warm to r.t. over 1.5 to 4.5 h and then hydrolyzed with sat.
aq NH4Cl (50 mL) and extracted with Et2O (3 × 20 mL). The com-
bined organic layers were washed with sat. aq NaCl (50 mL) and
dried (Na2SO4). After filtration, the solvent was removed under re-
duced pressure. A chromatographic purification afforded the prod-
ucts 24, 25, 33 and 34.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28NaO7S: 435.14480;
found: 435.14610.
6-Methyl-6-(4-methylbenzenesulfonyloxypropyl)-1,4,8,11-tet-
raoxadispiro[4.1.4.3]tetradecane (21)
According to GP1, the tosylate derivative 21 was prepared from the
corresponding alcohol (5.46 g, 20 mmol) and TsCl (4.59 g, 24.0
mmol), Et3N (4.2 mL, 30 mmol) and DMAP (0.24g, 2 mmol). Puri-
fication by column chromatography (silica gel; PE–EtOAc,
98:2→85:15 containing 1% of Et3N) afforded 21.
Yield: 5.36 g (62%); colorless solid; mp 71–72 °C.
1H NMR (300 MHz, CDCl3): d = 7.77 (d, J = 8.3 Hz, 2 H), 7.32 (d,
J = 7.9 Hz, 2 H), 4.01–3.75 (m, 10 H), 2.42 (s, 3 H), 1.85–1.35 (m,
10 H), 1.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.48 (ArC), 133.37 (ArC),
129.75 (ArC), 127.89 (ArC), 113.20 (OCO), 72.20 (CH2), 65.05
(OCH2), 63.98 (OCH2), 48.79 (CCH3), 29.82 (OCCH2), 26.28
(CH2), 25.05 (CH2), 21.62 (CCH3), 18.48 (CH2), 15.55 (CH3).
Acetylides of Type 26/27 and 35/36; General Procedure (GP4)
A dry, argon-flushed vessel equipped with a magnetic stirring bar,
condenser and dropping funnel was charged with 1-(trimethylsilyl)-
1-propyne (~0.16 M in THF, 1.6 equiv) and cooled to 0 °C. n-BuLi
(1.5 equiv) was added and, after 0.5 h, the THF solution of the io-
dides 22, 23, 31 or 32 (1.0 equiv) was added in one portion at 0 °C.
The reaction mixture was allowed to warm to r.t. over 1 h, hydro-
lyzed with sat. aq NH4Cl (60 mL) and extracted with Et2O (3 × 20
mL). The combined organic layers were washed with sat. aq NaCl
(50 mL) and dried (Na2SO4). After filtration, the solvent was re-
moved under reduced pressure. A chromatographic purification af-
forded the substituted products.
HRMS (ESI): m/z [M + Na]+ calcd for C21H30NaO7S: 449.16045;
found: 449.16093.
(S)-6-Methyl-6-(4-methylbenzenesulfonyloxypropyl)-1,4-di-
oxaspiro[4.4]nonane (29)
According to GP1, the tosylate derivative 29 was prepared from the
corresponding alcohol (12 g, 59.8 mmol) and TsCl (13.68 g, 71.1
mmol), Et3N (12.6 mL, 89.7 mmol) and DMAP (0.73 g, 6 mmol).
Purification by column chromatography (silica gel; PE–EtOAc,
98:2→85:15 containing 1% of Et3N) afforded 29.
These silytated intermediates were dissolved in absolute EtOH
(~0.05 M) and treated with NaOH (25 equiv) dissolved in the min-
imum amount of H2O during 1 h. Sat. aq NH4Cl was added and the
mixture was extracted with Et2O (3 × 20 mL). The combined organ-
ic layers were washed with sat. aq NaCl (50 mL) and dried
(Na2SO4). After filtration, the solvent was removed under reduced
pressure. A chromatographic purification afforded the products 26,
27, 35 and 36.
Yield: 16.7 g (78%); colorless liquid; [a]D20 +1.2 (c 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.78 (d, J = 8.2 Hz, 2 H), 7.33 (d,
J = 8.5 Hz, 2 H), 4.00 (t, J = 6.6 Hz, 2 H), 3.87–3.82 (m, 4 H), 2.44
(s, 3 H), 1.82–1.41 (m, 8 H), 1.32 (dd, J = 9.4, 7.5 Hz, 2 H), 0.89 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 144.62 (ArC), 133.33 (ArC),
129.81 (ArC), 127.92 (ArC), 119.39 (OCO), 71.69 (CH2O), 64.76
(OCH2), 64.51 (OCH2), 45.39 (CCH3), 35.43 (CH2), 33.35 (CH2),
30.71 (CH2), 24.59 (CH2), 21.66 (CCH3), 20.06 (CH3), 17.87 (CH2).
