A general synthesis of 2- or 3-alkyl substituted 5-hydroxymethyl-δ-valerolactones, precursors of 5-formyl-δ-valerolactones, via lithiated N-allyl(bisdimethylamino)-N-methylphosphoramide carbanions

Article abstract of DOI:10.1016/S0022-328X(99)00269-7

A convenient strategy is reported for the synthesis of 2- or 3-alkylsubstituted 5-hydroxymethyl and 5-formyl-δ-valerolactones, which are very useful starting blocks for the total synthesis of leukotrienes and lactonic pheromones. It has been found that li

Full text of DOI:10.1016/S0022-328X(99)00269-7

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 586 (1999) 208–217
A general synthesis of 2- or 3-alkyl substituted
5-hydroxymethyl-d-valerolactones, precursors of
5-formyl-d-valerolactones, via lithiated
N-allyl(bisdimethylamino)-N-methylphosphoramide carbanions
Philippe Coutrot *, Claude Grison, Catherine Boˆmont
Institut Nance´ien de Chimie Mole´culaire, FR CNRS 1742, Laboratoire de Chimie Organique II, UMR CNRS 7565, Uni6ersite´ Henri Poincare´,
Nancy I, BP 239, F-54506 Vandoeu6re les Nancy, Cedex, France
Received 25 January 1999
Abstract
A convenient strategy is reported for the synthesis of 2- or 3-alkylsubstituted 5-hydroxymethyl and 5-formyl-d-valerolactones,
which are very useful starting blocks for the total synthesis of leukotrienes and lactonic pheromones. It has been found that
lithiated enephosphoramide ambident anions reacted exclusively in the g position with 2,3-O-isopropylidene glycerol triflate to
give corresponding alkylated enephosphoramides by a C3ꢀC3 backbone connection. Enephosphoramide group was further
selectively hydrolyzed in the presence of isopropylidene function in mild acidic conditions and led to expected aldehydes in high
yields. Oxidation of these aldehydes using silver oxide or potassium permanganate afforded corresponding acids. Further
hydrolysis of the isopropylidene group led to unstable dihydroxyacids which directly lactonized. The latter were converted to
5-formyl-d-valerolactones using PDC oxidant. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Enephosphoramide; 2,3-O-Isopropylidene glycerol; Lithium reagents; d-Valerolactone
1. Introduction
Conceptually, a simple retrosynthetic pathway in-
volves the addition of a homoenolate anion 3 to the
suitable 2,3-O-isopropylidene glycerol derivative 4 to
build the required g-lactone 1 via a C3ꢀC3 backbone
connection (Scheme 1).
Many chiral functionalized g- or d-lactones are bio-
logically active compounds [1]. They are also important
synthetic building blocks used in natural product syn-
thesis. 5-hydroxymethyl d-valerolactone 1a, (R1=R2=
H) for example, has been prepared by various methods
in racemic and enantiomerically pure form [2], and has
been used as a key synthon for leukotriene LTB5 syn-
thesis. This compound is also potentially useful for the
preparation of a range of insect pheromones. However,
availability of this enantiomerically pure d-lactone 1a
and its oxidation product, 5-formyl d-valerolactone 2a
(R1=R2=H) is rather difficult [2]. Moreover the ac-
cess to 2- or 3-alkyl-substituted ring derivatives 1b–d or
2b–d is limited [2b,e,i]. It follows that the synthesis of
such a molecule represents an interesting target.
In earlier work we reported the suitability of lithiated
N-alkenyl-N-methyl-(bisdimethylamino)
phosphor-
amide anions (6) as an effective source of homoenolate
* Corresponding author. Tel.: +333-83-912100; fax: +333-83-
912393.
E-mail address: philippe.coutrot@1co2.u-nancy.fr (P. Coutrot)
Scheme 1.
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00269-7

P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
209
Scheme 2.
synthetic equivalents for the preparation of various
aldehydes [3] or g-lactols [4], and for the stereocon-
trolled synthesis of the sole 5-formyl-d-valerolactone
(1a) [5]. The synthetic value of this strategy is based on:
(i) the remarkable capacity of these lithiated allylphos-
phoramide ambident anions to react exclusively at the g
position with alkylhalides; and (ii) on the nature of the
conjugate enephosphoramide moiety present in 7 which
is stable to bases, but liberates the aldehydic group
under mild acid conditions.
Since 2,3-O-isopropylidene glycerol triflate 4 is easily
available, we have considered that its reaction with the
lithiated anions 6 would provide, after a series of
suitable transformations, a general and versatile ap-
proach to the synthesis of other diastereomeric substi-
tuted g-lactones 1 and 2 (Scheme 2). This paper
describes the details of this approach.
highest yields were obtained with lithiated anion 6a
derived from allylphosphoramide 5a. In all other cases
(5b–d), the presence of substituents in the b or g
position increased the hindrance of the corresponding
lithiated anions 6b–d and decreased their reactivity.
The effect of the stoichiometry was studied in these
cases. Using 2 equivalents of lithiated anions led to
conjugate enephosphoramides 7b and 7c with improved
yields (compare entries 3–5; 6–7). In contrast, the
addition of HMPT was quite ineffective under the same
conditions. No significant improvement in yields was
observed with increased reaction time beyond 1 h. In
the case of phosphoramide 5d, no further improvement
in yields was obtained by employing various reaction
conditions (entries 8–11).
The enephosphoramides 7a–d were obtained as a
mixture of diastereomers (two Z and E stereomers were
possible for 7a and 7d and four diastereomers were
possible for 7b and 7c which combined the different R,
S chiral centers and the Z,E carbon–carbon double
2. Results and discussion
1
bonds). As a result the H-NMR spectra of the crude
product mixtures were complex and difficult to assign.
Moreover, the crude product evolved slowly, which did
not facilitate its analysis: after hydrolysis of the reac-
tion mixture, the conjugate enephosphoramides 7 and 8
presented notable amounts of Z stereomers supposed to
be the result of an internal chelation of lithium with the
2.1. Reaction between lithiated anions 6 and
2,3-O-isopropylidene glycerol triflate 4
The lithiated anions 6 were prepared from the corre-
sponding enephosphoramides 5 by deprotonation with
n-BuLi at −50°C in THF as previously described [3].
As with alkyl halides, these ambident carbanions only
reacted at the g position [3] with triflate 4 to afford
after neutral hydrolysis the expected conjugate
enephosphoramides 7 but also recovered starting mate-
rials 5 and their transposed forms 8, resulting from the
a and g protonation of unreacted carbanions 6 during
hydrolysis (Schemes 2 and 3).
A series of experiments was performed in order to
determine alkylation factors as shown in Table 1. The
Scheme 3.

