An approach to enantioselective 5-endo halo-lactonization reactions

Article abstract of DOI:10.1002/ejoc.200700041

Enantioselective lactonization of 4-substituted but-3-enoic acids using iodobis(N-methylephedrine) hexafluoroantimonate in dichloromethane at low temperatures is reported. The presence of bis(N-methylephedrine)silver(I) hexafluoroantimonate, derived from

Full text of DOI:10.1002/ejoc.200700041

FULL PAPER
DOI: 10.1002/ejoc.200700041
An Approach to Enantioselective 5-endo Halo-Lactonization Reactions
Jean Marc Garnier,[a] Sylvie Robin,[a] and Gérard Rousseau*[a]
Keywords: N ligands / Iodine / Cyclization / Enantioselectivity / Lactones
Enantioselective lactonization of 4-substituted but-3-enoic
acids using iodobis(N-methylephedrine) hexafluoroantimon-
ate in dichloromethane at low temperatures is reported. The
presence of bis(N-methylephedrine)silver(I) hexafluoroanti-
monate, derived from the excess amounts of N-methyleph-
edrine and silver hexafluoroantimonate that were necessary
for the generation of the iodo complex in the reaction mix-
ture, is crucial for the success of this reaction. The different
parameters of these cyclization reactions have been exam-
ined.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
study we needed chiral halonium salts. These compounds
were prepared as shown in Scheme 1 by using two different
approaches. The first one involves the direct formation of
these salts by the reaction of a silver salt with 2 equivalents
of the desired chiral amines and 1 equivalent of halogen.
The proof of their synthesis was confirmed by iodine or
bromine discoloration and the formation of silver halide.
The second method involves the exchange of the collidines
in halo-bis(collidine) hexafluorophosphates for more basic
amines. In these cases, when the reaction mixtures were
warmed to room temperature, a black tar was formed.
Attempts to characterize the complexes formed by low-tem-
perature NMR spectroscopy were unsuccessful and the only
proof of their formation is based on their reactivity and
their thermal instability. These reagents were thus prepared
between –40 and –78 °C and used in situ in the subsequent
halo-lactonization reactions.
Introduction
Halo-promoted cyclization reactions of functionalized ω-
substituted carboxylic acids and amides are useful methods
for the construction of lactones or other heterocyclic com-
pounds.[1] The stereoselectivity of these reactions has been
extensively studied and is now well understood in the case
of substrate-controlled cyclization reactions (diastereoselec-
tive cyclizations). However, although enantioselective cycli-
zation reactions have been reported, the results have been
moderate. The most obvious method involves the inter-
vention of chiral halo reagents. By using this approach, dif-
ferent results have been reported. Low enantioselectivities
(ee Ͻ 10%) have been obtained using iodine complexes of
dihydroquinidine[2] or chiral pyridines.[3,4] Improved results
(ee Ͻ 45%) have been reported in reactions with ICl com-
plexed by chiral amines such as (R)-1-phenylethylamine or
(R)-1,2,3,4-tetrahydronaphthylamine.[4]
Enantioselective
The halo-lactonization reactions were carried out by ad-
dition at low temperature of the pent-4-enoic acids 12–14
to the preformed halo reagents. After 2 h at a low tempera-
ture, the acid was totally consumed and the iodolactones
were formed; the reaction mixture was then warmed to
room temperature and the lactones isolated (Scheme 2). GC
analysis using a cyclodextrin column gave the enantiomeric
excesses of the lactones 15 and 16. Our results are reported
in Table 1. With pent-4-enoic acid (12), whatever the chiral
reagent (entries a–g), no enantioselectivity was observed in
the formation of the halo-lactones 15a,b. With 4-phen-
ylpent-4-enoic acid (13), very low enantioselectivities were
obtained (entries h–l). No reaction was observed with the
acid 14. Under the conditions reported for the iodolactoni-
zation of 5-arylpent-4-enoic acids,[4] acid 12 led to the iodo-
lactone 15a with an ee of only 6%. In all these reactions,
the chiral ligands were quantitatively recovered and reused.
These modest results led us to examine 5-endo halo-lac-
tonization reactions. This type of cyclization reaction has
never been examined in detail[1] even though the first exam-
cyclization reactions of (E)-5-arylpent-4-enoic acids are re-
ported to be possible using catalytic amounts (30 mol-%)
of cinchonidine derivatives in the presence of iodine (ee Ͻ
42%).[5] Enantioselective iodolactonization of an α-hydroxy
unsaturated acid has also been reported to be effective by
complexation of the acid with a chiral titanium reagent.[6]
Results and Discussion
Our previous studies on the reactivity of halo-bis(collid-
ine) derivatives in cyclization reactions[7] have led us to look
at a chiral version of these reactions. We examined first the
halo-lactonization of pent-4-enoic acid derivatives. For this
[a] Laboratoire de Synthèse Organique et Méthodologie (UMR
CNRS 8182), Institut de Chimie Moléculaire et des Matériaux
d’Orsay,
Bât. 420, Université de Paris XI, 91405 Orsay, France
Fax: +33-1-69156278
E-mail: grousseau@icmo.u-psud.fr
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J. M. Garnier, S. Robin, G. Rousseau
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Scheme 1. Preparation of halo-bis(amine) salts.
ple was reported at the end of the nineteenth century.[8] We
chose (E)-4-phenylpent-3-enoic acid (17) as the substrate.[9]
Reaction with iodobis(collidine) hexafluorophosphate in
dichloromethane at room temperature led to the formation
of racemic iodolactone 18 in good yield (Scheme 3) whose
stereochemistry was secured by X-ray crystallography.
Scheme 2. Preparation of halo-lactones 15 and 16.
Table 1. Halo-lactonization reactions of pent-4-enoic acids 12–14
using chiral halonium salts.
Scheme 3. Iodolactonization of acid 17.
Entry
Acid
Halonium Lactone Yield (%)
reagent
ee (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
12
12
12
12
12
12
12
13
13
13
13
13
14
12
2a
2a
2a
3b
5a
9a
11b
2b
5a
5b
7b
7a
15a
15a
15a
15b
15a
15a
15b
16a
16a
16a
16b
16b
–
83
73
12
86
83
78
70
72
70
20
65
60
–
0[a]
0[b]
0[c]
0[b]
0[b]
0[b]
0[b]
5[a]
7[a]
2[a]
2[a]
3[a]
–
To study the enantioselective version of this reaction, we
chose (–)-N-methylephedrine (19) as the chiral amine. As
described above for the preparation of the iodo complexes
(Scheme 1), iodobis(N-methylephedrine) hexafluoroanti-
monate (20) was prepared by the reaction of 2 equivalents
of N-methylephedrine (19) with 1 equivalent of iodine in
the presence of 1 equivalent of silver hexafluoroantimonate
(Scheme 4). Like the complexes in Scheme 1, complex 20
was unstable at room temperature and was thus prepared
and used at a low temperature. In the absence of iodine,
silver complex 21 was formed. Attempts to characterize
these complexes using low-temperature NMR spectroscopy
were unsuccessful. N-Methylephedrine was systematically
recovered and reused.
