Stereoselective synthesis of β,ε-dihydroxy-α-amino acids by ring opening of 4,5-dihydroisoxazolyl derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.11.034

Enantiomerically pure β-(4,5-dihydroisoxazol-3-yl)-substituted β-hydroxy-α-amino acids were synthesised stereoselectively by means of an addition reaction between (5,5-disubstituted-4,5-dihydroisoxazol-3-yl)-carbaldehydes and (R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schoellkopf's reagent) as a chiral auxiliary. The addition gave mixtures of only two adducts with high diastereoselectivity. The steric configuration of the major diastereoisomer was assigned on the basis of spectroscopic data and the accepted model for the aldol condensation of the Schoellkopf's reagent. The subsequent acid-catalysed hydrolysis of the pyrazine ring led to a mixture of β-(4,5-dihydroisoxazol-3-yl)-β-hydroxy-α-amino methyl esters together with a mixture of two partially hydrolysed dipeptides. The final reductive cleavage of the 4,5-dihydroisoxazole ring of these compounds made it possible to obtain the methyl esters of β,ε-dihydroxy-γ-oxo-ε,ε-disubstituted α-amino acid derivatives.

Full text of DOI:10.1016/j.tetasy.2008.11.034

Tetrahedron: Asymmetry 19 (2008) 2850–2855
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of b,e-dihydroxy-a-amino acids by ring opening
of 4,5-dihydroisoxazolyl derivatives
Giuseppe Cremonesi a, Piero Dalla Croce b, Francesco Fontana b, Claudio Fiorelli b,1, Concetta La Rosa a,
*
a Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, V. Venezian 21, I-20133 Milano, Italy
b Dipartimento di Chimica Organica e Industriale and C.N.R.–I.S.T.M., V. Venezian 21, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure b-(4,5-dihydroisoxazol-3-yl)-substituted b-hydroxy-
a
-amino acids were synthes-
Received 14 October 2008
Accepted 21 November 2008
Available online 20 January 2009
ised stereoselectively by means of an addition reaction between (5,5-disubstituted-4,5-dihydroisoxazol-
3-yl)-carbaldehydes and (R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) as
a chiral auxiliary. The addition gave mixtures of only two adducts with high diastereoselectivity. The
steric configuration of the major diastereoisomer was assigned on the basis of spectroscopic data and
the accepted model for the aldol condensation of the Schöllkopf’s reagent. The subsequent acid-catalysed
hydrolysis of the pyrazine ring led to a mixture of b-(4,5-dihydroisoxazol-3-yl)-b-hydroxy-a-amino
methyl esters together with a mixture of two partially hydrolysed dipeptides. The final reductive cleav-
age of the 4,5-dihydroisoxazole ring of these compounds made it possible to obtain the methyl esters of
b,
e
-dihydroxy-
c-oxo-
e
,
e
-disubstituted
a
-amino acid derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
skeleton of numerous compounds with broad biological activities,8
and the particular nature of the 4,5-dihydroisoxazole ring is its ver-
satility as a synthetic intermediate because of the ease with which
it can be prepared and the numerous possible chemical transforma-
tions. Among these, reductive cleavage yields functional groups
b-Hydroxy-a-amino acids are the key structures of many bio-
logically active natural products such as vancomycin1a or polyox-
ins,1b cyclomarins1c and exochelins;1d their highly functionalised
nature also makes them very useful chiral building blocks for the
synthesis of numerous compounds.2
such as b-hydroxy carbonyls9 or -amino alcohols10 depending on
c
the experimental conditions. In this way, reaction between 2,5-
dihydro-3,6-dimethoxy-2-isopropylpyrazine (R)-1 and the 4,5-
dihydroisoxazole-3-carbaldehydes A, and the subsequent cleavage
of the dihydropyrazine and isoxazoline rings of adducts, could
Various approaches have already been developed for their ster-
eoselective synthesis,3 including asymmetric aldol reactions using
chiral auxiliaries4 or chiral catalysts.5
We had previously used ‘Schöllkopf’s reagent’ (i.e., (R) or (S)-2,5-
dihydro-3,6-dimethoxy-2-isopropylpyrazine) to synthesise b-hetero-
aryl-substituted alanines6a and serines,6b the antibiotic azatyrosine,6c
allow us to obtain b,
e
-dihydroxy-
c
-oxo-
a
-amino acids B (Fig. 1).
CH3O
N
N
d-heteroaryl-substituted b-hydroxy-
c
,d-unsaturated
a-amino
acids6d and, more recently, b-hydroxy-
a
-amino acids b-substituted
OCH3
with non-aromatic heterocycles.6e This reagent is a particularly
attractive chiral auxiliary because both the enantiopure (R)- and
(S)-forms are commercially available, and have been used in vari-
ous asymmetric syntheses.7
HO
N
OCH3
CHO
N
N
OCH3
N
O
O
Our interest in the stereoselective synthesis of new non-protein-
ogenic b-hydroxy-a-amino acids substituted with heterocyclic
rings led us to consider the reactions between the Schöllkopf’s
reagent (R)-1 and the 4,5-dihydroisoxazole-3-carbaldehydes. The
4,5-dihydroisoxazole (2-isoxazoline) nucleus constitutes the basic
A
OCH3
OCH3
HO
O
HO
O
NH2
NH2
O
N
OH
O
* Corresponding author.
E-mail address: concetta.larosa@unimi.it (C.L. Rosa).
Present address: Nerviano Medical Sciences, V.le Pasteur 10, I-2014 Nerviano,
B
1
Italy.
