Highly stereoselective trans addition of π-type nucleophiles to a bicyclic N-acyliminium ion - Application to the synthesis of indolizidine and pyrrolizidine alkaloids

Article abstract of DOI:10.1002/(SICI)1099-0690(199809)1998:9<1955::AID-EJOC1955>3.0.CO;2-U

Enantiopure bicyclic 5-ethoxytetrahydropyrrolo[1,2-c]oxazol-3-one 1b was prepared in two steps from the known tosylate 4, which is readily available from (S)-pyroglutamic acid. Trapping of the N-acyliminium ion (I), generated in situ from 1b in the presence of Lewis acid, with various silylated π-type nucleophiles gave rise selectively to trans adducts 2. The usefulness of this stereoselective access to trans-2,5-disubstituted pyrrolidines was illustrated by formal syntheses of 3,5-disubstituted indolizidine toxins, starting from 5-allyltetrahydropyrrolo[1,2-c]oxazol-3-one 2a. Moreover, an enantiodivergent synthesis of the pyrrolizidine alkaloids (+) and (-)-xenovenine was achieved starting from the same chiral building block 2a.

Full text of DOI:10.1002/(SICI)1099-0690(199809)1998:9<1955::AID-EJOC1955>3.0.CO;2-U

FULL PAPER
Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic
N-Acyliminium Ion – Application to the Synthesis of Indolizidine and
Pyrrolizidine Alkaloids
a
a
b
a
´
´
Hamid Dhimane , Corinne Vanucci-Bacque , Louis Hamon , and Gerard Lhommet*
a
´
´ ´
Universite P. et M. Curie, UMR 7611, Laboratoire de Chimie des Heterocycles ,
b
`
´
Laboratoire de Synthese Asymetrique ,
4 Place Jussieu, F-75252 Paris Cedex 05, France
Fax: (internat.) ϩ 33 (0)1/44273056
E-mail: lhommet@ccr.jussieu.fr
Received April 20, 1998
Keywords: N-Acyliminium / Pyrrolidine / Indolizidine / Pyrrolizidine / Stereoselective
Enantiopure bicyclic 5-ethoxytetrahydropyrrolo[1,2-c]oxa-
disubstituted pyrrolidines was illustrated by formal syntheses
zol-3-one 1b was prepared in two steps from the known of 3,5-disubstituted indolizidine toxins, starting from 5-
tosylate 4, which is readily available from (S)-pyroglutamic
acid. Trapping of the N-acyliminium ion (I), generated in situ enantiodivergent synthesis of the pyrrolizidine alkaloids (+)
from 1b in the presence of Lewis acid, with various silylated and (–)-xenovenine was achieved starting from the same
allyltetrahydropyrrolo[1,2-c]oxazol-3-one 2a. Moreover, an
π-type nucleophiles gave rise selectively to trans adducts 2. chiral building block 2a.
The usefulness of this stereoselective access to trans-2,5-
Introduction
Results and Discussion
Preparation and Reactivity of Chiral Oxazolidinone 1
Access to enantiopure trans-2,5-disubstituted pyrroli-
dines has attracted particular attention on account of their
occurrence in natural products such as pyrrolizidine[1] and
indolizidine[2] alkaloids, and of their utilisation as chiral
auxiliaries[3] in enantioselective synthesis. Consequently,
many efforts have been devoted to devise methods for their
preparation, with modest to high trans selectivities.[4]
Among these methods the nucleophilic addition of organo-
copper reagents to N-acyliminium ions derived from proline
constitutes a highly stereoselective route to trans-2,5-disub-
stituted pyrrolidines,[5] which has been exploited in the syn-
thesis of indolizidine alkaloids.[6] However, potentially more
versatile π-type nucleophiles are known to add to these lat-
ter N-acyliminium ions with a high degree of cis selec-
tivity.[7] In sharp contrast to these results, we recently found
that bicyclic N-acyliminium ion I, when treated with silyl-
ated π-type nucleophiles, selectively led to trans adducts 2[8]
(Scheme 1).
We initially envisioned straight access to the required am-
ino ether 1 by oxidation of the known readily available bi-
cyclic oxazolidinone 3.[9] Since ruthenium-catalysed α-oxi-
dation following MurahashiЈs procedure[10] was ineffective,
we considered α-electromethoxylation, which is known to
take place selectively at the less substituted α position of
the nitrogen atom.[11] Unfortunately, anodic electromethox-
ylation (CϪC, Et4NOTs, Ϫ10°C, MeOH) of bicyclic carba-
mate 3 mainly afforded the undesired regioisomer 1Јa along
with the expected compound 1a as an inseparable mixture
(ratio 1a/1Јa ϭ 1:3) (Scheme 2).
Scheme 2
Scheme 1
Screening of various conditions (temperature, electrolyte,
current density, etc.) did not significantly modify this result.
A similar reverse regioselectivity has been observed for elec-
tromethoxylation of bicyclic oxazinones.[12] These disap-
pointing results prompted us to consider the preparation of
We report herein our study toward the synthesis of carbi- compound 1 by a reductive method, starting from the
nolamine 1, precursor of iminium ion I, and its reactivity known tosylate 4,[13] easily available in multigram quantities
with various silylated π-type nucleophiles in the presence of from (S)-pyroglutamic acid (Scheme 3).
Lewis acid. Then, we describe the use of this methodology
in the synthesis of pyrrolizidine and indolizidine alkaloids, dride (SuperϪH) at Ϫ78°C and subsequent oxidative
constituents of ant venom and frog poison. workup resulted in the chemoselective partial reduction of
Treatment of compound 4 with lithium triethylborohy-
Eur. J. Org. Chem. 1998, 1955Ϫ1963
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
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1955

´
H. Dhimane, C. Vanucci-Bacque, L. Hamon, G. Lhommet
FULL PAPER
Scheme 3
adducts 2f, with a significant drop in facial selectivity (de ϭ
40%) (entry 8).
The stereochemistry of the major isomers was found to
be trans in all cases 2aϪ2f. On the one hand, the trans
stereochemistry of the major allylated adduct 2a was as-
signed based on chemical correlation after comparison of
its analytical data with those of a cis-enriched sample.[18]
On the other hand, X-ray analyses performed on two crys-
talline compounds secured the trans stereochemistry of the
major isomer of aromatic ketone 2c, and the cis stereo-
chemistry of the minor isomer of cyano adduct 2f. Finally,
examination of 13C-NMR data allowed the extension of
this stereochemical assignment to all the obtained major
oxazolidinones 2.[8]
The observed diastereoselectivity of the nucleophilic at-
tack of allyltrimethylsilane on iminium ion I was indeed
opposite to that obtained for the monocyclic iminium ion
II, which led preferentially to the cis stereoisomer[7]
(Scheme 4). The latter result was explained by Barrett et al.
as the result of a balance between steric and stereoelectronic
effects.[19] In the case of bicyclic iminium ion I, the observed
facial selectivity can be explained on the basis of steric ef-
fects due to its concave shape. However, in order to have
some more insight regarding these effects, we performed
AM1 calculations[20][21] on the initial states of the N-acylim-
inium moieties I and II, and on the transition states of the
nucleophilic reaction of allyltrimethylsilane on these species
(Table 2).
Reagents: (a) LiEt3BH, CH2Cl2, Ϫ78°C, then NaOH, H2O2. Ϫ (b)
EtOH-CHCl3, reflux.
the lactam moiety,[14] cleanly providing hemiaminal 5 as a
(1:1) diastereomeric mixture in a quantitative yield. When
refluxed without further purification in the binary system
CHCl3ϪEtOH, the latter compound gave rise to trans-α-
ethoxyoxazolidinone 1b in 43% overall yield starting from
4.[15] This chemical transformation is the result of a one-
pot two-step procedure, i.e. intramolecular nucleophilic dis-
placement of the tosylate by an N-Boc group,[16] then
etherification of the hemiaminal moiety, or vice versa.[17]
Attempts to perform the intramolecular nucleophilic dis-
placement prior to semireduction of the lactam group
failed, probably because of a low nucleophilicity of the N-
Boc moiety due to the delocalisation of the nitrogen lone
pair on the lactam carbonyl group. The N-Boc cleavage is
the only observed reaction when 4 is refluxed in toluene,
whereas no reaction was observed in other solvents (EtOH,
CHCl3, THF, etc.).