5b
[d]
15a
80
6[a]
[a] Reaction carried out at –78 °C. [b] Reaction carried out at
–40 °C. [c] Reaction carried out at –20 °C. [d] Reaction carried out
with a mixture of ICl and (R)-1-phenylethylamine.[4]
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Enantioselective 5-endo Halo-Lactonization Reactions
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Table 2. Enantioselective iodolactonization reactions of acid 17.
Entry
I2
N-Methylephedrine
AgSbF6
(equiv.)
Yield[a]
(%)
ee(%)
(equiv.)
(equiv.)
a
b
c
d
e
f
g
h
i
2.4
1
1
4.8
2
2.4
1
77
80
82
87
85
86
92
86
75
51
85
NR
0
0
4.8
4.8
4.8
4.8
4.8
4.8
2.4
4.8
2.4
4.8
2.4
2.4
2.4
2.4
2.4
2.4
1.2
1.2
2.4
0
21
19
26
41
45
43
40[b]
0
0.8
0.6
0.45
0.4
0.2
0.1
0.4
0.4
0.4
j
k
l
0
–
Scheme 4. Preparation of complexes 20 and 21.
[a] All the reactions were carried out at –78 °C in the presence of
1 equiv. of acid 17. Yields were calculated from the acid (entries a–
c) or from the iodine (entries d–l). [b] The ee was 5% when the
reaction was carried out at –20 °C.
The acid 17 was then added at –78 °C to a mixture of
complexes 20 and 21. After 2 h at this temperature, the reac-
tion mixture was analyzed. The iodolactone 18 was ob-
tained in good yield and its enantiomeric excess was deter-
mined by GC analysis (cyclodextrin column). The same re-
sults were obtained when iodine was added to a mixture of
the acid, silver hexafluoroantimonate and ephedrine. Our
results are reported in Table 2. When the cyclization reac-
tion was carried out with a stoichiometric AgSbF6/eph-
edrine/I2 ratio of 2:1:1, no enantioselectivity was observed
(entries a and b). However, if the amount of iodine was less
than this stoichiometry (that is, in the presence of the silver
complex 21), enantioselective cyclization reactions were ob-
served. We noticed that the ee of this iodolactonization pro-
cess increases in parallel with the increase in the amount of
Scheme 5. Preparation of lactone 22.
In a subsequent study we decided, using the previously
silver complex 21 present in the reaction mixture (see en- determined optimum reaction conditions (Table 2, entry g),
tries c–f). The best enantioselectivity (45%) was observed to examine various types of chiral amines. These amines
when the lactonization was carried out in the presence of were either commercially available or prepared using stan-
5 equivalents of the silver complex 21 relative to the iodine dard methods (see the Exptl. Sect.). We report in Scheme 6
complex (entry g). Larger excesses of complex 21 (entries h the enantiomeric excesses obtained in the reactions of the
and i) did not significantly modify the enantioselectivity of iodobis(amine) reagents with acid 17; iodolactones 18 were
the lactonization reaction. No selectivity was observed (en- obtained with the same absolute configuration as that ob-
tries j and k) when the ratio of 2:1 amine/AgSbF6 was not served in the reaction with N-methylephedrine. Replace-
respected (excess of amine or excess of silver hexafluo- ment of one or two of the methyl groups on the nitrogen
roantimonate) and in the absence of the silver salt no reac- atom of N-methylephedrine by other substituents (H, Et,
tion occurred at all (entry l). Thus, for the first time, we Bu, iBu and Bn) led to the formation of iodolactones 18
have been able to obtain an enantioselective 5-endo lacton- with lower enantiomeric excesses (amines 8 and 23–26).
ization product with an enantiomeric excess of 45%. This This is also the case for the cyclopentanic amine 27. Intro-
result appears to be comparable to those already reported duction of an additional alcohol function resulted in either
in the literature for 5-exo lactonization reactions under dif- a non-enantioselective cyclization (amine 29) or no reaction
ferent conditions. Total consumption of the acid 17 was ob- at all (amine 30). The diastereomer 32 of N-methyleph-
served (same enantiomeric excess for the iodolactone 18) by edrine gave a lower enantiomeric excess. The other struc-
increasing the amount of iodine, N-methylephedrine and tures examined (compounds 1, 6 and 33–38) gave less inter-
the silver salt by a factor of 2.5.
esting results. From these results it seems necessary to have
The absolute configuration of lactone 18 was determined a free hydroxy function (ee = 0 or no reaction with the
after its transformation into the known α,β-ethylenic lac- amines 31, 34 and 35) and two alkyl groups fixed on the
tone 22[10] (Scheme 5). The sign of the rotatory power of nitrogen atom, but these two groups should be small. How-
this lactone compared with that reported in the literature ever, the azetidine derivative 28 gave the almost racemic
allowed us to assign the (S) configuration to the quaternary iodolactone. It would have been interesting to examine the
centre. The (R) configuration for the carbon atom bearing case of the corresponding aziridine 43, however, we were
the iodine atom was then deduced from the mechanism of not able to obtain it from norephedrine 39; all our attempts
the iodolactonization reaction[1] and confirmed by the X- led to the exclusive formation of the cyclic amine 34.[11] In
ray crystal structure.
the same way, although protection of the alcohol function
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J. M. Garnier, S. Robin, G. Rousseau
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Scheme 6. ee values (%) measured for iodolactones 18 of (4R,5S) absolute configuration obtained by the iodolactonization of acid 17
with various amines.
Scheme 7. Attempts at the preparation of aziridine compound 43.
as a silyl ether led to the desired N-alkylated product 41,
subsequent attempts to form the aziridine ring gave rise to
an inseparable mixture of compounds 34 and 42. Treatment
of this mixture with fluoride reagents mainly caused ring-
opening of the aziridine and the six-membered heterocyclic
compound 34 was mainly isolated (Scheme 7).
Scheme 8. Preparation of diamines 44–48.
We report in Scheme 8 the case of diamines, which led
to the iodolactone 18 with the opposite (4S,5R) absolute
configuration. These compounds 44–48, analogues of N-
To improve the enantioselectivity of this iodolactoni-
methylephedrine in which the hydroxy group is replaced by zation reaction, we also examined other parameters of this
amino groups, were obtained from N-methylephedrine in reaction. The nature of the silver salt was found to be criti-
two steps by double inversion reactions[12] (Scheme 9). The cal. Lower enantioselectivity was obtained when the iodo-
best enantioselectivity was obtained with diamine 44 pos- bis(N-methylephedrine) salt was prepared from AgPF6 (ee
sessing an NH2 group. No iodolactonization was observed = 25%), whereas with AgBF4 a low enantioselectivity (ee =
from the iodonium reagents formed from sparteine or 10%) in favour of the opposite enantiomer was obtained.
Jacobsen ligands.
The nature of the iodo reagent used for the formation of
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Enantioselective 5-endo Halo-Lactonization Reactions
FULL PAPER
reactions at –78 °C. The presence of water, probably intro-
duced by hygroscopic silver salts, appears harmful for these
reactions.