Figure 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.034

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 2850–2855
2851
Table 1
To the best of our knowledge, these polyfunctionalised a-amino
Diastereomeric ratioa
acids (with a structure similar to carbohydrates) are not known,
5,6
R
Total yield (%)
and this prompted us to take this study further.
a
b
c
Ph
–(CH2)5–
CH3
66
68
64
93:7
95:5
90:10
2. Results and discussion
a
It was not possible to isolate the minor diastereoisomer whose configuration
The absence of a racemic stereocentre in the isoxazoline ring of
the aldehydes A allows us to minimise the total number of diaste-
reoisomers that are derivable from the reaction with Schöllkopf’s
reagent. As a result, we decided to use 4,5-dihydroisoxazole-3-car-
baldehydes disubstituted with two identical groups at the position
5 of the ring. Given the commercial availability of alkene precur-
sors of the isoxazoline ring, we selected aldehydes 5a–c (Scheme
1), which were not known but were prepared by means of a
base-catalysed condensation between ethyl nitroacetate and the
1,1-disubstituted alkenes 2a–c in accordance with a recently
reported method.11 The 5,5-disubstituted-4,5-dihydroisoxazole-3-
carboxylic acid ethyl esters 3a–c were obtained in good yields
and complete regioselectivity (Scheme 1). This is the first example
of the application of this method to 1,1-disubstituted alkenes.
remains unknown.
confirmed on the basis of analytical and spectroscopic data. The
(2S)-configuration of compounds 6a–c was established using the
5J5H/2H coupling constant value of approximately 3.5 Hz, which
corresponded to a trans-relationship between the 5-H and 2-H pro-
tons of the pyrazine ring.13 The (S)-configuration was assigned at
10-C by comparing the chemical shifts in the 1H and 13C NMR spec-
tra of diastereoisomers 6a–c and those reported for the known
5-phenylisoxazol-3-yl and (5-p-tolyl-isoxazol-3-yl)-ethenyl deriv-
atives.6a,d These configurations also agree with the widely accepted
model for the aldol-type addition of 1 to aldehydes,14,6e according
to which the exclusive formation of the two (2S)-epimers can be
explained via a transition state in which the aldehyde attacks the
azaenolate-pyrazine from the less-hindered side opposite the
isopropyl group. Moreover, the predominance of the (10S)-epimer
comes from a more favourable transition state in which the alde-
hyde substituent is far from the methoxy group and from the metal
atom (Fig. 2).
COOEt
COOEt
NO2
DABCO
EtOH
80°C
R
R
+
N
O
R
R
2a-c
3a-c
70-80%
R
CH2OH
CHO
M
O
N
CH3O
H
HO (S)
N
R
H
H
CH3O
H
MnO2
NaBH4
R
R
R
R
N
N
CH2Cl2
25°C
(R)
EtOH
O
O
H
N
H
(S)
N
0-25°C
4a-c
70-92%
5a-c
OCH3
OCH3
79-81%
Figure 2. Favoured Transition State leading to the major diastereoisomeric adducts.
2,3,4,5a : R = Ph
2,3,4,5b : R = -(CH2)5-
2,3,4,5c : R = CH3
These results are interesting because the reactions were extre-
mely diastereoselective, even though lithium was used as a coun-
ter-ion (Table 1). It is well known that the use of titanium, rather
than lithium, generally makes the reaction more diastereoselective
because of the tight transition state promoted by the titanium
ligand.6d,13a
Scheme 1.
Subsequent sodium borohydride reduction12 of the ester group
of 3a–c to alcohols 4a–c and oxidation of the latter with manga-
nese dioxide led to aldehydes 5a–c. The new products 3, 4 and
5a–c were completely characterised by means of their analytical
and spectroscopic data.
Adducts 6a–c were hydrolysed under controlled conditions: they
were treated with 3 equiv of 0.2 M HCl in methyl alcohol at room
temperature for 6 h, which allowed the isolation of b-hydroxy-
a-
In accordance with a general procedure, a solution of aldehydes
5a–c was added to the anion of the bislactim ether (R)-1 generated
by nBuLi in THF at T = ꢀ78 °C. TLC analysis and the 1H NMR spec-
trum of the crude reaction mixtures made it possible to establish
the presence of only two of the four possible diastereoisomers,
whose ratio was determined by integrating the pairs of doublets
corresponding to the isopropyl groups in the 1H NMR spectra
(Scheme 2 and Table 1).
amino esters 7a–c and dipeptides 8a–c (Scheme 3 and Table 2).
The 1H NMR spectra of the crude reaction mixtures also
revealed the presence of less than 6–8% of the other possible
dipeptide. The formation of these dipeptides is due to the partial
hydrolysis of the pyrazine ring that often occurs with the hydroly-
sis reaction.6e,15 We were unable to avoid this course even when
changing the solvent (methyl alcohol, acetonitrile or THF), temper-
ature (from T = 0 °C to room temperature), or the kind (HCl or TFA)
or concentration of the acid (from 0.2 M to 2 M). Products 7 and 8
were easily separated by means of column chromatography, and
The major diastereoisomers 6a–c were purified by means of
flash chromatography on silica gel, and their structures were
CHO
OCH3
HO
H
H
N
5
R
R
5,6a : R = Ph
Li
N
2
1'
CH3O
N
nBuLi
O
CH3O
N
5,6b: R = -(CH2)5-
N
R
R
THF
5a-c
5,6c
OCH3
: R = CH3
N
N
OCH3
-78°C
O
N
OCH3
(R)-1
6a-c
Scheme 2.

