A general synthesis of enantiopure 1,2-aminoalcohols via chiral morpholinones

Article abstract of DOI:10.1016/S0040-4020(99)00935-7

Eleven optically active 1,2-aminoalcohols 20a-i and 26b-c were prepared from D-phenylglycine via cyclic imines 7b-i (or enamine 7a). The key step of the strategy is the diastereoselective reduction of chiral oxazinones 7a-i.

Full text of DOI:10.1016/S0040-4020(99)00935-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 233–248
A General Synthesis of Enantiopure 1,2-Aminoalcohols
via Chiral Morpholinones
´
Fabienne Segat-Dioury, Olivier Lingibe, Bernadette Graffe, Marie-Claude Sacquet and
*
´
Gerard Lhommet
´
´ ´
´
Universite Pierre et Marie Curie (Paris VI), Laboratoire de Chimie des Heterocycles (associe au C.N.R.S.), 4 Place Jussieu,
F-75252 Paris Cedex 05, France
Received 1 February 1999; accepted 14 October 1999
Abstract—Eleven optically active 1,2-aminoalcohols 20a–i and 26b–c were prepared from d-phenylglycine via cyclic imines 7b–i (or
enamine 7a). The key step of the strategy is the diastereoselective reduction of chiral oxazinones 7a–i. ᭧ 1999 Elsevier Science Ltd. All
rights reserved.
Introduction
used a microbial epoxidation while the latter used an
enantioselective chemical one.
Optically active 1,2-aminoalcohols play an important role in
asymmetric synthesis.1 They are frequently used as chiral
synthons,2 and as precursors of chiral auxiliaries.3 In addi-
tion, enantiomerically pure 1,2-aminoalcohols have proven
to be efficient chiral ligands in many asymmetric reactions
involving achiral reagents such as Lewis acids,4 organo-
metallic reagents5 or metallic hydrides.6
Apart from these, Lee et al.11 described another synthesis of
1,2-aminoalcohols by addition of organometallic reagents
on enantiopure aziridine-2-carboxaldehydes. These enantio-
pure aldehydes were obtained after separation of a
diastereoisomeric mixture of corresponding esters.
So we wish to report here a convenient procedure for the
synthesis of both enantiomers of 1,2-aminoalcohols from
d- or l-phenylglycine via morpholinones in which the
heteroatoms were the precursors of amine and alcohol func-
tions. The retrosynthetic analysis outlined in Scheme 1
suggests two routes to morpholin-2-ones. The difference
between these two routes is the step of introduction of the
different R groups.
The most direct synthesis of optically active 1,2-amino-
alcohols is the reduction of natural a-aminoacids or deriva-
tives,7 but this method is limited by the nature of lateral
chains and optical antipode. Other racemic methods coupled
with enzymatic8a or chemical8b resolution have thus been
developed, providing a greater variety of 1,2-amino-
alcohols.
In route A, the introduction of R group takes place in an
alkylation step of a common b-enaminoester (divergent
strategy).
Few stereoselective preparations have been reported. The
synthesis of optically active 2-amino-1-phenylethanols
was carried out by Salvadori et al.9a from mandelic acid
and phenylethylamine. Akiba et al.9b described a more
general stereoselective synthesis of 1,2-aminoalcohols by
the diastereoselective addition of organometallic reagents
to an a-silyloximine derived from (S)-ethyl lactate. Another
approach was chosen by Umezawa et al.10a and by
Senanayake et al.10b to prepare optically active 1,2-amino-
alcohols via an oxazoline using asymmetric induction.
These two groups obtained optically active oxazoline by
enantioselective alkene epoxidation followed by opening
of the epoxide with an appropriate amine. The first group
In route B, the different R substituents must be present at the
early step of the synthesis and each chiral morpholinone
results from the condensation of phenylglycine with
different halomethylketones (linear strategy).
In each case, the use of either d- or l-phenylglycine as
starting material provides access to the corresponding (R)-
or (S)-enantiomer of the 1,2-aminoalcohols synthesised.
It is noteworthy that these two routes develop an ‘inverse’
approach to the one described by Dellaria et al.12a or by
Harwood et al.12b These authors used an aminoalcohol
(phenylglycinol) as chiral inductor to synthesise optically
Keywords: aminoalcohols; asymmetric induction; reduction; imines.
* Corresponding author. Tel.: ϩ33-01-44-27-3057; fax: ϩ33-01-44-27-
30-56; e-mail: lhommet@ccr.jussieu.fr
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00935-7

234
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
Scheme 1.
pure aminoacids via chiral oxazinone while our strategy
uses an aminoacid (phenylglycine) as chiral inductor to
synthesise optically pure aminoalcohols.
85% yield. This compound, after lactonisation and activa-
tion of the lactam function, was converted to the expected
b-enaminodiester 6. The monodecarboxylating transesteri-
fication step14 achieved by heating an ethanol solution of 6
at 230ЊC in an autoclave failed to give the desired enami-
noester 7a and the starting material was not recovered.
Results and Discussion
To prepare the desired compound 7a, we thus investigated
another approach in which the enamino ester 7a would
result from the cyclisation of the v-amino-b-ketoester 10a
(Scheme 3). The potassium salt of the N-protected (R)-
phenylglycine 8 was first condensed with methyl-4-chloro-
acetoacetate 9a following the method developed by Caplar
We first chose to explore the divergent strategy (Route A).
The initial steps of the synthesis leading to the intermediate
b-enamino ester 7a are outlined in Scheme 2. Treatment of
the sodium salt of (R)-phenylglycine 1 with the (chlorocar-
bonyl)methyl acetate 2 according to Schotten–Baumann’s
conditions13 gave, after saponification, the hydroxyacid 3 in
Scheme 2. a) (i) NaOH aq. 0.5 mol LϪ1 (1 equiv.); (ii) CH3CO2CH2COCl 2 in dioxane (1 equiv.), NaOH aq. 2 mol LϪ1 (1.1 equiv.), rt, 5 h; (iii) NaOH aq.
