Preparation of enantiopure 3,5,5-trialkyl-γ-butyrolactones by diastereospecific 5-endo halo lactonizations

Article abstract of DOI:10.1016/j.tetasy.2007.05.028

A new preparation of 3,5,5-trialkyl-γ-butyrolactones of defined absolute configuration is reported. This method involves the diastereoselective alkylation of 3,4-ethylenic acids after incorporation of a chiral Evans auxiliary, and then after separation of

Full text of DOI:10.1016/j.tetasy.2007.05.028

Tetrahedron: Asymmetry 18 (2007) 1434–1442
Preparation of enantiopure 3,5,5-trialkyl-c-butyrolactones by
diastereospecific 5-endo halo lactonizations
a
a
b
a,
*
´
´
Jean-Marc Garnier, Sylvie Robin, Regis Guillot and Gerard Rousseau
a
`
´
Laboratoire de Synthese Organique et Methodologie, ICMMO, Univ Paris-Sud, F-91405 Orsay, France
bICMMO, Univ Paris-Sud, F-91405 Orsay, France
Received 3 May 2007; accepted 23 May 2007
Available online 27 June 2007
Abstract—A new preparation of 3,5,5-trialkyl-c-butyrolactones of defined absolute configuration is reported. This method involves the
diastereoselective alkylation of 3,4-ethylenic acids after incorporation of a chiral Evans auxiliary, and then after separation of the two
diastereomers and hydrolysis of the auxiliary, stereospecific halo lactonizations. This method was applied to the preparation of a natural
product, present in a sponge.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The formation of c-butyrolactones by 5-endo halo lacton-
izations has been the subject of numerous reports since
the pioneering work of Fittig.1 The diastereoselectivity of
these reactions has also been studied for the preparation
of 3,4,5-trisubtituted-c-butyrolactones.2 We started a new
program concerning the synthesis of optically active c-
butyrolactones by 5-endo halo lactonizations. With this
objective, we recently found that such an aim could be
reached by enantioselective halo lactonizations using chiral
halo reagents.3 Herein we report our results concerning the
formation of enantiomerically pure 3,5,5-trialkyl-c-butyro-
lactones by diastereospecific halo lactonizations. Access to
such enantiomerically enriched or pure c-butyrolactones, is
rather rare,4 but shows the interest to find new methods to
synthesize this interesting family of compounds.
The approach we decided to examine involved the diaste-
reospecific lactonization of enantiopure 2-substituted 3,4-
ethylenic acids, using Evans methodology (Scheme 1).5
We first examined this methodology starting from (E)-4-
phenylpent-3-enoic acid 1 (Scheme 1).6 The corresponding
oxazolidinone 2 was prepared using a standard procedure
by reaction of the mixed anhydride obtained by reaction
of the acid with pivaloyl chloride, with the anion formed
from (R)-phenyloxazolidinone. The subsequent methyl-
ation of compound 2 led to a mixture (60:40) of the two
diastereomers 3a and 3b (Scheme 2). After separation of
these diastereomers by liquid chromatography over silica
gel, the (R)-stereochemistry of the major isomer 3a was
established from its NMR spectra, and secured by X-ray
crystallography. After hydrolysis of its chiral auxiliary,
R4
N
R4
O
R3
R3
R3
R1
R2
R1
R2
R1
R2
R1
O
O
O
OH
OH
N
R2
R2
X
O
O
O
O
O
O
R1
X = Br, I
Scheme 1.
*
Corresponding author. Tel.: +33 0 169157860; fax: +33 0 169156278; e-mail: grousseau@icmo.u-psud.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.028

J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
1435
Ph
O
Ph
Me
Me
Ph
Me
Ph
a
Me
Ph
Me
O
Me
Ph
a
O
OH
N
N
OH
O
O
O
O
O
1
2
3b
4b
Ph
Me
b
Me
Ph
O
O
N
Me
b
O
O
O
3a,b
Ph
I
Me
Ph
Me
Me
Ph
Me
Me
Ph
c
O
6b
N
OH
Scheme 3. (a) LiOH, H2O2, THF, H2O (62%); (b) I+(coll)2 PF6ꢀ, DCM
O
O
O
(91%).
3a
4a
Ph
b
a
Ph
Me
O
Ph
Me
O
OH
1
Me
N
N
d
O
O
O
O
Ph
X
7
8
Me
X = Br: 5a
X = I: 6a
Ph
Me
c
Ph
Me
O
O
Scheme 2. (a) (i) PivCl, Et3N, THF, 0 ꢁC; (ii) (R)-phenyl-oxazolidinone,
nBuLi, THF, ꢀ78 ꢁC to rt (85%); (b) LDA, HMPA, THF, ꢀ78 ꢁC then
MeI, THF, ꢀ78 ꢁC (60%: dr: 60:40); (c) LiOH, H2O2, THF, H2O (90%);
O
9a,b
(d) X+(coll)2 PF ꢀ, DCM (X = I; 93%. X = Br; 70%).
6
Ph
Me
Ph
Me
Me
Ph
Me
d
O
the corresponding enantiomerically pure acid (R)-4a was
submitted to halo lactonizations in dichloromethane using
halo(bis-collidine) hexafluorophosphate, to give the desired
halo lactones 5a and 6a. With both the bromo and iodo re-
agents, only one diastereomer was isolated.
N
OH
O
O
O
9a
10a
O
The structure of halo lactones 5a and 6a was established
from their spectral data. The structure of iodo lactone 6a
was also secured by X-ray crystallography. The configura-
tion of these lactones was found to be (3S,4R,5S). Simi-
larly, the hydrolysis of the minor diastereomer (S)-3b led
to the corresponding acid (S)-4b, which upon iodo lacton-
ization allowed the preparation of lactone 6b of
(3R,4S,5R)-configuration (Scheme 3). The comparable
absolute values measured for the [a]D of iodo lactones 6a
and 6b show that these two lactones are the two enantio-
mers of the same diastereomer.
Me
e
O
Me
I
Ph
11a
Scheme 4. (a) hm, heptane, rt (70%); (b) (i) PivCl, Et3N, THF, 0 ꢁC; (ii)
(R)-phenyl-oxazolidinone, nBuLi, THF, ꢀ78 ꢁC to rt (70%); (c) LDA,
HMPA, THF, ꢀ78 ꢁC then MeI, THF, ꢀ78 ꢁC (33%: dr: 70:30); (d)
LiOH, H2O2, THF, H2O (85%); (e) I+(coll)2 PF ꢀ, DCM (89%).
6
We next examined, the preparation of the diastereomer of
iodo lactone 6a. This preparation was initially started from
(Z)-4-phenyl-3-pentenoic acid. This acid was obtained by
photochemical isomerization of its (E)-isomer.3 The subse-
quent formation of the enantiomerically pure acid (R)-10a
was then accomplished by the same procedure reported for
the preparation of lactones 5a and 6a (Scheme 4). The
preparation of iodo lactone 11a was then carried out from
(R)-acid 10a using iodo(bis-collidine) hexafluorophosphate
as an electrophile. In this case, only one lactone was iso-
lated: iodo lactone 11a of (3R,4S,5R)-configuration. The
reaction with the minor diastereomer should lead, in the
same way, to the enantiomer of lactone 11a. Having estab-
lished that this methodology allows the preparation of the
four diastereomers of 3,5,5-trialkyl c-butyrolactones, we
decided to examine its scope. Oxazolidinone 2 was thus
alkylated using various alkyl halides. These alkylations
were carried out in THF at ꢀ78 ꢁC, using LDA as base.
Our results are reported in Table 1.
