Diastereoselective cycloaddition of alkylidenecyclopropane nitrones from palladium(0)-catalyzed nucleophilic substitution of asymmetric 1-alkenylcyclopropyl esters by amino acids

Article abstract of DOI:10.1016/S0957-4166(00)00006-9

The asymmetric construction of perhydropyrrolo[3,4-b]pyridine derivatives was performed by chemo- and regioselective formation of enantiopure alkylidenecyclopropane nitrones, followed by diastereoselective intramolecular 1,3-dipolar cycloaddition. The res

Full text of DOI:10.1016/S0957-4166(00)00006-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 897–909
Diastereoselective cycloaddition of alkylidenecyclopropane
nitrones from palladium(0)-catalyzed nucleophilic substitution of
asymmetric 1-alkenylcyclopropyl esters by amino acids
Federica Pisaneschi,a,b Franca M. Cordero,a Andrea Goti,a Renée Paugam,b Jean Ollivier,b
Alberto Brandi a,∗ and Jacques Salaün b,∗
aDipartimento di Chimica Organica ‘Ugo Schiff’, Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e
Ioro Applicazioni, CNR, Università degli Studi di Firenze, via G. Capponi 9, I-50121 Firenze, Italy
bLaboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Received 23 November 1999; accepted 31 December 1999
Abstract
The asymmetric construction of perhydropyrrolo[3,4-b]pyridine derivatives was performed by chemo- and
regioselective formation of enantiopure alkylidenecyclopropane nitrones, followed by diastereoselective intra-
molecular 1,3-dipolar cycloaddition. The resulting spirocyclopropane isoxazolidines then underwent thermally
induced regioselective ring expansion into optically active diazaheterocycles. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
In spite of their inherent ring strain (40.9 kcal mol−1) alkylidenecyclopropanes are now readily
available1 and form a class of olefinic compounds which offer a huge potential in organic synthesis.2,3
For instance, we have recently reported that the nitrones (S)-2, derived from the alkylidenecyclopropane
esters (S)-1, prepared from the palladium(0)-catalyzed alkylation of either N-tosyl α-amino acid esters
(X=NTs) or glycolic esters (X=O), spontaneously underwent regioselective intramolecular 1,3-dipolar
cycloaddition4 to provide the cis-fused tricyclic isoxazolidines 3 (Scheme 1).5 The diastereoselectivity
of the reaction appeared dependent on the steric effect of the substituents R of the α-amino acids; it was
complete only for phenylglycine and proline derivatives. The diastereomeric cycloadducts exo- or endo-3,
which were readily separated by chromatography, then underwent regio- and diastereoselective thermally
induced ring expansion into the octahydro-6H-pyrrolo[3,4-b]pyridin-4-ones or furano analogue 4.5
∗
Corresponding authors. E-mail: jasalaun@icmo.u-psud.fr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00006-9
tetasy 3229

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Scheme 1.
We report now that simple asymmetric substitution on the three-membered ring of the alkylidene
cyclopropane nitrones can improve the diastereoselectivity of the cycloaddition and offer straightforward
access to optically active diazaheterocycles of biological importance.6–8
2. Simple asymmetric induction
The (1R,2S)-2-methyl-1-tosyloxy-1-vinylcyclopropane 5 (Scheme 2), obtained in a diastereomer-
ically pure form from commercially available methyl (2S)-3-hydroxy-2-methylpropionate (>99% ee)9
or alternatively from dimethyl (2S)-2-methylsuccinate (enzymatic resolution)10 (de >92%) underwent
regioselective palladium(0)-catalyzed [Pd(dba)2, 2 PPh3] amination11 by methyl N-tosylglycinate 7a
in the presence of 1 equivalent of NaH in THF at room temperature to provide, through the π-1,1-
dimethyleneallyl palladium complex (2S)-6,12 an 85:15 diastereomeric mixture of (E)- and (Z)-methyl
N-[2-(2-methyl cyclopropylidene)ethyl]-N-tosylglycinates 8a, quantitatively.
Scheme 2.
While substitutions of the palladium complex (2S)-6 and derivatives at the cyclopropane terminus
by hard nucleophiles, i.e., azide9 and hydride (arising from n-butylzinc chloride or from sodium
formate),10,13 were highly diastereoselective (de: 92–100%), substitutions by soft nucleophiles, i.e., di-
alkyl sodiomalonates14 and α-amino acid derivatives, which occurred on the primary allylic end of (2S)-6
exclusively,12 unfortunately produced a mixture of (E)- and (Z)-alkylidene(2-methylcyclopropanes) (de:
64–70%). Attempts to increase the diastereoselectivity of the formation of (E)-8a, based on the steric
effect of the trivalent phosphorus ligands which are well known to dominate the chemical behaviour of
transition metal complexes,15 and which were highly effective in monitoring the regioselectivity of the
palladium(0)-catalyzed allyl esters reduction,13 failed; thus, for instance, dppe, tri(o-tolyl)- and tri(o-
anisyl)phosphines, and tri(2,6-dimethoxyphenyl)phosphine, induced lower diastereoselectivities (de:
40–58%) than triphenylphosphine (de: 70%).
Contrary to our previous report concerning the partial reduction of (S)-1,5 reduction of the esters (E)-
and (Z)-8a by 0.9 equivalent of DIBAH gave a mixture of the expected aldehydes, besides the correspon-
ding alcohols arising from overreduction, and unreacted 8a. To overcome this problem, the N0-methyl-
N0-methoxy-N-tosylglycinamide 7b (Scheme 3)16 was used instead of the methyl glycinate 7a as the
nucleophile to produce in 95% yield again as an 85:15 mixture of (E)- and (Z)-alkylidenecyclopropanes
8b, which after reduction by LiAlH4 in diethyl ether led to the expected aldehydes 9, in 88% yield.

