Truncated diastereoselective Passerini reaction, a rapid construction of polysubstituted oxazole and peptides having an α-hydroxy-β-amino acid component

Article abstract of DOI:10.1016/j.tet.2004.03.084

The reaction of aldehydes and ketones, including aliphatic and aromatic ones, with amides of α-isocyano-β-phenylpropionic acid in toluene in the presence of lithium bromide gives 2,4,5-trisubstituted oxazoles in good to excellent yield. Protected chiral α

Full text of DOI:10.1016/j.tet.2004.03.084

Tetrahedron 60 (2004) 4879–4885
Truncated diastereoselective Passerini reaction, a rapid
construction of polysubstituted oxazole and peptides having an
a-hydroxy-b-amino acid component
*
´
Guylaine Cuny, Rocio Gamez-Montan˜o and Jieping Zhu
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Received 10 February 2004; revised 16 March 2004; accepted 29 March 2004
Abstract—The reaction of aldehydes and ketones, including aliphatic and aromatic ones, with amides of a-isocyano-b-phenylpropionic acid
in toluene in the presence of lithium bromide gives 2,4,5-trisubstituted oxazoles in good to excellent yield. Protected chiral a-amino
aldehydes participate in this reaction to give, after hydrolysis of the oxazoles, norstatine-containing peptides in good overall yield. The
nucleophilic addition of isonitriles to N,N-dibenzylphenylalanal is investigated for the first time and is found to be stereoselective leading
predominantly to the anti-adduct (dr¼9/1). On the other hand, the reaction between the N-Boc phenylalanal and isonitrile is non-
stereoselective.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
oxazoles (1) by a truncated Passerini reaction between
aldehydes and a-alkyl-a-isocyano amides under mild
conditions13 and its application in the synthesis of peptides
having a b-amino-a-hydroxy acid fragment (Fig. 1). The
b-amino-a-hydroxy acid (norstatine) is the essential moiety
of a large number of well-known natural or synthetic
compounds that are endowed with powerful biological
activities. Anticancer drugs such as paclitaxel and
The reaction of an isonitrile, an aldehyde and a carboxylic
acid to provide an a-acyloxy amide was discovered by
Passerini about 80 years ago.1 Together with the Ugi
reaction, it is among the most powerful multicomponent
reactions and have found wide applications in the synthesis
of large arrays of chemical species.2 Recently, a sequence
involving Passerini reaction followed by an intramolecular
O to N-acyl migration has been developed by the group
of Banfi3 and Semple,4 respectively, for the rapid
atom-economy synthesis of enzyme inhibitors.5 Lewis
acid-mediated two-component variants leading to
a-hydroxycarboxylic amides has been described by
Seebach6 and more recently, an enantioselective version
has been uncovered by Denmark and Fan.7 Being interested
in the development of novel multicomponent synthesis of
heterocycles, we have described a three-component
synthesis of 5-aminooxazoles by condensation of aldehydes,
amines and a-isocyano amides8 and its subsequent trans-
formation to a variety of polyheterocycles9,10 and macro-
cycles.11 Ganem and co-workers subsequently reported a
Lewis acid promoted condensation between aldehydes and
a-isocyano amides for the synthesis of polysubstituted
5-aminooxazoles.12 As a continuation of our work in this
field, we report herein a synthesis of 2,4,5-trisubstituted
Keywords: Diastereoselectivity; N,N-Dibenzyl aminoaldehyde;
a-Hydroxy-b-amino acid; Multicomponent reaction; Oxazole; Passerini
reaction.
*
Corresponding author. Fax: þ33-1-69-07-72-47;
e-mail address: zhu@icsn.cnrs-gif.fr
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.084

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G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
14
`
taxotere, the potent aminopeptidase B inhibitor bestatine
(3)15 and potent HIV protease inhibitor (4)16 are notable
examples.
The reaction between a-isocyano b-phenyl propionamide
(5) and heptanal (6) was investigated under different set of
conditions following our previous work (Scheme 1). Table 1
summarized the results of reaction optimization under
different conditions varying the solvent, the temperature and
additives (weak Brønsted acids and weak Lewis acid). As
can be seen, no reaction occurred in MeOH (entry 1) and
toluene (entry 4) in the absence of promoters. However,
lithium bromide (LiBr),17 ammonium chloride (NH4Cl)18
and camphorsulphonic acid (CSA),19 were all able to assist
this transformation leading to the oxazole in good to
excellent yields. Interestingly, in the presence of these
promoters the condensation reaction took place in both polar
protic solvent (MeOH) and non-polar aprotic solvent
(toluene). The optimum conditions consist of heating the
isocyanide (5a) and heptanal (6a) in toluene (70 8C) in the
presence of 1 equiv. of LiBr. Under these conditions,
the desired oxazole 1a was isolated in 89% yield (entry 5). It
is worthy noting that LiBr and NH4Cl are sparsely soluble in
toluene, so the reaction is in fact catalytic in nature.
Scheme 1.