2852
G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 2850–2855
OCH3
HO
H
H
COOCH3
HO
H
H
N
HO
H
H
COOCH3
2
6,7,8a
6,7,8b
: R = Ph
NH2
2
3
3
0.2M HCl
2'
: R = -(CH2)5-
: R = CH3
N
NH2
NH
+
R
R
R
R
R
R
CH3OH
25°C
OCH3
6a-c
N
N
N
H
6,7,8c
O
O
O
O
8a-c
7a-c
Scheme 3.
as dipeptide bioisosteres16 and have been incorporated into bio-
logically active compounds, such as the anti-tumour drugs
acivicin.17
Table 2
6,7,8
R
Yield (%)
7
8
a
b
c
Ph
–(CH2)5–
CH3
20
28
20
48
42
63
4. Experimental
4.1. General methods
Melting points were measured using a Büchi apparatus and are
uncorrected. The 1H and 13C NMR spectra were recorded in CDCl3
using a Bruker AC 300 spectrometer; the chemical shifts (d) are gi-
ven in ppm relative to TMS, and all the coupling constants are in
Hertz. The optical rotation values were measured at 25 °C using a
JASCO P-1030 spectropolarimeter. The MS spectra were determined
using a VG Analytical 7070 EQ mass spectrometer with an attached
VG analytical 11/250 data system. The IR spectra (in cmꢀ1) were
determined using a Jasco FT-IR 4100 spectrometer.
their structure was assigned using analytical and spectroscopic
data. In particular, the 1H NMR spectra made it possible to assign
the structure of compounds 8: these dipeptides formally derive
from the formation of an amide bond between the valine carbox-
ylic group and the amino group of amino esters 7. For example,
the 1H NMR spectra of 8a show a dd at 4.93 d for proton 2-H with
a J2H/3H = 3.0 Hz with the doublet at 5.00 d relative to 3-H, and with
a J2H/NH = 9.3 Hz with the doublet at 8.05 d relative to a proton
which integrates 1H and which exchanges with D2O (NH
amide).15b,c
Finally, we carried out a hydrogenolysis–hydrolysis of the
4,5-dihydroisoxazole ring of the amino esters 7 and of the dipep-
tides 8 using the optimum reaction conditions reported by Curran
for this type of cleavage (H2 1 atm, 5/1 MeOH/H2O, 3 equiv of
B(OH)3, Raney-Ni as catalyst).9b Starting from products 7b–c, we
could not isolate the expected products, owing to a complete deg-
radation of compounds 7. The same result was observed using HCl
instead of B(OH)3 or Pd/C as a catalyst. Conversely, cleavage of
(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine 1, ethyl nit-
roacetate and the 1,1-disubstituted alkenes 2a–c were obtained
from commercial sources.
4.2. General procedure for the preparation of compounds 3a–c
A solution of alkene 2a–c (5 mmol, 1 equiv), ethyl nitroacetate
(10 mmol, 2 equiv) and DABCO (0.5 mmol, 0.1 equiv) in ethanol
(20 mL) was heated at 80 °C for five days in a sealed tube. The organic
solvent was evaporated off, and the products were purified by col-
umn chromatography on silica gel (hexane/ethyl acetate = 8/2).
dipeptides 8b–c allowed us to obtain the corresponding b,
e-dihy-
droxy- -oxo -amino acid derivatives 9b–c in good yields (Scheme
c
a
4). In no case we were able to detect any loss of stereochemical
purity.
4.3. 5,5-Diphenyl-4,5-dihydro-isoxazole-3-carboxylic acid ethyl
ester 3a18
These
a-amino acid derivatives have a highly functionalised
Colourless solid (75%); mp 87–88 °C (Et2O); 1H NMR: d 1.36 (3H,
t, J = 7.1, CH3); 3.85 (2H, s, 4-H); 4.33 (2H, q, J = 7.1, CH2); 7.30–7.50
(10H, m, Ph). 13C NMR: d 13.94 (CH3); 46.61 (4-C); 61.94 (O–CH2);
94.63 (5-C); 125.59, 127.86, 128.54, 142.87 (C–Ph); 150.97 (3-C);
160.37 (C@O). MS-EI (m/z): 295 (M+). Anal. Calcd for C18H17NO3:
C, 73.20; H, 5.80; N, 4.74. Found: C, 72.99; H, 5.88; N, 4.70. IR
(Nujol): 1717 (vC@O, C@O and vC@N, C@N).
structure, which makes them extremely attractive as potential
peptidomimetics.
3. Conclusion
We have reported another example of the synthesis of new,
enantiomerically pure, non-proteinogenic, b-(4,5-dihydroisoxa-
zol-3-yl)-substituted b-hydroxy-a-amino acids 7 and dipeptides
8 using the ‘Schöllkopf’s reagent’ as a chiral auxiliary. The hydrog-
enolysis–hydrolysis of products 8 allowed us to obtain the corre-
4.4. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid ethyl
ester 3b19
sponding b,e-dihydroxy-c-oxo a-amino acid derivatives 9, but the
hydrogenolysis of products 7 failed. However, compound 7 may
Colourless liquid (70%); 1H NMR: d 1.37 (3H, t, J = 7.1, CH3);
be interesting because 2-isoxazoline derivatives have been used
1.40–1.90 (10H, m, –(CH2)5–); 2.89 (2H, s, 4-H); 4.31 (2H, q,
HO
H
H2
Raney-Ni
HO
O
H
COOCH3
COOCH3
NH2
R
6
2
8,9b: R = -(CH2)5-
8,9c: R = CH3
NH2
3
R
R
CH3OH/H2O
B(OH)3
N
H NH
2'
R
OH
H NH
O
H
H
O
O
8b-c
9b-c
68-86%
Scheme 4.

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 2850–2855
2853
J = 7.1, CH2). 13C NMR: d 13.79 (CH3); 22.82, 24.48, 35.94 (–(CH2)5–);
43.0 (4-C); 61.4 (O–CH2); 90.36 (5-C); 150.48 (3-C); 160.77 (C@O).
158.71 (3-C); 185.43 (CO). MS-EI (m/z): 251 (M+). Anal. Calcd for
C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.12; H, 5.11;
N, 5.71. IR (Nujol): 1698 (vC@O, C@O), 1576 (vC@N, C@N).