210
P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
Table 1
Formation of conjugate enephosphoramides 7 by alkylation of lithiated anions 6 with triflate 4
Entry
5
R1
R2
5 (equivalent)a
Time (h)
5 c
8 c
7 c
7
(%) d
(E/Z) e
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5b
5c
5c
5d
5d
5d
5d
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
1.15
1.15 b
1.15
1.15 b
2
1.15
2
1.15
1.15 b
1.15
2
1
1
1
1
1
1
1
1
1
4
4
2
2
13
12
14
19
18
18
18
26
18
37
47
85
86
58
60
44
57
38
44
44
46
27
7a
7a
7b
7b
7b
7c
7c
7d
7d
7d
7d
98
99
65
69
88
65
76
50
51
52
53
(78/22)
(80/20)
(70/30) f
(72/28)
(69/31)
(32/68)
(35/65)
(93/7)
Me
Me
Me
Ph
Ph
H
H
H
H
28
21
38
25
44
30
37
17
27
g
–
–
–
10
11
a Equivalents relative to the triflate 4.
b Reactions were run in THF with one equivalent of HMPT/lithiated anion.
c Percentage of each phosphoramide in the crude mixture after hydrolysis.
d Percentage was determined by NMR measurements and based on the conversion of the starting substrate 4.
e Estimated ratio based on 31P-NMR spectrum of the crude mixture carried out after 15 h at room temperature.
f The E stereomer was itself a mixture of two E diastereomers (55/45), idem for the Z stereomer (ratio not determined).
g The E stereomer was itself a mixture of two E diastereomers (60/40), idem for the Z stereomer (70/30).
free nitrogen orbital, in the carbanionic precursors 6 [3]
(see Fig. 1).1
7b E. The enephosphoramide 7b E was revealed to be a
mixture of two diastereomers E (55/45). In the case of
the reaction between 6c and the chiral triflate 4, the
obtained enephosphoramide 7c (Z/E=68/32) did not
After 12 h at room temperature (r.t.) the enephos-
phoramides 7 Z or 8 Z turned into more stable E
isomers [3,6] except in the case of 7c. As a result,
accurate NMR assignments became possible for all
stereomers 7 E.
1
evolve with time, the H-NMR signals were well sepa-
rated and allowed the identification of two
diastereomers for 7c Z (70/30) and two diastereomers
for 7c E (60/40). From these two examples, it resulted
that the diastereoselectivity of the reaction between
6b–c and the chiral triflate 4 slightly increased with the
steric hindrance of R2.
The trans relationship of the hydrogens linked to the
double bond was assigned on the basis of the greatest
1H-NMR coupling constant 3Jtrans=14 Hz observed for
3
7a–c E compared with Jcis=10 Hz observed for 7c Z.
The E stereomers also presented a 31P-NMR downfield
chemical shift of 23.0–24.4 ppm, whereas Z stereomers
were characterized by a chemical shift to higher fields
of 25.1–25.4 ppm. In all cases 7a–d, only the
stereomers that differed in the ethylenic configuration
presented a different chemical shift in 31P-NMR. It was
also noteworthy that 31P-NMR data allowed the iden-
tification of 7d Z and 7d E by analogy with the
31P-NMR chemical shifts of corresponding 7a–c
stereomers, since in the case of 7d, a cis/trans relation-
ship based on the coupling constant values of two
vicinal hydrogens on a carbon–carbon double bond
was naturally impossible.
For the reasons mentioned above about the complex-
ity of the NMR spectra of the crude product just after
hydrolysis, a possible diastereoselectivity of the nucle-
ophilic substitution of the enephosphoramide anion 6b
on the chiral triflate 4 has only been estimated after the
complete conversion of the crude mixture 7b E/Z into
It was been otherwise noted that satisfactory condi-
tions for separation of the different enephosphoramides
7a–d from the crude mixture were not found. As a
result, yields were estimated from NMR data on the
crude products obtained after neutral hydrolysis. Fur-
ther acid hydrolysis was then carried out on 7a–d.
2.2. Acid hydrolysis of the conjugate enephosphoram-
ides 7
The sensitivity of 7a–d towards acids can be com-
pared with enamines for the enephosphoramide func-
tion and with acetals for the dioxolane protective
group. With a 2 N aqueous solution of hydrochloric or
sulfuric acid [3], both dioxolane and enephosphoramide
functionalities of 7a were hydrolyzed involving a direct
1 However it was only possible to assign the 1H-NMR signals to
the Z stereomer of 7c and not in the cases of 7a, 7b and 7d as a
consequence of a partial or total recovery with the signals of corre-
sponding E stereomers and with the signals of the recovered starting
product 5.
Fig. 1.

P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
211
Scheme 5.
2.4. Deprotecting step: hydrolysis of ketals 10
Hydrolysis of ketals 10 led directly to lactones 1, which
are very sensitive and unstable compounds. Their purifi-
cation either by column chromatography or distillation
could not be achieved without substantial loss of mate-
rial. Several groups reported their rapid polymerization
in the presence of water or impurities. Besides, lactones
are often prepared at the last step of a multistep synthetic
sequence and, as a result, are obtained in relatively small
amounts, which increases the difficulty in obtaining a
sufficient amount of pure product [9].
Scheme 4.
cyclization of the intermediate dihydroxyaldehyde 12a
into the lactol 13a (Scheme 4). An accurate study of the
hydrolysis of 7a–d determined the optimal conditions
for the chemoselective cleavage of the nitrogen–carbon
bond for each enephosphoramide 7a–d with sulfuric
acid at pH 2.5 and led to the corresponding aldehydes
9a–d in good yield (Table 2).
The hydrolysis of compound 10a (R1=R2=H), cho-
sen as a model substrate, was examined by using a variety
of conditions. Direct conversion of 10a to lactone 1a
using either acetic acid 80% or sulfuric acid under reflux
failed and decomposition of lactone 1a occurred.
Satisfying results were obtained, either with HCl (g) in
the presence of a trace amount of water, or with cationic
resins as described previously for the production of 1a
from 10a (entry 2) [10]. The results of Table 4 proved that
formation of substituted lactones 1b–d was preferentially
accomplished by stirring ketals 9b–d in the presence of
etheral HCl (g). On the other hand, 10a, the most
sensitive to acidic conditions, afforded preferentially 1a
using amberlyst 15 and molecular sieves. In all cases it
was never possible to isolate the intermediate dihy-
droxyacid 11.
2.3. Oxidation of aldehydes 9
The acetal group present in the aldehydes 9 limited the
choice of oxidants. Acetals are stable only in neutral or
basic conditions. Two types of oxidant were tested:
potassium permanganate [7], the most popular reagent
which can be used in neutral, acid or basic media, and
silver oxide [8]. Both oxidations were run in basic media.
The carboxylate was then protonated using a solution of
oxalic acid until pH 3.2 (Scheme 5, Table 3).
The reaction of 9a with potassium permanganate was
rapid and complete within 1 h (entry 1) whereas the
reaction of 9b was sluggish and required more forcing
conditions to give a product (entry 3). Reactions of 9c,
9d with permanganate failed. The result for 9c can be
explained by the presence of a phenyl substituent which
by its hindrance and its hydrophobic character limited
the reaction in aqueous media. In all cases, the pure acid
was obtained in fairly good yields when silver oxide was
used under very mild conditions.
2.5. Oxidation of 5-hydroxymethyl-l-6alerolactones 1
into 5-formyl-l-6alerolactones 2
During the course of the first total synthesis of
leukotriene B4, Corey used the couple PDC-activated
The results clearly indicate that silver nitrate is a fairly
specific oxidizing agent for aldehydes 9a–d and does not
readily attack the isopropylidene ketal group.
Table 3
Oxidation of aldehydes 9 into acids 10
Table 2
Entry
9
R1
R2
Oxidant
10
Yield (%) a
Chemoselective hydrolysis of enephosphoramides 7 into aldehydes 9
1
2
3
4
5
6
7
8
9a
9a
9b
9b
9c
9c
9d
9d
H
H
H
H
H
H
Me
Me
H
H
KMnO4
Ag2O
KMnO4
Ag2O
KMnO4
Ag2O
KMnO4
Ag2O
10a
10a
10b
10b
10c
10c
10d
10d
61
70
49
97
–
92
–
75
Entry
7
R1
R2
Time (min)
9
Yield (%) a
Me
Me
Ph
Ph
H
1
2
3
4
5
7a
7a
7b
7c
7d
H
H
H
H
H
H
Me
Ph
H
40
90
240
210
240
9a
9a
9b
9c
9d
77
87
82
93
68
Me
H
a Yields of pure products after chromatography.
a Yields of pure products after chromatography.