Acetylenic Esters of Type 9/28, 37/38 and 16/17, 39/40; General
Procedure (GP5)
A dry, argon-flushed vessel equipped with a magnetic stirring bar,
condenser and dropping funnel was charged with acetylide (~0.14
M in THF, 1.0 equiv) and cooled to –78 °C. n-BuLi (1.2 equiv) was
added dropwise. After 0.5 h, ClCO2Et was added in one portion at
–78 °C. The reaction mixture was allowed to warm to r.t. over 2–3
h, hydrolyzed with sat. aq NH4Cl and extracted with Et2O (3 × 20
mL). The combined organic layers were washed with sat. aq NaCl
(50 mL) and dried (Na2SO4). After filtration, the solvent was re-
moved under reduced pressure. The reaction mixture was treated
with a 10% HCl solution in THF (20 mL) for 3 h, extracted with
Et2O (3 × 20 mL) and dried (Na2SO4). After filtration, the solvent
was removed under reduced pressure. A chromatographic purifica-
tion afforded the acetylenic esters.
HRMS (ESI): m/z [M + H]+ calcd for C18H27O5S: 355.15737; found:
355.15767.
(S)-6-Methyl-6-(4-methylbenzenesulfonyloxypropyl)-1,4-di-
oxaspiro[4.5]decane (30)
According to GP1, the tosylate derivative 30 was prepared from the
corresponding alcohol (10.4 g, 48.8 mmol) and TsCl (11.17 g, 58.6
mmol), Et3N (10.3 mL, 73.2 mmol) and DMAP (0.59 g, 4.9 mmol).
Purification by column chromatography (silica gel; PE–EtOAc,
98:2→85:15 containing 1% of Et3N) afforded 30.
Yield: 16.53 g (91%); colorless liquid; [a]D20 –3.5 (c 0.99, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.0 Hz, 2 H), 7.34 (d,
J = 8.0 Hz, 2 H), 4.00 (t, J = 6.6 Hz, 2 H), 3.94–3.81 (m, 4 H), 2.45
(s, 3 H), 1.62–1.48 (m, 6 H), 1.41–1.33 (m, 6 H), 0.86 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.58 (ArC), 133.2 (ArC), 129.78
(ArC), 127.89 (ArC), 112.67 (OCO), 71.69 (CH2O), 64.88 (OCH2),
64.66 (OCH2), 40.81 (CCH3), 34.39 (CH2), 30.38 (CH2), 30.38
(CH2), 23.49 (CH2), 23.49 (CH2), 21.62 (CCH3), 20.75 (CH2), 19.32
(CH3).
6-Methyl-6-(4-methylbenzenesulfonyloxypropyl)-1,4,8,11-tet-
raoxadispiro[4.1.4.2]tridecane (20)
According to GP1, tosylate derivative 20 was prepared from the
corresponding alcohol (11.25 g, 43.5 mmol) and TsCl (9.96 g, 52.2
mmol), Et3N (9.2 mL, 65.3 mmol) and DMAP (0.53 g, 4.3 mmol).
Purification by column chromatography (silica gel; PE–EtOAc,
98:2→85:15 containing 1% of Et3N) afforded 20.
Yield: 14.7 g (82%); colorless solid; mp 107–109 °C.
1H NMR (300 MHz, CDCl3): d = 7.78 (d, J = 8.2 Hz, 2 H), 7.33 (d,
J = 8.1 Hz, 2 H), 3.98 (t, J = 6.8 Hz, 2 H), 3.94–3.78 (m, 8 H), 2.44
(s, 3 H), 1.95–1.80 (m, 4 H), 1.72–1.62 (m, 2 H), 1.44–1.28 (m,
2 H), 1.04 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H29O5S: 369.17302; found:
369.17268.
13C NMR (75 MHz, CDCl3): d = 144.52 (ArC), 133.33 (ArC),
129.76 (ArC), 127.92 (ArC), 117.29 (OCO), 71.87 (CH2O), 64.22
(OCH2), 64.08 (OCH2), 49.77 (CCH3), 32.23 (OCCH2), 25.01
(CH2), 23.68 (CH2), 21.64 (CCH3), 16.89 (CH3).
6-Methyl-6-(3-iodopropyl)-1,4,8,11-tetraoxa-
dispiro[4.1.4.2]tridecane (22)
According to GP2, the addition of NaI (2.82 g, 18.9 mmol) to tosy-
late 20 (1.94 g, 4.7 mmol) afforded the iodide derivative 22.
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PRACTICAL SYNTHETIC PROCEDURES
Yield: 1.72 g (quant); yellow oil.
