New synthetic routes toward enantiopure (2S,3R,4R)-4-hydroxyisoleucine by 1,3-dipolar cycloaddition of a chiral nitrone to C4 alkenes

Article abstract of DOI:10.1055/s-2007-990802

1,3-Dipolar cycloaddition reaction of a chiral nitrone derived from (-)-menthone to E/Z mixtures of crotonaldehyde or (Z)-but-2-en-1,4-diol opens, by simultaneous creation of three contiguous asymmetric centers, new access to enantiopure (2S,3R,4R)-4-hydroxyisoleucine, respectively in 13% (7 steps) and 34% (6 steps) overall yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990802

PAPER
3399
New Synthetic Routes toward Enantiopure (2S,3R,4R)-4-Hydroxyisoleucine
by 1,3-Dipolar Cycloaddition of a Chiral Nitrone to C4 Alkenes
Access to
E
nantiop
a
ure (2
S
,3
R
i
,4
R
)-4-
s
H
ydroxyisoleucine by Cy
A
cloaddition ouadi,a,b Erwann Jeanneau,c Moncef Msaddek,b Jean-Pierre Praly*a
a
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS, UMR5246, Université Lyon 1, CPE Lyon, bâtiment
308, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
Fax +33(4)72448349; E-mail: jean-pierre.praly@univ-lyon1.fr
Laboratoire de Synthèse Hétérocyclique, Chimie des Substances Naturelles, Faculté des Sciences de Monastir, Université de Monastir,
5019 Monastir, Tunisia
Centre de Diffractométrie Henri Longchambon, Université Lyon 1, Bât. Raulin, 43 Boulevard du 11 Novembre 1918, 69622
Villeurbanne, France
b
c
Received 12 June 2007; revised 19 July 2007
addition, 4-OH-Ile partly corrects hyperglycemia and glu-
cose intolerance.12b Other beneficial properties have been
claimed for 4-OH-Ile,13,14 which therefore appears as a
promising molecule of dietetic and cosmetic interest.
Abstract: 1,3-Dipolar cycloaddition reaction of a chiral nitrone de-
rived from (–)-menthone to E/Z mixtures of crotonaldehyde or (Z)-
but-2-en-1,4-diol opens, by simultaneous creation of three contigu-
ous asymmetric centers, new access to enantiopure (2S,3R,4R)-4-
hydroxyisoleucine, respectively in 13% (7 steps) and 34% (6 steps)
overall yield.
In this context, because of limitations in the extraction
procedure from natural sources (w/w extraction yield:
0.56%),9 several stereocontrolled synthetic routes to 4-
OH-Ile or the corresponding lactones10,11 have been inves-
tigated in recent years (Scheme 1). For example, the open-
ing of (2R,3R)-epoxybutane by a chiral glycine anion
equivalent was claimed to afford mainly the (3R,4R,5R)
lactone (see Scheme 1 for numbering),15 but this structure
was later suspected to be (3S,4R,5R) based on comparison
with (2R,3R,4R)- and (2S,3R,4R)-4-OH-Ile, synthesized
from benzyl 2,3-anhydro-4-O-(tert-butyldimethylsilyl)-
b-L-ribopyranoside, and on crystal analysis of the
(3R,4R,5R) lactone.16 Deprotonation of an oxazinone de-
rived from (1R,2R,5R)-(+)-2-hydroxypinan-3-one fur-
nished a glycine anion equivalent which by reaction with
butan-2,3-dione and dehydration afforded a didehy-
droamino acid derivative. Two reductive steps led to the
(3R,4R,5R) lactone, precursor of (2R,3R,4R)-4-OH-Ile.17
The same group reported a six-step synthesis of
Key words: chiral nitrone, 1,3-dipolar cycloaddition, isoxazo-
lidines, stereocontrol, 4-hydroxyisoleucine
The increasing prevalence of metabolic disorders such as
diabetes and obesity, and the need for a better understand-
ing of their etiology and more adequate treatments, has
stimulated many research efforts, in particular pharmaco-
logical approaches.1 Our contribution to this field con-
cerns the synthesis and evaluation of inhibitors of
glycogen phosphorylase of the following types: N-acyl-N-
glucopyranosylureas,2,3 5-substituted 3-C-glucopyrano-
syl-1,2,4-oxadiazoles,4 and isomeric 3-substituted 5-C-
glucopyranosyl-1,2,4-oxadiazoles,5 as well as 2-(C-b-D-
glucopyranosyl)hydro-, and benzoquinones,6 some of
them being among the most effective glucose-derived in-
hibitors.7 However, the pharmacopoeia from different ar-
eas offer examples of plants and herbs used traditionally
as hypoglycemic remedies, whose effectiveness has been
conclusively established in some cases, by identifying
the active molecule (from the plant), such as galegine
(Galega officinalis), salacinol (Salacia reticulata),8 and
(2S,3R,4S)-4-hydroxyisoleucine (Trigonella foenum-
graecum).9
bioconversions
Ref. 18, 19b
other methods
Ref. 20, 21d
sugars
Ref. 16
Me
3R
amino
acids
O
Ref. 15
Me
1
O
HO2C
2
5S
3S 4R
4S
2S
T. foenum-graecum (Leguminosae family), an annual her-
baceous plant commonly known as fenugreek, is widely
distributed across the Mediterranean area and Asia. After
several groups had found 4-hydroxyisoleucine (4-OH-
Ile), in particular, in Amanita phalloides10 and in the seeds
of T. foenum-graecum,11 Sauvaire and collaborators dem-
onstrated the insulinotropic properties of (2S,3R,4S)-4-
hydroxyisoleucine.9,12 Interestingly, this effect is glucose-
dependent and occurs only in the presence of moderate
(8.3 mM) or high (16.7 mM) glucose concentrations.9 In
– H2O
NH2 OH
and/or
stereoisomers
Ref. 17
H2N
Me
and this work
terpenes as
chiral auxiliary
for glycine
4-OH-ILe
dimethyl aminolactones
2
3
4
Yield
3
4
5
Yield
equivalents
21%16 14%17
10 steps 4 steps
R
S
S
R
S
R
R
R
R
S
R
R
S
S
R
26%16
9 steps
R
S
S
R
R
R
R
R
R
R
S
S
15%16
12%16
9 steps
10 steps
13%18 39%19b
13%18 50%19b
8 steps
6 steps 7 steps
7 steps
see 19b
see 19b
19%20
for all stereoisomers,
see patent 21b
10 steps
SYNTHESIS 2007, No. 21, pp 3399–3405
x
x.
x
x
.