F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
899
Scheme 3.
This 85:15 diastereomeric mixture of (E)- and (Z)-aldehydes 9 was then allowed to react with
MeNHOH·HCl either in a solution of 1.4 equivalents of pyridine in water or in a solution of triethylamine
in toluene to provide in 47 and 75% yields, respectively, an 85:15 diastereomeric mixture of the
isoxazolidines anti, exo-12 and anti, endo-13 (Scheme 4).17 First of all, it was noteworthy that 61:39
and 87:13 diastereomeric mixtures of (E)- and (Z)-aldehydes 9 led to the same 61:39 and 82:18
diastereomeric mixtures of fused cycloadducts 12 and 13. Thus the nitrone (E,Z)-1018 produced the
anti, exo (2S,30S,30aR,60aR)-spiro[(2-methylcyclopropane)-1,30-hexahydro-4H-pyrrolo[3,4-c]isoxazole]
12, while the nitrone (Z,Z)-11 led to the anti, endo (2S,30S,30aS,60aS)-2-methylpyrroloisoxazole 13,
exclusively. Therefore the cycloaddition can be regarded as totally regio- and diastereoselective.
Scheme 4.
Effectively, fused cycloadducts were only obtained because the strain experienced by the chain joining
the two reactive sites (i.e., the nitrone and the alkylidenecyclopropanes moieties) prevented the formation
of regioisomeric bridged cycloadducts.4 Thus, the coupling constant between the two bridgehead atoms
in anti, exo-12 (JH3 aH6 a=7.8 Hz) proved that this cycloadduct was really cis-fused.5 The formation of
the cycloadduct anti, exo-12, observed from the nitrone (E,Z)-10a, probably resulted from the single
possible (or most favourable due to the cyclopropanemethyl congestion) approach of the dipolarophile
by the (Z)-nitrone moiety, from the less hindered side of the alkylidenecyclopropane plane entailing an
anti relationship between the (2S)-methyl group and the new carbon–oxygen bond, while the formation of
the anti, endo-13 would result similarly from the nitrone (Z,Z)-11a involving the same anti relationship.
0
0

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Simple molecular mechanics calculations (Hyperchem)19 have supported these results;5 thus the
differences of energies between the conformations of the transition states (E,Z)-10a and (E,Z)-10b
(∆E=4.8 kcal mol−1) leading from the same nitrone (E,Z)-10 to either the anti, exo-12 or to the syn,
exo-14, respectively, and between the conformations of the transition states (Z,Z)-11a and (Z,Z)-11b
(∆E=1.7 kcal mol−1) leading from the nitrone (Z,Z)-11 to either the anti, endo-13 or to the syn, endo-15,
respectively, have confirmed the observed diastereoselectivity induced by the presence of the (2S)-methyl
group.
The 85:15 mixture of isoxazolidines 12 and 13, which were also inseparable by silica gel chromato-
graphy, then underwent thermal rearrangement on heating in xylene at reflux for 5 h to provide, in 80%
yield, a 47:25:20:8 diastereo- and enantiomeric mixture of pyrrolo[3,4-b]pyridin-4-ones 18a–d.

F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
901
First of all, the cyclopropane ring opening subsequent to the N–O isoxazolidine bond homolysis,
followed by intramolecular diradical coupling to provide bicyclic diazaheterocycles,5 appeared totally
regioselective. In fact only 2-methyl derivatives 17a–d, resulting from the cleavage of the more substitut-
ed cyclopropane bond of the isoxazolidines anti, exo-12 and anti, endo-13 into the diradical intermediate
16, were formed as proved by 13C NMR data (i.e., tertiary carbons in α of a nitrogen at δ 66.2, 53.9,
64.3 and 46.1 ppm, respectively) (Scheme 5). The pyridones 17a and 17c were readily isolated and
purified by simple flash chromatography; the pyridone 17b was obtained in a mixture with 17a, and the
minor product 17d was not isolated. NOESY experiments disclosed a cis relationship for the H2 and
H7a protons of the major adduct 17a. However, this ring closure was not totally diastereoselective as a
67:33 mixture of 17a,c (with a (2R)-methyl) and 17b,d (with a (2S)-methyl) was obtained from the 85:15
mixture of isoxazolidines anti, exo-12 and anti, endo-13. The pyridones 17c and 17d were derived from
epimerization of the carbon 4a, due to the easy enolization of the carbonyl group at C4. Effectively, a
mixture of 17a,b, obtained by flash chromatography, underwent epimerization into 17c,d upon treatment
with NaH in THF at room temperature overnight.
Scheme 5.
The diradical intermediate 16, resulting from the ring opening of the diastereomeric cyclopropyloxy
radicals arising from the 85:15 mixture of the isoxazolidines 12 and 13, respectively, was obtained as an
85:15 enantiomeric mixture. Thus all the products 17a–d were generated in 70% enantiomeric excesses,
proved unambiguously by 1H NMR spectra recorded in the presence of the shift reagent Eu(hfc)3, which
disclosed the shift of the N-methyl singlets.