Once the access to the required ion precursor 1b was
settled, we investigated its reactivity towards various silyl-
ated π-type nucleophiles (Table 1). Reaction of 1b was first
examined with allyltrimethylsilane as nucleophile catalysed
by a variety of Lewis acids (BF3·OEt2, TiCl4, TMSOTf),
giving rise to compound 2a. Except for some differences in
the chemical yields, the observed diastereoselectivity (96:4)
remained unchanged whatever the nature of the Lewis acid
used (entries 1Ϫ3). Extension of this study to silylated enol
ethers showed that only TMSOTf gave satisfactory results
in term of chemical yields, while the diastereomeric ex-
cesses, ranging from 88 to 100%, were in all cases satisfac-
tory (entries 4Ϫ7). However, attempted reaction of 1b with
Scheme 4
The main difference between these substrates lies in the
tert-butyl isocyanide, 1-trimethylsiloxy-1,3-butadiene, azi- geometry around the nitrogen atom. It appears that the
dotrimethylsilane or [(1-ethoxycyclopropyl)oxy]trimethylsi- five-membered ring monocyclic iminium ion II exhibits
lane failed, resulting in unidentifiable dark mixtures. Lastly, only very little distortion from planarity, whereas the nitro-
the small nucleophile cyanotrimethylsilane reacted ef- gen atom of bicyclic iminium I, due to the presence of two
ficiently with substrate 1b, to afford cyanooxazolidinone five-membered fused rings, shows an important distortion
Table 1: Reactions of aminoether 1b with various π-type nucleophiles
Entry
NuTMS
Lewis acid
RϪ
Yield[a] of 2 (%)
Ratio[b] trans/cis
1
2
3
4
5
6
7
8
CH2ϭCHCH2TMS
CH2ϭCHCH2TMS
CH2ϭCHCH2TMS
Me2CϭCHOTMS
CH2ϭC(Ph)OTMS
CH2ϭC(tBu)OTMS
Me2CϭC(OMe)OTMS
NϵCTMS
BF3·Et2O
TiCl4
CH2ϭCHCH2Ϫ
CH2ϭCHCH2Ϫ
CH2ϭCHCH2Ϫ
HOCCMe2Ϫ
PhCOCH2Ϫ
tBuCOCH2Ϫ
MeO2CCMe2Ϫ
NCϪ
2a (60)
2a (90)
2a (65)
2b (43)[c]
2c (86)
2d (83)
2e (73)
2f (95)
96:4
95:5
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
96:4
100:0
94:6
100:0
97:3
70:30
[a]
[b]
[c]
Isolated yields. Ϫ The diastereomeric ratios were determined by capillary GC. Ϫ This yield does not take into account an other
batch of aldehyde 2b which remained contaminated by an unidentified compound after chromatography.
1956
Eur. J. Org. Chem. 1998, 1955Ϫ1963

Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic N-Acyliminium Ion
FULL PAPER
Table 2. Variation in dihedral angles for trans and cis approaches some indolizidine (gephyrotoxines) and pyrrolizidine (xeno-
of the allytrimethylsilane nucleophile
venines) alkaloids in order to illustrate the usefulness of the
chiral synthon trans 5-allyloxazolidinopyrrolidine 2a, read-
ily available on multigram scale. The stereoselective con-
struction of the bicyclic skeletons relies on catalytic hydro-
genation of the transient iminium ion III, generated in situ
by debenzyloxycarbonylation and subsequent annulative
amination from appropriate ketopyrrolidines. The latter
compound can be elaborated from chiral synthon 2a, de-
pending on the required substituents (Scheme 5).
Scheme 5
[a]
[b]
Nu ϭ allyl. Ϫ Dihedral angles for transition states.
from planarity, the dihedral angle between AcylϪNϪC5
and C2ϪNϪC5 being 150.3° (instead of 180° for a planar
nitrogen atom). As expected in the monocyclic compound
II, the ester group is in a pseudoaxial position due to the
steric repulsion with the N-acyl substituent. The facial se-
lectivity in the approach of the allylsilane depends essen-
tially upon steric hindrance between the incoming allyl
group and the substituents (X,Y) of the iminium moiety,
but also upon the changes in hindrance between the latter.
For the bicyclic iminium ion I, an insight in the dihedral
angles in the transition states reveals that the steric hin-
drance between the incoming allyl moiety and the carba-
mate group is more important for the cis approach (␾ ഠ
40°) than for the trans one (␾ ഠ 110°). Such a discrimi-
nation does not appear for the monocyclic iminium ion II.
For this latter ion however, the important term seems to be
the changes in the dihedral angle between the two meth-
oxycarbonyl groups. The allyl attack on the double bond
pushes the acyl substituent on the nitrogen atom towards
the opposite side to minimise the steric hindrance between
these groups (allyl and carbamate). During the approach
trans to the ester substituent, the dihedral angle between
the two methoxycarbonyl groups diminishes, thus increas-
ing the steric hindrance. Conversely, cis approach pushes
the N-acyl group apart from the ester one, widening this
dihedral angle. As a conclusion, trans attack on the bicyclic
iminium ion I is favoured due to lower steric hindrance be-
tween the incoming nucleophile and the N-acyl group,
whereas for the monocyclic ion II, the cis approach is pre-
ferred due to a relief in the steric hindrance existing between
the two methoxycarbonyl groups. Moreover, the calculated
values of the differences in the energy of the transition
states between the trans and cis approaches of iminium ions
I and II are indicative of the observed diastereoselectivities,
even if they do not fit exactly with the experimental data
[for I: ∆E(trans Ϫ cis) ϭ Ϫ1.34 kcal molϪ1; for II: ∆E(trans
Ϫ cis) ϭ 3.24 kcal molϪ1].
Previous investigations in our laboratory have revealed
that the enantiopure trans-5-butyl-2-(2-oxoethyl)pyrrolidine
compound 10 serves as a common chiral building block in
the preparation of (Ϫ)-indolizidines 223AB[22] and
239AB,[4e] which are extracted from the skin of the Col-
ombian poison-frog Dendrobates histrionicus[23] (Scheme 6).
Scheme 6: Formal synthesis of (Ϫ)-indolizidines 223AB and
239AB
Reagents: (a) 30% KOH-1,4-dioxane, reflux. Ϫ (b) C6H5CH2O-
COCl, Na2CO3, CH2Cl2. Ϫ (c) p-TsCl, NEt3, CH2Cl2. Ϫ (d)
nPr2CuLi, Et2O, Ϫ20°C. Ϫ (e) Cat.OsO4, NaIO4, THF/H2O.
In our case, this intermediate was obtained in five steps
from key compound 2a (Scheme 6). Opening of oxazolidi-
none ring was achieved by the action of aqueous 30% KOH
in refluxing 1,4-dioxane to give quantitatively amino al-
cohol 6, which was converted without further purification
to the N-(benzyloxycarbonyl)prolinol derivative 7 in 87%
overall yield. Treatment of the latter with tosyl chloride and
NEt3 in CH2Cl2 smoothly gave p-toluenesulfonate 8 in 98%
yield. Subsequent 3-carbon homologation, necessary to in-
Synthesis of Naturally Occuring Alkaloids
As an application of this highly stereoselective method- stall the n-butyl group, was accomplished by the action of
ology for the obtention of chiral trans 2,5-disubstituted pyr- (n-C3H7)2CuLi in Et2O at Ϫ20°C to afford compound 9 in
rolidines, we now describe the (formal or total) syntheses of 78% yield. Finally, ozonolysis at Ϫ78°C of the allyl group
Eur. J. Org. Chem. 1998, 1955Ϫ1963
1957

´
H. Dhimane, C. Vanucci-Bacque, L. Hamon, G. Lhommet
FULL PAPER
of 9 resulted in formation of the target aldehyde 10 in mod- obtained exhibited 1H- and 13C-NMR analytical data in full
erate yield (50%). The latter, however, was raised to 70% accordance with those reported for dextrorotatory enanti-
by treating 9 with a catalytic amount of OsO4 in the pres- omer.[25][27] Moreover, the optical rotation of (Ϫ)-13 was
ence of NaIO4 in THF·H2O.
Ϫ11.4 (c ϭ 1.37, CHCl3), which is very close to the values
On the other hand, trans-2,5-disubstituted pyrrolidine of Ϫ11.6 (c ϭ 0.6, CHCl3) and Ϫ11.5 (c ϭ 0.5, CHCl3)
substructures are equally found in some naturally occuring cited for samples obtained by Oppolzer et al.[26] and Mo-
pyrrolizidines.[1] We thus envisioned enantiodivergent syn- mose et al.[27], respectively.
thesis of both enantiomers of xenovenine 13, which is found
Scheme 8: Total synthesis of (Ϫ)-xenovenine
in ant venom[24] (Solenopsis xenovenum), starting from the
common key intermediate 8, previously involved in the for-
mal synthesis of (Ϫ)-indolizidines 223AB and 239AB. Ad-
equate functional transformations of both 2- and 5-sub-
stituents of enantiopure pyrrolidine 8 must indeed selec-
tively lead to either (ϩ)- or (Ϫ)-xenovenines. As depicted
in Scheme 7, the synthesis of (ϩ)-xenovenine began with
treatment of tosylate 8 with SuperϪH in THF at room tem-
perature giving rise to pyrrolidine 11 in 79% yield. Sub-
sequent oxidative hydroboration of the allyl substituent af-
forded alcohol 12 in 76% yield. This compound exhibited
analytical spectroscopic data identical with those of the
synthetic material previously obtained in our laboratory[25]
by kinetically controlled carbamate formation of a (1:1) dia-
stereomeric mixture of the corresponding amino alcohols.
The effective transformation of 12 into (ϩ)-xenovenine has
indeed already been established.[25]
Reagents: (a) nHex2CuLi, Et2O, Ϫ20°C. Ϫ (b) BH3·(CH3)2S, then
NaOH, H2O2. Ϫ (c) (COCl)2, DMSO, NEt3, CH2Cl2. Ϫ60°C. Ϫ
(d) MeMgCl, THF. Ϫ (e) (COCl)2, DMSO, NEt3, CH2Cl2. Ϫ (f)
H2, Pd/BaSO4, MeOH.
Scheme 7: Formal synthesis of (ϩ)-xenovenine
Conclusion
The first part of this study was devoted to the reactivity
of the bicyclic N-acyliminium ion I towards various π-type
nucleophiles. In most cases, the nucleophilic additions took
place with good to excellent facial selectivity giving rise to
trans-2,5-disubstituted pyrrolidine derivatives. The effective-
ness of this method was then illustrated by using the allylic
adduct 2a as a common precursor in the formal or total
syntheses of some naturally occuring indolizidine and pyr-
rolizidine alkaloids.