2
0
0
7
Advanced online publication: 16.10.2007
DOI: 10.1055/s-2007-990802; Art ID: Z14507SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Various syntheses towards 4-OH-isoleucine and corre-
sponding lactones

3400
K. Aouadi et al.
PAPER
(2S,3R,4S)-4-OH-Ile, with an enzymatic resolution by hy- trolled synthesis of amino acids,24 this method has been
drolysis using immobilized penicillin acylase as the key further developed as an access to (2S,3R,4R)-4-OH-Ile.
step.18 In an attempt to design a synthesis of (2S,3R,4S)-4-
Based on a retrosynthetic analysis, the construction of 4-
OH-Ile that can be applied to large-scale production, a
OH-Ile by 1,3-dipolar cycloaddition of a nitrone as a gly-
process involving a biotransformation with Geotrichum
cine equivalent requires use of C4 alkenes as dipolaro-
philes. For practical reasons (availability, easy handling,
candidum and an asymmetric Strecker synthesis was pub-
lished and patented.19 In another approach, ethyl (R)-hy-
limited volatility), (E/Z)-crotonaldehyde and (Z)-but-2-
droxybutanoate was elaborated into an unsaturated
en-1,4-diol appeared suitable partners for cycloadditions
with chiral nitrone (–)-1 (Scheme 2). In both cases, cy-
cloaddition proceeded in refluxing toluene, albeit at dif-
trichloroacetimidate suitable for palladium(II)-catalyzed
3,3-sigmatropic rearrangement. Conditions could be opti-
mized so as to obtain (2S,3S,4R)-4-OH-Ile as the major
ferent rates since complete conversion of 1 required either
product.20 Lately, short syntheses of isoxazole-3-carboxy-
one week [(E/Z)-crotonaldehyde, 5.34 equiv] or 48 hours
[(Z)-but-2-ene-1,4-diol, 3 equiv]. In the first case, the ob-
tained cycloadducts 2 and 3 could be purified by column
chromatography, but they appeared to be labile, and prone
lic acid and imino-oxopentanoic acid as achiral
precursors21a of 4-OH-Ile have been reported, as well as
the amino acid-catalyzed synthesis of amino-oxopentano-
ic acid derivatives.21b–d We recently described22 an access
to transformation when dissolved in CDCl3 as indicated
to enantiopure dihydroxylated amino acids by cycloaddi-
by NMR spectroscopy and TLC examination. Therefore,
tion of chiral nitrones23 derived from (+)- or (–)-menthone
the reaction products were reduced with NaBH4 in aque-
to substituted alkenes. Considering the potential of such
ous alcoholic medium. TLC examination indicated the
chiral nitrones as glycine equivalents for the stereocon-
CHO
Me
O
E/Z
Me
CHO
H
CHO
H
+
5
4
3
O
1
O
2
N
N
N
+
O
O
O
b
a
N
N
N
(–)-1
2
3
Me
Me
O
Me
O
CH2OH
H
CH2OH
CH2I
4
H
O
H
O
N
N
N
d
c
+
O
O
N
N
N
79%
79%
from 5
4, 16%
Me
5, 33%
(4R)-6
Me
Me
Me
Me
3R
H
H
O
HO
HN
HO2C
2S
e
N
f
O
O
4R
OH
99%
65%
N
N
NH2
7
8
9
75%
i
HOH2C
CH2OH
IH2C
HOH2C
O
CH2I
H
CH2OH
+
H
O
g
h
N
N
(–)-1
O
O
70%
2 steps
N
N
11
10
Scheme 2 Reagents and conditions: (a) crotonaldehyde (E/Z ratio: 93.5:6.5, 5.34 equiv), toluene, 110 °C, 7 d; (b) NaBH4, MeOH–H2O, r.t.;
(c) I2 (2 equiv), Ph3P (3 equiv), imidazole (3 equiv), toluene, 110 °C; (d) H2 (1 atm), Pd(OH)2, MeOH, K2CO3 (1 equiv), r.t.; (e) H2 (1 atm),
Pd(OH)2, MeOH, r.t.; (f) i. 3 N HCl, AcOH, 80 °C; ii. LiOH·H2O, THF–H2O, r.t.; (g) (Z)-but-2-en-1,4-diol (3 equiv), toluene, 110 °C, 48 h;
(h) I2 (4 equiv), Ph3P (6 equiv), imidazole (6 equiv), toluene, 110 °C; (i) H2 (1 atm), Pd(OH)2, MeOH, K2CO3 (2 equiv), r.t.
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York

PAPER
Access to Enantiopure (2S,3R,4R)-4-Hydroxyisoleucine by Cycloaddition
3401
presence of two major products, besides unidentified trace the N–O bond (5 days). Finally, the chiral auxiliary was
compounds. Chromatography afforded stable spirocyclic liberated first by acid-catalyzed hydrolysis (3 N HCl,
carbinols 4 and 5 which were obtained in 16% and 33% AcOH, 80 °C, 2 h), and then by amide hydrolysis
isolated yield, respectively. Upon treatment with iodine (LiOH·H2O, THF–H2O, r.t., 2 h), the recovery of (–)-men-
and triphenylphosphine in the presence of imidazole thone being feasible by extraction with an organic solvent.
