The synthesis of 4-hydroxypipecolic acids by stereoselective cycloaddition of configurationally stable nitrones

Article abstract of DOI:10.1002/ejoc.200600104

The diastereoselective synthesis of trans- and cis-4-hydroxypipecolic acids has been achieved with geometry-controlled nitrone cycloaddition chemistry. The cycloaddition of 3-butenol to enantiopure C-aminocarbonyl and C-alkoxycarbonyl nitrones having a de

Full text of DOI:10.1002/ejoc.200600104

FULL PAPER
DOI: 10.1002/ejoc.200600104
The Synthesis of 4-Hydroxypipecolic Acids by Stereoselective Cycloaddition of
Configurationally Stable Nitrones
Franca M. Cordero,*[a] Simona Bonollo,[a] Fabrizio Machetti,[b] and Alberto Brandi*[a]
Keywords: Amino acids / Cycloaddition / Diastereoselectivity / Nitrogen heterocycles
The diastereoselective synthesis of trans- and cis-4-hydroxy- (2S,4S)-4-hydroxypipecolic acids, respectively, in four steps.
pipecolic acids has been achieved with geometry-controlled
nitrone cycloaddition chemistry. The cycloaddition of 3-but-
enol to enantiopure C-aminocarbonyl and C-alkoxycarbonyl
nitrones having a definite (Z) and (E) configuration, respec-
tively, occurs with complete regio- and exo selectivity. The
acyclic (Z)-nitrone 12 affords two cycloadducts in a 1:1 ratio,
which can be separated and converted into (2R,4R)- and
The cyclic (E)-nitrone 17 reacts with complete diastereofacial
selectivity and the elaboration of its sole adduct gives the
methyl ester of (2R,4S)-4-hydroxypipecolic acid, albeit in low
yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
of both enantiomers of 4-oxopipecolic ester 8 using the chi-
ral nitrone 3 derived from N-[(1R)-phenylethyl]hydroxyl-
amine and ethyl glyoxylate (Scheme 1).[7a]
Introduction
4-Hydroxypipecolic acids 1 and 2 (Figure 1) are non-pro-
teinogenic amino acids which have been isolated from se-
veral plants[1] and, together with the 4-oxo derivatives, are
present in many biologically active natural and synthetic
products such as depsipeptide antibiotics,[2] HIV protease
inhibitors,[3] and NMDA receptor antagonists.[4] Recently,
the 4-oxygenated pipecolic acids have also been used as key
intermediates in the syntheses of conformationally con-
strained amino acids and peptidomimetics.[5]
Figure 1. trans- and cis-hydroxypipecolic acids.
Because of their biological importance and synthetic
value, much effort has been devoted to their preparation,
and several different synthetic approaches have been re-
ported,[6] including the nitrone 1,3-dipolar cycloaddition
(1,3-DC).[7]
Nitrone 1,3-DC followed by suitable elaboration of cy-
cloadducts is a well-established and valuable tool for the
synthesis of variously substituted nitrogen heterocycles.[8]
This approach has been applied to the multigram synthesis
Scheme 1.
The cycloaddition of 3 to butenol 4 proceeded in high
yield (98%) with complete regioselectivity but was totally
stereo-random, affording all four possible isomers of 5 in
an equimolar mixture. No attempt was made to separate
this complex mixture, which was sequentially treated with
MsCl/TEA and DABCO in acetonitrile to afford a two-
component mixture of easily separable 4-oxopipecolic acid
derivatives 7.
[a] Dipartimento di Chimica Organica “Ugo Schiff”, Università
degli Studi di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
[b] Istituto di chimica dei composti organometallici del CNR c/o
Dipartimento di Chimica Organica “Ugo Schiff”,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
The poor stereoselectivity of the 1,3-DC can be ascribed
to the nitrone counterpart. C-Alkoxycarbonyl nitrones such
as 3 exist as rapidly equilibrating mixtures of (E) and (Z)
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F. M. Cordero, S. Bonollo, F. Machetti, A. Brandi
FULL PAPER
isomers in solution.[9] Accordingly, diastereomers 5 arise
from the reaction of both (E)-3 and (Z)-3 with butenol 4
with no π-facial discrimination (Scheme 2).
Scheme 3. (a) NEt3, molecular sieves (4 Å), CH2Cl2, room temp.,
65 h, 68% (crude). (b) DIC, HOBt, NEtiPr2, CH2Cl2, room temp.,
24 h; 10: 55%; 11: 50%; 12: 52%.
tative nitrone (11: ∆δ/∆T = –1.11 ppb/K), are in agreement
with the involvement of the amide proton in a strong intra-
molecular hydrogen bond in 10–12.[13]
Scheme 2. The exo approach of 4 to both faces of (Z)-3 and (E)-3.
A high exo selectivity of the dipolarophile is expected in
the cycloaddition,[10] but it cannot be observed as the exo
adducts of (Z)-3 are identical to the endo adducts of (E)-3,
and vice versa.
Figure 2. Hydrogen bonding in the (Z)-C-aminocarbonyl nitrones.
In a logical extension of the nitrone approach to pipec-
olic acid derivatives, we studied the cycloaddition and sub-
sequent adduct elaboration of nitrones closely related to 3
but having a definite configuration. Here, we report on the
preparation of trans- and cis-4-hydroxypipecolic acids 1 and
2 in an enantiopure form by diastereoselective cycload-
dition of butenol 4 to an acyclic (Z)-C-aminocarbonyl
nitrone and a cyclic (E)-C-alkoxycarbonyl nitrone, respec-
tively.
Nitrones 10–12 are thermally more stable than 9 and re-
act with butenol 4 at 90–100 °C to give a roughly equimolar
mixture of only two diastereomers. This result suggests that
no (E)/(Z) isomerization of nitrones occurs upon heating.
Accordingly, the relative configuration of the resulting isox-
azolidines was assumed to be 3,5-cis as a result of the ap-
proach of reagents in an exo manner.
The lack of stereocontrol by the benzylic stereogenic cen-
ter in 10 is consistent with the previous results obtained
with nitrone 3, as the chiral auxiliary at the nitrogen atom
of the acyclic nitrones experiences a considerable configura-
tional freedom and is not able to discriminate the nitrone
faces. However, 11 and 12 also afforded a mixture of two
cycloadducts in roughly equal proportions, thereby reveal-
ing that the introduction of a second stereogenic center
does not affect the cycloaddition stereochemistry either.