1H NMR (300 MHz, CDCl3): d = 4.01–3.83 (m, 8 H), 2.14–2.11 (m,
2 H), 1.97–1.82 (m, 5 H), 1.55–1.52 (m, 4 H), 1.09 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 4.03–3.83 (m, 8 H), 3.14 (t,
J = 7.1 Hz, 2 H), 1.95–1.80 (m, 6 H), 1.60–1.51 (m, 2 H), 1.09 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 117.38 (OCO), 64.69 (OCH2),
64.15 (OCH2), 50.01 (CCH3), 32.28 (OCCH2), 30.61 (CH2), 28.58
(CH2), 17.09 (CH3), 8.45 (CH2).
13C NMR (75 MHz, CDCl3): d = 117.52 (OCO), 84.95 (C≡CH),
68.02 (C≡CH), 64.70 (OCH2), 64.15 (OCH2), 50.18 (CCH3), 32.35
(OCCH2), 28.79 (CH2), 23.39 (CH2), 19.59 (CH2), 17.02 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NaO4: 289.14103;
found: 289.14205.
HRMS (ESI): m/z [M + Na]+ calcd for C13H21INaO4: 391.03767;
found: 391.03799.
6-Methyl-6-(pent-4-ynyl)-1,4,8,11-tetraoxadispiro[4.1.4.3]tet-
radecane (25)
According to GP3, the acetylenic derivative 25 was prepared from
the tosylate 21 (0.65 g, 2.3 mmol) and lithium acetylide ethylenedi-
amine complex (0.21 g, 3.5 mmol) and purified by column chroma-
tography (silica gel; PE–EtOAc, 70:30 containing 1% Et3N),
furnishing compound 25.
6-Methyl-6-(3-iodopropyl)-1,4,8,11-tetraoxadispiro[4.1.4.3]tet-
radecane (23)
According to GP2, the addition of NaI (4.79 g, 32 mmol) to tosylate
21 (3.0 g, 8.0 mmol) afforded iodide 23.
Yield: 2.8 g (quant); yellow oil.
Yield: 0.38 g (88%); colorless oil.
IR (ATR): 3288 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.98–3.86 (m, 8 H), 2.12–2.07 (m,
2 H), 1.90 (t, J = 2.7 Hz, 1 H), 1.65–1.53 (m, 10 H), 1.07 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 113.40 (OCO), 85.01 (C≡CH),
67.97 (C≡CH), 65.11 (OCH2), 64.01 (OCH2), 49.19 (CCH3), 30.13
(CH2), 29.99 (OCCH2), 24.61 (CH2), 19.81 (CH2), 18.58 (CH2),
15.56 (CH3).
1H NMR (300 MHz, CDCl3): d = 4.00–3.87 (m, 8 H), 3.13 (t,
J = 6.9 Hz, 2 H), 1.98–1.88 (m, 2 H), 1.68–1.51 (m, 8 H), 1.08 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 113.28 (OCO), 65.10 (OCH2),
64.10 (OCH2), 49.09 (CCH3), 31.91 (CH2), 29.90 (OCCH2), 29.70
(CH2), 18.56 (CH2), 15.74 (CH3), 9.38 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H23INaO4: 405.05332;
found: 405.05351.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24NaO4: 303.15668;
(S)-6-(3-Iodopropyl)-6-methyl-1,4-dioxaspiro[4.4]nonane (31)
According to GP2, the addition of NaI (5.92 g, 39.5 mmol) to tosy-
late 29 (3.5 g, 9.9 mmol) afforded iodide 31.
Yield: 3.17 g (quant); yellow oil; [a]D20 –1.9 (c 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.94–3.85 (m, 4 H), 3.16 (t,
J = 7.1 Hz, 2 H), 1.93–1.50 (m, 8 H), 1.44 (dd, J = 9.3, 7.5 Hz, 2 H),
0.95 (s, 3 H).
found: 303.15671.
(R)-6-Methyl-6-(pent-4-ynyl)-1,4-dioxaspiro[4.4]nonane (33)
According to GP3, the acetylenic derivative 33 was prepared from
the tosylate 29 (3.29 g, 9.2 mmol) and lithium acetylide ethylenedi-
amine complex (1.11 g, 12 mmol) and purified by column chroma-
tography (silica gel; PE–EtOAc, 95:5 containing 1% Et3N),
furnishing compound 33.
13C NMR (75 MHz, CDCl3): d = 19.50 (OCO), 64.79 (OCH2), 64.61
(OCH2), 45.58 (CCH3), 36.20 (CH2), 35.51 (CH2), 33.39 (CH2),
29.50 (CH2), 20.26 (CH3), 17.94 (CH2), 8.15 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C11H20IO2: 311.05025; found:
311.04984.
Yield: 1.55 g (80%); colorless oil; [a]D20 +4.6 (c 1.00, CHCl3).
