1,3-Dipolar cycloaddition of a chiral nitrone to (E)-1,4-dichloro-2-butene: A new efficient synthesis of (2S,3S,4R)-4-hydroxyisoleucine

Article abstract of DOI:10.1016/j.tetlet.2012.03.110

1,3-Dipolar cycloaddition of a chiral nitrone derived from (-)-menthone to (E)-1,4-dichlorobut-2-ene was the key step in a novel 5 step synthesis of (2S,3S,4R)-4-hydroxyisoleucine, obtained in 21% overall yield with high enantiopurity.

Full text of DOI:10.1016/j.tetlet.2012.03.110

Tetrahedron Letters 53 (2012) 2817–2821
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,3-Dipolar cycloaddition of a chiral nitrone to (E)-1,4-dichloro-2-butene:
a new efficient synthesis of (2S,3S,4R)-4-hydroxyisoleucine
Kaïss Aouadi a,b,c,d,e, , Erwann Jeanneau f, Moncef Msaddek e, Jean-Pierre Praly a,b,c,d,
⇑
⇑
a Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires associé au CNRS (ICBMS), UMR 5246, groupe de Chimie Organique 2-Glycochimie,
Bâtiment Curien, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
b Université Lyon 1, F-69622 Villeurbanne, France
c CNRS, UMR5246, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), groupe de Chimie Organique 2-Glycochimie, Bâtiment Curien,
43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
d CPE-Lyon, F-69616 Villeurbanne, France
e Université de Monastir, Laboratoire de Synthèse Hétérocyclique, Chimie des Substances Naturelles, Faculté des Sciences de Monastir, Avenue de l’Environnement, 5000 Monastir,
Tunisia
f Université Lyon 1, Centre de Diffractométrie Henri Longchambon, Bâtiment 305, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition of a chiral nitrone derived from (À)-menthone to (E)-1,4-dichlorobut-2-ene
was the key step in a novel 5 step synthesis of (2S,3S,4R)-4-hydroxyisoleucine, obtained in 21% overall
yield with high enantiopurity.
Received 23 February 2012
Revised 21 March 2012
Accepted 26 March 2012
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Menthone
Chiral nitrone
1,3-Dipolar cycloaddition
Isoxazolidines
4-Hydroxyisoleucine
Diabetes has been classified as insulin dependent (type 1) and
non-insulin dependent (type 2). Non-insulin dependent (type 2)
diabetes is the commonest form of diabetes comprising 90% of
the diabetic population.1,2 Together with obesity, its prevalence
in more affluent societies is spectacular and of general concern.3
In fact, metabolic syndrome is a worldwide threat as the preva-
lence of type 2 diabetes has increased substantially over recent
decades in developing countries as well. Therefore, new therapies
are being widely explored, in particular those based on pharmaco-
logical approaches.4 In this context, we were interested in the
synthesis and evaluation of glucose-based inhibitors of glycogen
phosphorylase, and we showed that glucopyranosyl-heterocycles,5
glucopyranosylidene-spiro-heterocycles,6,7 and analogues8 are to
date among the best known inhibitors of this class.9 However,
the pharmacopoeia from different areas offers examples of plants
and herbs used traditionally as hypoglycemic remedies, whose
effectiveness has been conclusively established in some cases, by
identifying the active molecule (in the plant), such as galegine
(Galega officinalis), salacinol (Salacia reticulata),10 and (2S,3R,4S)-
4-hydroxyisoleucine (Trigonella foenum-graecum).11 Interestingly,
galegine, a naturally-occurring isoamyleneguanidine [2-(3-meth-
ylbut-2-en-1-yl)guanidine] led to the development of the
biguanides.12
Trigonella foenum-graecum (Leguminosae family), an annual
herbaceous plant commonly known as fenugreek, is widely distrib-
uted across the Mediterranean area and Asia. After several groups
found 4-hydroxyisoleucine (4-OH-Ile) in particular in Amanita
phalloides13 and the seeds of T. foenum-graecum,14 Sauvaire and
co-workers demonstrated the insulinotropic properties of (2S,3R,
4S)-4-OH-Ile.11,15 Interestingly, this effect is glucose-dependent
and occurs only in the presence of moderate (8.3 mM) or high
(16.7 mM) glucose concentrations.11 In addition, 4-OH-Ile partly
corrects hyperglycemia and glucose-intolerance,15b and a study
of the effect of fenugreek 4-OH-Ile on liver function biomarkers
and glucose in diabetic and fructose-fed rats indicated 4-OH-Ile
as a useful and well-tolerated treatment of insulin resistance.15e
Other beneficial properties have been claimed for 4-OH-Ile,16,17
which therefore appears as a promising molecule of dietetic and
cosmetic interest.