2 mol LϪ1 (1.1 equiv.), rt; (iv) HCl aq. 6 mol LϪ1 (2.1 equiv.). b) CH3SO3H (0.3 equiv.), CH3CN/PhH (6/1), molecular sieves 3 A, reflux 48 h. c) (i) Et3OBF4
˚
(2 equiv.), CH2Cl2, reflux 36 h; (ii) phosphate buffer, pH 7. d) Meldrum’s acid (1.1 equiv.), Ni(Acac)2 (3×10Ϫ3 equiv.), CHCl3, reflux 48 h. e) CH3OH,
autoclave, 230ЊC, 30 min.

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
235
Scheme 3. a) (i) NaOH aq. (1 equiv.); (ii) PhCH2OCOCl (1.1 equiv.) in dioxane, NaOH aq. (1.1 equiv.); (iii) HCl aq. (1.1 equiv.). b) KOH in CH3OH
(1 equiv.), rt, 30 min. c) 9a (XˆCl, RˆCH2CO2CH3) (1.1 equiv.), KI (0.1 equiv.), CH3CN or DMF, rt, 15 h. d) H2, 1 atm, 10% Pd/C, CH3CO2CH3, rt, 6 h. e) (i)
HBr (9 equiv.) in CH3CO2H, rt, 30 min; (ii) solid K2CO3.
et al.15 (DMF, rt) and led to the expected v-amino-b-ketoe-
ster 10a in moderate yield (38%). However, we found that
by very slow dropwise addition of the highly reactive chlor-
oketoester 9a to a solution of 8 containing potassium iodide
(cat.) the product yield was increased to 65%. It must be
emphasised that self condensation of compound 9a (bearing
both a nucleophilic site and an electrophilic site) competes
with the desired condensation thus limiting the yield of the
reaction.16
imino forms 12 and 13 (Scheme 4). An equilibration
between two regioisomeric imines has previously been
observed by Harwood and co-workers on neighbouring
structures.12b,18
To confirm this hypothesis, we thus prepared the corre-
sponding N-benzylated enamino ester 1419 for which such
an equilibrium would not occur. This compound was
obtained in good yield from N-benzylphenylglycine follow-
ing a similar route as previously described for the preparation
of enamino ester 7a. In this way we verified that purification
of N-benzylated enamino ester 14 by chromatography on
silica gel, that acid treatment, and that prolonged stirring
on silica, did not cause racemisation of compound 14.
The cyclisation of the N-protected aminoketodiester 10a
proved to proceed spontaneously after removal of its
N-protecting group. Indeed, under neutral catalytic hydro-
genolysis conditions, the N-benzyloxycarbonyl group of
compound 10a was cleaved, releasing an aminoketone inter-
mediate that cyclised to the expected enamino ester 7a in
83% yield.17
These experiments demonstrated that the equilibrium
enamine/imine (Scheme 4) was probably responsible for
the racemisation of the enamino ester 7a.
Furthermore, the yield of the cyclisation was improved to
96% by treatment of the aminoketodiester 10a with a solu-
tion of hydrobromic acid in acetic acid.15 The stable hydro-
bromide intermediate was then neutralised by addition of
solid potassium carbonate thus giving rise to the free amino-
ketone that cyclised spontaneously to enaminoester. This
enaminoester was sufficiently pure to be used in the next
step without purification.
Attempts to alkylate the b-enamino ester 7a did not afford
the expected compounds under the conditions investigated
(Scheme 5); either the starting material 7a was recovered
intact or it was transformed to the dihydro oxazole 15.20 The
C-alkylation of the previously prepared N-protected
enamino ester 14 also failed.
So we investigated the alkylation of the v-amino-b-keto-
ester 10a, the linear precursor of the enamino ester 7a.
Attempts to alkylate 10a provided a mixture of the desired
monoalkylated product, dialkylated and O-alkylated by-
products, together with the unreacted starting material.
The two methods of cyclisation led to the b-enamino ester
7a with an identical optical activity. However, an attempt to
purify this compound by chromatography on silica gel led to
a total loss of its optical activity. It was suspected that the
observed racemisation might result from the acid-catalysed
equilibrium between the enamino ester (Ϫ)-7a and the two
The best result was obtained when 10a was treated with
Scheme 4.

236
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
Scheme 5. a) CH3I, reflux, 24 h. b) (i) NaH (1.1 equiv.), PhCH3, reflux, 30 min; (ii) n-PrI (1.3 equiv.), PhCH3, reflux, 3–12 h.
Scheme 6. b: RˆꢀCH2†2CO2CH3; c: RˆꢀCH2†3CO2CH3; d: RˆCH3; e: RˆC2H5; f: Rˆi-C3H7; g: Rˆn-C4H9; h: Rˆi-C4H9; i: Rˆt-C4H9. For a) and b) see
Ref. 15.
iodomethane in the presence of potassium carbonate in ace-
tone at room temperature,21 the 2-methyl-3-oxo-4-[(R)-
(phenyl)(phenylmethoxycarbonylamino)acetoxy]butyric
acid methyl ester 16 was isolated in 18% yield after chro-
matography as an equimolar mixture of diastereoisomers.
ester 7a was chromatographed on silica gel, the imines
7b–i were not purified, and the crude products were suffi-
ciently pure to be used in the next step (purityˆ95% by
NMR and GC analysis).
We have studied various diastereocontrolled reduction
reactions leading to the morpholinones 17a–i and/or
18a–i (Scheme 7). The results are summarised in
Table 1. We first examined various catalytic hydrogenation
conditions. The best yields and the best diastereoselectiv-
ities were obtained when the reactions were carried out
using PtO2 as catalyst, in methanol, under atmospheric
pressure of hydrogen and at room temperature (Table 1,
method A).24
With regard to the problems encountered for the alkylation
of the enamino ester 7a and the v-amino-b-ketoester 10a,
we thus investigated the second envisaged approach to
enantiopure 1,2-aminoalcohols (Scheme 1, Route B). This
route (linear strategy) implies the preparation of a wide
range of a-halomethylketones 9, precursors to a variety of
chiral morpholinones 7b–i. The halomethylketones 9b–i,
prepared according to literature procedures,22,23 were
condensed with the potassium salt of (R)-N-(benzyloxy-
carbonyl)phenylglycine
8
in dimethylformamide as
Indeed, under these conditions, the yields ranged from 73 to
89%, except for enamino ester 7a and for iminoester 7c. The
reduction of enamino ester 7a (entry 1, method A) afforded
only a small amount (18%) of the expected morpholinone
17a. This reduction was limited by the undesirable opening
of the morpholinone ring.25
described by Caplar et al.15 This procedure provided the
desired aminoketoesters 10b–i in high yield (83–98%).