(Garegg’s conditions), the major alcohol 5 was converted The crude reaction mixture which showed a single spot on
into the corresponding iodide (4R)-6 (79%) which upon TLC plates was processed and purified by C18-reversed
crystallization afforded single crystals suitable for struc- phase chromatography to afford 9 as a crystalline material
ture analysis by diffractometry (Figure 1).25 Reduction of whose physical data were similar with those reported for
the iodide (4R)-6 was first achieved upon stirring under (2S,3R,4R)-4-OH-Ile.16,21d Under normal conditions,
H2 (1 atm) in the presence of catalytic Pd(OH)2 and compound 9 showed no alteration which might be due to
K2CO3 (1 equiv) to afford within 4 hours the tricyclic racemization or lactonization.
compound 7 with high chemoselectivity. Since this route
NMR Spectroscopy provided also valuable data for struc-
suffered from the limited stereoselectivity of the cycload-
ture elucidation, as the vicinal coupling constants of pro-
dition step and drawbacks due to chromatographic resolu-
tons attached to the isoxazolidine ring (numbered as
shown in Scheme 2) and observations from NOE experi-
ments. The observed values of the vicinal coupling con-
stants for the oxazolidine protons were found to be as
tion of product mixtures, we considered (Z)-but-2-en-1,4-
diol as a more promising dipolarophile because its Z-con-
figured symmetrical structure supported the expectation
of a single cycloadduct upon reaction with (–)-1 via the
follows in 5 and (4R)-6: J3,4 = ~0 Hz, J4,5 not determined,
exo approach. This was confirmed since diodide 11 was
J5,6 = 6.3 Hz; for 4 and (4S)-6: J3,4 = 8.4, 7.8 Hz, J4,5 = 9.6,
isolated in 70% yield (two steps) after the diol 10 was sub-
8.7 Hz, J5,6 = 6 Hz, respectively. The opposite absolute
jected the Garegg’s conditions. Cycloadduct 10 could not
configurations at C4 in (4S)-6 and (4R)-6 are clearly re-
be separated from small amounts of unreacted (Z)-but-2-
flected by the vicinal constants, as already observed.22 In
1D NOE experiments with (4S)-6 in CDCl3 (Figure 2), se-
lective irradiation of 3-H induced the following enhance-
ene-1,4-diol neither by column chromatography, because
they both had similar mobilities, nor by crystallization of
10 from the mixture. Diodide 11 gave again nice single
ments (%): vicinal 4-H proton 4.24; CH(CH3)2 3.16;
crystals which allowed unambiguous structure determina-
CH(CH3)2 3.87; H-5 0.88. In addition, selective irradia-
tion of 5-H induced the following enhancements (%): 4-H
1.24; Hc-Hex 2.17. These results showed conclusively that
the C-3–H bond points towards the isopropyl group, while
tion by crystallography (Figure 1).25 Diodide 11 was con-
verted into 7 by reduction under the conditions applied for
(4R)-6, although two equivalents of K2CO3 were required.
After 7 could be obtained in appreciable amounts by two the 3-H and 5-H protons attached to the isoxazolidine ring
routes, the rest of the sequence to the amino acid involved point to opposite directions, as also observed in the solid
reductive cleavage of the isoxazolidine N–O bond to af- state for (4R)-6 and 11 (Figure 1).
ford after 5 days the imidazolidinone 8 in excellent yield.
The structure of 10, based on that of 11 (Figure 1), clearly
Clearly, the rates of reductive steps differed substantially
indicated that the cycloaddition between the nitrone and
if one compares the reduction of iodides to 7 [within 4 h,
symmetrical (Z)-but-2-en-1,4-diol involved, as usually
with both (4R)-6 and 11] with the reductive cleavage of
observed, a transition state based on exo approach [shown
Figure 1 ORTEP representations of the crystal structures of iodides (4R)-6 and 11
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York

3402
K. Aouadi et al.
PAPER
crotonaldehyde, in accordance with the higher reactivity
observed for (Z)-but-2-en-1,4-diol, and suggested the pos-
sibility of an E/Z isomerization of crotonaldehyde, in
keeping with previous observations.22
1.24
H3C
I
H
H
H
0.88
4.24
O
H
3.87
2.17
In conclusion, 1,3-dipolar cycloaddition of a menthone-
based nitrone to (E/Z)-crotonaldehyde and (Z)-but-2-en-
1,4-diol afforded, with simultaneous creation of three ste-
reogenic centers, cycloadducts which led to (2S,3R,4R)-4-
OH-Ile in 13% and 34% overall yield (7 and 6 steps, re-
spectively). Clearly, (Z)-but-2-en-1,4-diol, a reactive
symmetrical dipolarophile, appeared to be the best sub-
strate.
3.16
N
O
N
H
Figure 2 1D NOE measured for iodide (4S)-6
CHO
Crotonaldehyde (available as a 93.5:6.5 E/Z isomeric mixture as es-
timated by H NMR spectroscopy) and (Z)-but-2-en-1,4-diol were
1
Me
Me
O
used as purchased from Aldrich. Petroleum ether (PE) used had
boiling range 40–65 °C. TLC was performed on silica gel 60 F254
(Merck). The plates were visualized under UV light, or by gentle
heating, or for amines, by ninhydrin spray, followed by heating.
Preparative C18 reverse-phase chromatography (RP-18) was per-
formed using a 15 × 15 mm column of fully endcapped silica gel
100 C18 (>400 mesh, Fluka). Optical rotations were determined with
a Perkin-Elmer model 241 polarimeter in a 1 dm cell. Melting
points were measured with a Büchi apparatus (values are uncorrect-
ed). 1H and 13C NMR spectra were recorded using a Bruker
DRX300 spectrometer. Chemical shifts are quoted in parts per mil-
lion, referenced to the residual solvent peak.26 Coupling constants
are reported in Hertz (Hz). HRMS (LSIMS) data were recorded in
the positive mode (unless otherwise stated) using a Thermo Finni-
gan Mat 95 XL spectrometer. MS (ESI) data were recorded in the
positive mode using a Thermo Finnigan LCQ spectrometer.
H
H
O
N
H
CHO
H
a
N
N
O
+
–
O
N
OHC
H
H
Me
O
CHO
H
O
N
b
Me
H
N
N
O–
+
O
N
OHC
Me
Me
O
(1S,2S,2¢R,3¢S,3¢aS,5R)-3¢-(Hydroxymethyl)-2-isopropyl-2¢,5,5¢-
trimethyl-3¢,3¢a-dihydro-2¢H-spiro{cyclohexane-1,6¢-imid-
azo[1,5-b]isoxazol}-4¢(5¢H)-one (4) and (1S,2S,2¢R,3¢R,3¢aS,5R)-
3¢-(Hydroxymethyl)-2-isopropyl-2¢,5,5¢-trimethyl-3¢,3¢a-dihy-
dro-2¢H-spiro{cyclohexane-1,6¢-imidazo[1,5-b]isoxazol}-
4¢(5¢H)-one (5)
CHO
H
H
O
N
H
N
c
H
N
N
O–
+
O
To a solution of (E/Z)-crotonaldehyde (35.9 mmol, 3 mL) in toluene
(13 mL) was added nitrone (–)-122,24b (6.72 mmol, 1.6 g) and the
mixture was stirred at reflux (110 °C) for 7 days. TLC showed the
complete conversion of 1 and the formation of two cycloadducts, 2
and 3. [Their separation by column chromatography (mobile phase:
EtOAc–PE, 3:7) was achieved, but the products were found to be la-
bile]. The crude solution was concentrated and the residue, dis-
solved in a mixture of MeOH (1.5 mL) and H2O (13.5 mL), was
reduced with NaBH4 (16.6 mmol, 632 mg) for 2 h at r.t. AcOH was
added carefully until H2 evolution had ceased and the solution was
evaporated to dryness. Boric acid was removed by addition of
MeOH (1 mL) followed by concentration (5 ×). The obtained resi-
due was purified by flash chromatography (EtOAc–PE, 1:1) to af-
ford the compounds 4 and 5.