Table 1. Screening of reaction conditions for the synthesis of 1a
Entry
Solvent
Additive
Temperature (8C)
Yield (%)a
1
2
3
4
5
6
7
MeOH
MeOH
MeOH
Toluene
Toluene
Toluene
Toluene
—
55
55
55
70
70
70
70
0
LiBrb
NH4Clb
—
86
30
0
89
68
50
Figure 2.
LiBrb
NH4Clb
CSAc
philicity and/or the low stability of the resulting benzyl
alcohol. The amine part of the a-isocyano-b-phenyl-
propionamide influenced the reaction efficiency as well as
the stability of adducts. Thus, piperidine-containing
oxazoles are less stable than the morpholine derivatives
(1a vs. 1b, and 1h vs. 1i). In fact, it is rather difficult to
obtain analytically pure 1b and 1i due to their low stability
that partly explained the decreased yield of oxazoles 1b and
1i.
a
Isolated yield.
1 equiv.
CSA¼camphorsulphonic acid, 0.1 equiv.
b
c
The generality of this transformation was demonstrated by
applying the procedure to various aldehydes and a-alkyl
a-isocyanoacetamides. Figure 2 lists 2-hydroxyalkyl-5-
amino oxazoles synthesized by this new protocol. Aliphatic
carbonyl compounds, including linear (heptanal),
a-branched aldehydes (isobutyraldehyde) and activated
aldehydes or ketones such as ethyl glyoxylate and keto
malonate participate in this transformation to give the
corresponding adducts. Aromatic aldehydes with electron
withdrawing group or moderate electron donating group
react smoothly leading to the oxazoles (1g to 1k). However,
4-methoxybenzaldehyde failed to produce the correspond-
ing oxazole, presumably because of its lower electro-
It is important to note that it is essential to use the a-alkyl
a-isocyanoacetamide since the reaction of heptanal and
isocyanoacetate under identical conditions provided a
complex reaction mixture.
Synthesis of non-proteinogenic b-amino-a-hydroxy acids
(norstatines),20 followed by peptide coupling is the
conventional way to prepare the peptide of general structure

G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
4881
2 (Fig. 1). Since 5-aminooxazole can be hydrolyzed to the
acetamido amide under mild acidic conditions,21 a two-step
synthesis of norstatine-containing peptides can thus be
envisaged starting from chiral non-racemic amino
aldehydes. Indeed, the reaction of L-N-Boc-phenylalanal 7
with 5a and dipeptidic isocyanide 922 provided the
corresponding oxazoles 8 and 10 in 87 and 96% yields,
respectively. Unfortunately, the diastereoselectivity of this
transformation was unacceptably low (dr¼3/2). The
chirality of a-isocyano amide (5a) has no influence on the
diastereoselectivity since both (L) and racemic form
provided similar results (Scheme 2).
Scheme 2.
The low selectivity in the formation of compounds 8 and 10
was not unexpected since the Passerini reaction involving
chiral carbonyl compounds produce generally low to
moderate diastereoselectivity, due to the low steric require-
ment of isocyano group. Recent elegant work from
Marcaccini, Torroba23 and Lamberth24 nevertheless
illustrated that excellent diastereoselectivity could be
achieved if appropriate chiral starting materials were used.
In light of Reetz’s original contributions25 and our own
experiences on the diastereoselective transformation of
N,N-dibenzylamino aldehyde,26 the N,N-dibenzyl phenyl-
alanal 11 was next examined. To our delight, the reaction of
5a and 11 is much more stereoselective leading to the
formation of two diastereomeric amino alcohols in a ratio of
Scheme 3.
dibenzylamino aldehydes leading to anti-adducts is well-
known25 and can be explained by the usual Felkin–Anh
model (Fig. 3).27
1
9:1 (determined from the H NMR spectra of the crude
reaction mixture) and the major stereomer 12 was isolated in
64% yield. Hydrolysis of 12 under acidic conditions
(THF–H2O, TFA, room temperature) proceeded smoothly
to provide the dipeptide 14 in 86% yield. The protonation of
the C-4 carbon was non-stereoselective leading to the
formation of dipeptide as a mixture of two separable
diastereomers. Both diastereomers (14a and 14b) were
transformed to the corresponding oxazolidinone (16) in
order to determine the relative stereochemistry of the amino
alcohol (Scheme 3). Thus, hydrogenolysis of 14 under
standard conditions [Pd(OH)2, H2, 1 atm, MeOH] provided
the corresponding amino alcohol 15 which was reacted
with triphosgene in the presence of pyridine to provide
the oxazolidinone in 78% yield. The coupling constant
(JHa–Hb¼8.5 Hz) indicated a cis relation for these two
protons and hence the anti stereochemistry of the amino
alcohol in compound 12. Nucleophilic addition to N,N-
Figure 3.