To examine the scope of this reaction, we checked the
reactivity of some 4-arylalk-3-enoic acids. The acids 50b–d
were prepared by Knoevenagel condensation of aldehydes
49b–d with malonic acid, followed by decarboxylation and
isomerization of the carbon–carbon double bond. (Z)-4-
Phenylpent-3-enoic acid (51) was obtained by photoisomer-
ization of the corresponding (E) isomer 17, followed by sep-
aration of the two isomers by liquid chromatography
(Scheme 10). With these acids, as with acid 17, only the 5-
endo lactonization reactions were observed (Scheme 11).
Scheme 9. ee values (%) measured for iodolactones 18 of (4S,5R)
absolute configuration obtained by the iodolactonization of acid
17 with diamines 44–48.
the complex is also very important. Instead of iodine, we
investigated the use of other iodo reagents. With ICl we
–
–
observed no reaction, whereas with Me3S+I3 , Bu4N+I3 or
iodobis(collidine) hexafluorophosphate we obtained the ra-
cemic iodolactone 18. Only NIS, in addition to iodine, led
to an enantioselective reaction (ee = 25%). The final pa-
rameters to be examined were the temperature and the pres-
ence of water. In general, the best results were obtained by Scheme 10. Preparation of 4-arylbut-3-enoic acids 50b–d and 51.
Scheme 11. Iodolactonization of acids 50a–d and 51.
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J. M. Garnier, S. Robin, G. Rousseau
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Scheme 12. Iodolactonization of salts 56 and 57.
The iodolactones 52a,b were obtained from the (E) acids
50a,b by reaction with iodobis(N-methylephedrine) hexa-
fluoroantimonate (20) in the presence of bis(N-methyl-
ephedrine)silver hexafluoroantimonate (21) and were iden-
tified by spectroscopic methods. In the two cases, the pro-
portions of the two enantiomers were deduced from GC
chromatograms. The absolute configuration (4R,5S) is iden-
tical to that of the lactone 18. The unsaturated lactone 53
was isolated as the sole product from the acid 50c (70%
yield). The lactonization of acid 50d led to iodolactone 54
with a (4S,5R) configuration. The iodolactone 55 with ab-
solute configuration (4R,5R), obtained from the acid 51,
was unstable at room temperature, quantitatively trans-
forming into the unsaturated lactone 22 with (R) configura-
tion {[α]2D0 = +42.0 (c = 0.8, CH2Cl2); ee = 20%}
(Scheme 11).
Different hypotheses have been considered to explain the
enantioselectivity observed in these reactions. The simplest
explanation is the formation of ammonium carboxylates.
We prepared the tetrabutylammonium carboxylate 56 to ex-
amine whether a simple ammonium salt could be involved
in this kind of cyclization reaction. By reaction with iodob-
is(N-methylephedrine) hexafluoroantimonate (20) in the
presence of the silver complex 21, we obtained the racemic
iodolactone 18 (90% yield). Similar results were obtained
from the chiral ammonium salt 57 in its reaction with iodo-
bis(collidine) hexafluorophosphonate or iodobis(N-methyl-
ephedrine) hexafluoroantimonate (21) (Scheme 12).
The formation of an ammonium carboxylate appearing
improbable, we examined the possible formation of a chiral
silver carboxylate intermediate. The reaction of 2 equiva-
lents of N-methylephedrine with the insoluble silver carbox-
ylate 58 led to a homogeneous solution of the correspond-
ing salt (Scheme 13) which was characterized from its NMR
spectra. After cooling to –78 °C, the complex 59 was treated
with iodobis(collidine) hexafluorophosphate or a mixture
of iodobis(N-methylephedrine) hexafluoroantimonate (20)
and bis(N-methylephedrine)silver hexafluoroantimonate
(21) to give in both cases the racemic lactone 18 in good
yields.[13]
Scheme 13. Preparation and iodolactonization of the silver com-
plex 59.
of the reactions. Another hypothesis to explain the enantio-
selectivity is that the iodolactonization reactions result from
the reaction of the multicomponent complex 60
(Scheme 14). This complex could be obtained by an ar-
rangement of five nitrogen ligands of complexes 21 around
the iodine atom of complex 20. This intermediate should
have a pentagonal bipyramidal geometry according to the
valence-shell electron-pair repulsion theory (VSEPR) and
the geometry of seven-coordinate molecules.[14] The need
The possibility of complexation of the double bond of
the acid with several molecules of silver complexes 21 can
also probably be ruled out as the order of addition of the
different reagents has no influence on the enantioselectivity Scheme 14. Postulated structure of complex 60.
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Enantioselective 5-endo Halo-Lactonization Reactions
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Scheme 15. Preparation of lactone 62.
at –78 °C,
a
dichloromethane solution (7.7 mL) of iodine
for a free alcohol function on the ephedrine structure seems
to imply the formation of hydrogen bonds between the dif-
ferent hydroxy functions. This architecture can be destabi-
lized in the presence of counteranions other than the hexa-
fluroantimonate group as they should lead to closer ap-
proaches to the iodonium. Work is in progress to test these
hypotheses. In addition, we observed that under the condi-
tions used for the iodolactonization of acid 17, no enantio-
selectivity could be obtained for substrates studied pre-
viously.[2–5] Equally, by using the conditions reported in the
literature,[2–5] we observed no enantioselectivity for the
halo-lactonization reactions of acid 17. These observations
lead us to conclude, for the moment, that it is difficult to
find general conditions that are applicable to a variety of
unsaturated acids.[15]
(1.42 mmol) was added dropwise. We observed rapid iodine decol-
orization and the formation of a yellow solid (AgI). The same pro-
cedure was used for the formation of bromobis(amine) hexafluo-
roantimonate and other silver salts.
Method 2: Dichloromethane (10 mL) was added to a Schlenk flask
containing iodobis(collidine) hexafluorophosphate[20] (0.73 g,
1.42 mmol) . After cooling to –40 °C, a dichloromethane solution
(2 mL) of the desired amine (2.84 mmol) was added dropwise. After
1 h at this temperature, the iodobis(amine) hexafluorophosphate
had formed and was used in subsequent reactions.
Preparation of Pent-4-enoic Acids 12–14: Pent-4-enoic acid (12) is
commercially available. Acid 14 was prepared as previously re-
ported.[21] Suzuki coupling of this acid with phenylboronic acid led
to 4-phenylpent-4-enoic acid (13).[4]
General Procedure for the Iodolactonization of Acids 12–14: Acids
12–14 (1.42 mmol) were added to the halobis(amine) salts pre-
viously prepared at low temperatures. After 2 h at the desired tem-
perature, the reaction mixture was warmed to room temp. and hy-
drolyzed with an aqueous 1  HCl solution (10 mL). The solid was
filtered. The aqueous phase was extracted with dichloromethane
(3ϫ10 mL). The organic phase was then washed with a sat.
Na2S2O3 solution (5 mL), brine (5 mL) and dried (MgSO4). After
concentration under vacuum, the residue was purified by liquid
chromatography over silica gel (petroleum ether/diethyl ether,
90:10). Our results are reported in Table 1. 4,5-Dihydro-5-(iodo-
methyl)furan-2(3H)one (15)[2] and 4,5-dihydro-5-(iodomethyl)-5-
phenylfuran-2(3H)one (16)[4] have been already described.