IR (ATR): 3296 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.92–3.86 (m, 4 H), 2.16 (td,
J = 6.7, 2.7 Hz, 2 H), 1.94 (t, J = 2.7 Hz, 1 H), 1.88–1.74 (m, 2 H),
1.69–1.39 (m, 8 H), 0.95 (s, 3 H).
(S)-6-(3-Iodopropyl)-6-methyl-1,4-dioxaspiro[4.5]decane (32)
According to GP2, the addition of NaI (4.45 g, 29.7 mmol) to tosy-
late 30 (2.73 g, 7.4 mmol) afforded iodide 32.
Yield: 2.41 g (quant); yellow oil; [a]D20 –10.6 (c 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.98–3.88 (m, 4 H), 3.16 (md,
J = 7.0, 8.9 Hz, 2 H), 1.79 (dq, J = 9.2, 7.1 Hz, 2 H), 1.63–1.40 (m,
10 H), 0.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 112.78 (OCO), 64.97 (OCH2),
64.75 (OCH2), 41.07 (CCH3), 35.89 (CH2), 34.53 (CH2), 30.48
(CH2), 28.38 (CH2), 23.57 (CH2), 20.85 (CH2), 19.67 (CH3), 8.33
(CH2).
13C NMR (75 MHz, CDCl3): d = 119.66 (OCO), 84.87 (C≡CH),
68.13 (C≡CH), 64.80 (OCH2), 64.63 (OCH2), 45.77 (CCH3), 35.33
(CH2), 34.33 (CH2), 33.44 (CH2), 24.21 (CH2), 20.07 (CH3), 19.46
(CH2), 17.93 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C13H21O2: 209.15361; found:
209.15344.
(S)-6-Methyl-6-(pent-4-ynyl)-1,4-dioxaspiro[4.5]decane (34)
According to GP3, the acetylenic derivative 34 was prepared from
the tosylate 30 (3.3 g, 9 mmol) and lithium acetylide ethylenedi-
amine complex (1.07 g, 11.6 mmol) and purified by column chro-
matography (silica gel; PE–EtOAc, 95:5 containing 1% Et3N),
furnishing compound 34.
HRMS (ESI): m/z [M + H]+ calcd for C12H22IO2: 325.0659; found:
Yield: 1.74 g (88%); colorless oil; [a]D20 –7.2 (c 1.00, CHCl3).
325.06598.
IR (ATR): 3312 cm–1.
6-Methyl-6-(pent-4-ynyl)-1,4,8,11-tetraoxa-
dispiro[4.1.4.2]tridecane (24)
1H NMR (300 MHz, CDCl3): d = 3.97–3.87 (m, 4 H), 2.18–2.13 (m,
2 H), 1.95 (t, J = 2.6 Hz, 1 H), 1.64–1.37 (m, 12 H), 0.91 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 112.91 (OCO), 84.86 (C≡CH),
68.10 (C≡CH), 64.94 (OCH2), 64.73 (OCH2), 41.12 (CCH3), 34.29
(CH2), 33.92 (CH2), 30.49 (CH2), 23.60 (CH2), 23.02 (CH2), 20.83
(CH2), 19.47 (CH2), 19.43 (CH3).
According to GP3, the acetylenic derivative 24 was prepared from
the tosylate 20 (3.66 g, 8.7 mmol) and lithium acetylide ethylenedi-
amine complex (1.2 g, 13 mmol) and purified by column chroma-
tography (silica gel; PE–EtOAc, 70:30 containing 1% Et3N), to
afford compound 24.
Yield: 1.81 g (78%); colorless oil.
IR (ATR): 3286 (s) cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C14H23O2: 223.16926; found:
223.16912.
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PRACTICAL SYNTHETIC PROCEDURES
Racemic and Enantiomerically Pure Acetylenic w-Keto Esters
177
Procedure 4
(0.81 mL, 5.38 mmol) with n-BuLi (3.9 mL, 5 mmol, 1.3 M in hex-
anes). The crude mixture was treated with NaOH (3.36 g, 84 mmol)
to afford compound 36.
6-Methyl-6-(hex-5-ynyl)-1,4,8,11-tetraoxadispiro[4.1.4.2]tri-
decane (26)
According to GP4, the acetylenic derivative 26 was prepared from
the iodide 22 (1.19 g, 3.23 mmol) and 1-(trimethylsilyl)-1-propyne
(0.77 mL, 5.17 mmol) with n-BuLi (3 mL, 4.84 mmol, 1.6 M in hex-
anes). The crude mixture was treated with NaOH (3.23 g, 80.7
mmol). Purification by column chromatography (silica gel; PE–
EtOAc, 90:10→80:20) afforded compound 26.
Yield: 0.84 g (100%); colorless oil; [a]D20 –3.6 (c 1.00, CHCl3).