This type of 3,4-unsaturated oxazolidinone was found to
be less reactive than the saturated ones.5 With the excep-

1436
J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
Table 1.
Entry
Alkylating agent
PhCH2Br
Oxazolidinone (yield; %; dr)
Acida
Halo lactone (yield; %)
Other product(s), (yield; %)
O
Ph
Ph
Ph
O
Ph
Me
Ph
Me
O
N
O
O
OH
a
Ph
X
Ph
Me
O
14 X = I (91%)
13
12 (70%; 88:12)
15 X = Br (80%)
O
O
Pr
Ph
O
Pr
Pr
Pr
Me
Ph
Me
Ph
O
O
N
Ph
OH
X
b
PrI
Me
Ph
Br
O
O
O
Me
18 X = I (92%)
17
20 (17%)
16 (36%; 77:23)
19 X = Br (67%)
O
O
Ph
O
Me
Ph
Me
Me
Ph
O
N
O
c
Br
OH
OH
Ph
Ph
I
O
I
O
O
Me
24 (54%; 45:55b)
22
21 (55%; 70:30)
23 (27%)
O
Ph
Me
Me
Me
Me
Me
Me
Me
O
O
N
d
MeI
Me
O
O
I
O
Me
26
25 (60%; 80:20)
27 (76%)
a Major diastereomer isolated after separation of the two diastereoisomeric oxazolidinones and hydrolysis.
b Proportion of the two diastereomers.
tion of benzyl bromine (entry a), for which we observed a
good yield in the alkylation of ozaxolidinone 2, with other
alkylating agents moderate yields were obtained (entries b–
d). However, only products corresponding to the alkyl-
ation at the 2-position were isolated. After separation of
the two diastereomers, cyclization of the major diastereo-
mer of the acids, obtained by hydrolysis of the correspond-
ing oxazolidinones, led to the halo lactones in high yields.
With iodo(bis-collidine) hexafluorophosphate, the cycliza-
tions were always diastereospecific. With the bromo re-
agent, as in the case of acid 17, a mixture of the two
diastereomers was isolated (entry b). In the case of acid
22 issued from the major diastereomer of oxazolidinone
21, a competition between the 5-endo and the 5-exo iodo
lactonizations was observed. It is interesting to note that
the 5-exo lactonization was not diastereospecific, since a
mixture of the two diastereomers 24 was isolated. This
result shows than when the stereogenic center is at the
b-position of the carbon–carbon double bond, approach
of the iodo reagent is not stereochemically controlled.
The same diastereospecific 5-endo iodo lactonization was
observed for the iodo lactonization of (R)-2,4-dimethyl-
pent-3-enoic acid 26 (entry d). This result shows that this
methodology can be also used for the formation of enantio-
pure lactones in which the two substituents in 4-position
are two alkyl groups. A stereospecific preparation of
such 3,4-unsaturated carboxylic esters has recently been
reported.7
The low reactivity of the anion formed from oxazolidinone
2 was confirmed by the fact that the desired alkylations
were not observed with ClSiPh2Me, PhSeCH2Br, Me3Si-
CH2I, HCO2Et, CO2, trioxane or CH2ClI.
3. Application
Two c-lactones possessing a dialkylated carbon at the 4-
position have recently been isolated from the dark brown
sponge Plakortis nigra.8 The absolute configurations of
these lactones were not assigned. We decided to apply
our methodology to the synthesis of one of these com-
pounds (compound 33 in Scheme 5). The first steps of this
synthesis involve the dehalogenation of lactone 5a or 6a
followed by oxidative degradation of the phenyl group
(Scheme 5). The next reaction involves the preparation of
aldehyde 31, which was obtained after reduction of acid
29 into alcohol 30 using borane, followed by Dess–Martin
oxidation. The carbon chain was then introduced by a Wit-
tig reaction, and the desired lactone was obtained by
hydrogenation over palladium. The yields corresponding
to the preparation of compounds 32 and 33 have not been
optimized. The spectra of lactone 33 are in agreement
with those reported for the natural product.8 The rota-
tory power found for this compound was [a]D = ꢀ8.5
(c 0.2, MeOH), comparable to the [a]D = ꢀ7.1 (c
0.13, MeOH) reported.8 This negative value allows us to

J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
1437
O
warmed at 0 ꢁC for 45 min, and cooled again at ꢀ78 ꢁC.
This cold solution was cannulated to a second flask, cooled
at the same temperature, and containing the lithium salt
(R)-4-phenyloxazolidin-2-one in THF (5 mL), which was
prepared by dropwise addition of butyl lithium (1.78 mL
of a 1.6 M solution in hexane, 2.84 mmol) to oxazolidine
(0.463 g, 2.84 mmol). After 20 min at ꢀ78 ꢁC, the flask
was warmed at room temperature. After 2 h, an ammo-
nium chloride solution (20 mL) was added, and the sol-
vents removed under vacuum. The residue was then
purified by liquid chromatography (pentane/diethyl ether:
O
O
Me
Me
Me
a
b
O
O
O
Ph
X
Ph
HO2C
Me
Me
Me
5a or 6a
28
29
O
O
Me
c
e
d
Me
O
O
HOH2C
OHC
Me
Me
31
80–20), to give compound 2 (0.463 g, 85%) as a solid
20
(mp: 105 ꢁC), ½aꢁD ¼ ꢀ85:9 (c 1.6, CH2Cl2). 1H NMR
30
(CDCl3, 360 MHz) d (ppm): 7.38–7.22 (m, 10H), 5.98 (t,
J = 6.8 Hz, 1H), 5.45 (dd, J = 8.6 and 4.0 Hz, 1H), 4.71
(dd, J = 8.6 Hz and 8.6 Hz, 1H), 4.30 (dd, J = 9.0 and
3.6 Hz, 1H), 3.88 (d, J = 6.8 Hz, 1H), 2.04 (s, 3H). 13C
NMR (CDCl3, 90 MHz) d (ppm): 169.9, 153.2, 142.4,
138.8, 138.0, 128.6, 128.0, 127.7, 126.6, 125.4, 125.2,
118.1, 69.5, 57.0, 35.2, 15.9. IR (film) m (cmꢀ1): 3056,
2985, 2920, 2360, 2340, 1782, 1708. ES MS: 344.1
(M+Na). ES HRMS (M+Na) for C20H19O3NNa:
344.1263. Found: 344.1281.
O
O
Me
Me
O
f
O
Ph ( )10
Ph
( )11
Me
Me
33
32
Scheme 5. (a) Bu3SnH, AIBN, benzene (92% from 6a; 87% from 5a); (b)
RuCl3, NaIO4, CCl4–MeCN–H2O, 70 ꢁC, 3 h; (c) BH3–THF, 16 h, 0 ꢁC
(56% from 28; E/Z: 77–23); (d) Dess–Martin periodinane, DCM, 1 h, rt;
ꢀ
þ
(e) PhðCH2Þ11PPh3 Br , THF, n-BuLi, 15 h, ꢀ78 ꢁC to rt (53%; E/Z: 77–
23); (f) H2, AcOEt, Pd(OH)2 (31%).