MS-EI (m/z): 211 (M+). IR (Nujol): 1717 vC@N, C@N), 1740 (vC@O
C@O).
,
4.12. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde 5b
4.5. 5,5-Dimethyl-4,5-dihydro-isoxazole-3-carboxylic acid ethyl
ester 3c20
Colourless liquid (79%); 1H NMR: d 1.50–1.90 (10H, m, –(CH2)5–);
2.84 (2H, s, 4-H); 9.95 (1H, s, CHO). 13C NMR: d 23.09, 24.71, 36.28
(–(CH2)5–); 40.13 (4-C); 92.43 (5-C); 158.01 (3-C); 186.43 (CO).
Colourless liquid (80%); 1H NMR: d 1.40 (3H, t, J = 7.1, CH3); 1.49
(6H, s, 5,5-di-CH3); 2.99 (2H, s, 4-H); 4.37 (2H, q, J = 7.1, CH2). 13C
NMR: d 13.71 (CH3); 26.97 (5,5-di-CH3); 45.0 (4-C); 61.61 (O–CH2);
88.2 (5-C); 150.84 (3-C); 160.84 (C@O). MS-EI (m/z): 171 (M+). IR
(Nujol): 1722 (vC@N, C@N), 1728 (vC@O, C@O).
MS-EI (m/z): 167 (M+). IR (Nujol): 1695 (vC@O, C@O), 1573 (vC@N
C@N).
,
4.13. 5,5-Dimethyl-4,5-dihydro-isoxazole-3-carbaldehyde 5c
4.6. General procedure for the preparation of compounds 4a–c
Colourless liquid (80%); 1H NMR: d 1.51 (6H, s, 5,5-di-CH3); 2.90
(2H, s, 4-H); 9.93 (1H, s, CHO). 13C NMR: d 27.11 (5,5-di-CH3);
41.87 (4-C); 89.92 (5-C); 159.17 (3-C); 186.17 (CO). MS-EI (m/z):
127 (M+). IR (Nujol): 1692 (vC@O, C@O), 1572 (vC@N, C@N).
A solution of ester 3a–c (10 mmol, 1 equiv) in ethanol (10 mL)
(ethanol/CH2Cl2 = 1/1 for 3a) was added dropwise to a cold
(T = 0 °C) suspension of NaBH4 (26 mmol, 2.6 equiv) in ethanol
(20 mL). The reaction mixture was stirred at room temperature
for 6 h. The organic solvent was evaporated off, and the residue
was poured into water. Acetic acid was added until pH 6, and the
mixture was extracted with several portions of ethyl acetate. The
combined extracts were dried over Na2SO4 and concentrated at re-
duced pressure. The crude alcohols were purified by column chro-
matography on silica gel (hexane/ethyl acetate = 6/4).
4.14. General procedure for the reactions of (R)-1 with 5a–c
To a solution of (R)-1 (0.47 mL, 2.62 mmol, 1.05 equiv) in anhy-
drous THF (3 mL), cooled at –78 °C, butyl lithium (1.8 mL of a 1.6 M
solution in hexane, 2.88 mmol, 1.15 equiv) was added, and the
mixture was stirred for 45 min. The appropriate aldehyde 5a–c
(2.5 mmol, 1 equiv) in THF (3 mL) was added, and the mixture
was stirred at ꢀ78 °C for 1 h, and then at ꢀ18 °C for 16 h. The reac-
tion mixture was allowed to warm to 0 °C, after which pH 7 phos-
phate buffer solution (10 mL) was added and the mixture was
extracted with CH2Cl2. The organic phase was separated and dried
with Na2SO4, and the solvent was evaporated in vacuo. Compounds
6a–c were purified by means of flash chromatography on silica gel
(hexane/ethyl acetate = 80/20).
4.7. (5,5-Diphenyl-4,5-dihydro-isoxazol-3-yl)-methanol 4a20
Colourless solid (92%); mp 103–104 °C (Et2O); 1H NMR: d 1.70
(1H, br, OH); 3.69 (2H, s, 4-H); 4.40 (2H, s, CH2-O); 7.25–7.45
(10H, m, Ph). 13C NMR: d 47.84 (4-C); 57.70 (CH2–O); 91.49 (5-
C); 125.84, 127.51, 128.27, 143.68 (C–Ph); 158.84 (3-C). MS-EI
(m/z): 253 (M+). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
12.63. Found: C, 75.82; H, 5.85; N, 12.70. IR (Nujol): 3187 (vO–H
,
4.15. (S)-(5,5-Diphenyl-4,5-dihydro-isoxazol-3-yl)-[(2S,5R)-5-
OH), 1650 (vC@N, C@N).
isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl]-methanol 6a
4.8. (1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-methanol 4b
Colourless solid (60.5%); mp 170–171 °C (n-hexane); ½a D20
¼
ꢁ
ꢀ14:4 (c 0.60, CHCl3). 1H NMR: d 0.67, 1.00 (6H, 2d, J = 6.8,
CH(CH3)2); 2.22 (1H, m, CH(CH3)2); 2.79 (1H, d, J = 7.7, OH); 3.51
(3H, s, OCH3); 3.67 (3H, s, OCH3); 3.77 (2H, s, 4-CH2); 3.93 (1H, t,
J = 3.5, 5-H); 4.19 (1H, t, J = 3.5, 2-H); 4.92 (1H, dd, J = 7.7, 3.5, 10-
H); 7.25–7.45 (10H, m, Ph); (by deuteration, the signal at 2.79 dis-
appeared, and the signal at 4.92 turned into a doublet with J = 3.5).
