New synthesis of (±)-sitophilate using carboxylic acid dianion methodology - A stereoselectivity study

Article abstract of DOI:10.1055/s-2005-918466

A simple two-step synthesis of (±)-sitophilate in has been developed by addition of propanal to the lithium enediolate of propanoic acid and subsequent esterification with 3-pentanol under standard Fischer conditions. Efforts to control the diastereoselectiv-ity to generate the syn isomer are described. A modest degree of asymmetric induction is found using chiral amides as base. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918466

PAPER
3451
New Synthesis of ( )-Sitophilate Using Carboxylic Acid Dianion Methodology
– A Stereoselectivity Study
Synthesis of
(
a
)-Sitophila
l
te vador Gil, Margarita Parra,* Pablo Rodriguez, Enrique Sotoca
Department de Organic Chemistry, Universitat de València, C/Dr. Moliner 50, 46100 Burjassot, Spain
Fax +34(9)639083152; E-mail: Margarita.Parra@uv.es
Received 18 July 2005
Dedicated to Professor Steven V. Ley on the occasion of his 60th birthday
synthesis of ( )-sitophilate. We will emphasize the effects
of the amide base as well as the ratio of reagents and ad-
ditives on the stereoselectivity of this synthesis.
Abstract: A simple two-step synthesis of ( )-sitophilate in has
been developed by addition of propanal to the lithium enediolate of
propanoic acid and subsequent esterification with 3-pentanol under
standard Fischer conditions. Efforts to control the diastereoselectiv-
ity to generate the syn isomer are described. A modest degree of
asymmetric induction is found using chiral amides as base.
( )-Sitophilate is an aggregation pheromone from the
male granary weevil, Sitophilus granarius, which is a pest
that causes commercially important damage to stored ce-
real grains. This pheromone was identified by Phyllips et
al.21 as 3-pentyl (2R*,3S*)-3-hydroxy-2-methylpen-
tanoate (1) (Figure 1).
Key words: carboxylic acids, aldehyde, addition reaction, amino
alcohols, diastereoselectivity
Regio- and stereoselectivity studies on the reaction of
lithium enediolates, generated from carboxylic acids, with
several electrophiles have been reported in the last years.1–5
Double deprotonation of carboxylic acids by lithium di-
alkylamides is the most common method for the genera-
tion of lithium enediolates6–8 due to their wide range of
nucleophilicity combined with their solubility in non-po-
lar solvents.9,10 In most cases a sub-stoichiometric amount
of the amine, leading to its lithium amide, allows the gen-
eration of enediolates, from the corresponding acid, with-
out Barbier reduction or Michael adduct formation.6–11
OH
O
OH
O
O
O
CH3
CH3
1
2
Figure 1
Biological studies with 1 have demonstrated that the race-
mic mixture is comparable to the naturally produced pher-
omone in attracting male and female granary weevils.
However, the synthetic anti diastereomer 2 (either racem-
ic or enantiomerically pure) is significantly less attractive.
It is well established that lithium enolates exist as com-
plex ion pair aggregates whose metal centre may coordi-
nate to solvent molecules or other chelating ligands, such
as amines resulting from deprotonation of the acid by the
lithium amide.12–14 The available data confirm the com-
plexity present in these aggregated reactive species,
whose reactivity and selectivity can be influenced by
many different factors.15–19
Several racemic or asymmetric syntheses, involving sev-
eral steps with overall yields ranging from moderate to
low, have been reported.22–28 Most of them did not lead to
the required syn isomer, requiring an additional Mitsuno-
bu reaction in order to force a configurational inversion at
the centre bearing the hydroxy group.29
Herein, we report a simple synthesis of ( )-sitophilate in
two steps: addition of propanal to the lithium enediolate of
propanoic acid and subsequent esterification with 3-pen-
tanol under standard Fischer conditions (Scheme 1).
From the relatively low number of structural and rate
studies as well as the vast quantity of empirical observa-
tions, a series of dictums have emerged that describe the
reactivity of organolithiums. Three of these are frequently
reiterated: 1) strong donor solvents (ligands) promote
conversion of aggregates to monomers or ion pairs; 2)
monomers are more reactive than aggregates; 3) strong
donor solvents enhance reactivity.20 However, factors
governing the stereoselectivity of the reactivity of ene-
diolates with electrophiles are less well understood.
