Synthesis of 3-acetonyl- and 3-(2-oxoethyl)glutarates

Article abstract of DOI:10.1016/j.tet.2005.05.084

Several synthetic routes to 3-acetonyl- and 3-(2-oxoethyl)glutarates 1-5 have been explored. The most advantageous involves, as the key steps, the conjugate addition of an appropriately substituted vinylmagnesium bromide to an alkylidenemalonic ester, a b

Full text of DOI:10.1016/j.tet.2005.05.084

Tetrahedron 61 (2005) 7693–7702
Synthesis of 3-acetonyl- and 3-(2-oxoethyl)glutarates
´
´
Mercedes Amat, Oriol Bassas, Margalida Canto, Nuria Llor, Maria M. M. Santos
*
and Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 21 April 2005; accepted 26 May 2005
Available online 15 June 2005
Abstract—Several synthetic routes to 3-acetonyl- and 3-(2-oxoethyl)glutarates 1–5 have been explored. The most advantageous involves, as
the key steps, the conjugate addition of an appropriately substituted vinylmagnesium bromide to an alkylidenemalonic ester, a bis-
homologation of the resulting diester and, finally, the reductive ozonolysis of the carbon–carbon double bond. The synthesis can be
satisfactorily conducted in good overall yield on a multigram scale.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
With the exception of ketodiester 3b, for which a convenient
preparation has already been reported,4 there are no
precedents for the synthesis of 3-substituted glutarates
1–5. We report here our synthetic efforts directed to the
preparation of these d-oxodiesters, culminating in the
development of a general, high-yield synthetic route that
can be conducted on a multigram scale.
Some glutaric esters bearing a functionalized carbon chain
(e.g., acetonyl, 1-cyanopropyl) at the 3-position have
classically been used as building blocks for the synthesis
of indolo[2,3-a]- and benzo[a]quinolizidine alkaloids.1
In recent work, we have reported2 the use of prochiral or
racemic 3-substituted glutarates 1–5 (Fig. 1) as the
substrates in highly enantioselective cyclocondensation
reactions with chiral aminoalcohols, leading to enantiopure
bicyclic lactams. These processes involve the desymme-
trization of two enantiotopic (from 1 and 3) or diastereo-
topic (from 2, 4, and 5) acetate chains, in the latter case with
a simultaneous dynamic kinetic resolution3 (DKR) that
promotes the epimerization of the configurationally labile
stereocenter a to the aldehyde or ketone carbonyl group.
This methodology provides straightforward access to
polysubstituted enantiopure piperidines.
2. Results
For the synthesis of aldehyde diester 1a we initially planned
to start from a,b-unsaturated ester 6, which was prepared in
35% yield from methyl crotonate following a previously
reported procedure5 (Scheme 1).
Conjugate addition of tert-butyl methyl malonate to 6,
followed by treatment of the resulting triester 8 with TFA in
the presence of thioanisole,6 and subsequent heating in
refluxing toluene, led to the target ester 1a in 46% overall
yield. This sequence could not be extended to the
preparation of the ethyl substituted analogue 2a since the
conjugate addition of malonate esters to a,b-unsaturated
ester 9, which was prepared as in the above deethyl series
from methyl-2-hexenoate, was unsuccessful.7
Alternatively, 1a was prepared from 6 by conjugate addition
of the lithium salt derived from methyl 1,3-dithiolane-2-
carboxylate, followed by nickel boride desulfurization and
chemoselective hydrolysis of the acetal function with LiBF4
in wet acetonitrile.8 The overall yield of this three-step
sequence was 39%.
Figure 1. Target d-oxodiesters.
Keywords: d-Oxodiesters; 3-Acetonylglutarates; 3-(2-Oxoethyl)glutarates;
Bis-homologation; Ozonolysis; Conjugate addition.
*
Corresponding author. Tel.: C34 93 4024538; fax: C34 93 4024539;
e-mail: joanbosch@ub.edu
The main drawback of the above approaches was the
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.084

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M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
Scheme 2. Reagents: (i) NaOEt or t-BuOK, CH3COCH2CO2R1, EtOH or
t-BuOH; (ii) DBU, Pd(acac)2, Ph3P, allyl acetate; (iii) H2, Pd–C; (iv) TFA,
C6H5SMe, then toluene, reflux.
(Scheme 2). However, alkylation of 16 with ethyl iodide
under a variety of conditions resulted in failure. Also
unsuccessful were the attempts to directly prepare the
alkylated product by Michael addition of ethyl 2-ethyl-3-
oxobutanoate to diethyl glutaconate.
In contrast, satisfactorily, 16 underwent a Pd-catalyzed
C-allylation by treatment with allyl acetate.12 Catalytic
hydrogenation of the resulting product 17 gave the propyl
substituted derivative 18. However, the difficulties
encountered in the deethoxycarbonylation of 18 prompted
us to develop a similar sequence starting from tert-butyl
acetylacetate. Thus, triester 19 was prepared in 74% yield,13
allylated to 20 (69%), and then hydrogenated to give 21
(73%). Removal of the tert-butoxycarbonyl group with TFA
and thioanisole6 led to the propyl substituted ketodiester 5b
in 86% yield.
Scheme 1. Reagents: (i) 6: see Ref. 5, 35%; 9: LDA, HMPA, Me3SiCl, then
ZnBr2, HC(OMe)3; (ii) NaH, t-BuO2CCH2CO2Me; (iii) TFA, C6H5SMe,
then toluene, reflux; (iv) LDA, methyl 1,3-dithiolane-2-carboxylate;
(v) NiCl2.6H2O, NaBH4; (vi) LiBF4, MeCN, 2% H2O; (vii) See Refs. 1a,
d, 85%; (viii) LiCl, DMSO, H2O; (ix) Raney-Ni, NaH2PO2; (x) See
Refs. 1a,d.
moderate yield and regioselectivity in the preparation of 6,
since the a-addition product 7 was also formed to a
considerable extent.
Although racemic ketodiester 5b was a suitable substrate to
study cyclocondensation reactions involving tandem DKR-
diastereoselective differentiation processes,2 the scope of
the above synthetic route is quite limited as a consequence
of the need to introduce an allyl group on b-ketoester moiety
of 16 or 19. For this reason, and also taking into account the
inconveniences of the synthetic routes depicted in Scheme 1,
we designed a new synthetic route that could provide
general access to 3-(2-oxoethyl)- and 3-acetonylglutarates.
It involves the introduction of an alkene moiety as a latent
form of the aldehyde or ketone carbonyl group by conjugate
addition14 of an appropriately substituted vinylmagnesium
bromide 22 to an alkylidenemalonic ester 23, a bis-
homologation of the resulting diester and, finally, the
reductive ozonolysis of the carbon–carbon double bond
(Scheme 3).
The ethyl ester analog 1b was prepared from the known
intermediate 13, which was easily accessible by Michael
condensation of diethyl glutaconate with ethyl cyano-
acetate.1a,d Selective hydrolysis-decarboxylation of 13
under Krapcho conditions,9 followed by controlled Raney
Ni reduction10 of the resulting nitrile 14 gave d-oxodiester
1b. A similar reduction was used to obtain the ethyl
substituted aldehyde diester 2b from the known nitrile 15,
although in moderate yield. This nitrile was prepared in
excellent yield by alkylation of 13 as previously reported,1a,d
followed by hydrolysis-decarboxylation under Krapcho
conditions.9
An important limitation of the above routes involving the
controlled reduction of a cyano function is that the yield of
the reduction step was somewhat erratic, leading to mixtures
of the desired aldehydes 1b and 2b with the respective
starting nitriles, which were difficult to separate.
To check the viability of this synthetic route we considered
the synthesis of the ethyl substituted ketone 4a, which had
been inaccessible by the route depicted in Scheme 2.
Conjugate addition of isopropenylmagnesium bromide (22;
R2ZMe, R3ZH) to diethyl propylidenemalonate (23; R1Z
Et) in the presence of CuCl gave the malonic ester
derivative 24a in 70% yield. LiAlH4 reduction, followed
by tosylation of the resulting diol 25a and subsequent
substitution of tosylate 26a with NaCN gave dinitrile 27a,
The synthesis of the ethyl substituted ketodiester 4b was
initially attempted by a route similar to that previously
employed for the preparation of 15. The required
b-ketoester 16 was obtained in 62% yield by Michael
addition of ethyl acetylacetate to diethyl glutaconate11

M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
7695
Scheme 3. Reagents and conditions: (i) CuCl; (ii) LiAlH4; (iii) KOH, TsCl; (iv) NaCN; (v) 35% aq. NaOH, MeOH, then 6 N HCl; (vi) Me3ClSi; (vii) O3, Me2S.
Table 1. Synthesis of the target d-oxodiesters
Compound
R1
R2
R3
24 (%)
25 (%)
26 (%)
27 (%)
28 (%)
29 (%)
1a, 2a, 4a (%)
a
b
c
Et
Et
Et
H
Me
H
H
H
Me
H
70
74
92
—
93
94
97
71
87
88
88
96
90
90
88
91
90
82
95
92
91
92
92
88
65 (4a: R1ZEt; R2ZMe)
64 (2a: R1ZEt, R2ZH)
75 (2a: R1ZEt, R2ZH)
84 (1a: R1ZR2ZH)
d
H
H
which was then converted to diester 29a via diacid 28a. This
bis-homologation sequence from 24a took place in 60%
overall yield. Finally, reductive ozonolysis of 29a led to the
target d-oxodiester 4a in 65% yield.
iodoplatinate reagent. Column chromatography was carried
out using the flash chromatography technique. All non-
aqueous reactions were performed under an inert atmo-
sphere. Solvents for chromatography were distilled at
atmospheric pressure prior to use and dried following
standard procedures. Drying of the organic extracts during
the workup of reactions was performed over anhydrous
Na2SO4 or MgSO4. Evaporation of solvents was accom-
plished with a rotatory evaporator. Microanalyses and
A similar reaction sequence allowed us to prepare aldehyde
diester 2a, following two alternative routes (Table 1).