13C NMR: d 16.85, 19.05 (CH(CH3)2); 32.02 (CH(CH3)2); 48.81 (4-C);
52.99 (3- and 6-OCH3); 60.68, 61.65 (2-C and 5-C pyr.); 69.54 (10-
C); 92.16 (5-C isox.); 126.41, 127.86, 128.54, 145.05 (Ph); 160.42,
161.22, 167.51 (3-C and 6-C pyr., 3-C isox.). MS-EI (m/z): 435
(M+), 300, 185. Anal. Calcd for C25H29N3O4: C, 68.95; H, 6.71; N,
9.65. Found: C, 68.9; H, 6.54; N, 9.45. IR (Nujol): 3381 (vOH, OH),
1697 (vC@N, C@N).
Colourless liquid (89%); 1H NMR: d 1.46–1.82 (10H, m, –(CH2)5–);
2.54 (1H, br, OH); 2.78 (2H, s, 4-H); 4.39 (2H, s, CH2–O). 13C NMR: d
23.81, 25.4, 36.74 (–(CH2)5–); 45.33 (4-C); 58.86 (CH2–O); 87.47
(5-C); 158.51 (3-C). MS-EI (m/z): 169 (M+). IR (Nujol): 3374 (vO–H
OH), 1625 (vC@N, C@N).
,
4.9. (5,5-Dimethyl-4,5-dihydro-isoxazol-3-yl)-methanol 4c20
Colourless liquid (70%); 1H NMR: d 1.45 (6H, s, 5,5-di-CH3); 2.40
(1H, br, OH); 2.84 (2H, s, 4-H); 4.41 (2H, s, CH2–O). 13C NMR: d
26.93 (5,5-di-CH3); 46.61 (4-C); 57.84 (CH2–O); 84.57 (5-C);
158.81 (3-C). MS-EI (m/z): 129 (M+). IR (Nujol): 3387 (vO–H, OH),
1625 (vC@N, C@N).
4.16. (S)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-
4.10. General procedure for the preparation of compounds 5a–c
2-yl]-(1-oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-methanol 6b
MnO2 (5/1 = w/w) was added to a solution of alcohol 4a–c
(10 mmol) in CH2Cl2 (15 mL), and the reaction mixture was stirred
at room temperature for 12 h. The MnO2 was filtered through Cel-
ite, and the organic solvent was evaporated off. The resulting alde-
hydes were pure enough for the subsequent reaction.
Colourless solid (64.6%); mp 133–136 °C (n-hexane); ½a D20
¼
ꢁ
ꢀ45:0 (c 0.58, CHCl3). 1H NMR: d 0.75, 1.08 (6H, 2d, J = 6.8,
CH(CH3)2); 1.47–1.92 (10H, m, –(CH2)5–); 2.29 (1H, m, CH(CH3)2);
2.78 (1H, d, J = 7.5, OH); 2.86 (2H, s, 4-CH2); 3.71 (3H, s, OCH3);
3.79 (3H, s, OCH3); 4.06 (1H, t, J = 3.5, 5-H); 4.22 (1H, t, J = 3.5, 2-
H); 4.91 (1H, dd, J = 7.5, 3.5, 10-H); (by deuteration, the signal at
2.78 disappeared, and the signal at 4.91 turned into a doublet with
J = 3.5). 13C NMR: d 16.76, 19.01 (CH(CH3)2); 23.47, 25.08, 36.34 (–
(CH2)5–); 31.84 (CH(CH3)2); 44.94 (4-C); 52.73 (3- and 6-OCH3);
59.07, 61.00 (2-C and 5-C pyr.); 69.33 (10-C); 87.06 (5-C isox.);
159.12, 161.03, 166.51 (3-C and 6-C pyr., 3-C isox.). MS-EI (m/z):
4.11. 5,5-Diphenyl-4,5-dihydro-isoxazole-3-carbaldehyde 5a
Colourless solid (81%); mp 86–88 °C (n-hexane); 1H NMR: d 3.76
(2H, s, 4-H); 7.30–7.40 (10H, m, Ph); 9.95 (1H, s, CHO). 13C NMR: d
43.34 (4-C); 95.87 (5-C); 125.74, 128.03, 128.45, 142.57 (C–Ph);

2854
G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 2850–2855
351 (M+), 308, 290, 183. Anal. Calcd for C18H29N3O4: C, 61.52; H,
8.32; N, 11.96. Found: C, 61.47; H, 8.25; N, 11.94. IR (Nujol):
3407 (vOH, OH), 1696 (vC@N, C@N).
(MH+). IR (Nujol): 3351 (vOH, vNH, OH, NH2), 1743 (vC@O, C@O ester),
1666 (vC@N C@O, C@N and C@O amide).
,
4.21. (2S,3S)-2-Amino-3-hydroxy-3-(1-oxa-2-aza-spiro[4.5]dec-
2-en-3-yl)-propionic acid methyl ester 7b
4.17. (S)-(5,5-Dimethyl-4,5-dihydro-isoxazol-3-yl)-[(2S,5R)-5-
isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl]-methanol 6c
Amorphous solid (28%); Rf = 0.45 (ethyl acetate:methanol =
Colourless solid (57.6%); mp 86–88 °C (n-hexane); ½a D20
¼ ꢀ57:2
ꢁ
7:3); ½a 2D0
ꢁ
¼ 15:4 (c 0.22, CH3OH). 1H NMR: d 2.50–2.80 (3H, br,
(c 0.84, CHCl3). 1H NMR: d 0.75, 1.08 (6H, 2d, J = 6.8, CH(CH3)2);
1.46, 1.47 (6H, 2s, 5,5-di-CH3); 2.31 (1H, m, CH(CH3)2); 2.81 (1H,
d, J = 8.0, OH); 2.90 (2H, s, 4-CH2); 3.72 (3H, s, OCH3); 3.79 (3H, s,
OCH3); 4.06 (1H, t, J = 3.5, 5-H); 4.22 (1H, t, J = 3.5, 2-H); 4.91
(1H, dd, J = 8.0, 3.5, 10-H); (by deuteration, the signal at 2.81 disap-
peared, and the signal at 4.91 turned into a doublet with J = 3.5).