Reagents: (a) LiEt3BH, THF, room temp. Ϫ (b) BH3·(CH3)2S,
Et2O, then NaOH, H2O2.
After this formal synthesis, we undertook the total syn-
thesis of levorotatory enantiomer (Ϫ)-xenovenine (Scheme
8). Our synthesis was initiated with the nucleophilic dis-
placement of the tosylate group of intermediate 8 with n-
Hex2CuLi in Et2O at Ϫ20°C in 78% yield. Resulting trans-
pyrrolidine 14 was next subjected to oxidative hydrobora-
tion to afford alcohol 15 in 79% yield. Further oxidation
of this primary alcohol 15 using pyridinium dichromate as
reagent gave aldehyde 16 only in modest yield (47%) after
two days reaction. Compound 16 was, however, smoothly
obtained in better yield (87%) following SwernЈs con-
ditions. The transformation of aldehyde 16 into the required
methyl ketone 18 was performed according to a two-step
Experimental Section
General: Unless otherwise specified, materials were purchased
from commercial suppliers and used without further purification.
Ϫ THF and Et2O were distilled from Na benzophenone ketyl im-
mediately prior to use. Ϫ CH2Cl2 was distilled from calcium hy-
dride. Ϫ All reactions involving organometallic reagents were car-
ried out under argon. Ϫ Analytical thin-layer chromatography was
procedure, i.e. nucleophilic addition of methylmagnesium performed on Merck precoated silica gel (60 F254) plates and col-
umn chromatography on silica gel Gerudan SI 60 (40Ϫ60 µm)
(Merck). Ϫ Melting points are uncorrected. Ϫ IR: Philips PU 9700.
Ϫ Optical rotations: Perkin-Elmer 241 polarimeter. Ϫ Elemental
chloride and subsequent Swern oxidation of the resulting
diastereomeric mixture of alcohols 17. Finally, exposure of
18 to hydrogen in the presence of Pd/BaSO4 as a catalyst in
methanol provided the desired pyrrolizidine alkaloid (Ϫ)-
xenovenine 13, along with its C-5 epimer[24] (10% as esti-
mated by GC). The obtained diastereoselectivity is compar-
able with that reported previously by Oppolzer and cowork-
ers[26] in similar conditions starting from 18. Removal of
the minor C-5 epimer by column chromatography gave the
´
´
analyses: Service Regional de Microanalyse de lЈUniversite P. et M.
Curie. Ϫ NMR: Bruker ARX 250 spectrometer (250 MHz and 62.9
MHz for 1H and 13C, respectively). Spectra were recorded in CDCl3
as solvent, and chemical shifts (δ) were expressed in ppm relative
1
to residual CHCl3 at δ ϭ 7.27 for H and to CDCl3 at δ ϭ 77.1
for 13C. When an acyclic carbamate moiety is present in a molecule,
peak doubling due to the presence of two rotamers is observed in
pure (Ϫ)-xenovenine (13) in 60% yield. The sample thus 1H and 13C NMR.
1958
Eur. J. Org. Chem. 1998, 1955Ϫ1963

Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic N-Acyliminium Ion
FULL PAPER
Electromethoxylation of Oxazolidinone 3: A 25-ml undivided
H), 4.50 (dd, J ϭ 1 and 8.5 Hz, 1 H), 5.17 (dd, J ϭ 4.8 and 6.4
Hz, 1 H). Ϫ 13C NMR: δ ϭ 14.86, 31.17, 33.77, 57.81, 64.30, 67.93,
jacketed cell was charged with a magnetic stir-bar, oxazolidinone
3[9] (1 g, 7.87 mmol), dry MeOH (15 ml) and tetraethylammonium 90.13, 160.72. Ϫ C8H13NO3 (171.19): calcd. C 56.12, H 7.65, N
p-toluenesulfonate (0.31 g, 2 mmol). Two graphite plates (2.5 ϫ 3
cm) spaced 4Ϫ5 mm apart were immersed into the methanolic solu-
tion. While the electrolysis cell temperature was maintained at
Ϫ5°C, under inert atmosphere, a constant current of 0.12 A (volt-
age 8Ϫ12 V) was passed through the solution. Progress of the an-
odic oxidation was monitored by GC. After 4 F/mol had passed
through the solution, the electrolysis was stopped and the reaction
mixture was concentrated in vacuo. The resulting residue was dis-
solved in CH2Cl2 (15 ml) and washed with water (20 ml). The aque-
ous phase was extracted with CH2Cl2 (2 ϫ 10 ml) and the com-
bined organic extract dried with Na2SO4 and concentrated in
vacuo. Examination of the NMR data of the crude residue essen-
tially revealed the presence of a mixture of isomers 1a and 1Јa (ratio
1:3 according to GC). The oily residue was chromatographed
(AcOEt/cyclohexane, 1:2) to give 707 mg (57%) of an inseparable
mixture of 1a and 1Јa, which were characterised as follow.[28]
8.18; found C 56.29, H 7.60, N 8.11.
(5S,7aS)-5-Allyltetrahydropyrrolo[1,2-c]oxazol-3-one (2a): To a
cooled stirred solution of 1b (3.35 g, 19.6 mmol) and allyltrimeth-
ylsilane (15.6 ml, 98.1 mmol) in CH2Cl2 (150 ml) at Ϫ78°C under
argon, was added dropwise TiCl4 (2.36 ml, 21.5 mmol). The reac-
tion mixture was allowed to warm slowly to room temp. under
stirring overnight. Hydrolysis with saturated aqueous NaHCO3
solution (150 ml) was followed by extraction with CH2Cl2 (3 ϫ 100
ml). The combined organic layers were washed with water (100 ml),
then dried with Na2SO4 prior to concentration. Column chroma-
tography (AcOEt/cyclohexane, 1:1) of the residue afforded 2.95 g
22
(90%) of oily 2a. Ϫ [α]D ϭ Ϫ75 (c ϭ 1.02, MeOH). Ϫ IR (neat):
1
ν
˜
ϭ 1740 cmϪ1. Ϫ H NMR: δ ϭ 1.4Ϫ1.7 (m, 2 H), 2.0Ϫ2.1
max
(m, 1 H), 2.1Ϫ2.4 (m, 3 H), 3.9Ϫ4 (m, 2 H), 4.19 (dd, J ϭ 3.2 and
8.9 Hz, 1 H), 4.5 (dd, J ϭ 7.9 and 8.9 Hz, 1 H), 5.1Ϫ5.2 (m, 2 H),
5.75Ϫ5.9 (m, 1 H). Ϫ 13C NMR: δ ϭ 31.46, 31.96, 40.27, 58.20,
58.90, 67.46, 117.52, 134.22, 161.53. Ϫ C9H13NO2 (167.21): calcd.
C 64.65, H 7.83, N 8.37; found C 64.50, H 7.91, N 8.35.
(5R,7aS)-5-Methoxytetrahydropyrrolo[1,2-c]oxazol-3-one (1a):
IR (neat): ν˜max ϭ 1755 cmϪ1. Ϫ 1H NMR: δ ϭ 1.4Ϫ1.55 (m, 1 H),
1.75Ϫ1.9 (m, 1 H), 2.05Ϫ2.15 (m, 1 H), 2.3Ϫ2.45 (m, 1 H), 3.36
(s, 3 H), 3.95Ϫ4.10 (m, 2 H), 4.45 (td, J ϭ 1 and 8.6 Hz, 1 H),
5.01 (dd, J ϭ 4.7 and 6.4 Hz, 1 H). Ϫ 13C NMR: δ ϭ 30.10, 33.28,
55.73, 57.45, 67.75, 91.38, 160.20.
Typical Procedure for Reaction of π-Type Nucleophiles with 1b in
the Presence of TMSOTf as Lewis Acid: To a cooled stirred solu-
tion of 1b (100 mg, 0.584 mmol) and nucleophile (5 equiv.) in
CH2Cl2 (5 ml) at Ϫ78°C under argon, was added dropwise
TMSOTf (3 equiv.). The reaction mixture was allowed to warm
slowly to room temp. under stirring overnight. Hydrolysis with
saturated aqueous NaHCO3 solution (10 ml) was followed by ex-
traction with CH2Cl2 (3 ϫ 20 ml). The combined organic layers
were washed with water (20 ml), then dried with Na2SO4 prior to
concentration and purification by column chromatography.
7a-Methoxytetrahydropyrrolo[1,2-c]oxazol-3-one
(1Јa):
1H
NMR: δ ϭ 1.85Ϫ2 (m, 1 H), 2.1Ϫ2.3 (m, 3 H), 3.25 (s, 3 H),
3.3Ϫ3.4 (m, 1 H), 3.55Ϫ3.7 (m, 1 H), 4.17 (d, J ϭ 10.3 Hz, 1 H),
4.43 (d, J ϭ 10.3 Hz, 1 H). Ϫ 13C NMR: δ ϭ 25.6, 37.1, 44.6, 49.5,
69.7, 98.9, 158.7.