Initially, we started from the malonic ester derivative 24b,
which was obtained in 74% yield by conjugate addition of
2-methyl-1-propenylmagnesium bromide (22; R2ZH, R3Z
Me) to diethyl propylidenenalonate (23; R1ZEt). However,
the yields of both the conjugate addition reaction and the
final ozonolysis step were improved starting from vinyl-
magnesium bromide (22; R2ZR3ZH): diester 24c was
obtained in 92% yield, and the overall yield for the seven-
step sequence leading to 2a was 45%. The synthesis can be
satisfactorily conducted on a 50–100 g scale and most of the
steps take place in excellent yield.
´
HRMS were performed by Centre D’Investigacio i
Desenvolupament (CSIC), Barcelona and Unidade de
Espectrometria de Masas, Santiago de Compostela.
3.1.1.
Dimethyl
2-(tert-butoxycarbonyl)-3-(2,2-
dimethoxyethyl)glutarate (8). tert-Butyl methyl malonate
(762 mg, 4.38 mmol) and ester 65 (504 mg, 2.9 mmol) were
added to a cooled (0 8C) suspension of NaH (55% in oil
dispersion, 23 mg, 0.58 mmol) in anhydrous THF (30 mL).
The mixture was heated at reflux until disappearance of the
starting compound was observed by TLC. The reaction was
quenched with brine at 0 8C, and the aqueous phase was
extracted with EtOAc. The combined organic extracts were
dried and concentrated. Column chromatography (gradient
of eluents hexane/EtOAc) of the residue afforded triester 8
Illustrating the general scope of the above route, aldehyde
diester 1a was satisfactorily obtained in 42% overall yield
from the commercially available malonic ester derivative
24d, via the known intermediates 25d–29d.15 In this series
ozonolysis of the alkene moiety took place in 84% yield.
1
(540 mg, 80%): IR (film) 1736 cmK1; H NMR (CDCl3,
In conclusion, the synthetic sequence depicted in Scheme 3
provides a general, high yield route for the preparation of
diversely substituted 3-(2-oxoethyl)- and 3-acetonyl-
glutarates on a multigram scale.
300 MHz) d 1.45 (s, 9H, CCH3), 1.79 (m, 2H, CH2CHO),
2.59 (m, 2H, 2H-4), 2.72 (m, 1H, H-3), 3.30 (s, 6H, OCH3),
3.60 (dd, JZ5.7, 1.9 Hz, 1H, H-2), 3.68 (s, 3H, CO2CH3),
3.72 (s, 3H, CO2CH3), 4.46 (t, JZ5.4 Hz, 1H, CHOCH3);
13C NMR (CDCl3, 75.4 MHz) d 27.8 (CH3), 31.2 (CH), 34.2
(CH2), 35.8 (CH2), 51.5 (CH3), 52.1 (CH3), 52.5 (CH3), 52.9
(CH3), 54.8 (CH), 82.1 (C), 103.0 (CH), 167.3 (C), 169.1
(C), 172.6 (C).
3. Experimental
3.1. General experimental procedures
3.1.2. Methyl 4-(dimethoxymethyl)-2-hexenoate (9). A
solution of methyl 2-hexenoate5 (1 g, 7.8 mmol) in
anhydrous THF (2 mL) was slowly added to a cooled
(K78 8C) solution of LDA (1.5 M in THF, 7.8 mmol) and
HMPA (1.6 mL, 9.36 mmol) in anhydrous THF (6 mL), and
the resulting mixture was stirred for 30 min at this
temperature. Then, a solution of Me3SiCl (1.55 mL,
12.2 mmol) in anhydrous THF (2 mL) was slowly added,
and the stirring was continued at room temperature for 2 h.
Melting points were determined in a capillary tube on a
Bu¨chi apparatus and are uncorrected. NMR spectra were
recorded at 200, 300 or 400 MHz (1H) and 50.3, 75 or
100.6 MHz (13C), and chemical shifts are reported in d
values downfield from TMS. Only noteworthy IR absorp-
tions are listed. Thin-layer chromatography (TLC) was done
on SiO2 (silica gel 60 F254), and the spots were located with
aqueous potassium permanganate solution or with

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M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
The mixture was diluted with pentane, washed with brine,
dried, filtered, and concentrated. The ketene acetal obtained
was dissolved in anhydrous CH2Cl2 (10 mL) and stirred in
presence of anhydrous ZnBr2 (1.75 g, 7.8 mmol) and
anhydrous methyl ortoformate (2.6 mL, 23.4 mmol) at
room temperature for 16 h. The crude mixture was poured
into brine and extracted with EtOAc. The organic extracts
were dried, filtered, and concentrated. Flash chromato-
graphy (hexane) of the residue afforded compounds 9
(230 mg, 15%) and 10 (460 mg, 30%). 9: IR (film)
filtered, and concentrated to give 12 (432 mg, 67%), which
was used in the next reaction without further purification: IR
1
(film) 1736 cmK1; H NMR (CDCl3, 300 MHz) d 1.68 (t,
JZ5.9 Hz, 2H, CH2CHO), 2.42–2.48 (m, 5H, CH(CH2-
CO2)2), 3.30 (s, 6H, OCH3), 3.67 (s, 6H, CO2CH3), 4.45 (t,
JZ5.9 Hz, 1H, CHOCH3); 13C NMR (CDCl3, 75.4 MHz) d
28.3 (CH), 36.2 (CH2), 38.1 (CH2), 51.4 (CH3), 52.5 (CH3),
102.7(CH), 172.5 (C).
3.1.5. Diethyl 3-(cyanomethyl)glutarate (14). Triester
131a,d (391 mg, 1.30 mmol) and LiCl (61 mg, 1.43 mmol)
were dissolved in DMSO (2 mL) containing a few drops of
H2O, and the mixture was stirred at 140 8C for 4 h. Then the
mixture was cooled, dissolved in EtOAc, and washed with
H2O. The combined organic solutions were dried, filtered,
and concentrated to give an oil. Flash chromatography (1:9
hexane/EtOAc) afforded 14 (222 mg, 75%) as an oil: IR
1
1727 cmK1; H NMR (CDCl3, 300 MHz) d 0.86 (t, JZ
7.5 Hz, 3H, H-6), 1.37 (ddd, JZ15.0, 9.6, 7.5 Hz, 1H, H-5),
1.67 (tdd, JZ15.0, 7.5, 3.9 Hz, 1H, H-5), 2.41 (ddd, JZ9.6,
6.3, 2.4 Hz, 1H, H-4), 3.34 (s, 3H, OCH3), 3.36 (s, 3H,
OCH3), 3.73 (s, 3H, CO2CH3), 4.25 (d, JZ6.3 Hz, 1H,
CHOCH3), 5.88 (dd, JZ15.6, 0.6 Hz, 1H, H-2), 6.81 (dd,
JZ15.6, 9.6 Hz, 1H, H-3); 13C NMR (CDCl3, 75.4 MHz) d
11.4 (CH3), 22.3 (CH2), 47.5 (CH), 51.4 (CH3), 54.0 (CH3),
54.3 (CH3), 106.1 (CH), 122.6 (CH), 147.8 (CH), 166.6 (C).
HRMS calcd for C10H18O4 202.1202, found 202.1205. 10:
IR (film) 1748 cmK1; 1H NMR (CDCl3, 300 MHz) d 0.98 (t,
JZ7.5 Hz, 3H, H-6), 2.12 (ddd, JZ15.0, 7.5, 1.5 Hz, 1H,
H-5), 3.31 (s, 3H, OCH3), 3.39 (s, 3H, OCH3), 3.69 (s, 3H,
CO2CH3), 3.70 (masked, 1H, H-2), 4.68 (d, JZ7.8 Hz, 1H,
CHOCH3), 5.37 (dd, JZ11.4, 1.5 Hz, 1H, H-4), 5.64 (m,
1H, H-3); 13C NMR (CDCl3, 75.4 MHz) d 13.7 (CH3), 20.9
(CH2), 48.0 (CH), 51.8 (CH3), 52.8 (CH3), 54.7 (CH3),
104.2 (CH), 121.4 (CH), 136.3 (CH), 171.4 (C). HRMS
calcd for C10H18O4 202.1202, found 202.1205.
1
(film) 2246, 1726 cmK1; H NMR (CDCl3, 200 MHz) d
1.27 (t, JZ7.4 Hz, 6H, CH3), 2.53 (d, JZ5.2 Hz, 4H,
CH2CO2), 2.66 (masked, 1H, CH), 2.68 (d, JZ2.2 Hz, 2H,
CH2CN), 4.17 (q, JZ7.4 Hz, 4H, OCH2); 13C NMR
(CDCl3, 50.3 MHz) d 14.0 (CH3), 21.3 (CH2), 28.7 (CH),
36.9 (CH2), 60.7 (CH2), 117.6 (C), 170.8 (C).
3.1.6. Diethyl 3-(1-cyanopropyl)glutarate (15). Com-
pound 13 was ethylated following a previously reported
procedure.1a,d The product (219 mg, 0.73 mmol), was
treated with LiCl (34 mg, 0.80 mmol) in DMSO (2 mL)
containing a few drops of H2O, as in the above deethyl
series, to give pure 15 (85 mg, 74%) after flash chromato-
3.1.3. Methyl 2-[1-(methoxycarbonylmethyl)-3,3-
dimethoxypropyl]-1,3-dithiolane-2-carboxylate (11).
Methyl 1,3-dithiolane-2-carboxylate (625 mg, 3.5 mmol)
was added to a cooled (K78 8C) solution of LDA (1.5 M in
ciclohexane, 7.19 mmol) in anhydrous THF (30 mL), and
the mixture was stirred for 15 min at this temperature. Then,
a solution of acetal 6 (1.2 g, 7.56 mmol) in anhydrous THF
(1 mL) was slowly added, and the mixture was stirred at
room temperature for 4 h. The mixture was poured into
brine, the aqueous layer was extracted with EtOAc, and the
combined organic extracts were dried and concentrated.