5.2. (R)-3-((E)-2-Methyl-4-phenylpent-3-enoyl)-4-phenyl-
oxa-zolidin-2-one 3a and 3b
To diisopropylamine (0.270 mL, 1.925 mmol) in THF
(4.5 mL) was added at 0 ꢁC butyl lithium (0.456 mL of a
1.6 M solution in hexane, 1.95 mmol) and HMPA
(0.45 mL). After stirring for 30 min at 0 ꢁC, the solution
was cooled to ꢀ78 ꢁC and a THF solution (4 mL) of oxa-
zolidinone 2 (0.515 g, 1.61 mmol) was added. After 1 h at
this temperature, methyl iodide (0.30 mL, 4.83 mmol) was
added, and after 30 min of stirring, the solution was
warmed at ꢀ40 ꢁC. After 1 h at this temperature, the solu-
tion was warmed at ꢀ10 ꢁC, and a saturated solution of
ammonium chloride (10 mL) was added. The solvents were
removed under vacuum, and the aqueous phase extracted
with diethyl ether (3 · 5 mL). The combined organic phases
were washed successively with 0.5 M HCl (3 mL), H2O
(3 mL), and a saturated NaCl solution (3 mL). After drying
over MgSO4, the solvents were removed under vacuum and
the residue purified by liquid chromatography (pentane/
diethyl ether: 85–15) to give 0.195 mg of the major diaste-
reomer 3a (36%) and 0.130 mg of the minor diastereomer
3b (24%).
conclude that the natural product 33 has a (3R,5S)-abso-
lute configuration.
4. Conclusion
We have reported a methodology, which allows the pre-
paration of 3,5,5-trialkyl-c-butyrolactones of defined
absolute configuration. This method involves the diastereo-
selective alkylation of 3,4-ethylenic acids after incorpo-
ration of an Evan’s chiral auxiliary, followed after
separation of the two diastereomers and hydrolysis of the
auxiliary, and stereospecific halo lactonizations. This meth-
od was applied to the preparation of a natural product,
present in a sponge. The absolute configuration of this nat-
ural product was also established.
5. Experimental
(E)-4-Phenylpent-3-enoic acid 1,3,6 (R)-4-phenyloxazol-
idin-2-one,9 (Z)-4-phenylpent-3-enoic acid 7,3 iodo- and
bromo(bis-collidine) hexafluorophosphates10 have been
prepared as previously reported. Purification of com-
pounds has been carried out by column flash chromatogra-
phy on silica gel.
5.3. (R)-3-((R,E)-2-Methyl-4-phenylpent-3-enoyl)-4-phenyl-
oxazolidin-2-one 3a
20
White solid mp = 138 ꢁC, ½aꢁD ¼ ꢀ149:0 (c 0.96, CH2Cl2).
1H NMR (CDCl3, 360 MHz) d ppm: 7.41–7.23 (m, 10H),
5,88 (d, J = 9.4 Hz, 1H), 5.43 (dd, J = 8.6 and 3.6 Hz,
1H), 4.90 (m, 1H), 4.68 (dd, J = 9.0 Hz, J = 9.0 Hz, 1H),
4.27 (dd, J = 9.0 and 3.9 Hz, 1H), 2.12 (s, 3H), 1.27 (d,
J = 7.2 Hz, 3H). 13C NMR (CDCl3; 62.9 MHz) d ppm:
174.7, 153.2, 142.8, 139.0, 136.7, 129.0, 128.7, 128.5,
128.0, 126.9, 126.2, 125.6, 69.6, 57.6, 37.7, 18.3, 16.1. IR
(solution) m (cmꢀ1): 3054, 2987, 2305, 1781, 1705. MS
ES+: 358,2 (M+Na)+. ES HRMS (M+Na) calculated for
pour C21H21O3NNa: 358.1419. Found: 358.1424.
5.1. (R)-3-((E)-4-Phenylpent-3-enoyl)-4-phenyloxazolidin-
2-one 2
To acid 1 (0.50 g, 2.84 mmol) in solution in THF (45 mL)
cooled at ꢀ78 ꢁC was added successively NEt3 (0.478 mL,
3.41 mmol) and pivaloyl chloride (0.382 mL, 3.12 mmol).
This mixture was stirred 15 min at this temperature,

1438
J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
5.4. (4R)-3-((2S,3E)-2-Methyl-4-phenylpent-3-enoyl)-4-phen-
yl-1,3oxazolidine-2-one 3b
(CDCl3, 360 MHz) d ppm: 7.57–7.54 (m, 2H), 7.41–7.34
(m, 3H), 4.02 (d, J = 11.9 Hz, 1H), 2.96 (dq, J = 11.9 Hz,
J = 7.2 Hz, 1H), 1.96 (s, 3H), 1.36 (d, J = 7.2 Hz, 3H).
13C NMR (CDCl3; 62.9 MHz) d ppm: 174.2, 141.5, 128.4,
128.1, 124.1, 85.4, 45.4, 34.6, 26.6, 12.3. IR (CDCl3) m
cmꢀ1: 3155, 2984, 2937, 1774. MS ES+: 339.0 (M+Na)+.
An X-ray crystal structure of this iodo lactone has been
carried out.
1
Oil. H NMR (CDCl3, 360 MHz) d ppm: 7.38–7.23 (m,
5H), 5.96 (d, J = 6.8 Hz, 1H), 5.47 (dd, J = 9.0 and
4.7 Hz, 1H), 4.90 (m, 1H), 4.70 (dd, J = 8.7 Hz,
J = 8.7 Hz, 1H), 4.23 (dd, J = 8.7 and 4.3 Hz, 1H), 2.11
(s, 3H), 1.28 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
62.9 MHz) d ppm: 174.6, 153.2, 142.7, 138.7, 137.6,
128.9, 128.4, 127.9, 126.9, 126.1, 125.6, 69.5, 57.6, 38.1,
17.1, 16.1. IR (film) m (cmꢀ1): 3052, 2986, 2304, 1780,
1707. ES MS: 358.2 (M+Na)+. ES HRMS (M+Na) for
C21H21O3NNa: 358.1419. Found: 358.1418.
5.9. (3R,4S,5R)-4-Iodo-3,5-dimethyl-5-phenyldihydrofuran-
2(3H)-one 6b
This lactone was obtained using the method described for
20
the preparation of lactone 5a. ½aꢁD ¼ þ47:0 (c 0.95,
5.5. (R,E)-2-Methyl-4-phenylpent-3-enoic acid 4a
CH2Cl2). White solid: mp 100.5 ꢁC. Its spectra were identi-
cal to those of lactone 6a.
To ozaxolidinone 3a (0.190 g, 1 mmol) in solution in a mix-
ture of THF–H2O (10 mL, 3:1) was added dropwise 30%
hydrogen peroxide (0.364 mL, 6 mmol) and an aqueous
solution (2 mL) of lithium hydroxide (0.064 g, 2.5 mmol).
After 2 h at 0 ꢁC, a 1.3 M sodium sulfite solution (12 mL)
was added, and the solution was stirred 30 min at rt. The
organic phase was removed under vacuum, and the aque-
ous phase extracted with dichloromethane (3 · 20 mL),
and acidified (pH 1). The resulting aqueous phase was ex-
tracted with dichloromethane (3 · 20 mL). The combined
organic phases were dried over MgSO4, and concentrated
under vacuum. Acid 4a, isolated as a white solid (mp
81 ꢁC), was pure enough to be used without further purifi-
5.10. (R)-3-((Z)-4-Phenylpent-3-enoyl)-4-phenyloxazolidin-
2-one 8
This compound was obtained using the method reported
for the preparation of compound 2, as a yellow oil
20
1
(85%). ½aꢁD ¼ ꢀ30:7 (c 1.2, CH2Cl2). H NMR (CDCl3,
360 MHz) d (ppm): 7.37–7.19 (m, 8H), 7.11–7.09 (m, 2H),
5.61 (t, J = 7.2 Hz, 1H), 5.34 (dd, J = 8.6 and 3.6 Hz,
1H), 4.57 (dd, J = 9.0 Hz, J = 9.0 Hz, 1H), 4.16 (dd,
J = 9.0 and 3.6 Hz, 1H), 3.59 (m, 2H), 2.04 (s, 3H). 13C
NMR (CDCl3, 90 MHz) d (ppm): 170.8, 152.4, 142.9,
138.7, 135.0, 129.3, 128.8, 128.0, 127.1, 127.0, 125.7,
118.4, 66.0, 55.0, 37.6, 16.3. IR (film) m (cmꢀ1): 3057,
3034, 2973, 2916, 1780, 1705, 1600, 1575, 1493, 1456. MS
ES+: 344.1 (M+Na)+. ES HRMS (M+Na) calculated for
C20H19O3NNa: 344.1263. Found: 344.1262.