Scheme 3 Proposed transition states for the cycloaddition of nitrone
(–)-1 to (E/Z)-crotonaldehyde
in Scheme 3c for (Z)-crotonaldehyde]. Among the two
routes to 7, this one based on (Z)-but-2-en-1,4-diol was
clearly more efficient, essentially because this dipolaro-
phile allowed a fast and highly selective cycloaddition.
Structures 2 and 3 showed that the cycloaddition of (–)-1
to crotonaldehyde proceeded with a regioselectivity
which could be rationalized on the basis of electronic fac-
tors (attack of the electron-rich oxygen atom of the nitrone
to the d-carbon of crotonaldehyde). The stereoselectivity
issue was more complex and the minor cycloadduct 2
should be formed from (E)-crotonaldehyde as shown in
Scheme 3a, in a mode of approach which placed the
methyl group away from the spirocyclic nitrone. The re-
versed presentation with the methyl ‘inside’ as in
Scheme 3b appeared to be, for steric reasons, disfavored
and not productive, without formation of the correspond-
ing product. The major cycloadduct 3 corresponded to the
reaction of (Z)-crotonaldehyde, although it is present in
small amounts. This indicated the higher reactivity of (Z)-
4
Yield: 334 mg (16%); yellow syrup; [a]22 +85 (c 1, CH2Cl2);
Rf = 0.12 (EtOAc–PE, 2:3).
1H NMR (CDCl3, 300 MHz): d = 0.84 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 0.86 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.86 (m, 1 H), 0.93
(d, J = 6.3 Hz, 3 H, CH3), 1.23 (d, J = 6.0 Hz, 3 H, CH3), 1.26 (t,
J = 12.9 Hz, 1 H), 1.34 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.82
(m, 1 H), 2.01 (m, 1 H), 2.05 (m, 1 H), 2.68 (ddd, J = 4.8 Hz, J = 9.3
Hz, J4,5 = 9.6 Hz, J4,3 = 8.4 Hz, 1 H, H-4), 2.76 (s, 3 H, NCH3), 3.64
(dq, J = 6.0 Hz, J5,4 = 9.6 Hz, 1 H, H-5), 3.78 (dd, J = 9.3 Hz,
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York

PAPER
Access to Enantiopure (2S,3R,4R)-4-Hydroxyisoleucine by Cycloaddition
3403
Jgem = 12.0 Hz, 1 H), 3.89 (dd, J = 4.8 Hz, Jgem = 12.0 Hz, 1 H), 4.12
(d, J3,4 = 8.4 Hz, 1 H, H-3), 4.29 (br s, 1 H, OH).
70%); colorless oil; [a]22 +123 (c 1, CH2Cl2); Rf = 0.71 (EtOAc–PE,
3:7).
13C NMR (CDCl3, 75 MHz): d = 16.6 (CH3), 18.2 [CH(CH3)2], 22.0
(CH2), 22.3 (CH3), 24.0 [CH(CH3)2], 24.3 [CH(CH3)2], 26.1
(NCH3), 29.4 (CH), 34.4 (CH2), 40.4 (CH2), 48.0 (CH), 54.8 (CH),
59.5 (CH2OH), 68.5 (CH), 74.5 (CH), 90.1 (Cq), 172.4 (C=O).
1H NMR (CDCl3, 300 MHz): d = 0.84 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 0.85 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 0.88 (m, 1 H), 0.92
(d, J = 6.3 Hz, 3 H, CH3), 1.25 (t, J = 12.9 Hz, 1 H), 1.29 (d, J = 5.7
Hz, 3 H, CH3), 1.37 (m, 2 H), 1.59 (m, 1 H), 1.68 (m, 1 H), 1.81 (m,
1 H), 1.99 (m, 1 H), 2.01 (dt, J = 2.4, 12.9 Hz, 1 H), 2.71 (s, 3 H,
NCH3), 2.79 (m, 1 H, H-4), 3.15 (dd, J = 6.9, 9.9 Hz, 1 H), 3.63 (dq,
J = 6.0 Hz, J5,4 = 8.7 Hz, 1 H, H-5), 3.78 (dd, J = 8.4, 9.9 Hz, 1 H),
4.02 (d, J3,4 = 7.8 Hz, 1 H, H-3).
13C NMR (CDCl3, 75 MHz): d = –1.5 (CH2I), 17.2 (CH3), 18.3
[CH(CH3)2], 22.2 (CH2), 22.3 (CH3), 24.1 [CH(CH3)2], 24.2
[CH(CH3)2], 25.9 (NCH3), 29.3 (CH), 34.6 (CH2), 40.8 (CH2), 48.0
(CH), 55.3 (CH), 67.6 (CH), 77.2 (CH), 89.1 (Cq), 170.3 (C=O).
MS (ESI+): m/z (%) = 311.1 (70, [M + H]+), 333.1 (20, [M + Na]+),
643.1 (100, [2 M + Na]+).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C17H31N2O3:
311.2335; found: 311.2336.
5
Yield: 688 mg (33%); yellow syrup; [a]22 +24 (c 1, CH2Cl2);
Rf = 0.10 (EtOAc–PE, 2:3).