The cyclisation of aminoketoesters 10b–i took place under
conditions similar to those described for 10a (hydrobromic
acid in acetic acid), and led to chiral oxazinones 7b–i in
quantitative yields (Scheme 6). The cyclisation of 10b–i
thus provided imines 7b–i with an endocyclic carbon–nitro-
gen double bond while the cyclisation of 10a led to the
conjugate enamino ester 7a.
The reduction of the imino ester 7c (entry 3, method A) took
place but the intermediate morpholinones 17c and 18c spon-
taneously cyclised to the corresponding lactams while,
under the same conditions, imino ester 7b provided the
expected morpholinones 17b and 18b without further
cyclisation (entry 2, method A).
To prevent the racemisation observed when the enamino
Scheme 7.

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
237
Table 1. Reductions of compounds 7a–i.
Entry
Compound 7
R
Method Aa
Yield%d 17
Method Bb
Method Cc
Yield%d 17 d.e.%e
d.e.%e
Yield%d 17
d.e.%e
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
CH2CO2CH3
(CH2)2CO2CH3
(CH2)3CO2CH3
CH3
C2H5
iC3H7
nC4H9
iC4H9
tC4H9
18f
73
–
73
82
84
78
76
89
–
70
–
82
72
80
66
70
86
26
63
60
74
78
73
75
80
83
40
60
60
64
82
70
60
80
86
Trace
80
76
89
90
93
87
92
71
–
90
92
Ͼ98
92
96
92
92
84
g
a Method AˆH2, 1 atm, PtO2, CH3OH, 4–6 h.
b Method BˆNaBH(OAc)3 (1.6 equiv.), TMSCl (1.2 equiv.), 4 h.
c Method CˆBH3–THF (1.4 equiv.), CH3CN, 4 h.
d Yield referred to chromatographed product.
1
e Determined by H-NMR analysis of the crude products.
f Methanolysis and hydrogenolysis by-products were also obtained, see Ref. 25.
g The morpholinones 17i and 18i were obtained in mixture with corresponding bicyclic lactams.
The diastereoselectivity of the catalytic hydrogenation
varies from 66 to 86%, and the cis stereochemistry of the
major diastereoisomer 17 was established unambiguously
by a positive NOE experiment between hydrogens H-3
and H-5. No NOE effect was observed for the minor
diasteroisomer 18.
morpholinone 17a could be obtained in modest yield
(23.5% after chromatography) by catalytic hydrogenation
using 10% Pt/C as the catalyst.25 We also found that the
cis morpholinone 17a could be prepared in higher yield
from the previously prepared N-benzylmorpholinone 14 as
depicted in Scheme 8.
In order to improve the diastereoselectivity of the reaction,
we next envisaged chemical reduction of compounds 7
(methods B and C). With potassium borohydride, in aceto-
nitrile, reduction of imines 7b–i or enamine 7a did not
occur, and the starting material was either decomposed
(7a) or recovered unchanged (7b–i). The addition of
trimethylsilylchloride according to Giannis26 promoted
the reductions, but the diastereoselectivity was modest.
We found that with the more bulky metal borohydride,
sodium triacetoxyborohydride, the diastereoisomeric
excesses and the yields could be improved (method
B). Thus the cis morpholinones 17b–i were obtained
with yields and diastereoisomeric excesses comparable
to those obtained by catalytic hydrogenation (method A)
except for the cis morpholinone 17a which was formed in
better yield (26%) but with only a moderate diastereoiso-
meric excess (40%) (entry 1, method B).
Indeed, the reduction of N-protected enamino ester 14
with sodium triacetoxyborohydride occurred with a
good diastereoselectivity (d.e. 94%) and enabled us to
isolate the cis product 19 in 71% yield. A subsequent
deprotection by regioselective catalytic hydrogenolysis
of the intermediate 19 led to the expected cis morpho-
linone 17a in good diastereoisomeric excess (84%) and
in 64% yield.
In order to obtain the desired aminoalcohols 20 it was
necessary to cleave the morpholine ring of 17. For this,
two routes were envisaged: the intramolecular hydro-
genolysis of the N-benzyl bond followed by the hydrolysis
of the ester, or the initial lactone opening followed by the
hydrogenolysis of the N-benzyl bond.
Examining the first route, compounds 17d–i were treated
under classical hydrogenolysis conditions. Under atmos-
pheric pressure of hydrogen, over Pd/C or Pd(OH)2 as
catalyst, at room temperature or at reflux, under neutral or
acidic conditions, no hydrogenolysis occurred even after
prolonged reaction time (6 days). This result was predict-
able from the experiments using PtO2 to prepare these
morpholinones 17d–i (see Table 1, method A). When the
reaction was carried out in methanol for a long time, only
Finally, we found that the best results (except for the enam-
ino ester 7a which was recovered unreacted) were obtained
when the reduction was performed using the borane–tetra-
hydrofuran complex in acetonitrile (method C). Under these
conditions the imines 7b–i were reduced into morpho-
linones 17b–i with good diastereoselectivity (84–98%)
and good chemical yields (71–93%). Nevertheless the cis
Scheme 8. a) (i) NaBH4 (6 equiv.), CH3CO2H (60 equiv.), CH3CN, 10ЊC; (ii) chromatography on SiO2. b) H2, 1 atm, 10% Pd/C, (1 equiv. in weight),
CH3CO2CH3, rt, 1 day.

238
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
Scheme 9. a) H2, 150 atm, 10% Pd/C, CH3OH.
lactone methanolysis took place. Attempted hydrogenolysis
with ammonium formate over Pd/C also failed.
aminotriols 24a–c thus obtained in 69–74% yield were
submitted to catalytic hydrogenolysis conditions. At room
temperature, even under high hydrogen pressure, the
cleavage of the N-benzyl bond failed. However, hydrogen-
olysis of the N-benzyl bond succeeded under atmospheric
pressure of hydrogen, in methanol at 50ЊC. Under these
conditions the aminotriols 24a–c gave enantiopure (S)-
aminodiols 20a–c in 71–88% yield. Furthermore, this
second route also provided access to the cyclic amino-
alcohols prolinol 26b and pipecolinol 26c from bicyclic
lactams 23b and 23c following the sequence of reactions
outlined in Scheme 11.