IR (ATR): 3308 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.97–3.86 (m, 4 H), 1.94 (td,
J = 7.0, 2.6 Hz, 2 H), 1.67 (t, J = 2.7 Hz, 1 H), 1.63–1.28 (m, 14 H),
0.90 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 113.04 (OCO), 84.76 (C≡CH),
68.09 (C≡CH), 64.97 (OCH2), 64.78 (OCH2), 41.27 (CCH3), 34.13
(CH2), 33.80 (CH2), 30.52 (CH2), 29.55 (CH2), 23.66 (CH2), 22.62
(CH2), 20.90 (CH2), 19.45 (CH3), 18.45 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C15H25O2: 237.18491; found:
237.18472.
Yield: 0.59 g (66%); colorless oil.
IR (ATR): 3286 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.99–3.84 (m, 8 H), 2.18 (td,
J = 6.8, 2.7 Hz, 2 H), 1.97–1.82 (m, 4 H), 1.51–1.35 (m, 7 H), 1.09
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 117.62 (OCO), 84.96 (C≡CH),
67.92 (C≡CH), 64.72 (OCH2), 64.16 (OCH2), 50.25 (CCH3), 32.42
(OCCH2), 29.73 (CH2), 28.69 (CH2), 23.03 (CH2), 18.38 (CH2),
17.08 (CH3).
Procedure 5
Ethyl 6-(6-Methyl-7-oxo-1,4-dioxaspiro[4.4]nonan-6-yl)hex-2-
ynoate (9)
HRMS (ESI): m/z [M + Na]+ calcd for C16H24NaO4: 303.15668;
found: 303.15790.
According to GP5, the unsaturated ester 9 was prepared from the
acetylenic derivative 24 (1.81 g, 6.83 mmol), n-BuLi (5.8 mL, 8.19
mmol, 1.26 M in hexanes), and ClCO2Et (1.3 mL, 13.65 mmol). The
mixture was purified by column chromatography (silica gel; PE–
EtOAc, 80:20) to yield the corresponding ester as a colorless oil (2.0
g, 90%). Acidic treatment with TsOH adsorbed on silica gel in
CH2Cl2 afforded the derivative 9.
6-Methyl-6-(hex-5-ynyl)-1,4,8,11-tetraoxadispiro[4.1.4.3]tetra-
decane (27)
According to GP4, the acetylenic derivative 27 was prepared from
the iodide 23 (1.48 g, 3.87 mmol) and 1-(trimethylsilyl)-1-propyne
(0.93 mL, 6.19 mmol) with n-BuLi (4.2 mL, 5.81 mmol, 1.38 M in
hexanes). The crude mixture was treated with NaOH (3.27 g, 82
mmol). Purification by column chromatography (silica gel; PE–
EtOAc, 90:10→80:20) afforded compound 27.
Yield: 0.79 g (86%); colorless oil.
IR (ATR): 2233 (s), 1739 (s), 1703(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.20 (q, J = 7.2 Hz, 2 H), 4.04–
3.94 (m, 4 H), 2.38 (t, J = 8.1 Hz, 2 H), 2.31–2.42 (m, 2 H), 2.17–
1.98 (m, 2 H), 1.66–1.54 (m, 4 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.03 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 217.70 (C=O), 153.80 (CO2Et),
116.13 (OCO), 88.86 (C≡CCO2Et), 73.41 (C≡CCO2Et), 65.07
(OCH2), 64.70 (OCH2), 61.79 (CO2CH2CH3), 53.76 (CCH3), 35.15
(CH2), 31.51 (CH2), 29.95 (CH2), 22.54 (CH2), 19.34 (CH2), 15.72
(CO2CH2CH3), 14.04 (CH3).
Yield: 0.69 g (72%); colorless oil.
IR (ATR): 3302 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.99–3.87 (m, 8 H), 2.18 (td,
J = 6.7, 2.5 Hz, 2 H), 1.91–1.89 (m, 1 H), 1.64–1.45 (m, 12 H), 1.09
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 113.51 (OCO), 85.03 (C≡CH),
67.89 (C≡CH), 65.13 (OCH2), 64.09 (OCH2), 49.25 (CCH3), 30.15
(CH2), 30.04 (OCCH2), 24.52 (CH2), 18.60 (CH2), 18.46 (CH2),
15.60 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C16H22NaO5: 317.13594;
found: 317.13638.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26NaO4: 317.17233;
found: 317.17298.