Flash chromatography of the resulting yellow oil (8:2
hexane/EtOAc) afforded pure compound 11 (1.1 g, 95%):
graphy (EtOAc): IR (film) 2978, 1736 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 1.15 (t, JZ7.2 Hz, 3H, CH3), 1.27 (t,
JZ7.0 Hz, 6H, CH3), 1.66 (qd, JZ7.2, 2.3 Hz, 2H, CH2),
2.40–2.58 (m, 4H, H-2 and H-4), 2.60 (m, 1H, CHCN), 2.88
(ddd, JZ8.4, 6.3, 4.2 Hz, 1H, H-3), 4.16 (qd, JZ7.0,
2.1 Hz, 4H, OCH2); 13C NMR (CDCl3, 75.4 MHz) d 12.0
(CH3), 14.0 (CH3), 23.3 (CH2), 33.0 (CH), 35.1 (CH2), 36.5
(CH2), 36.9 (CH), 60.7 (CH2), 60.8 (CH2), 120.0 (C), 171.2
(C), 171.3 (C).
3.1.7. Diethyl 2-acetyl-3-(ethoxycarbonylmethyl)gluta-
rate (16). Ethyl acetylacetate (22 g, 0.16 mmol) and a
0.57 M solution of NaOEt in EtOH (5 mL) were added to a
solution of diethyl glutaconate (10 mL, 0.05 mmol) in
absolute EtOH (20 mL), and the mixture was heated at
reflux for 4 h. Then, 0.57 M NaOEt (5 mL) was added at
intervals of 14, 8 and 14 h. After 6 h of additional reflux,
concentrated AcOH (2 mL) was added, and the mixture was
evaporated. The brown residue was dissolved in Et2O, and
the organic solution was exhaustively washed with NaHCO3
and brine, dried, and evaporated to give an oil. Purification
by fractional distillation (150 8C, 1 mmHg) gave triester 16
(11 g, 62%): IR (film) 1736, 1657 cmK1; 1H NMR (CDCl3,
300 MHz) d 1.25 (t, JZ7.2 Hz, 6H, CH3), 1.26 (t, JZ
7.2 Hz, 3H, CH3), 2.27 (s, 3H, COCH3), 2.47 (dd, JZ16.5,
7.5 Hz, 1H, CH2CO), 2.49 (dd, JZ16.5, 4.5 Hz, 1H,
CH2CO), 2.54 (dd, JZ4.5, 6.3 Hz, 1H, CH2CO), 2.59 (dd,
JZ16.5, 1.8 Hz, 1H, CH2CO), 3.05 (ddt, JZ13.0, 6.9,
1.8 Hz, 1H, H-3), 3.93 (d, JZ6.9 Hz, 1H, H-2), 4.11 (q, JZ
7.2 Hz, 4H, OCH2), 4.16 (q, JZ7.2 Hz, 2H, OCH2); 13C
NMR (CDCl3, 75.4 MHz) d 13.8 (CH3), 13.9 (CH3), 29.9
(CH3), 30.7 (CH), 35.2 (CH2), 35.5 (CH2), 60.4 (CH2), 60.5
1
IR(film) 1737 cmK1; H NMR (CDCl3, 300 MHz) d 1.65
(ddd, JZ14.1, 10.1, 6.0 Hz, 1H, H-4), 1.84 (ddd, JZ14.1,
5.4, 2.9 Hz, 1H, H-4), 2.49 (dd, JZ16.5, 6.0 Hz, 1H, H-2),
2.79 (dd, JZ16.5, 4.0 Hz, 1H, H-2), 3.13 (m, 1H, H-3), 3.28
(s, 6H, OCH3), 3.30–3.41 (m, 4H, S(CH2)2S), 3.69 (s, 3H,
CO2CH3), 3.78 (s, 3H, CO2CH3), 4.47 (t, JZ5.4 Hz, 1H,
CHOCH3); 13C NMR (CDCl3, 75.4 MHz) d 37.1 (CH2),
37.3 (CH2), 38.3 (CH), 39.8 (CH2), 39.9 (CH2), 51.6 (CH3),
51.9 (CH3), 53.3 (CH3), 53.6 (CH3), 75.9 (CH and C), 171.9
(C), 172.9 (C). HRMS calcd for C13H22O6S2 338.0859,
found 338.0857.
3.1.4. Dimethyl 3-(2,2-dimethoxyethyl)glutarate (12).
Compound 11 (900 mg, 2.6 mmol) was dissolved in a
mixture of MeOH/THF (2:1, 7.5 mL) at 0 8C. Then,
NiCl2$6H2O (5 g, 18.2 mmol) and NaBH4 (2 g,
54.2 mmol) were added, and the resulting mixture was
stirred at 0 8C for 30 min. The crude mixture was
concentrated to give an oil, which was dissolved in
EtOAc. The organic layer was washed with brine, dried,

M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
7697
(CH2), 61.3 (CH2), 61.5 (CH), 168.3 (C), 171.7 (C), 202.2
(C). HRMS calcd for C15H24O7 316.1526, found 316.1522.
3.80 (d, JZ7.0 Hz, 1H, H-2), 4.13 (q, JZ7.5 Hz, 4H,
OCH2); 13C NMR (CDCl3, 75.4 MHz) d 14.0 (CH3), 27.9
(CH3), 29.9 (CH3), 30.7 (CH), 35.2 (CH2), 35.5 (CH2), 60.3
(CH2), 61.5 (CH), 82.3 (C), 167.4 (C), 171.6 (C), 171.7 (C),
202.3 (C). HRMS calcd for C17H28O7 344.1463, found
344.1460.
3.1.8. Diethyl 2-acetyl-2-allyl-3-(ethoxycarbonylmethyl)
glutarate (17). DBU (1.3 mL, 8.7 mmol), Pd(acac)2
(132 mg, 0.4 mmol), Ph3P (457 mg, 1.7 mmol), and allyl
acetate (1.4 mL, 13.5 mmol) were added to a solution of
triester 16 (2.6 g, 8.7 mmol) in anhydrous toluene (43 mL),
and the resulting mixture was heated at reflux for 6 h. The
solvent was eliminated under reduced pressure, and the
residue was dissolved in EtOAc. The organic extract was
washed with aqueous 2 N HCl, dried, filtered, and
concentrated to give a brown oil (3.7 g). Flash chromato-
graphy (hexane) afforded 17 (1.89 g, 64%) as a transparent
3.1.11. Ethyl tert-butyl 2-acetyl-2-allyl-3-(ethoxycar-
bonylmethyl)glutarate (20). Operating as described for
the preparation of 17, pure compound 20 (470 mg, 69%)
was obtained from ketotriester 19 (610 mg, 1.77 mmol)
after flash chromatography (hexane): IR (film) 1709,
1
1736 cmK1; H NMR (CDCl3, 300 MHz) d 1.25 (t, JZ
7.2 Hz, 6H, CH3), 1.49 (s, 9H, CH3), 2.18 (s, 3H, CH3CO),
2.25 (dd, JZ15.6, 8.4 Hz, 1H, CH2CO), 2.32 (dd, JZ16.5,
9.3 Hz, 1H, CH2CO), 2.53 (dd, JZ15.6, 3.6 Hz, 1H,
CH2CO), 2.59 (d, JZ1.8 Hz, 2H, CH2CH]), 2.63 (dd,
JZ16.5, 2.4 Hz, 1H, CH2CO), 3.19 (m, 1H, H-3), 4.12 (qd,
JZ7.2, 2.4 Hz, 4H, OCH2), 5.06–5.14 (m, 2H, CH2]), 5.75
(dd, JZ17.1, 10.2 Hz, 1H, CH]); 13C NMR (CDCl3,
75.4 MHz) d 14.0 (CH3), 14.1 (CH3), 27.9 (CH3), 28.3
(CH3), 34.5 (CH), 36.3 (CH2), 36.9 (CH2), 37.1 (CH2), 60.5
(CH2), 60.6 (CH2), 66.8 (C), 82.8 (C), 118.8 (CH2]), 132.6
(CH]), 169.7 (C), 171.9 (C), 172.1 (C), 204.2 (C).
oil: IR (film) 1639, 1735 cmK1 1H NMR (CDCl3,
;
300 MHz) d 1.25 (t, JZ7.2 Hz, 6H, CH3), 1.27 (t, JZ
7.2 Hz, 3H, CH3), 2.18 (s, 3H, COCH3), 2.30 (dd, JZ16.0,
8.4 Hz, 1H, CH2CO), 2.41 (dd, JZ16.0, 8.4 Hz, 1H,
CH2CO), 2.55 (dd, JZ16.0, 3.9 Hz, 1H, CH2CO), 2.58
(dd, JZ16.0, 3.9 Hz, 1H, CH2CO), 2.63 (d, JZ10.2 Hz, 2H,
CH2CH]), 3.20 (dt, JZ6.9, 3.9 Hz, 1H, H-3), 4.12 (ddd,
JZ14.4, 7.2, 3.0 Hz, 4H, OCH2), 4.24 (ddd, JZ14.4, 7.2,
0.6 Hz, 2H, OCH2), 55.07–5.15 (m, 2H, CH2]), 5.74 (dd,
JZ17.1, 10.2 Hz, 1H, CH]); 13C NMR (CDCl3,
75.4 MHz) d 14.0 (CH3), 14.1 (CH3), 28.2 (CH3), 34.5
(CH), 35.8 (CH2), 36.7 (CH2), 36.9 (CH2), 60.5 (CH2), 60.6
(CH2), 61.5 (CH2), 66.3 (C), 119.1 (CH2]), 132.3 (CH]),
170.7 (C), 171.8 (C), 172.1 (C), 204.0 (C).