Finally, when the morpholinones 17d–i were submitted to
high hydrogen pressure (150 atm) in methanol, over Pd/C,
the chiral inductor moiety was cleaved by simultaneous
N-benzyl bond hydrogenolysis and lactone methanolysis
(Scheme 9). The (S)-aminoalcohols 20d–i were directly
obtained with good yields (78–89%).
When we applied the same conditions to the functionalised
morpholinones 17a–c, these compounds proved to be resis-
tant to hydrogenolysis: the morpholinone 17a was only
methanolysed and gave a mixture of aminoalcohol diester
21 and butyrolactone 22, whereas the morpholinones 17b
and 17c were converted to the corresponding bicyclic
lactams 23b and 23c.27
The simultaneous reduction of lactone and lactam functions
were realised with the borohydride–tetrahydrofuran
complex and provided the cyclic aminodiols 25b–c (yield
88–90%) which were N-deprotected by hydrogenolysis at
room temperature in methanol to give (S)-prolinol 26b and
(S)-pipecolinol 26c.
Since the first protocol failed to transform the morpho-
linones 17a–c to the expected amino alcohol esters we
decided to examine the second route leading to aminodiols
20a–c.
Conclusion
Cleavage of the lactone ring, in morpholinones 17a–c, was
achieved by treatment with lithium aluminium hydride in
tetrahydrofuran at room temperature (Scheme 10). The
The strategy described here, involving the use of phenyl-
glycine as the chiral inductor, gave access to both the (R)
and (S) optical antipodes of the targeted 1,2-aminoalcohols.
Scheme 10. a) LiAlH4, THF, rt, 5 h. b) H2, 1 atm, 10% Pd/C, CH3OH, 50ЊC, 4 h.

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
239
Scheme 11. a) BH3–THF, rt, 3 h (88% of 25b and 90% of 25c). b) H2, 1 atm, 10% Pd/C, rt, 2 h (90%).
Moreover, the chiral induction step proceeds with high
diastereoselectivity, thus providing an efficient route to
1,2-aminoalcohols which are tools of great interest for
asymmetric synthesis. Application of this methodology
enabled us to prepare a variety of enantiomerically pure
1,2-aminoalcohols (linear and cyclic) and aminodiols.
then removed under reduced pressure. The resulting solid
was dissolved in 300 mL of dichloromethane. The solution
was washed with a phosphate buffer (pH 7; NaH2PO4/
Na2HPO4 1/2.7) (2×50 mL). The organic layer was dried
over anhydrous sodium sulphate then concentrated under
reduced pressure to give a solid that was recrystallised in
cyclohexane/ethylacetate (1/1) to obtain 5.49 g of (3R)-(Ϫ)-
phenylmorpholine-2,5-dione 4 (28.7 mmol) as a white solid.
Mp 167–169ЊC. Yield 77%. [a]2D0 Ϫ83.0 (c 1.00; CH3OH).
IR (Nujol) n cmϪ1 3320 (NH); 1720 (CyOlactone); 1675
Experimental
1
(CyOlactame). H NMR (DMSO-d6) d 4.89 (s, 2H, H-6);
The melting points were measured with a Bu¨chi 535 appa-
ratus. Infrared spectra were recorded on a Philips PU 9706
5.47 (s, 1H, H-3); 7.40–7.55 (m, 5H, Har); 9.10 (s, 1H,
NH). 13C NMR (DMSO-d6) d 56.9 (C-3); 67.7 (C-6);
127.4, 128.7, 128.9 and 136.3 (Car); 165.4 and 166.7
(2×CO). Anal. Calcd for C10H9NO3: C, 62.82; H, 4.75; N,
7.33. Found C, 62.84; H, 4.76; N, 7.35.
1
instrument. H- and 13C NMR spectra were recorded on a
Bruker ARX 250 instrument, chemical shifts are expressed
1
in ppm (d) from TMS for H spectra and from CDCl3
(77.7 ppm) for 13C spectra. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter (589 nm).
(Ϫ)-(3R)-5-Ethoxy-3-phenyl-3,6-dihydro-1,4-oxazin-2-
one (5). A freshly prepared solution of trimethyloxonium
fluoroborate29 in dichloromethane (51.0 mmol; 1.9 equiv.)
was added dropwise to a suspension of 5 g (26.2 mmol) of
dione 4 in 90 mL of anhydrous dichloromethane. The
mixture was stirred and refluxed until complete consump-
tion of starting dione (monitored by TLC, about 1.5 days).
The resulting iminium salt was rapidly filtered on Bu¨chner
under a nitrogen flow and dissolved in 100 mL of dichloro-
methane. The organic solution was washed with a phosphate
buffer (pH 7; NaH2PO4/Na2HPO4 1/2.7) (2×50 mL), dried
over anhydrous sodium sulphate and concentrated under
reduced pressure to give a solid that was purified by chro-
matography on silica gel (chloroform) to obtain 4.25 g of 5
as a white solid (19.4 mmol). Mp 80–81ЊC. Yield 74%.