13C NMR: d 16.63, 18.92 (CH(CH3)2); 26.91, 27.01 (5,5-di-CH3);
31.70 (CH(CH3)2); 46.73 (4-C); 52.61 (3- and 6-OCH3); 59.15,
60.84 (2-C and 5-C pyr.); 69.09 (10-C); 84.69 (5-C isox.); 159.55,
160.30, 166.28 (3-C and 6-C pyr., 3-C isox.). MS-EI (m/z): 311
(M+), 296, 253, 183. Anal. Calcd for C15H25N3O4: C, 57.86; H,
8.09; N, 13.49. Found: C, 57.77; H, 8.18; N, 13.36. IR (Nujol):
3430 (vOH, OH), 1697 (vC@N, C@N).
OH, NH2); 2.69, 2.86 (2H, AB-system, JAB = 17.1, 4-CH2-isox.); 3.78
(3H, s, OCH3); 4.01 (1H, br d, J = 2.68, 2-H); 4.65 (1H, br d,
J = 2.68, 3-H). 13C NMR: d 23.40, 25.00, 36.36 (–(CH2)5–); 44.87
(4-C-isox.); 52.55 (OCH3); 56.22 (2-C); 68.80 (3-C); 87.22 (5-C-
isox.); 158.50, 172.92 (C@N, C@O). MS-FAB+ (m/z): 257 (MH+). IR
(Nujol): 3363 (vOH, vNH, OH, NH2), 1740 (vC@O, C@O), 1680 (vC@N
C@N).
,
4.22. (2S,3S,20R)-2-(2-Amino-3-methyl-butyrylamino)-3-
hydroxy-3-(1-oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-propionic acid
methyl ester 8b
Amorphous solid (42%); Rf = 0.31 (ethyl acetate:metha-
nol = 7:3); ½a 2D0
ꢁ
¼ ꢀ1:7 (c 0.76, CHCl3). 1H NMR: d 0.89, 1.02 (6H,
4.18. General procedure for the hydrolysis of adducts 6a-c
2d, J = 6.9, CH(CH3)2); 1.30–1.80 (10H, m, –(CH2)5–); 2.2–2.7 (4H,
br m, CH(CH3)2, OH, NH2); 2.74, 2.88 (2H, AB-system, JAB = 16.9,
4-CH2-isox.); 3.30 (1H, br d, J = 3.8, 20-H); 3.81 (3H, s, OCH3);
4.92 (1H, dd, J = 9.3, 2.3, 2-H); 4.97 (1H, br s, 3-H); 8.23 (1H, d,
J = 9.3, NH-CO); (by deuteration, the signals at 2.2–2.7 and 8.23 dis-
appeared, and the signals at 3.30, 4.92 and 4.97 turned into three
broad singlets). 13C NMR: d 16.11, 19.55 (CH(CH3)2); 23.32, 24.89,
36.17, 36.31 (–(CH2)5–); 31.08 (CH(CH3)2); 44.35 (4-C-isox.);
52.68 (OCH3); 54.45 (20-C); 60.21 (2-C); 68.90 (3-C); 87.90 (5-C-
isox.); 157.83, 170.07, 175.05 (C@N, C@O ester and amide). MS-
FAB+ (m/z): 356 (MH+). IR (Nujol): 3455 (vOH, vNH, OH, NH2), 1738
Adducts 6a–c (0.5 mmol) were dissolved in methyl alcohol
(7.5 mL), and a 0.2 M solution of HCl (7.5 mL, 1.5 mmol, 3 equiv)
was added. The mixture was stirred for 6 h at room temperature,
and then extracted with diethyl ether in order to remove non-basic
organic compounds. The mixture was diluted with CHCl3 (20 mL),
and 25% ammonia was added until pH 8–10 under stirring. The lay-
ers were separated, and the aqueous layer was extracted twice
with CHCl3 (2 ꢂ 20 mL). The combined organic layers were dried
with Na2SO4, and the solvent was removed in vacuo. Compounds
7 and 8 were separated by flash chromatography (SiO2, ethyl ace-
tate:methanol = 98:2, developer: I2 or ninhydrine).
(vC@O, C@O ester), 1652 (vC@N, C@O, C@N and C@O amide).
4.23. (2S,3S)-2-Amino-3-(5,5-dimethyl-4,5-dihydro-isoxazol-3-
yl)-3-hydroxy-propionic acid methyl ester 7c
4.19. (2S,3S)-2-Amino-3-(5,5-diphenyl-4,5-dihydro-isoxazol-3-
yl)-3-hydroxy-propionic acid methyl ester 7a
Amorphous solid (20%); Rf = 0.41 (ethyl acetate:methanol =
Amorphous solid (20%); Rf = 0.52 (ethyl acetate:methanol =
85:15); ½a 2D0
ꢁ
¼ þ4:7 (c 0.32, CHCl3). 1H NMR: d 1.45, 1.47 (6H, 2s,
98:2); ½a 2D0
ꢁ
¼ þ8:0 (c 0.37, CHCl3). 1H NMR: d 1.80–2.20 (3H, br,
5,5-di-CH3); 2.20–2.60 (3H, br, OH, NH2); 2.81, 2.94 (2H, AB-sys-
tem, JAB = 16.9, 4-CH2-isox.); 3.82 (3H, s, OCH3); 3.99 (1H, br d,
J = 2.8, 2-H); 4.67 (1H, br d, J = 2.8, 3-H). 13C NMR: d 26.81 (5,5-
di-CH3); 46.26 (4-C-isox.); 51.71 (OCH3); 58.37 (2-C); 68.77
(3-C); 83.48 (5-C-isox.); 160.23, 173.47 (C@N, C@O). MS-FAB+ (m/
OH, NH2); 3.73 (3H, s, OCH3); 3.72, 3.83 (2H, AB-system,
JAB = 17.2, 4-CH2-isox.); 3.99 (1H, br d, J = 3.2, 2-H); 4.69 (1H, br
d, J = 3.2, 3-H); 7.3–7.5 (10H, m, Ph). 13C NMR: d 47.93 (4-C-isox.);
52.80 (OCH3); 56.03 (2-C); 67.95 (3-C); 93.01 (5-C-isox.); 125.94,
126.07, 127.68, 128.40, 143.0 (Ph); 158.23, 172.55 (C@N, C@O).