In summary, we have developed a new synthesis of 2,4,5-
trisubstituted oxazole by reaction of aldehyde with peptidic
isocyanide. Using N,N-dibenzylamino phenylalanal, a
highly diastereoselective Passerini reaction occurred to
provide, after acidic hydrolysis of oxazole, the phenyl-
norstatine-containing dipeptide. To the best of our knowl-
edge, this is the first example in which N,N-dibenzylamino
aldehyde was used as chiral carbonyl input in the Passerini
reaction. We expect the further application of the readily

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G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
available N,N-dibenzylamino aldehydes in the Passerini as
well as in the Ugi type multicomponent reactions.
oxazole 1a (49.3 mg, 89% yield). Rf¼0.39 (eluant: AcOEt/
Hept¼2/3); IR (CHCl3) n 3416, 2929, 2860, 1737, 1665,
1454, 1376, 1264, 1115 cm21; 1H NMR (300 MHz, CDCl3,
293 K) d 0.87 (m, 3H), 1.25 (m, 8H), 1.73–1.86 (m, 2H),
2.94 (m, 4H), 3.70 (m, 4H), 3.80 (s, 2H), 4.61 (br t, 1H,
J¼6.2 Hz), 7.18–7.24 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 14.1, 22.6, 25.1, 28.9, 31.4, 31.7, 51.1, 66.9, 71.9, 124.7,
128.3–128.4, 139.3, 151.9, 160.7; MS (ESI) m/z 359
(MþH), 381 (MþNa); HRMS (ESI) m/z calculated for
C21H30N2O3þNa: 381.21333, found 381.2132.
2. Experimental
2.1. Preparation of isonitrile 5a and 9
These two isonitriles were obtained by dehydration of the
corresponding N-formyl derivatives.22 Typical procedure: A
stirred solution of morpholinyl amide of N-formyl phenyl-
alanine (10 mmol) and triethylamine (50 mmol) in 50 mL of
dry dichloromethane was cooled to 220 to 2308C.
Phosphorus oxychloride (15 mmol) was added dropwise
and the reaction mixture was stirred for 2 h at 220 to
2308C. An aqueous solution of sodium bicarbonate was
introduced dropwise so that the temperature of mixture was
maintained at 220 to 2308C. The mixture was stirred for
0.5 h and raised to room temperature. The aqueous layer
was separated and extracted with dichloromethane. The
organic extracts were combined, washed with brine, dried
over anhydrous sodium sulfate and evaporated under
reduced pressure. The crude reaction mixture was purified
by flash column chromatography on silica gel to provide the
isocyanide 5a.
Compounds 1b–1k, 8, 10 and 12 were prepared under
identical conditions.
2.2.1. Compound 1b. Rf¼0.68 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3411, 2930, 2860, 1723, 1631, 1496, 1453,
1
1269, 1125 cm21; H NMR (300 MHz, CDCl3, 293 K) d
0.87 (m, 3H), 1.27 (m, 8H), 1.52 (m, 2H), 1.61 (m, 4H), 1.83
(m, 2H), 2.94 (m, 4H), 3.78 (s, 2H), 4.60 (br t, 1H,
J¼5.8 Hz), 7.24 (m, 5H); 13C NMR (75 MHz, CDCl3) d
14.1, 22.5, 22.6, 23.9, 25.9, 28.9, 31.4, 31.7, 52.2, 71.7,
123.4, 128.5, 139.7, 153.5, 159.9; MS (ESI) m/z 357
(MþH), 379 (MþNa).
2.2.2. Compound 1c. Rf¼0.70 (eluant: AcOEt/Hept¼1/1);
1H NMR (250 MHz, CDCl3, 293 K) d 0.87 (m, 3H), 0.98 (t,
6H, J¼7.3 Hz), 1.26 (m, 8H), 1.83 (m, 2H), 2.71 (d, 1H,
J¼5.5 Hz, OH), 2.95 (q, 4H, J¼7.3 Hz), 3.77 (s, 2H), 4.62
(m, 1H), 7.25 (m, 5H); MS (ESI) m/z 367 (MþNa), 383
(MþK).
2.1.1. Compound 5a. Yield: 95%; eluant: Hept/EtOAc¼2/
1; white solid, mp 79–818C; IR (CHCl3) n 2928, 2863,
1
2142, 1668, 1496, 1456, 1116 cm21; H NMR (250 MHz,
CDCl3): d 3.13–3.78 (m, 10H), 4.55 (t, 1H, J¼7.3 Hz),
7.22–7.40 (m, 5H); 13C NMR (CDCl3, 62.5 MHz): d 39.1,
42.9, 46.2, 55.0, 65.9, 66.4, 127.7, 128.8 (2CH), 129.4
(2CH), 135.0, 159.8, 163.5; MS (EI): m/z 244.