3. Double asymmetric induction
In the same way, nucleophilic substitution of the palladium complex (2S)-6,9 by the N0-methyl N0-
methoxy-N-tosyl-L-alaninamide (2S)-18,16 in the presence of NaH in THF produced in 86% yield an
81:19 diastereomeric mixture of (E)- and (Z)-alkylidene(2-methylcyclopropane) (2S,20S)-19, which upon
reduction by LiAlH4 in diethyl ether gave the crude aldehydes (2S,20S)-20 (Scheme 6).
Reaction of this crude diastereomeric aldehyde mixture (2S,20S)-20 (de: 62%) with MeNHOH, HCl
in toluene containing 1 equivalent of diisopropylethylamine (DIPEA) produced in 70% overall yield
from (2S,20S)-19 a 65:20:15 diastereomeric mixture of tricycloadducts 21–23 (Scheme 7). The anti, exo
stereochemistry of the major isoxazolidine (2S,30aR,60S,60aR)-21, isolated by simple chromatography,
1
0
has been established from its H NMR coupling data; thus, after irradiation of the methyl on carbon C6 ,
0
0
the measured coupling value of JH6 H6 a=4.9 Hz proved the trans relationship of these two vicinal pyrrol-

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F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
Scheme 6.
idine protons. Moreover, NOESY effects were observed between the methyl group on the cyclopropane
0
0
carbon (2S) and the proton on carbon C3 a, as well as between the methyl on carbon C6 and the proton
0
on carbon C6 a. The minor cycloadduct 22 was isolated by recrystallization and 23 was obtained as a
0
0
mixture with 22; the cis relationship between the protons on carbons C6 and C6 a of 22 and 23 was also
deduced from their 1H NMR coupling constant values (JH6 H6 a=7.9 Hz).
0
0
Scheme 7.
It is likely that the major adduct anti, exo-21 (65%) arose from the 1,3-dipolar cycloaddition of the
(E,Z)-nitrone 24a,18 resulting from the most favoured anti approach of the dipolarophile by the nitrone
moiety entailing the formation of an exo-methyl on carbon (2S), while the anti, endo-22 (20%) arose from
the nitrone (Z,Z)-25a. However, as shown from molecular mechanics calculation20 the weaker difference
of energies between the conformation of the corresponding transition states (∆E=0.7 kcal mol−1, vide
supra) allowed, from the (E,Z)-nitrone 24a, also the syn approach of the dipolarophile and the formation
of syn, exo-23 (15%).
The cycloaddition of (S)-2, prepared from methyl alaninate (R=Me, X=NTs), has been reported
to provide a 45:55 diastereomeric mixture of exo- and endo-isoxazolidines 3 (R=Me, X=NTs) (de:
10%). Therefore the diastereoselectivity was slightly increased by the simple introduction of a methyl
substituent on the cyclopropane ring, since a 65:35 diastereomeric mixture of exo-21 and endo-22+2321
(de: 30%) was obtained, most likely due to the matched interaction between the two stereocentres. Higher
diastereoselectivity can therefore be expected from bulkier groups, both on the alkylidenecyclopropane
moiety and nitrone moieties.

F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
903
Finally, thermally induced ring expansion (xylenes, 115°C) of the pure anti, exo-21 provided, in 55%
isolated yield, a 48:31:21 diastereomeric mixture of enantiomerically pure 1,2,7-trimethylpyrrolo[3,4-
b]pyridin-4-ones 26a–c (Scheme 8); all were separated by flash chromatography and their structures
determined from NOESY effects observed between the methyl on carbon C7 and the protons on carbons
C4a and C7a on the diazaheterocycles 26a and 26b, and between the protons on the carbons C2 and C7a
on 26b.
Scheme 8.
In conclusion, while the inseparable diastereomeric isoxazolidines 12 and 13 provided with 70%
enantiomeric excesses the bicyclic diazaheterocycles 17a–d, because the thermal N–O bond cleavage
entailed the formation of the diradical intermediate 16 (70% ee), on the other hand the thermal ring
expansion of the isolated pure isoxazolidine 21, likely involving an enantiomerically pure radical
intermediate, led to the pyrrolo[3,4-b]pyridin-4-ones 26a–c, with>98% enantiomeric excesses. The
partial epimerization on carbon C4a which provided 17c,d and 26c was likely the result of the increased
strain in the cis-fused bicyclic heterocycles induced by the methyl substituent; this fact was not observed
in the previous examples when this substituent was absent.5
4. Experimental
4.1. General
All the reactions requiring anhydrous conditions were carried out under nitrogen and the solvents were
appropriately dried before use. Rf values refer to TLC on 0.25 mm silica gel plates (Merck F254) obtained
using the same eluent as in the column chromatographies, except where indicated. Melting points were
determined on an RCH Kofler or on a Mettler FP-5 apparatus. Polarimetric measures were performed on
a JASCO DIP-370 or on a Perkin–Elmer 241 polarimeter. NMR spectra were recorded on Varian Gemini
(1H 200 MHz), Bruker AC200 (1H 200 MHz), Bruker AM250 (1H 250 MHz), VXR 300 (1H 300 MHz)
and Bruker DRX 500 (1H 500 MHz), with CDCl3 as solvent except where indicated; the NMR data are
reported in δ (ppm) from TMS. IR spectra were recorded in CDCl3 solution on a Perkin–Elmer 881 or
on a Perkin–Elmer 682 spectrophotometer. Mass spectra were recorded on a QMD 1000 Carlo–Erba,
Hewlett–Packard 5792A or Nermag R-10 coupled with an OKI DP 125 gas chromatograph. Relative
percentages are shown in brackets. Accurate mass spectra were recorded on an MAT 95S. Elemental
analyses were performed with a Perkin–Elmer 2400 C analyser or by the Service de Microanalyse,
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette.