212
P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
Table 4
Lactonization of acids 10 into 1
R1
R2
Resins acid a
Molecular sieves (A)
Time (h)
1
Yield (%)
,
Entry
10
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10b
10b
10c
10c
10d
10d
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Ph
Ph
H
HCl
200 b
200 b
15 a
–
3
4
4
4
–
4
–
4
–
1
15
12
6
17
1
70
1
4
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
54
70
72
75
93
96
87
98
75
73
15 c
HCl
15 c
HCl
15 c
HCl
Me
Me
10
H
1
a Resins were used in presence of molecular sieves.
b Amberlite 200.
c Amberlyst 15.
powdered molecular sieve in suspension in
dichloromethane in order to oxidize the enantiomeri-
cally pure 5-hydroxymethyl-d-valerolactone (1a) to 5-
formyl-d-valerolactone (2a) [2a]. Application of this
procedure to 5-hydroxymethyl-d-valerolactones (1a–d)
gave satisfying yields of crude products 2a–d in consid-
eration of their high sensitivity. Yields were determined
that this method could led to an enantioselective syn-
thesis of 1a and 2a when the (R)-(−) or (S)-(+)-2,3-
O-isopropylidene glycerol is used as the starting
compound [5].
4. Experimental
1
by H-NMR measurements based on percentage con-
version of 1a–d (2a, 58%; 2b, 75%; 2c, 67%; 2d, 67%)
4.1. General methods
(Scheme 6).2
IR spectra were obtained using a Nicolet 205 spec-
1
trometer and are given in cm−1. H-NMR spectra were
3. Conclusions
recorded using a Bruker AM400 or AC250 and 31P-
NMR/13C-NMR spectra were recorded using a Bruker
1
A convenient route to 2- or 3-alkyl substituted 5-hy-
droxymethyl-d-valerolactones 1 diastereomers, precur-
sors of 5-formyl-d-valerolactones 2 diastereomers, was
proposed based on the reaction between lithiated N-
alkenyl-N-methyl-(bisdimethylamino) phosphoramide
anions (6) and 2,3-O-isopropylideneglycerol triflate. Al-
though it was not possible to determine the stereoselec-
tivity of the different steps involved in this approach,
nevertheless, the formation of pure diastereomers 1 was
possible after chromatographic separation but with a
substantial loss of material. On the other hand, the
great fragility of 2- or 3-alkyl substituted 5-formyl-d-
valerolactones (2) prevented any attempt of
diastereomeric purification on the crude mixture result-
ing from the oxidation of 1. These aldehydes had to be
used immediately for further synthetic purpose. As a
consequence, the formation of each diastereomer of 2
was only possible from pure diastereomer 1 obtained
after column chromatography. It should also be noted
AC250. Data for H-NMR spectra are reported in l
units downfield from internal Me4Si or from the CHCl3
solvent peak at 7.26 ppm relative to Me4Si. Orthophos-
phoric acid (85%) was used as an external standard for
31P-NMR. 13C-NMR spectra were referenced to the
CDCl3 peak at 77.2 ppm relative to Me4Si. Multiplic-
ities are reported as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet). Mass spectra were obtained
with a TRIO 1000 FISONS spectrometer. Analytical
chromatography was performed on silica gel 60 F254
plates. Products were revealed by spraying sulfuric acid
followed by calcination, or by iodine. Preparative chro-
matographic separations were carried out on Merck
silica gel 60 (230–400 mesh). Et2O was distilled over
P2O5 and stored over Na. THF was freshly distilled
from Na/naphtalene prior to use. HMPA was distilled
2 We noted that this step was very sensitive to reaction conditions.
Oxidation was optimal for amounts of starting compound 1 up to 100
mg . In these conditions no more than 40 mg of crude aldehyde 2
could be obtain with about 90% purity estimated from the 1H-NMR
data. Moreover, these aldehydes rapidly degraded and had to be used
immediately [5].
Scheme 6.

P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
213
from CaH2 at reduced pressure and stored over molecu-
3J(CH3ꢀNꢀP)=8.5 Hz), 2.59 (CH3ꢀNꢀP, d, 12H,
3J(CH3ꢀNꢀP)=9 Hz), 2.40–1.38 (H4, H3, m, 3H), 1.34
(CH3, s, 3H), 1.27 (CH3, s, 3H), 0.96 (CH3ꢀCH3, d, 3H,
3J(CH3ꢀH3)=6.5 Hz). 7b (Z) (30%). 31P-NMR (170
MHz, CDCl3), l: 25.3.
,
lar sieves (3 A). Hexane was distilled over Na and dried
,
over molecular sieves (3 A). n-Butyllithium was pur-
chased from Aldrich and was titrated using the Watson
and Eastham procedure [11].
4.2. General procedure for the preparation of
enephosphoramides 7
4.2.3. [3-phenyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-
butenyl] pentamethylphosphoric triamide 7c
IR (neat) cm−1: 1650 (CꢁC), 1380, 1370 (CH3). 7c
To a stirred solution of enephosphoramide 5 (10.0
mmol) [3] in THF (60 ml) at −50°C was added 7.2 ml
(11.5 mmol) of a 1.6 M n-butyllithium in hexane. After
stirring for 3 h under nitrogen at −50°C, 2.4 g (9
mmol) of triflate [12] 4 in THF (5 ml) at −50°C was
added slowly. The mixture was stirred for 1 h at the
same temperature and then hydrolyzed with water (30
ml). The aqueous solution was extracted with
methylene chloride (3×20 ml). The combined organic
layers were dried (MgSO4) and the solvent was removed
under reduced pressure. The crude enephosphoramides
(7) were obtained as pale yellow oils and were stored
under nitrogen at −20°C.