2.2.3. Compound 1d. Rf¼0.43 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3411, 2964, 2927, 2856, 1638, 1454, 1262,
1115 cm21; 1H NMR (300 MHz, CDCl3, 293 K) d 0.92 (d,
3H, J¼6.7 Hz), 0.96 (d, 3H, J¼6.7 Hz), 2.11 (m, 1H), 2.95
(m, 4H), 3.72 (m, 4H), 3.82 (s, 2H), 4.39 (d, 1H, J¼6.7 Hz),
7.19–7.30 (m, 5H); 13C NMR (75 MHz, CDCl3) d 17.5,
18.4, 31.8, 33.5, 51.2, 66.9, 73.05, 124.7, 126.3, 128.5,
139.4, 152.1, 160.1; MS (ESI) m/z 317 (MþH), 339
2.1.2. Compound 9. Yield 98% (eluant: EtOAc/Hept¼1/5);
IR (CHCl3, cm21) n 3009, 2142, 1751, 1677, 1497, 1456,
1439, 1407, 1366, 1238, 1183, 1121, 1080, 1032;
[a]D¼28.3 (c¼0.12, CHCl3); 1H NMR (300 MHz,
CDCl3, ppm), two rotamers (4/1 ratios) d 3.08 (3.02) (s,
3H), 3.15 (dd, J¼8.7, 14.0 Hz, 1H), 3.28 (dd, J¼5.3,
14.0 Hz, 1H), 3.76 (s, 3H), 4.02 (3.90) [d, J¼17.3 (17.2) Hz,
1H], 4.26 (4.09) (d, J¼17.3 (17.2) Hz, 1H), 4.62 (4.39) [d,
J¼5.5 (5.5), 8.7 (8.8) Hz, 1H], 7.20–7.36 (5H, m); 13C
NMR (62.5 MHz, CDCl3, ppm), two rotamers (4/1 ratios) d
35.90, 36.75, 38.68, 39.03, 50.14, 51.22, 52.39, 55.80,
127.7, 128.8, 129.5, 135.2, 160.0, 165.8, 168.9; MS (EI) m/z
260, 233, 201, 174. Anal. Calcd for C14H16N2O3: C, 64.62;
H, 6.15; N, 10.77. Found: C, 64.77; H, 6.07; N, 10.74.
(MþNa).;
HRMS
(ESI)
m/z
calculated
for
C18H24N2O3þNa: 339.1664, found 339.1665.
2.2.4. Compound 1e. Rf¼0.50 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3519, 2862, 2142, 1743, 1664, 1453, 1265,
1
1115 cm21; H NMR (300 MHz, CDCl3, 293 K) d 1.26 (t,
3H, J¼7.3 Hz), 2.97 (m, 4H), 3.72 (m, 4H), 3.82 (s, 2H),
4.31 (m, 2H), 5.16 (s, 1H), 7.23 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 13.9, 31.6, 50.7, 62.6, 66.6, 67.1, 125.1,
127.6, 128.3, 129.3, 139.1, 154.2, 163.4, 169.9; MS (ESI)
m/z 347 (MþH), 369 (MþNa), 385 (MþK); HRMS (ESI)
m/z calculated for C18H22N2O5þNa: 369.1426, found
369.1381.
2.2. Typical procedure for the truncated Passerini
reaction, synthesis of compound 1a
To a solution of heptanal (6a, 0.20 mmol, 26.9 mL) and
a-isocyano b-phenyl propionamide (5a) (0.15 mmol,
37.6 mg) in dry toluene (0.30 mL) was added lithium
bromide (0.15 mmol, 13.4 mg.). The reaction mixture is
stirred at 60 8C for 4 h. After the disappearance of isonitrile,
the reaction mixture was cooled to room temperature,
diluted with water and extracted with ethyl acetate. The
combined organic phase was washed with brine, dried over
anhydrous sodium sulfate and evaporated under reduced
pressure. The crude reaction mixture was purified by flash
chromatograph (AcOEt/Hept 1/2) to give the corresponding
2.2.5. Compound 1f. Rf¼0.49 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3494, 2987, 1747, 1660, 1453, 1264,
1
1115 cm21; H NMR (250 MHz, CDCl3, 293 K) d 1.29 (t,
6H, J¼7.0 Hz), 2.95 (m, 4H), 3.71 (m, 4H), 3.83 (s, 2H),
4.36 (m, 4H), 7.24 (m, 5H); 13C NMR (75 MHz, CDCl3) d
13.9, 31.8, 50.8, 63.5, 66.7, 125.1, 126.2, 128.3, 128.5,
139.2, 152.3, 153.0, 166.8; MS (ESI) m/z 419 (MþH),
441 (MþNa), 457 (MþK), 859 (2MþNa); HRMS (ESI)
m/z calculated for C21H26N2O7þNa: 441.1638, found
441.1599.

G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
4883
2.2.6. Compound 1g. Rf¼0.34 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3400, 2925, 2860, 1666, 1529, 1454, 1349,
(m, 10H); 13C NMR (75 MHz, CDCl3) d 28.3, 29.4, 29.7,
31.7, 50.9, 53.8, 66.8, 79.7, 126.4, 128.4, 129.0, 137.5,
139.3, 152.3, 157.5; MS (ESI) m/z 516 (MþNa).
1
1264, 1115 cm21; H NMR (300 MHz, CDCl3, 293 K) d
2.92 (m, 4H), 3.71 (m, 4H), 3.80 (s, 2H), 5.76 (s, 1H), 7.21
(m, 5H), 7.65 (d, 2H, J¼8.8 Hz), 8.22 (d, 2H, J¼8.8 Hz);
13C NMR (75 MHz, CDCl3) d 31.7, 50.9, 66.8, 69.0, 123.8,
124.6, 126.5, 127.4, 127.8, 128.5, 128.6, 128.9, 129.5,
139.0, 146.3, 147.8, 152.9, 157.9; MS (ESI) m/z 396
(MþH), 418 (MþNa); HRMS (ESI) m/z calculated for
C21H21N3O5þNa: 418.1379, found 418.1398.