cation. Oxazolidinone 3a was quantitatively recovered in
20
the first dichloromethane phase. ½aꢁD ¼ ꢀ53:1 (c 1.15,
CH2Cl2). 1H NMR (CDCl3, 360 MHz) d (ppm): 7.40–
7.24 (m, 5H), 5.76 (d, J = 9.2 Hz, 1H), 3.54 (dq, J = 9.2
and 7.0 Hz, 1H), 1.82 (s, 3H), 1.36 (d, J = 7 Hz, 3H).
5.11. (R)-3-((R,Z)-2-Methyl-4-phenylpent-3-enoyl)-4-phen-
yl-oxazolidin-2-one 9a
5.6. (S,E)-2-Methyl-4-phenylpent-3-enoic acid 4b
20
White solid: mp 81 ꢁC, ½aꢁD ¼ þ54:0 (c 1.20, CH2Cl2).
This compound has been obtained using the method re-
ported for the preparation of compound 3a as a mixture
of two diastereomers (70:30), 33% yield. After liquid chro-
matography, the major diastereomer 9a was obtained in a
5.7. (3S,4R,5S)-4-Bromo-3,5-dimethyl-5-phenyldihydro-
furan-2(3H)-one 5a
20
1
pure form. Oil, ½aꢁD ¼ ꢀ100:3 (c 0.5, CH2Cl2). H NMR
(CDCl3, 360 MHz) d (ppm): 7.38–7.10 (m, 10H), 5.59 (d,
J = 9.0 Hz, 1H), 5.28 (dd, J = 8.7 and 3.6 Hz, 1H), 4.56
(dd, J = 8.7 Hz, J = 8.7 Hz, 1H), 4.46 (m, 1H), 4.17 (dd,
J = 8.7 and 3.6 Hz, 1H), 2.04 (s, 3H), 1.18 (d, J = 6.9 Hz,
3H). 13C NMR (CDCl3, 62.9 MHz) d ppm: 174.3, 152.4,
139.1, 138.8, 136.7, 129.0, 128.5, 127.9, 127.4, 125.7,
125.6, 125.5, 69.6, 57.5, 37.7, 25.8, 19.1. IR (film) m
(cmꢀ1), 3055, 2988, 1783, 1701. MS ES+: 358.1
(M+Na)+. ES HRMS (M+Na) calculated for C21H21O3N-
Na: 358.1419. Found: 358.1418.
To a dichloromethane solution (20 mL) of acid 3a (0.142 g,
0.748 mmol) was added bromo(I)(bis-collidine) hexafluoro-
phosphate (0.420 g, 0.822 mmol). After stirring for 2 h at
rt, the mixture was concentrated under vacuum, and the
residue purified by liquid chromatography (pentane/diethyl
ether: 90–10), to give 0.136 g of lactone 5a (68%). White
20
solid: mp = 76.2 ꢁC (CH2Cl2), ½aꢁD ¼ ꢀ25:4 (c 3, CH2Cl2).
1H NMR (CDCl3, 360 MHz) d ppm: 7.55–7.53 (m, 2H),
7.41–7.32 (m, 3H), 4.07 (d, J = 11.2 Hz, 1H), 3.01 (dq,
J = 11.2 and 6.8 Hz), 1.86 (s, 3H), 1.36 (d, J = 6.8 Hz,
3H). 13C NMR (CDCl3; 62.9 MHz) d ppm: 174.0, 142.1,
128.6, 128.3, 124.1, 86.1, 57.4, 44.3, 24.9, 12.5. IR (CDCl3)
m cmꢀ1: 3155, 3065, 2984, 2938, 1778.
5.12. (R,Z)-2-Methyl-4-phenylpent-3-enoic acid 10a
This acid was prepared using the procedure reported
20
1
5.8. (3S,4R,5S)-4-Iodo-3,5-dimethyl-5-phenyldihydrofuran-
2(3H)-one 6a
for acid 4a. Oil, ½aꢁD ¼ ꢀ252:8 (c 1.2, CH2Cl2). H NMR
(CDCl3, 360 MHz) d (ppm): 7.36–7.32 (m, 2H), 7.28–7.25
(m, 1H), 7.21–7.19 (m, 2H), 5.49 (d, J = 10.0 Hz, 1H),
3.20 (dq, J = 10.0 and 7.2 Hz, 1H), 2.05 (s, 3 H), 1.19 (d,
J = 7.2 Hz, 3H). 13C NMR (CDCl3, 90 MHz) d ppm:
181.6, 141.2, 139.3, 128.3, 127.7, 127.0, 125.4, 39.6, 25.8,
This iodo lactone was obtained using the protocol used for
the preparation of bromo lactone 5a (93%). White solid:
20
mp 100.5 ꢁC, ½aꢁD ¼ ꢀ45:9 (c 0.90, CH2Cl2). 1H NMR

J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
1439
18.3. IR (film) m (cmꢀ1): 3054, 2987, 1707, 1601, 1551, 1494,
(R)-3-((R,E)-4-phenyl-2-propylpent-3-enoyl)-4-phenylox-
1421.
azolidin-2-one 16a was isolated in a pure form. Oil,
20
½aꢁD ¼ ꢀ128:1 (c 0.99, CH2Cl2). 1H NMR (CDCl3,
5.13. (3S,4R,5R)-4-Iodo-3,5-dimethyl-5-phenyldihydro-
furan-2(3H)-one 11a
360 MHz) d (ppm): 7.39–7.19 (m, 10H), 5.80 (d,
J = 9.7 Hz, 1H), 5.41 (dd, J = 9.0 and 3.8 Hz, 1H), 4.94
(m, 1H), 4.64 (dd, J = 9.0 Hz, J = 9.0 Hz, 1H), 4.24 (dd,
J = 9.0 and 3.8 Hz, 1H), 2.12 (s, 3H), 1.75 (m, 2H), 1.46
(m, 2H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
90 MHz) d (ppm): 174.5, 153.3, 143.1, 139.2, 137.7, 129.1,
128.6, 128.1, 127.0, 125.8, 125.6, 117.9, 69.6, 57.8, 42.8,
35.7, 20.0, 16.6, 13.9. IR (film) m cmꢀ1: 2958, 2930, 2872,
1779, 1702. MS ES+: 386.1 (M+Na)+. ES HRMS
(M+Na) calculated for C23H25O3NNa: 386.1732. Found:
386.1739.
This lactone was obtained from acid 10a, using the proce-
dure reported for the preparation of lactone 5a.