(Z) (68%). 31P-NMR (170 MHz, CDCl3), l: 25.1. First
1
diastereomer (70%). H-NMR: (400 MHz, CDCl3), l:
7.40–7.20 (C6H5, m, 5H), 6.10 (H1, dd, 1H,
3J(H1ꢀH2)=10 Hz, 3J(H1ꢀP)=6 Hz), 4.56 (H2, dt, 1H,
3J(H2ꢀH1)=3J(H2ꢀH3)=10 Hz, 3J(H2ꢀP)=2 Hz),
2
3
4.03 (H6, H6%, dd, 2H, J(H6ꢀH6%)=8 Hz, J(H6ꢀH5)=
6 Hz), 3.60–3.24 (H5, H3, m, 2H), 3.05 (CH3ꢀNꢀP, d,
3H, 3J(CH3ꢀNꢀP)=9 Hz), 2.60 (CH3ꢀNꢀP, d, 6H,
3J(CH3ꢀNꢀP)=9 Hz), 2.58 (CH3ꢀNꢀP, d, 6H,
3J(CH3ꢀNꢀP)=9 Hz), 2.05–1.65 (H4, m, 2H), 1.42
(CH3, s, 3H), 1.30 (CH3, s, 3H). Second diastereomer
(30%). 1H-NMR (400 MHz, CDCl3), l: 7.40–7.20
3
(C6H5, m, 5H), 5.97 (H1, dd, 1H, J(H1ꢀH2)=10 Hz,
3J(H1ꢀP)=6 Hz), 4.80 (H2, dt, 1H, 3J(H2ꢀH1)=
3J(H2ꢀH3)=10 Hz, 3J(H2ꢀP)=2 Hz), 3.80 (H6, H6%,
2
3
4.2.1. [4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-butenyl]-
pentamethyl phosphoric triamide 7a
dd, 2H, J(H6ꢀH’6)=8 Hz, J(H6ꢀH5)=6 Hz), 3.60–
3.24 (H5, H3, m, 2H), 2.65 (CH3ꢀNꢀP, d, 3H,
3J(CH3ꢀNꢀP)=9 Hz), 2.59 (CH3ꢀNꢀP, d, 6H,
3J(CH3ꢀNꢀP)=9 Hz), 2.57 (CH3ꢀNꢀP, d, 6H,
3J(CH3ꢀNꢀP)=9 Hz), 2.05–1.65 (H4, m, 2H), 1.36
(CH3, s, 3H), 1.28 (CH3, s, 3H). 7c (E) (32%). 31P-
NMR (170 MHz, CDCl3), l: 23.3. First diastereomer
(60%). 1H-NMR: (CDCl3, 400 MHz), l: 7.15–7.45
IR (neat) cm−1: 1655 (CꢁC), 1375, 1365 (CH3). 7a
(E) (78%). 31P-NMR (170 MHz, CDCl3), l: 24.3. H-
1
NMR: (400 MHz, CDCl3), l: 6.32 (H1, dd, 1H,
3
3J(H1ꢀH2)=14.0 Hz, J(H1−P)=6.0 Hz), 4.45 (H2,
dt, 1H, 3J(H2ꢀH1)=14.0 Hz, 3J(H2ꢀH3)=7.0 Hz),
4.10–3.90 (H6, H6%, m, 2H), 3.50–3.40 (H5, m, 1H), 2.65
(CH3ꢀNꢀP, d, 3H, 3J(CH3ꢀNꢀP)=8.0 Hz), 2.56
3
(C6H5, m, 5H), 6.30 (H1, dd, 1H, J(H1ꢀH2)=14 Hz,
3
3
(CH3ꢀNꢀP, d, 12H, J(CH3ꢀNꢀP)=9.0 Hz), 2.15–1.40
3J(H1ꢀP)=6.5 Hz), 4.73 (H2, dd, 1H, J(H2ꢀH1)=14
(H3, H4, m, 4H), 1.34 (CH3, s, 3H), 1.28 (CH3, s, 3H).
Hz, J(H2ꢀH3)=7.0 Hz). Second diastereomer (40%).
3
7a (Z) (22%). 31P-NMR (170 MHz, CDCl3), l: 25.4.
1H-NMR (CDCl3, 250 MHz), l: 7.15–7.45 (C6H5, m,
5H), 6.36 (H1, dd, 1H, 3J(H1ꢀH2)=13,5 Hz,
3
3J(H1ꢀP)=6.5 Hz), 4.70 (H2, dd, 1H, J(H2ꢀH1)=13,5
3
4.2.2. [3-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-
butenyl] pentamethyl phosphoric triamide 7b
Hz, J(H2ꢀH3)=6.0 Hz).
IR (neat) cm−1: 1650 (CꢁC), 1375, 1365 (CH3). 7b
4.2.4. [2-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-
butenyl] pentamethyl phosphoric triamide 7d
(E) (70%). 31P-NMR (170 MHz, CDCl3), l: 24.4. First
1
diastereomer (55%). H-NMR (400 MHz, CDCl3), l:
IR (neat) cm−1 1660, 1375, 1365 (CH3). 7d (E)
(93%). 31P-NMR (170 MHz, CDCl3), l: 23.0. 1H-
NMR: (400 MHz, CDCl3), l: 5.79 (H1, m, 1H), 4.20–
4.00 (H6, H6%, m, 2H), 3.70–3.40 (H5, m, 1H), 2.79
(CH3ꢀNꢀP, d, 3H, 3J(CH3ꢀNꢀP)=9 Hz), 2.68
3
3
6.31 (H1, ddd, 1H, J(H1ꢀH2)=14.0 Hz, J(H1ꢀP)=6
Hz, 4J(H1ꢀH3)=0.5 Hz), 4.26 (H2, dd, 1H,
3J(H2ꢀH1)=14.0 Hz, J(H2ꢀH3)=9.0 Hz), 4.15–3.90
3
(H6, H6%, 2H), 3.60–3.32 (H5, 1H), 2.69 (CH3ꢀNꢀP, d,
3
3
3H, J(CH3ꢀNꢀP)=8.5 Hz), 2.57 (CH3ꢀNꢀP, d, 12H,
(CH3ꢀNꢀP, d, 12H, J(CH3ꢀNꢀP)=9 Hz), 2.20–1.45
3J(CH3ꢀNꢀP)=9 Hz), 2.40–1.38 (H4, H3, m, 3H), 1.33
(CH3, s, 3H), 1.25 (CH3, s, 3H), 3H), 0.97 (CH3ꢀCH3,
d, 3H, 3J(CH3ꢀH3)=6.5 Hz). Second diastereomer
(H3, H4, m, 4H), 1.74 (CH3ꢀC2, s, 3H), 1.41 (CH3, s,
3H), 1.35 (CH3, s, 3H). 7d (Z) (7%). 31P-NMR (170
MHz, CDCl3), l: 25.3.
(45%). H-NMR (400 MHz, CDCl3), l: 6.27 (H1, ddd,
1
1H,
3J(H1ꢀH2)=14.0
Hz,
3J(H1ꢀP)=6
Hz,
4.3. General procedure for the preparation of adehydes 9
4J(H1ꢀH3)=0.5 Hz), 4.36 (H2, dd, 1H, J(H2ꢀH1)=
3
14.0 Hz, J(H2ꢀH3)=9.0 Hz), 4.15–3.90 (H6, H6%, 2H),
Enephosphoramide 7 (2.00 mmol) was dissolved in
Et2O (25 ml) and a 2 N aqueous solution of sulfuric
3
3.60–3.32 (H5, 1H), 2.68 (CH3ꢀNꢀP, d, 3H,

214
P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
acid was added up to pH 2.5. Then, the mixture was
stirred for the time indicated in Table 2, according to
the nature of the enephosphoramide 7. The pH of the
aqueous layer was readjusted every hour to its initial
value by addition of a 2 N aqueous solution of H2SO4.
The course of the reaction was monitored by IR. Once
the IR aldehydic absorption stabilized, the aqueous
layer was extracted with Et2O (3×15 ml). The ether
layer was dried over MgSO4 and the solvent was re-
moved under reduced pressure. The residue was chro-
matographed on a silica gel column (1:1 Et2O–hexane)
to give the aldehyde 9 as a yellow clear oil.
4.3.3. 3-phenyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
nal 9c
Rf: 0.72 (1:1 EtOAc–Ep). IR: 2720 (CHO), 1720
(CꢁO), 1380, 1370 (CH3). First diastereomer (77%).
1H-NMR (400 MHz, CDCl3), l: 9.59 (H1, t, 1H,
3J(H1ꢀH2)=2 Hz), 7.50–7.10 (C6H5, m, 5H), 3.94 (H6,
dd, 1H, 2J(H6ꢀH6%)=8 Hz, 3J(H6ꢀH5)=6 Hz), 3.84
(H5, q, 1H, 3J(H6ꢀH5)=3J(H6%ꢀH5)=3J(H5ꢀH4)=
3J(H5ꢀH4%)=6 Hz), 3.80–3.72 (H3, m, 1H), 3.66 (H6%,
2
3
dd, 1H, J(H6%ꢀH6)=8 Hz, J(H6%ꢀH5)=6 Hz), 2.80–
2.63 (H2, H2%, m, 2H), 1.99 (H4, ddd, 1H, J(H4ꢀH4%)=
2
13 Hz, 3J(H4ꢀH5)=6 Hz, 3J(H4ꢀH3)=8.5 Hz),
1.80–1.64 (H4%, m, 1H), 1.31 (CH3, s, 3H), 1.21 (CH3, s,
3H). 13C-NMR (62 MHz, CDCl3), l: C1 201.5; C6H5
142.8, 128.8, 127.5, 127.2; C(CH3)2 108.6; C5 73.9; C6
69.3; C2, C4 50.5, 40.8; C3 37.2; (CH3)2ꢀC 27.0, 25.6.