2.2.12. Compound 8b. Rf¼0.45 (eluant: AcOEt/Hept¼
1/1); [a]D¼26 (CHCl3, c 1.4); IR (CHCl3) n 3439, 2927,
2862, 1705, 1495, 1454, 1368, 1162, 1114 cm21; 1H NMR
(300 MHz, CDCl3, 293 K) d 1.30 (s, 9H), 2.92 (m, 6H), 3.69
(m, 4H), 3.74 (d, 1H, J¼15.4 Hz), 3.76 (d, 1H, J¼15.4 Hz),
4.23 (m, 1H), 4.50 (d, 1H, J¼2.9 Hz), 4.91 (br d,
1H, J¼10.3 Hz), 7.14–7.28 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 28.3, 29.4, 29.7, 31.7, 50.9, 53.8,
66.8, 79.7, 126.4, 128.4, 129.0, 137.5, 139.3, 152.3, 157.5;
MS (ESI) m/z 494 (MþH), 516 (MþNa); HRMS (ESI)
m/z calculated for C28H35N3O5þNa: 516.2430, found
516.2429.
2.2.7. Compound 1h. Rf¼0.45 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3391, 2968, 2921, 2861, 1664, 1453, 1263,
1114 cm21; 1H NMR (300 MHz, CDCl3, 293 K) d 2.92 (m,
4H), 3.69 (m, 4H), 3.80 (s, 2H), 5.63 (s, 1H), 7.23 (m, 9H);
13C NMR (75 MHz, CDCl3) d 31.6, 51.0, 66.7, 69.2, 122.6,
124.4, 125.4, 126.3, 128.5, 129.4, 129.7, 131.3, 139.3,
141.7, 152.6, 158.6; MS (ESI) m/z 429, 431 (MþH), 451,
453 (MþNa), 467, 469 (MþK); HRMS (ESI) m/z calculated
for C21H21N2O3BrþNa: 451.0633 and 453.0613, found
451.0662 and 453.0630.
2.2.13. Compound 10a. Rf¼0.45 (eluant: AcOEt/
Hept¼1/1); [a]D¼23 (CHCl3, c 0.9); IR (CHCl3) n 3434,
1
2931, 1710, 1497, 1368, 1164 cm21; H NMR (300 MHz,
CDCl3, 293 K) d 1.30 (s, 9H), 2.83 (s, 3H), 2.91 (d, 2H,
J¼8.1 Hz), 3.67 (s, 3H), 3.68 (s, 2H), 3.72 (d, 1H,
J¼15.4 Hz), 3.80 (d, 1H, J¼15.4 Hz), 4.20 (m, 1H), 4.47
(d, 1H, J¼2.9 Hz), 4.93 (br d, 1H, J¼9.6 Hz), 7.16–7.27
(m, 10H); 13C NMR (75 MHz, CDCl3) d 28.2, 29.7, 31.4,
37.7, 40.9, 51.8, 55.7, 68.1, 79.2, 126.1, 126.5, 128.4, 128.5,
129.4, 137.9, 139.4, 152.3, 157.7, 170.6; MS (ESI) m/z 510
(MþH), 532 (MþNa), 548 (MþK).
2.2.8. Compound 1i. IR (CHCl3) n 3403, 2942, 2858, 1631,
1453, 1271, 1073 cm21 1H NMR (300 MHz, CDCl3,
;
293 K) d 1.50–1.60 (m, 6H), 2.90 (m, 4H), 3.77 (s, 2H),
5.60 (s, 1H), 7.19–7.29 (m, 6H), 7.32 (d, 1H, J¼7.4 Hz),
7.41 (d, 1H, J¼8.0 Hz), 7.60 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 22.7, 25.9, 31.7, 52.0, 69.3, 122.6, 122.9, 125.2,
126.2, 128.5, 129.4, 129.7, 131.2, 139.5, 141.8, 154.2,
157.8; MS (ESI) m/z 427, 429 (MþH); 449, 451 (MþNa);
HRMS (ESI) m/z calculated for C22H23N2O2BrþNa:
449.0796 and 451.0775, found 449.0802 and 451.0791.
2.2.14. Compound 10b. Rf¼0.42, (eluant: AcOEt/
Hept¼1/1); [a]D¼27 (CHCl3, c 0.8); IR (CHCl3) n 3434,
1
2931, 1710, 1497, 1368, 1164 cm21; H NMR (300 MHz,
CDCl3, 293 K) d 1.37 (s, 9H), 2.70 (dd, 1H, J¼6.4,
13.8 Hz), 2.76 (dd, 1H, J¼6.4, 13.8 Hz), 2.86 (s, 3H), 3.69
(s, 7H), 3.82 (s, 2H), 4.30 (m, 1H), 4.64 (d, 1H, J¼2.9 Hz),
5.12 (br d, 1H, J¼9.6 Hz), 7.14–7.25 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 28.2, 29.7, 31.4, 37.7, 40.9, 51.8, 55.7,
68.1, 79.2, 126.1, 126.5, 128.4, 128.5, 129.4, 137.9, 139.4,
152.3, 157.7, 170.6; MS (IE) m/z 509 (M)þ.