Starting material, (1R,2S) 2-Methyl-1-tosyloxy-1-vinylcyclopropane 5, was prepared according to
published procedures.9,10

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4.2. General procedure for the synthesis of N0-methyl, N0-methoxyamide of N-tosylamino acids
To a 0.04 M solution of methyl N-tosyl aminocarboxylate (1 equiv.) in dichloromethane
MeNHOMe·HCl (1.5 equiv.), pyridine (2 equiv.) and DCC (1.5 equiv.) were added. The mixture
was stirred overnight, then the organic phase was washed with a saturated solution of NaCl and dried
over Na2SO4. After filtration and evaporation at reduced pressure, diethyl ether was added and salts
were removed by filtration. After purification on silica gel, the desired products were obtained.
4.2.1. N0-Methyl-N0-methoxy-N-tosylglycinamide 7b
1
White solid, 85% yield (eluent petroleum ether:diethyl ether 1:5, Rf=0.15); H NMR (200 MHz) δ
7.69 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.20 (bs, 1H), 3.83 (s, 2H), 3.58 (s, 3H), 3.05 (s, 3H),
2.35 (s, 3H); 13C NMR (50.3 MHz) δ 168.1 (s), 143.4 (s), 135.9 (s), 129.5 (d), 127.0 (d), 61.3 (q), 42.9
(t), 32.1 (q), 21.2 (q); IR 3674, 2940, 1705, 1665, 1362, 1220, 1157 cm−1; MS m/z (EI) 273 (59), 225
(10), 212 (15), 184 (98), 155 (100), 91 (91).
4.2.2. N0-Methyl-N0-methoxy-N-tosylalaninamide 18
Yellow oil, 74% yield (eluent diethyl ether, Rf=0.41); 1H NMR (200 MHz) δ 7.69 (d, J=8.4 Hz, 2H),
7.25 (d, J=8.1 Hz, 2H), 5.71 (bd, J=9.2 Hz, 1H), 4.29 (m, 1H), 3.52 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H),
1.26 (d, J=6.9 Hz, 3H); 13C NMR (50 MHz) δ 172.2 (s), 143.3 (s), 137.0 (s), 129.4 (d), 127.2 (d), 61.3
(q), 48.7 (q), 32.0 (d), 21.3 (q), 19.8 (q); IR 3322, 2978, 2937, 1660, 1380, 1336, 1145, 1079 cm−1; MS
m/z 287 (MH+, 2), 199 (10), 198 (91), 155 (93), 91 (100).
4.3. General procedure for the palladium(0)-catalyzed nucleophilic substitution of (1R,2S) 2-methyl-
1-tosyloxy-1-vinylcyclopropane 5
A solution of Pd(dba)2 (5 mol%) and PPh3 (12 mol.%) was degassed under vacuum for 1 h and put
under argon or nitrogen atmosphere. Then a 0.05 M solution of (1R,2S)-516 (from 0.20 to 0.79 mmol) in
THF was added. After 10 min the mixture, which had turned green, was added to a solution of sodium salt
of the nucleophile prepared in a separate flask from the amino acid derivatives 7a,b and 18 (1.1 equiv.),
0.06 M in THF, which was added slowly to pentane (or petroleum ether) washed sodium hydride (1.5
equiv.). After the mixture was stirred from 1 h to 1 day at room temperature, evaporation of the solvent
and flash chromatography on silica gel of the residue gave the alkylidenecyclopropanes 8a,b and 19 as a
mixture of two inseparable diasteroisomers.
4.3.1. Methyl N-[2-(2-methylcyclopropylidene)ethyl]-N-tosylglycinate 8a
1
Yellow oil, 100% yield (eluent petrol ether:diethyl ether 9:1, Rf=0.18); H NMR (200 MHz, major
diastereoisomer) δ 7.75 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 5.6 (tq, J=7.0, 1.9 Hz, 1H), 4.0 (dd,
J=7.7, 4.1 Hz, 2H), 4.0 (s, 3H), 3.62 (s, 2H), 2.43 (s, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.60–0.50 (m, 3H); 13
C
NMR (50.3 MHz, major diastereoisomer) δ 169.5 (s), 143.3 (s), 137.0 (s), 135.8 (s), 128.6 (d), 127.3 (d),
111.1 (d), 52.0 (q), 49.3 (t), 46.9 (t), 21.5 (q), 17.7 (t), 10.0 (d), 9.1 (t); IR (mixture of diastereoisomers)
+
2960, 1760, 1440, 1350, 1220, 1160 cm−1; MS (mixture of diastereoisomers) m/z (EI) 341 (MNH4 ,
40), 324 (MH+·, 23), 323 (M+·, 11), 261 (23), 170 (81), 168 (100), 155 (5), 108 (37); HRMS found:
323.1196; required for C16H21NO4S: 323.1191.