⇑
Corresponding authors. Address: Université Claude-Bernard Lyon 1, Institut de
Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS UMR CNRS-UCBL n°
5246), équipe de Chimie Organique II-Glycochimie, CPE-Lyon, Bât. 308, 43
Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France. Tel.: +33
(0)472431161; fax: +33 (0)472448109 (J.-P.P.).
E-mail address: jean-pierre.praly@univ-lyon1.fr (J.-P. Praly).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.110

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K. Aouadi et al. / Tetrahedron Letters 53 (2012) 2817–2821
In this context, because of the limitations in the extraction
de, >99% ee).26 Another synthesis,27 with a biosynthetic step
exploiting the metabolism of Bacillus thuringiensis,28 and reviews29
have been reported.
procedure from natural sources (w/w extraction yield: 0.56%),11
several stereocontrolled synthetic routes to 4-OH-Ile or the corre-
sponding lactones13,14 have been investigated in recent years. For
example, the opening of (2R,3R)-epoxybutane by a chiral glycine
anion equivalent was claimed to mainly afford the (3R,4R,5R)-lac-
tone,18 but this structure was later suspected to be (3S,4R,5R) based
on the comparison with (2R,3R,4R) and (2S,3R,4R) 4-OH-Ile synthe-
Our group has reported an efficient synthesis of (2S,3R,4R)-4-
OH-Ile with total control of the stereochemistry,30 and approaches
toward analogues of (2S,3R,4S)-4-OH-Ile, prepared either from
D
-glucose,31 or by cycloaddition,32 including a direct access to
4(S)-4-hydroxy-L
-ornithine.33 We now report a stereocontrolled
sized from benzyl 2,3-anhydro-4-O-(tert-butyldimethylsilyl)-b-
L
-
synthesis of (2S,3S,4R)-4-OH-Ile with, as the key step, a 1,3-dipolar
cycloaddition reaction between a (À)-menthone-derived nitrone
and (E)-1,4-dichlorobut-2-ene.
ribopyranoside, and studied by X-ray diffraction.19 Deprotonation
of an oxazinone derived from (1R,2R,5R)-(+)-2-hydroxypinan-3-
one furnished a glycine anion equivalent which by reaction with
butan-2,3-dione and dehydration afforded a didehydroamino acid
derivative. Two reductive steps led to the (3R,4R,5R)-lactone, pre-
cursor of (2R,3R,4R)-4-OH-Ile.20 The same group reported a six-step
synthesis of (2S,3R,4S)-4-OH-Ile, with as the key step an enzymatic
resolution by hydrolysis using immobilized penicillin acylase.21 In
an attempt to design a synthesis of (2S,3R,4S)-4-OH-Ile that can
be applied to large-scale production, a process involving a biotrans-
formation with Geotrichum candidum and an asymmetric Strecker
synthesis was published and patented.22 Lately, short syntheses
of isoxazole-3-carboxylic acid and imino-oxopentanoic acid as
achiral precursors23a of 4-OH-Ile have been reported, as well as
the amino acid-catalyzed synthesis of amino-oxopentanoic acid
derivatives.23b–d By applying a palladium(II) catalyzed 3,3-sigma-
tropic rearrangement, Jamieson24a performed the first enantiose-
lective synthesis of (2S,3S,4R)-4-OH-Ile,24b obtained in 19.3%
overall yield after 10 steps. Recently, the synthesis of hydantoin
analogues of (2S,3R,4S)-4-OH-Ile with insulinotropic properties
has been reported,25 as well as a practical total synthesis through
Cycloaddition of chiral nitrone (À)-134,35 with (E)-1,4-dichloro-
but-2-ene (E/Z ratio: ꢀ98:2) was carried out in toluene at reflux.