Optically active γ-butyrolactones and α-methylene-γ-bu-
tyrolactones are important compounds owing to their po-
tential antibiotic, fungal, anthelmintic and antitumour ac-
tivities.[16] Reaction of lactone 18 with tributyltin hydride in
the presence of AIBN led to the deiodinated butyrolactone
61 (Scheme 15). This was easily transformed into the α-
methylene-γ-butyrolactone 62 using a standard procedure.
This method thus allows an easy access to this optically
active lactone previously obtained by a different path-
way.[17]
(E)-4-Phenylpent-3-enoic Acid (17):[9,22] A mixture of 2-phenylpro-
panal (10 g, 74.5 mmol), triethylamine (15.7 mL, 111.8 mmol,
1.5 equiv.) and malonic acid (7.75 g, 74.5 mmol) was refluxed over-
night. After cooling to room temp. diethyl ether was added (30 mL)
and the mixture was acidified by the addition of an aqueous 1 
HCl solution (pH 1). The aqueous phase was extracted with diethyl
ether (30 mL) and then an aqueous 1  NaOH solution (pH 10)
was added. After extraction with diethyl ether (3ϫ20 mL), this
aqueous phase was acidified by addition of an aqueous 1  HCl
solution (pH 1) and extracted with diethyl ether (3ϫ30 mL). The
combined organic phases were washed with brine (10 mL), dried
(MgSO4) and concentrated under vacuum. The residue was puri-
fied by liquid chromatography over silica gel (CH2Cl2/Et2O, 90:10)
to give 5.90 g of (E)-4-phenylpent-3-enoic acid (5.90 g, 45%) and
(Z)-4-phenylpent-3-enoic acid (0.66 g, 5%). (E) isomer: m.p. 78–
79 °C. 1H NMR (CDCl3, 360 MHz): δ = 11.60 (br. s), 7.40–7.24
(m, 5 H), 5.93 (t, J = 6.1 Hz, 1 H), 3.30 (d, J = 7.2 Hz, 2 H), 2.07
(s, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 178.4, 142.8, 138.7,
Experimental Section
NMR spectra were recorded in CDCl3. GC was performed with a
40 m cyclodextrin DM column. The enantiomeric excesses of the
different lactones were calculated by integration of the peaks of the
two enantiomers in GC chromatograms. (S)-4,5-Dihydro-4-phenyl-
oxazole (1) was prepared by reaction of (S)-2-amino-2-phenyl-
ethanol with ethyl orthoformate in the presence of trifluoroacetic
acid in dichloromethane (55% yield).[18] (R)-1-Phenylethylamine
(4), (R)-1,2,3,4-tetrahydronaphthalen-1-amine (6), (1R,2S)-eph-
edrine (8), (1R,2S)-2-dibutylamino-1-phenylpropan-1-ol (25),
(1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol (27) and (S)-2-
(methylamino)-2-phenylethanol (36) are commercially available.
Ethyl (S)-1-methylpyrrolidine-2-carboxylate (10) was obtained in
three steps from -proline by N-methylation using formaldehyde,
followed by catalytic hydrogenation (99% yield)[19] and esterifica-
tion (EtOH, cat. SOCl2) (90% yield). 4-Phenylbut-3-enoic acid
(50a) is commercially available. The products were purified by flash
chromatography.
128.7, 127.7, 125.7, 118.3, 34.1, 16.2 ppm. IR (film): ν = 3022,
˜
1710 cm–1.
General Procedure for the Preparation of Halobis(amine) Salts.
Method 1: Dichloromethane (16 mL) was added to a Schlenk flask
containing dry AgSbF6 (0.488, 1.42 mmol) maintained under ar-
gon. After cooling to –78 °C, a dichloromethane solution (2 mL)
of the desired amine (2.84 mmol) was added dropwise. After 15 min
4,5-Dihydro-4-iodo-5-methyl-5-phenylfuran-2(3H)one
(18):
A
dichloromethane solution (20 mL) of iodobis(collidine) hexafluoro-
phosphate[20] (0.617 g, 12 mmol, 1.2 equiv.) was added to a dichlo-
romethane solution (10 mL) of acid 17 (0.162 g, 10 mmol) during
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0.5 h. After 1 h at room temp. the solvent was removed under vac-
uum and the residue purified by liquid chromatography over silica
uum and a mixture ethanol/toluene (1:1, 10 mL) was added. The
solution was concentrated under vacuum to give quantitatively the
N-methylamine, which was pure enough to be used without purifi-
gel to give iodolactone 18 (0.241 g, 82% yield). White solid: m.p.
1
89.5–90 °C. H NMR (CDCl3, 200 MHz): δ = 7.45–7.26 (m, 5 H), cation. This method was used for the preparation of amines 19, 30,
4.65 (t, J = 6.4 Hz, 1 H), 3.00 (dd, J = 6.2 and 18.2 Hz, 1 H), 3.21
(dd, J = 7.2 and 16.8 Hz, 1 H), 1.94 (s, 3 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 183.6, 140.8, 128.9, 128.5, 124.3, 88.1, 42.2,
32, 33, 37, and 38. The same procedure was used with isobutyral-
dehyde for the preparation of N-isobutylephedrine (26).
N-Ethylephedrine (23): Compound 23 was prepared in two steps
from ephedrine by reaction with acetonitrile, followed by reaction
with H2 on Pd/C following a known procedure.[23]
30.5, 27.7 ppm. IR (film): ν = 2984, 1784 cm–1. C H IO (302.18):
˜
11 11
2
calcd. C 43.73, H 3.67; found C 43.66, H 3.61. The crystal structure
of 18 was established by single-crystal X-ray diffraction.
N-Benzylephedrine (24): Compound 24 was prepared in two steps
from ephedrine by reaction with benzaldehyde (preparation of
amine 35), followed by reaction with sodium borocyanohydride/
TMSCl in acetonitrile.[24]
Representative Procedure for the Enantioselective Iodolactonization
of Acid 17: At –78 °C under argon, a dichloromethane solution
(2 mL) of (–)-(1R,2S)-N-methylephedrine (0.508 g, 2.84 mmol) was
added dropwise to a Schlenk flask containing a dichloromethane
solution (16 mL) of dry AgSbF6 (0.488 g, 1.42 mmol). After 15 min
at –78 °C, a dichloromethane solution of I2 (1.28 mL of 0.18 
solution, 0.23 mmol) was added dropwise. After 15 min, a dichloro-
methane solution (2 mL) of (E)-4-phenylpent-3-enoic acid (17)
(0.1 g, 0.568 mmol) was added dropwise. After 2 h at –78 °C, the
reaction mixture was warmed to room temp. and an aqueous 1 
HCl solution (10 mL) was added. After filtration of the silver salts,
the aqueous phase was extracted with dichloromethane
(3ϫ10 mL). The combined organic phases were washed with brine,
dried (MgSO4) and concentrated under vacuum. The residue was
purified by liquid chromatography over silica gel (petroleum ether/
diethyl ether, 90:10) to give iodolactone 18 (86 mg). [α]2D0 = +22.1
(c = 1.2, CHCl3). The aqueous phase was basified by addition of
1  NaOH (pH10) and extracted with dichloromethane
(3ϫ15 mL). After drying (MgSO4), this organic phase was concen-
trated under vacuum to give (–)-(1R,2S)-N-methylephedrine
(0.50 g, 98% yield).