The synthesis can be easily performed in good yield, but
the resulting diastereomeric mixture is the major dis-
advantage of this addition. We undertook a study aimed
at controlling the diasteroselectivity of this addition
(Table 1).
Thus, on reaction with propanal the enediolate of pro-
panoic acid, generated under standard conditions, led to a
diastereomeric mixture of b-hydroxyacids 3 and 4 in 57%
yield. As expected, the diasteromeric ratio (43:57) favors
the anti product and the starting acid was recovered in
28% yield (Table 1, entry 1).
Following our studies on the stereoselectivity of the addi-
tion of enediolates, generated from carboxylic acids, to
carbonyl compounds, we report here its application to the
SYNTHESIS 2005, No. 19, pp 3451–3455
x
x.
x
x
.
2
0
0
5
Changing the reaction conditions, in particular the amine
used for base generation, was expected to improve these
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918466; Art ID: C08105SS
© Georg Thieme Verlag Stuttgart · New York

3452
S. Gil et al.
PAPER
O
OH
O
OH
O
Base
OH
OLi
OLi
H
OH
+
OH
O
CH3
CH3
3
4
H+
OH
OH
O
OH
O
+
O
O
1
CH3
CH3
2
Scheme 1
results for two reasons. It was previously shown that the state involved in this reaction to allow, a priori, an accu-
reactivity of the intermediate system could be controlled rate prediction of the required amine structure. Previous
by changing its aggregation state. Also, the possibility of studies, on alkylation reactions, indicate that an additional
asymmetric induction promoted by chiral bases may lead hydroxy group, on the carbon adjacent to that bearing the
to improved results.
amine, is a good combination for optimum chelation.
We used several bases for dianion generation, which were Surprisingly, the use of a sub-stoichiometric amount of
chosen with the aim of using them, in a homochiral form, amine does not improve the yield despite the fact that the
to effect chiral induction. It is clear that chiral lithium amount of starting acid recovered decreased considerably
amides promote intermolecular chirality transfer,30–32 but (Table 1, entries 5, 7, and 9). To date we have not be able
to date there is no information available on the transition to find a clear explanation of this phenomenon.
Table 1 Control of Diastereoselectivity
Entry
Amine
Amine (equiv) Reaction conditions Propanal (equiv) Yield (%)
Products (%)
3
4
Acid
28
24
10
9
1
2
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
i-Pr2NH
i-Pr2NH
AZAa
2
1 h, r.t.
1 h, r.t.
4 h, r.t.
4 h, –78 °C
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1 h, r.t.
1
3
3
1
1
1
1
1
1
1
1
1
1
1
3
57
66
59
51
23
54
30
43
28
28
33
31
29
57
70
31
33
38
45
45
39
41
44
39
32
39
24
35
33
35
41
43
52
50
55
50
53
49
44
37
46
44
51
48
49
2
3
2
4
2
5
0.5
2
–
6
11
6
7
0.5
2
8
7
9
AZA
0.5
2
17
32
15
32
31
20
10
10
11
12
13
14
15
BAPOb
PMOc
BACHd
ESPe
2
2
2
EFEf
2
EFEg
2
a AZA: 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane.
b BAPO: 1-(benzylamino)propan-2-ol.
c PMO: pirrolidin-2-metanol.
d BACH: 2-(benzylamino)cyclohexanol.
e ESP: sparteine.
f EFE: ephedrine, dried over CaH2.
g Dried over Li.
Synthesis 2005, No. 19, 3451–3455 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-Sitophilate
3453
O
H
OLi
Some conclusions can be extracted from Table 1. The op-
timum conditions include an excess of propanal with a re-
action time of one hour at room temperature. This can be
due to the reversible nature of the process along with the
fact that propanoic acid dianion generation must be slow
and incomplete, this is similar to what is observed for the
acetic acid dianion.7 Thus, deprotonation equilibrium
seems to be slightly displaced to the right and many fac-
tors can move the equilibrium towards the propanoate ion
by reprotonation of the dianion by the amine. This would
explain why a variable percentage of starting acid is al-
ways observed in the crude reaction; in some cases, quite
a large amount of acid is recovered (Table 1, entries 10,
12, and 13).