After one week, the reaction, which created simultaneously three
adjacent stereogenic centers, was complete (TLC) and no optimiza-
tion was undertaken. After workup and column chromatography,
the isoxazolidines 2, 3, and 4 were obtained in 70%, 9%, and 3% iso-
lated yields, respectively (Scheme 1).36 The structures of 2 and 3
were unambiguously determined by a single crystal X-ray analysis
(Fig. 1).37 This provided evidence that both cycloadducts 2 and 3
resulted from the E-isomer, and the isolated yields were indicative
of the excellent diastereoselectivity of the reaction in favor of
isomer 2. The minor cycloadduct 4 was formed by cycloaddition
from the minor Z-isomer, a process shown to be highly selective,
providing 4 in 88% yield by reaction of (Z)-1,4-dichlorobut-2-ene
and nitrone (À)-1.35 Similarly high yields were observed for the
cycloaddition of (À)-1 and (Z)-but-2-en-1,4-diol,30,32b or (Z)-pent-
2-enol.32b
The major isoxazolidine 2 was treated with 10 equiv sodium io-
dide for 7 days in dry acetone at reflux. While TLC examination
showed only one spot on the plates and although the homoge-
neous fraction recovered after column chromatography exhibited
a
chiral N-protected
c-keto-a-aminoester which delivers
(2S,3R,4S)-4-OH-Ile via a four-step route (22% overall yield, >99%
Scheme 1. Reagents and conditions (a) E-1,4-dichloro-2-butene (E/Z ratio: ꢀ98:2, 3 equiv), toluene, 110 °C, 7 days; (b) NaI, acetone, reflux, 7 days; (c) H2 (1 atm), Pd(OH)2/C,
MeOH, K2CO3, rt, 4 h; (d) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 4 days; (e) (i) 3 N HCl, AcOH, 80 °C, 2 h, (ii) LiOHÁH2O, THF–H2O, rt, 2 h.

K. Aouadi et al. / Tetrahedron Letters 53 (2012) 2817–2821
2819
Figure 1. ORTEP representations of the crystal structures of 2 (left) and 3 (right).
ClH2C
H
ClH2C
H
CH2Cl
N
exo-approach
O
O
O
ClH2C
ClH2C
H
N
N
CH2Cl
N
N
N
O
O
O
favoured TS
disfavoured TS
ClH2C
H
ClH2C
O
H
CH2Cl
H
CH2Cl
CH2Cl
H
H
N
H
H
H
O
H
CH2Cl
N
O
N
O
O
O
N
N
N
3
2
4
Scheme 2. Proposed transition states for the cycloaddition of nitrone (À)-1 to 1,4-dichlorobut-2-ene.
an apparently simple 1H NMR spectrum (a N-CH3 signal as one sin-
glet), the 13C NMR spectra showed two sets of signals for several
carbon resonances, indicating the presence of iodide and di-iodide
5 and 6 (ꢀ1/2 ratio), in accordance with mass spectroscopy data. In
our hands, these compounds could not be separated, neither by
column chromatography, because of similar mobility, nor by
crystallization. Therefore, the mixture of 5 and 6 was subjected
to catalytic hydrogenation in the presence of Pd(OH)2/C and
K2CO3 to afford within 4 h isoxazolidines 7 and 8, obtained respec-
tively in 22% and 41% isolated yields, after column chromatogra-
phy.36 The structures were established by X-ray diffraction of
monocrystals37 and by 1D and 2D NMR spectroscopy which pro-
vided informations in agreement with the literature data: for isox-
azolidines 2, 7, and 8, the vicinal coupling constants J3,4 were
higher (respectively 9.0, 8.7, 8.4 Hz) indicating a syn relationship32a
between H-3 and H-4, compared to those measured for their ster-
eoisomers 3 and 4 (respectively, J3,4 = 2.7, and ꢀ1 Hz) and related
analogues.30,32,35 The 1H NMR chemical shifts for the chlorometh-
ylene protons at positions 6 and 7 in 2, 3, and 4 depended on the
environment of the group considered: while both protons were
superimposed at d ꢀ3.68 ppm for freely rotating chloromethylenes
(C6-H2 in 2, C6-H2 and C7-H2 in 4), differentiated d (ppm) are
found for these groups in 3 (C6-H2 = 3.62; C7-H2 = 3.77). But, the
orientation of the C7-H2Cl group toward the concave side of 2
resulted in steric hindrance with restricted bond rotation and
well-separated proton signals were observed at d = 3.54 and
4.31 ppm. In the next step, compound 8 was converted into 9 by
reductive cleavage of the isoxazolidine NÀO bond, which occurred
upon stirring in MeOH under H2 (1 atm) in the presence of
Pd(OH)2/C (4 days, rt). Finally, the obtained imidazolidinone 9
was transformed into the corresponding amino acid 10 by acid-cat-
alyzed hydrolysis (3 N HCl, AcOH, 80 °C), and then by amide hydro-
lysis (LiOH2O, THF–H2O, rt). (2S,3S,4R)-4-Hydroxyisoleucine 10
was obtained as a ꢀ95:5 epimeric (probably 2S/2R) mixture, as

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K. Aouadi et al. / Tetrahedron Letters 53 (2012) 2817–2821
shown by 1H NMR spectroscopy. Presumably epimerization of the
C-2 stereogenic center (which did not happen for previous synthe-
ses)30,32 occurred to a limited extent during the cleavage of the
chiral auxiliary in 9. As exemplified in related previous works,32
cycloaddition of the enantiomeric nitrone derived from (+)-menth-
one to (E)-1,4-dichlorobut-2-ene would lead to the enantiomeric
final product, namely (2R,3R,4S)-4-hydroxyisoleucine.