3.1.12. Ethyl tert-butyl 2-acetyl-3-(ethoxycarbonyl-
methyl)-2-propylglutarate (21). Operating as described
for the preparation of 18, ketotriester 21 (800 mg, 73%) was
obtained from 20 (1.2 g, 3.1 mmol) after flash chromato-
3.1.9. Diethyl 2-acetyl-3-(ethoxycarbonylmethyl)-2-
propylglutarate (18). Pd–C (10%, 125 mg) was added to
a solution of 17 (500 mg, 1.4 mmol) in MeOH (28 mL), and
the resulting suspension was hydrogenated at atmospheric
pressure for 4 h. The catalyst was removed by filtration, and
the solution was concentrated to give 18 as an oil (430 mg,
85%), which was used in the next reaction without further
purification: IR (film) 1709, 1736 cmK1; 1H NMR (CDCl3,
300 MHz) d 0.93 (t, JZ7.2 Hz, 3H, CH3), 1.16 (m, 2H,
CH2), 1.25 (t, JZ7.2 Hz, 6H, CH3), 1.29 (t, JZ7.2 Hz, 3H,
CH3), 1.31 (t, JZ7.2 Hz, 2H, CH2), 2.18 (s, 3H, CH3CO),
2.27 (dd, JZ15.6, 8.4 Hz, 1H, CH2CO), 2.33 (dd, JZ16.5,
8.4 Hz, 1H, CH2CO), 2.53 (dd, JZ15.6, 3.5 Hz, 1H,
CH2CO), 2.62 (dd, JZ16.5, 3.5 Hz, 1H, CH2CO), 3.18
(dt, JZ7.2, 3.5 Hz, 1H, H-3), 4.12 (ddd, JZ14.4, 7.2,
1.8 Hz, 4H, OCH2), 4.23 (ddd, JZ14.4, 7.2, 1.8 Hz, 2H,
OCH2); 13C NMR (CDCl3, 75.4 MHz) d 14.0 (CH3), 14.1
(CH3), 14.2 (CH3), 14.5 (CH3), 17.5 (CH2), 28.1 (CH3), 34.1
(CH), 34.6 (CH2), 35.9 (CH2), 36.8 (CH2), 60.5 (CH2), 60.6
(CH2), 61.3 (CH2), 66.1 (C), 171.2 (C), 171.9 (C), 172.2 (C),
204.6 (C).
graphy (hexane): IR (film) 1708, 1732 cmK1 1H NMR
;
(CDCl3, 300 MHz) d 0.90 (t, JZ6.0 Hz, 3H, CH3), 1.24
(masked, 2H, CH2), 1.25 (t, JZ7.2 Hz, 6H, CH3), 1.49 (s,
9H, CH3), 1.77 (td, JZ11.7, 5.4 Hz, 2H, CH2), 2.18 (s, 3H,
CH3CO), 2.20 (dd, JZ15.9, 7.8 Hz, 1H, CH2CO), 2.26 (dd,
JZ16.5, 9.3 Hz, 1H, CH2CO), 2.52 (dd, JZ15.9, 4.2 Hz,
1H, CH2CO), 2.62 (dd, JZ16.5, 3.0 Hz, 1H, CH2CO), 3.16
(m, 1H, H-3), 4.09 (qd, JZ7.2, 2.4 Hz, 4H, OCH2); 13C
NMR (CDCl3, 75.4 MHz) d 13.0 (CH3), 14.0 (CH3), 14.5
(CH3), 17.3 (CH2), 27.8 (CH3), 28.0 (CH3), 33.9 (CH), 34.5
(CH2), 36.2 (CH2), 37.1 (CH2), 60.3 (CH2), 60.5 (CH2), 66.5
(C), 82.4 (C), 170.1 (C), 171.9 (C), 172.1 (C), 204.6 (C).
HRMS calcd for C20H34O7 386.2618, found 386.2609.
3.1.13. Ethyl 3-(ethoxycarbonylmethyl)-4-propyl-5-oxo-
hexanoate (5b). Thioanisole (1.9 mL) and TFA (1.5 mL,
19.9 mmol) were added to a cooled (0 8C) solution of 21
(770 mg, 1.9 mmol) in CH2Cl2 (9.6 mL). The mixture was
stirred at room temperature for 8 h and concentrated. The
residue was dissolved in anhydrous toluene (4 mL). The
resulting solution was heated at reflux for 3 h and
concentrated to dryness. Flash chromatography (hexane)
afforded 5b (660 mg, 86%): IR (film) 1738 cmK1; 1H NMR
(CDCl3, 300 MHz) d 0.88 (t, JZ10.5 Hz, 3H, CH3), 1.25
(td, JZ10.5, 6.0 Hz, 6H, CH3), 1.27 (masked, 3H,
CH2CH2), 1.61 (m, 1H, CH2CH2), 2.21 (s, 3H, CH3CO),
2.26 (d, JZ11.0 Hz, 1H, CH2CO), 2.36 (d, JZ8.0 Hz, 1H,
CH2CO), 2.39 (d, JZ11.0 Hz, 1H, CH2CO), 2.41 (masked,
1H, H-3), 2.42 (d, JZ8.0 Hz, 1H, CH2CO), 2.70 (m, 1H,
H-4), 4.13 (q, JZ10.5 Hz, 4H, OCH2); 13C NMR (CDCl3,
75.4 MHz) d 14.1 (CH3), 14.2 (CH3), 21.0 (CH3), 29.0
(CH2), 30.5 (CH3), 32.6 (CH), 35.1 (CH2), 36.5 (CH2), 53.8
(CH), 60.5 (CH2), 172.1 (C), 211.2 (C). HRMS calcd for
C15H26O5 286.1517, found 286.1520.
3.1.10. Ethyl tert-butyl 2-acetyl-3-(ethoxycarbonyl-
methyl)glutarate (19). Operating as described for the
preparation of 16, compound 19 was prepared from diethyl
glutaconate (9.5 mL, 0.053 mmol), tert-butyl acetylacetate
(9.2 g, 0.058 mmol), and 1 M t-BuOK in t-BuOH (5 mL) in
anhydrous t-BuOH (11 mL). After fractionated distillation
(150 8C, 1 mmHg), a mixture (16 g) of ketotriester 19 and
starting material was obtained. Flash chromatography
(hexane) afforded 19 (13.7 mg, 74%) as a transparent oil:
IR (film) 1737 cmK1; 1H NMR (CDCl3, 300 MHz) d 1.24 (t,
JZ7.5 Hz, 6H, CH3), 1.95 (s, 9H, CH3), 2.25 (s, 3H,
CH3CO), 2.39–2.61 (m, 4H, CH2CO), 3.0 (m, 1H, H-3),

7698
M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
3.1.14. Diethyl 2-(1-ethyl-2-methyl-2-propenyl)malonate
(24a). Diethyl 2-propylidenemalonate16 (23, R1ZEt;
45.5 g, 0.21 mol) in anhydrous Et2O (500 mL) was added
to a cooled (K78 8C) suspension of CuCl (0.41 g,
4.1 mmol) and isopropenylmagnesium bromide (22, R2Z
Me, R3ZH; 0.5 M in THF, 500 mL, 0.25 mol), and the
mixture was stirred until the temperature was raised to
25 8C. Then saturated aqueous NH4Cl (200 mL) was added,
and the aqueous layer was extracted with Et2O. The
combined organic extracts were washed with brine, dried,
and filtered. Flash chromatography (gradient hexane/
EtOAc) afforded pure 24a (41.3 g, 75%): IR (film)
(CH2), 137.7 (CH), 168.0 (C), 168.2 (C). HRMS calcd for
C12H20O4 (MCCH) m/z 228.1362, found 229.1439.
3.1.17. 2-(1-Ethyl-2-methyl-2-propenyl)-1,3-propanediol
(25a). A solution of malonate 24a (15.3 g, 0.06 mol) in Et2O
(100 mL) was slowly added to a suspension of LiAlH4 (6 g,
0.16 mol) in anhydrous Et2O (100 mL) at 0 8C. The mixture
was stirred under Ar at 0 8C for 30 min, at room temperature
for 30 min, and heated at reflux for 8 h. Then, the
temperature was lowered to 0 8C, and EtOH was slowly
added until the formation of a transparent solution. After
30 min the solvent was eliminated under reduced pressure.
The residue was dissolved in 20% aqueous KOH, and the
mixture was heated at reflux for 2 h. The solution was
extracted with Et2O, and the combined ethereal extracts
were dried, filtered, and concentrated to give diol 25a
1735 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.82 (t, JZ7.2 Hz, 3H, CH3), 1.22 (t, JZ
7.2 Hz, 3H, CH3), 1.27 (t, JZ7.2 Hz, 3H, CH3), 1.30 (m,
1H, CH2), 1.50 (m, 1H, CH2), 1.68 (dd, JZ1.5, 0.9 Hz, 3H,
CH3), 2.77 (td, JZ11.1, 3.6 Hz, 1H, CHC]), 3.42 (d, JZ
11.1 Hz, 1H, H-2), 4.12 (q, JZ7.2 Hz, 1H, CH2O), 4.13 (q,
JZ7.2 Hz, 1H, CH2O), 4.20 (q, JZ7.2 Hz, 2H, CH2O),
4.79 (m, 1H, ]CH2), 4.85 (m, 1H, ]CH2); 13C NMR
(CDCl3, 100.6 MHz, HETCOR) d 11.2 (CH3), 13.9 (CH3),
14.0 (CH3), 18.7 (CH3), 23.5 (CH2), 48.4 (CH), 56.3 (CH),
61.0 (CH2), 61.2 (CH2), 114.2 (CH2), 143.2 (CH), 167.9
(C), 168.3 (C). Anal. Calcd for C13H22O4: C, 64.44; H, 9.15.
Found: C, 64.37; H, 9.12.