O
OLi
Li
Li
coordinated
O
H
H
CH3
O
CH3
A
B
H
CO2H
CO2H
CH3
S*
S*
H
OH
H
OH
CH3
H
H
syn
anti
R*
S*
O
H
OLi
Li
O
H
OLi
Li
H
CH3
uncoordinated
H
CH3
Unfortunately, the diastereoselectivity of this reaction
favours the anti isomer and we have been unsuccessful in
modifying this. Approximately, a 42:58 ratio for R*S* and
R*R* isomers is always obtained.
O
O
D
C
Scheme 2
Following the work of Mulzer32 four geometries can be
considered for the transition state (Scheme 2): two of
them, A and C produce the anti isomer, whereas B and D
lead to the syn isomer. Structures A and D minimize hin-
drance between bulkier groups. So from a chelated transi-
tion state the anti isomer is always the major product.
Therefore, a strong chelating agent, able to break the sta-
bility of A in favor of D, is required. We considered amino
alcohols as bases, which could act as chelating agents.
Unfortunately, despite the variety of amines added, the
anti isomer has always been the major product.
Now we report the first study of chiral induction in the re-
action of enediolates, generated from carboxylic acids,
with carbonyl compounds using chiral amines as bases,
both for enediolate generation and as chiral auxiliaries.
Using the addition of the enediolate of propanoic acid to
propanal as the standard reaction, we were able to demon-
strate the influence of several additives on the diastereo-
selectivity of the process (Table 2).
As can be seen, (–)-sparteine and both enantiomers of
ephedrine have been used to generate the lithium amide
base and at the same time induce chirality.
At this point, despite the lack of diastereoselective con-
trol, we have achieved a new synthesis of racemic ( )-si-
tophilate in two steps: addition of the enediolate of
propanoic acid, generated from ephedrine, and esterifica-
tion with 3-pentanol in 52% yield overall. Isomerization
to the syn isomer can be achieved through a Mitsunobu-
mediated inversion.
Under the standard conditions used for the racemic lithi-
um amides, a 13% ee was obtained for both the S*R* and
S*S* diastereomers. We would like to emphasise that the
best ee values were obtained in those reactions with a low
yield, except for those reactions run at low temperature
where low yields along with a surprising loss of enantio-
selectivity were obtained. The presence of LiCl or LiBr
Table 2 Influence of Additives on the Diastereoselectivity
Entry
Amine
Additive
Yield
70
deb (%)
16
eec (S*R*, %)
eed (S*S*, %)
1
2
3
4
5
6
7
8
(+)-EFE
(+)-EFEa
(+)-EFE
(+)-EFEa
(+)-EFE
(+)-EFEa
(–)-EFE
(–)-ESP
–
13
11
13
10
–
55
16
LiBr
LiBr
LiCl
LiCl
–
63
21
17
>10
>10
16
23
18
>10
18
25
26
30
25
>10
21
>10
22
30
49
–
29
19
28
29
a Conditions: 12 hours at –78 °C.
b S*S* configuration for the major diastereoisomer.
c SR configuration for the major enantiomer.
d SS configuration for the major enantiomer.
Synthesis 2005, No. 19, 3451–3455 © Thieme Stuttgart · New York

3454
S. Gil et al.
PAPER
Reaction of Enediolates with Electrophiles; General Procedure
n-BuLi (1.6 M in hexane) was introduced into a reaction flask that
had been purged. Hexane was evaporated under vacuum and THF
(2 mL) followed by the amine (5 mmol) were added at –78 °C. The
mixture was stirred for 15 min at 0 °C. The acid (2.25 mmol) was
added slowly at –78 °C. After 30 min at 0 °C, propanal (2.5 mmol)
in THF (2 mL) was added slowly at –78 °C. The solution was stirred
at r.t. for 1 h and quenched with H2O (15 mL). The reaction mixture
was extracted with Et2O (3 × 15 mL). The aqueous phase was acid-
ified with conc. HCl to pH 1 and then extracted with EtOAc (3 × 15
mL).
does not modify the enantioselectivity results to a large
extent.