The treatment of nitrone 12 with butenol 4 at 100 °C for
22 h afforded the readily separable isoxazolidines 13a and
13b in good overall yield (86%) after chromatographic sep-
aration (Scheme 4). The pairs of diastereomeric cycload-
ducts derived from 10 and 11 could not be separated by
chromatography on silica gel, therefore they were not
studied further.
Results and Discussion
The simplest C-carboxy nitrone 9,[11] which is readily
prepared by condensation of glyoxylic acid with N-[(1R)-1-
phenylethyl]hydroxylamine (XRNHOH)[12] in the presence
of molecular sieves (Scheme 3), exists exclusively in a (Z)
configuration. Unfortunately, nitrone 9 does not react ap-
preciably with butenol 4 at temperatures up to 50–60 °C,
even with extended reaction times, and decomposes at
higher temperatures. In search for an alternative, 9 was con-
verted into nitrones 10, 11, and 12 by coupling with ben-
zylamine and (1S)- and (1R)-1-phenylethylamine, respec-
tively. The C-aminocarbonyl nitrones 10–12 also exist en-
tirely as (Z) isomers in solution[11] (Scheme 3).
This selectivity is almost certainly due to the strong hy-
drogen bond that stabilizes the (Z) configuration of the
nitrone (Figure 2). The existence of an intramolecular hy-
drogen bond was confirmed by the FT-IR spectra of 10–
12 recorded under conditions at which aggregation is not
significant (room temp., about 2 m CDCl3 solution). In
particular, all the samples show a band at 3243–3254 cm–1
ascribed to the hydrogen-bonded N–H stretch. In addition,
Scheme 4.
The relative and absolute configurations of 13a and 13b,
the high value of the amide hydrogen chemical shifts mea- as shown in Scheme 4, were determined by chemical corre-
sured in 2 m CDCl3 solutions (δNH = 10.13–10.19 ppm), lation and comparison of their specific rotations with the
and the low temperature coefficient recorded for a represen- known enantiopure trans-4-hydroxypipecolic acids (see be-
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Synthesis of 4-Hydroxypipecolic Acids
FULL PAPER
low). The 3,5-cis configuration of adducts 13 confirmed the chemical assignment for the cycloaddition step and the con-
assumed reaction pathway through the exo addition of the figurations of all the intermediates were also established.
dipolarophile to both the diastereotopic faces of the (Z)-C-
The present synthesis of enantiopure 4-hydroxypipecolic
aminocarbonyl nitrone.
acids by 1,3-DC of (Z)-C-aminocarbonyl nitrone 12 is far
Isoxazolidines 13a and 13b were converted into (+)- and superior to that using the C-alkoxycarbonyl nitrone 3.[7a]
(–)-trans-4-hydroxypipecolic acids (1a and 1b), respectively, The remarkable configurational stability of 12 allows the
by mesylation followed by catalytic hydrogenation and hy- complete control of the relative configuration in the cyclo-
drolysis of the [(1-phenylethyl)amino]carbonyl moiety un- addition step, and this is maintained in the final products.
der acidic conditions (Schemes 5 and 6). All the crude inter- The use of such a nitrone is suggested for other applications
mediates were used in the following step without purifica- in 1,3-dipolar cycloaddition chemistry.
tion, although samples of pure derivatives 15a and 16a
A similar reaction sequence was applied to the enantio-
could be easily obtained by chromatography on silica gel pure (E)-C-carboxy nitrone 17[15] in search of the cis-4-hy-
and fully characterized.
droxypipecolic acid. The cyclic nitrone 17 prepared from
(2R)-2-amino-2-phenylethanol was more reactive and selec-
tive than the acyclic nitrone 12, and afforded the sole cy-
cloadduct 18 upon treatment with butenol 4 in CH2Cl2 at
room temperature (Scheme 7). The structure and configura-
tion of 18 were unambiguously established by X-ray analy-
sis of a single crystal (Figure 3).[16] As expected,[15] isoxazol-
idine 18 forms by exo addition of 4 to the less-hindered side
of the (E)-nitrone 17, opposite the phenyl ring. In this case,
the complete π-facial selectivity is ascribed to the more rigid
structure of 17 with the chiral auxiliary embedded in the
ring system.
Scheme 5. (a) MsCl, NEt3, CH2Cl2, 0 °C Ǟ room temp.; (b) (i) H2,
10% Pd/C, MeOH, 1 atm, room temp., 19–22 h, (ii) Ambersep 900
OH, MeOH, room temp., 2 h; (c) 6  HCl, reflux, 22 h. *: Yield of
crude product; §: Yield of purified product from 13a.
Scheme 7.
Scheme 6. (a) MsCl, NEt3, CH2Cl2, 0 °C Ǟ room temp.; (b) (i) H2,
10% Pd/C, MeOH, 1 atm, room temp., 19 h, (ii) Ambersep 900
OH, MeOH, room temp., 2 h; (c) 6  HCl, reflux, 22 h.
Catalytic hydrogenation of salts 14 [catalyst: Pd/C or
Pd(OH)2/C, room temp., 1 atm, 15–96 h] induced the com-
plete opening of the isoxazolidinium ring, whereas the de-
benzylation of the endocyclic nitrogen atom was not repro-
ducible, giving a mixture of 15 and 16 in most cases.
Eventually, a second run of the hydrogenation step gave the
complete conversion of 15. Both catalysts Pd/C and
Pd(OH)2/C give similar results in the debenzylation of 15.
The synthesis of both enantiomers of 1 was completed
by amide hydrolysis in refluxing 6  aqueous HCl. After
Figure 3. ORTEP drawing of the X-ray crystal structure of cycload-
duct 18.[16]
Mesylation of 18 followed by spontaneous cyclization by
purification on a cation-exchange resin (Dowex 50W X8), nucleophilic substitution afforded the tricyclic intermediate
the trans-4-hydroxypipecolic acids 1a and 1b were recovered 19, which was directly hydrogenated in the presence of Pd/
in 52–54% yield based on the corresponding isoxazolidines C in methanol to cleave the isoxazolidine N–O bond and
13 (Schemes 5 and 6).
the N-benzyl moiety. The reduction mixture was then
The relative and absolute configurations of 1a and 1b treated with a basic ion-exchange resin (Ambersep 900 OH)
were unambiguously determined by comparison of the op- to remove the mesylate anion and induce methanolysis of
tical rotations and NMR spectra of the resulting amino ac- the lactone. The pipecolic ester 21 was finally recovered in
ids with literature values.[1f,14] Consequently, the stereo- 8% yield, based on 18, after silica gel chromatography of
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F. M. Cordero, S. Bonollo, F. Machetti, A. Brandi
FULL PAPER
0.77 mmol) in CH2Cl2 (0.8 mL). Benzylamine (102 µL, 0.93 mmol)
and diisopropyl(ethyl)amine (DIPEA; 135 µL, 0.78 mmol) were
then added sequentially. The reaction mixture was stirred at room
temperature for 24 h and then the solvent was evaporated under
reduced pressure. The residue was dissolved in EtOAc and washed
with 5% KHSO4 aqueous solution (3×3 mL) and H2O (3×3 mL).