2.2.9. Compound 1j. Rf¼0.67 (eluant: AcOEt/Hept¼1/1);
IR (CHCl3) n 3417, 2932, 1728, 1633, 1455, 1383,
1
1073 cm21; H NMR (300 MHz, CDCl3, 293 K) d 0.94 (t,
6H, J¼7.3 Hz), 2.92 (q, 4H, J¼7.3 Hz), 3.77 (s, 2H), 5.63
(br s, 1H), 7.19–7.27 (m, 6H), 7.32 (d, 1H, J¼7.3 Hz), 7.42
(dd, 1H, J¼1.7, 7.3 Hz), 7.58 (d, 1H, J¼1.7 Hz); 13C NMR
(75 MHz, CDCl3) d 13.2, 31.4, 47.8, 69.5, 122.6, 125.2,
126.1, 127.9, 128.3, 128.5, 128.6, 129.7, 129.9, 130.1,
131.3, 139.3, 141.9, 151.7, 159.0; MS (IE) m/z 414, 416
(M)þ; HRMS (ESI) m/z calculated for C21H23N2O2BrþNa:
437.0841 and 439.0820, found 437.0864 and 439.0850.
2.2.15. Compound 12. Rf¼0.65 (eluant: AcOEt/Hept¼1/1);
[a]D¼213 (CHCl3, c 0.7); IR (CHCl3) n 3400, 2927, 1495,
1
1454, 1114 cm21; H NMR (300 MHz, CDCl3, 293 K) d
2.75 (m, 4H), 2.86–2.93 (dd, 1H, J¼7.7, 13.7 Hz), 2.98–
3.05 (dd, 1H, J¼6.0, 13.7 Hz), 3.37–3.43 (m, 1H), 3.53 (d,
2H, J¼13.7 Hz), 3.59 (d, 2H, J¼13.7 Hz), 3.64 (m, 4H),
3.69 (d, 1H, J¼15.4 Hz), 3.75 (d, 1H, J¼15.4 Hz), 4.71 (br
d, 1H, J¼3.8 Hz), 7.15–7.26 (m, 20H); 13C NMR (75 MHz,
CDCl3) d 29.4, 31.7, 51.0, 54.7, 63.4, 66.8, 125.2, 126.0,
126.1, 127.1, 127.4, 128.3, 128.33, 128.5, 128.6, 128.9,
129.1, 129.13, 129.4, 139.3, 151.9, 158.9. MS (ESI) m/z 596
(MþNa); HRMS (ESI) m/z calculated for C37H39N3O3þNa:
596.2889, found 596.2871.
2.2.10. Compound 1k. Rf¼0.41 (eluant: AcOEt/Hept¼
1/1); IR (CHCl3) n 3404, 2967, 2922, 2861, 1636, 1495,
;
1453, 1263, 1114 cm21 1H NMR (300 MHz, CDCl3,
293 K) d 2.39 (s, 3H), 2.89 (m, 4H), 3.69 (m, 4H), 3.81
(s, 2H), 5.90 (s, 1H), 7.19–7.27 (m, 9H); 13C NMR
(75 MHz, CDCl3) d 19.1, 31.6, 51.0, 66.8, 67.5, 124.5,
126.2, 126.6, 128.4, 128.5, 129.1, 130.6, 130.8, 136.0,
137.7, 139.3, 146.3, 152.3, 159.1; MS (ESI) m/z 365
(MþH), 387 (MþNa), 403 (MþK); HRMS (ESI) m/z
calculated for C22H24N2O3þNa: 387.1685, found 387.1664.
2.2.16. Compound 13. Rf¼0.67 (eluant: AcOEt/Hept 1:1)
[a]D¼þ11 (CHCl3, c 0.2); IR (CHCl3) n 3401, 2925, 1497,
1454, 1115 cm21; 1H NMR (300 MHz, CDCl3, 293 K) d
2.56 (dd, 1H, J¼7.1, 14.3 Hz), 2.66 (m, 4H), 3.08 (dd, 1H,
J¼5.5, 14.3 Hz), 3.42–3.48 (m, 1H), 3.47 (d, 2H,
J¼13.2 Hz), 3.59 (m, 4H), 3.68 (s, 2H), 3.93 (d, 2H,
J¼13.2 Hz), 4.57 (d, 1H, J¼9.3 Hz), 6.98–7.34 (m, 20H);
13C NMR (75 MHz, CDCl3) d 29.4, 31.7, 51.0, 54.7, 63.4,
66.8, 125.2, 126.0, 126.1, 127.1, 127.4, 128.3, 128.33,
2.2.11. Compound 8a. Rf¼0.41 (eluant: AcOEt/Hept¼1/1);
[a]D¼21 (CHCl3, c 1.9); IR (CHCl3) n 3439, 2927, 2862,
1705, 1495, 1454, 1368, 1162, 1114 cm21 1H NMR
;
(300 MHz, CDCl3, 293 K) d 1.38 (s, 9H), 2.76 (dd, 1H,
J1¼6.3 and J2¼13.9 Hz), 2.78 (dd, 1H, J¼6.3, 13.9 Hz),
2.93 (m, 4H), 3.72 (m, 4H), 3.79 (s, 2H), 4.32 (m, 1H), 4.67
(d, 1H, J¼2.9 Hz), 5.07 (br d, 1H, J¼9.0 Hz), 7.11–7.35

4884
G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
128.5, 128.6, 128.9, 129.1, 129.13, 129.4, 139.3, 151.9,
158.9; MS (ESI) m/z 574 (MþH), 596 (MþNa); HRMS
(ESI) m/z calculated for C37H39N3O3 (MþH)þ 574.3070,
found 574.3074.