MS (ESI+): m/z (%) = 421 (65, [M + H+]), 443 (100, [M + Na+]),
1H NMR (CDCl3, 300 MHz): d = 0.84 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.86 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.88 (m, 1 H), 0.92
(d, J = 6.6 Hz, 3 H, CH3), 1.23 (d, J = 6.3 Hz, 3 H, CH3), 1.26 (t,
J = 12.0 Hz, 1 H), 1.37 (m, 2 H), 1.58 (m, 1 H), 1.69 (m, 1 H), 1.81
(m, 1 H), 1.96 (dt, J = 2.2, 12.6 Hz, 1 H), 2.05 (m, 1 H), 2.74 (s, 3
H, NCH3), 2.86 (m, 1 H, H-4), 3.06 (br s, 1 H, OH), 3.72 (dd,
J = 7.3, 11.0 Hz, 1 H), 3.86 (dd, J = 7.3, 11.0 Hz, 1 H), 3.98 (m, 1
H, H-5), 3.99 (br s, 1 H, H-3).
862.9 (85, [2 M + Na+]).
HRMS (ESI+): m/z [M + H+] calcd for C17H30IN2O2: 421.1352;
found: 421.1352.
(1S,2S,2¢R,3¢R,3a¢S,5R)-2-Isopropyl-2¢,3¢,5,5¢-tetramethyl-
3¢,3¢a-dihydro-2¢H-spiro{cyclohexane-1,6¢-imidazo[1,5-b]isox-
azol}-4¢(5¢H)-one (7)
From (4R)-6: A solution of (4R)-6 (1.42 mmol, 600 mg) was dis-
solved in MeOH (15 mL). K2CO3 (1.42 mmol, 200 mg), and then
Pd(OH)2/C (20%, 90 mg) were added, whereupon 6 was trans-
formed after stirring at r.t. for 4 h under H2 (1 atm) into a more polar
compound. The mixture was filtered over a Celite pad, concentrat-
ed, and the residue was purified by flash chromatography (EtOAc–
PE, 3:7) to afford compound 7 (399 mg, 95%) as a yellow syrup;
[a]22 +26 (c 1, CH2Cl2); Rf = 0.54 (EtOAc–PE, 3:7).
13C NMR (CDCl3, 75 MHz): d = 13.1 (CH3), 18.3 [CH(CH3)2], 22.1
(CH2), 22.3 (CH3), 24.1 [CH(CH3)2], 24.3 [CH(CH3)2], 26.0
(NCH3), 29.5 (CH), 34.5 (CH2), 40.3 (CH2), 47.9 (CH), 51.5 (CH),
60.3 (CH2OH), 69.0 (CH), 74.8 (CH), 89.9 (Cq), 173.1 (C=O).
MS (ESI+): m/z (%) = 311.1 (65, [M + H]+), 333.1 (25, [M + Na]+),
643 (100, [2 M + Na]+).
HRMS (ESI+): m/z [M + H]+ calcd for C17H31N2O3: 311.2335;
found: 311.2334.
From 11: Similar conditions [H2,Pd(OH)2/C (20%), MeOH, K2CO3
(2 equiv), 4 h] applied to 11 (100 mg) afforded 7 (40.5 mg, 75%).
(1S,2S,2¢R,3¢R,3¢aS,5R)-3¢-(Iodomethyl)-2-isopropyl-2¢,5,5¢-tri-
methyl-3¢,3¢a-dihydro-2¢H-spiro{cyclohexane-1,6¢-imidazo[1,5-
b]isoxazol}-4¢(5¢H)-one [(4R)-6]
1H NMR (CDCl3, 300 MHz): d = 0.84 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.85 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.88 (m, 1 H), 0.92
(d, J = 6.3 Hz, 3 H, CH3), 1.11 (d, J = 7.5 Hz, 3 H, CH3), 1.14 (d,
J = 6.3 Hz, 3 H, CH3), 1.26 (t, J = 12.6 Hz, 1 H), 1.36 (m, 2 H), 1.58
(m, 1 H), 1.71 (m, 1 H), 1.81 (m, 1 H), 1.97 (dt, J = 2.2, 12.6 Hz, 1
H), 2.06 (m, 1 H), 2.73 (s, 3 H, NCH3), 2.78 (dq, J4,5 = 4.5 Hz,
J = 7.5 Hz, 1 H, H-4), 3.61 (br s, 1 H, H-3), 3.90 (dq, J5,4 = 4.5 Hz,
J = 6.3 Hz, 1 H, H-5).
13C NMR (CDCl3, 75 MHz): d = 12.7 (CH3), 13.2 (CH3), 18.1
[CH(CH3)2], 21.9 (CH2), 22.2 (CH3), 23.9 [CH(CH3)2], 24.0
[CH(CH3)2], 25.7 (NCH3), 29.3 (CH), 34.3 (CH2), 40.2 (CH2), 43.6
(CH), 47.7 (CH), 73.5 (CH), 75.3 (CH), 89.7 (Cq), 172.6 (C=O).
A solution of 5 (1.93 mmol, 600 mg) was dissolved in toluene (20
mL). I2 (3.86 mmol, 975 mg), Ph3P (5.79 mmol, 1.5 g), and then
imidazole (5.79 mmol, 395 mg) were added, and the mixture was
stirred at reflux for 6 h. TLC showed that the starting material
[Rf = 0.10 (EtOAc–PE, 2:3)] had changed into a less polar com-
pound [Rf = 0.62 (EtOAc–PE, 3:7)]. The mixture was filtered over
Celite, evaporated, and the residue was purified by flash chromatog-
raphy (EtOAc–PE, 3:7) to afford compound (4R)-6 which crystal-
lized from Et2O as colorless prisms; yield: 642 mg (79%); mp 107–
110 °C (Et2O); [a]22 +12 (c 1, CH2Cl2).
1H NMR (CDCl3, 300 MHz): d = 0.85 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.86 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.88 (m, 1 H), 0.92
(d, J = 6.3 Hz, 3 H, CH3), 1.21 (d, J = 6.3 Hz, 3 H, CH3), 1.27 (t,
J = 12.9 Hz, 1 H), 1.39 (m, 2 H), 1.64 (m, 2 H, CH2), 1.81 (m, 1 H),
1.97 (dt, J = 2.4, 12.9 Hz, 1 H), 1.99 (m, 1 H), 2.74 (s, 3 H, NCH3),
3.10 (m, 1 H, H-4), 3.24 (t, J = 10.2 Hz, 1 H), 3.38 (dd, J = 5.7, 10.0
Hz, 1 H), 3.99 (m, 1 H, H-5), 4.00 (br s, 1 H, H-3).