Second diastereomer (23%). 1H-NMR (400 MHz,
4.3.1. 4-(2,2-dimethyl-1,3-dioxolan-4-yl)butanal 9a
Rf: 0.68 (1:1 ethyl acetate–hexane). IR: 2720 (CHO),
1
1720 (CꢁO), 1384, 1375 (CH3). H-NMR (400 MHz,
3
CDCl3), l: 9,71 (H1, t, 1H, J(H1ꢀH2)=1.5 Hz), 4.20–
CDCl3) l: 9.58 (H1, t, 1H, J(H1ꢀH2)=1.5 Hz), 7.50–
3
4.00 (H6, H5, m, 2 H), 3.45 (H6%, dd with the appearance
7.10 (C6H5, m, 5H), 3.50 (H6, dd, 1H, J(H6ꢀH6%)=
2
3
of a triplet, 1H, J(H5ꢀH6)=2J(H6%ꢀH6)=7 Hz), 2.43
3J(H6ꢀH5)=7.5 Hz), 3.42–3.32 (H3, m, 1H), 3.24 (H6%,
3
3
(H2, dt, 2H, J(H2ꢀH3)=7 Hz, J(H2ꢀH1)=1.5 Hz),
1.78–1.45 (H3, H4, m, 4H), 1.38 (CH3, s, 3H), 1.32
(CH3, s, 3H). 13C-NMR (62 MHz, CDCl3): C1 201.9;
C(CH3)2 108.7; C5 75.5; C6 69.1; C2, C4 43.5, 32.8; CH3:
26.8, 25.5; C3 18.3. Anal. Calc. for C9H16O3: C% 62.77;
H% 9.36. Found: C% 62.50; H% 9.40.
2
dd, 1H, J(H6%ꢀH6)=3J(H6%ꢀH5)=7.5 Hz), 3.20 (H5, q,
1H,
3J(H5ꢀH6%)=3J(H5ꢀH6%)=3J(H5ꢀH4)=3J(H5ꢀ
H4%)=7.5 Hz), 2.80–2.63 (H2, H2%, m, 2H), 1.87 (H4,
ddd, 1H, Hz,
2J(H4ꢀH4%)=13
3J(H4ꢀH5)=
3J(H4ꢀH3)=8 Hz) 1.80–1.64 (H4%, m, 1H), 1.33 (CH3,
s, 3H), 1.21 (CH3, s, 3H). 13C-NMR (62 MHz, CDCl3),
l: C1 201.45; C6H5 142.9, 128.7, 127.5, 126.9; C(CH3)2
108.7; C5 73.4; C6 69.2; C2, C4 49.9, 40.1; C3 36.6;
(CH3)2ꢀC 26.9, 25.6. Anal. Calc. for C15H20O3: C%
72.55; H% 8.12. Found: C% 72.63; H% 7.98.
4.3.2. 3-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
nal 9b
Rf: 0.79 (1:1 EtOAc–Ep). IR: 2720 (CHO), 1720
(CꢁO), 1384, 1380 (CH3). First diastereomer (70%).
1H-NMR (400 MHz, CDCl3), l: 9.87 (H1, t, 1H,
3J(H1ꢀH2)=2 Hz), 4.12–4.02 (H6, m, 1H), 3.98 (H5, m,
1H), 3.43 (H6%, dd, 1H, 2J(H6%ꢀH6)=2J(H6ꢀH5)=7.5
Hz), 2.45 (H2, ddd, 1H, 2J(H2ꢀH2%)=16.0 Hz,
4.3.4. 2-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
nal 9d
Rf: 0.71 (1:1 EtOAc–Ep). IR: 2720 (CHO), 1720
(CꢁO), 1384, 1370 (CH3). First diastereomer (60%).
1H-NMR (250 MHz, CDCl3), l: 9.63 (H1, d, 1H,
3J(H1ꢀH2)=2 Hz), 4.15–4.10 (H6, m, 2H), 4.10–4.00
(H5, m, 1H), 3.52 (H6%, m, 1H), 2.30 (H2, m, 1H),
2.00–1.45 (H3, H4, m, 4H), 1.40 (CH3ꢀC, s, 3H), 1.35
(CH3ꢀC, s, 3H), 1.12 (CH3ꢀCH2, d, 3H,
3J(CH3ꢀCH2)=7 Hz). Second diastereomer (40%), l:
3
3J(H2ꢀH3)=5.5 Hz, J(H2ꢀH1)=2 Hz), 2.21 (H2%, ddd,
1H, 2J(H2%ꢀH2)=16.0 Hz, 3J(H2%ꢀH3)=7.5 Hz,
3J(H2%ꢀH1)=2Hz), 2.28–2.10 (H3, m, 1H), 1.55 (H4,
ddd, 2H, 2J(H4ꢀH4%)=14.0 Hz, 3J(H4ꢀH5)=7.5 Hz,
2
3J(H4ꢀH3)=6.5 Hz, 1.43 (H4%, ddd, 1H, J(H4%ꢀH4)=
14.0 Hz, 3J(H4%ꢀH5)=7.5 Hz, 3J(H4%ꢀH3)=6.5 Hz),
1,32 (CH3ꢀC, s, 3H), 1,27 (CH3ꢀC, s, 3H), 0.96
3
9.62 (H1, d, 1H, J(H1ꢀH2)=2 Hz), 4.15–4.10 (H6, m,
3
(CH3ꢀCH3, d, 3H, J(CH3ꢀCH3)=6.5 Hz). 13C-NMR
1H), 4.10–4.00 (H5, m, 1H), 3.63 (H6%, m, 1H), 2.30
(H2, m, 1H), 2.00–1.45 (H3, H4, m, 4H), 1.40 (CH3ꢀC,
s, 3H), 1.35 (CH3ꢀC, s, 3H), 1.125 (CH3ꢀCH2, d, 3H,
3J(CH3ꢀCH2)=7 Hz). Anal. Calc. for C10H18O3: C%
64.49; H% 9.74. Found: C% 64.20; H% 9.58.
(62 MHz, CDCl3), l: C1 201.6; C(CH3)2 96.2; C5 73.9;
C6 69.7; C2, C4 50.6, 40.3; (CH3)2ꢀC 27.1, 25.8;
1
CH3ꢀCH 20.6. Second diastereomer (30%). H-NMR
3
(400 MHz, CDCl3), l: 9.87 (H1, t, 1H, J(H1ꢀH2)=1.5
Hz), 4.20–4.08 (H6, H5, m, 2H), 3.62–3.53 (H6%, m,
1H), 2.45 (H2, dd, 2H, 3J(H2ꢀH1)=1.5 Hz,
3J(H2ꢀH3)=7 Hz), 2.19–1.55 (H3, H4, m, 3H), 1.40
(CH3ꢀC, s, 3H), 1.30 (CH3ꢀC, s, 3H), 0.97 (CH3ꢀCH3,
4.4. General procedure for the preparation of acids 10
With silver nitrate: silver nitrate powder (3.954 g, 23
mmol) was added slowly at 5°C to a cold stirred
solution of sodium hydroxide (1.86 g, 46 mmol) in
distilled water (14 ml). After stirring for 10 min, alde-
hyde 9 (11.63 mmol) was added dropwise with a sy-
ringe. The mixture was stirred for 1 h and filtered. The
d,
3H,
3J(CH3ꢀCH3)=7Hz).