20
½aꢁD ¼ ꢀ66:3 (c 0.9, CH2Cl2). White solid: mp 99 ꢁC
(CH2Cl2). 1H NMR (CDCl3, 360 MHz) d (ppm): 7.43-
7.32 (m, 5H), 4.16 (d, J = 12.6 Hz, 1H), 2.71 (dq,
J = 12.6 and 6.8 Hz, 1H), 1.89 (s, 3H), 1.33 (d,
J = 6.8 Hz, 3H). 13C NMR (CDCl3; 62.9 MHz) d ppm:
175.9, 139.4, 128.5, 127.9, 126.5, 86.5, 44.0, 35.2, 26.3,
12.4. IR (CDCl3) m cmꢀ1: 3054, 2986, 1781, 1600, 1551,
1498, 1438. Anal. Calcd for C12H13IO2: C, 45.59; H,
4.14. Found: C 45.45; H 4.15.
5.17. (R,E)-4-Phenyl-2-propylpent-3-enoic acid 17
This acid was obtained using the method used for the prep-
20
5.14. (R)-3-((E)-2-Benzyl-4-phenylpent-3-enoyl)-4-phenyl-
oxazolidin-2-one 12
aration of acid 4a. Oil, ½aꢁD ¼ ꢀ54:8 (c 1.98, CH2Cl2).
1H NMR (CDCl3, 250 MHz) d (ppm): 11.22 (br, 1H,
COOH), 7.41–7.21 (m, 5H), 5.73 (d, J = 9.8 Hz, 1H),
3.45 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.63 (m, 1H),
1.40 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3,
62.9 MHz) d (ppm): 181.0, 143.0, 137.9, 128.2, 127.1,
125.8, 125.3, 45.1, 35.0, 20.3, 16.4, 13.9. IR (film) m
(cmꢀ1): 3054, 2961, 2933, 2874, 1705. MS ES+: 457.2
2(MꢀH+Na)+. ES HRMS (M+Na) calculated for
C28H34O4Na: 457.2355. Found: 457.2352.
This compound has been obtained using the method re-
ported for the preparation of compound 3a as a mixture
of two diastereomers (88:12), 70% yield. Only the major
diastereomer 12a could be isolated in a pure form. White
20
solid: mp 140.1 ꢁC (CH2Cl2), ½aꢁD ¼ ꢀ196:8 (c 1.33,
CH2Cl2). 1H NMR (CDCl3, 360 MHz) d (ppm): 7.30–
7.03 (m, 15H), 5.82 (d, J = 9.7 Hz, 1H), 5.40 (dd, J = 8.6
and 3.6 Hz, 1H), 5.28 (ddd, J = 9.7, 7.9 and 6.8 Hz, 1H),
4.64 (dd, J = 8.6 Hz, J = 8.6Hz, 1H), 4.21 (dd, J = 8.6
and 3.6 Hz, 1H), 3.13 (dd, J = 12.9 and 6.8 Hz, 1H), 2.73
(dd, J = 13.0 and 7.9 Hz, 1H), 1.84 (s, 3H). 13C NMR
(CDCl3, 90 MHz) d (ppm): 173.5, 153.2, 142.9, 138.8,
138.7, 138.0, 129.4, 129.0, 128.2, 128.1, 128.0, 127.0,
126.2, 125.7, 125.5, 124.3, 69.5, 57.6, 44.8, 39.4, 16.2. IR
(film) m cmꢀ1: 3054, 2986, 2922, 2305, 1781, 1702. MS
ES+: 434.2 [M+Na]+. ES HRMS (M+Na) calculated for
C27H25O3NNa: 434.1732. Found: 434.1730.
5.18. (R)-3-(2-((E)-2-Phenylprop-1-enyl)pent-4-enoyl)-4-
phenyloxazolidin-2-one 21
The alkylation of compound 2 with allyl bromide was car-
ried using the method reported for the preparation of com-
pound 3. A mixture of two diastereomers (70:30) was
obtained (55% yield). Only the major diastereomer (R)-3-
((R)-2-((E)-2-phenylprop-1-enyl)pent-4-enoyl)-4-phenylox-
azolidin-2-one) 21a was isolated in a pure form as an oil,
20
½aꢁD ¼ ꢀ151:0 (c 1.1, CH2Cl2). 1H NMR (CDCl3,
5.15. (R,E)-2-Benzyl-4-phenylpent-3-enoic acid 13
250 MHz) d (ppm): 7.40–7.25 (m, 10H), 5.80 (d,
J = 9.8 Hz, 1H), 5.71 (m, 1H), 5.42 (dd, J = 8.8 and
3.8 Hz, 1H), 5.06 (m, 1H), 4.88 (m, 2H), 4.63 (dd,
J = 8.8 Hz, J = 8.8 Hz, 1H), 4.27 (dd, J = 8.8 and 3.7 Hz,
1H), 2.52 (m, 1H), 2.26 (m, 1H), 2.12 (s, 3H). 13C NMR
(CDCl3, 62.9 MHz) d ppm: 173.7, 153.3, 142.9, 139.0,
138.0, 134.2, 128.9, 128.6, 128.1, 127.0, 126.0, 125.7,
This acid was obtained using the method used for the prep-
aration of acid 4a. White solid: mp 81.2 ꢁC (CH2Cl2),
20
½aꢁD ¼ ꢀ154:1 (c 1.08, CH2Cl2). 1H NMR (CDCl3,
360 MHz) d (ppm): 11.50 (br, 1H, COOH), 7.31–7.17 (m,
10H), 5.75 (d, J = 9.7 Hz, 1H), 3.68 (ddd, J = 9.7, 7.9
and J = 6.5 Hz, 1H), 3.20 (dd, J = 13.3 Hz and 6.5 Hz,
1H), 2.87 (dd, J = 13.3 and 7.9 Hz, 1H), 1.82 (s, 3H). 13C
NMR (CDCl3, 90 MHz) d (ppm): 180.3, 142.9, 138.9,
138.4, 129.1, 128.3, 127.2, 126.5, 125.8, 124.0, 47.4, 38.7,
16.2. IR (CDCl3) m cmꢀ1: 3085, 3064, 3030, 2926, 2861,
1706. MS ES+: 553.2 2[(MꢀH)+Na]+. ES HRMS
(M+Na) calculated for C36H34O4Na: 553.2355. Found:
553.2379.
124.7, 117.4, 69.6, 57.8, 42.7, 37.7, 16.6. IR (film) m cmꢀ1
:
3054, 2987, 1780, 1702, 1602, 1551, 1494, 1421. MS ES+:
384.1 (M+Na)+. ES HRMS (M+Na) calculated for
C23H23O3NNa: 384.1576. Found: 384.1576.
5.19. (R)-2-((E)-2-Phenylprop-1-enyl)pent-4-enoic acid 22
This acid was obtained using the method used for the prep-
20
aration of acid 4a. Oil, ½aꢁD ¼ ꢀ80:2 (c 2.1, CH2Cl2).
5.16. (R)-3-((E)-4-Phenyl-2-propylpent-3-enoyl)-4-phenyl-
oxazolidin-2-one
1H NMR (CDCl3, 360 MHz) d (ppm): 10.95 (br, 1H,
COOH), 7.39–7.22 (m, 5H), 5.83 (m, 1H), 5.72 (d,
J = 11.2 Hz, 1H), 5.13 (dd, J = 17.0 and 1.2 Hz, 1H),
5.06 (dd, J = 10.0 and 1.2 Hz, 1H), 3.51 (m, 1H), 2.60
(ddd, J = 14.2 Hz, J = 7.1 Hz, J = 7.1 Hz, 1H), 2.40
(ddd, J = 14.1 Hz, J = 7.1 Hz, J = 7.1 Hz, 1H), 2.09 (s,
3H). 13C NMR (CDCl3, 90 MHz) d ppm: 180.0, 142.9,
The alkylation of compound 2 with 1-iodopropane has
been carried using the method reported for the preparation
of compound 3. A mixture of two diastereomers (77:23)
was obtained (36% yield). Only the major diastereomer

1440
J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
138.5, 128.2, 127.2, 125.9, 124.4, 117.3, 45.2, 39.6, 16.5. IR
(film) m cmꢀ1: 3054, 2987, 1708, 1600, 1551, 1494, 1421. MS
ES+: 453.1 2(MꢀH+Na)+.