(5S)-1-[(tert-Butyloxy)carbonyl]-2-hydroxy-5-(toluene-4-sul-
fonyloxymethyl)pyrrolidine (5): To a stirred cooled solution of 4[13]
(10 g, 27 mmol) in CH2Cl2 (100 ml) at Ϫ78°C under argon, was
added dropwise a 1  solution of LiEt3BH in THF (40 ml, 40
mmol). The mixture was stirred for 4 h at this temperature, then
quenched with saturated aqueous NaHCO3 solution (75 ml). The
reaction mixture was slowly allowed to reach 0°C, then 35% H2O2
solution (10 ml) was carefully added. After stirring for an ad-
ditional 2 h at room temp., the reaction mixture was concentrated
in vacuo, then extracted with CH2Cl2 (3 ϫ 150 ml). The organic
layer was dried with Na2SO4 and concentrated to yield crude, sy-
rupy (1:1) diastereomeric mixture of compound 5 (10.1 g) virtually
pure as seen by NMR and TLC, and which was used in the next
step without further purification. Ϫ IR (neat): ν˜max ϭ 3360, 1750
(5S,7aS)-5-(1,1-Dimethyl-2-oxoethyl)tetrahydropyrrolo[1,2-c]-
oxazol-3-one (2b): The crude product obtained from 1b and 2-
methyl-1-(trimethylsiloxy)-1-propene as outlined in the typical pro-
cedure was purified by column chromatography (AcOEt/cyclohex-
ane, 1:1) to give 50 mg (43%) of pure 2b as an oil. Ϫ [α]D22 ϭ Ϫ64
1
(c ϭ 0.75, MeOH). Ϫ IR (neat): ν˜max ϭ 1755 cmϪ1. Ϫ H NMR:
δ ϭ 1.07 (s, 3 H), 1.13 (s, 3 H), 1.4Ϫ1.5 (m, 1 H), 1.7Ϫ1.8 (m, 1
H), 1.8Ϫ2.2 (m, 2 H), 3.8Ϫ3.85 (m, 1 H), 3.92 (t, J ϭ 8.1 Hz, 1
H), 4.17 (dd, J ϭ 2.5 and 9 Hz, 1 H), 4.46 (dd, J ϭ 7.9 and 9 Hz,
1 H), 9.6 (s, 1 H). Ϫ 13C NMR: δ ϭ 18.39, 19.36, 28.14, 31.53,
50.07, 60.30, 64.09, 66.99, 162.18, 205.11. Ϫ C10H15NO3 (197.23):
calcd. C 60.89, H 7.66, N 7.10; found C 61.01, H 7.62, N 7.02.
(5S,7aS)-5-(2-Oxo-2-phenylethyl)tetrahydropyrrolo[1,2-c]
oxazol-3-one (2c): The crude product obtained from 1b and 1-
phenyl-1-(trimethylsiloxy)ethylene as outlined in the typical pro-
cedure was purified by column chromatography (AcOEt/cyclohex-
ane, 1:1) to give 126 mg (88%) of 2c as a white solid. Recrystalli-
sation from AcOEt/cyclohexane afforded white crystals which
structure was confirmed by X-ray analysis[31], m.p. 93Ϫ94°C. Ϫ IR
1
cmϪ1. Ϫ H NMR: δ ϭ 1Ϫ2.2 (series of m including s, 13 H), 2.3
(s, 3 H), 3.39Ϫ3.42 and 3.86Ϫ4.17 (m, 4 H), 5.1Ϫ5.4 (m, 1 H), 7.20
(br. d, J ϭ 6.3 Hz, 2 H), 7.7 (dd, J ϭ 6.5 and 8.4 Hz, 2 H). Ϫ 13C
NMR: δ ϭ 21.62, 24.90, 25.75, 28.22, 30.42, 30.86, 31.57, 55.84,
62.72, 81.14, 82.17, 82.76, 127.81, 127.92, 129.92, 132.74, 145.03,
154.35.
1
(neat): ν˜max ϭ 1750, 1680, 1600 cmϪ1. Ϫ H NMR: δ ϭ 1.45Ϫ1.6
(5R,7aS)-5-Ethoxytetrahydropyrrolo[1,2-c]oxazol-3-one (1b): A
stirred solution of crude 5 (10.1 g, 27 mmol) in a mixture of EtOH
(250 ml)/CHCl3 (30 ml) was refluxed for 24 h. The solvents were
evaporated and the oily residue was dissolved in CH2Cl2. The or-
ganic layer was washed with 1  NaOH solution (50 ml), dried
with Na2SO4, then concentrated in vacuo. The residue was chroma-
tographed (AcOEt/cyclohexane, 1:1) to give 2 g (43% overall from
5) of expected 1b, as white solid, m.p. 76°C (AcOEt/cyclohexane).
(m, 1 H), 1.65Ϫ1.8 (m, 1 H), 2Ϫ2.1 (m, 1 H), 2.45Ϫ2.55 (m, 1 H),
3.15 (dd, J ϭ 9 and 16.9 Hz, 1 H), 3.48 (dd, J ϭ 4 and 16.9 Hz, 1
H), 3.95Ϫ4.1 (m, 1 H), 4.14 (dd, J ϭ 3.7 and 8.9 Hz, 1 H), 4.25Ϫ4.4
(m, 1 H), 4.46 (t, J ϭ 8.3 Hz, 1 H), 7.4Ϫ7.6 (m, 3 H), 7.95 (m, 2
H). Ϫ 13C NMR: δ ϭ 31.76, 33.51, 44.61, 55.53, 59.00, 67.82,
128.02, 128.65, 133.32, 136.63, 161.29, 197.79. Ϫ C14H15NO3
(245.28): calcd. C 68.55, H 6.16, N 5.71; found C 68.32, H 6.21,
N 5.73.
21
Ϫ [α]D ϭ Ϫ7.3 (c ϭ 1.05, MeOH). Ϫ IR (CHBr3): ν˜max ϭ 1750
1
cmϪ1. Ϫ H NMR: δ ϭ 1.21 (t, J ϭ 7 Hz, 3 H), 1.4Ϫ1.5 (m, 1 H),
(5S,7aS)-5-(3,3-Dimethyl-2-oxobutyl)tetrahydropyrrolo[1,2-c]-
1.8Ϫ2 (m, 1 H), 2.1Ϫ2.2 (m, 1 H), 2.3Ϫ2.4 (m, 1 H), 3.58 (qd, J ϭ oxazol-3-one (2d): The crude product obtained from 1b and (2,2-
7 and 9 Hz, 1 H), 3.75 (qd, J ϭ 7 and 9 Hz, 1 H), 4.0Ϫ4.1 (m, 2 dimethyl-1-methylenepropoxy)trimethylsilane as outlined in the
Eur. J. Org. Chem. 1998, 1955Ϫ1963
1959

´
H. Dhimane, C. Vanucci-Bacque, L. Hamon, G. Lhommet
FULL PAPER
typical procedure was purified by column chromatography (AcOEt/
washed with CH2Cl2. Concentration and purification of the residue
cyclohexane, 1:1) to give 109 mg (83%) of 2d as a white solid, m.p. by column chromatography (AcOEt/cyclohexane, 1:1) yielded 0.54
21
22
95.5°C. Ϫ [α]D ϭ Ϫ66 (c ϭ 0.77, MeOH). Ϫ IR (neat): ν˜max
ϭ
g (87% overall from 6) of 7 as an oil. Ϫ [α]D ϭ Ϫ 54 (c ϭ 0.99,
1740, 1700 cmϪ1. Ϫ H NMR: δ ϭ 1.14 (s, 9 H), 1.45Ϫ1.65 (m, 2
CHCl3). Ϫ IR (neat): ν˜max ϭ 3400, 1670 cmϪ1. Ϫ H NMR: δ ϭ
1
1
H), 2.05Ϫ2.1 (m, 1 H), 2.45Ϫ2.5 (m, 1 H), 2.74 (dd, J ϭ 9 and 1.67Ϫ1.75 (m, 2 H), 1.91Ϫ2.16 (m, 3 H), 2.4Ϫ2.55 (m, 0.7 H),
17.7 Hz, 1 H), 3.03 (dd, J ϭ 3.8 and 17.7 Hz, 1 H), 4Ϫ4.1 (m, 1 2.6Ϫ2.75 (m, 0.3 H), 3.4Ϫ3.75 (m, 2 H), 3.85Ϫ4.10 (m, 3 H),
H), 4.1Ϫ4.2 (m, 1 H), 4.16 (dd, J ϭ 3.7 and 8.8 Hz, 1 H), 4.49 (dd, 4.95Ϫ5.05 (m, 2 H), 5.15 (m, 2 H), 5.55Ϫ5.8 (m, 1 H), 7.35 (m, 5
J ϭ 8 and 8.8 Hz, 1 H). Ϫ 13C NMR: δ ϭ 26.30, 31.84, 33.62,
H). Ϫ 13C NMR: δ ϭ 25.89, 26.20, 27.40, 36.66, 37.94, 57.90,
42.60, 44.16, 55.32, 59.11, 67.80, 161.33, 213.83. Ϫ C12H19NO3 58.88, 60.15, 63.07, 65.13, 66.49, 66.94, 117.12, 117.37, 127.74,
(225.29): calcd. C 63.97, H 8.50, N 6.21; found C 64.00, H 8.60, 127.89, 128.34, 134.56, 135.03, 136.25, 136.58, 154.13, 155.78. Ϫ
N 6.14.
C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N 5.09; found C
69.67, H 7.76, N 5.03.