(9.32 g, 93%): IR (film) 3100–3500 cmK1 1H NMR
;
(CDCl3, 400 MHz, COSY, HETCOR) d 0.80 (t, JZ
7.2 Hz, 3H, CH3), 1.21–1.30 (m, 1H, CH2), 1.55–1.70 (m,
2H, CH2 and CH2C]), 1.60 (s, 3H, CH3), 1.95 (s, 2H, OH),
2.09 (ddd, JZ10.8, 10.4, 3.6 Hz, 1H, H-2), 3.69 (dd, JZ
10.0, 6.0 Hz, 1H, CH2O), 3.77–3.82 (m, 2H, CH2O), 3.96
(dd, JZ10.8, 3.2 Hz, 1H, CH2O), 4.76 (m, 1H, ]CH2), 4.85
(m, 1H, ]CH2); 13C NMR (CDCl3, 100.6 MHz, HETCOR)
d 11.9 (CH3), 18.2 (CH3), 22.4 (CH2), 43.3 (CH), 46.8 (CH),
63.7 (CH2), 64.7 (CH2), 113.3 (CH2), 145.0 (C).
3.1.15. Diethyl 2-(1-ethyl-3-methyl-2-butenyl)malonate
(24b). Operating as above, pure 24b (18.4 g, 74%) was
obtained from 2-methyl-1-propenylmagnesium bromide
(22, R2ZH, R3ZMe; 0.5 M in THF, 216 mL, 0.11 mol),
CuCl (0.19 g, 1.8 mmol), and diethyl 2-propyl-
idenemalonate16 (23, R1ZEt; 18.0 g, 0.09 mol) after flash
chromatography (hexane, 25:1 hexane/EtOAc): IR (film)
3.1.18. 2-(1-Ethyl-3-methyl-2-butenyl)-1,3-propanediol
(25b). Operating as above, diol 25b (20.4 g, 94%) was
obtained from diester 24b (32.3 g, 0.13 mol) after purifi-
cation of the crude mixture by flash chromatography (Et2O):
1
IR (film) 2800–3500 cmK1; H NMR (CDCl3, 400 MHz,
COSY, HETCOR) d 0.81 (t, JZ7.6 Hz, 3H, CH3), 1.13–
1.24 (m, 1H, CH2), 1.49–1.59 (m, 1H, CH2), 1.61 (d, JZ
1.2 Hz, 3H, CH3C]), 1.65–1.71 (m, 1H, H-2), 1.72 (d, JZ
1.2 Hz, 3H, CH3C]), 2.22–2.29 (m, 1H, CHC]), 2.38 (br
s, 1H, OH), 2.52 (br s, 1H, OH), 3.68–3.78 (m, 2H, CH2O),
3.82–3.87 (m, 2H, CH2O), 4.86 (m, 1H, ]CH); 13C NMR
(CDCl3, 100.6 MHz, HETCOR) d 11.7 (CH3), 18.2 (CH3),
25.7 (CH3), 25.9 (CH2), 38.3 (CH), 46.3 (CH), 64.8 (CH2),
65.4 (CH2), 126.7 (CH), 133.0 (C); mp 43–46 8C (hexane).
HRMS calcd for C14H24O4 (MCCH) m/z 172.1463, found
173.1541. Anal. Calcd for C10H20O2: C, 69.72; H, 11.70.
Found: C, 69.67; H, 11.70.
1732 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.83 (t, JZ7.2 Hz, 3H, CH3), 1.15–1.21 (m,
1H, CH2), 1.22 (t, JZ7.2 Hz, 3H, CH3), 1.26 (t, JZ7.2 Hz,
3H, CH3), 1.48–1.58 (m, 1H, CH2), 1.65 (d, JZ1.6 Hz, 3H,
CH3C]), 1.69 (d, JZ1.6 Hz, 3H, CH3C]), 2.96 (qd, JZ
9.6, 3.2 Hz, 1H, CHCH2), 3.24 (d, JZ9.6 Hz, 1H, H-2),
4.07–4.16 (m, 2H, CH2O), 4.18 (q, JZ7.2 Hz, 2H, CH2O),
4.88 (m, 1H, ]CH); 13C NMR (CDCl3, 100.6 MHz,
HETCOR) d 11.4 (CH3), 13.9 (CH3), 14.0 (CH3), 18.2
(CH3), 25.8 (CH3), 26.4 (CH2), 39.9 (CH), 57.2 (CH), 60.8
(CH2), 61.0 (CH2), 124.2 (CH), 134.4 (C), 168.2 (C), 168.5
(C). HRMS calcd for C14H24O4 256.1675, found 256.1675.
Anal. Calcd for C14H24O4: C, 65.50; H, 9.44. Found: C,
65.43; H, 9.66.
3.1.19. 2-(1-Ethyl-2-propenyl)-1,3-propanediol (25c).
Operating as above, diol 25c (12.3 g, 97%) was obtained
from malonate 24c (32.3 g, 0.13 mol): IR (film) 3000–
3600 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
3.1.16. Diethyl 2-(1-ethyl-2-propenyl)malonate (24c).
Operating as above, pure 24c (67.9 g, 92%) was obtained
from vinylmagnesium bromide (22, R2ZR3ZH; 0.5 M in
THF, 390 mL, 0.39 mol), CuCl (0.65 g, 6.5 mmol), and
diethyl 2-propylidenemalonate16 (23, R1ZEt; 65 g,
0.32 mol) after flash chromatography (hexane, 95:5 hexane/
EtOAc): IR (film) 1732 cmK1; 1H NMR (CDCl3, 400 MHz,
COSY, HETCOR) d 0.88 (t, JZ7.6 Hz, 3H, CH3), 1.24 (t,
JZ7.2 Hz, 3H, CH3), 1.27 (t, JZ7.2 Hz, 3H, CH3), 1.29 (m,
1H, CH2), 1.53 (m, 1H, CH2), 2.68 (qd, JZ9.2, 3.6 Hz, 1H,
CHCH2), 3.35 (d, JZ9.2 Hz, 1H, H-2), 4.15 (q, JZ7.2 Hz,
2H, CH2O), 4.19 (q, JZ7.2 Hz, 2H, CH2O), 5.07–5.12 (m,
2H, ]CH2), 5.59–5.68 (m, 1H, ]CH–); 13C NMR (CDCl3,
75.4 MHz, HETCOR) d 11.4 (CH3), 14.0 (CH3), 25,2
(CH2), 45.6 (CH), 56.6 (CH), 61.0 (CH2), 61.1 (CH2), 117.3
HETCOR) d 0.86 (t, JZ7.2 Hz, 3H, CH3), 1.28 (m, 1H,
CH2), 1.55 (m, 1H, CH2), 1.73 (m, 1H, H-2), 2.01 (m, 1H,
CHC]), 2.70 (br s, 2H, OH), 3.71 (dd, JZ10.4, 7.6 Hz,
1H, CH2O), 3.76 (dd, JZ10.4, 7.6 Hz, 1H, CH2O), 3.85 (dd,
JZ10.4, 3.6 Hz, 2H, CH2O), 5.02 (dd, JZ16.8, 2.0 Hz, 1H,
]CH2 trans), 5.06 (dd, JZ10.0, 2.0 Hz, 1H, ]CH2 cis),
5.55 (ddd, JZ16.8, 10.0, 10.0 Hz, 1H, ]CH); 13C NMR
(CDCl3, 75.4 MHz, HETCOR) d 11.8 (CH3), 24.7 (CH2),
44.8 (CH), 45.2 (CH), 63.7 (CH2), 64.3 (CH2), 116.0 (CH2),
139.8 (CH). Anal. Calcd for C8H16O2$1/4 EtOAc: C, 65.03;
H, 10.91. Found: C, 65.09; H, 11.20.
3.1.20. 2-(1-Ethyl-2-methyl-2-propenyl)propane-1,3-diol
ditosylate (26a). A solution of diol 25a (8.70 g, 0.058 mol)

M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
7699
and tosyl chloride (66 g, 0.35 mol) in anhydrous THF
(200 mL) was added to a suspension of KOH (30 g,
0.52 mol) in anhydrous THF (100 mL) at 0 8C. The crude
mixture was stirred at 0 8C for 2 h and at room temperature
for additional 3 days. The organic solvent was removed at
reduced pressure, and the resulting residue was dissolved in
CH2Cl2 (400 mL). The organic solution was washed with
ice-water, the aqueous layer was extracted with CH2Cl2, and
the combined organic extracts were washed with brine,
dried, and filtered. Removal of the solvent followed by flash
chromatography (gradient hexane/EtOAc) afforded dito-
10.0 Hz, 1H, ]CH), 7.35 (m, 4H, ArH), 7.74 (m, 4H, ArH);
13C NMR (CDCl3, 75.4 MHz, HETCOR) d 11.4 (CH3), 21.6
(CH3), 24.1 (CH2), 41.1 (CH), 43.5 (CH), 67.3 (CH2), 67.5
(CH2), 118.0 (CH2), 127.7 (CH), 127.8 (CH), 129.7 (CH),
129.8 (CH), 132.3 (C), 132.4 (C), 137.5 (CH), 144.8 (C),
144.9 (C). Anal. Calcd for C22H28O6S2: C, 58.39; H, 6.24;
S, 14.17. Found: C, 58.58; H, 6.30; S, 13.90.