The organic phase was dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
chromatography on silica gel (EtOAc/petroleum ether = 1:3 then
1:2) to give 10 (120 mg, 55%) as a colorless oil. Rf = 0.1 (EtOAc/
the multistep reaction mixture. The rather low yield of 21
is probably caused by difficulty in forming the strained tri-
cyclic isoxazolidinium salt 19 (Scheme 8).
1
petroleum ether = 1:3). [α]2D0 = –14.4 (c = 0.88, CHCl3). H NMR
Scheme 8. (a) MsCl, NEt3, CH2Cl2, 0 °C Ǟ room temp.; (b) (i) H2,
10% Pd/C, MeOH, 1 atm, room temp., 4 d, (ii) Ambersep 900 OH,
MeOH, room temp., 2 h; (d) TMS-Cl, MeOH, 0 °C.
(400 MHz): δ = 1.83 (d, J = 6.9 Hz, 3 H, CH3), 4.47 (A part of an
ABX system, J = 15.0, 5.7 Hz, 1 H, NCHH), 4.55 (B part of an
ABX system, J = 15.0, 6.0 Hz, 1 H, NCHH), 5.08 (q, J = 6.9 Hz,
1 H, CHCH3), 7.21 (s, 1 H, HC=N), 7.34–7.23 (m, 5 H, Ph), 7.38–
The structure and configuration of 20 were verified by
comparison of the optical rotation and NMR spectra of the 7.45 (m, 5 H, Ph), 10.13 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz):
δ = 18.7 (q, CH3), 43.1 (t, NCH2), 76.4 (d,
corresponding piperidinium chloride salt 21 with literature
values.[17]
CH3CHNO), 127.4 (d, C=N), 127.5 (d, 2 C, Ph), 127.9 (d, 2 C,
Ph), 128.6 (d, 2 C, Ph), 129.0 (d, 2 C, Ph), 129.5 (d, 2 C, Ph), 136.6
(s, Ph), 137.5 (s, Ph), 160.7 (s, CO) ppm. IR (CDCl ): ν = 3254,
˜
3
3033, 2930, 1651, 1529, 1455 cm–1. MS (70 eV, EI): m/z (%) = 282
(7) [M+], 177 (17), 161 (13), 104 (100), 76 (62). C17H18N2O2
(282.34): calcd. C 72.32, H 6.43, N 9.92; found C 72.21, H 6.30, N
10.09.
Conclusions
The synthesis of both enantiomers of trans-4-hydroxypi-
pecolic acid has been accomplished in five steps in a com-
bined overall yield of 45.6% starting from nitrone 12. The
(2Z)-2-{Oxido[(1R)-1-phenylethyl]imino}-N-[(1S)-1-phenylethyl]-
relative configuration of the two stereocenters of 1 was set ethanamide (11): The crude nitrone 9 (502 mg, 2.60 mmol) was cou-
pled with (1S)-1-phenylethylamine (402 µL, 3.12 mmol) under the
same conditions as described for the synthesis of 10. The purifica-
tion of the crude product by chromatography on silica gel (EtOAc/
petroleum ether = 1:3 then 1:2) afforded nitrone 11 (390 mg, 50%)
as a pale-yellow oil. Rf = 0.3 (EtOAc/petroleum ether = 1:2). [α]2D0
up through the 1,3-DC of butenol 4 to the (Z)-nitrone 12,
which occurs exclusively in an exo manner. Similarly, the
(E)-nitrone 17 affords a derivative of the (2R,4S) enanti-
omer of the cis-4-hydroxypipecolic acid. In this case, the
cycloaddition is completely diastereoselective, although
subsequent elaboration of the adduct afforded the methyl
ester of 2 in a lower yield (4% over five steps starting from
17).
1
= +30.0 (c = 0.27, CHCl3). H NMR (400 MHz): δ = 1.52 (d, J =
6.9 Hz, 3 H, CH3CHNH), 1.84 (d, J = 6.9 Hz, 3 H, CH3CHNO),
5.07 (q, J = 6.9 Hz, 1 H, CH3CHNO), 5.15 (pseudo-quint, J =
7.2 Hz, 1 H, CHNH), 7.16 (s, 1 H, HC=N), 7.20–7.33 (m, 5 H,
Ph), 7.37–7.43 (m, 5 H, Ph), 10.17 (br. d, J = 7.1 Hz, 1 H, NH)
ppm. 13C NMR (50 MHz): δ = 18.7 (q, CH3CHNO), 22.4 (q,
CH3CHNH), 48.8 (d, CHNH), 76.3 (d, CH3CHNO), 126.2 (d, 2
C, Ph), 127.2 (d, C=N), 127.4 (d, 2 C, Ph), 128.6 (d, 2 C, Ph), 129.0
(d, 2 C, Ph), 129.4 (d, Ph), 129.7 (d, Ph), 136.5 (s, Ph), 142.8 (s,
Experimental Section
General: All reactions requiring anhydrous conditions were carried
out under nitrogen and the solvents were dried appropriately before
use. NMR spectra were recorded in CDCl3 (unless otherwise
stated) and the data are reported in δ (ppm) from TMS. The multi-
plicities of the 13C NMR signals were determined by means of APT
and HSQC experiments. Relative percentages in the mass spectra
are given in parentheses. Rf values refer to TLC on 0.25-mm silica
gel plates (Merck F254).
Ph), 159.8 (s, CO) ppm. IR (CDCl ): ν = 3243, 3032, 2929, 1649,
˜
3
1554, 1526, 1455 cm–1. MS (70 eV, EI): m/z (%) = 296 (1) [M+], 192
(13), 175 (11), 145 (7), 130 (14), 104 (100), 76 (86). C18H20N2O2
(296.36): calcd. C 72.95, H 6.80, N 9.45; found C 72.90, H 6.94, N
9.36.