13C NMR (CDCl3, 75 MHz): d = 3.3 (CH2I), 13.0 (CH3), 18.3
[CH(CH3)2], 22.1 (CH2), 22.3 (CH3), 24.0 [CH(CH3)2], 24.2
[CH(CH3)2], 26.0 (NCH3), 29.4 (CH), 34.5 (CH2), 40.5 (CH2), 47.8
(CH3), 52.1 (CH), 72.2 (CH), 75.4 (CH), 89.7 (Cq), 171.9 (C=O).
MS (ESI+): m/z (%) = 295.1 (100, [M + H]+), 317.1 (18, [M +
Na]+), 611.1 (100, [2 M + Na]+).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C17H31N2O2:
295.2386; found: 295.2387.
(1S,2S,2¢S,3¢R,3¢aS,5R)-2¢,3¢-Bis(iodomethyl)-2-isopropyl-5,5¢-
dimethyl-3¢,3¢a-dihydro-2¢H-spiro{cyclohexane-1,6¢-imid-
azo[1,5-b]isoxazol}-4¢(5¢H)-one (11)
Nitrone (–)-1 (0.84 mmol, 200 mg) and (Z)-but-2-en-1,4-diol (2.52
mmol, 223 mg) were stirred at reflux in toluene (10 mL) for 48 h,
whereupon 1 was completely converted. Since the cycloadduct and
unreacted (Z)-but-2-en-1,4-diol had similar mobilities on TLC
plates, column chromatography (CHCl3–i-PrOH, 98:2) afforded a
crude product (247 mg, ~0.75 mmol), shown by 1H NMR to contain
a minor amount of unreacted olefin. To the crude diol, dissolved in
toluene (10 mL) were added I2 (3.03 mmol, 765 mg), Ph3P (4.54
mmol, 1176 mg), and then imidazole (4.54 mmol, 310 mg), and the
mixture was stirred at reflux for 6 h. The mixture was filtered over
Celite, evaporated, and the residue was purified by flash chromatog-
raphy (EtOAc–PE, 3:7) to afford compound 11 as colorless blocks;
MS (ESI+): m/z (%) = 421.1 (85, [M + H]+), 443 (35, [M + Na]+),
862.8 (100, [2 M + Na]+).
(1S,2S,2¢R,3¢S,3¢aS,5R)-3¢-(Iodomethyl)-2-isopropyl-2¢,5,5¢-tri-
methyl-3¢,3¢a-dihydro-2¢H-spiro{cyclohexane-1,6¢-imidazo[1,5-
b]isoxazol}-4¢(5¢H)-one [(4S)-6]
As described above for the synthesis of (4R)-6 from 5, alcohol 4
(0.64 mmol, 200 mg) was converted into the iodide (4S)-6 (189 mg,
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York

3404
K. Aouadi et al.
PAPER
(2) Nagy, V. PhD Thesis; University of Debrecen: Hungary,
yield: 321 mg (70%); mp 134–135 °C (Et2O); [a]22 +34 (c 1,
CH2Cl2); Rf = 0.48 (EtOAc–PE, 2:8).
2003.
(3) Oikonomakos, N. G.; Kosmopoulou, M.; Zographos, S. E.;
Leonidas, D. D.; Chrysina, E. D.; Somsák, L.; Nagy, V.;
Praly, J.-P.; Docsa, T.; Tóth, B.; Gergely, P. Eur. J.
Biochem. 2002, 269, 1684.
(4) Benltifa, M.; Vidal, S.; Fenet, B.; Msaddek, M.; Goekjian, P.
G.; Praly, J.-P.; Brunyánszki, A.; Docsa, T.; Gergely, P. Eur.
J. Org. Chem. 2006, 4242.
1H NMR (CDCl3, 300 MHz): d = 0.84 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 0.85 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.90 (m, 1 H), 0.95
(d, J = 6.3 Hz, 3 H, CH3), 1.28 (t, J = 12.6 Hz, 1 H), 1.39 (m, 2 H),
1.67 (m, 2 H, CH2), 1.83 (m, 1 H), 2.05 (dt, J = 2.4, 12.6 Hz, 1 H),
2.06 (m, 1 H), 2.75 (s, 3 H, NCH3), 3.28 (m, 5 H, H-4 among oth-
ers), 4.06 (br s, 1 H, H-3), 4.14 (m, 1 H, H-5).
13C NMR (75 MHz, CDCl3): d = –1.5, 1.1 (2 CH2I), 18.4
[CH(CH3)2], 22.2 (CH2), 22.3 (CH3), 24.1 [CH(CH3)2], 24.2
[CH(CH3)2], 26.1 (NCH3), 29.5 (CH), 34.5 (CH2), 40.7 (CH2), 47.9
(CH), 51.5 (CH), 72.5 (CH), 80.1 (CH), 90.0 (Cq), 171.2 (C=O).
(5) Benltifa, M.; Vidal, S.; Gueyrard, D.; Goekjian, P. G.;
Msaddek, M.; Praly, J.-P. Tetrahedron Lett. 2006, 47, 6143.
(6) He, L.; Zhang, Y.-Z.; Tanoh, M.; Chen, G.-R.; Praly, J.-P.;
Chrysina, E. D.; Tiraidis, C.; Kosmopoulou, M.; Leonidas,
D. D.; Oikonomakos, N. G. Eur. J. Org. Chem. 2007, 596.
(7) (a) Oikonomakos, N. G. Curr. Protein Pept. Sci. 2002, 3,
561. (b) Somsák, L.; Nagy, V.; Hadady, Z.; Docsa, T.;
Gergely, P. Curr. Pharm. Des. 2003, 9, 1177. (c) Somsák,
L.; Nagy, V.; Hadady, Z.; Felföldi, N.; Docsa, T.; Gergely,
P. In Frontiers in Medicinal Chemistry, Vol. 2; Reitz, A. B.;
Kordik, C. P.; Choudhary, M. I.; Atta-ur-Rahman, Eds.;
Bentham Science Publishers: Hilversum, The Netherlands,
2005, 253.
(8) (a) Nasi, R.; Sim, L.; Rose, D. R.; Pinto, M. B. J. Org. Chem.