3.1.23. 3-(1-Ethyl-2-methyl-2-propenyl)pentanedinitrile
(27a). Compound 26a (3.8 g, 8.15 mmol) and NaCN (1.6 g,
33 mmol) were dissolved in anhydrous DMSO (30 mL), and
the mixture was stirred under Ar at room temperature for
10 min and at 75 8C for 20 h. The crude mixture was diluted
with EtOAc (100 mL) and ice-H2O (100 mL). The aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with brine, dried, and concentrated to
give an oil, which was chromatographed (6:1 hexane/
1
sylate 26a (17.3 g, 64%): IR (film) 1178, 1364 cmK1; H
NMR (CDCl3, 400 MHz, COSY, HETCOR) d 0.67 (t, JZ
7.2 Hz, 3H, CH3), 1.10 (m, 1H, CH2), 1.32 (m, 1H, CH2),
1.46 (d, JZ0.4 Hz, 3H, CH3), 1.90 (m, 1H, CHC]), 1.95
(qd, JZ10.4, 3.6 Hz, 1H, H-2), 2.45 (s, 3H, CH3Ar), 2.46 (s,
3H, CH3Ar), 3.79 (dd, JZ10.4, 7.6 Hz, 1H, CH2O), 4.00
(dd, JZ10.4, 5.6 Hz, 1H, CH2O), 4.02 (dd, JZ10.4, 6.8 Hz,
1H, CH2O), 4.15 (dd, JZ10.4, 3.2 Hz, 1H, CH2O), 4.61 (m,
1H, ]CH2), 4.77 (m, 1H, ]CH2), 7.33 (d, JZ8.0 Hz, 2H,
ArH), 7.35 (d, JZ8.0 Hz, 2H, ArH), 7.71 (d, JZ8.0 Hz, 2H,
ArH), 7.75 (d, JZ8.0 Hz, 2H, ArH); 13C NMR (CDCl3,
100.6 MHz, HETCOR) d 11.4 (CH3), 17.6 (CH3), 21.6
(CH3), 21.7 (CH2), 39.7 (CH), 45.7 (CH), 66.7 (CH2), 67.9
(CH2), 115.0 (CH2), 127.6 (CH), 127.7 (CH), 129.7 (CH),
129.8 (CH), 132.2 (C), 132.4 (C), 142.5 (CH), 144.8 (C),
144.9 (C). Anal. Calcd for C23H30O6S2: C, 59.20; H, 6.48;
S, 13.74. Found: C, 59.39; H, 6.56; S, 13.88.
EtOAc) to give pure 27a (1.24 g, 86%): IR (film) 2243 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY, HETCOR) d 0.87 (t,
JZ7.2 Hz, 3H, CH3), 1.28 (m, 1H, CH2), 1.57 (m, 1H,
CH2), 1.61 (s, 3H, CH3), 2.05 (m, 2H, H-3 and CHC]),
2.40 (dd, JZ17.2, 7.6 Hz, 1H, CH2CN), 2.58 (dd, JZ17.2,
6.4 Hz, 1H, CH2CN), 2.64 (dd, JZ17.2, 2.6 Hz, 1H,
CH2CN), 2.76 (dd, JZ17.2, 3.6 Hz, 1H, CH2CN), 4.89
(m, 1H, ]CH2), 5.00 (m, 1H, ]CH2); 13C NMR (CDCl3,
100.6 MHz, HETCOR) d 11.6 (CH3), 17.8 (CH3), 19.5
(CH2), 20.7 (CH2), 22.2 (CH2), 34.8 (CH), 51.1(CH), 116.4
(CH2), 117.0 (C), 117.4 (C), 142.2 (C). Anal. Calcd for
C11H16N2: C, 74.96; H, 9.15; N, 15.89. Found: C, 75.01; H,
9.15; N, 15.71.
3.1.21. 2-(1-Ethyl-3-methyl-2-butenyl)-1,3-propanediol
ditosylate (26b). Operating as above (reaction conditions:
18 h at 0 8C), ditosylate 26b (43.9 g, 88%) was obtained
from diol 25b (18.0 g, 0.10 mol) after flash chromatography
(8:1 hexane/EtOAc): IR (film) 1177, 1362 cmK1; 1H NMR
(CDCl3, 400 MHz, COSY, HETCOR) d 0.70 (t, JZ7.2 Hz,
3H, CH3), 0.96–1.08 (m, 1H, CH2), 1.29–1.38 (m, 1H,
CH2), 1.49 (d, JZ0.8 Hz, 3H, CH3C]), 1.63 (d, JZ1.2 Hz,
3H, CH3C]), 1.83 (m, 1H, H-2), 2.18–2.26 (m, 1H,
CHC]), 2.46 (s, 6H, CH3Ar), 3.85 (dd, JZ10.0, 7.6 Hz,
1H, CH2O), 3.96–4.06 (m, 3H, CH2O), 4.62 (m, 1H, ]CH),
7.34 (d, JZ8.0 Hz, 2H, ArH), 7.35 (d, JZ8.0 Hz, 2H, ArH),
7.71 (d, JZ8.4 Hz, 2H, ArH), 7.74 (d, JZ8.4 Hz, 2H, ArH);
13C NMR (CDCl3, 100.6 MHz, HETCOR) d 11.3 (CH3),
18.3 (CH3), 21.6 (CH3), 25.2 (CH2), 25.8 (CH3), 37.1 (CH),
42.2 (CH), 67.6 (CH2), 67.8 (CH2), 124.5 (CH), 127.8 (CH),
127.9 (CH), 129.8 (CH), 129.9 (CH), 132.5 (C), 132.6 (C),
135.2 (C), 144.8 (C), 144.9 (C). HRMS calcd for
C24H32O6S2 (MCCH) m/z 480.1640, found 481.1719.
Anal. Calcd for C24H32O6S2: C, 59.97; H, 6.71; S, 13.34.
Found: C, 60.04; H, 6.96; S, 13.24.
3.1.24. 3-(1-Ethyl-3-methyl-2-butenyl)pentanedinitrile
(27b). Operating as above, dinitrile 27b (15.5 g, 90%) was
obtained from ditosylate 26b (43.5 g, 0.09 mol) after flash
chromatography (3:7 hexane/EtOAc): IR (film) 2247 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY, HETCOR) d 0.86 (t,
JZ7.2 Hz, 3H, CH3), 1.20 (m, 1H, CH2), 1.54 (m, 1H,
CH2), 1.68 (d, JZ1.2 Hz, 3H, CH3C]), 1.77 (d, JZ1.2 Hz,
3H, CH3C]), 2.02 (m, 1H, H-3), 2.34–2.42 (m, 2H,
CH2CN and CHC]), 2.52–2.65 (m, 3H, CH2CN), 4.75
(dm, JZ10.4 Hz, 1H, ]CH); 13C NMR (CDCl3,
100.6 MHz, HETCOR) d 11.4 (CH3), 18.5 (CH3), 19.4
(CH2), 19.9 (CH2), 25.5 (CH2), 25.9 (CH3), 37.4 (CH), 41.6
(CH), 117.4 (C), 117.8 (C), 123.3 (CH), 137.0 (C). HRMS
calcd for C12H20N2 (MCCH) m/z 190.1470, found
191.1548. Anal. Calcd for C12H18N2: C, 75.74; H, 9.53;
N, 14.72. Found: C, 75.94; H, 9.60; N, 14.76.
3.1.25. 3-(1-Ethyl-2-propenyl)pentanedinitrile (27c).
Operating as above (reaction time 8 h), compound 27c
(24.6 g, 88%) was obtained from 26c (78 g, 0.17 mol) after
flash chromatography (4:1 hexane/EtOAc): IR (film)
3.1.22. 2-(1-Ethyl-2-propenyl)-1,3-propanediol dito-
sylate (26c). Operating as above, ditosylate 26c (81.1 g,
88%) was obtained from diol 25c (15 g, 0.10 mol) after flash
chromatography (4:1 hexane/EtOAc): IR (NaCl) 1167,
2247 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.91 (t, JZ7.2 Hz, 3H, CH3), 1.32 (m, 1H,
CH2), 1.54 (m, 1H, CH2), 2.11 (m, 2H, H-3 and CHC]),
2.39 (dd, JZ17.2, 8.0 Hz, 1H, CH2CN), 2.58 (dd, JZ17.2,
6.4 Hz, 1H, CH2CN), 2.61 (dd, JZ10.0, 6.0 Hz, 1H,
CH2CN), 2.65 (dd, JZ10.0, 4.0 Hz, 1H, CH2CN), 5.21
(ddd, JZ16.8, 10.0, 0.4 Hz, 1H, ]CH2 trans), 5.27 (dd, JZ
10.0, 1.6 Hz, 1H, ]CH2 cis), 5.45 (ddd, JZ16.8, 10.0,
10.0 Hz, 1H, ]CH); 13C NMR (CDCl3, 75.4 MHz,
HETCOR) d 11.3 (CH3), 19.2 (CH2), 19.7 (CH2), 24.2
(CH2), 35.8 (CH), 47.7 (CH), 117.1 (C), 117.3 (C), 119.4
1360 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.75 (t, JZ7.6 Hz, 3H, CH3), 1.14 (m, 1H,
CH2), 1.34 (m, 1H, CH2), 1.96 (m, 2H, CHC] and H-2),
2.46 (s, 6H, CH3Ar), 3.85 (dd, JZ10.0, 7.6 Hz, 1H, CH2O),
3.98 (dd, JZ10.0, 5.2 Hz, 1H, CH2O), 4.04 (dd, JZ10.0,
4.8 Hz, 1H, CH2O), 4.08 (dd, JZ10.0, 4.0 Hz, 1H, CH2O),
4.88 (dd, JZ16.8, 1.6 Hz, 1H, ]CH2 trans), 5.00 (dd, JZ
10.0, 1.6 Hz, 1H, ]CH2 cis), 5.32 (ddd, JZ16.8, 10.0,

7700
M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
(CH2), 136.2 (CH). Anal. Calcd for C10H14N2: C, 74.03; H,
8.70; N, 17.27. Found: C, 73.63; H, 8.67; N, 17.14.
room temperature for 24 h. The solvent was eliminated
under reduced pressure, and the residue was dissolved in
Et2O and washed with 5% aqueous NaHCO3. The aqueous
layer was extracted with Et2O, and the combined organic
extracts were washed with brine, dried, and evaporated to
give pure 29a (19.6 g, 91%): IR (film) 1739 cmK1; 1H NMR
(CDCl3, 400 MHz, COSY, HETCOR) d 0.80 (t, JZ7.2 Hz,
3H, CH3), 1.19–1.31 (m, 1H, CH2), 1.45–1.54 (m, 1H,
CH2), 1.62 (s, 3H, CH3), 1.94–2.00 (m, 1H, CHC]), 2.28–
2.52 (m, 5H, H-2, H-4 and H-3), 3.65 (s, 3H, OCH3), 3.66 (s,
3H, OCH3), 4.70 (m, 1H, ]CH2), 4.87 (m, 1H, ]CH2);
13CNMR (CDCl3, 100.6 MHz, HETCOR) d 12.1 (CH3),
19.0 (CH3), 22.0 (CH2), 34.1 (CH), 35.8 (CH2), 36.7 (CH2),
51.3 (CH3), 51.4 (CH3), 51.7 (CH), 113.9 (CH2), 144.6 (C),
173.1 (C). Anal. Calcd for C13H22O4: C, 64.44; H, 9.15.