(5S,7aS)-5-(1-Methoxycarbonyl-1-methylethyl)tetrahydropyr-
rolo[1,-2c]oxazol-3-one (2e): The crude product obtained from 1b
and [(1-methoxy-2-methyl-1-propenyl)oxy]trimethylsilane as out-
lined in the typical procedure was purified by column chromatogra-
phy (AcOEt/cyclohexane, 1:1) to give 99 mg (73%) of 2e. Ϫ
(2S,5S)-5-Allyl-1-[(benzyloxy)carbonyl]-2-(toluene-4-sulfonyl-
oxymethyl)pyrrolidine (8): To an ice-cooled solution of alcohol 7
(9.36 g, 34 mmol) in CH2Cl2 (100 ml) was added NEt3 (9.4 ml,
67.4 mmol), then p-TsCl (9.4 g, 49.3 mmol) portionwise. The reac-
tion mixture was stirred at room temp. for 4 h, then concentrated
in vacuo. The resulting residue was dissolved in NEt3 (15 ml) and
water was added (40 ml). The mixture was stirred for an additional
4 h. The aqueous layer was extracted with CH2Cl2 (3 ϫ 100 ml)
and the combined organic layers were washed successively with 1
 HCl solution (2 ϫ 100 ml), saturated aqueous NaHCO3 solution
(100 ml) and brine (100 ml). After drying with Na2SO4 and concen-
tration, purification of the residue by column chromatography (Ac-
[α]D22 ϭ Ϫ53 (c ϭ 1.045, MeOH). Ϫ IR (neat): νmax ϭ 1745 cmϪ1
.
˜
1
Ϫ H NMR: δ ϭ 1.20 (s, 3 H), 1.28 (s, 3 H), 1.4Ϫ1.55 (m, 1 H),
1.75Ϫ1.9 (m, 1 H), 2Ϫ2.25 (m, 2 H), 3.67 (s, 3 H), 3.85Ϫ3.95 (m,
1 H), 4.0 (t, J ϭ 8 Hz, 1 H), 4.15 (dd, J ϭ 2.5 and 8.9 Hz, 1 H),
4.48 (dd, J ϭ 7.8 and 8.9 Hz, 1 H). Ϫ 13C NMR: δ ϭ 20.69, 23.54,
28.30, 31.39, 46.49, 51.79, 60.15, 65.49, 66.85, 161.98, 176.35. Ϫ
C11H17NO4 (227.25): calcd. C 58.13, H 7.54, N 6.16; found C
58.07, H 7.54, N 5.97.
OEt/cyclohexane, 1:2) afforded 14.3 g (98%) of 8 as an oil. Ϫ
5-Cyanotetrahydropyrrolo[1,2-c]oxazol-3-one (2f): The crude
product obtained from 1b and cyanotrimethylsilane as outlined in
the typical procedure was purified by column chromatography (Ac-
OEt) to give 31 mg of pure trans-2f as an oil, and 53 mg of a
mixture of trans- and cis-2f (95% overall yield).
22
[α]D ϭ Ϫ45 (c ϭ 0.98, CHCl3). Ϫ IR (neat): ν˜max ϭ 1680 cmϪ1
.
Ϫ
1H NMR: δ ϭ 1.63Ϫ1.77 (m, 1 H), 1.80Ϫ2.03 (m, 4 H),
2.25Ϫ2.40 (m including 2 s at δ ϭ 2.34 and 2.36, 3.4 H), 2.5Ϫ2.6
(m, 0.6 H), 3.75Ϫ4.18 (m, 4 H), 4.85Ϫ5.05 (m, 4 H), 5.55Ϫ5.70
(m, 1 H), 7.1Ϫ7.28 (m, 7 H), 7.65 (dd, J ϭ 8.3 and 19.6 Hz, 2 H).
13C NMR: δ ϭ 21.52, 25.25, 26.10, 27.49, 36.63, 38.14, 55.70,
(5S,7aS)-5-Cyanotetrahydropyrrolo[1,2-c]oxazol-3-one (trans-
Ϫ
1
2f): Oil. Ϫ IR (neat): ν˜max ϭ 2240, 1750 cmϪ1. Ϫ H NMR: δ ϭ
56.33, 57.50, 57.92, 66.67, 68.99, 69.29, 117.49, 127.62, 127.73,
127.89, 128.42, 129.79, 132.59, 132.73, 134.51, 134.69, 136.25,
136.34, 144.69, 144.79, 153.42, 154.05. Ϫ C23H27NO5S (429.53):
calcd. C 64.31, H 6.33, N 3.26; found C 64.16, H 6.43, N 3.22.
1.35Ϫ1.7 (m, 1 H), 2.2Ϫ2.4 (m, 2 H), 2.55Ϫ2.65 (m, 1 H), 4.0Ϫ4.18
(m , 1 H), 4.27 (dd, J ϭ 2.7 and 9.2 Hz, 1 H), 4.60 (dd, J ϭ 7.5
and 9.2 Hz, 1 H), 4.71 (dd, J ϭ 6.1 and 8.3 Hz, 1 H). Ϫ 13C NMR:
δ ϭ 30.10, 32.34, 47.43, 58.96, 67.66, 118.72, 160.09.
(2S,5R)-2-Allyl-1-[(benzyloxy)carbonyl]-5-butylpyrrolidine (9):
To a cold stirred suspension of CuI (3.43 g, 18 mmol) in Et2O (40
ml) at Ϫ40°C was added dropwise a solution of 1-propyllithium,
freshly prepared from lithium (570 mg, 82.1 mmol) and 1-bromo-
propane (3.3 ml, 36.8 mmol) in Et2O (30 ml). Stirring was con-
tinued at Ϫ30 to Ϫ35°C for 30 min, then a solution of 8 (1.32 g,
3.09 mmol) in Et2O (10 ml) was added dropwise by syringe. The
reaction mixture was allowed to stir overnight at Ϫ20°C, then
quenched with saturated aqueous NH4Cl solution (30 ml). After
stirring for an additional 20 min, the reaction mixture was filtered
through a Celite pad, and the solid residue washed with Et2O (200
ml). The organic layer was washed with brine (20 ml), dried with
Na2SO4 and concentrated. Purification by column chromatography
(AcOEt/cyclohexane, 5:95) gave 718 mg (78%) of 9 as an oil. Ϫ
(5R,7aS)-5-Cyanotetrahydropyrrolo[1,2-c]oxazol-3-one (cis-2f):
Recrystallization from Et2O of a cis-enriched sample afforded
colourless needles whose structure was confirmed by X-ray analy-
sis[31], m.p. 114Ϫ115°C. Ϫ 1H NMR: δ ϭ 1.85Ϫ1.95 (m, 1 H),
2.2Ϫ2.3 (m, 1 H), 2.5Ϫ2.7 (m, 2 H), 4.15Ϫ4.25 (m, 2 H), 4.35 (dd,
J ϭ 1.7 and 8 Hz, 1 H), 4.55Ϫ4.65 (m, 1 H). Ϫ 13C NMR: δ ϭ
30.55, 35.17, 45.40, 59.78, 69.38, 116.36, 156.79.
(2S,5S)-5-Allyl-2-hydroxymethylpyrrolidine (6): A stirred solu-
tion of oxazolidinone 2a (0.38 g, 2.27 mmol) in a mixture of 30%
aqueous KOH solution (5 ml) and 1,4-dioxane (10ml) was refluxed
for 64 h. The reaction mixture was concentrated and the resulting
residue was partitioned between CH2Cl2 (20 ml) and brine (15 ml).
The aqueous layer was extracted with CH2Cl2 (3 ϫ 15 ml) and the
combined organic phases were dried with Na2SO4. Concentration
in vacuo gave 0.32 g (100%) of amino alcohol 6 as a yellow oil,
which was used in the next step without further purification. Ϫ 1H
NMR: δ ϭ 1.30Ϫ1.45 (m, 2 H), 1.8Ϫ1.95 (m, 2 H), 2.18 (t, J ϭ
6.7 Hz, 2 H), 2.4 (br. s, 2 H), 3.1Ϫ3.15 (m, 1 H), 3.25 (dd, J ϭ 7
and 9.6 Hz, 1 H), 3.3Ϫ3.5 (m, 2 H), 5.0Ϫ5.1 (m, 2 H), 5.7Ϫ5.84
(m, 1 H). Ϫ 13C NMR: δ ϭ 27.07, 31.15, 39.97, 56.67, 58.69, 64.52,
116.28, 135.35.
[α]D22 ϭ Ϫ64 (c ϭ 1.115, CHCl3). Ϫ IR (neat): ν˜max ϭ 1680 cmϪ1
1H NMR: δ ϭ 0.72 and 0.82 (2 t, J ϭ 6.1 Hz, 3 H), 1.0Ϫ1.3
.
Ϫ
(m, 5 H), 1.5Ϫ1.65 (m, 2.5 H), 1.8Ϫ2.0 (m, 3.5 H), 2.3Ϫ2.4 (m,
0.5 H), 2.55Ϫ2.7 (m, 0.5 H), 3.65Ϫ3.9 (m, 2 H), 4.8Ϫ5.2 (m, 4 H),
5.5Ϫ5.8 (m, 1 H), 7.20Ϫ7.30 (m, 5 H). Ϫ 13C NMR: δ ϭ 13.89,
14.02, 22.43, 22.57, 26.10, 26.35, 27.08, 27.35, 28.66, 32.22, 33.58,
36.90, 38.34, 56.87, 57.24, 57.90, 58.38, 66.29, 116.97, 127.71,
127.77, 128.28, 135.08, 135.28, 136.93, 154.06, 154.15.
Ϫ
C19H27NO2 (301.42): calcd. C 75.71, H 9.03, N 4.64; found C
75.74, H 8.98, N 4.60.