Examples are known in which lithium enolates prepared
from carbonyl compounds and lithium amides react less
stereoselectively with alkyl halides at the early stages of
the reaction, but become more stereoselective as the alkyl-
ation proceeds.33 This phenomenon is explained by the
parallel generation of LiBr whose concentration increases
as the reaction proceeds. However, external addition of
LiBr cannot reproduce its effect when it is slowly re-
leased.17 This can explain the small modification in selec-
tivity promoted by these Lewis acids (Table 2, entries 3 to
6). Most surprising was the lack of effect the additives
3-Hydroxy-2-methylpentanoic Acid
Prepared from propanoic acid (167 mg, 2.25 mmol) and propanal
(131 mg, 2.25 mmol); yield: 286 mg (63%); yellow oil.
have on the de – again they are not able to break transition IR (KBr): 3500–3100, 2969, 2931, 1718, 1459, 1406, 1383, 1206,
1094, 974 cm–1.
states A and B described above (Scheme 2).
2S*3R*
Similar results were obtained with either (–)-ephedrine or
1H NMR (400 MHz, CDCl3): d = 6.31 (br s, 1 H, OH), 3.90 (br s, 1
H, CHOH), 2.65 (m, 1 H, CHCH3), 1.54 (m, 2 H, CH3CH2CH), 1.23
(d, J = 7.1 Hz, 3 H, CH3CHCHOH), 1.01 (t, J = 7.4 Hz, 3 H,
CH3CH2CHOH).
13C NMR (100 MHz, CDCl3): d = 180.7 (COOH), 73.4 (CHOH),
43.8 (CHCH3), 27.2 (CH2CH3), 10.4 (CH3CH), 10.1 (CH3CH).
(–)-sparteine, but in these cases, the major enantiomer ob-
tained was antipodal in reaction to the previous entries for
both diastereomers (Table 2, entries 7 and 8).
Despite the modest degree of asymmetric induction ob-
served the method offers the following advantages: 1) its
operational simplicity; 2) chiral compounds were ob-
tained in a single step; and 3) the chiral bases were easily
recovered during work-up in a re-usable form. Obviously,
a deeper knowledge about the aggregation state and a suit-
able chiral base are required in order to improve the chiral
induction in this reaction.
2R*3R*
1H NMR (400 MHz, CDCl3): d = 6.31 (br s, 1 H, OH), 3.66 (br s, 1
H,CHOH), 2.60 (q, J = 7.1 Hz, 1 H, CHCH3), 1.67–1.62 (m, 1 H,
CH3CH2CH), 1.55–1.50 (m, 1 H, CH3CH2CH), 1.27 (d, J = 7.1 Hz,
3 H, CH3CHCHOH), 1.02 (t, J = 7.4 Hz, 3 H, CH3CH2CHOH).
13C NMR (100 MHz, CDCl3): d = 180.7 (COOH), 74.7 (CHOH),
45.1 (CHCH3), 26.6 (CH2CH3), 14.2 (CH3CH), 9.7 (CH3CH).
IR spectra were obtained with a Matteson Satellite FTIR, type 3000,
spectrophotometer. NMR spectra were obtained in CDCl3 solution
on: Varian UNITY 300 VXR (300MHz) and Bruker, ADVANCE
AC-300 (300 MHz), AC-400 (400 MHz), and AC-500 (500 MHz).
HRMS were determined with a Fisons VG Autoespec. Silica gel
Merck 60 (230–400 mesh) was used for flash column chromatogra-
phy. TLC plates were developed with bromocresol green indicator.
MS: m/z (%) = 115 (M – OH, 5), 114 (M – H2O, 6), 103 (M – Et,
26), 85 (M – OH – Et, 70), 74 (CH3CHCOOH + 1, 100), 56
(CH3CH2CO, 33).
HRMS: m/z calcd for C6H10O2 [M – H2O]+: 114.0681; found:
114.0659.
3-Pentyl 3-Hydroxy-2-methylpentanoate
All reactions were carried out under argon, using standard condi-
tions, in oven-dried glassware. THF was freshly distilled from blue
benzophenone ketyl. Et2NH, i-Pr2NH, and sparteine were distilled
from CaH2. 1,3,3-Trimethyl-6-azabicyclo[3.2.1]octane and anti-2-
(benzylamino)cyclohexanol were used without any further purifica-
tion. (+)-Ephedrine was obtained from (+)-ephedrine hydrochlo-
ride.34 Ephedrine (5 mmol) was dissolved in freshly distilled THF
(2 mL) and dried with CaH2 under Ar 24 h prior to use. The reaction
temperature of –78 °C was achieved by cooling with a CO2–acetone
bath. Organic extracts were dried over anhyd MgSO4 and evaporat-
ed under reduced pressure by a rotary evaporator and a bath at 40
°C.