[a]D20 Ϫ89.0 (c 7.55; CHCl3). IR (CHBr3) n cmϪ1 1745
(Ϫ)-(R)-[((2-Hydroxy)acetyl)amino][phenyl] acetic acid
(3). To a cooled and vigorously stirred solution of
50.0 mmol of (R)-phenylglycine (7.55 g) in 100 mL of
aqueous sodium hydroxide 0.5 mol LϪ1 (50.0 mmol;
1.0 equiv.), 6.82 g of (chlorocarbonyl)methyl acetate 2
(500 mmol; 1.0 equiv.) in 25 mL of dioxane and 27.5 mL
of 2 mol LϪ1 aqueous sodium hydroxide (55.0 mmol;
1.1 equiv.) were simultaneously added dropwise. After
completion of the additions, the resulting mixture was
vigorously stirred at room temperature for 2 h. The resulting
mixture was acidified with 17.5 mL of 6 mol LϪ1 aqueous
solution of HCl (105 mmol; 2.1 equiv.) and then extracted
with ethylacetate (4×50 mL). The organic extracts were
combined, dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The solid residue
1
(CyO); 1675 (CyN). H NMR (CDCl3) d 1.37 (t, 3H,
was recrystallised in water to give 8.88 g of
3
(42.5 mmol). Mp 180–182ЊC. Yield 85%. [a]2D0 Ϫ220.0 (c
0.25; C2H5OH). IR (CHBr3) n cmϪ1 3340 (NH); 3200–2500
(OH); 1720 (CyOacid); 1610 (CyOamide and CyCar). 1H
NMR (DMSO-d6) d 3.90 (s, 2H, CH2); 5.40 (d, 1H,
Jˆ7.5, CH); 5.50–5.75 (br s, 2H, OH); 7.40 (s, 5H, Har);
8.10 (d, 1H, Jˆ7.5, NH). 13C NMR (DMSO-d6) d 55.5
(CH); 61.2 (CH2); 127.4 and 137.5 (Car); 171.3 and 171.7
(2×CO). Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N,
6.70. Found C, 57.94; H, 5.42; N, 6.80.
Jˆ7.1, CH3); 4.33 (q, 2H, Jˆ7.1, CH2CH3); 4.82 (s, 2H,
CH2); 5.44 (s, 1H, CH); 7.32–7 40 (m, 5H, Har). 13C
NMR (CDCl3) 14.6 (CH3); 61.1 (CH); 63.3 and 65.7
(2×CH2); 127.4, 128.6, 129.2 and 136.6 (Car); 161.1 and
168.6 (CO and CN). Anal. Calcd for C12H13NO3: C,
65.74; H, 5.98; N, 6.39. Found C, 65.78; H, 6.01; N, 6.32.
(Ϫ)-2,2-Dimethyl-5-[(6-oxo-5-(R)-phenyl)morpholin-3-
yliden]-1,3-dioxan-4,6-dione (6). To a stirred solution of
2.45 g of lactim ether 5 (11.2 mmol) in 15 mL of chloro-
form, 1.80 g of 2,2-dimethyl-1,3-dioxane-4,6-dione
(Meldrum’s acid; 12.5 mmol; 1.1 equiv.) and 9 mg of nickel
acetylacetonate (0.035 mmol; 0.003 equiv.) were added.
The reaction mixture was stirred and refluxed until complete
consumption of starting lactim ether (monitored by TLC,
about 2 days). The resulting reddish mixture was concen-
trated under reduced pressure to give a red solid that was
triturated with ether and filtered on Bu¨chner to give a pink
(Ϫ)-(3R)-Phenylmorpholine-2,5-dione (4). To a solution
of 7.80 g of (R)-[((2-hydroxy)acetyl)amino][phenyl] acetic
acid 3 (37.3 mmol) in 375 mL of anhydrous acetonitrile and
65 mL of anhydrous benzene, 1.10 g of methanesulfonic
acid (11.4 mmol; 0.3 equiv.) were added. The mixture was
stirred and refluxed in a Soxhlet apparatus (cartridge filled
28
˚
with 3 A molecular sieves) until completion of the reac-
tion (monitored by TLC, about 2 days). The solvent was

240
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
flaky solid. This solid was recrystallised in n-hexane/tetra-
hydrofuran (1/4) to obtain 1.29 g (4.08 mmol) of 6. Mp
192–193ЊC. Yield 37%. [a]2D0 Ϫ1.5 (c 3.00; CHCl3). IR
(Nujol) n cmϪ1 3100 (NH); 1735, 1700 and 1650 (CyO);
1590 (CyC). 1H NMR (CDCl3) d 1.75 (s, 6H, 2×CH3); 5.46
(s, 1H, CH); 5.57 (d, 1H, Jˆ18.2, CH2); 5.97 (d, 1H,
Jˆ18.2, CH2); 7.33–7.47 (m, 5H, Har); 11.58 (br s, 1H,
NH). 13C NMR (CDCl3) d 27.2 and 27.7 (2×CH3); 58.0
(CH); 67.3 (CH2); 105.0 (O–C–O); 130.4, 130.5 and
132.6 (Car); 162.7, 165.4, 166.6 and 167.2 (CO and CyC).
Anal. Calcd for C16H15NO6: C, 60.56; H, 4.77; N, 4.41.
Found C, 60.65; H, 4.77; N, 4.25.
1-Bromo-3,3-dimethylbutan-2-one (9i). Bp 81ЊC
(23 mmHg). Lit. 72ЊC (15 mmHg).32 Yield 83%. IR (neat)
n cmϪ1 1720. 1H NMR (CDCl3) d 1.24 (s, 9H, 3×CH3); 4.23
(s, 2H, H-1). 13C NMR (CDCl3) d 26.5 (3×CH3); 31.9 (C-1);
44.0 (C-3); 205.6 (C-2).
Aminoketo esters (10)
(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
esters (10)
(Ϫ)-3-Oxo-4-[(R)-(phenyl)(phenylmethoxycarbonylami-
no)acetoxy]butanoic acid methyl ester (10a). This product
was obtained according to a modified procedure of Caplar et
Haloketones (9)
al.15
A solution of methyl 4-chloroacetoacetate 9a
1-Halo-2-alkanones (9a–i): 1-Chloromethylketones 9a and
9d were purchased from Aldrich and distilled before use;
9b, 9c, 9e, 9g, and 9h were prepared according to the litera-
ture procedures22 from methyl 2-chloro-3-oxoalkanoates.