(2S,5S)-5-Allyl-1-[(benzyloxy)carbonyl]-2-hydroxymethyl-
pyrrolidine (7): A mixture of 6 (0.32 g, 2.27 mmol), benzyl chloro-
formate (0.36 ml, 2.52 mmol) and Na2CO3 (0.46 g, 4.34 mmol) in
CH2Cl2 (15 ml) was stirred overnight at room temp. The reaction
(2S,5R)-1-[(Benzyloxy)carbonyl]-5-butyl-2-(2-oxoethyl)pyr-
rolidine (10): To a stirred solution of 9 (312 mg, 1.03 mmol) in a
mixture was then filtered and the solid residue was thoroughly 1:1 mixture of THF/H2O (14 ml) was added a 4% (w/w) solution
1960 Eur. J. Org. Chem. 1998, 1955Ϫ1963

Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic N-Acyliminium Ion
FULL PAPER
of OsO4 in H2O (0.45 ml, 0.07 mmol). The reaction mixture was (60 ml) at Ϫ50°C, was added dropwise a 2.5  commercial solution
stirred for 15 min until becoming dark brown, then NaIO4 (650 of n-hexyllithium in hexane (19 ml, 47.5 mmol). After stirring at
mg, 3.1 mmol) was added portionwise. Stirring was continued for Ϫ40 to Ϫ30°C for 40 min, the dark reaction mixture was cooled
20 min, and the obtained white precipitate was collected on a Celite to Ϫ50°C and a solution of tosylate 8 (2 g, 4.75 mmol) in Et2O
pad. After washing the latter with Et2O (150 ml), the organic layer (20 ml) was added dropwise by syringe. The reaction mixture was
was washed with 15% aqueous Na2S2O4 solution (10 ml), saturated stirred overnight at Ϫ20°C. After warming to 0°C, the reaction
Na2S2O3 solution (25 ml), then brine. After drying with Na2SO4
was quenched by addition of a (1:1) mixture of saturated aqueous
and concentration, the dark residue was purified by column chro- NH4Cl solution (30 ml) and concentrated aqueous NH4OH solu-
matography (AcOEt/cyclohexane, 2:8) to yield 221 mg (70%) of
tion (30 ml). The mixture was vigorously stirred for 30 min, then
aldehyde 10[22][4e] as a colourless oil. Ϫ [α]D22 ϭ Ϫ46.3 (c ϭ 1.505, filtered through a Celite pad. The solid residue was thoroughly
1
CHCl3). Ϫ IR (neat): ν˜max ϭ 1730, 1700 cmϪ1. Ϫ H NMR: δ ϭ washed with CH2Cl2, and the organic layer was washed successively
0.81 and 0.88 (2t, J ϭ 6.8 Hz, 3 H), 1.1Ϫ1.4 (m, 6 H), 1.55Ϫ1.75
with a (1:1) mixture of saturated solution of NH4Cl/NH4OH (30
(m, 2 H), 1.8Ϫ2.0 (m, 1 H), 2.05Ϫ2.20 (m, 1 H), 2.3Ϫ2.45 (m, 1 ml) and water (30 ml), then dried with Na2SO4. Concentration gave
H), 2.75Ϫ2.85 (m, 0.4 H), 3.1Ϫ3.2 (m, 0.6 H), 3.75Ϫ3.85 (m, 1 H), an oily yellow residue which was purified by column chromatogra-
4.20Ϫ4.40 (m, 1 H), 5.02Ϫ5.19 (m, 2 H), 7.25Ϫ7.35 (m, 5 H), 9.61 phy (AcOEt/cyclohexane, 5:95) yielding 1.28 g (79%) of 14 as a
22
(s, 0.4 H), 9.75 (t, J ϭ 1.75 Hz, 0.6 H). Ϫ 13C NMR: δ ϭ 14.02,
colourless oil. Ϫ [α]D ϭ Ϫ56.7 (c ϭ 1.015, CHCl3). Ϫ IR (neat):
14.14, 22.53, 22.68, 26.45, 27.49, 28.45, 28.73, 29.34, 32.27, 33.56, ν˜max ϭ 1710 cmϪ1. Ϫ 1H NMR: δ ϭ 0.88 (t, J ϭ 6.4 Hz, 3 H),
47.93, 48.95, 52.04, 52.72, 57.96, 58.47, 66.76, 127.98, 128.14, 1.12Ϫ1.4 (m, 11 H), 1.6Ϫ1.8 (m, 2.5 H), 1.85Ϫ2.15 (m, 3.5 H),
128.49, 136.72, 154.40, 200.53, 200.77.
2.40Ϫ2.45 (m, 0.5 H), 2.60Ϫ2.70 (m, 0.5 H), 3.75Ϫ4 (m, 2 H),
4.95Ϫ5.25 (m, 4 H), 5.60Ϫ5.80 (m, 1 H), 7.30Ϫ7.40 (m, 5 H). Ϫ
13C NMR: δ ϭ 14.17, 22.69, 26.24, 26.49, 26.68, 27.22, 27.49,
29.28, 29.42, 29.49, 29.62, 31.88, 32.69, 34.05, 37.06, 38.49, 57.02,
57.38, 58.08, 58.59, 66.46, 117.14, 127.92, 128.45, 135.29, 135.47,
137.09, 154.34. Ϫ C22H33NO2 (343.50): calcd. C 76.92, H 9.68, N
4.07; found C 76.99, H 9.75, N 4.03.
(2S,5R)-2-Allyl-1-[(benzyloxy)carbonyl]-5-methylpyrrolidine
(11): To a stirred cooled solution of tosylate 8 (372 mg, 0.866
mmol) in THF (6 ml) at 0°C was added dropwise a 1  solution
of LiEt3BH in THF (2.5 ml, 2.5 mmol). The reaction mixture was
stirred at room temp. for 4 h. Then, water (0.5 ml), 3  NaOH
solution (1 ml, 3 mmol) and 35% H2O2 solution (1 ml, 1 mmol)
were successively added, before stirring for an additional 30 min.
The reaction mixture was concentrated in vacuo, then extracted
with CH2Cl2 (3 ϫ 10 ml). The organic layer was washed with water,
dried with Na2SO4 and concentrated. Purification by column chro-
matography (AcOEt/cyclohexane, 1:9) yielded 177 mg (79%) of
(2S,5R)-1-[(Benzyloxy)carbonyl]-5-heptyl-2-(3-hydroxy-
propyl)pyrrolidine (15): To an ice-cooled stirred solution of 14 (555
mg, 1.61 mmol) in Et2O (10 ml), was added dropwise by syringe a 2
 solution of BH3·(CH3)2S in THF (0.5 ml, 1 mmol). The reaction
mixture was stirred at room temp. under inert atmosphere for 4 h.
EtOH (2 ml) was then added, followed by 3  aqueous NaOH
solution (0.25 ml, 0.75 mmol). After cooling the reaction mixture
to 0°C, 35% H2O2 solution (0.2 ml, 2 mmol) was carefully added.
The cooling bath was then removed and the reaction mixture was
heated at reflux for 1 h. The reaction mixture was then poured into
ice-cold water (15 ml) and extracted with Et2O (3 ϫ 40 ml). The
organic layer was washed with water, dried with Na2SO4 and con-
centrated in vacuo. Column chromatography of the residue (Ac-
OEt/cyclohexane, 1:1) afforded 463 mg (79%) of alcohol 14 as a
22
pyrrolidine 11. Ϫ [α]D ϭ Ϫ56.5 (c ϭ 1.01, CHCl3). Ϫ IR (neat):
ν˜max ϭ 1680 cmϪ1. Ϫ 1H NMR: δ ϭ 1.12 and 1.19 (2d, J ϭ 6.3
Hz, 3 H), 1.47Ϫ1.55 (m, 1 H), 1.70Ϫ1.75 (m, 1 H), 1.95Ϫ2.10 (m,
3 H), 2.35Ϫ2.45 (m, 0.5 H), 2.5Ϫ2.7 (m, 0.5 H), 3.85Ϫ4.0 (m, 2
H), 5.0Ϫ5.2 (m, 4 H), 5.6Ϫ5.8 (m, 1 H), 7.26Ϫ7.37 (m, 5 H). Ϫ
13C NMR: δ ϭ 19.41, 20.61, 25.95, 26.94, 29.51, 30.41, 37.13,
38.50, 53.34, 53.77, 57.11, 57.51, 66.46, 117.13, 127.86, 128.46,
135.21, 135.40, 137.05, 154.39. Ϫ C16H21NO2 (259.34): calcd. C
74.10, H 8.16, N 5.40; found C 73.98, H 8.26, N 5.31.
22
colourless oil. Ϫ [α]D ϭ Ϫ50.4 (c ϭ 1.31, CHCl3). Ϫ IR (neat):
(2S,5R)-1-[(Benzyloxy)carbonyl]-2-(3-hydroxypropyl)-5-meth-
ylpyrrolidine (12): To an ice-cooled stirred solution of 11 (250 mg,
0.965 mmol) in Et2O (5 ml), was added dropwise by syringe a 2 
solution of BH3·(CH3)2S in THF (0.19 ml, 0.366 mmol). The reac-
tion mixture was stirred at room temp. under inert atmosphere for
4 h. EtOH (1 ml) was then added, followed by 3  aqueous NaOH
solution (0.12 ml, 0.36 mmol). After cooling the reaction mixture
to 0°C, 35% H2O2 solution (0.1 ml, 1 mmol) was carefully added.
The cooling bath was then removed and the reaction mixture was
heated at reflux for 1 h. The reaction mixture was then poured into
ice water (10 ml) and extracted with Et2O (3 ϫ 20 ml). The organic
layer was washed with water, dried with Na2SO4 and concentrated
in vacuo. Column chromatography of the residue (AcOEt/cyclohex-
ane, 1:1) afforded 203 mg (76%) of alcohol 12 as a colourless oil.