MS-FAB+ (m/z): 341 (MH+). IR (Nujol): 3357 (vOH, vNH, OH, NH2),
1742 (vC@O, C@O), 1671 (vC@N, C@N).
z): 217 (MH+). IR (Nujol): 3332 (vOH, vNH, OH, NH2), 1741 (vC@O
C@O), 1676 (vC@N, C@N).
,
4.24. (2S,3S,20R)-2-(2-Amino-3-methyl-butyrylamino)-3-(5,5-
dimethyl-4,5-dihydro-isoxazol-3-yl)-3-hydroxy-propionic acid
methyl ester 8c
4.20. (2S,3S,20R)-2-(2-Amino-3-methyl-butyrylamino)-3-(5,5-
diphenyl-4,5-dihydro-isoxazol-3-yl)-3-hydroxy-propionic acid
methyl ester 8a
Amorphous solid (63%); Rf = 0.26 (ethyl acetate:methanol =
Amorphous solid (48%); Rf = 0.25 (ethyl acetate:metha-
85:15); ½a 2D0
ꢁ
¼ þ10:9 (c 1.27, CHCl3). 1H NMR: d 0.91, 1.04 (6H,
nol = 98:2); ½a 2D0
ꢁ
¼ ꢀ1:8 (c 1.13, CHCl3). 1H NMR: d 0.78, 0.89
2d, J = 6.9, CH(CH3)2); 1.40, 1.46 (6H, 2s, 5,5-di-CH3); 2.05–2.15
(3H, br, OH, NH2); 2.29 (1H, m, CH(CH3)2); 2.79, 2.85 (2H, AB-sys-
tem, JAB = 16.9, 4-CH2-isox.); 3.35 (1H, br d, J = 3.9, 20-H); 3.82 (3H,
s, OCH3); 4.97 (1H, dd, J = 9.2, 2.7, 2-H); 4.99 (1H, br d, J = 2.7, 3-H);
8.18 (1H, d, J = 9.2, NH–CO); (by deuteration, the signals at 2.05–
2.15 and 8.18 disappeared, and the signals at 3.35, 4.97 and 4.99
turned into three sharp doublets with J = 3.9, 2.7 and 2.7, respec-
tively). 13C NMR: d 16.17, 19.53 (CH(CH3)2); 27.01, 27.13 (5,5-di-
CH3); 31.13 (CH(CH3)2); 46.22 (4-C-isox.); 52.70 (OCH3); 54.53
(20-C); 60.26 (2-C); 69.17 (3-C); 85.57 (5-C-isox.); 158.28, 170.08,
175.12 (C@N, C@O ester and amide). MS-FAB+ (m/z): 316 (MH+).
(6H, 2d, J = 6.8, CH(CH3)2); 1.70–2.10 (3H, br, OH, NH2); 2.16 (1H,
m, CH(CH3)2); 2.97 (1H, m, 20-H); 3.62, 3.76 (2H, AB-system,
JAB = 17.1, 4-CH2-isox.); 3.71 (3H, s, OCH3); 4.93 (1H, dd, J = 9.3,
3.0, 2-H); 5.00 (1H, br d, J = 3.0, 3-H); 7.25–7.5 (10H, m, Ph); 8.05
(1H, d, J = 9.3, NH–CO); (by deuteration, the signals at 1.7–2.1
and 8.05 disappeared, and the signals at 2.97, 4.93 and 5.00 turned
into three doublets with J = 3.4, 3.2 and 3.2, respectively). 13C NMR:
d 16.19, 19.34 (CH(CH3)2); 30.81 (CH(CH3)2); 47.39 (4-C-isox.);
52.74 (OCH3); 54.69 (20-C); 59.73 (2-C); 69.05 (3-C); 92.58 (5-C-
isox.); 125.71, 126.02, 127.67, 128.36, 143.55 (Ph); 158.56,
169.97, 174.41 (C@N, C@O ester and amide). MS-FAB+ (m/z): 440

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 2850–2855
2855
IR (Nujol): 3423 (vOH, vNH, OH, NH2), 1736 (vC@O, C@O ester), 1654
(vC@N C@O, C@N and C@O amide).
and amide). MS-FAB+ (m/z): 319 (MH+). IR (Nujol): 3348 (vOH, vNH
,
OH, NH2), 1744, 1719, 1669 (vC@O, C@O ketone, ester, amide).
,
4.25. General procedure for the reduction of compounds 8b–c
References
To a solution of 8b–c (0.4 mmol, 1 equiv) in 5/1 methanol/water
(10 mL) were added boric acid (1.2 mmol, 3 equiv) and a spatula
tip of Raney-Ni. The mixture was stirred vigorously under hydro-
gen for 6 h, and then filtered through Celite. After evaporation of
the solvent, the residue was treated with water and extracted with
ethyl acetate (5 ꢂ 10 mL). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Compounds 9b–c were
pure enough for the spectroscopic and analytical characterisation.