1-Bromomethylketones 9f and 9i were prepared according
to the literature procedure.23
(0.10 mmol; 1.0 equiv.) in 65 mL of dimethylformamide
or acetonitrile was added dropwise very slowly (about
12 h) to a solution of the potassium salt of N-protected
amino acid 8 in 65 mL of dimethylformamide (or 130 mL
of acetonitrile) containing 1.66 g of potassium iodide
(0.01 mol; 0.1 equiv.). The reaction mixture was stirred
for 5 h at room temperature then concentrated under
reduced pressure. The crude brownish residue was dissolved
in 125 mL of dichloromethane, washed with water until
neutrality, dried over anhydrous sodium sulphate then
concentrated under reduced pressure. The residue obtained
was filtered on silica gel (cyclohexane/ethylacetate: 8/2)
leading to compound 10a as an oil that crystallised. Mp
55–56ЊC. Yield 65%. [a]2D0 Ϫ73.5 (c 3.26, CHCl3). IR
(CHBr3) n cmϪ1 3400 (N–H); 1750, 1720 (CyO). 1H
NMR (CDCl3) d 3.40 (s, Ͻ2H, COCH2CO); 3.70, 3.73
(enol) (2s, 3H, CH3); 4.81 (s, 2H, OCH2CO); 5.12 (d, 2H,
Jˆ12.1, OCH2Ph); 5.49 (d, 1H, Jˆ7.1, CHN); 5.76 (d, 1H,
Jˆ7.1 NH); 7.31–7.43 (m, 10H, Har); 12.0 (s, Ͻ1H, OHenol).
13C NMR (CDCl3) d 46.1 (COCH2CO); 52.1 (CH3enol);
53.2 (CH3); 58.6 (CHN); 63.4 (OCH2COenol); 67.8
(OCH2Ph); 69.2 (OCH2CO); 89.6 (CyCHenol); 128.0,
128.8, 129.1, 129.5, 129.7, 136.3, 136.6 (Car); 156.0
(NCOO); 167.2, 170.7 (COO); 196.6 (CO); Anal.
Calcd for C21H21NO7: C, 63.15; H, 5.30; N, 3.51.
Found C, 63.12; H, 5.27; N, 3.51.
5-Chloro-4-oxopentanoic acid methyl ester (9b). Bp 81ЊC
(0.01 mmHg). Lit. 100ЊC (0.2 mmHg).30 Yield 76%. IR
1
(neat) n cmϪ1 1735, 1720. H NMR (CDCl3) d 2.65 (t,
2H, H-2); 2.90 (t, 2H, H-2); 3.65 (s, 3H, OCH3); 4.10 (s,
2H, H-5). 13C NMR (CDCl3) d 27.7 (C-2); 34.3 (C-3); 48.1
(C-5); 51.8 (OCH3); 172.7 (C-1); 201.1 (C-4).
6-Chloro-5-oxohexanoic acid methyl ester (9c). Bp 81ЊC
(0.01 mmHg). Yield 80%. IR (neat) n cmϪ1 1740, 1725. 1H
NMR (CDCl3) d 1.95 (m, 2H, H-3); 2.4 (t, 2H, H-2); 2.70 (t,
2H, H-4); 3.70 (s, 3H, OCH3); 4.10 (s, 2H, H-6). 13C NMR
(CDCl3) d 18.7 (C-3); 32.7, 38.5 (C-2, C-4); 48.1 (C-6);
51.6 (OCH3); 172.4 (C-1); 202.8 (C-5). Anal. Calcd for
C7H11ClO3: C, 47.06; H, 6.16. Found: C, 47.11; H, 6.12.
1-Chlorobutan-2-one (9e). Bp 78ЊC (80 mmHg). Yield
1
86%. IR (neat) n cmϪ1 1730. H NMR (CDCl3) d 1.10 (t,
3H, H-4); 2.60 (q, 2H, H-3); 4.10 (s, 2H, H-1). 13C NMR
(CDCl3) d 7.5 (C-4); 33.0 (C-3); 47.9 (C-1); 203.0 (C-2).
1-Bromo-3-methylbutan-2-one (9f). Bp 60–62ЊC
(13 mmHg). Lit. 83–86ЊC (54 mmHg).23 Yield 85%. IR
The addition of halomethylketones 9b–i to the potassium
salt of (R)-(phenyl)(phenylmethoxycarbonylamino)acetic
acid 8 was performed according to the procedure previously
described by Caplar et al.15
1
(neat) n cmϪ1 1720. H NMR (CDCl3) d 1.16 (d, 6H,
2×CH3); 3.00 (m, 1H, H-3); 4.00 (s, 2H, H-1). 13C NMR
(CDCl3) d 16.5 (2×CH3); 33.1 (C-1); 38.3 (C-3); 205.3
(C-2).
(Ϫ)-4-Oxo-5-[(R)-(phenyl)(phenylmethoxycarbonyl-
amino)acetoxy]pentanoic acid methyl ester (10b). The
product could be obtained pure by recrystallisation (ethyl-
acetate/n-hexane: 1/1). Mp 74–76ЊC. Yield 94%. [a]D20
Ϫ80.0 (c 2.45, CHCl3). IR (CHBr3) n cmϪ1 3410 (N–H);
1740, 1715 (CyO). 1H NMR (CDCl3) d 2.60–2.65 (2s, 4H,
2×CH2CO); 3.65 (s, 3H, OCH3); 4.70 (s, 2H, OCH2CO);
5.10 (s, 2H, OCH2Ph); 5.50 (d, 1H, CHN); 6.60 (d, 1H,
NH); 7.20–7.60 (m, 10H, Har). 13C NMR (CDCl3) d 26.8,
32.8 (2×CH2CO); 51.5 (OCH3); 57.8 (CHN) 66.6
(OCH2Ph); 68.4 (OCH2CO); 127.0, 127.8, 128.0, 128.3,
135.7 and 135.9 (Car); 155.3 (NCOO); 169.9 (COOC);
172.3 (COOCH3); 201.6 (CO). Anal. Calcd for
C22H23NO7: C, 63.92; H, 5.57; N, 3.39. Found C, 63.92;
H, 5.51; N, 3.37.
1-Chlorohexan-2-one (9g). Bp 73ЊC (16 mmHg). Lit. 73ЊC
(20 mmHg).31 Yield 94%. IR (neat). n cmϪ1 1730. 1H NMR
(CDCl3) d 0.80 (t, 3H, CH3); 1.10–2.15 (m, 4H, H-4 and H-
5); 2.60 (t, 2H, H-3); 4.20 (s, 2H, H-1). 13C NMR (CDCl3) d
13.7 (C-6); 22.2, 25.7 (C-4 and C-5); 48.1 (C-3); 52.4 (C-1);
202.7 (C-2).