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905
4.3.2. N0-Methyl-N0-methoxy-N-[2-(2-methyl)-cyclopropylidene)ethyl]-N-tosylglycinamide 8b
1
Yellow oil, 95% yield (eluent petrol ether:diethyl ether 1:1, Rf=0.14); H NMR (200 MHz, major
diastereoisomer) δ 7.80 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 5.71 (tq, J=6.6 Hz, 2.19 Hz, 1H),
4.24 (s, 2H), 4.01 (d, J=6.6 Hz, 2H), 3.67 (s, 3H), 3.12 (s, 3H), 2.42 (s, 3H), 1.07 (d, J=5.8 Hz, 3H),
1.60–0.45 (m, 3H); 13C NMR (50.3 MHz, major diastereoisomer) δ 169.2 (s),142.9 (s), 137.3 (s), 135.0
(s), 129.2 (d), 127.3 (d), 111.5 (d), 61.1 (q), 48.9 (t), 45.7 (t), 32.2 (q), 21.3 (q), 17.5 (q), 9.7 (d), 9.0 (t);
IR (mixture of diastereoisomers) 3049, 2959, 1679, 1598, 1443, 1335, 1151, 1088 cm−1; MS (mixture
of diastereoisomers) m/z (EI) 264 (1), 197 (43), 155 (29), 109 (24), 108 (100), 91 (79). HRMS (M+Na)
found: 375.13553; required for C17H24N2O4SNa: 375.13540.
4.3.3. N0-Methyl-N0-methoxy-N-[2-(2-methylcyclopropylidene)ethyl]-N-tosyl-L-alaninamide 19
Yellow oil, 86% yield (eluent petroleum ether:diethyl ether 1:1, Rf=0.21); 1H NMR (200 MHz) (major
diastereoisomer) δ 7.69 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 5.83 (m, 1H), 5.10 (q, J=7.0 Hz,
1H), 4.26–4.01 (m, 2H), 3.76 (s, 3H), 3.08 (s, 3H), 2.40 (s, 3H), 1.25 (d, J=7.3 Hz, 3H), 1.07 (d, J=5.9
Hz, 3H), 1.49–0.62 (m, 3H) and (minor diastereoisomer) 5.73 (m, 1H).13C NMR (50.3 MHz) (major
diastereoisomer) δ 172.2 (s), 143.1 (s), 137.5 (s), 131.6 (s), 129.3 (d), 127.3 (d), 115.2 (d), 61.5 (q), 51.1
(q), 46.1 (t), 32.0 (d), 21.3 (q), 17.5 (q), 15.7 (q), 9.5 (d), 9.3 (t); (minor diastereoisomer: distinguishable
signals) 45.8 (t), 17.4 (q), 15.2 (q), 10.0 (d); IR (mixture of diastereoisomers) 2976, 1660, 1445, 1335,
1151 cm−1; MS m/z (EI) (mixture of diastereoisomers) 278 (5), 211 (18), 155 (26), 123 (10), 91 (71), 84
(100).
4.4. N-[2-(2-Methylcyclopropylidene)ethyl]-N-tosylaminoethanal (E)- and (Z)-9
4.4.1. From direct reduction of 8a
To a solution of 320 mg (0.99 mmol) of 8a in 20 ml of CH2Cl2 at −78°C 1.19ml (0.9 equiv., 0.89
mmol) of 1 M solution of DIBALH in hexane was added dropwise. The mixture was stirred for 20 min
at −78°C and then hydrolyzed by methanol and by a saturated sodium and potassium tartrate solution in
water. The aqueous phase was extracted four times with CH2Cl2. The combined organic extracts were
dried on anhydrous Na2SO4; evaporation of the solvent gave the crude aldehydes 9 purified by flash
chromatography, besides unreacted 8a and the corresponding alcohol.
4.4.2. From reduction of 8b
To a solution of 166.8 mg of 8b (0.47 mmol) in 25 ml of diethyl ether were added 28.4 mg of LiAlH4
(0.71 mmol) and the mixture was stirred for 2 h. Then wet Na2SO4 was added, salts were filtered through
a short pad of Celite and dried on Na2SO4. After purification on silica gel, 120.6 mg of desired aldehyde
9 were obtained, as a mixture of two inseparable diastereoisomers.
(E)- and (Z)-(9): Yellow oil, 99% yield (eluent petroleum ether:diethyl ether 1:1, Rf=0.30); 1H NMR
(200 MHz) (major (E)-diastereoisomer) δ 9.56 (t, J=1.5 Hz, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3,
2H), 5.70 (tq, J=7.32, 1.59 Hz, 1H), 3.89 (d, J=7.32 Hz, 2H), 3.69 (d, J=1.5 Hz, 2H), 2.45 (s, 3H), 1.06
(d, J=6.5 Hz, 1H), 0.5–1.5 (m, 3H); 13C NMR (50 MHz) (major diastereoisomer) 199.3 (d), 144.3 (s),
137.7 (s), 135.9 (s), 130.3(d), 127.7 (d), 111.2 (d), 56.7 (t), 51.5 (t), 21.9 (q), 17.7 (q), 10.7 (d), 9.7 (t);
IR (mixture of diastereoisomers) 2980, 1740, 1350, 1260, 1170 cm−1; MS m/z (CI, NH3) (mixture of
diastereoisomers) 264 (15),155 (45), 138 (33), 91 (84), 81 (100).

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F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
4.5. 2-{N-[2-(2-Methylcyclopropylidene)ethyl]-N-tosylamino}propanal 20
To a solution of 237.1 mg of 19 (0.65 mmol) in 18 ml of diethyl ether was added, at 0°C, 0.97 ml of a
1 M solution of LiAlH4 (0.97 mmol) in THF and the mixture was stirred for 40 min. Then wet Na2SO4
was added and the salts were removed by filtration through a short pad of Celite and dried on Na2SO4.
After evaporation under reduced pressure, 218.4 mg of expected aldehyde 20 were obtained, as a mixture
of inseparable diastereoisomers, which were used in the next step without further purification.