Ethyl 6-(6-Methyl-7-oxo-1,4-dioxaspiro[4.5]decan-6-yl)hex-2-
ynoate (28)
(R)-6-Methyl-6-(hex-5-ynyl)-1,4-dioxaspiro[4.4]nonane (35)
According to GP4, the acetylenic derivative 35 was prepared from
the iodide 31 (2.64 g, 8.51 mmol) and 1-(trimethylsilyl)-1-propyne
(2 mL, 13.6 mmol) with n-BuLi (10 mL, 12.7 mmol, 1.26 M in hex-
anes). The crude mixture was treated with NaOH (8.5 g, 213 mmol)
to afford compound 35.
According to GP5, the unsaturated ester 28 was prepared from the
acetylenic derivative 25 (0.37 g, 1.38 mmol), n-BuLi (1.15 mL, 1.58
mmol, 1.38 M in hexanes) and ClCO2Et (0.25 mL, 2.64 mmol). The
mixture was purified by column chromatography (silica gel; PE–
EtOAc, 80:20) yielding the corresponding ester as a colorless oil
(0.34 g, 73%). An acidic treatment with TsOH adsorbed on silica
gel afforded the derivative 28.
Yield: 2.04 g (100%); colorless oil; [a]D20 +4.6 (c 1.00, CHCl3).
Yield: 0.34 g (84%); colorless oil.
IR (ATR): 2234 (s), 1703 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.15 (q, J = 7.2 Hz, 2 H), 3.92–
3.86 (m, 4 H), 2.45–2.19 (m, 4 H), 2.08–1.97 (m, 1 H), 1.89 (td,
J = 12.8, 4.5 Hz, 1 H), 1.80–1.50 (m, 5 H), 1.30–1.15 (m, 1 H), 1.25
(t, J = 7.2 Hz, 3 H), 0.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 211.76 (CO), 153.65 (CO2Et),
113.61 (OCO), 88.53 (C≡CCO2Et), 73.60 (C≡CCO2Et), 65.32
(OCH2), 65.19 (OCH2), 61.75 (CO2CH2CH3), 58.78 (CCH3), 37.12
(CH2), 34.03 (CH2), 29.49 (CH2), 22.53 (CH2), 19.35 (CH2), 19.15
(CH2), 14.00 (CO2CH2CH3), 13.53 (CH3).
IR (ATR): 3298 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.92–3.87 (m, 4 H), 2.20 (td,
J = 7.0, 2.7 Hz, 2 H), 1.93 (t, J = 2.6 Hz, 1 H), 1.88–1.28 (m, 12 H),
0.95 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 119.73 (OCO), 84.75 (C≡CH),
68.08 (C≡CH), 64.77 (OCH2), 64.62 (OCH2), 45.90 (CCH3), 35.19
(CH2), 34.28 (CH2), 33.46 (CH2), 29.51 (CH2), 23.90 (CH2), 19.99
(CH3), 18.42 (CH2), 17.91 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H23O2: 223.16926; found:
223.16956.
(R)-6-Methyl-6-(hex-5-ynyl)-1,4-dioxaspiro[4.5]decane (36)
According to GP4, the acetylenic derivative 36 was prepared from
the iodide 32 (1.09 g, 3.36 mmol) and 1-(trimethylsilyl)-1-propyne
HRMS (ESI): m/z [M + Na]+ calcd for C17H24NaO5: 331.15159;
found: 331.15304.
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PRACTICAL SYNTHETIC PROCEDURES
Ethyl 7-(6-Methyl-7-oxo-1,4-dioxaspiro[4.4]nonan-6-yl)hept-2-
ynoate (16)
HRMS (ESI): m/z [M + Na]+ calcd for C14H20NaO3: 259.13047;
found: 259.13175.
According to GP5, the unsaturated ester 16 was prepared from the
acetylenic derivative 26 (0.59 g, 2.11 mmol), n-BuLi (1.8 mL, 2.53
mmol, 1.41 M in hexanes) and ClCO2Et (0.4 mL, 4.24 mmol). The
mixture was purified by column chromatography (silica gel; PE–
EtOAc, 80:20) yielding the corresponding ester as a colorless oil
(0.67 g, 90%). An acidic treatment acid with TsOH adsorbed on sil-
ica gel afforded the derivative 16.
Ethyl (S)-6-(1-Methyl-2-oxocyclohexyl)hex-2-ynoate (38)
According to GP5, the unsaturated ester 38 was prepared from the
acetylenic derivative 34 (1.68 g, 7.6 mmol), n-BuLi (7 mL, 9.1
mmol, 1.3 M in hexanes) and ClCO2Et (1.45 mL, 15.2 mmol). The
mixture was hydrolyzed with a 10% HCl solution and purified by
column chromatography (silica gel; PE–EtOAc, 90:10) affording
the corresponding ester 38.
Yield: 0.59 g (quant); yellow oil.
IR (ATR): 2233 (s), 1738 (s), 1703 (s) cm–1.
Yield: 1.39 g (73%); colorless oil; [a]D20 –40.3 (c 1.01, CHCl3).