2007, 72, 180; and references cited therein. (b) Tanabe, G.;
Yoshikai, K.; Hatanaka, T.; Yamamoto, M.; Shao, Y.;
Minematsu, T.; Muraoka, O.; Wang, T.; Matsuda, H.;
Yoshikawa, M. Bioorg. Med. Chem. 2007, 15, 3926; and
references cited therein.
MS (ESI+): m/z (%) = 547.0 (67, [M + H]+), 569.0 (45, [M + Na]+),
1114.7 (100, [2 M + Na]+).
(3S,5R,6S,9R)-3-[(1R,2R)-2-Hydroxy-1-methylpropyl]-6-iso-
propyl-1,9-dimethyl-1,4-diazaspiro[4,5]decan-2-one (8)
A suspension of 7 (1.36 mmol, 400 mg) and Pd(OH)2/C (20%, 86
mg) was stirred in MeOH (10 mL) at r.t. under H2 (1 atm) for 5 days.
TLC monitoring showed the formation of a more polar compound.
The mixture was filtered over Celite, evaporated, and purified by
flash chromatography (EtOAc–PE, 3:7) to give compound 8 as a
colorless syrup; yield: 400 mg (99%); [a]22 +19 (c 1, CH2Cl2);
Rf = 0.18 (EtOAc–PE, 3:7).
1H NMR (CDCl3, 300 MHz): d = 0.87 [t, J = 7.2 Hz, 6 H,
CH(CH3)2], 0.89 (m, 1 H), 0.93 (d, J = 6.6 Hz, 3 H, CH3), 1.00 (d,
J = 7.2 Hz, 3 H, CH3), 1.16 (d, J = 6.3 Hz, 3 H, CH3), 1.33 (m, 3 H),
1.53 (m, 3 H), 1.69 (m, 2 H), 1.78 (m, 1 H), 1.86 (ddd,
J = 1.2, 2.4, 7.2 Hz, 1 H), 2.77 (s, 3 H, NCH3), 3.70 (d, J = 2.4 Hz,
1 H), 4.02 (dq, J = 1.2, J = 6.3 Hz, 1 H), 5.10 (br s, 1 H, NH).
(9) Sauvaire, Y.; Petit, P.; Broca, C.; Manteghetti, M.; Baissac,
Y.; Fernandez-Alvarez, J.; Gross, R.; Roye, M.; Leconte, A.;
Gomis, R.; Ribes, G. Diabetes 1998, 47, 206.
(10) (a) Wieland, T.; Wehrt, H. Justus Liebigs Ann. Chem. 1966,
700, 120. (b) Wieland, T.; Hasan, M.; Pfaender, P. Justus
Liebigs Ann. Chem. 1968, 717, 205. (c) Wieland, T.;
Fahrmeir, A. Justus Liebigs Ann. Chem. 1970, 736, 95.
(d) Gieren, A.; Narayanan, P.; Hoppe, W.; Hasan, M.; Michl,
K.; Wieland, T.; Smith, H. O.; Jung, G.; Breitmaier, E.
Justus Liebigs Ann. Chem. 1974, 1561. (e) Hasan, M.;
Georgopoulos, D.; Wieland, T. Justus Liebigs Ann. Chem.
1976, 781.
(11) (a) Fowden, L.; Pratt, H. M.; Smith, A. Phytochemistry
1973, 12, 1707. (b) Alcock, N. W.; Crout, D. H. G.;
Gregorio, M. V. M.; Lee, E.; Pike, G.; Samuel, C. J.
Phytochemistry 1989, 28, 1835.
(12) (a) Sauvaire, Y.; Girardon, P.; Baccou, J. C.; Ristérucci, A.
M. Phytochemistry 1984, 23, 479. (b) Broca, C.; Gross, R.;
Petit, P.; Sauvaire, Y.; Manteghetti, M.; Tournier, M.;
Maseillo, P.; Gomis, R.; Ribes, G. Am. J. Physiol.
Endocrinol. Metab. 1999, 277, E617. (c) Broca, C.;
Manteghetti, M.; Gross, R.; Baissac, Y.; Jacob, M.; Petit, P.;
Sauvaire, Y.; Ribes, G. Eur. J. Pharmacol. 2000, 390, 339.
(d) Broca, C.; Breil, V.; Cruciani-Guglielmacci, C.;
Manteghetti, M.; Rouault, C.; Derouet, M.; Rizkalla, S.; Pau,
B.; Petit, P.; Ribes, G.; Ktorza, A.; Gross, R.; Reach, G.;
Taouis, M. Am. J. Physiol. Endocrinol. Metab. 2004, 287,
E463.
(13) Narender, T.; Puri, A.; Shweta; Khaliq, T.; Saxena, R.;
Bhatia, G.; Chandra, R. Bioorg. Med. Chem. Lett. 2006, 16,
293.
(14) (a) Potier, P.; Ouazzani, J.; Rodelet, J.-F.; Sasaki, N. A.;
Zhu, W. Q. European Patent 1495753, 2004; Chem. Abstr.
2004, 142, 62343. (b) Dal Farra, C.; Domloge, N.; Peyronel,
D. European Patent 1620185, 2004; Chem. Abstr. 2004, 141,
319491. (c) Dal Farra, C.; Domloge, N.; Peyronel, D. French
Patent 2887773, 2007; Chem. Abstr. 2007, 146, 128031.
(15) Gull, R.; Schöllkopf, U. Synthesis 1985, 1052.
13C NMR (CDCl3, 75 MHz): d = 8.4 (CH3), 18.5 [CH(CH3)2], 20.9
(CH3), 22.0 (CH3), 22.2 (CH2), 23.8 [CH(CH3)2], 24.4 [CH(CH3)2],
25.1 (NCH3), 28.8 (CH), 34.3 (CH2), 40.1 (CH), 46.7 (CH), 47.6
(CH2), 64.7 (CH), 68.3 (CH), 80.7 (Cq), 172.9 (C=O).
MS (ESI+): m/z (%) = 297.1 (100, [M + H]+), 615.1 (65, [2 M +
Na]+).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C17H33N2O2:
297.2542; found: 297.2543.