13C-NMR
(62
MHz,CDCl3), l: C1 201.55; C(CH3)2 108.9; C5 74.1; C6
69.8; C2, C4 50.6, 40.8; (CH3)2ꢀC 27.1, 25.6; CH3ꢀCH
20.2. Anal. Calc. for C10H18O3: C% 64.49; H% 9.74.
Found: C% 64.10; H% 9.52.

P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
215
2
filtrate was acidified to pH 3.75 with a saturated solu-
tion of oxalic acid. The aqueous solution was extracted
with ethyl acetate (3×25 ml), dried and concentrated.
The residue was purified by column chromatography
(SiO2, ethyl acetate).
3.58–3.47 (H6%, m, 1H), 2.46 (H2, dd, 1H, J(H2ꢀH2%)=
15Hz, 3J(H2ꢀH3)=6Hz), 2.22 (H2%, dd, 1H,
2J(H2%ꢀH2)=15 Hz, 3J(H2%ꢀH3)=7.5 Hz), 1.80–1.52
(H4, m, 2H), 1.41 (CH3ꢀC, s, 3H), 1.35 (CH3ꢀC, s, 3H),
1.02 (CH3ꢀCH3, d, 3H, 3J(CH3ꢀCH3=6.5 Hz). 13C-
NMR (62 MHz, CDCl3), l: C1 178,3; (CH3)2ꢀC 109.0;
C5 74.1; C6 69.6; C2, C4 41.6, 40.3; (CH3)2ꢀC 27.6, 26.3;
CH3ꢀCH3 20.7. Anal. Calc. for C10H18O4: C% 59.39;
H% 8.97. Found: C% 59.69; H% 8.39.
With potassium permanganate: KMnO4 (0.754g, 4.77
mmol) was added in small portions at 5°C to a stirred
and ice-cooled mixture of aldehydes 9 (5.8 mmol) and
KOH (0.512 g, 9.12 mmol) in H2O (20 ml). After the
completion of addition, the reaction mixture was stirred
at r.t. until all the permanganate was completely con-
sumed. The precipitated MnO2 was removed by filtra-
tion through celite and the solution was neutralized
with 1 M H2SO4 using phenolphthalein as indicator.
The total aqueous solution was evaporated to dryness
in vacuo. After addition of CH2Cl2, the inorganic salt
precipitated and was filtered; the filtrate was dried over
anhydrous magnesium sulfate. The potassium salt of 10
was obtained as a white pasty solid after vacuum
evaporation. This solid was dissolved in the mixture
CH2Cl2 (50 ml)/Et2O (30 ml). The addition of HCl (g)
in Et2O (6 ml) led to the acid 10 after centrifugation
and evaporation under vacuum. The crude acid was
purified by column chromatography (SiO2, ethyl
acetate).
4.4.3. 3-phenyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
noic acid 10c
Rf: 0.73 (EtOAc). IR: 3700–2400 (OH), 1750 (CꢁO),
1
1720 (CꢁO), 1384, 1377 (CH3). First diastereomer. H-
NMR (400 MHz, CDCl3), l: 9.00 (OH, s, 1H), 7.35–
7.15 (C6H5, m, 5H), 3.99 (H6, dd, 1H, J(H6ꢀH6%)=7.5
2
Hz, J(H5ꢀH6)=6 Hz), 3.90–3.70 (H5, m, 1H), 3.56
3
(H6%, dd with the appearance of
a triplet, 1H,
2J(H6%ꢀH6)=3J(H6%ꢀH5)=7.5 Hz), 3.14–3.05 (H3, m,
1H), 2.77–2.59 (H2, H2%, m, 2H), 2.08 (H4, ddd, 1H,
3
3
2J(H4ꢀH4%)=13 Hz, J(H4ꢀH3)=6 Hz, J(H4ꢀH5)=9
Hz), 1.83 (H4%, ddd, 1H, 2J(H4ꢀH4%)=13 Hz,
3J(H4%ꢀH3)=6 Hz, J(H4%ꢀH5)=9 Hz), 1.38 (CH3, s,
3
3H), 1.26 (CH3, s, 3H). 13C-NMR (62 MHz, CDCl3), l:
C1 177.0; C6H5 142.6, 128.5, 128.4, 127.0; (CH3)2ꢀC
108.6; C5 73.4; C6 68.8; C2, C4 40.8, 39.5; C3 38.4;
(CH3)2ꢀC 26.6, 25.4. Second diastereomer. 1H-NMR
(400 MHz, CDCl3), l: 9.00 (OH, s, 1H), 7.35–7.15
4.4.1. 4-(2,2-dimethyl-1,3-dioxolan-4-yl) butanoic acid
10a
Rf: 0.73 (EtOAc). IR: 3700–2400 (OH), 1750 (CꢁO),
(C6H5, m, 5H), 4.10 (H6, dd, 1H, J(H6ꢀH6%)=7.5 Hz,
2
1
1720 (CꢁO), 1384, 1377 (CH3). H-NMR (400 MHz,
3J(H5ꢀH6)=6 Hz, 1H), 3.90–3.70 (H5, m, 1H), 3.68
CDCl3), l: 9.5 (OH, s, 1H), 4.14–4.03 (H6, H5, m, 2H),
3.55–3.49 (H6%, dd with the appearance of a triplet, 1H,
2J(H6%ꢀH6)=3J(H6%ꢀH5)=7.0 Hz, 1H), 2.41 (H2, t, 2H,
3J(H2ꢀH3)=7 Hz), 1.80 −1.50 (H3, H4, m, 4H), 1.41
(CH3, s, 3H), 1.36 (CH3, s, 3H). 13C-NMR (62 MHz,
CDCl3), l: C1 178.8; (CH3)2C 108.5; C5 75.6; C6 69.1;
C2, C4 33.7, 32.7; (CH3)2C 26.8, 25.5; C3 20.9. Anal.
Calc. for C9H16O4: C% 57.43; H% 8.57. Found: C%
57.61; H% 8.39.
(H6%, dd, 1H, J(H6%ꢀH6)=7.5 Hz, J(H6%ꢀH5)=6 Hz),
3.37–3.30 (H3, m, 1H), 2.77–2.59 (H2, H2%, m, 2H), 1.91
(H4, ddd, 1H, 2J(H4ꢀH4%)=13.5 Hz, 3J(H4ꢀH5)=
8.5 Hz, 3J(H4ꢀH3)=5 Hz), 1.82 (H4%, ddd, 1H,
2J(H4%ꢀH4)=13.5 Hz, 3J(H4%ꢀH5)=8.5 Hz, 3J(H4%ꢀ
H3)=5 Hz), 1.38 (CH3, s, 3H), 1.26 (CH3, s, 3H).
13C-NMR (62 MHz, CDCl3), l: C1 177.2; C6H5 142.8,
128.4, 127.3, 126.7; (CH3)2ꢀC 108.5; C5 74.0; C6 69.1;
C2, C4 41.2, 40.2; C3 38.9; (CH3)2ꢀC 26.8, 25.4. Anal.
Calc. for C15H20O4: C% 68.16; H% 7.63. Found: C%
68.34; H% 7.52.