(2Z)-2-{Oxido[(1R)-1-phenylethyl]imino}-N-[(1R)-1-phenylethyl]-
ethanamide (12): The crude nitrone 9 (1.71 g, 8.86 mmol) was cou-
pled with [(1R)-1-phenylethyl]amine (400 µL, 1.29 g, 10.64 mmol)
under the same conditions as described for the synthesis of 10. The
purification of the crude product by chromatography on silica gel
(EtOAc/petroleum ether = 1:3 then 1:2) afforded nitrone 12 (1.35 g,
52%) as a white solid. Rf = 0.40 (EtOAc/petroleum ether = 1:2);
m.p. 120–122 °C. [α]2D3 = –88.8 (c = 1.09, CHCl3). 1H NMR
(400 MHz): δ = 1.50 (d, J = 6.9 Hz, 3 H, CH3CHNH), 1.83 (d, J
= 6.9 Hz, 3 H, CH3CHNO), 5.08 (q, J = 6.9 Hz, 1 H, MeCHNO),
5.15 (pseudo-quint, J = 7.2 Hz, 1 H, CHNH), 7.18 (s, 1 H, HC=N),
7.21–7.36 (m, 5 H, Ph), 7.37–7.47 (m, 5 H, Ph), 10.19 (br. d, J =
7.0 Hz, 1 H, NH) ppm. 13C NMR (50 MHz): δ = 18.6 (q,
CH3CHNO) 22.4 (q, CH3CHNH), 48.7 (d, CHNH), 76.3 (d,
MeCHNO), 126.2 (d, 2 C, Ph), 127.3 (d, C=N), 127.5 (d, 2 C, Ph),
128.6 (d, 2 C, Ph), 129.0 (d, 2 C, Ph), 129.5 (d, Ph), 129.7 (d, Ph),
(2Z)-{Oxido[(1R)-1-phenylethyl]imino}ethanoic Acid (9): [(1R)-1-
(hydroxyammonio)ethyl]benzene oxalate (9.08 g, 0.04 mol) and
TEA (5.53 mL, 0.04 mol) were added to a suspension of glyoxylic
acid monohydrate (3.68 g, 0.04 mol) and activated powdered mo-
lecular sieves in CH2Cl2 (50 mL). The reaction mixture was stirred
at room temperature for 65 h and then washed with water. The
organic phase was dried with Na2SO4, filtered, and the solvent was
removed under reduced pressure to give crude 9 as an orange oil
(5.28 g, 68%), which was used in the next step without further puri-
fication. 1H NMR (200 MHz): δ = 1.90 (d, J = 6.9 Hz, 1 H, CH3),
5.16 (q, J = 6.9 Hz, 1 H, CHCH3), 7.32 (s, 1 H, HC=N), 7.44 (br.
s, 5 H, Ph) ppm.
(2Z)-N-Benzyl-2-{oxido[(1R)-1-phenylethyl]imino}ethanamide (10):
Diisopropylcarbodiimide (DIC; 121 µL, 0.78 mmol) was added
dropwise to a solution of crude nitrone 9 (150 mg, 0.78 mmol) and
hydroxybenzotriazole hydrate (HOBt; 12 wt.-% H2O; 117 mg,
136.5 (s, Ph), 142.9 (s, Ph), 159.8 (s, CO) ppm. IR (CDCl ): ν =
˜
3
3243, 2983, 1649, 1526, 1454 cm–1. MS (70 eV, EI): m/z (%) = 192
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Synthesis of 4-Hydroxypipecolic Acids
(4) [M+ – 104], 175 (4), 147 (5), 131 (6), 119 (5), 104 (100), 77 (20). (ddd, J = 12.9, 9.3, 7.9 Hz, 1 H, 4-H), 3.53 (pseudo-t, J = 5.8 Hz,
FULL PAPER
C18H20N2O2 (296.36): calcd. C 72.95, H 6.80, N 9.45; found C
73.09, H 7.01, N 9.77.
2 H, CH2OH), 3.96 (dd, J = 8.2, 5.1 Hz, 1 H, 3-H), 3.97 (q, J =
6.6 Hz, 1 H, CH3CHNO), 4.19 (dq, J = 4.9, 7.5 Hz, 1 H, 5-H),
4.44 (A part of an ABX system, J = 15.0, 5.7 Hz, 1 H,
CH3CHHNH), 4.53 (B part of an ABX system, J = 15.0, 6.4 Hz,
1 H, CH3CHHNH), 7.16–7.37 (m, 10 H, Ph), 7.84 (m, 1 H, NH)
ppm. 13C NMR (100 MHz) selected data: one isomer: δ = 21.3 (q,
CH3), 36.6 (t, CH2CH2OH), 36.7 (t, C-4), 43.0 (t, CH2Ph), 60.4 t
(t, CH2OH), 63.6 (d, CH3CHNO), 65.8 (d, C-3), 76.1 (d, C-5),
138.2 (s, Ph), 141.7 (s, Ph), 171.8 (s, CO) ppm; other isomer: δ =
20.8 (q, CH3), 36.0 (t, CH2CH2OH), 39.0 (t, C-4), 43.1 (t, CH2Ph),
60.5 t (t, CH2OH), 64.3 (d, CH3CHNO), 65.6 (d, C-3), 76.4 (d, C-
5) ppm.
Cycloadducts of Nitrone 12 with 3-Buten-1-ol (Representative Cyclo-
addition)
(3R,5S)- and (3S,5R)-5-(2-Hydroxyethyl)-N,2-bis[(1R)-1-(phenyl-
ethyl)]-3-isoxazolidinecarboxamide (13a and 13b): A solution of
nitrone 12 (1.35 g, 4.56 mol) in butenol 4 (96% purity, 2 mL) was
heated at 100 °C for 21 h. The solution was then cooled and the
excess of butenol was removed under reduced pressure. The crude
mixture of the two diastereomers 13a and 13b was separated by
chromatography on silica gel (EtOAc/petroleum ether, 2:1) to give
13a (715 mg, 43%) and 13b (729 mg, 43%) as colorless oils.