The proposed transition states for the cycloaddition are shown
in Scheme 2. (Z)-1,4-Dichlorobut-2-ene, present in small amounts,
reacts on the less hindered face of the nitrone (À)-1 according to
the exo-approach to give exclusively the cycloadduct 4.35 The (E)-
1,4-dichlorobut-2-ene reacts with the nitrone (À)-1 via two possi-
ble TS to give predominantly compound 2 (Scheme 2). This is not
surprising on the basis of data reported for the cycloaddition of
(À)-1 to allylic and pent-2-ene derivatives,32 3-glycopyranosyl-
prop-1-enes,34 and various allyl N-, O-, S-glycosides33 where a
number of crystal structures are available. In fact this selectivity
is easy to rationalize, as in the TS leading to 3, steric clashes can
be anticipated between a chloromethyl group and the cyclohexyl
residue.
8. Alexacou, K.-M.; Zhang, Y. Z.; Praly, J.-P.; Zographos, S. E.; Chrysina, E. D.;
Oikonomakos, N. G.; Leonidas, D. D. Bioorg. Med. Chem. 2011, 19, 5125–5136.
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L. Brit. J. Pharmacol. 2008, 153, 1669–1677.
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The 1,3-dipolar cycloaddition between a chiral nitrone derived
from (À)-menthone and (E)-1,4-dichlorobut-2-ene gave access to
(2S,3S,4R)-4-hydroxyisoleucine in 21% overall yield. With regard
to atom-economy, it is worth noting that three stereogenic centers
were formed simultaneously at the key cycloaddition step and that
the chiral auxiliary can be recovered. Therefore, this novel 5 step
route compares favorably with the previously reported one (10
steps). Considering the high potential of this approach for the
16. Narender, T.; Puri, A.; Shweta; Khaliq, T.; Saxena, R.; Bhatia, G.; Chandra, R.
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Région Rhône-Alpes is gratefully thanked for financial support
(via SRESR2007-2010/Cluster de Recherche 2009 n°5/Chimie:
Molécules Bioactives) and stipend to KA (via CMIRA ACCUEIL PRO
2010 program). Other supports from University Claude-Bernard
Lyon1 and CNRS are also acknowledged. We thank F. Albrieux, C.
Duchamp, and N. Henriques from the Centre Commun de Spec-
trométrie de Masse (ICBMS UMR-5246), for assistance and access
to the Mass Spectrometry facilities.
Supplementary data
Supplementary data (general experimental details and analyti-
cal data for compounds 2–4 and 7–10) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.03.110.
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Berzsenyi, E.; Teilhet, C.; Czifrák, K.; Batta, G.; Docsa, T.; Gergely, P.; Somsák, L.;
Praly, J.-P. Bioorg. Med. Chem. 2009, 17, 5696–5707.
7. Benltifa, M.; Hayes, J. M.; Vidal, S.; Gueyrard, D.; Goekjian, P. G.; Praly, J.-P.;
Kizilis, G.; Tiraidis, C.; Alexacou, K.-M.; Chrysina, E. D.; Zographos, S. E.;
Leonidas, D. D.; Archontis, G.; Oikonomakos, N. G. Bioorg. Med. Chem. 2009, 17,
7368–7380.