Ϫ [α]D22 ϭ Ϫ56 (c ϭ 1.01, CHCl3) {ref.[25] [α]D22 ϭ Ϫ55 (c ϭ 1.36,
1
ν˜max ϭ 3440, 1710 cmϪ1. Ϫ H NMR: δ ϭ 0.86 (t, J ϭ 6.3 Hz, 3
H), 1.20Ϫ2.4 (series of m, 21 H), 3.4Ϫ3.9 (m, 4 H), 5.03 and 5.04
(1/2 AB q, J ϭ 12.4 Hz, 1 H), 5.17 and 5.19 (1/2 AB q, J ϭ 12.4
Hz, 1 H), 7.30Ϫ7.35 (m, 5 H). Ϫ 13C NMR: δ ϭ 14.05, 22.56,
26.57, 26.99, 27.46, 27.61, 29.13, 29.33, 29.51, 29.64, 30.25, 31.74,
32.49, 33.79, 57.31, 57.71, 58.22, 61.95, 62.28, 66.37, 66.48, 127.80,
128.33, 136.64, 136.78, 154.14, 154.47. Ϫ C22H35NO3 (361.51):
calcd. C 73.09, H 9.76, N 3.87; found C 73.09, H 9.82, N 3.79.
(2S,5R)-1-[(Benzyloxy)carbonyl]-5-heptyl-2-(3-oxopropyl)pyr-
rolidine (16): To a stirred cooled solution of oxalyl chloride (0.28
ml, 3.22 mmol) in CH2Cl2 (8 ml) at Ϫ60°C, was added dropwise
by syringe a solution of DMSO (0.46 ml, 6.45 mmol) in CH2Cl2
(1.5 ml). After 5 min stirring, a solution of alcohol 15 (1.06 g, 2.93
mmol) in CH2Cl2 (4 ml) was slowly added. Stirring was continued
for an additional 45 min at Ϫ60°C, then NEt3 (2 ml, 14.66 mmol)
was added and the reaction mixture was allowed to warm slowly
to room temp. Water (25 ml) was then added and the aqueous layer
was extracted with CH2Cl2 (3 ϫ 30 ml). The combined organic
layers were washed successively with 1% HCl solution (20 ml), 2%
aqueous NaHCO3 solution (20 ml) and brine (20 ml). After drying
CHCl3)}. Ϫ IR (neat): ν˜max ϭ 3420, 1680 cmϪ1. Ϫ H NMR: δ ϭ
1
1.10 and 1.17 (2 d, J ϭ 6.3 Hz, 3 H), 1.20Ϫ1.65 (m, 6 H), 1.7Ϫ2.3
(series of m, 3 H), 3.4Ϫ4.0 (series of m, 4 H), 5.0Ϫ5.2 (m, 2 H),
7.28Ϫ7.36 (m, 5 H). Ϫ 13C NMR: δ ϭ 19.05, 20.21, 26.45, 27.17,
28.97, 29.12, 29.39, 29.46, 30.22, 52.83, 53.25, 57.39, 57.48, 61.73,
61.98, 66.20, 66.30, 127.62, 128.19, 136.66, 154.03, 154.35.
(2S,5R)-2-Allyl-1-[(benzyloxy)carbonyl]-5-heptylpyrrolidine with Na2SO4 and concentration, column chromatography of the
(14): To a stirred cold suspension of CuI (4.5 g, 23.6 mmol) in Et2O
residue (AcOEt/cyclohexane, 1:2) yielded 935 mg (89%) of alde-
1961
Eur. J. Org. Chem. 1998, 1955Ϫ1963

´
H. Dhimane, C. Vanucci-Bacque, L. Hamon, G. Lhommet
FULL PAPER
hyde 16 as an oil. Ϫ [α]D24 ϭ Ϫ67 (c ϭ 1.00, CHCl3). Ϫ IR (neat):
CHCl3)}. Ϫ H NMR: δ ϭ 0.86 (t, J ϭ 6.1 Hz, 3 H), 1.08 (d, J ϭ
1
1
ν˜max ϭ 1720, 1680 cmϪ1. Ϫ H NMR: δ ϭ 0.85 (t, J ϭ 6.4 Hz, 3
6.3 Hz, 3 H), 1.10Ϫ1.6 (m, 16 H), 1.85Ϫ2.05 (m, 4 H), 2.55Ϫ2.65
H), 1.20Ϫ1.25 (m, 11 H), 1.55Ϫ2.45 (series of m, 9 H), 3.75Ϫ3.85 (m, 1 H), 2.70Ϫ2.80 (m, 1 H), 3.55Ϫ3.65 (m, 1 H). Ϫ 13C NMR:
(m, 2 H), 5.05 and 5.17 (AB q, J ϭ 12.4 Hz, 2 H), 7.28Ϫ7.35 (m, δ ϭ 14.07, 21.74, 22.65, 27.24, 29.33, 29.86, 31.66, 31.86, 32.04,
5 H), 9.56 and 9.73 (2 s, 1 H). Ϫ 13C NMR: δ ϭ 14.06, 22.57,
25.48, 26.56, 26.93, 27.59, 29.15, 29.33, 31.75, 32.42, 33.80, 40.95,
41.05, 55.69, 57.22, 57.87, 58.39, 66.52, 127.87, 128.09, 128.40,
136.80, 154.00, 154.45, 201.47, 201.89.
32.40, 34.42, 36.90, 61.78, 65.04, 66.72.
X-ray Crystal Structure of trans-2c: All data were obtained with
an Enraf Nonius CAD4 diffractometer with graphite-monochrom-
ated Mo-Kα radiation. Accurate unit-cell dimensions and crystal-
orientation matrix together with their estimated standard devi-
ations were obtained from least-squares refinements of the setting
angles of 25 reflections. Crystal data: C14H15NO3 (245.27); mono-
clinic, space group P21; a ϭ 5.791(1), b ϭ 23.826(4), c ϭ 9.412(1)
(2S,5R)-1-[(Benzyloxy)carbonyl]-5-heptyl-2-(3-hydroxy-
butyl)pyrrolidine (17): To an ice-cooled solution of aldehyde 16
(385 mg, 1.07 mmol) in THF (10 ml) was added dropwise a com-
mercial 3  solution of MeMgCl in THF (1.8 ml, 5.4 mmol). After
stirring for 1.5 h at 0°C, the reaction mixture was quenched with
ice-cold water (10 ml). The aqueous phase was extracted with Et2O
(3 ϫ 20 ml) and the combined organic layers were washed with
brine (20 ml) and dried with Na2SO4. Concentration in vacuo and
purification by column chromatography (AcOEt/cyclohexane, 1:1)
gave 349 mg (86%) of a diastereomeric mixture of alcohol 17. Ϫ
A, β ϭ 104.82 (1)°, V ϭ 1255,4(4) A3; Z ϭ 4; D ϭ 1.30 g cmϪ3
;
˚
˚
F(000) ϭ 520.15; µ(Mo-Kα) ϭ 0.9 cmϪ1. The intensities were
measured using ω/2θ scans up to 56°. Two standard reflections were
monitored periodically and remained constant during data collec-
tion. Lorentz and polarization factors were applied while absorp-
tion corrections were no considered as necessary. Of the 3093 inde-
pendent reflections collected, 892 reflections with I > 3 σ(I) were
used for the structure determination and refinement. The structure
was solved by direct methods using SHELXS86.[29] Computations
were performed using a PC version of CRYSTALS.[30] Scattering
factors for all atoms were as incorporated in CRYSTALS. All re-
maining non-hydrogen atoms were found by electron-density map
calculations. Their atomic coordinates were refined together with
the isotropic displacement parameter. All hydrogen atoms were cal-
culated at geometrical position with an overall isotropic tempera-
ture factor. The refinement of atomic parameters was carried out
by full-matrix least-squares refinement. The final refinement con-
verged with R ϭ 0.077 and Rw ϭ 0.072 for 147 parameters. The
minimum and maximum peaks in the final difference Fourier map
1
IR (neat): ν˜max ϭ 3440, 1700, 1680 cmϪ1. Ϫ H NMR: δ ϭ 0.85
(t, J ϭ 6.3 Hz, 3 H), 1Ϫ1.5 (m, 17 H), 1.5Ϫ2.1 (m, 7 H), 3.6Ϫ3.9
(m, 3 H), 5Ϫ5.25 (m, 2 H), 7.25Ϫ7.35 (m, 5 H). Ϫ 13C NMR: δ ϭ
14.15, 22.67, 23.27, 23.47, 26.68, 27.26, 27.57, 29.26, 29.46, 29.62,
30.22, 31.85, 32.61, 33.89, 35.79, 36.03, 56.99, 57.47, 57.77, 57.88,
58.05, 58.34, 66.53, 67.63, 68.00, 68.51, 127.95, 128.18, 128.45,
136.98, 154.23, 154.59. Ϫ C23H37NO3 (375.55): calcd. C 73.56, H
9.93, N 3.73; found C 73.45, H 10.15, N 3.73.