4.6. General procedure for the nitrone formation and intramolecular cycloaddition
To 0.02 M solutions of the aldehydes 9 and 20 in toluene, cooled to 0°C, were added 1.5 equiv. of
N-methylhydroxylamine hydrochloride and 1.5 equiv. of triethylamine (or i-Pr2EtN). The mixture was
stirred overnight at room temperature and the salts were eliminated by filtration over Celite, the solvent
was removed under reduced pressure and the crude mixture was separated by chromatography on silica
gel to give the expected isoxazolidines. From glycine derivatives, two inseparable isoxazolidines 12 and
13 were obtained; from L-alanine ones, three isoxazolidines 21–23 were obtained: two of them were
isolated and the third one was obtained as a mixture with the second one.
4.7. 10,2-Dimethyl-50-tosylspiro[cyclopropane-1,30-hexahydro-4H-pyrrolo[3,4-c]isoxazoles]
(2S,30S,30aR,60aR)-12 and (2S,30S,30aS,60aS)-13
1
White solid, 75% yield (eluent petroleum ether: diethyl ether 1:9, Rf=0.31); H NMR (200 MHz)
(mixture of diastereomers) δ 7.70 (d, J=6.6 Hz, 2H), 7.34 (d, J=6.6 Hz, 2H), 3.90–3.60 (m, 2H), 3.55–3.44
(m, 1H), 3.12–3.00 (m, 1H), 2.96–2.84 (m, 2H), 2.63 (s, 3H), 2.45 (s, 3H), 1.42–0.69 (m, 2H), 0.99 (d,
J=6.0 Hz, 3H), 0.35 (t, 1H, minor diastereomer), 0.10 (t, 1H, major diastereomer); 13C NMR (50.3 MHz)
(major diastereomer) δ 144.2 (s), 132.5 (s), 130.2 (d), 128.4 (d), 73.5 (d), 69.9 (s), 52.5 (t), 52.2 (t), 50.9
(d), 44.7 (q), 21.9 (q), 19.0 (q), 14.6 (d), 11.6 (t); MS m/z (EI) 155 (7), 153 (67), 124 (61), 112 (100), 91
(32), 42 (38); IR (mixture of diastereomers) 3002, 2960, 2930, 2880, 1350, 1185 cm−1; MS m/z (CI with
NH3) (mixture of diastereomers) 323 (MH+, 12), 322 (M+, 8), 309 (26), 292 (49), 136 (100). Anal. calcd
for C16H22N2O3S: C, 59.60; H, 6.88; N, 8.69. Found: C, 59.44; H, 6.94; N, 8.61.
4.8. (50-Tosyl-10,2,60-trimethylspiro[cyclopropane-1,30-hexahydro-4H-pyrrolo[3,4-c]isoxazole]
(2S,30S,30aR,60S,60aS)-21
White solid, 46% yield (eluent petroleum ether: diethyl ether 1:1, Rf=0.06); Mp=102–104°C;
24
[α] =−156 (CHCl3, c=0.415 g cm−3); 1H NMR (500 MHz) δ 7.71 (d, J=8.2 Hz, 2H), 7.32 (d, J=7.7 Hz,
D
2H), 3.69 (dd, J=9.5, 7.5 Hz, 1H), 3.30 (dd, J=6.8, 5.6 Hz, 1H), 3.22 (dq, J=6.7, 5.7 Hz, 1H), 3.03–2.96
(m, 2H), 2.59 (s, 3H), 2.43 (s, 3H), 1.51 (d, J=6.7 Hz, 3H), 1.07–1.01 (m, 1H), 0.95 (d, J=6.1 Hz, 3H),
0.69 (dd, J=9.8, 6.7 Hz, 1H), −0.04 (t, J=6.3 Hz, 1H); 13C NMR (50 MHz) δ 143.6 (s), 133.3 (s), 129.6
(d), 127.9 (d), 81.9 (d), 69.4 (s), 60.8 (d), 52.9 (t), 45.3 (d), 41.8 (q), 21.5 (q), 20.3 (q), 18.5 (q), 14.2 (d),
11.2 (t); IR (CDCl3) 2961, 2928, 1341, 1157 cm−1; MS m/z (EI) 336 (M+, 0.24), 222 (27), 181 (27), 155
(5), 91 (63), 56 (100). Anal. calcd for C17H24N2O3S: C, 60.69; H, 7.19; N, 8.33. Found: C, 60.66; H,
7.26; N, 8.16.

F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
907
4.8.1. (2S,30S,30aS,60S,60aR)-22
24
D
White solid, 14% yield (eluent: petroleum ether: diethyl ether 1:1, Rf=0.15); [α] =+93.6 (CHCl3,
c=0.415 g cm−3); 1H NMR (500 MHz) δ 7.72 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 3.70 (dq, J=7.3,
6.7 Hz, 1H), 3.51 (t, J=7.9 Hz, 1H), 3.41 (dd, J=10.9, 5.5 Hz, 1H), 2.85 (dt, J=7.9, 5.5 Hz, 1H), 2.63 (s,
3H), 2.43 (s, 3H), 1.35 (d, J=6.7 Hz, 3H), 1.07 (d, J=6.1 Hz, 3H), 0.90–0.82 (m, 2H), 0.47 (t, J=6.1 Hz,
1H); 13C NMR (50 MHz) δ 143.5 (s), 135.1 (s), 129.7 (d), 127.7 (d), 75.2 (d), 69.6 (s), 58.4 (d), 50.4 (t),
50.3 (d), 45.9 (q), 21.5 (q), 19.9 (q), 15.2 (q), 13.9 (d), 11.0 (t); IR 2994, 2966, 2935, 1339, 1155, 1085
cm−1; MS m/z (EI) 336 (0.19), 222 (19), 181 (20), 155 (14), 91 (41), 56 (100).