2
3
4.4.2. 3-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
noic acid 10b
Rf: 0.74 (EtOAc). IR: 3700–2300 (OH), 1740 (CꢁO),
1720 (CꢁO), 1384, 1377 (CH3). First diastereomer
(64%). 1H-NMR (400 MHz, CDCl3), l: 8.06–9.26
(OH, s, 1H), 4.23–4.14 (H6, m, 1H), 4.11–4.03 (H5, m,
1H), 3.58–3.47 (H6%, m, 1H), 2.43 (H2, dd, 1H,
4.4.4. 2-methyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)buta-
noic acid 10d
Rf: 0.73 (EtOAc). IR: 3750–2400 (OH), 1740 (CꢁO),
1
1725 (CꢁO), 1384, 1377 (CH3). First diastereomer. H-
3
2J(H2ꢀH2%)=15 Hz, J(H2ꢀH3)=6 Hz), 2.24 (H2%, dd,
NMR (400 MHz, CDCl3), l: 9.50 (OH, s, 1H), 4.15–
4.00 (H6, H5, m, 2H), 3.55–3.48 (H6%, m, 1H),
2.55–2.40(H2, m, 1H), 1.92–1.53 (H3, H4, m, 4H), 1.40
(CH3ꢀC, s, 3H), 1.34 (CH3ꢀC, s, 3H), 1.20 (CH3ꢀCH2,
d, 3H, 3J(CH3ꢀCH2)=7 Hz). 13C-NMR (62 MHz,
CDCl3), l: C1 181.70; (CH3)2ꢀC 108.78; C5 75.65; C6
69.1; C2 39.3; C4 36.75; (CH3)2ꢀC 31.2, 29.7; CH3ꢀCH2
26.8. Second diastereomer. 1H-NMR (400 MHz,
CDCl3), l: 9.50 (OH, s, 1H), 4.15–4.00 (H6, H5, m,
1H, 2J(H2%ꢀH2)=15 Hz, 3J(H2%ꢀH3)=7.5 Hz), 1.70–
1.52 (H4, m, 2H), 1.41 (CH3–C, s, 3H), 1.36 (CH3ꢀC, s,
3
3H), 1.05 (CH3ꢀCH3, d, 3H, J(CH3ꢀCH3=6.5 Hz).
13C-NMR (62 MHz, CDCl3), l: C1 178.2; (CH3)2ꢀC
108.8; C5 74.0; C6 69.5; C2, C4 41.0, 39.9; (CH3)2ꢀC
26.9, 26.3; CH3ꢀCH3 21.0. Second diastereomer (36%).
1H-NMR (400 MHz, CDCl3), l: 8.06–9.26 (OH, s,
1H), 4.23–4.14 (H6, m, 1H), 4.11–4.03 (H5, m, 1H),

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P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
2H), 3.55–3.48 (H6%, m, 1H), 2.70–2.55(H2, m, 1H),
1.92–1.53 (H3, H4, m, 4H), 1.40 (CH3ꢀC, s, 3H), 1.34
(CH3ꢀC s, 3H), 1.19 (CH3ꢀCH2, d, 3H, 3J(CH3ꢀ
CH2)=7 Hz). 13C-NMR (62 MHz, CDCl3), l: C1
181.73; (CH3)2ꢀC 108.80; C5 75.59; C6 69.2; C2 39.0; C4
36.68; (CH3)2ꢀC 30.9, 29.3; CH3ꢀCH2 25.6. Anal. Calc.
for C10H18O4: C% 59.39; H% 8.97. Found: C% 59.54;
H% 9.22.
Hz), 3.69 (H6%, dd, 1H, 2J(H6%ꢀH6)=12.5 Hz,
3J(H6%ꢀH5)=5 Hz), 3.46–3.34 (H3, m, 1H), 2.77 (H2,
H2%, dd, 2H, 2J(H2%ꢀH2)=17.5 Hz, 3J(H2,2%ꢀH3)=5.5
Hz), 2.23 (H4, ddd, 1H, 2J(H4%ꢀH4)=14.0 Hz,
3
3J(H4ꢀH3)=8.5 Hz, J(H4ꢀH5)=6Hz), 2.12–1.90 (H4%,
m, 1H). 13C-NMR (62 MHz, CDCl3), l: C1 171.9; C6H5
142.5, 128.8, 127.0, 126.5; C5 77.9, C6 64.2; C2 36.9; C3
34.4; C4 30.9. Second diastereomer (40%). 1H-NMR
(400 MHz, CDCl3), l: 7.38–7.10 (C6H5, m, 5H), 4.58–
2
4.5. General procedure for the preparation of hydroxy-
methyl l-6alerolactones 1
4.50 (H5, m, 1H), 3.85 (H6, dd, 1H, J(H6ꢀH6%)=12.5
Hz, 3J(H6ꢀH5)=3.0 Hz), 3.69 (H6%, dd, 1H,
2J(H6%ꢀH6)=12.5 Hz, 3J(H6%ꢀH5)=5 Hz), 3.26–3.15
2
Activated 4 A molecular sieves (120 mg), Amberlyst
(H3, m, 1H), 2.90 (H2, dd, 1H, J(H2%ꢀH2)=17.5 Hz,
,
15 H+ resin (120 mg) were added to a solution of acid
10 (100 mg) in acetonitrile (10 ml). The mixture was
stirred vigorously at room temperature. The reaction
was monitored by TLC. The mixture was then filtered
and evaporated under reduced pressure. The residue
was chromatographed on silica gel (eluting with
AcOEt) to give the pure lactone.
3J(H2ꢀH3)=5.5 Hz), 2.55 (H2%, dd, 1H, J(H2%ꢀH2)=
2
3
17.5 Hz, J(H2%ꢀH3)=5.5 Hz), 2.12–1.90 (H4%, m, 2H).
13C-NMR (62 MHz, CDCl3), l: C1 171.1; C6H5 142.4,
128.8, 127.1, 126.3; C5 81.0, C6 64.4; C2 37.4; C3 35.6;
C4 31.4. MS m/z 206 (M+). Anal. Calc. for C12H14O3:
C% 69.89; H% 6.84. Found: C% 70.08; H% 6.7.
4.5.4. 5ꢀHydroxymethyl-2-methyl-l-6alerolactone 1d
Rf: 0.33 (EtOAc). IR: 3416 (OH), 1727 (CꢁO). First
4.5.1. 5ꢀHydroxymethyl-l-6alerolactone 1a
1
diastereomer (60%): H (400 MHz, CDCl3), l: 4.48–
1
Rf: 0.29 (EtOAc). IR: 3445 (OH), 1720 (CꢁO). H-
2
4.39 (H5, m, 1H), 3.69 (H6, dd, 1H, J(H6ꢀH6%)=14Hz,
NMR (400 MHz, CDCl3), l: 4.50–4.35 (H5, m, 1H),
3.85–3.60 (H6, m, 2H), 3.20 (OH, s, 1H), 2.70–2.35
(H2, m, 2H), 2.05–1.60 (H4, H3, m, 4H). MS m/z 130
(M+). Anal. Calc. for C6H10O3: C% 55.37; H% 7.74.
Found: C% 55.85; H% 8.02 (see Ref. [2a, 5]).
2
3J(H6ꢀH5)=6 Hz), 3.65 (H6%, dd, 1H, J(H6ꢀH6%)=14
3
Hz, J(H6ꢀH5)=6 Hz), 2.68–2.57 (H2, m, 1H), 2.15–
1.50 (H3, H4, m, 4H), 1.31 (CH3ꢀ, d, 3H,
1
3J(CH3ꢀCH2)=7 Hz). Second diastereomer (40%). H-
NMR (400 MHz, CDCl3), l: 4.48–4.39 (H5, m, 1H),
3.79 (H6, dd, 1H, 2J(H6ꢀH6%)=8Hz, 3J(H6ꢀH5)=
3.5Hz), 3.77 (H6%, dd, 1H, 2J(H6ꢀH6%)=8Hz,
3J(H6ꢀH5)= = 3.5 Hz), 2.68–2.57 (H2, m, 1H), 2.15–
1.50 (H3, H4, m, 4H), 1.27 (CH3ꢀ, d, 3H,
3J(CH3ꢀCH2)=7 Hz). MS m/z 144 (M+). Anal. Calc.
for C7H12O3: C% 58.32; H% 8.39. Found: C% 58.11;
H% 8.48.