(2S,3R,4R)-4-Hydroxyisoleucine (9)
A solution of 8 (0.27 mmol, 59 mg) and AcOH (22 mL) in aq 3 N
HCl (27 mL) was heated to 80 °C for 2 h. The mixture was then con-
centrated to dryness and LiOH·H2O (180 mg) in THF–H2O (1:1, 9
mL) was added. The resulting mixture was stirred at r.t. for 2 h, then
concentrated and purified by reverse-phase flash chromatography
(C18) to afford the desired amino acid 9 as a white powder; yield: 19
mg (65%); mp 200–202 °C (EtOH); [a]22 –20 (c 0.4, H2O) {Lit.21d
[a] –21.6 (c 0.5, H2O); mp 202–204 °C (subl.); Lit.16 [a] –24.9 (c
1.17, D2O), mp ~220 °C (subl.)}; Rf = 0.84 (MeOH–H2O, 9:1).
1H NMR (D2O, 300 MHz): d = 0.99 (d, J = 7.2 Hz, 3 H, CH3), 1.17
(d, J = 6.6 Hz, 3 H, CH3), 1.99 (m, 1 H, H-3), 3.65 (d, J = 4.5 Hz, 1
H, H-2), 4.03 (dq, J = 3.0, 6.6 Hz, 1 H, H-4).
13C NMR (D2O, 75 MHz): d = 9.1 (CH3), 20.4 (CH3), 39.9 (C-3),
59.8 (C-2), 68.9 (C-4), 176.5 (C=O).
MS (CI, isobutane): m/z (%) = 130 (66, [MH – H2O]+), 148 (100,
[M + H]+).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C6H14NO3:
148.0974; found: 148.0972.
References
(1) Ross, S. A.; Gulve, E. A. Chem. Rev. 2004, 104, 1255.
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York

PAPER
Access to Enantiopure (2S,3R,4R)-4-Hydroxyisoleucine by Cycloaddition
3405
(16) Inghardt, T.; Fredj, G.; Svensson, G. Tetrahedron 1991, 47,
6469.
(17) Kassem, T.; Wehbe, J.; Rolland-Fulcrand, V.; Rolland, M.;
Roumestant, M.-L.; Martinez, J. Tetrahedron: Asymmetry
2001, 12, 2657.
(25) Crystal data of compound (4R)-6: C17H29IN2O2, M = 420.33,
orthorhombic, P212121, a = 8.761(5) Å, b = 10.744(5) Å,
c = 20.202(5) Å, V = 1901.6(18) Å3, Z = 4, Dx = 1.468 Mg
m–3, m (Mo-Ka) = 1.69 mm–1, F(000) = 856, colorless block,
0.05 × 0.05 × 0.05 mm, 4201 reflections measured
(Rint = 0.000), 4183 unique, wR2 = 0.040, conventional
R = 0.032 on F values of 3704 reflections with I > 2.0 s(I),
(D/s)max = 0.001), S = 1.06 for all data and 200 parameters.
Unit cell determination and intensity data collection
(qmax = 27.83°) were performed on a Nonius KappaCCD at
293 (2) K. Structure solutions were found by direct methods
and refinements were achieved by full-matrix least-squares
methods on F. Further details of the crystal structure
investigation can be obtained from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK (CCDC deposition no. 641986).
(18) Rolland-Fulcrand, V.; Rolland, M.; Roumestant, M. L.;
Martinez, J. Eur. J. Org. Chem. 2004, 873.
(19) (a) Ouazzani, J.; Potier, P.; Sasaki, N. A.; Wang, Q.
European Patent 1268397, 2001; Chem. Abstr. 2001, 135,
273168. (b) Wang, Q.; Ouazzani, J.; Sasaki, N. A.; Potier, P.
Eur. J. Org. Chem. 2002, 834.
(20) (a) Jamieson, A. G.; Sutherland, A.; Willis, C. L. Org.
Biomol. Chem. 2004, 2, 808. (b) For a related racemic
synthesis, see: Dong, Y.; Pai, N. N.; Ablaza, S. L.; Yu, S.-X.;
Bolvig, S.; Forsyth, D. A.; Le Quesne, P. W. J. Org. Chem.
1999, 64, 2657.
(21) (a) Becht, J.-M.; De Lamo Marin, S.; Maruani, M.; Wagner,
A.; Mioskowski, C. Tetrahedron 2006, 62, 4430.
(b) Mioskowski, C.; Wagner, A.; De Lamo, M. S.; Catala,
C.; Becht, J. M. European Patent 1572623, 2004; Chem.
Abstr. 2004, 141, 23901. (c) Mioskowski, C.; Wagner, A.;
Catala, C. European Patent 1620390, 2004; Chem. Abstr.
2004, 141, 395803. (d) Mioskowski, C.; Wagner, A.
European Patent 1657236, 2006; Chem. Abstr. 2006, 144,
433106.
Crystal data of compound 11: C17H28I2N2O2, M = 546.23,
orthorhombic, P212121, a = 8.116(5) Å, b = 8.878(5) Å,
c = 28.745(5) Å, V = 2071.2(18) Å3, Z = 4, Dx = 1.752 Mg
m–3, m (Mo-Ka) = 3.05 mm–1, F(000) = 1064, colorless
prism, 0.39 × 0.25 × 0.23 mm, 9967 reflections measured
(Rint = 0.095), 4488 unique, wR2 = 0.052, conventional
R = 0.045 on F values of 2322 reflections with I > 2.0 s(I),
(D/s)max = 0.001), S = 1.12 for all data and 209 parameters.
Unit cell determination and intensity data collection
(qmax = 27.83°) were performed on a Nonius KappaCCD at
293 (2) K. Further details of the crystal structure
(22) Aouadi, K.; Vidal, S.; Msaddek, M.; Praly, J.-P. Synlett
2006, 3299.
(23) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007,
485.
investigation can be obtained from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK (CCDC deposition no. 641985).
(24) (a) Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C.
Tetrahedron 1997, 53, 5725. (b) Vogt, A.; Altenbach, H.-J.;
Kirschbaum, M.; Hahn, M. G.; Matthäus, M. S. P.;
Hermann, A. R. European Patent 976721, 2000; Chem.
Abstr. 2000, 132, 108296. (c) Westermann, B.; Walter, A.;
Flörke, U.; Altenbach, H.-J. Org. Lett. 2001, 3, 1375.
(26) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
Synthesis 2007, No. 21, 3399–3405 © Thieme Stuttgart · New York