Found: C, 64.40; H, 9.10.
3.1.26. 3-(1-Ethyl-2-methyl-2-propenyl)pentanedioic
acid (28a). A mixture of dinitrile 27a (1.05 g, 6 mmol)
and 35% aqueous NaOH solution (15 g) in MeOH (20 mL)
was heated at reflux for 4 h. The MeOH was eliminated
under reduced pressure, and the aqueous solution was
heated at reflux temperature for additional 2 h. The crude
mixture was cooled at 0 8C and brought to pH 1 by careful
addition of 6 N aqueous HCl. The aqueous layer was
extracted with EtOAc, and the combined organic extracts
were washed with brine, dried, and concentrated. Flash
chromatography (Et2O) gave diacid 28a (1.1 g, 86%): IR
(film) 1724, 2500–3500 cmK1; 1H NMR (CDCl3, 400 MHz,
COSY, HETCOR) d 0.83 (t, JZ7.2 Hz, 3H, CH3), 1.31 (m,
1H, CH2), 1.53 (m, 1H, CH2), 1.65 (s, 3H, CH3), 1.83 (m,
1H, CHC]), 2.16 (m, 2H, CH2CO), 2.46 (m, 1H, H-3), 2.57
(dd, JZ16.0, 2.0 Hz, 1H, CH2CO), 2.63 (dd, JZ14.4,
2.8 Hz, 1H, CH2CO), 4.72 (m, 1H, ]CH2), 4.92 (m, 1H,
]CH2); 13C NMR (CDCl3, 100.6 MHz, HETCOR) d 12.4
(CH3), 19.4 (CH3), 22.4 (CH2), 35.0 (CH), 38.1 (CH2), 38.7
(CH2), 53.4 (CH), 114.8 (CH2), 144.6 (C), 180.6 (C). Anal.
Calcd for C11H18O4: C, 61.66; H, 8.47. Found: C, 61.25; H,
8.58.
3.1.30. Dimethyl 3-(1-ethyl-3-methyl-2-butenyl)pentane-
dioate (29b). Operating as above, pure compound 29b
(16.4, 92%) was obtained from diacid 28b (15.9 g,
0.07 mol) after flash chromatography (Et2O): IR (film)
1739 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.81 (t, JZ7.2 Hz, 3H, CH3), 1.10–1.22 (m,
1H, CH2), 1.42–1.53 (m, 1H, CH2), 1.57 (d, JZ1.6 Hz, 3H,
CH3C]), 1.71 (d, JZ1.2 Hz, 3H, CH3C]), 2.18–2.46 (m,
6H, H-2, H-3, H-4, and CHC]), 3.65 (s, 6H, OCH3), 4.78
(dm, JZ10.4 Hz, 1H, ]CH); 13C NMR (CDCl3,
100.6 MHz, HETCOR) d 11.9 (CH3), 18.2 (CH3), 25.6
(CH2), 25.9 (CH3), 35.3 (CH2), 36.4 (CH), 36.7 (CH2), 42.3
(CH), 51.3 (CH3), 51.4 (CH3), 125.4 (CH), 134.3 (C), 173.3
(C), 173.6 (C). HRMS calcd for C14H24O4 256.1675, found
256.1675. Anal. Calcd for C14H24O4$1/4 EtOAc: C, 64.72;
H, 9.41. Found: C, 65.01; H, 9.71.
3.1.27. 3-(1-Ethyl-3-methyl-2-butenyl)pentanedioic acid
(28b). Operating as above, pure diacid 28b (16.7 g, 82%)
was obtained from compound 27b (17.0 g, 0.09 mol) after
flash chromatography (Et2O): IR (film) 1697, 2800–
3500 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY,
HETCOR) d 0.83 (t, JZ7.2 Hz, 3H, CH3), 1.20 (m, 1H,
CH2), 1.43–1.51 (m, 1H, CH2), 1.60 (s, 3H, CH3C]), 1.72
(s, 3H, CH3C]), 2.18–2.31 (m, 3H, CH2CO, CHC] and
H-3), 2.40–2.53 (m, 3H, CH2CO), 4.79 (d, JZ10.4 Hz, 1H,
]CH), 6.10 (s.a., 2H, OH); 13C NMR (CDCl3, 100.6 MHz,
HETCOR) d 11.8 (CH3), 18.3 (CH3), 25.7 (CH2), 25.9
(CH3), 35.6 (CH2), 36.5 (CH), 37.8 (CH2), 43.2 (CH), 125.1
(CH), 134.5 (C), 178.9 (C); mp 99–101 8C. HRMS calcd for
C12H20O4 228.1362, found 228.1362. Anal. Calcd for
C10H20O4: C, 63.14; H, 8.83. Found: C, 63.34; H, 8.98.
3.1.31. Dimethyl 3-(1-ethyl-2-propenyl)pentanedioate
(29c). Operating as above, pure 29c (27.1 g, 92%) was
obtained from diacid 28c (25.8 g, 0.13 mol) after flash
1
chromatography (Et2O): IR (film) 1739 cmK1; H NMR
(CDCl3, 400 MHz, COSY, HETCOR) d 0.87 (t, JZ7.2 Hz,
3H, CH3), 1.27 (m, 1H, CH2), 1.47 (m, 1H, CH2), 1.98 (m,
1H, CHC]), 2.19 (dd, JZ16.8, 10.0 Hz, 1H, H-2), 2.37 (m,
2H, H-2), 2.44 (m, 2H, H-2 and H-3), 3.65 (s, 3H, OCH3),
3.66 (s, 3H, OCH3), 5.01 (ddd, JZ17.2, 2.0, 0.8 Hz, 1H,
]CH2 trans), 5.11 (dd, JZ10.4, 2.0 Hz, 1H, ]CH2 cis),
5.47 (ddd, JZ16.8, 10.4, 9.2 Hz, 1H, ]CH); 13C NMR
(CDCl3, 75.4 MHz, HETCOR) d 11.9 (CH3), 24.4 (CH2),
35.0 (CH2), 35.4 (CH), 36.7 (CH2), 48.6 (CH), 51.2 (CH3),
51.3 (CH3), 117.3 (CH2), 138.3 (CH), 172.8 (C), 173.0 (C).
Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C,
63.00; H, 8.79.
3.1.28. 3-(1-Ethyl-2-propenyl)pentanedioic acid (28c).
Operating as above, diacid 28c (25.8 g, 95%) was obtained
from 27c (22 g, 0.14 mol): IR (film) 1721, 2500–3500 cmK1
;
1H NMR (CDCl3, 400 MHz, COSY, HETCOR) d 0.89 (t,
JZ7.2 Hz, 3H, CH3), 1.34 (m, 1H, CH2), 1.48 (m, 1H,
CH2), 1.91 (m, 1H, CH), 2.16 (dd, JZ15.2, 12.0 Hz, 1H,
CH2CO), 2.25 (dd, JZ14.0, 11.2 Hz, 1H, CH2CO), 2.44
(ddd, JZ14.0, 2.0, 0.8 Hz, 1H, CH2CO), 2.56 (m, 2H, H-3,
CH2CO), 5.04 (ddd, JZ16.8, 2.0, 0.8 Hz, 1H, ]CH2 trans),
5.14 (dd, JZ10.4, 2.0 Hz, 1H, ]CH2 cis), 5.50 (ddd, JZ
16.8, 10.4, 9.2 Hz, 1H, ]CH); 13C NMR (CDCl3,
100.6 MHz, HETCOR) d 11.9 (CH3), 24.6 (CH2), 35.9
(CH), 36.1 (CH2), 38.7 (CH2), 50.4 (CH), 117.8 (CH2),
138.1 (CH), 180.1 (C), 180.2 (C); mp 78–79 8C (hexane).
Anal. Calcd for C10H16O4: C, 59.98; H, 8.05. Found: C,
60.15; H, 8.05.
3.1.32. Dimethyl and diethyl 3-(2-oxoethyl)glutarate (1).
Method A. Operating as described for the preparation of
compound 5b (reaction time 16 h), methyl ester 1a
(70.3 mg, 57%) was obtained from triester 8 (211 mg,
0.60 mmol) after flash chromatography (hexane): IR (film)
1
1735 cmK1; H NMR (CDCl3, 300 MHz) d 2.46 (dd, JZ
6.6, 4.2 Hz, 4H, H-2 and H-4), 2.64 (dd, JZ6.3, 1.5 Hz, 2H,
CH2CHO), 2.88 (td, JZ13.2, 6.3 Hz, 1H, H-3), 3.67 (s, 6H,
OCH3), 9.79 (s, 1H, CHO); 13C NMR (CDCl3, 75.4 MHz) d
26.5 (CH), 37.6 (CH2), 47.3 (CH2), 51.6 (CH3), 172.1 (C),
200.4 (C). HRMS calcd for C9H14O5 202.1723, found
202.1719.