(1R,2S)-2-(Azetidin-1-yl)-1-phenylpropan-1-ol (28): Compound 28
was obtained by reaction of norephedrine with 1,3-dibromopro-
pane using a reported procedure.[25] 1H NMR (CDCl3, 250 MHz):
δ = 7.27–7.20 (m, 5 H), 4.65 (d, J = 2.7 Hz, 1 H), 3.26 (m, 2 H),
3.17 (m, 2 H), 2.36 (dq, J = 2.7 and 6.5 Hz, 1 H), 1.99 (m, 2 H),
0.56 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ
= 141.4, 127.6, 126.4, 125.8, 125.6, 70.7, 69.0, 53.1 (2 C), 16.4,
8.5 ppm.
(1R,2S)-2-[(3-Hydroxypropyl)(methyl)amino]-1-phenylpropan-1-ol
(29): Compound 29 was obtained in two steps by reaction of eph-
edrine 39 with 3-hydroxypropanenitrile, followed by hydrogenation
on Pd/C.[23]
(1R,2S)-1-Methoxy-N,N-dimethyl-1-phenylpropan-2-amine (31):
Compound 31 was prepared by O-methylation of N-methyleph-
edrine following a reported procedure.[26]
(1R,2S)-[2-(tert-Butyldimethylsilyloxy)-1-methyl-2-phenylethyl]-
amine (40): Compound 40 was prepared following a reported pro-
cedure.[27]
Iodobis(N-methylephedrine) Hexafluoroantimonate (20): Iodo com-
plex 20 was prepared at –78 °C following the procedure (method
1) reported for the preparation of the halobis(amine) salts. This
salt was unstable at a temperature above –20 °C and could not be
characterized.
(1R,2S)-2-[2-(tert-Butyldimethylsilyloxy]-1-methyl-2-phenylethyl-
amino]ethanol (41): A toluene solution (5 mL) of 2-bromoethanol
(0.329 g, 2.71 mmol) was added to a toluene solution (5 mL) of
amine 40 (0.72 g, 2.7 mmol) and the mixture was refluxed for 18 h.
Na2CO3 (0.574 g, 5.42 mmol) was added and the mixture was re-
fluxed again for 18 h. After cooling, the solid was filtered through
Celite. The filtrate was dried (MgSO4) and concentrated under vac-
uum. The residue was then purified by chromatography over silica
gel to give the amino alcohol 41 (0. 48 g, 58%). 1H NMR (CDCl3,
250 MHz): δ = 7.35–7. 26 (m, 5 H), 4.63 (d, J = 4.5 Hz, 1 H), 3.52
Bis(N-methylephedrine)silver Hexafluoroantimonate (21): The silver
salt 21 was prepared using the procedure used for the preparation
of the iodo complex 20. This salt was unstable at room temp. and
could not be characterized. Its reaction at –78 °C with iodine gave
rise to the formation of iodobis(N-methylephedrine) hexafluo-
roantimonate (20).
(S)-5-Methyl-5-phenylfuran-2(5H)-one (22): Iodolactone 18 (75 mg, (t, J = 5.5 Hz, 2 H), 2.87 (m, 1 H), 2.75 (m, 2 H), 1.80 (br. s, 1 H),
0.248 mmol) and NaBH4 (12 mg, 0.496 mmol) were added to a
flask containing HMPA (13 mL). The mixture was stirred for 3 h
at room temp. and then for 1 h at 50 °C. After cooling, water was
added (70 mL) and the aqueous phase was extracted with diethyl
ether (3ϫ20 mL). The combined organic phases were washed with
water (20 mL) and brine (20 mL) and then dried (MgSO4). After
concentration under vacuum, the residue was purified by liquid
chromatography over silica gel (pentane/CH2Cl2, 90:10 to 80:20) to
give lactone 22 (30 mg, 70%) as a yellow oil. [α]2D0 = –92.0 (c = 1,
CHCl3; ee = 45%) {lit.:[10] [α]2D0 = –274.3 (c = 1.2, CHCl3; ee Ͼ
98%)}. 1H NMR (CDCl3, 200 MHz): δ = 7.58 (d, J = 5.5 Hz, 1
H), 7.30–7.27 (m, 5 H), 5.99 (d, J = 5.5 Hz, 1 H), 1.76 (s, 3 H) ppm.
13C NMR (CDCl3, 63 MHz): δ = 171.3, 159.4, 138.2, 127.8, 127.3,
123.7, 118.3, 87.9, 25.3 ppm.
1.00 (d, J = 6.2 Hz, 3 H), 0.91 (s, 9 H), 0.04 (s, 3 H), –0.18 (s, 3
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 142.7, 127.9, 127.1,
126.7, 77.7, 60.8, 59.3, 48.3, 25.8 (3 C), 18.2, 15.3, –4.5, –5.0 ppm.
HRMS: calcd. for C17H21NO2Si 309.2124; found 309.2126.
Preparation of Compound 42: 1,1Ј-Carbonyldiimidazole (0.377 g,
2.3 mmol) was added to a dichloromethane solution (10 mL) of
amino alcohol 41 (0.71 g, 2.3 mmol). After one night at room temp.
water was added (5 mL) and the aqueous phase was extracted with
dichloromethane (2ϫ5 mL). The combined organic phases were
dried (MgSO4) and concentrated under vacuum. The residue was
then purified by liquid chromatography over silica gel to give
(0.63 g) an inseparable mixture of compounds 42 and 34 (1:1.6).
1
Compound 42: H NMR (CDCl3, 250 MHz): δ = 7.38–7.25 (m, 5
H), 5.03 (d, J = 5.5 Hz, 1 H), 3.86 (m, 1 H), 1.29–1.23 (m, 4 H),
1.19 (d, J = 7.0 Hz, 3 H), 0.95 (s, 9 H), 0.05 (s, 3 H), –0.24 (s, 3
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 143.0, 129.3, 128.9,
127.7, 77.9, 65.1, 27.0, 19.3, 19.2, 13.1, –3.5, –4.6 ppm.
C17H29NOSi (291.50): calcd. C 70.04, H 10.03; found C 70.21, H
10.12.