4.8.2. (2S,30R,30aS,60S,60aR)-23
White solid, 10.5% yield (eluent: petroleum ether: diethyl ether 1:1, Rf=0.15); 1H NMR (500 MHz) δ
7.73 (d, J=8.5 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H), 4.00 (dp, J=7.3, 6.7 Hz, 1H), 3.78 (dd, J=11.6, 8.5 Hz,
1H), 3.59 (t, J=7.9 Hz, 1H), 3.32 (dd, J=11.6, 8.5 Hz, 1H), 2.81 (bq, J=8.5 Hz, 1H), 2.73 (s, 3H), 2.63 (s,
3H), 1.29 (d, J=6.71 Hz, 3H), 1.25–1.19 (m, 1H), 1.07 (d, J=6.7 Hz, 3H), 1.02 (dd, J=10.4, 5.5 Hz, 1H),
0.38 (t, 1H).
4.9. General procedure for the thermal rearrangement of adducts anti, exo-12 and anti, endo-13, or anti,
exo-21
A solution of 0.40 mmol of the mixture of adducts in 5 ml of xylenes was heated at reflux for 4 h. After
cooling to room temperature, the solvent was removed under reduced pressure and the crude mixture was
purified by chromatography on silica gel to give the diazaheterocycles 17a–d and 26a–c in 80 and 57%
yields, respectively.
4.10. 1,2-Dimethyl-4-oxo-6-tosyloctahydro-1H-pyrrolo[3,4-b]pyridines 17a,c
4.10.1. (2R,4aR,7aR)-17a
24
Colourless oil (eluent ethyl acetate, Rf=0.23); [α] =+24.6 (CHCl3, c=0.72 g cm−3); 1H NMR (200
D
MHz) δ 7.71 (d, J=8.3 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 3.80 (dd, J=10.0, 3.9 Hz, 1H), 3.71 (bq, J=7.6
Hz, 1H), 3.43 (dd, J=9.4, 7.4 Hz, 1H), 3.31 (dd, J=10.1, 7.5 Hz, 1H), 2.96–2.89 (m, 3H), 2.44 (s, 3H),
2.38 (s, 4H), 2.25 (dd, J=8.4, 4.7 Hz, 1H), 1.09 (d, J=6.3 Hz, 3H); 13C NMR (50.3 MHz) δ 206.5 (s),
144.1 (s), 135.7 (s), 130.1 (d), 128.1 (d), 64.3 (d), 53.8 (d), 49.9 (q), 47.5 (t), 46.4 (t), 46.1 (t), 39.9 (d),
22.0 (q), 18.3 (q); IR 2940, 1730, 1680, 1605, 1460, 1350, 1170 cm−1; MS m/z (CI, NH3) 323 (MH+,
100), 322 (M+, 19), 167 (6).
4.10.2. (2R,4aSR,7aR)-17c
24
D
Colourless oil (eluent petroleum ether: ethyl acetate 1:1, Rf=0.23); [α] =−12.5 (CHCl3, c=0.36 g
cm−3); 1H NMR (200 MHz) δ 7.71 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 3.68 (dd, J=9.8, 6.3 Hz,
1H), 3.59 (dd, J=10.7, 8.8 Hz, 1H), 3.37 (dd, J=10.7, 7.8 Hz, 1H), 3.19 (dt, J=8.7, 6.8 Hz, 1H), 2.99 (bq,
J=8.3 Hz, 1H), 2.76 (dd, J=9.3, 6.8 Hz, 1H), 2.84–2.70 (m, 1H), 2.46 (dd, J=17.1, 4.4 Hz, 1H), 2,44 (s,
3H), 2.19 (s, 3H), 2.14 (dd, J=17.1, 10.3 Hz, 1H), 1.07 (d, J=6.3 Hz, 1H); 13C NMR (50.3 MHz) δ 206.9
(s), 129.9 (s), 129.7 (d), 127.9 (d), 127.3 (s), 66.2 (d), 55.9 (d), 53.9 (d), 49.5 (q), 47.5 (t), 47.2 (t), 39.5
(t), 21.5 (q), 20.3 (q); IR 3000, 1740, 1610, 1350, 1170 cm−1; MS m/z (CI, NH3) 323 (MH+,100), 322
(M+, 5), 167 (5). Anal. calcd for C16H22N2O3S: C, 59.60; H, 6.88; N, 8.69. Found: C, 59.64; H, 6.99; N,
9.06.

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F. Pisaneschi et al. / Tetrahedron: Asymmetry 11 (2000) 897–909
4.11. 4-Oxo-6-tosyl-1,2,7-trimethyloctahydro-1H-pyrrolo[3,4-b]pyridines 26a–c
4.11.1. (2S,4aR,7S,7aR)-26a
24
D
Colourless oil (eluent petroleum ether: ethyl ether 1:3, Rf=0.16); [α] =−33.4 (CHCl3, c=0.16 g
1
cm−3); H NMR (500 MHz) δ 7.74 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.72 (dd, J=10.0, 7.7
Hz, 2H), 3.72–3.69 (m, 1H), 3.50 (dd, J=9.7, 8.0 Hz, 1H) 3.04–2.98 (m, 2H). 2.89 (q, J=7.2 Hz, 1H),
2.44 (s, 3H), 2.44 (dd, J=14.2, 4.5 Hz, 1H), 2.24 (s, 3H), 2.10 (dd, J=14.2, 5.7 Hz, 1H), 1.32 (d, J=6.8
Hz, 3H), 0.95 (d, J=6.8 Hz, 3H); 13C NMR (50.3 MHz) δ 206.7 (s), 143.3 (s), 135.2 (s), 129.3 (d), 127.7
(d), 70.5 (d), 57.7 (d), 55.4 (d), 48.6 (d), 48.2 (t), 44.8 (t), 38.8 (q), 21.5 (q), 21.4 (q), 13.6 (q); IR 2960,
2927, 2857, 1711, 1450, 1342, 1159 cm−1; MS m/z (EI) 181 (28), 155 (2), 149 (8), 138 (34), 126 (26),
91 (26), 56 (100). Anal. calcd for C17H24N2O3S: C, 60.69; H, 7.19; N, 8.33. Found: C, 60.51; H, 6.89;
N, 8.45.