3.1.29. Dimethyl 3-(1-ethyl-2-methyl-2-propenyl)
pentanedioate (29a). Me3SiCl (50 mL, 393 mol) was
added to a solution of diacid 28a (19.1 g, 89 mmol) in
anhydrous MeOH (300 mL), and the mixture was stirred at

M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
7701
Method B. A solution of LiBF4 (132 mg, 1.3 mmol) in
acetonitrile (15 mL) containing 2% of H2O was added via
cannula to a solution of acetal 12 (326 mg, 1.31 mmol) in
acetonitrile (2.5 mL), and the resulting solution was stirred
at room temperature for 3 h. The crude mixture was poured
into brine, and the aqueous layer was extracted with EtOAc.
The combined organic extracts were dried, filtered, and
concentrated. The resulting oil was chromatographed
(hexane) affording compound 1a (161 mg, 61%).
300 MHz, COSY, HETCOR) d 0.96 (t, JZ7.2 Hz, 3H,
CH3), 1.67–1.82 (m, 1H, CH2), 1.42–1.56 (m, 1H, CH2),
2.40–2.48 (m, 5H, H-2, H-4 and CHCHO), 2.80 (m, 1H,
H-3), 3.67 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 9.66 (d, JZ
2,4 Hz, 1H, CHO); 13C NMR (CDCl3, 75.4 MHz,
HETCOR) d 12.0 (CH3), 18.6 (CH2), 31.3 (CH), 35.4
(CH2), 35.7 (CH2), 51.6 (CH3), 51.7 (CH3), 55.4 (CH),
172.2 (C), 172.3 (C), 203.5 (C).
Method C. Operating as described in the above Method D,
diester 2a (1.09 g, 75%) was obtained from 29c (1.5 g,
6.6 mol) after flash chromatography (1:1 hexane/EtOAc).
Method C. A mixture of nitrile 15 (222 mg, 0.98 mmol),
NaH2PO2 (650 mg), and Raney Ni (108 mg) in pyridine-
AcOH-H2O (2:1:1, 8 mL) was stirred at 50 8C for 5 h. The
catalyst was removed by filtration, and the solvent was
evaporated. The residue was dissolved in EtOAc, and the
organic layer was washed with H2O, dried, filtered, and
concentrated to give a yellow oil (169 mg), which was
chromatographed (1:1 hexane/EtOAc) affording ethyl
glutarate 1b (143 mg, 64%) as a transparent oil: IR (film)
3.1.34. Dimethyl 3-(1-ethyl-2-oxopropyl)pentadionate
(4a). Diester 29a (2.5 g, 10 mmol) was ozonolyzed as
described in the above Method D. After stirring in the
presence of SMe2 for 20 h and flash chromatography
(gradient hexane–EtOAc), ketodiester 4a (1.76 g, 65%)
was obtained: IR (film) 1710, 1735 cmK1 1H NMR
;
1
1736 cmK1; H NMR (CDCl3, 300 MHz) d 1.25 (t, JZ
(CDCl3, 400 MHz, COSY, HETCOR) d 0.85 (t, JZ
7.2 Hz, 3H, CH3), 1.35–1.45 (m, 1H, CH2), 1.60–1.71 (m,
1H, CH2), 2.21 (s, 3H, CH3), 2.28 (dd, JZ16.0, 8.0 Hz, 1H,
H-2 or H-4), 2.37–2.49 (m, 3H, H-2 and H-4), 2.62–2.71 (m,
2H, H-3 and CHCO), 3.66 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3); 13C NMR (CDCl3, 50 MHz, HETCOR) d 12.0
(CH3), 20.0 (CH2), 30.6 (CH3), 32.3 (CH), 34.7 (CH2) 36.1
(CH2), 51.5 (CH3), 55.5 (CH), 172.3 (C), 172.4 (C), 210.9
(C). Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C,
58.73; H, 8.23.
7.2 Hz, 6H, CH3), 2.45 (dd, JZ6.6, 4.2 Hz, 4H, H-2 and
H-4), 2.63 (dd, JZ6.6, 1.2 Hz, 2H, CH2CHO), 2.88 (q, JZ
6.6 Hz, 1H, H-3), 4.11 (q, JZ7.2 Hz, 4H, CH2), 9.75 (s, 1H,
CHO); 13C NMR (CDCl3, 75.4 MHz) d 14.2 (CH3), 26.5
(CH), 37.9 (CH2), 47.3 (CH2), 60.4 (CH2), 171.6 (C), 200.5
(C).
Method D. Malonate (24d) was converted to dimethyl
3-allylpentadioate (29d) via the intermediates 25d–28d in
the yields indicated in Table 1, following reported
procedures.15 A stream of ozone gas was bubbled through
a cooled (K78 8C) solution of diester 29d (2.5 g,
12.5 mmol) in CH2Cl2 (40 mL) until it turned pale blue.
The solution was purged with Ar until disappearance of the
blue color. Then SMe2 (35 mL, 475 mmol) was added, and
the temperature was raised to 25 8C. After 30 h of stirring,
the crude mixture was evaporated under reduced pressure.
The residue was dissolved in CH2Cl2 and washed with H2O.
The aqueous layer was extracted with CH2Cl2, and the
combined organic extracts were washed with brine, dried,
and filtered to give, after column chromatography (3:1
hexane/EtOAc), pure methyl ester 1a (2.10 g, 84%).
Acknowledgements
This work was supported by the Ministry of Science and
Technology (Spain)-FEDER through project BQU2003-
00505. Thanks are also due to the DURSI, Generalitat de
Catalunya, for Grant 2001SGR-0084 and the Ministry of
Education, Culture and Sport (Spain) for a fellowship to
ˆ
O.B., and the Fundac¸a˜o para a Ciencia e Tecnologia
(Portugal) for a postdoctoral Grant to M.M.M. Santos.
3.1.33. Dimethyl and diethyl 3-(1-formylpropyl)glutar-
ate (2). Method A. Nitrile 15 (100 mg, 0.39 mmol) was
reduced operating as described in the above Method C, with
addition of NaH2PO2 (273 mg) and Raney Ni (65 mg) at
intervals of 6 h during 24 h. After flash chromatography (1:1
hexane/EtOAc) a 4:1 mixture of 2b and 15 (71 mg, 57%)
References and notes
1. (a) Evstigneeva, R. P.; Preobrazhensky, N. A. Tetrahedron
1958, 4, 223. (b) van Tamelen, E. E.; Aldrich, P. E.; Hester,
J. B., Jr. J. Am. Chem. Soc. 1959, 81, 6214. (c) Winterfeldt, E.
Chem. Ber. 1964, 97, 2463. (d) van Tamelen, E. E.; Hester,
J. B., Jr. J. Am. Chem. Soc. 1969, 91, 7342. (e) van Tamelen,
E. E.; Placeway, C.; Schiemenz, G. P.; Wright, I. G. J. Am.
1
was obtained; H NMR (CDCl3, 300 MHz) d 0.95 (t, JZ
7.4 Hz, 3H, CH3), 1.25 (t, JZ7.6 Hz, 6H, CH3), 1.69 (dd,
JZ7.6, 2.2 Hz, 2H, CH2), 2.37–2.55 (m, 4H, H-2 and H-4),
2.61 (m, 1H, H-3), 2.83 (m, 1H, CHCHO), 4.07–4.21 (m,
4H, CH2), 9.66 (d, JZ2.2 Hz, 1H, CHO); 13C NMR
(CDCl3, 75.4 MHz) d 12.1 (CH3), 14.1 (CH3), 22.2 (CH2),
33.2 (CH), 33.6 (CH2), 33.7 (CH2), 49.2 (CH), 60.4 (CH2),
60.5 (CH2), 172.0 (C), 172.2 (C), 203.7 (C).
¨
Chem. Soc. 1969, 91, 7359. (f) Logers, M.; Overman, L. E.;
Welmaker, G. S. J. Am. Chem. Soc. 1995, 117, 9139.
´ ´
2. (a) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.; Perez, M.;
Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335. (b) Amat, M.;
`
´
Bassas, O.; Pericas, M. A.; Pasto, M.; Bosch, J. Chem.
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M.; Griera, R.; Molins, E.; Amat, M.; Bosch, J. Org. Lett.,
2005, 7, 0000.
Method B. Diester 29b (262 mg, 1.02 mmol) was ozono-
lyzed as described in the above Method D. After stirring in
the presence of SMe2 for 4 h and flash chromatography (1:1
hexane/EtOAc), ketodiester 2a (150 mg, 64%) was
3. For a recent review, see: Pellissier, H. Tetrahedron 2003, 59,
8291.
obtained: IR (film) 1735 cmK1
;
1H NMR (CDCl3,

7702
M. Amat et al. / Tetrahedron 61 (2005) 7693–7702
´
4. Luckes, R.; Palecek, J. Coll. Czech. Chem. Commun. 1964, 29,
1073.
1992, 114, 10181. (b) Flanagan, D. M.; Joullie, M. M. Synth.
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B. J. Chem. Soc. 1962, 3961.
5. Chow, H.-F.; Fleming, I. J. Chem. Soc., Perkin Trans. 1 1998,
2651. We used t-BuMe2SiCl instead of Me3SiCl as described
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11. For a similar preparation of the methyl ester analog of 16, see
Ref. 1e.
6. (a) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111,
1063. (b) Fujii, N.; Otaka, A.; Ikemura, O.; Akaji, K.;
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1988, 53, 5328. (b) Moreno-Man˜as, M.; Prat, M.; Ribas, J.;
Virgili, A. Tetrahedron Lett. 1988, 29, 581. (c) Prat, M.;
Moreno-Man˜as, M. Tetrahedron 1988, 44, 7205.
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3273.
7. The conjugate addition of the lithium enolates derived from
methyl or tert-butyl acetate, or methyl 1,3-dithiolane-2-
carboxylate to 9 was also unsuccessful.
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