128.6, 127.2, 125.5, 85.9, 51.9, 32.0, 31.1, 27.2. IR
(CH2Cl2) m cmꢀ1: 3066, 3032, 1778. MS ES+: 367.0, 369.0
(M+Na)+.
5.20. (R)-3-(2,4-Dimethylpent-3-enoyl)-4-phenyloxazolidin-
2-one 25
5.24. (3S,4R,5S)-4-Iodo-5-methyl-5-phenyl-3-propyl-
dihydrofuran-2(3H)-one 18
The alkylation of compound 2 with methyl iodide has been
carried using the method reported for the preparation of
compound 3. A mixture of two diastereomers (85:15)
was obtained (60% yield). Only the major diastereomer
(R)-3-((R)-2,4-dimethylpent-3-enoyl)-4-phenyloxazolidin-2-
This iodo lactone was obtained using the method reported
for the preparation of lactone 5a (92% yield). White solid:
20
1
mp 109.9 ꢁC (CH2Cl2), ½aꢁD ¼ ꢀ18:9 (c 0.75, CH2Cl2). H
NMR (CDCl3, 250 MHz) d (ppm): 7.55–7.53 (m, 2H),
7.41–7.35 (m, 3H), 4.15 (d, J = 11.5 Hz, 1H), 2.96 (m,
1H), 1.96 (s, 3H), 1.76 (m, 2H), 1.57 (m, 1H), 1.45 (m,
1H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3,
62.9 MHz) d ppm: 174.4, 142.0, 128.7, 128.3, 124.4, 85.6,
one 25a was isolated in a pure form as an oil,
20
½aꢁD ¼ ꢀ157:0 (c 2.0, CH2Cl2). 1H NMR (CDCl3,
360 MHz)
d (ppm): 7.36–7.26 (m, 5H), 5.38 (dd,
J = 8.6 Hz, J = 3.6 Hz, 1H), 5.21 (d, J = 9.4 Hz, 1H),
4.70 (m, 1H), 4.63 (dd, J = 8.6 Hz, J = 8.6 Hz, 1H), 4.22
(dd, J = 9.0 and 3.6 Hz, 1H), 1.70 (s, 3H), 1.68 (s, 3H),
1.14 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 90 MHz) d
(ppm): 175.4, 153.2, 139.2, 134.2, 128.5, 125.6, 123.0,
69.6, 57.6, 37.0, 25.6, 18.3, 18.1. IR (film) m (cmꢀ1): 3054,
2986, 1781, 1704. MS ES+: 296.1 (M+Na)+. ES HRMS
(M+Na) calculated for C16H19O3NNa: 296.1263. Found:
296.1261.
50.1, 32.4, 29.6, 27.6, 19.2, 14.0. IR (CH2Cl2) m cmꢀ1
:
3054, 2987, 1775, 1604, 1551, 1496, 1421. MS ES+: 367.0
(M+Na)+. ES HRMS (M+Na) calculated for
C14H17O2Na: 367.0171. Found: 367.0170.
5.25. 4-Bromo-5-methyl-5-phenyl-3-propyldihydrofuran-
2(3H)-ones 19 and 20
These bromo lactones were obtained using the method
reported for the preparation of lactone 5a (67% yield).
An inseparable mixture (80:20) of two diastereomers was
isolated. (3S,4R,5S)-4-Bromo-5-methyl-5-phenyl-3-propyl-
5.21. (R)-2,4-Dimethylpent-3-enoic acid 26
1
This acid was obtained using the method used for the prep-
dihydrofuran-2(3H)-one 19. (major diastereomer) Oil. H
20
aration of acid 4a (86%). Oil, ½aꢁD ¼ ꢀ310:0 (c 2.0,
NMR (CDCl3, 360 MHz) d (ppm): 7.53–7.51 (m, 2H),
7.43–7.32 (m, 3H), 4.20 (d, J = 10.8 Hz, 1H), 3.02, (dt,
J = 10.6 and 6 Hz, 1H), 1.86 (s, 3H), 1.76–1.49 (m, 4H),
0.95 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 62.9 MHz) d
ppm: 173.9, 142.3, 128.7, 128.3, 124.1, 86.0, 55.4, 48.7,
29.9, 25.5, 19.4, 13.9. IR (CH2Cl2) m cmꢀ1: 2964, 2935,
2876, 1778. (3S,4S,5R)-4-Bromo-5-methyl-5-phenyl-3-prop-
yldihydrofuran-2(3H)-one 20. (minor diastereomer), oil.
1H NMR (CDCl3, 250 MHz) d (ppm): 7.53–7.51 (m, 2H),
7.43–7.32 (m, 3H), 4.91 (d, J = 5.4 Hz, 1H), 2.62, (dt,
J = 9.4 and 5.2 Hz, 1H), 1.86 (s, 3H), 1.76–1.49 (m, 4H),
0.88 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 62.9 MHz) d
ppm: 174.0, 142.3, 129.0, 128.3, 124.1, 88.1, 62.3, 45.5,
29.8, 29.2, 20.2, 13.7.
CH2Cl2). 1H NMR (CDCl3, 360 MHz) d (ppm): 11.70
(br, 1H, COOH), 5.14 (d, J = 13.3 Hz, 1H), 3.45 (m, 1H),
1.73 (s, 3H), 1.68 (s, 3H), 1.22 (d, J = 10.0 Hz). 13C
NMR (CDCl3; 62.9 MHz) d ppm: 182.0, 134.7, 123.1,
38.8, 25.6, 17.9, 17.7. IR (film) m cmꢀ1: 3054, 2985, 1707.
5.22. (3S,4R,5S)-3-Benzyl-4-iodo-5-methyl-5-phenyl-
dihydrofuran-2(3H)-one 14
This iodo lactone was obtained using the method reported
for the preparation of lactone 5a (91% yield). White solid:
20
mp 85.8 ꢁC, ½aꢁD ¼ þ4:2 (c 1.25, CH2Cl2). 1H NMR
(CDCl3, 360 MHz) d (ppm): 7.29–7.23 (m, 10H), 3.91 (d,
J = 11.2 Hz, 1H), 3.30 (dd, J = 14.0 and 4.0 Hz, 1H),
3.24 (ddd, J = 11.2, 5.5 and 4.0 Hz, 1H), 3.03 (dd,
J = 14.0 and 5.5 Hz, 1H), 1.95 (s, 3H). 13C NMR (CDCl3,
62.9 MHz) d ppm: 173.7, 141.4, 136.0, 129.5, 128.7, 128.6,
128.3, 127.2, 124.6, 85.9, 51.9, 32.0, 31.1, 27.2. IR (CH2Cl2)
m cmꢀ1: 3066, 3031, 2929, 1774. MS ES+: 414.9 (M+Na)+.