4.11.2. (2R,4aR,7S,7aR)-26b
21
D
Colourless oil (eluent petroleum ether: ethyl acetate 1:1, Rf=0.12); [α] =+17.9 (CHCl3, c=0.24 g
cm−3); 1H NMR (500 MHz) δ 7.76 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.00 (q, J=6.8 Hz, 1H),
3.61 (t, J=9.1 Hz, 1H), 3.44 (t, J=10.2 Hz, 1H), 3.06–2.97 (m, 1H), 2.44 (s, 3H), 2.32–2.28 (m, 1H),
2.16–2.13 (m, 2H), 2.00 (s, 3H), 1.29 (d, J=6.8 Hz, 3H), 0.94 (d, J=5.7 Hz, 3H); 13C NMR (50.3 MHz) δ
206.4 (s), 143.2 (s), 129.5 (s), 129.2 (d), 127.8 (d), 74.2 (d), 61.8 (d), 58.2 (d), 50.3 (d), 49.6 (t), 45.9 (t),
39.2 (q), 21.7 (q), 21.5 (q), 21.3 (q); IR 3050–2803, 1715, 1658, 1598, 1343, 1161, 1091 cm−1; MS m/z
(EI) 336 (M+,4), 293 (6), 251 (3), 222 (3), 191 (28), 155 (6), 138 (42), 126 (43), 56 (100). Anal. calcd
for C17H24N2O3S: C, 60.69; H, 7.19; N, 8.33. Found: C, 60.90; H, 7.26; N, 8.73.
4.11.3. (2S,4aS,7S,7aR)-26c
24
D
Colourless oil (eluent petroleum ether: ethyl acetate 2:3, Rf=0.30); [α] =+39.0 (CHCl3, c=0.27 g
cm−3); 1H NMR (500 MHz) δ 7.72 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.09 (dd. J=11.4, 3.4 Hz,
1H), 3.37 (dd, J=10.8, 6.8 Hz, 1H), 3.30 (p, J=6.3 Hz, 1H), 3.18 (t, J=7.0 Hz, 1H), 2.81 (td, J=6.8, 3.4
Hz, 1H), 2.75 (ddd J=12.5, 5.7, 1.1 HZ, 1H), 2.55–2.48 (m, 1H), 2.50 (s, 3H), 2.43 (s, 3H), 2.42 (dd,
J=12.5, 9.1 Hz, 1H), 1.42 (d. J=6.3 Hz, 1H), 0.79 (d, J=6.8 Hz, 1H); 13C NMR (75 MHz) δ 207.0 (s),
143.2 (s), 134.9 (s), 129.3 (6), 127.8 (d), 74.4 (d), 57.5 (d), 55.3 (d), 47.1 (d), 46.3 (t), 43.8 (d), 40.6 (q),
21.6 (q), 21.5 (q), 12.5 (q); IR 3400–2800, 1710, 1598, 1448, 1341, 1263, 1160, 1083 cm−1; MS m/z
(EI) 181 (24), 138 (25), 126 (18), 91 (24), 56 (100); MS m/z (CI, NH3) 337 (MH+, 100), 336 (M+, 47);
HRMS (M+Na) found: 359.14140; required for C17H24N2O3SNa: 359.14053.
Acknowledgements
This work was financially supported by the CNRS (France) and the CNR (Italy) within a
French–Italian Cooperation Programme and through grants from the ERASMUS European Programme.
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17. anti, exo concerns the trans relationship between the methyl on the carbon (2S) and the newly formed C–O bond and the
exo-position of this (2S)-methyl relatively to the convex face of the tricyclic isoxazolidines, while anti, endo concerns the
endo-position of the (2S)-methyl group relatively to the convex face.
18. Nitrones are considered to react under the most stable Z-configuration. See: De Shong, P.; Lander Jr, S. W.; Leginus, J. M.;
Dicken, C. M. Adv. Cycloaddit. 1988, 1, 87.
19. Molecular mechanics calculations have been performed with the Hyperchem version using an MM-2 type force field. The
minima were found through a complete geometrical optimization of the transition states for which the distances between the
0
0
0
0
atoms forming the new C3 –O2 and C3 a–C6 a bonds were constrained to 2.2 Å, as determined from transition state search
by semi-empirical PM3 calculations, according to: Cossio, F. P.; Morao, I.; Jiao, H.; Schleyer P. v. R. J. Am. Chem. Soc.
1999, 121, 6737.
20. In this case the semi-empirical PM3 calculations imposed a 3 Å value for the distances between the atoms forming the new
0
0
0
0
C3 –O2 and C3 a–C6 a bonds, and therefore the geometrical optimization of the transition states was performed with these
data.
0
21. exo and endo concern here the configurations of the methyl on the carbon C6 , relative to the convex face of the
isoxazolidines.