1-Chloro-4-methylpentan-2-one (9h). Bp 79–80ЊC
(35 mmHg). Lit. 55–59ЊC (11 mmHg).22 Yield 95%. IR
1
(neat) n cmϪ1 1730. H NMR (CDCl3) d 0.90 (d, 6H,
2×CH3); 2.20 (m, 1H, H-4); 2.50 (d, 2H, H-3); 4.10 (s,
2H, H-1). 13C NMR (CDCl3) d 22.5 (2×CH3); 24.6 (C-4);
48.5, 48.7 (C-1 and C-3); 202.2 (C-2).

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
241
(Ϫ)-5-Oxo-6-[(R)-(phenyl)(phenylmethoxycarbonyl-
amino)acetoxy]hexanoic acid methyl ester (10c). The
product could be obtained pure by recrystallisation (ethyl-
acetate/n-hexane: 1/1). Mp 82–83ЊC. Yield 98%. [a]D20
Ϫ70.0 (c 1.35, CHCl3). IR (CHBr3) n cmϪ1 3400 (N–H)
1750, 1720 (CyO). 1H NMR (CDCl3) d 1.85 (m, 2H,
CH2CH2COOCH3); 2.30 (m, 4H, CH2COOCH3 and
CH2CH2CO); 3.65 (s, 3H, OCH3); 4.60 (s, 2H, OCH2CO);
5.10 (s, 2H, OCH2Ph); 5.50 (d, 1H, CHN); 5.80 (d, 1H, NH);
7.20–7.40 (m, 10H, Har). 13C NMR (CDCl3) d 18.2
(CH2CH2COOCH3); 32.7, 37.5 (CH2COOCH3, CH2CO);
51.6 (OCH3); 58.0 (CHN); 67.3 (OCH2Ph); 68.8
(OCH2CO); 127.5, 128.2, 128.6, 128.9, 129.1, 134.9 and
136.1 (Car); 155.3 (NCOO); 170.3 (COOC); 173.3
(COOCH3); 202.7 (CO). Anal. Calcd for C23H25NO7: C,
64.64; H, 5.85; N, 3.28. Found C, 64.65; H, 5.95; N, 3.16.
2/1). mp 85–86ЊC. Yield 88%. [a]2D0 Ϫ82.6 (c 3.00,
CHCl3). IR (CHBr3) n cmϪ1 3420, 3320 (N–H); 1750,
1715 (CyO). 1H NMR (CDCl3) d 0.85 (t, 3H, CH3);
1.25–1.50 (m, 4H, 2×CH2); 2.25 (t, 2H, CH2CO); 4.60 (s,
2H, OCH2CO); 5.10 (s, 2H, OCH2Ph); 5.50 (d, 1H, CHN);
5.80 (d, 1H, NH); 7.35 (m, 10H, Har). 13C NMR (CDCl3) d
13.8 (CH3); 22.2, 25.2 (2×CH2); 38.5 (CH2CO); 58.1
(CHN); 67.2 (OCH2CO); 127.5, 128.3, 128.6, 128.9, 129.1
and 136.1 (Car); 155.3 (NCOO); 170.3 (COO); 203.5 (CO).
Anal. Calcd for C22H25NO5: C, 68.93; H, 6.53; N, 3.65.
Found C, 68.94; H, 6.50; N, 3.62.
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
acid 4-methyl-2-oxo-pentyl ester (10h). The product could
be obtained pure by recrystallisation (diethylether/n-
pentane: 1/1). Mp 67–69ЊC. Yield 83%. [a]2D0 Ϫ67.9 (c
3.00, CHCl3). IR (CHBr3) n cmϪ1 3420, 3330 (N–H)
1745, 1720 (CyO). 1H NMR (CDCl3) d 0.85 (d, 6H,
2×CH3); 1.95-2.20 (m, 3H, CH(CH3)2 and CH2CO); 4.60
(s, 2H, OCH2CO); 5.10 (s, 2H, OCH2Ph); 5.50 (d, 1H,
CHN); 5.80 (d, 1H, NH); 7.35 (m, 10H, Har). 13C NMR
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
acid 2-oxo-propyl ester (10d). The product could be
obtained pure by recrystallisation (ethylacetate/n-hexane:
1/2). Mp 99ЊC. Yield 98%. [a]2D0 Ϫ90.6 (c 3.00, CHCl3).
IR (CHBr3) n cmϪ1 3420, 3320 (N–H); 1745, 1715 (CyO).
1H NMR (CDCl3) d 2.05 (s, 3H, CH3); 4.65 (s, 2H,
OCH2CO); 5.10 (s, 2H, OCH2Ph); 5.50 (d, 1H, CHN);
5.80 (d, 1H, NH); 7.35 (m, 10H, Har). 13C NMR (CDCl3)
(CDCl3)
d
22.5 (2×CH3); 24.3 (CH(CH3)2); 47.8
(CH2CO); 58.0 (CHN); 67.3 (OCH2Ph); 69.3 (OCH2CO);
127.5, 128.3, 128.6, 128.9, 129.1 and 136.1 (Car); 155.3
(NCOO); 170.3 (COO); 202.5 (CO). Anal. Calcd for
C22H25NO5: C, 68.93; H, 6.53; N, 3.65. Found C, 68.89;
H, 6.55; N, 3.62.
d
26.0 (CH3); 58.3 (CHN); 67.4 (OCH2Ph); 69.3
(OCH2CO); 127.5, 128.2, 128.3, 128.6, 129.0, 129.1 and
136.3 (Car); 155.0 (NCOO); 170.3 (COO); 200.9 (CO).
Anal. Calcd for C19H19NO5: C, 66.86; H, 5.57; N, 4.10.
Found C, 66.90; H, 5.53; N, 4.05.
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
acid 3,3-dimethyl-2-oxo-butyl ester (10i). The product
could be obtained pure by recrystallisation (ethylacetate/n-
hexane; 1/60). Mp 70–71ЊC. Yield 90%. [a]2D0 Ϫ76.9 (c
1.30, CHCl3). IR (CHBr3) n cmϪ1 3420, (N–H); 1745,
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
acid 2-oxo-butyl ester (10e). The product could be obtained
pure by recrystallisation (ethylacetate/n-hexane: 2/1). Mp
94–96ЊC. Yield 98%. [a]2D0 Ϫ30.5 (c 2.47, CHCl3). IR
(CHBr3) n cmϪ1 3420, 3320 (N–H); 1745, 1715 (CyO).