The acid (74.4 mg, 5.64 mmol) was dissolved in a solution of H2SO4
(5%, 0.25 mL) in 3-pentanol (5 mL) and heated under reflux. The
reaction was followed by TLC developed with bromocresol green
until the acid had disappeared. The reaction was quenched by the
addition of a sat. soln of NaHCO3 (20 mL) and extracted with Et2O
(4 × 15 mL). The diastereomers were separated by column chroma-
tography (Et2O–hexane, 1:8) giving the 2R*3S* isomer, followed
by the 2S*3S* isomer.
Yield: 102 mg (90%).
3-Pentyl (2R*,3S*)-3-Hydroxy-2-methylpentanoate
Yellow oil.
Enantiomers were separated and quantified using a Chiralpak AD-
H chiral HPLC column on a Waters R-401 HPLC apparatus (hep-
tane–i-PrOH–TFA, 90:10:0.1).
IR (NaCl): 3400–3000, 2971, 2939, 2881, 1729, 1462, 1384, 1334,
1258, 1189, 1104, 1039, 978, 918, 889 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.79 (tt, J1 = 6.9 Hz, J2 = 5.5 Hz,
1 H, COOCH), 3.80 (dt, J1 = 4.9 Hz, J2 = 3.8 Hz, 1 H, CHOH), 2.53
(dq, J1 = 7.2 Hz, J2 = 3.8 Hz, 1 H, CHCOO), 1.6–1.4 (m, 6 H,
CHOHCH2CH3, 2 × COOCHCH2CH3), 1.19 (d, J = 7.2 Hz, 3 H,
CH3CHCOO), 0.97 (t, J = 6.4 Hz, 3 H, CHOHCH2CH3), 0.89 (t,
J = 7.4 Hz, 3 H, CH3CH2CHCOO), 0.88 (t, J = 7.4 Hz, 3 H,
CH3CH2CHCOO).
13C NMR (100 MHz, CDCl3): d = 176.2 (COO), 76.9 (COOCH),
73.2 (CHOH), 44.1 (CHCOO), 26.7 (COOCHCH2CH3), 26.5
(COOCHCH2CH3), 22.6 (CH3CH2CHOH), 14.0 (CH3CH2CHOH),
trans-2-(Benzylamino)cyclohexanol
Cyclohexene oxide (20 mmol, 1.96 g), LiClO4 (20 mmol, 2.13g),
and benzylamine (20 mmol, 2.14 g) were dissolved in MeCN (20
mL) and refluxed for 16 h. The reaction was quenched with H2O (10
mL), extracted with CH2Cl2 (3 × 15 mL), dried with MgSO4, and
evaporated under reduced pressure. The analytical data are consis-
tent with those reported previously.35
Synthesis 2005, No. 19, 3451–3455 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-Sitophilate
3455
10.8
(CH3CHCOO),
9.8
(CH3CH2CHOOC),
9.5
(7) Parra, M.; Sotoca, E.; Gil, S. Eur. J. Org. Chem. 2003, 1386.
(8) Sotoca, E.; Bouillon, J. P.; Gil, S.; Parra, M.; Portella, C.
Tetrahedron Lett. 2004, 45, 8315.
(9) Mekelburger, H. B.; Wilcos, C. S. Formation of Enolates, In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: Oxford, 1991, 99–131.
(10) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.;
Mukhopedhyay, T.; Simon, M.; Seebach, D. Synthesis 1993,
1271.
(11) Eames, J. Eur. J. Org. Chem. 2002, 393.
(12) Streitwieser, A.; Pratt, L. M. J. Org. Chem. 2003, 68, 7937.
(13) Streitwieser, A.; Facchetti, A. J. Org. Chem. 2004, 69, 8345.
(14) Scott, R.; Gremader, J.; Dimer, P.; Hilmersson, G.
Tetrahedron: Asymmetry 2004, 15, 267.
(15) Streitwieser, A.; Weng, Z.-R. J. Am. Chem. Soc. 1999, 121,
6213.