Cycloadducts of Nitrone 11 with 3-Buten-1-ol
13a: Rf = 0.1 (EtOAc/petroleum ether = 2:1). [α]2D0 = –13.9 (c =
1
(3R,5S)- and (3S,5R)-5-(2-Hydroxyethyl)-2-[(1R)-1-phenylethyl]-N-
[(1S)-1-phenylethyl]-3-isoxazolidinecarboxamide (mixture of two in-
separable diastereomers): Rf = 0.12 (EtOAc/petroleum ether =
1.5:1). 1H NMR (400 MHz): one isomer: δ = 1.48 (d, J = 6.4 Hz, 3
H, CH3CHNO), 1.50 (d, J = 6.8 Hz, 3 H, CH3CHNH), 1.83–1.90
(m, 2 H, CH2CH2OH), 2.33 (ddd, J = 12.8, 7.3, 3.6 Hz, 1 H, 4-H),
2.72 (ddd, J = 12.8, 9.4, 7.8 Hz, 1 H, 4-H), 3.63 (dd, J = 9.4, 3.6 Hz,
1 H, 3-H), 3.77 (tm, J = 5.8 Hz, 2 H, CH2OH), 3.89 (q, J = 6.4 Hz,
1 H, CH3CHNO), 4.47 (dq, J = 5.3, 7.3 Hz, 1 H, 5-H), 5.00 (dq,
J = 8.1, 7.0 Hz, 1 H, CH3CHNH), 7.16–7.37 (m, 10 H, Ph), 7.68
(br. d, J = 8.6 Hz, 1 H, NH) ppm; other isomer: δ = 1.42 (d, J =
6.6 Hz, 3 H, CH3CHNO), 1.52 (d, J = 6.8 Hz, 3 H, CH3CHNH),
1.58 (q, J = 5.7 Hz, 2 H, CH2CH2OH), 2.13 (ddd, J = 12.7, 7.3,
5.6 Hz, 1 H, 4-H), 2.66 (ddd, J = 12.7, 8.9, 6.6 Hz, 1 H, 4-H), 3.49
(pseudo-t, J = 5.8 Hz, 2 H, CH2OH), 3.91 (dd, J = 8.9, 5.6 Hz, 1
H, 3-H), 3.99 (q, J = 6.6 Hz, 1 H, CH3CHNO), 4.16 (br. quint, J
= 6.9 Hz, 1 H, 5-H), 5.09 (dq, J = 8.3, 7.0 Hz, 1 H, CH3CHNH),
7.16–7.37 (m, 10 H, Ph), 7.78 (br. d, J = 7.5 Hz, 1 H, NH) ppm.
13C NMR (100 MHz): one isomer: δ = 21.2 (q, CH3), 21.7 (q, CH3),
36.4, 36.6 (t, CH2CH2OH, C-4), 48.2 (d, CH3CHNH), 60.3 (t,
CH2OH), 63.8 (d, CH3CHNO), 65.8 (d, C-3), 76.3 (d, C-5), 126.0
(d, 2 C, Ph), 127.1 (d, Ph), 127.5 (d, 2 C, Ph), 128.1 (d, Ph), 128.5
(d, 2 C, Ph), 128.9 (d, 2 C, Ph), 141.7 (s, Ph), 143.0 (s, Ph), 170.8
(s, CO) ppm; other isomer: δ = 20.6 (q, CH3), 22.2 (q, CH3), 36.0
(t, CH2CH2OH), 39.1 (t, C-4), 48.4 (d, CH3CHNH), 60.4 (t,
CH2OH), 64.4 (d, CH3CHNO), 65.7 (d, C-3), 76.4 (d, C-5), 125.9
(d, 2 C, Ph), 127.2 (d, Ph), 127.4 (d, 2 C, Ph), 127.7 (d, Ph), 128.5
(d, 2 C, Ph), 128.6 (d, 2 C, Ph), 141.7 (s, Ph), 143.2 (s, Ph), 170.8
(s, CO) ppm.
0.28, CHCl3). H NMR (400 MHz): δ = 1.33 (d, J = 6.6 Hz, 3 H,
CH3CHNO), 1.51 (d, J = 7.0 Hz, 3 H, CH3CHNH), 1.69–1.76 (m,
2 H, CH2CH2OH), 2.23 (ddd, J = 12.6, 7.7, 5.7 Hz, 1 H, 4-H), 2.72
(ddd, J = 12.6, 8.9, 6.9 Hz, 1 H, 4-H), 3.58 (t, J = 5.8 Hz, 2 H,
CH2OH), 3.87 (dd, J = 8.9, 5.7 Hz, 1 H, 3-H), 3.94 (q, J = 6.6 Hz,
1 H, CH3CHNO), 4.19 (br. quint, J = 6.8 Hz, 1 H, 5-H), 5.12 (dq,
J = 8.0, 7.0 Hz, 1 H, CH3CHNH), 7.27–7.29 (m, 10 H, Ph), 7.77
(br. d, J = 8.0 Hz, 1 H, NH) ppm. 13C NMR (50 MHz): δ = 20.2
(q, CH3), 21.5 (q, CH3), 35.8 (t, CH2CH2OH), 38.7 (t, C-4), 48.0
(d, CH3CHNH), 59.3 (t, CH2OH), 63.7 (d, CH3CHNO), 65.2 (d,
C-3), 75.5 (d, C-5), 125.5 (d, 2 C, Ph), 126.9 (d, 3 C, Ph), 127.1 (d,
Ph), 128.0 (d, 2 C, Ph), 128.3 (d, 2 C, Ph), 141.6 (s, Ph), 142.6 (s,
Ph), 170.8 (s, CO) ppm. IR (CDCl ): ν = 3367, 3031, 2978, 2932,
˜
3
1664, 1515, 1454 cm–1. MS (70 eV, EI): m/z (%) = 368 (1) [M+], 220
(41), 116 (46), 105 (100), 77 (33). C22H28N2O3 (368.47): calcd. C
71.71, H 7.66, N 7.60; found C 71.25, H 7.99, N 7.64.