(2S,5R)-1-[(Benzyloxy)carbonyl]-5-heptyl-2-(3-oxobutyl)pyr-
rolidine (18): To a stirred cooled solution of oxalyl chloride (0.1 ml,
1.14 mmol) in CH2Cl2 (4 ml) at Ϫ60°C, was added dropwise by
syringe a solution of DMSO (0.16 ml, 2.25 mmol) in CH2Cl2 (1
ml). After 5 min stirring, a solution of alcohol 17 (349 mg, 0.93
mmol) in CH2Cl2 (2 ml) was slowly added. Stirring was continued
for an additional 45 min at Ϫ60°C, then NEt3 (0.65 ml, 4.72 mmol)
was added and the reaction mixture was allowed to warm slowly
to room temp. Water (10 ml) was then added and the aqueous layer
was extracted with CH2Cl2 (3 ϫ 15 ml). The combined organic
layers were washed successively with 1% HCl solution (10 ml), 2%
aqueous NaHCO3 solution (10 ml) and brine (10 ml). After drying
with Na2SO4 and concentration, column chromatography of the
residue (AcOEt/cyclohexane, 1:2) yielded 300 mg (86%) of ketone
were Ϫ0.38 and 0.44 e AϪ3. The supplementary material includes
˚
the list of atomic coordinates, the bond lengths and angles.[31]
X-ray Crystal Structure of cis-2f: All data were obtained with an
Enraf Nonius CAD4 diffractometer with graphite-monochromated
Mo-Kα radiation. Accurate unit-cell dimensions and crystal-orien-
tation matrix together with their estimated standard deviations
were obtained from least-squares refinements of the setting angles
of 25 reflections. Crystal data: C7H8N2O2 (152.15); monoclinic,
˚
space group P21, a ϭ 6.5015(9), b ϭ 8.253(7), c ϭ 7.343(1) A, β ϭ
114.10 (1)°, V ϭ 359,7(3) A3; Z ϭ 2; D ϭ 1.40 g cmϪ3; F(000) ϭ
˚
23
18 as an oil. Ϫ [α]D ϭ Ϫ61.4 (c ϭ 1.1, CHCl3). Ϫ IR (neat):
160.04 ; µ(Mo-Kα) ϭ 1.0 cmϪ1. The intensities were measured using
ω/2θ scans up to 60°. Two standard reflections were monitored
periodically and remained constant during data collection. Lorentz
and polarization factors were applied while absorption corrections
were not considered as necessary. Of the 1115 independent reflec-
tions collected, 897 reflections with I > 3 σ(I) were used for the
structure determination and refinement. The structure was solved
by direct methods using SHELXS86.[29] Computations were per-
formed using a PC version of CRYSTALS.[30] Scattering factors
for all atoms were as incorporated in CRYSTALS. All remaining
non-hydrogen atoms were found by electron-density map calcu-
ν
ϭ 1700 cmϪ1. Ϫ 1H NMR: δ ϭ 0.86 (t, J ϭ 6.5 Hz, 3 H),
˜
max
1.1Ϫ1.35 (m, 11 H), 1.45Ϫ1.70 (m, 4 H), 1.8Ϫ2.5 (series of m in-
cluding 2 s at 1.99 and 2.13, 8 H), 3.65Ϫ3.85 (m, 2 H), 5.05 and
5.16 (ABq, J ϭ 12.4 Hz, 2 H), 7.27Ϫ7.4 (m, 5 H). Ϫ 13C NMR:
δ ϭ 14.06, 22.57, 26.58, 26.86, 26.97, 27.32, 27.60, 27.75, 28.25,
29.15, 29.36, 29.49, 29.64, 31.75, 32.44, 33.85, 40.87, 41.05, 56.83,
57.31, 57.76, 58.34, 66.45, 127.84, 128.10, 128.36, 136.88, 154.06,
154.42, 208.04, 208.45. Ϫ C23H35NO3 (373.53): calcd. C 73.95, H
9.44, N 3.75; found C 73.90, H 9.44, N 3.71.
(3R,5S,8R)-3-Heptyl-5-methylpyrrolizidine [(؊)-Xenovenine]
(13): A suspension of ketone 18 (300 mg, 0.8 mmol) and 10% Pd/ lations. Their atomic coordinates were refined together with the
BaSO4 (90 mg) in MeOH (10 ml) was vigorously stirred under hy- anisotropic displacement parameter. All hydrogen atoms were lo-
drogen for 6 h. The insoluble material was removed by filtration cated from difference electron-density maps; their coordinates were
and the filtrate was concentrated to give a residue. The latter was refined with an overall isotropic temperature factor. The refinement
treated with 1  aqueous NaOH solution (10 ml) and the aqueous
of atomic parameters was carried out by full-matrix least-squares
layer was extracted with Et2O (3 ϫ 15 ml). Drying of the organic refinement. The final refinement converged with R ϭ 0.037 and
layer with Na2SO4 and concentration gave a residue which was col-
Rw ϭ 0.035 for 125 parameters. The minimum and maximum peaks
umn-chromatographed (CH2Cl2/MeOH, 4:1) yielding 110 mg
in the final difference Fourier map were Ϫ0.19 and 0.18 e AϪ3. The
˚
23
(60%) of (Ϫ)-(13) Ϫ [α]D ϭ Ϫ11.4 (c ϭ 1.37, CHCl3) {ref.[26] supplementary material includes the list of atomic coordinates, the
20
24
[α]D ϭ Ϫ11.6 (c ϭ 0.6, CHCl3); ref.[27] [α]D ϭ Ϫ11.5 (c ϭ 0.5,
bond lengths and angles.[31]
1962
Eur. J. Org. Chem. 1998, 1955Ϫ1963

Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic N-Acyliminium Ion
FULL PAPER
[1]
A. R. Mattock, in Chemistry and Toxycology of Pyrrolidine
Alkaloids, Academic Press, London, 1986.
opposite sequence,[8] i.e. allylation of a monocyclic N-Boc pro-
tected iminium of type II (X ϭ CO2tBu, Y ϭ CO2Me), followed
by a three-step procedure leading to the required bicyclic oxazo-
lidinone.
[2]
T. Tokuyama, N. Nishimori, I. L. Karle, M. W. Edwards, J. W.
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[3] [3a]
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[20]
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[3b]
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L.-Y. Chen, L. Ghosez, Tetrahedron Lett.
[3c]
1990, 31, 4467Ϫ4470. Ϫ
K. Fugi, M. Node, Y. Naniwa, T.
The geometries of the initial states were optimised by using the
Davidson-Fletcher-Powell algorithm (FLEPO procedure), min-
imising the energy with respect to all internal coordinates. Ap-
proximate transition states were obtained from the energy pro-
files in a reaction path (the reaction coordinates being the dis-
tance between the carbon atom of CϭN and the reactive ter-
minal carbon atom of the allylsilane); then the transition states
were optimised by minimising the energy gradient (NLLSQ pro-
cedure).
[3d]
Kawabata, Tetrahedron Lett. 1990, 31, 3175Ϫ3178. Ϫ
J. K.
Whitesell, Chem. Rev. 1989, 89, 1581Ϫ1590 and references cited
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[4]
[4a] P. Q. Huang, S. Arseniyadis, H. P. Husson, Tetrahedron Lett.
[4b]
1987, 28, 547Ϫ550. Ϫ
H. Takahata, H. Takehara, N.
Ohkubo, T. Momose, Tetrahedron: Asymmetry 1990, 1,
[4c]
561Ϫ566. Ϫ
M. Skrinjar, L. G. Wistrand, Tetrahedron Lett.
[4d]
[21]
[22]
[23]
´ ´
S. Rosset, J.-P. Celerier, G. Lhom-
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M. J. Dewar, E. G. Zoebisch, E. F. Herly, J. J. P. Stewart, J.
Amer. Chem. Soc. 1985, 107, 3902Ϫ3909; AMPAC version 2.14.
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´ ´
J.-P. Celerier, G. Lhommet, Tetrahedron: Asymmetry 1996, 7,
´ ´
A. Fleurant, J.-C. Celerier, G. Lhommet, Tetrahedron: Asym-
[4f]
´ ´
2211Ϫ2212. Ϫ
G. Vo Thanh, J.-P. Celerier, A. Fleurant, C.
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J. W. Daly, J. Nat. Prod. 1998, 61, 162Ϫ172.
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[6]
[7]
[24b]
L. G. Wistrand, M. Skrinjar, Tetrahedron 1991, 47, 573Ϫ582.
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T. H. Jones, S. M. Stahly, A. W. Don, M.
[24c]
´
`
C. Celimene, H. Dhimane, G. Lhommet, Tetrahedron, in press.
T. Shono, T. Fujita, Y. Matsumura, Chem. Lett. 1991, 81,
80Ϫ84.
S. Blum, J. Chem. Ecol. 1988, 14, 2197. Ϫ
The optical ro-
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[8]
[25]
[26]
[27]
[28]
´ ´
H. Dhimane, C. Vanucci, G. Lhommet, Tetrahedron Lett. 1997,
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[10]
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Compound 1a was equally prepared by refluxing 5 in MeOH
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[11]
[12]
[13]
T. Shono, Tetrahedron 1984, 40, 811Ϫ850.
[29]
[30]
[31]
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[14]
[15]
C. Pedregal, J. Ezquerra, A. Escribano, M. C. Carreno, J. L.
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Various binary systems ROH/CHCl3 (R ϭ Me, iPr, CF3CH2)
were tested without notable improvement of the observed yield
(36 to 42%).[8]
D. J Watkin, C. K Prout, R. J Carruthers, P. W Betteridge,
CRYSTALS, Issue 10, Chemical Crystallography Laboratory,
Oxford, UK, 1996.
Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publi-
cation no. CCDC-101210. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: int. code ϩ 44-(1223)336-033,
e-mail: deposit@ccdc.cam.ac.uk].
[16]
[17]
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A
stepwise procedure, i.e. etherification of compound 5
[HC(OMe)3, PPTS, MeOH] followed by cyclisation, resulted in
a poor overall yield of 1a (25%).
A cis-enriched sample of 2a was synthesised according to an
[18]
[98174]
Eur. J. Org. Chem. 1998, 1955Ϫ1963
1963