General Method for the Methylation of Amines: A 39% aqueous
formaldehyde solution (21 mmol) and a catalytic amount of 10%
Pd/C were added to a methanol solution (5 mL) of the amine
(10 mmol) . This mixture was stirred overnight under hydrogen
(1 atm). After filtration, the filtrate was concentrated under vac-
3288
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Eur. J. Org. Chem. 2007, 3281–3291

Enantioselective 5-endo Halo-Lactonization Reactions
FULL PAPER
(1R,2S)-NЈ,NЈ-Dimethyl-1-phenylpropane-1,2-diamine (44): Trieth-
1 H), 2.78 (m, 1 H), 2.65 (m, 1 H), 2.30 (s, 6 H), 1.00 (d, J =
ylamine (2.35 mL, 16.7 mmol) and a THF solution (10 mL) of 6.8 Hz, 3 H), 0.68 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3,
methanesulfonyl chloride (0.86 mL, 11.17 mmol) was added to a
THF solution (22 mL) of (1R,2S)-N-methylephedrine. NaN3
(1.085 g, 16.7 mmol) and HMPA (13 mL) were added to the chlora-
mine thus formed at room temp.. After 30 min, a THF solution
(8 mL) of LiAlH4 (0.835 g, 22.2 mmol) was added and after a fur-
ther 30 min, the mixture was hydrolyzed by successive addition of
water (0.84 µL), an aqueous 1  KOH solution (0.84 mL) and
water (2.5 mL). The aqueous phase was extracted with diethyl
ether (3 ϫ 15 mL). The organic phases were washed with water
(3ϫ15 mL), dried (MgSO4) and concentrated under vacuum. The
residue was purified by chromatography on silica gel (eluent
CH2Cl2/MeOH/NH4OH, 90:10:0.2) to give the product in 80 %
yield as a yellow oil. [α]2D0 = –10.3 (c = 2, CH2Cl2). 1H NMR
(CDCl3, 250 MHz): δ = 7.33–7.16 (m, 5 H), 4.18 (d, J = 4.5 Hz, 1
H), 2.48 (m, 1 H), 2.27 (s, 6 H), 1.65 (br. s, 2 H, NH2), 0.88 (d, J
= 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 144.4, 127.8,
126.5, 126.2, 65.6, 56.2, 42.6, 9.7 ppm. HRMS: calcd. for
C11H18N2Na 201.1368; found 201.1369.
General Procedure for the Preparation of Diamines 45–48:[12] Trieth-
ylamine (4.18 mL, 0.03 mol) and then dropwise a THF solution
(20 mL) of methanesulfonyl chloride (1.57 mL, 0.02 mol) were
added to a solution of (1R,2S)-N-methylephedrine (8) in THF
(40 mL) at 0 °C. After 1 h the solvent was removed under vacuum.
The desired amine (0.09 mol, 3 equiv.) in THF/HMPA (1:3) solu-
tion (8 mL) was added, and the mixture was heated for 12 h at
80 °C. After cooling and addition of water (6 mL), the aqueous
phase was extracted with Et2O (3ϫ15 mL). The organic phases
were washed with water (3ϫ15 mL), dried (MgSO4) and concen-
trated under vacuum. The residue was purified by chromatography
on silica gel (eluent CH2Cl2/MeOH/NH4OH, 90:10:0.2).
63 MHz): δ = 142.8, 141.7, 128.1, 127.8, 127.3, 126.7, 126.5, 71.6,
65.5, 61.4, 55.9, 42.7, 15.1, 10.4 ppm. HRMS: calcd. for
C20H28ON2Na 335.2099; found 335.2100.
Preparation of 2-Phenylbutanal (49b):[28] Dess–Martin periodinate
(1.55 g, 3.66 mmol, 1.1 equiv.) was added to a dichloromethane
solution (5 mL) of 2-phenylbutanol (0.5 g, 3.33 mmol). The mix-
ture was stirred for 1 h at room temp. and then a saturated aqueous
solution of Na2S2O3 (10 mL) and a 10 % aqueous solution of
NaHCO3 were added. After separation of the organic phase, the
aqueous phase was extracted with dichloromethane (3 ϫ5 mL).
The combined organic phases were dried (MgSO4) and concen-
trated under vacuum to give the aldehyde 49b (0.48 g, 97% yield),
which was pure enough for the next step. 1H NMR (CDCl3,
250 MHz): δ = 9.68 (s, 1 H), 7.38–7.18 (m, 5 H), 3.41 (t, J = 7.5 Hz,
1 H), 2.15 (m, 1 H), 1.74 (m, 1 H), 0.91 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (CDCl3, 90 MHz): δ = 200.9, 136.2, 128.9, 128.7, 127.4,
60.8, 22.9, 11.6 ppm.
(E)-4-Phenylhex-3-enoic Acid (50b): Compound 50b was prepared
using the procedure described above for the preparation of acid 17.
The crude reaction mixture showed the formation of a mixture
(80:20) of two diastereomers. The pure (E) isomer was obtained as
an oil by liquid chromatography on silica gel (22% yield). 1H NMR
(CDCl3, 360 MHz): δ = 11.70 (br. s, 1 H), 7.37–7.21 (m, 5 H), 5.79
(t, J = 7.2 Hz, 1 H), 3.29 (d, J = 7.0 Hz, 2 H), 2.50 (q, J = 7.2 Hz,
2 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz):
δ = 178.7, 145.4, 139.1, 128.2, 127.0, 126.4, 117.9, 33.8, 23.3,
13.2 ppm. C12H14O2 (190.24): calcd. C 75.76, H 7.42; found C
75.82, H 7.56.
4,4-Diphenylbut-3-enoic Acid (50c): Compound 50c was prepared
following the procedure described above for the preparation of acid
17 (48% yield). This compound has already been reported in the
literature.[29]
(1R,2S)-N,N,NЈ,NЈ-Tetramethyl-1-phenylpropane-1,2-diamine (45):
Yield: 74%. White crystal: m.p. 52 °C. [α]2D0 = –25 (c = 1.0,
CH2Cl2).1H NMR (CDCl3, 250 MHz): δ = 7.35–7.22 (m, 3 H),
7.12–7.08 (m, 2 H), 3.36 (d, J = 10.7 Hz, 1 H), 3.19 (m, 1 H), 2.10
(s, 6 H), 2.06 (s, 6 H), 1.11 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 135.5, 129.2, 127.2, 126.6, 72.2, 58.2, 41.1,
40.2, 8.6 ppm. ES-MS: m/z = 162.2 [M – N(Me)2]+. C13H22N2
(206.32): calcd. C 75.68, H 10.75; found C 75.74, H 10.81.
(E)-4-(4-Methoxyphenyl)pent-3-enoic Acid (50d): Compound 50d
was prepared from aldehyde 49d following the procedure described
above for the preparation of acid 17.[30] An 80:20 mixture of the
two diastereomers was obtained. The pure (E) isomer was obtained
as an oil by liquid chromatography on silica gel (CH2Cl2/Et2O,
1
95:5). Yield: 42%. H NMR (CDCl3, 250 MHz): δ = 10.66 (br. s,
(1R,2S)-NЈ,NЈ-Dimethyl-1-phenyl-N-[(R)-1-phenylethyl]propane-
1,2-diamine (46): Yield: 94%. Yellow oil. [α]2D0 = –139.5 (c = 2.1,
1 H), 7.36–7.32 (m, 2 H), 6.88–6.83 (m, 2 H), 5.85 (t, J = 7.2 Hz,
1 H), 3.81 (s, 3 H), 3.28 (d, J = 9.5 Hz, 2 H), 2.05 (s, 3 H) ppm.
13C NMR (CDCl3, 63 MHz): δ = 178.3, 158.8, 137.9, 135.4, 128.6,
116.7, 113.4, 55.2, 34.1, 16.2 ppm. C12H14O3 (206.24): calcd. C
69.88, H 6.84; found C 69.91, H 6.93.