13b: Rf = 0.2 (EtOAc/petroleum ether = 2:1). [α]2D0 = –17.1 (c =
1
0.34 in CHCl3). H NMR (400 MHz): δ = 1.43 (d, J = 7.0 Hz, 3
H, CH3CHNH), 1.50 (d, J = 6.4 Hz, 3 H, CH3CHNO), 1.67–1.76
(m, 2 H, CH2CH2OH), 2.24 (ddd, J = 12.8, 7.0, 3.5 Hz, 1 H, 4-H),
2.68 (ddd, J = 12.8, 8.8, 8.5 Hz, 1 H, 4-H), 3.63–3.69 (m, 3 H, 3-
H and CH2OH), 3.90 (q, J = 6.4 Hz, 1 H, CH3CHNO), 4.42 (dq,
J = 5.3, 7.3 Hz, 1 H, 5-H), 4.96 (dq, J = 8.3, 7.0 Hz, 1 H,
CH3CHNH), 7.26–7.36 (m, 10 H, Ph), 7.72 (br. d, J = 8.3 Hz, 1
H, NH) ppm. 13C NMR (50 MHz): δ = 21.4 (q, CH3CHNO), 22.2
(q, CH3CHNH), 36.6 (t, CH2CH2OH), 36.8 (t, C-4), 48.3 (d,
CH3CHNH), 60.4 (t, CH2OH), 63.8 (d, CH3CHNO), 65.8 (d, C-
3), 76.0 (d, C-5), 125.9 (d, 2 C, Ph), 127.0 (d, Ph), 127.4 (d, 2 C,
Ph), 128.1 (d, Ph), 128.5 (d, 2 C, Ph), 128.9 (d, 2 C, Ph), 141.8 (s,
(2R,4R)-4-Hydroxy-N,1-bis[(1R)-1-phenylethyl]-2-piperidinecarbox-
amide (15a): Freshly distilled MsCl (166 µL, 2.13 mmol) was cooled
in an ice/water bath and then added dropwise to a solution of isox-
azolidine 13a (715.3 mg, 1.94 mmol) and anhydrous NEt3 (403 µL,
2.91 mmol) in anhydrous CH2Cl2 (6.5 mL) at 0 °C under nitrogen.
The reaction mixture was stirred at 0 °C for 3 h and then at room
Ph), 143.4 (s, Ph), 170.9 (s, CO) ppm. IR (CDCl ): ν = 3372, 3032,
˜
3
2931, 1664, 1518, 1454 cm–1. MS (70 eV, EI): m/z (%) = 368 (2)
[M+], 220 (43), 116 (46), 105 (100), 77 (32). C22H28N2O3 (368.47):
calcd. C 71.71, H 7.66, N 7.60; found C 71.60, H 7.98, N 7.44.
Cycloadducts of Nitrone 10 with 3-Buten-1-ol
(3R,5S)- and (3S,5R)-N-Benzyl-5-(2-hydroxyethyl)-2-[(1R)-1-phen- temperature for 2 h, diluted with THF (18 mL), and concentrated
ylethyl]-3-isoxazolidinecarboxamide (mixture of two inseparable
diastereomers): Rf = 0.27 (EtOAc). H NMR (400 MHz): one iso-
mer: δ = 1.47 (d, J = 6.4 Hz, 3 H, CH3CHNO), 1.80–1.88 (m, 2 H,
under reduced pressure. The residue was dissolved in MeOH
(28 mL) and hydrogenated in the presence of 10% Pd/C (310 mg)
at room temperature and atmospheric pressure for 19 h. The cata-
1
CH2CH2OH), 2.35 (ddd, J = 12.9, 7.2, 3.5 Hz, 1 H, 4-H), 2.74 lyst was removed by filtration through a short pad of Celite and
(ddd, J = 12.9, 9.3, 7.9 Hz, 1 H, 4-H), 3.69 (dd, J = 9.5, 3.4 Hz, 1 the filtrate was concentrated under reduced pressure. The residue
H, 3-H), 3.74 (pseudo-t, J = 5.9 Hz, 2 H, CH2OH), 3.90 (q, J = was dissolved in MeOH, treated with Ambersep 900 OH at room
6.4 Hz, 1 H, CH3CHNO), 4.31 (A part of an ABX system, J = temperature for 2 h, filtered, and concentrated under reduced pres-
15.0, 5.4 Hz, 1 H, CH3CHHNH), 4.49 (B part of an ABX system,
sure to give crude 15a, containing traces of 16a, as a yellow oil
J = 15.0, 7.0 Hz, 1 H, CH3CHHNH), 4.42–4.49 (m, 1 H, 5-H), (546 mg, 80% based on 13a), which was used in the next step with-
7.16–7.37 (m, 10 H, Ph), 7.75 (m, 1 H, NH) ppm; other isomer: out further purification. A sample purified by chromatography on
δ = 1.38 (d, J = 6.6 Hz, 3 H, CH3CHNO), 1.64–1.72 (m, 2 H,
silica gel (CH2Cl2/MeOH/NH3 = 50:1:0.01) afforded analytically
CH2CH2OH), 2.25 (ddd, J = 12.9, 7.7, 5.3 Hz, 1 H, 4-H), 2.74 pure 15a as a colorless oil (76% yield based on 13a). Rf = 0.21
Eur. J. Org. Chem. 2006, 3235–3241
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3239

F. M. Cordero, S. Bonollo, F. Machetti, A. Brandi
FULL PAPER
(CH2Cl2/MeOH/NH3 = 50:1:0.01). [α]2D0 = +24.7 (c = 0.45 in
CHCl3). 1H NMR (400 MHz): δ = 1.32 (d, J = 6.7 Hz, 3 H,
CH3CHNCH2), 1.50 (d, J = 7.0 Hz, 3 H, CH3CHNH), 1.52–1.64
(m, 4 H, 3-H, 2×5-H, OH), 2.33 (br. dt, J = 12.9, 4.4 Hz, 1 H, 3-
(2S,4S)-4-Hydroxy-2-piperidinecarboxylic Acid (1b): Freshly dis-
tilled MsCl (169 µL, 2.18 mmol) was cooled in an ice/water bath
and then added dropwise to a solution of isoxazolidine 13b
(728.8 mg, 1.98 mmol) and anhydrous NEt3 (411 µL, 2.97 mmol)
H), 2.54–2.70 (m, 2 H, 2×6-H), 3.65 (br. t, J = 4.7 Hz, 1 H, 2-H), in anhydrous CH2Cl2 (6.6 mL) at 0 °C under nitrogen. The reaction
3.78–3.87 (m, 1 H, 4-H), 3.93 (q, J = 6.7 Hz, 1 H, CHNCH2), 5.12
(dq, J = 7.9, 7.0 Hz, 1 H, CHNH), 7.21–7.38 (m, 10 H, Ph), 7.45
(br. d, J = 7.9 Hz, 1 H, NH) ppm. 13C NMR (100 MHz): δ = 21.1
(q, CH3CHNCH2), 22.1 (q, CH3CHNH), 29.9 (t, C-5), 32.2 (t, C-
3), 42.5 (t, C-6), 48.4 (d, CHNH), 58.2 (d, C-2), 59.0 (d, CHNCH2),
mixture was stirred at 0 °C for 3 h and then at room temperature
for 2 h, diluted with THF (18 mL), and concentrated under re-
duced pressure. The residue was dissolved in MeOH (28 mL) and
hydrogenated in the presence of 10% Pd/C (316 mg) at room tem-
perature and atmospheric pressure for 19 h. The catalyst was re-
65.5 (d, C-4), 126.0 (d, 2 C, Ph), 127.3 (d, Ph), 127.4 (d, Ph), 127.6 moved by filtration through a short pad of Celite and the filtrate
(d, 2 C, Ph), 128.5 (d, 2 C, Ph), 128.7 (d, 2 C, Ph), 142.9 (s, Ph),
was concentrated under reduced pressure. The residue was dis-
solved in MeOH, treated with Ambersep 900 OH at room tempera-
ture for 2 h, filtered, and concentrated under reduced pressure. The
residue was dissolved in 6  aqueous HCl (19 mL) and the resulting
solution was treated under the same conditions as described for the
hydrolysis of 16a. The purification of the crude product by ion-
exchange chromatography afforded the amino acid 1b (156 mg,
54% yield based on 13b) as a white solid. [α]2D0 = –11.7 (c = 0.5,
H2O) {ref.[14] [α]2D0 = –12.6 (c = 0.8, H2O); ref.[1f] [α]2D0 = –13 0.4
(1% in H2O)}. 1H NMR spectrum identical with that of the enanti-
omer 1a.