4.5.2. 5ꢀHydroxymethyl-3-methyl-l-6alerolactone 1b
Rf: 0.32 (EtOAc). IR: 3400 (OH), 1730 (CꢁO). First
1
diastereomer (60%). H-NMR (400 MHz, CDCl3), l:
2
4.50–4.40 (H5, m, 1H), 3.85 (H6, dd, 1H, J(H6ꢀH6%)=
13 Hz, 3J(H6ꢀH5)=3 Hz), 3.62 (H6%, dd, 1H,
2J(H6%ꢀH6)=13 Hz, 3J(H6%ꢀH5)=3 Hz), 3.30–2.90
(OH, s, 1H), 2.78–2.70 (H2, m, 1H), 2.52 (H2%, dd,1H,
2J(H2%ꢀH2)=15 Hz, 3J(H2%ꢀH3)=5 Hz), 2.20–1.45 (H3,
H4, m, 3H), 1.05 (CH3, d, 3H, 3J(CH3ꢀ CH3)=6.5 Hz).
13C-NMR (62 MHz, CDCl3), l: C1 172.2; C5 77.8; C6
64.8; C2 37.5; C3 30.7; C4 24.0; CH3ꢀCH3 21.05. Second
4.6. Typical procedure for the preparation of 5-formyl-
l-6alerolactone 2
,
Freshly activated 4 A molecular sieves (800 mg) and
1
diastereomer (40%). H-NMR (400 MHz, CDCl3), l:
anhydrous PDC (1.808 g) were added slowly to a
solution of lactone 1 (100 mg) in methylene chloride (5
ml) at 23°C. The mixture was stirred vigorously at
room temperature. The reaction was followed by TLC.
The mixture was then dissolved in Et2O, filtered under
nitrogen and concentrated to give the crude lactone 2.
Due to its inherent instability and difficulties in purifi-
cation, the crude lactone 2 has to be used immediately
[5].
2
4.57–4.50 (H5, m, 1H), 3.80 (H6, dd, 1H, J(H6ꢀH6%)=
13 Hz, 3J(H6ꢀH5)=3 Hz), 3.58 (H6%, dd, 1H,
2J(H6%ꢀH6)=13 Hz, 3J(H6%ꢀH5)=3 Hz), 3.30–2.90
(OH, s, 1H), 2.80–2.40 (H2, H2%, m, 2H), 2.20–1.45 (H3,
3
H4, m, 3H), 0.99 (CH3, d, 3H, J(CH3ꢀH3)=6.5 Hz).
13C-NMR (62 MHz, CDCl3), l: C1 171.2, C5 81.1, C6
64.8; C2 38.2 C3 32.4 C4 26.4 CH3− CH3 21.5. MS m/z
144 (M+). Anal. Calc. for C7H12O3: C% 58.32; H%
8.39. Found: C% 57.90; H% 8.15.
4.6.1. 5-formyl-l-6alerolactone 2a
1
4.5.3. 5ꢀHydroxymethyl-3-phenyl-l-6alerolactone 1c
Rf: 0.38 (EtOAc). IR: 3416 (OH), 1729 (CꢁO). First
IR (neat) cm−1: 1729 (CꢁO). H-NMR (250 MHz,
CDCl3), l: 9.70 (H6, s, 1H), 5.20–4.80 (H5, m, 1H),
2.70–2.20 (H2, m, 2H), 2.00–1.50 (H3, H4, m, 4H).
13C-NMR (CDCl3, 62 MHz): l: C6 190.3; C1 170.6; C5
80.2; C2 32.6; C3 29.6; C4 23.7
1
diastereomer (60%). H-NMR (400 MHz, CDCl3), l:
7.38–7.10 (C6H5, m, 5H) 4.50–4.43 (H5, m, 1H), 3.78
(H6, dd, 1H, 2J(H6ꢀH6%)=12.5 Hz, 3J(H6ꢀH5)=3.5

P. Coutrot et al. / Journal of Organometallic Chemistry 586 (1999) 208–217
217
4.6.2. 5-formyl-3-methyl-l-6alerolactone 2b
References
IR (neat) cm−1: 1728 (CꢁO), 1718 (CꢁO). First
1
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Tetrahedron Lett. 35 (1994) 115.
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9.72 (H6, s, 1H), 4.88 (H5, dd with the appearance of a
3
triplet, 1H, J(H5ꢀH4)=3J(H5ꢀH4%)=5.5Hz, 2.75–2.45
(H2,H2%, m, 2H), 2.20–1.40 (H4, H4%, H3, m, 3H), 1.00
3
(CH3ꢀ, d, 3H, J(CH3ꢀCH3%)=6.0Hz). 13C-NMR (62
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(1983) 4883. (b) D.B. Gerth, B.J. Giese, J. Org. Chem. 51
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4750.
MHz, CDCl3), l: C6 198.4; C1 169.3; C5 81.1; C2 37.7;
C3 29.6; C2 23.8; CH3ꢀ20.7. Second diastereomer (28%),
1H-NMR (250 MHz, CDCl3), l: 9.60 (H6, s, 1H), 5.07
3
3
(H5, dd, 1H, J(H5ꢀH4)=2.5 Hz, J(H5ꢀH4%)=5.5 Hz),
0.95 (CH3ꢀ, d, 3H, J(CH3ꢀCH3%)=6.0 Hz). 13C-NMR
3
(62 MHz, CDCl3), l: C6 197.5, C1 170.1, C5 82.3, C2
37.6, C3 29.4, C4 23.5, CH3ꢀ 21.0.
4.6.3. 5-formyl-3-phenyl-l-6alerolactone 2c
IR (neat) cm−1: 1735 (CꢁO), 1725 (CꢁO). First
1
diastereomer (71%). H-NMR (250 MHz, CDCl3), l:
9.75 (H6, s, 1H), 7.35–7.05 (C6H5, m, 5H), 5.10–4.50
(H5, m, 1H), 3.30–3.05 (H3, m, 1H), 2.95–2.50 (H2, H2%,
m, 2H), 2.50–1.75 (H4, H4%, m, 2H). 13C-NMR (62
MHz, CDCl3), l: 197.8, 172.4. Second diastereomer
(29%). 1H-NMR (250 MHz, CDCl3): l: 9.65 (H6, s,
1H). 13C-NMR (62 MHz, CDCl3), l: 197.0, 172.1.
4.6.4. 5-formyl-2-methyl-l-6alerolactone 2d
IR (neat) cm−1: 1730 (CꢁO), 1725 (CꢁO). First
1
diastereomer (65%). H-NMR (250 MHz, CDCl3), l:
9.75 (H6, s, 1H), 5.02–4.80 (H5, m, 1H), 2.70–2.52 (H2,
m, 1H), 2.20–1.40 (H3, H4, m, 4H), 1.28 (CH3ꢀ, d, 3H,
3J(CH3ꢀCH2)=6.5Hz). 13C-NMR (62 MHz, CDCl3),
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165.
1
l: 198.6, 172.5. Second diastereomer (35%). H-NMR
(250 MHz, CDCl3), l: 9.70 (H6, s, 1H), 1.25 (CH3ꢀ, d,
3H, 3J(CH3ꢀCH2)=6.5Hz). 13C-NMR (62 MHz,
CDCl3), l: 197.4, 171.2.
[12] R.R. Schmidt, U. Moering, M. Reichrath, Chem. Ber. 115
(1982) 39.
.
.