IR (ATR): 2239 (s), 1712 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.20 (q, J = 7.2 Hz, 2 H), 4.00–
3.98 (m, 4 H), 2.40–2.25 (m, 4 H), 2.20–2.00 (m, 3 H), 1.60–1.35
(m, 5 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 218.03 (CO), 153.83 (CO2Et),
116.23 (OCO), 89.13 (C≡CCO2Et), 73.23 (C≡CCO2Et), 65.11
(OCH2), 64.65 (OCH2), 61.77 (OCH2CH3), 53.92 (CCH3), 35.12
(CH2), 31.72 (CH2), 30.00 (CH2), 28.15 (CH2), 22.96 (CH2), 18.49
(CH2), 15.51 (OCH2CH3), 14.04 (CH3).
1H NMR (300 MHz, CDCl3): d = 4.21 (q, J = 7.2 Hz, 2 H), 2.38 (t,
J = 6.2 Hz, 2 H), 2.33 (t, J = 6.8 Hz, 2 H), 1.88–1.37 (m, 10 H), 1.30
(t, J = 7.1 Hz, 3 H), 1.07 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 215.51 (CO), 153.74 (CO2Et),
88.72 (C≡CCO2Et), 73.50 (C≡CCO2Et), 61.79 (CO2CH2CH3),
48.35 (CCH3), 39.19 (CH2), 38.72 (CH2), 36.76 (CH2), 27.44 (CH2),
22.55 (CO2CH2CH3), 22.24 (CH2), 21.00 (CH2), 19.23 (CH2), 14.02
(CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H24O5: 309.16965; found:
309.16963.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NaO3: 273.14612;
found: 273.14714.
Ethyl 7-(6-Methyl-7-oxo-1,4-dioxaspiro[4.5]decan-6-yl)hept-2-
ynoate (17)
Ethyl (R)-7-(1-Methyl-2-oxocyclopentyl)hept-2-ynoate (39)
According to GP5, the unsaturated ester 39 was prepared from the
acetylenic derivative 35 (2.64 g, 8.51 mmol), n-BuLi (8.1 mL, 10.21
mmol, 1.26 M in hexanes) and ClCO2Et (1.62 mL, 17 mmol). The
mixture was purified by column chromatography (silica gel; PE–
EtOAc, 98:2–90:10) affording the corresponding ester as a colorless
oil (1.42 g, 57%). An acidic treatment with 10% HCl and purifica-
tion by column chromatography (silica gel; PE–EtOAc, 98:5) af-
forded the ester 39.
According to GP5, the unsaturated ester 17 was prepared from the
acetylenic derivative 27 (0.37 g, 1.32 mmol) and n-BuLi (1.15 mL,
1.58 mmol, 1.38 M in hexanes), ClCO2Et (0.25 mL, 2.64 mmol).
The mixture was purified by column chromatography (silica gel;
PE–EtOAc, 80:20) affording the corresponding ester as a colorless
oil (0.38 g, 87%). An acidic treatment with TsOH adsorbed on sil-
ica gel afforded the derivative 17.
Yield: 0.35 g (quant); colorless oil.
IR (ATR): 2232 (s), 1703(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.20 (qd, J = 7.2, 1.1 Hz, 2 H),
3.95–3.91 (m, 4 H), 2.47–2.36 (m, 1 H), 2.31 (t, J = 7.1 Hz, 2 H),
2.08–2.03 (m, 1 H), 1.88–1.60 (m, 6 H), 1.55 (t, J = 7.1 Hz, 2 H),
1.43–1.34 (m, 1 H), 1.29 (t, J = 7.1, 0.7 Hz, 3 H), 1.16–1.09 (m,
1 H), 1.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 211.94 (CO), 153.77 (CO2Et),
113.77 (OCO), 88.79 (C≡CCO2Et), 73.40 (C≡CCO2Et), 65.38
(OCH2), 65.23 (OCH2), 61.79 (OCH2CH3), 59.03 (CCH3), 37.28
(CH2), 34.58 (CH2), 29.55 (CH2), 28.05 (CH2), 23.36 (CH2), 19.44
(CH2), 18.45 (CH2), 14.04 (OCH2CH3), 13.33 (CH3).
Yield: 0.92 g (84%); colorless oil; [a]D20 +4.0 (c 1.00, CHCl3).