143.4 (s, Ph), 172.2 (s, CO) ppm. IR (CDCl ): ν = 3609, 3358, 3031,
˜
3
2932, 1664, 1505, 1453 cm–1. MS (70 eV, EI): m/z (%) = 352 (0.1)
[M+], 204 (97), 105 (100), 100 (90), 77 (53). C22H28N2O2 (352.47):
calcd. C 74.97, H 8.01, N 7.95; found C 74.48, H 8.45, N 8.04.
(2R,4R)-4-Hydroxy-N-[(1R)-1-phenylethyl]-2-piperidinecarbox-
amide (16a): Crude 15a (546 mg, 1.55 mmol) was dissolved in
MeOH (22 mL) and hydrogenated in the presence of 10% Pd/C
(247 mg) at room temperature and atmospheric pressure for 22 h.
The catalyst was removed by filtration through a short pad of Ce-
lite and the filtrate was concentrated under reduced pressure. The
residue was dissolved in MeOH, treated with Ambersep 900 OH at
room temperature for 2 h, filtered, and concentrated under reduced
pressure to give crude 16a as a yellow oil (quantitative yield), which
was used in the next step without further purification. A sample
purified by chromatography on silica gel (EtOAc followed by
EtOAc/MeOH/NH3 = 10:1:0.01, then MeOH/NH3 = 1:0.01) af-
forded analytically pure 16a as a colorless oil (87% yield based on
(2R,3aR,7R)-2-(2-Hydroxyethyl)-7-phenyltetrahydroisoxazolo-
[3,2-c][1,4]oxazin-4(2H)-one (18): A solution of nitrone 17[15]
(1.44 g, 7.55 mmol) and butenol 4 (1.3 mL, 15 mmol) in CH2Cl2
(3.7 mL) was stirred at room temperature for 41 h. The mixture
was concentrated under reduced pressure and the pale-yellow solid
obtained was recrystallized (iPr2O/EtOAc = 1:1) to give the prod-
uct 18 (989 mg, 50%) as white crystals. Rf = 0.48 (EtOAc/petroleum
15a; 70% yield based on 13a). Rf = 0.28 (MeOH/NH3 = 1:0.01). ether = 1:2); m.p. 126–128 °C (iPr2O/EtOAc = 1:1). [α]2D3 = –123.4
[α]2D0 = +40.6 (c = 0.18 in CHCl3). H NMR (400 MHz): δ = 1.48
(d, J = 6.9 Hz, 3 H, CH3), 1.50–1.60 (m, 1 H, 5-H), 1.70–1.88 (m,
(c = 1.0, CHCl3). 1H NMR (400 MHz): δ = 1.75–1.92 (m, 2 H,
CH2CH2OH), 2.18 (br. s, 1 H, OH), 2.52 (ddd, J = 12.8, 9.3,
1
4 H, 3-H, 5-H, NHCH2, OH), 1.94–2.02 (m, 1 H, 3-H), 2.80 (ddd, 6.3 Hz, 1 H, 3-H), 2.88 (dt, J = 12.8, 7.5 Hz, 1 H, 3-H), 3.66 (br.
J = 12.9, 5.6, 4.4 Hz, 1 H, 6-H), 3.11 (ddd, J = 12.9, 9.4, 3.5 Hz,
1 H, 6-H), 3.73 (dd, J = 8.5, 4.0 Hz, 1 H, 2-H), 4.04 (m, 1 H, 4-
H), 5.08 (pseudo-quint, J = 7.2 Hz, 1 H, MeCH), 7.22–7.36 (m, 5
H, Ph), 7.41 (br. d, J = 7.6 Hz, 1 H, NHCO) ppm. 13C NMR
t, J = 5.9 Hz, 2 H, CH2OH), 4.11 (A part of an ABC system, J =
10.0, 3.6 Hz, 1 H, 7-H), 4.22 (B part of an ABC system, J = 11.6,
10.0 Hz, 1 H, 6-H), 4.28 (C part of an ABC system, J = 11.6,
3.6 Hz, 1 H, 6-H), 4.32–4.41 (m, 2 H, 3a-H, 2-H), 7.30–7.44 (m, 5
(100 MHz): δ = 21.9 (q, CH3), 33.3 (t, C-5), 36.7 (t, C-3), 40.3 (t, H, Ph) ppm. 13C NMR (100 MHz): δ = 36.2 (t, CH2CH2OH), 38.8
C-6), 48.2 (d, CHCH3), 55.0 (d, C-2), 64.4 (d, C-4), 126.1 (d, 2 C,
Ph), 127.2 (d, Ph), 128.6 (d, 2 C, Ph), 143.2 (s, Ph), 172.7 (s, CO) 6), 74.0 (d, C-2), 127.4 (d, 2 C, Ph), 128.6 (d, Ph), 128.8 (d, 2 C,
ppm. IR (CDCl ): ν = 3609, 3367, 3032, 2929, 1661, 1512, Ph), 135.4 (s, Ph), 169.7 (s, C-4) ppm. IR (KBr): ν = 3557, 3035,
(t, C-3), 59.6 (t, CH2OH), 61.9 (d, C-7), 62.1 (d, C-3a), 69.6 (t, C-
˜
˜
3
1451 cm–1. MS (70 eV, EI): m/z (%) = 248 (0.4) [M+], 104 (29), 100 2926, 1724, 1247, 1063 cm–1. MS (70 eV, EI): m/z (%) = 263 (2)
(100), 82 (54). C14H20N2O2 (248.32): calcd. C 67.71, H 8.12, N
11.28. found C 67.22, H 7.78, N 11.41.