ES HRMS (M+Na) calculated for C18H17O2INa:
415.0171. Found: 415.0177.
5.26. (3S,4R,5S)-3-Allyl-4-iodo-5-methyl-5-phenyl-
dihydrofuran-2(3H)-one 23
The iodo lactonization of the corresponding acid 22 led to
a mixture of three iodo lactones: (3S,4R,5S)-3-Allyl-4-
iodo-5-methyl-5-phenyldihydrofuran-2(3H)-one 23 and 5-
iodomethyl-3-(3-phenylbut-2-en-1-yl)dihydrofuran-2-ones
20
24. Lactone 23. Oil, ½aꢁD ¼ ꢀ30:1 (c 0.9, CH2Cl2). 1H
5.23. (3S,4R,5S)-3-Benzyl-4-bromo-5-methyl-5-phenyl-
dihydrofuran-2(3H)-one 15
NMR (CDCl3, 250 MHz) d (ppm): 7.54–7.50 (m, 2H),
7.40–7.36 (m, 3H), 5.71 (m, 1H), 5.18 (d, J = 9.2 Hz,
1H), 5.14 (d, J = 9.2 Hz, 1H), 4.15 (d, J = 11.8 Hz, 1H),
3.06 (m, 1H), 2.72 (m, 1H), 2.46 (m, 1H), 1.97 (s,
3H).13C NMR (CDCl3, 62.9 MHz) d ppm: 173.6, 141.8,
132.1, 128.7, 128.4, 124.5, 120.0, 86.0, 50.1, 31.0, 30.6,
27.4. IR (film) m cmꢀ1: 3155, 2983, 1776. MS ES+: 365.1
(M+Na)+. ES HRMS (M+Na) calculated for C14H15O2I-
Na: 365.0014. Found: 365.0021. Lactone 24. Isolated as a
mixture of two diastereomers (45:55). Oil. Main diastereo-
This bromo lactone was obtained using the method re-
ported for the preparation of lactone 5a (84% yield). White
20
solid: mp 93.0 ꢁC, ½aꢁD ¼ ꢀ11:0 (c 1.07, CH2Cl2). 1H NMR
(CDCl3, 360 MHz) d (ppm): 7.31–7.19 (m, 10H), 4.03 (d,
J = 10.8 Hz, 1H), 3.32 (ddd, J = 10.8, 5.8 and 5.0 Hz,
1H), 3.18 (dd, J = 14.1 and 5.0 Hz, 1H), 3.06 (dd,
J = 14.1 and 5.8 Hz, 1H), 1.86 (s, 3H). 13C NMR (CDCl3,
62.9 MHz) d ppm: 173.7, 141.4, 136.0, 129.5, 128.7,
1
mer: H NMR (CDCl3, 250 MHz) d (ppm): 7.42–7.26 (m,

J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
1441
5H), 5.71 (d, J = 8.3 Hz, 1H), 4.49 (m, 1H), 3.80 (m, 1H),
5.30. (3R,5R)-5-(Hydroxymethyl)-3,5-dimethyldihydro-
furan-2(3H)-one 30
3.47 (m, 1H), 3.33 (m, 1H), 2.83 (ddd, J = 13.0, 9.0 and
5.7 Hz, 1H), 2.43 (m, 1H), 2.12 (s, 3H). 13C NMR (CDCl3,
62.9 MHz) d ppm: 176.4, 142.2, 140.5 (2C), 128.2, 127.3,
The crude acid 29 was dissolved in THF (4 mL), and
cooled at 0 ꢁC. A borane solution (0.734 mL of a 1 M solu-
tion in THF, 0.734 mmol) was added, and the solution was
stirred 16 h at 0 ꢁC. After hydrolysis by the addition of a
saturated solution of NH4Cl (10 mL), the THF was re-
moved under vacuum. The aqueous phase was extracted
with diethyl ether (3 · 10 mL). The combined ether phases
were then washed with 0.5 M HCl solution (5 mL), satu-
rated NaCl solution (5 mL), and dried over MgSO4. The
organic phase was concentrated under vacuum, to give
alcohol 30, which was purified by liquid chromatography
(pentane/diethyl ether: 75–25). Yield: 0.085 g, 56% (from
1
125.7, 76.5, 41.5, 36.7, 16.6, 6.7. Minor diastereomer: H
NMR (CDCl3, 250 MHz) d (ppm): 7.42–7.26 (m, 5H),
5.66 (d, J = 8.7 Hz, 1H), 4.68, (m, 1H), 3.80 (m, 1H),
3.47 (m, 1H), 3.33 (m, 1H), 2.41 (m, 1H), 2.16 (s, 3H),
1.83 (m, 1H). 13C NMR (CDCl3, 62.9 MHz) d ppm:
176.4, 142.2, 140.5 (2C), 128.1, 127.4, 125.2, 76.5, 39.8,
35.0, 16.5, 7.3.
5.27. (3S,4R)-4-Iodo-3,5,5-trimethyldihydrofuran-2(3H)-one
27
20
1
28). Oil, ½aꢁD ¼ ꢀ4:9 (c 0.9, CH2Cl2). H NMR (CDCl3,
360 MHz) d (ppm): 3.71 (d, J = 12.2 Hz, 1H), 3.46 (d,
J = 12.2 Hz, 1H), 2.86 (m, 1H), 2.13 (bs, 1H), 2.08 (m,
2H), 1.35 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 90 MHz) d ppm: 172.3, 84.1, 67.7, 36.7, 35.0,
22.3, 15.4. IR (film) m cmꢀ1: 3450, 3054, 2986, 1766. MS
ES+: 167.1 (M+Na)+.
This iodo lactone was obtained using the method reported
for the preparation of lactone 5a. White solid.
20
½aꢁD ¼ ꢀ16:7 (c 2.0, CH2Cl2). 1H NMR (CDCl3,
360 MHz) d (ppm): 3.87 (d, J = 12.2 Hz, 1H), 2.80 (m,
1H), 1.59 (s, 3H), 1.50 (s, 3H), 1.31 (d, J = 6.8 Hz). 13C
NMR (CDCl3, 90 MHz) d ppm: 174.6, 84.3, 44.8, 32.8,
26.0, 25.7, 12.4. IR (CDCl3) m cmꢀ1: 3054, 2987, 1775.
Anal. Calcd for C7H11IO2: C, 33.09; H, 4.36. Found: C,
33.14; H, 4.31.
5.31. (2R,4R)-2,4-Dimethyl-5-oxotetrahydrofuran-2-carb-
aldehyde 31
To hydroxy lactone 30 (80 mg, 0.555 mmol) in dichloro-
methane solution (3 mL) was added a Dess–Martin period-
inane (35.3 mg, 0.833 mmol), and the solution was stirred
at rt for 1 h. Saturated NaHCO3 (3 mL) and saturated
Na2S2O3 solutions (3 mL) were added, and the aqueous
phase was extracted with dichloromethane (3 · 5 mL).
The combined organic phases were dried over MgSO4,
and concentrated under vacuum, to give aldehyde 31
(73 mg, 92% yield). This aldehyde was unstable over silica
5.28. (3S,5S)-3,5-Dimethyl-5-phenyldihydrofuran-2(3H)-one
28
To iodo lactone 5a (0.18 g, 0.57 mmol) in solution in benz-
ene (7 mL) was added azabisisobutyronitrile (3 mg) and
tributyltin hydride (0.1657 mg, 0.57 mmol). The solution
was heated at 80 ꢁC for 15 h. After cooling, acetonitrile
(10 mL) was added, and the resulting solution washed
with pentane (3 · 5 mL), and concentrated under vacuum.
1
gel and was used without purification for the next step. H
NMR (CDCl3, 360 MHz) d (ppm): 10.0 (s, 1H), 2.06 (m,
2H), 1.60 (m, 1H), 1.55 (s, 3H), 1.22 (d, J = 7.5 Hz, 3H).