IR (ATR): 2233 (s), 1733 (s), 1704 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.21 (q, J = 7.2 Hz, 2 H), 2.33 (t,
J = 7.0 Hz, 2 H), 2.29–2.13 (m, 2 H), 1.94–1.82 (m, 3 H), 1.79–1.70
(m, 1 H), 1.61–1.36 (m, 6 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 223.49 (CO), 153.82 (CO2Et),
88.95 (C≡CCO2Et), 73.36 (C≡CCO2Et), 61.79 (CO2CH2CH3),
48.20 (CCH3), 37.65 (CH2), 35.98 (CH2), 35.61 (CH2), 27.98 (CH2),
23.6 (CH2), 21.80 (CO2CH2CH3), 18.70 (CH2), 18.55 (CH2), 14.04
(CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NaO3: 273.14612;
found: 273.14699.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26NaO5: 345.16725;
found: 345.16781.
Ethyl (R)-7-(1-Methyl-2-oxocyclohexyl)hept-2-ynoate (40)
According to GP5, the unsaturated ester 40 was prepared from the
acetylenic derivative 36 (0.84 g, 3.36 mmol), n-BuLi (2.5 mL, 4
mmol, 1.6 M in hexanes) and ClCO2Et (0.64 mL, 6.7 mmol). The
mixture was purified by column chromatography (silica gel; PE–
EtOAc, 98:2→90:10) yielding the corresponding ester as a color-
less oil (0.76 g, 74%). An acidic treatment with 10% HCl and puri-
fication by column chromatography (silica gel; PE–EtOAc, 98:5)
afforded the ester 40.
Yield: 0.47 g (83%); colorless oil; [a]D20 –36.6 (c 1.00, CHCl3).
IR (ATR): 2232 (s), 1701(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.20 (q, J = 7.3 Hz, 2 H), 2.39–
2.30 (m, 4 H), 1.89–1.35 (m, 12 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.05
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 215.88 (CO), 153.81 (CO2Et),
88.97 (C≡CCO2Et), 73.36 (C≡CCO2Et), 61.79 (CO2CH2CH3),
48.47 (CCH3), 39.19 (CH2), 38.78 (CH2), 36.92 (CH2), 28.09 (CH2),
Ethyl (R)-6-(1-Methyl-2-oxocyclopentyl)hex-2-ynoate (37)
According to GP 5, the unsaturated ester 37 was prepared from the
acetylenic derivative 33 (1.47 g, 7 mmol), n-BuLi (6.7 mL, 8.47
mmol, 1.26 M in hexanes) and ClCO2Et (1.35 mL, 14.1 mmol). The
mixture was hydrolyzed with a 10% HCl solution and purified by
column chromatography (silica gel; PE–EtOAc, 90:10) yielding the
corresponding ester 37.
Yield: 1.51 g (91%); colorless oil; [a]D20 –48.3 (c 1.00, CHCl3).
IR (ATR): 2233 (s), 1732 (s), 1703(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.21 (q, J = 7.2 Hz, 2 H), 2.36–
2.13 (m, 4 H), 1.93–1.41 (m, 8 H), 1.30 (t, J = 7.3 Hz, 3 H), 1.00 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 223.05 (CO), 153.77 (CO2Et),
88.62 (C≡CCO2Et), 73.47 (C≡CCO2Et), 61.82 (CO2CH2CH3),
48.04 (CCH3), 37.56 (CH2), 35.87 (CH2), 35.75 (CH2), 27.74 (CH2),
21.66 (CO2CH2CH), 19.20 (CH2), 18.66 (CH2), 14.04 (CH3).
Synthesis 2010, No. 1, 171–179 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Racemic and Enantiomerically Pure Acetylenic w-Keto Esters
179
27.46 (CH2), 23.10 (CH2), 22.63 (CO2CH2CH3), 21.05 (CH2), 18.55
(CH2), 14.04 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C16H24NaO3: 287.16177;
(7) (a) Schick, H.; Schwarz, H.; Finger, A. Tetrahedron 1982,
38, 1279. (b) Nayyar, S.; Trehan, I.; Kaur, J. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2002, 41,
2342.
found: 287.16247.
(8) (a) Brooks, D. W.; Mazdiyasni, H.; Chakrabarti, S.
Tetrahedron Lett. 1984, 25, 1241. (b) Brooks, D. W.;
Mazdiyasni, H.; Grothaus, P. G. J. Org. Chem. 1987, 52,
3223.
Acknowledgment
Support for this work was provided by Université de Strasbourg,
CNRS and ANR (N°07-PCVI-0016). M.-P.B. thanks MRT for a re-
search fellowship. The authors thank Dr. Jennifer Wytko for assi-
stance in preparing this manuscript.
(9) (a) Katoh, T.; Mizumoto, S.; Fudesaka, M.; Nakashima, T.;
Node, M. Synlett 2006, 2176. (b) Katoh, T.; Mizumoto, S.;
Fudesaka, M.; Takeo, M.; Kajimoto, T.; Node, M.
Tetrahedron: Asymmetry 2006, 17, 1655.
(10) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89,
5505.
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Synthesis 2010, No. 1, 171–179 © Thieme Stuttgart · New York