(16) Balomrju, Y.; Sharp, C. D.; Gammill, W.; Manuel, N.; Pratt,
L. M. Tetrahedron 1998, 54, 7357.
(17) Brun, E. M.; Gil, S.; Parra, M. Tetrahedron: Asymmetry
2001, 12, 915.
(18) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synlett 2001,
(CH3CH2CHOOC).
HRMS: m/z calcd for C6H11O2 [M+ – OCH(CH2CH3)2], 115.0759;
found, 115.0741.
+
MS: m/z (%) = 115 {[M – OCH(CH2CH3)2], 7}, 85 (C4H5O2 , 12),
74 (C3H6O2 , 100), 71 [CH(CH2CH3)2 , 17], 69 (C5H9 , 15).
+
+
+
3-Pentyl (2S*,3S*)-3-Hydroxy-2-methylpentanoate
Yellow oil.
IR (NaCl): 3600–3000, 2971, 2881, 1714, 1462, 1384, 1262, 1258,
1188, 1116, 1053, 976, 916, 889 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.80 (tt, J1 = 7.0 Hz, J2 = 5.4 Hz,
1 H, COOCH), 3.57 (ddd, J1 = 8.3, J2 = 6.2, J3 = 4.1 Hz, 1 H,
CHOH), 2.69 (br s, 1 H, OH), 2.53 (dq, J1 = 7.2 Hz, J2 = 6.2 Hz, 1
H, CHCOO), 1.6–1.2 (m,
6
H, CHOHCH2CH3,
2
×
COOCHCH2CH3), 1.22 (d, J = 7.2 Hz, 3 H, CH3CHCOO), 0.98 (t,
J = 7.4 Hz, 3 H, CHOHCH2CH3), 0.89 (t, J = 7.4 Hz, 6 H,
CH3CH2CHCOO).
13C NMR (100 MHz, CDCl3): d = 176.1 (COO), 76.9 (COOCH),
74.7 (CHOH), 45.0 (CHCOO), 27.7 (COOCHCH2CH3), 26.5
(CHOHCH2CH3), 14.6 (CH3CHOH), 9.9 (CH3CH2CHOH), 9.6
(CH3CH2CHOOC).
156.
(19) Eames, J.; Suggate, M. J. Angew. Chem. Int. Ed. 2005, 44,
186.
(20) Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120,
4081.
HRMS: m/z calcd for C11H23O3 [M+ + 1], 203.1647; found,
203.1660.
(21) Phillips, J. K.; Miller, S. P. F.; Andersen, J. F.; Fales, H. M.;
Burkholder, W. E. Tetrahedron Lett. 1987, 28, 6145.
(22) Mori, K.; Ishikura, M. Liebigs Ann. Chem. 1989, 1263.
(23) Chang, J. M. Tetrahedron 1989, 45, 623.
(24) Sugai, T.; Sakuma, D.; Kobayashi, N.; Ohta, H. Tetrahedron
1991, 47, 7237.
MS: m/z (%) = 203 (M + 1, 2), 173 (M – Et, 12), 144 (M – 2 Et, 16),
+
+
115 [M – OCH(CH2CH3)2, 100], 103 (C4H7O3 , 51), 85 (C4H5O2 ,
+
+
+
16), 74 (C3H6O2 , 81), 71 [CH(CH2CH3)2 , 18], 69 (C5H9 , 16), 59
(CH3CH2COH+, 22)
(25) Cheskis, B. A.; Shpiro, N. A.; Noiseenkov, M. Bull. Acad.
Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1991, 40, 2205.
(26) Razkin, J.; Gonzalez, A.; Gil, P. Tetrahedron: Asymmetry
1996, 7, 3479.
(27) Gil, P.; Razkin, J.; Gonzalez, A. Synthesis 1998, 386.
(28) Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.;
Almeida, W. P. Tetrahedron 2001, 57, 6901.
(29) Mitsunobu, O. Synthesis 1981, 1.
Acknowledgment
We acknowledge support from the Dirección General de Ciencia y
Tecnología, project PPQ2002-00986, and from the Agencia Valen-
ciana de Ciencia y Tecnología (IVCiT), for the program Grupos
I+D+I, GRUPOS03/206. E.S. thanks the University of Valencia for
a predoctoral fellowship.
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Synthesis 2005, No. 19, 3451–3455 © Thieme Stuttgart · New York