1
CH2Cl2). H NMR (CDCl3, 250 MHz): δ = 7.36–7.15 (m, 10 H),
3.57 (d, J = 4.5 Hz, 1 H), 3.37 (q, J = 6.6 Hz, 1 H), 2.21 (m, 1 H),
2.02 (s, 6 H), 1.92 (br. s, 1 H), 1.35 (d, J = 7.0 Hz, 3 H), 0.89 (d, J
= 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 145.6, 142.8,
128.0, 127.9, 126.8, 126.6, 126.3, 65.9, 60.3, 54.6, 42.9, 24.2,
11.0 ppm. ES-MS: m/z = 162.2 [M – N(Me)Ph]+. C19H26N2
(282.42): calcd. C 80.80, H 9.28; found C 80.82, H 9.33.
(Z)-4-Phenylpent-3-enoic Acid (51): (E)-4-Phenylpent-3-enoic acid
(17) (0.5 g, 2.84 mmol) in heptane (180 mL) was placed in a Pyrex
photochemical reactor and was irradiated for 5 h at 253.7 nm using
a mercury lamp. The solution was concentrated under vacuum and
the residue purified by liquid chromatography on silica gel to give
the (Z) acid 51 (0.38 g, 77%) and the remaining (E) isomer 17
(0.12 g, 23%). 1H NMR (CDCl3, 250 MHz): δ = 7.38–7.16 (m, 5
H), 5.63 (t, J = 7 Hz, 1 H), 3.05 (d, J = 7 Hz, 2 H), 2.09 (s, 3
H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 178.9, 140.9, 140.7,
128.3, 127.7, 127.0, 117.6, 34.5, 25.6 ppm.
(1R,2S)-NЈ,NЈ-Dimethyl-1-phenyl-N-[(S)-1-phenylethyl]propane-1,2-
diamine (47): Yield: 95%. Yellow oil. [α]2D0 = –142 (c = 1.05,
CH2Cl2). 1H NMR (CDCl3, 63 MHz): δ = 7.33–7.18 (m, 10 H),
4.07 (d, J = 4.3 Hz, 1 H), 3.63 (q, J = 6.5 Hz, 1 H), 2.50 (m, 1 H),
2.30 (s, 6 H), 1.31 (d, J = 6.1 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (CDCl3, 250 MHz): δ = 146.8, 142.7, 128.1,
127.8, 127.7, 126.5, 126.4, 126.3, 65.5, 61.4, 54.1, 42.8, 21.8,
10.5 ppm. C19H26N2 (282.42): calcd. C 80.80, H 9.28; found C
80.75, H 9.34.
Iodolactonization of Acids 50a–d and 51: These iodolactonization
reactions were carried out as reported for the iodolactonization of
acid 17 using the conditions reported in Table 2, entry g. GC analy-
sis (40 m cyclodextrin DM column) of the reaction mixtures al-
lowed the ee of lactones 52a,b, 54, 55 to be calculated (Scheme 11).
(1R,2S)-2-{[(1R,2S)-2-(Dimethylamino)-1-phenylpropyl]amino}-1-
phenylpropan-1-ol (48): Yield: 48 %. White crystal: m.p. 102 °C.
1
[α]2D0 = –28 (c = 1.05, CH2Cl2). H NMR (CDCl3, 360 MHz): δ =
7.37–7.18 (m, 10 H), 4.86 (d, J = 3.2 Hz, 1 H), 4.02 (d, J = 4.7 Hz, Their absolute configurations were deduced, by comparison with
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J. M. Garnier, S. Robin, G. Rousseau
FULL PAPER
lactone 18, from the relative intensity of the two peaks of the
enantiomers.
Silver Complex 59: Silver 4-phenylpent-3-enoate (58) (0.1,
0.353 mmol) was added to a flask containing dichloromethane
(5 mL). (1R,2S)-N-Methylephedrine (0.126 g, 0.706 mmol, 2 equiv.)
was added to this solid suspension. After stirring at room temp.
for 1 h in the dark, the homogeneous solution was concentrated
under vacuum to give the silver complex 59 (100% yield). 1H NMR
(CDCl3, 200 MHz): δ = 7.33–7.14 (m, 15 H), 6.06 (t, J = 7.2 Hz, 1
H), 5.13 (m, 2 H), 3.16 (d, J = 7.2 Hz, 2 H), 2.56 (s, 12 H), 2.41
(m, 2 H), 1.97 (s, 3 H), 0.92 (d, J = 6.2 Hz, 6 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 178.8, 143.4, 142.5, 135.4, 128.0, 126.8,
126.4, 125.8, 125.6, 123.3, 70.7, 67.8, 45.6, 37.2, 15.9, 10.8 ppm.
(4R,5S)-4,5-Dihydro-4-iodo-5-phenylfuran-2(3H)-one (52a): The ra-
cemic lactone has already been reported in the literature.[31] [α]2D0
+5.3 (c = 1.25; CH2Cl2; ee: 15%).
=
(4R,5S)-5-Ethyl-4,5-dihydro-4-iodo-5-phenylfuran-2(3H)-one (52b):
1H NMR (CDCl3, 360 MHz): δ = 7.40–7.26 (m, 5 H), 4.69 (dd, J
= 5.0 Hz, J = 5.0 Hz, 1 H), 3.20 (dd, J = 18.4 and 7.6 Hz, 1 H),
3.00 (dd, J = 5.0 and 18.0 Hz, 1 H), 2.21 (q, J = 7.2 Hz, 2 H), 0.76
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 63 MHz): δ = 173.6,
138.9, 128.9, 128.3, 125.0, 90.1, 42.3, 36.6, 29.1, 9.0 ppm. HRMS:
calcd. for C12H13INaO2 338.9858; found 338.9859.
Iodolactonization of Silver Complex 59: (–)-N-Methylephedrine
(50.6 mg, 0.282 mmol, 2 equiv.) was added to a dichloromethane
solution (2 mL) of silver complex 59 (40 mg, 0.141 mmol, 1 equiv.).
After 30 min at room temp. the flask was cooled to –78 °C. (–)-N-
Methylephedrine (70.8 mg, 0.396 mmol, 2.8 equiv.) was added to a
second flask containing a dichloromethane solution (5 mL) of
AgSbF6 (68 mg, 0.198 mmol, 1.4 equiv.) cooled to –78 °C. After
15 min a dichloromethane solution of iodine (0.314 mL of a 0.18 
solution, 0.4 equiv.) was added. After 15 min at –78 °C the content
of the first flask was added through a cannula to the second flask.