The diastereomer 15b was prepared from 14b following the
identical procedure.
Compound 15b. Rf¼0.14 (eluant: AcOEt/Hept 9:1);
[a]D¼22 (CHCl3, c 0.3); IR (CHCl3) n 3392, 2928, 1638,
1518, 1445, 1268, 1115 cm21 1H NMR (300 MHz,
;
2.2.17. Compound 14. To the solution of oxazole 12
(72 mg, 0.13 mmol) in THF (0.3 mL) and water (0.3 mL),
was added trifluoroacetic acid (0.3 mL). After being stirred
at room temperature for 30 min, the reaction mixture was
diluted with CH2Cl2, and washed with a saturated solution
of NaHCO3. The aqueous portion is extracted with CH2Cl2.
The combined organic phase was washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. The crude
product was then purified on preparative TLC (eluant:
AcOEt/methanol 10:0.1) to give 14 as a mixture of two
separable diastereomers (1/1) in 86% yield.
CD3OD, 293 K) d 2.78 (dd, 1H, J¼8.5, 14.6 Hz), 2.94–
3.08 (m, 5H), 3.17–3.23 (m, 2H), 3.43–3.61 (m, 4H), 3.78–
3.80 (m, 1H), 4.31 (br d, 1H, J¼2.4 Hz), 4.95 (m, 1H),
7.25–7.32 (m, 10H); 13C NMR (75 MHz, CD3OD) d 34.6,
39.4, 43.7, 47.4, 51.3, 56.8, 67.2, 67.4, 71.6, 128.3, 128.4,
129.8, 129.9, 130.1, 130.5, 130.7, 136.9, 137.4, 171.4,
172.2; MS (ESI) m/z 412 (MþH); HRMS (ESI) m/z
calculated for C23H29N3O4þH: 412.2236, found 412.2248.
2.2.19. Compound 16. A solution of trisphosgene (19.7 mg,
0.07 mmol) in CH2Cl2 (0.3 mL) was added dropwise to a
solution of pyridine (65 mL, 0.79 mmol) and the amino
alcohol 15a (54.6 mg, 0.13 mmol) in CH2Cl2 (0.45 mL)
cooled to 270 8C. Once addition was completed, the
cooling bath was removed and the reaction mixture was
allowed to warm to room temperature. The resultant
homogenous solution was quenched with saturated
ammonium chloride and the aqueous portion was separated
and extracted with CH2Cl2. The organic extract were
washed with 1 N HCl, saturated aqueous NaHCO3, brine,
dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified on preparative TLC (eluant:
AcOEt/methanol 10:1) to give the desired oxazolidinone
16a (45 mg, 78% yield): Rf¼0.60 (eluant: AcOEt/methanol
10/1); [a]D¼2100 (CHCl3, c 0.8); IR (CHCl3) n 3399,
2927, 1777, 1678, 1643, 1521, 1445, 1267, 1115 cm21; 1H
NMR (300 MHz, CDCl3, 293 K) d 2.11 (dd, 1H, J¼12.7,
12.8 Hz), 2.81 (dd, 1H, J¼12.8, 2.8 Hz), 2.97–3.34 (m,
6H), 3.37–3.63 (m, 4H), 4.11 (ddd, 1H, J¼2.8, 8.4,
12.7 Hz), 5.02 (d, 1H, J¼8.4 Hz), 5.20–5.26 (m, 1H),
7.08–7.35 (m, 10H), 7.56 (d, 1H, J¼8.5 Hz); 13C NMR
(75 MHz, CDCl3) d 29.7, 36.5, 39.8, 42.4, 46.0, 49.2, 55.5,
66.1, 66.5, 127.2, 127.4, 128.3, 128.7, 128.8, 129.1, 129.3,
129.5, 129.6, 135.7, 136.1, 165.8, 169.1; MS (ESI) m/z 460
(MþNa). The diastereomer 16b was prepared from 15b
following the identical procedure.
Diastereomer 14a. Rf¼0.17 (eluant: AcOEt/Hept 2/1);
[a]D¼23 (CHCl3, c 0.3); IR (CHCl3) n 3400, 2963, 1638,
1
1496, 1455, 1262, 1113, 1018 cm21; H NMR (300 MHz,
CDCl3, 293 K) d 2.60–2.76 (m, 4H), 3.10–3.22 (m, 4H),
3.28–3.39 (m, 4H), 3.52 (m, 1H), 3.59 (d, 2H, J¼13.7 Hz),
3.76 (d, 2H, J¼13.7 Hz), 3.97 (br d, 1H, J¼3.6 Hz), 4.97–
5.05 (m, 1H), 7.07–7.10 (m, 1H), 7.19–7.34 (m, 20H), 7.74
(br d, 1H, J¼8.2 Hz); 13C NMR (75 MHz, CDCl3) d 30.4,
40.2, 41.9, 45.7, 48.9, 53.4, 54.9, 63.7, 65.8, 66.1, 68.4, 126.2,
127.1, 127.5, 128.4, 128.5, 128.6, 128.7, 128.9, 129.1, 129.5,
129.6, 136.2, 138.2, 138.9, 139.5, 169.1, 172.7; MS (ESI) m/z
592 (MþH), 614 (MþNa), 630 (MþK); HRMS (ESI) m/z
calculated for C37H41N3O4þH: 592.3175, found 592.3207.