35. Aouadi, K. Université de Lyon, PhD thesis, n° 248-2006.
36. Procedures for: (a) cycloaddition: Nitrone (À)-1 (3.06 mmol, 730 mg) was
added to a solution of E-1,4-dichlorobut-2-ene (9.44 mmol, ꢀ3 equiv, 1.18 mL)
in toluene (15 mL) and the mixture was refluxed at 110 °C with stirring under
argon atmosphere. After 7 days, TLC showed the complete conversion of (À)-1
and the formation of three new products. The solvent was evaporated under
reduced pressure and the crude mixture was purified by column
chromatography on silica gel (EtOAc/petroleum ether 2:8) to afford three

K. Aouadi et al. / Tetrahedron Letters 53 (2012) 2817–2821
2821
cycloadducts 2 (777 mg, 70%), 3 (100 mg, 9%), and 4 (33 mg, 3%); (b) halogen
exchange and reduction: Sodium iodide (1.24 g, 8.3 mmol) was added in excess
to a solution of compound 2 (300 mg, 0.83 mmol) in acetone (10 mL) and the
solution was refluxed for 7 days under argon. TLC showed that the starting
material was converted into less polar products with similar mobilities
resulting in a single spot visible on the plates. The reaction mixture was
concentrated under reduced pressure and the residue was extracted with
CH2Cl2 (3 Â 20 mL). The combined organic phases were dried over MgSO4 and
evaporated. The residue was subjected to silica-gel column chromatography
(EtOAc–petroleum ether, 2:8) to afford an inseparable mixture of 5 and 6
(370 mg), as evidenced by NMR. This mixture was treated with Pd(OH)2/C
(20%, 47 mg) and K2CO3 (95 mg) in MeOH (10 mL) under H2 (1 atm) at room
temperature for 4 h. The medium was filtered over Celite, evaporated, and
purified by flash chromatography (EtOAc/petroleum ether 8:2) to afford 7
(61 mg, 22% yield), and 8 (100 mg, 41% yield), as separable compounds; (c) N–O
reductive cleavage in isoxazolidine: A suspension of 8 (0.27 mmol, 79 mg) and
Pd(OH)2/C (20%, 17 mg) was stirred in MeOH (7 mL) at rt under H2 (1 atm) for
4 days. TLC monitoring showed the formation of a more polar compound. The
mixture was filtered over celite, evaporated, and purified by flash
was heated to 80 °C for 2 h. The reaction mixture was then concentrated to
dryness and LiOHÁH2O (130 mg) in THF–H2O (1:1, 14 mL) was added. The
resulting mixture was stirred at rt for 2 h, then evaporated to dryness and
purified by reverse-phase flash chromatography (C18) to afford the desired
amino acid 10 (27 mg, 80% yield) as a white solid (ratio 2S/2R: 95:5). For this
small-scale experiment, no efforts were made for recovering the (À)-menthone
liberated, as achieved on related gram-scale assays.
37. Crystal data for compound 2:
Orthorhombic, P212121, a = 8.486 (5) Å, b = 8.922 (5) Å, c = 24.206 (5) Å,
= b = Z = 4, independent reflections = 4193
= 90°, Dcalc = 1.317 g cmÀ3
(Rint = 0.065), values [I >2 (I), 3069 reflections]: R1 = 0.054, wR2 = 0.059;
S = 1.09; CCDC 652340.
Crystal data for compound 3:
17H28Cl2N2O2, Mr = 363.33 g molÀ1
Orthorhombic, P212121, a = 8.278 (5) Å, b = 9.391 (5) Å, c = 24.072 (5) Å,
= b = Z = 4, independent reflections = 4111
= 90ꢀ, Dcalc = 1.290 g cmÀ3
(Rint = 0.059), values [I >2 (I), 2652 reflections]: R1 = 0.045, wR2 = 0.051;
C ,
17H28Cl2N2O2, Mr = 363.33 g molÀ1
a
c
,
R
r
C
,
a
c
,
R
r
S = 1.10; CCDC 652341. Crystallographic data (excluding structure factors) for
the structures in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
chromatography (EtOAc–petroleum ether, 3:7) to give compound
9 as a
colorless syrup (71 mg, 89% yield); (d) hydrolytic removal of the chiral auxiliary:
A solution of 9 (0.23 mmol, 69 mg) and AcOH (18 mL) in aq HCl (3 N, 23 mL)