The residue was purified by liquid chromatography, to give
20
0.100 g of lactone 28 as an oil (92% yield). ½aꢁD ¼ ꢀ32:0 (c
0.33, CH2Cl2). 1H NMR (CDCl3, 360 MHz) d (ppm): 7.37–
7.26 (m, 5H), 2.77 (dd, J = 12.2 and 8.3 Hz, 1H), 2.53 (ddq,
J = 6.8 Hz, 8.3 and 12.2 Hz, 1H), 2.00 (dd, J = 12.2 Hz,
J = 12.2 Hz, 1H), 1.73 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H).
13C NMR (CDCl3, 62.9 MHz) d ppm: 179.2, 143.8, 128.5,
5.32. Triphenyl(11-phenylundecyl)phosphonium bromide
A mixture of the commercially available (11-bromounde-
cyl)-benzene (0.50 g, 1.73 mmol) and triphenylphosphine
(2.27 g, 8.65 mmol) in acetonitrile (20 mL) was heated
overnight at reflux. After cooling, the solvent was removed
under vacuum, and the solid washed with diethyl ether
(5 · 5 mL). The resulting solid was used without further
purification. 1H NMR (MeOH-d4, 360 MHz) d (ppm):
7.90–7.72 (m, 15H), 7.26–7.12 (m, 5H), 3.48 (m, 2H),
2.58 (t, J = 7.6 Hz, 2H), 1.67–1.52 (m, 6H), 1.30–1.26 (m,
12H). 13C NMR (MeOH-d4, 90 MHz) d (ppm): 143.9,
136.2, 134.8, 134.7, 134.5, 131.6, 131.4, 130.0, 129.7,
129.6, 129.4, 129.2, 126.2, 120.6, 119.2 (2C), 36.9, 32.7,
31.7, 31.4, 30.5, 30.3, 29.9, 23.6, 23.5, 23.1, 22.3. ES HRMS
(MꢀBr) calculated for C35H42P+: 493.3019. Found:
493.3023.
127.6, 124.1, 84.4, 45.0, 34.9, 30.3, 14.6. IR (film) m cmꢀ1
:
3064, 3029, 2982, 2934, 2876, 1767, 1496, 1448. MS ES+:
213.1 (M+Na)+. ES HRMS (M+Na) calculated for
C12H14O2Na: 213.0891. Found: 213.0898.
5.29. (2R,4R)-2,4-Dimethyl-5-oxotetrahydrofuran-2-
carboxylic acid 29
To lactone 28 (0.200 g, 1.05 mmol) in solution in a mixture
acetonitrile/water/tetrachloromethane (7:3.5:3.5 mL) was
added at rt sodium periodate (4.50 g, 21 mmol) and
RuCl3ÆnH2O (0.0216 g, 0.105 mmol). After heating for 3 h
at 70 ꢁC, the cooled solution was filtered over Celite. The
filtrate was extracted with diethyl ether (3 · 5 mL). The so-
lid was well washed with diethyl ether, and the combined
ether phases dried over MgSO4, and concentrated under
vacuum, to give acid 29 (0.116 g, 70%), which was used
for the next step without purification.
5.33. (3R,5R)-3,5-Dimethyl-5-(13-phenyldodec-1-
enyl)dihydrofuran-2(3H)-one 32
To a suspension of triphenyl(11-phenylundecyl)phospho-
nium bromide (0.231 g, 0.422 mmol) in THF (1 mL) cooled

1442
J.-M. Garnier et al. / Tetrahedron: Asymmetry 18 (2007) 1434–1442
at ꢀ78 ꢁC was added butyl lithium (0.281 mL of a 1.5 M
sol. in hexane, 0.422 mmol). The mixture was stirred
30 min at ꢀ78 ꢁC then warmed at 0 ꢁC. A solution of alde-
hyde 31 in THF (1 mL) was added dropwise, and the solu-
tion was stirred overnight at rt. A saturated solution of
NH4Cl was added and the organic solvents removed under
vacuum. The aqueous phase was extracted with diethyl
ether (3 · 1 mL). The combined organic phases were dried
over MgSO4 and concentrated under vacuum. The residue
was purified by liquid chromatography to give 0.043 g
ES HRMS (M+Na) calculated for C24H38O2Na
381.2770. Found 381.2772.
6. X-ray-structures
CCDC-643270 and CCDC-643271 contain the supplemen-
tary crystallographic data for compounds 3a and 6a. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1
(53%) of compound 32 (E/Z: 77–23). E-isomer: H NMR
(CDCl3, 360 MHz) d (ppm): 7.27–7.29 (m, 2H), 7.19–7.16
(m, 3H), 5.36 (m, 2H), 2.59 (t, J = 7.3, 2H), 2.27 (m,
1H), 2.00 (m, 2H), 1.60 (m, 3H), 1.43 (s, 3H), 1.31–1.26
(m, 18H). Z-isomer: 1H NMR (CDCl3, 360 MHz) d
(ppm): 7.27–7.29 (m, 2H), 7.19–7.16 (m, 3H), 6.39 (d,
J = 11 Hz, 1H), 5.66 (dt, J = 11.6 and 7.3, 1H), 2.59 (t,
J = 7.3, 2H), 2.27 (m, 1H), 2.00 (m, 2H), 1.60 (m, 3H),
1.42 (s, 3H), 1.31–1.26 (m, 18H).
References
1. Fittig, R.; Frost, B. Justus Liebigs Ann. Chem. 1884, 226,
363–376.
2. (a) Corey, E. J.; Hase, T. Tetrahedron Lett. 1979, 335–338; (b)
Yu, H.; Simon, H. Tetrahedron 1991, 47, 9035–9052; (c)
Reetz, M. T.; Lauterbach, E. H. Heterocycles 1993, 35, 627–
630.
5.34. (3R,5S)-3,5-Dimethyl-5-(12-phenyldodecyl)dihydro-
furan-2(3H)-one 33
3. Garnier, J.M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem.
2007, in press.
4. (a) White, J. D.; Jonhson, A. J. J. Org. Chem. 1994, 59, 3347–
3358; (b) Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004,
4567–4581; (c) Huang, L.-L.; Xu, M.-H.; Lin, G.-Q. J. Org.
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8. Sandler, J. S.; Colin, P. L.; Hooper, J. N. A.; Faulkner, D. J.
J. Nat. Prod. 2002, 65, 1258–1261.
An ethyl acetate solution (2 mL) of unsaturated lactone 32
(35 mg, 0.098 mmol) containing Pd(OH)2 (3 mg) was stir-
red under a hydrogen atmosphere for 15 h. After filtration,
the filtrate was concentrated under vacuum, and the resi-
due was purified by liquid chromatography (pentane/
diethyl ether: 95–5) to give lactone 33 (11 mg, 31%) as an
20
oil. ½aꢁD ¼ ꢀ8:5 (c 0.20, MeOH). 1H NMR (CDCl3,
360 MHz) d (ppm): 7.27–7.29 (m, 2H), 7.19–7.16 (m, 3H),
2.60 (t, J = 7.50 Hz, 1H), 2.27 (m, 1H), 1.72 (m, 1H),
1.67 (m, 2H), 1.59 (m, 2H), 1.34 (s, 3H), 1.31–1.22 (m,
21H). 13C NMR (MeOD, 90 MHz) d ppm: 181.6, 143.8,
129.2, 126.4, 86.1, 42.6, 42.4, 36.8, 31.0, 30.6–30.5 (6C),
30.1, 24.9, 24.8, 15.5. IR (film) m cmꢀ1: 3054, 2986, 1767.
9. Scholz, K. H.; Heine, H. G.; Hartmann, W. Org. Synth. 1984,
62, 149–157.
10. Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 2000, 77,
206–211.