1. (a) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915–
6922; (b) Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490–7505;
(c) Renner, M. K.; Shen, Y.-C.; Cheng, X.-C.; Jensen, P. R.; Frankmoelle, W.;
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Biochem. J. 1995, 305, 187–196.
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4.26. (2S,3S,20R)-2-(2-Amino-3-methyl-butyrylamino)-3-
hydroxy-5-(1-hydroxy-cyclohexyl)-4-oxo-pentanoic acid
methyl ester 9b
5. (a) Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248–12249; (b)
Mettath, S.; Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L. J. Org. Chem. 2004,
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6. (a) Dalla Croce, P.; Ferraccioli, R.; La Rosa, C.; Pizzatti, E. Heterocycles 2000, 52,
1337–1344; (b) Dalla Croce, P.; La Rosa, C.; Pizzatti, E. Tetrahedron: Asymmetry
2000, 11, 2635–2642; (c) Cremonesi, G.; Dalla Croce, P.; La Rosa, C.; Pizzatti, E.
Heterocycles 2003, 61, 563–567; (d) Cremonesi, G.; Dalla Croce, P.; Fontana, F.;
La Rosa, C. Tetrahedron: Asymmetry 2006, 17, 2637–2641; (e) Cremonesi, G.;
Dalla Croce, P.; Fontana, F.; Forni, A.; La Rosa, C. Tetrahedron: Asymmetry 2007,
18, 1667–1675.
Amorphous solid (86%); ½a D20
ꢁ
¼ þ57:25 (c 0.29, CHCl3). 1H NMR: d
0.79, 0.95 (6H, 2d, J = 6.7, CH(CH3)2); 1.20–1.80 (10H, m, –(CH2)5–);
2.20 (1H, m, CH(CH3)2); 2.20–2.70 (4H, br, 2 OH, NH2); 2.75, 2.84
(2H, AB-system, JAB = 15.7, 5-CH2); 3.20 (1H, br s, 20-H); 3.78 (3H,
s, OCH3); 4.78 (1H, br s, 3-H); 5.20 (1H, br d, J = 8.4, 2-H); 7.91
(1H, br d, J = 8.4, NH–CO); (by deuteration, the signals at
2.20–2.70 and 7.91 disappeared, and the signals at 3.20, 4.78 and
5.20 turned into three broad singlets). 13C NMR: d 15.98, 19.49
(CH(CH3)2); 21.92, 25.36, 37.28, 38.04 (–(CH2)5–); 30.92
(CH(CH3)2); 48.80 (5-C); 52.92 (OCH3); 53.78 (20-C); 59.92 (2-C);
71.16 (6-C); 77.62 (3-C); 169.75, 174.89, 209.49 (C@O ester, ketone
7. Schöllkopf, U. Top. Curr. Chem. 1983, 109, 65–84.
8. Grünanger, P.; Vita-Finzi, P. In The Chemistry of Heterocyclic Compounds; Taylor,
E. C., Ed.; J. Wiley and Sons: New York, 1991; Vol. 49, pp 572–602.
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12. Caldirola, P.; De Amici, M.; De Micheli, C. Tetrahedron 1986, 42, 5267–5272.
13. (a) Busch, K.; Groth, U. M.; Kühnle, W.; Schöllkopf, U. Tetrahedron 1992, 48,
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14. Grauert, M.; Schöllkopf, U. Liebigs Ann. Chem. 1985, 1817–1824.
15. (a) Beulshhauer, T.; Groth, U.; Schöllkopf, U. Liebigs Ann. Chem. 1991, 1207–
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16. Chung, Y. J.; Ryu, E. J.; Keum, G.; Kim, B. H. Bioorg. Med. Chem. 1996, 4, 209–225.
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18. Only the melting point of compound 3a has been reported in Patent: US
5,516,750, 1996.
and amide). MS-FAB+ (m/z): 359 (MH+). IR (Nujol): 3347 (vOH, vNH
OH, NH2), 1747, 1709, 1660 (vC@O, C@O ketone, ester, amide).
,
4.27. (2S,3S,20R)-2-(2-Amino-3-methyl-butyrylamino)-3,6-
dihydroxy-6-methyl-4-oxo-eptanoic acid methyl ester 9c
Amorphous solid (68%); ½a D20
ꢁ
¼ þ6:8 (c 0.28, CH3OH). 1H NMR: d
0.81, 1.02 (6H, 2d, J = 6.8, CH(CH3)2); 1.26, 1.30 (6H, 2s, C(CH3)2);
2.25 (1H, m, CH(CH3)2); 2.30–2.70 (4H, br, OH, NH2); 2.86 (2H, s,
5-CH2); 3.21 (1H, br d, J = 3.3, 20-H); 3.64 (3H, s, OCH3); 4.76 (1H,
br s, 3-H); 5.20 (1H, br d, J = 9.2, 2-H); 8.13 (1H, d, J = 9.2, NH-CO);
(by deuteration, the signals at 2.30–2.70 and 8.13 disappeared, and
the signals at 3.21, 4.76 and 5.20 turned into three broad singlets).
13C NMR: d 16.07, 19.40 (CH(CH3)2); 27.04, 28.14 (C(CH3)2); 31.06
(CH(CH3)2); 49.66 (5-C); 52.82 (OCH3); 53.50 (20-C); 60.34 (2-C);
69.94 (6-C); 77.46 (3-C); 169.67, 174.41, 209.48 (C@O ester, ketone
19. Compound 3b has been mentioned in Patent: WO 2008013925, 2008, but it has
not been described.
20. Compounds 3c, 4a, 4c have been mentioned in: Kai, H.; Matsumoto, H.; Hattori,
N.; Takase, A.; Fujiwara, T.; Sugimoto, H. Bioorg. Med. Chem. Lett. 2001, 11,
1997–2000 but they have not been described.