[M+], 160 (3), 130 (12), 105 (100), 90 (12). C14H17NO4 (263.29):
calcd. C 63.87, H 6.51, N 5.32; found C 63.65, H 6.36, N 5.45.
(2R,4R)-4-Hydroxy-2-piperidinecarboxylic Acid (1a): Crude 16a
from the previous step was dissolved in 6  aqueous HCl (19 mL)
and the resulting solution was refluxed for 22 h. After concentra-
tion under vacuum, the product was treated with saturated aqueous
Na2CO3 and washed with EtOAc to remove the (R)-(phenylethyl)-
amine. The aqueous solution was acidified to pH = 1 with 6 
HCl and then the solvent was completely removed under reduced
pressure. The residue was redissolved in a minimum amount of
H2O and adsorbed on a column of cation-exchange resin (Dowex
50W X-8, 100–200 mesh). The resin was washed with distilled water
until neutral and then the amino acid was eluted with 6% aqueous
ammonia. The collected solution was concentrated under reduced
pressure to give a yellow solid, which was washed with EtOH and
lyophilized to give 1a (147 mg, 65% yield based on 15a; 52% yield
based on 13a) as a white solid. [α]2D0 = +12.6 (c = 0.3, H2O) {ref.[14]
[α]2D0 = +12.6 (c = 0.8, H2O)}. 1H NMR (400 MHz, D2O): δ = 1.81–
1.97 (m, 3 H, 3-H + 5-H2), 2.16–2.23 (m, 1 H, 3-H), 3.26–3.29 (m,
Methyl (2R,4S)-4-Hydroxy-2-piperidinecarboxylate (20): Freshly
distilled MsCl (136 µL, 1.75 mmol) was cooled in an ice/water bath
and then added dropwise to a solution of 18 (419 mg, 1.59 mmol)
and anhydrous NEt3 (330 µL, 2.39 mmol) in anhydrous CH2Cl2
(5.3 mL) at 0 °C under nitrogen. The reaction mixture was stirred
at 0 °C for 4 h and then at room temperature for 30 min, diluted
with THF (2.5 mL), and concentrated under reduced pressure. The
residue was dissolved in MeOH (26.6 mL) and hydrogenated in the
presence of 10 % Pd/C (34 mg) at room temperature and atmo-
spheric pressure for 4 d. The catalyst was removed by filtration
through a short pad of Celite and the filtrate was concentrated
under reduced pressure. The residue was dissolved in MeOH,
treated with Ambersep 900 OH at room temperature under mag-
netic stirring for 2 h, filtered, and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica gel
(CH2Cl2/MeOH/NH3 = 15:1:0.01), to give the oxazinone 20
1
(20 mg, 8% yield) as a yellow oil. H NMR (200 MHz): δ = 1.24–
2 H, 6-H2), 3.89 (dd, J = 11.9, 3.7 Hz, 1 H, 2-H), 4.21 (m, 1 H, 4- 1.56 (m, 2 H, 3-H, 5-H), 1.86–2.00 (m, 1 H, 5-H), 2.23–2.36 (m, 1
H) ppm.
H, 3-H), 2.63 (br. s, 2 H, NH, OH), 2.64 (dt, J = 2.6, 12.1 Hz, 1
3240
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3235–3241

Synthesis of 4-Hydroxypipecolic Acids
FULL PAPER
M. Alesiani, V. Carlà, B. Natalini, M. Marinozzi, R. Pellicciari,
F. Moroni, Eur. J. Pharmacol. 1994, 251, 201–207; e) R. Pellic-
ciari, B. Natalini, G. Constantino, A. Garzon, R. Luneia,
M. R. Mahmoud, M. Marinozzi, M. Roberti, G. C. Rosato,
S. A. Shiba, Farmaco 1993, 48, 151–157.
H, 6-H), 3.22 (dt, J = 12.7, 3.9 Hz, 1 H, 6-H), 3.40 (dd, J = 10.7,
3.1 Hz, 1 H, 2-H), 3.64–3.81 (m, 1 H, 4-H), 3.74 (s, 3 H, CH3)
ppm. 13C NMR (50 MHz): δ = 34.7 (t, C-5), 37.8 (t, C-3), 42.7 (t,
C-6), 52.0 (q, OCH3), 56.7 (d, C-2), 67.8 (d, C-4), 172.9 (s, CO)
ppm.
[5] a) F. Machetti, F. M. Cordero, F. De Sarlo, A. M. Papini,
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101–130.
(2R,4S)-4-Hydroxy-2-(methoxycarbonyl)piperidinium Chloride (21):
Chlorotrimethylsilane (0.2 mL, 1.58 mmol) was added to a solution
of 20 (4.3 mg, 0.027 mmol) in MeOH (2 mL) at 0 °C. The reaction
mixture was stirred at room temperature for 24 h, then the solvent
was evaporated under reduced pressure to give 21 (5.3 mg, quanti-
tative yield). [α]2D3 = –9.6 (c = 0.45, MeOH) {ref.[17] [α]2D5 = +9.9 (c
= 1.01, MeOH) for the (2S,4R) enantiomer}.
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Acknowledgments
The authors thank MIUR (projects PRIN 2003, 2004 and FIRB
2001-RBNE017F8N) for financial support, and Ente Cassa di Ris-
parmio di Firenze for granting funds to the Department of Organic
Chemistry for the acquisition of a 400 MHz NMR spectrometer.
Dr. C. Faggi (University of Firenze; X-ray determination) and Mrs.
B. Innocenti and Mr. M. Passaponti (University of Firenze; techni-
cal support) are gratefully acknowledged.
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Received: February 7, 2006
Published Online: May 17, 2006
Eur. J. Org. Chem. 2006, 3235–3241
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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