The reaction mixture was maintained for 2 h at –78 °C and then
work up was carried out as previously reported. The racemic iodol-
actone 18 was obtained (32 mg, 76%)
5,5-Diphenylfuran-2(5H)-one (53): Compound 55 has already been
reported in the literature.[32]
(4S,5R)-4,5-Dihydro-4-iodo-5-(4-methoxyphenyl)-5-methylfuran-
2(3H)-one (54): [α]2D0 = –1.5 (c = 0.75, CH2Cl2; ee: 13.5%). 1H
NMR (CDCl3, 250 MHz): δ = 7.37–7.33 (m, 2 H), 6.95–6.88 (m, 2
H), 4.59 (t, J = 7.0 Hz, 1 H), 3.80 (s, 3 H), 3.20 (dd, J = 18.2 and
7.5 Hz, 1 H), 2.99 (dd, J = 18.0 and 6.5 Hz, 1 H), 1.91 (s, 3 H) ppm.
13C NMR (CDCl3, 63 MHz): δ = 173.6, 159.5, 132.6, 125.6, 114.1,
88.1, 55.3, 42.1, 30.2, 27.7 ppm. HRMS: calcd. for C12H13INaO3
354.9802; found 354.9805.
(4R,5R)-4,5-Dihydro-4-iodo-5-methyl-5-phenylfuran-2(3H)-one (55):
1H NMR (CDCl3, 360 MHz): δ = 7.41–7.26 (m, 5 H), 4.70 (dd, J
= 7.2 and 4.7 Hz, 1 H), 3.51 (dd, J = 18.4 and 7.0 Hz, 1 H), 3.12
(dd, J = 18.4 and 4.7 Hz, 1 H), 1.87 (s, 3 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 183.5, 143.2, 128.2, 128.1, 124.9, 89.1, 42.5,
28.4, 25.6 ppm. HRMS: calcd. for C11H11IO2 301.9804; found
301.9805.
(S)-4,5-Dihydro-5-methyl-5-phenylfuran-2(3H)-one (61): AIBN
(3.5 mg) and Bu3SnH (0.110 g, 0.381 mmol) were added to a ben-
zene solution (4 mL) of iodolactone 18 (0.115 g, 0.381 mmol). The
solution was refluxed overnight. After cooling, the solution was
concentrated under vacuum. Acetonitrile (6 mL) was added and
the solution was washed with pentane (3ϫ10 mL). The acetonitrile
solution was concentrated under vacuum and the residue purified
by liquid chromatography on silica gel (pentane/diethyl ether,
80:20) to give lactone 61 as an oil (57 mg, 85% yield). [α]2D0 = –29.5
(c = 0.95, CH2Cl2; ee: 45%) {ref.[34] [α]2D0 = –34.1 (MeOH; ee:
90%)}.
Tetrabutylammonium (E)-4-Phenylpent-3-enoate (56): This salt was
prepared following a known procedure.[33] A 25% MeOH solution
of tetrabutylammonium hydroxide (0.571 mmol, 1.005 equiv.) was
added to a dichloromethane solution (1 mL) of (E)-4-phenylpent-
3-enoic acid (17) (0.1 g, 0.568 mmol). After stirring for 1 h at room
temp. the solution was concentrated under vacuum. Toluene
(2ϫ1 mL) was added to the residue and the mixture was concen-
trated under vacuum to give salt 56 (0.235 g, 100% yield). 1H NMR
(CDCl3, 200 MHz): δ = 7.44–7.14 (m, 5 H), 6.26 (t, J = 7.2 Hz, 1
H), 3.30 (m, 8 H), 3.15 (d, J = 7.0 Hz, 2 H), 2.03 (s, 3 H), 1.60 (m,
8 H), 1.42 (m, 8 H), 0.97 (t, J = 7.0 Hz, 12 H) ppm. 13C NMR
(CDCl3, 63 MHz): δ = 176.7, 144.0, 132.9, 127.8, 126.0, 125.9,
125.2, 58.4, 38.9, 23.7, 19.5, 15.7, 13.4 ppm.
(S)-4,5-Dihydro-5-methyl-3-methylene-5-phenylfuran-2(3H)-one
(62): An ethereal solution (1 mL) of ethyl formate (13 mg,
0.176 mmol) and lactone 61 (31 mg, 0.176 mmol) was added during
1 h to a suspension of NaH (7 mg, 0.176 mmol) in diethyl ether
(1 mL) maintained under argon. After 15 h at room temp. the sol-
vent was removed under vacuum. THF (2 mL) and paraformalde-
hyde (27 mg, 0.88 mmol) were successively added. The mixture was
refluxed for 3 h and after cooling an aqueous 6  HCl solution
(2 mL) was added. The aqueous phase was extracted with diethyl
ether (3ϫ3 mL). The organic phases were then washed with an
aqueous saturated NaHCO3 solution (3 mL), dried (MgSO4) and
concentrated under vacuum. The residue was purified by liquid
chromatography on silica gel (pentane/diethyl ether, 80:20) to give
lactone 62 (25 mg, 75%). [α]2D0 = –2.2 (c = 0.25, CH2Cl2) {ref.[16]
[α]2D0 = –11.3 (c = 1.2, CHCl3)}.
N-Methylephedrinium (E)-4-Phenylpent-3-enoate (57): The pro-
cedure reported for the preparation of compound 56 was followed.
1H NMR (CDCl3, 200 MHz): δ = 7.38–7.14 (m, 10 H), 6.08 (t, J
= 6.5 Hz, 1 H), 5.31 (m, 1 H), 3.11 (d, J = 6.5 Hz, 3 H), 3.04 (m,
1 H), 2.56 (s, 3 H), 1.97 (s, 3 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (CDCl3, 90 MHz): δ = 178.0, 143.1, 134.8, 127.7, 127.6,
126.7, 126.1, 125.4, 125.2, 122.7, 70.2, 65.7, 40.3, 36.7, 15.5,
5.9 ppm.
Crystallographic Data: CCDC-626505 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/datarequest/cif.
Silver 4-Phenylpent-3-enoate (58): 4-Phenylpent-3-enoic acid (17)
(0.5 g) was added to a flask containing a 25% aqueous solution
of NH4OH (0.45 mL, 1 equiv.). After dissolution, AgNO3 (0.58 g,
1.2 equiv.) was added and the mixture was stirred for 1 h at room
temp. in the dark. The white solid was filtered, washed with water
and dried under high vacuum (0.48 g, 60 %). M.p. 154 °C (de-
1
Acknowledgments
comp.). H NMR ([D6]DMSO, 63 MHz): δ = 7.40–7.19 (m, 5 H),
6.00 (t, J = 7.5 Hz, 1 H), 3.06 (d, J = 7.2 Hz, 2 H), 1.98 (s, 3
H) ppm. 13C NMR ([D6]DMSO, 63 MHz): δ = 175.0, 143.0, 134.0, J. M. G. thanks the French Ministry of Education and Research
128.2, 126.6, 125.2, 124.1, 36.9, 15.6 ppm. C11H11AgO2 (283.07): for a grant. The authors express their thanks to Régis Guillot
calcd. C 46.67, H 3.92; found C 46.27, H 3.91.
(ICMMO) for the X-ray structure determination of lactone 18.
3290
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3281–3291

Enantioselective 5-endo Halo-Lactonization Reactions
FULL PAPER
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Received: January 18, 2007
Published Online: May 22, 2007
Eur. J. Org. Chem. 2007, 3281–3291
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3291