Diastereomer 14b. Rf¼0.42 (eluant: AcOEt/Hept 2/1);
[a]D¼214 (CHCl3, c 0.5); IR (CHCl3) n 3400, 2963,
1638, 1496, 1455, 1262, 1113, 1018 cm21 1H NMR
;
(300 MHz, CDCl3, 293 K) d 2.59–3.44 (m, 13H), 3.48 (d,
2H, J¼13.8 Hz), 3.72 (d, 2H, J¼13.8 Hz), 3.90 (d, 1H,
J¼3.6 Hz), 4.99 (td, 1H, J¼5.0, 8.9 Hz), 7.16–7.34 (m,
20H), 7.76 (d, 1H, J¼8.9 Hz); 13C NMR (75 MHz, CDCl3)
d 30.3, 40.2, 41.9, 45.7, 48.9, 54.9, 63.8, 65.8, 66.1, 68.4,
126.2, 127.1, 127.5, 128.4, 128.6, 128.7, 128.9, 129.5,
129.6, 136.2, 138.9, 139.5, 169.1, 172.7; MS (ESI) m/z 592
(MþH), 614 (MþNa); HRMS (ESI) m/z calculated for
C37H41N3O4þH: 592.3175, found 592.3212.
Compound 16b. Rf¼0.61 (eluant: AcOEt/methanol 10/1);
[a]D¼2123 (CHCl3, c 0.6); IR (CHCl3) n 3399, 2927,
1777, 1678, 1643, 1521, 1445, 1267, 1115 cm21; 1H NMR
(300 MHz, CDCl3, 293 K) d 2.40 (dd, 1H, J¼11.8,
13.2 Hz), 2.91–3.08 (m, 7H), 3.33–3.55 (m, 4H), 4.24
(ddd, 1H, J¼2.9, 8.5, 11.8 Hz), 5.05 (d, 1H, J¼8.5 Hz), 5.13
(q, 1H, J¼8.0 Hz), 7.18–7.32 (m, 10H), 7.70 (d, 1H,
J¼8.0 Hz); 13C NMR (75 MHz, CDCl3) d 36.8, 39.3, 42.4,
46.1, 49.5, 55.7, 66.1, 66.5, 127.3, 127.5, 128.8, 129.1,
129.5, 135.7, 136.2, 156.6, 166.1, 169.3; MS (ESI) m/z 460
(MþNa); HRMS (ESI) m/z calculated for C24H27N3O5þNa:
460.1848, found 460.1848.
2.2.18. Compound 15. A solution of diastereomerically
pure compound 14 (diastereomer 14a, 191 mg, 0.32 mmol)
in MeOH was stirred in the presence of palladium hydroxide
under hydrogen pressure for 3 h. The reaction mixture was
filtered through a Celite pad and washed with methanol. The
resulting filtrate is evaporated under reduced pressure to
give the desired free amino alcohol 15a (140 mg, 97%
yield): Rf¼0.10 (eluant: AcOEt/Hept 4:1); [a]D¼21
(CHCl3, c 0.6); IR (CHCl3) n 3392, 2928, 1638, 1518,
1445, 1268, 1115 cm21 1H NMR (300 MHz, CD3OD,
;
293 K) d 2.49 (dd, 1H, J¼4.8, 14.4 Hz), 2.64 (dd, 1H,
J¼9.7, 14.4 Hz), 2.94 (dd, 1H, J¼7.8, 13.3 Hz), 2.98 (dd,
1H, J¼7.8, 13.3 Hz), 3.44–3.58 (m, 8H), 3.70 (m, 1H), 4.29
(br d, 1H, J¼2.4 Hz), 5.04 (t, 1H, J¼7.8 Hz), 7.18–7.36 (m,
10H); 13C NMR (75 MHz, CD3OD) d 34.3, 39.3, 43.7, 47.5,
51.0, 56.3, 67.3, 67.4, 71.9, 128.3, 128.5, 129.7, 130.0,
130.5, 130.7, 136.9, 137.5, 171.5, 172.3. MS (ESI) m/z 412
(MþH); HRMS (ESI) m/z calculated for C23H29N3O4þNa:
434.2056, found 434.2048.
Acknowledgements
We thank CNRS for Financial support. A doctoral fellow-
ship from this institute to Guylaine Cuny and a post-doctoral
´
research fellowship from CONACYT, Mexico to Rocio

G. Cuny et al. / Tetrahedron 60 (2004) 4879–4885
4885
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Gamez-Montan˜o are gratefully acknowledged. We thank
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