1H NMR (CDCl3) d 1.00 (t, 3H, CH3); 2.27 (q, 2H,
CH2CO); 4.66 (s, 2H, OCH2CO); 5.10 (s, 2H, OCH2Ph);
5.50 (d, 1H, CHN); 5.65 (d, 1H, NH); 7.35 (m, 10H, Har).
13C NMR (CDCl3) d 7.0 (CH3); 32.0 (CH2CO); 58.0 (CHN);
67.2 (OCH2Ph); 68.6 (OCH2CO); 127.5, 128.2, 128.6,
128.7, 129.0 and 136.1 (Car); 155.4 (NCOO); 170.3
(COO); 203.9 (CO). Anal. Calcd for C20H21NO5: C, 67.60;
H, 5.91; N, 3.94. Found C, 67.66; H, 5.97; N, 3.97.
1
1715 (CyO). H NMR (CDCl3) d 1.10 (s, 9H, 3×CH3);
4.80 (s, 2H, OCH2CO); 5.05 (s, 2H, OCH2Ph); 5.50 (d,
1H, CHN); 6.00 (d, 1H, NH); 7.35 (m, 10H, Har). 13C
NMR (CDCl3) d 25.9 (3×CH3); 42.6 (C(CH3)3); 57.8
(CHN); 65.3 (OCH2Ph); 66.9 (OCH2CO); 127.4, 128.0,
128.3, 128.4, 128.7, 136.0 and 136.2 (Car); 155.3
(NCOO); 170.3 (COO); 206.5 (CO). Anal. Calcd for
C22H25NO5: C, 68.93; H, 6.53; N, 3.65. Found C, 68.66;
H, 6.62; N, 3.68.
Oxazinones (7) and (14)
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarbonylamino)acetic
acid 3-methyl-2-oxo-butyl ester (10f). The product could
be obtained pure by recrystallisation (ethylacetate/n-
hexane: 1/20). Mp 67–68ЊC. Yield 92%. [a]2D0 Ϫ81.2 (c
3.00, CHCl3). IR (CHBr3) n cmϪ1 3400 (N–H); 1745,
General procedure for the preparation of imines or
enamine (7). Compounds 7 were prepared from halo-
methylketones 9 following a similar procedure to that
used by Caplar et al.15 In our methodology, hydrobromides
were not isolated and were neutralised by addition of solid
potassium carbonate. The purity of oxazinones 7 is superior
to 95% based on NMR and GC analyses.
1
1715 (CyO). H NMR (CDCl3) d 1.05 (d, 6H, 2×CH3);
2.50 (m, 1H, CH(CH3)2); 4.50 (s, 2H, OCH2CO); 5.05 (s,
2H, OCH2Ph); 5.45 (d, 1H, CHN); 5.80 (d, 1H, NH); 7.35
(m, 10H, Har). 13C NMR (CDCl3) d 17.8 (2×CH3); 37.5
(CH(CH3)2); 58.3 (CHN); 67.3, 67.5 (OCH2CO and
OCH2Ph); 127.5, 128.2, 128.3, 128.6, 128.8, 129.1, 133.5
and 136.4 (Car); 155.2 (NCOO); 170.3 (COO); 206.2 (CO).
Anal. Calcd for C21H23NO5: C, 68.29; H, 6.23; N, 3.79.
Found C, 68.00; H, 6.27; N, 3.61.
(Ϫ)-(Z)-[(6-Oxo-5R-phenyl)morpholin-3-yliden]acetic
acid methyl ester (7a). Yield 96%. [a]2D0 Ϫ453.4 (c 1.01,
1
CHCl3). IR (Nujol) n cmϪ1 3320 (NH); 1765 (CyO). H
NMR (CDCl3) d 3.72 (s, 3H, CH3); 4.71 (dd, 2H, Jˆ14.8
and 21.1, H-2); 4.80 (s, 1H, CyCH); 5.32 (d, 1H, H-5); 7.43
(m, 5H, Har); 8.80 (br s, 1H, NH). 13C NMR (CDCl3) d 51.4
(CH3); 58.2 (C-5); 67.7 (C-2); 83.2 (CyCH); 126.8, 128.0,
129.6, 130.0 and 134.7 (Car); 152.7, 168.2, 170.9 (2×COO
and CyCH).
(Ϫ)-(R)-(Phenyl)(phenylmethoxycarboxylamino)acetic
acid 2-oxo-hexyl ester (10g). The product could be
obtained pure by recrystallisation (diethylether/n-pentane:

242
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
1
3-(6-Oxo-5R-phenyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-
propanoic acid methyl ester (7b). Yield 94%. IR (CHBr3)
n cmϪ1 1735, 1720 (CyO); 1675 (CyN). 1H NMR (CDCl3)
d 2.60–2.80 (m, 4H, CH2CO2CH3 and CH2CN); 3.65 (s, 3H,
OCH3); 4.90 (d, 2H, Jˆ1.7, H-2); 5.45 (s, 1H, H-5); 7.25–
7.40 (m, 5H, Har). 13C NMR (CDCl3) d 28.5, 29.2 (2×CH2);
51.3 (OCH3); 62.0 (C-5); 68.9 (C-2); 126.8, 127.7, 128.2
and 135.1 (Car); 166.6, 167.3 (2×COO); 172.5 (CN).
(CyO); 1670 (CyN). H NMR (CDCl3) d 1.20 (s, 9H,
3×CH3); 4.80 (s, 2H, H-6); 5.30 (s, 1H, H-3); 7.30 (m,
5H, Har). 13C NMR (CDCl3) d 26.1, 27.2 (3×CH3 and
C(CH3)3); 62.9 (C-3); 65.8 (C-6); 127.2, 128.0, 128.7 and
135.1 (Car); 168.7 (CN); 175.6 (COO).
Preparation of enamine (7a) by cyclisation with H2 over
Pd/C: To a solution of 27.5 mmol of 3-oxo-4-[(R)-
(phenyl)(phenylmethoxycarbonylamino) acetoxy]butanoic
acid methyl ester 10a in 170 mL of methyl acetate, 10%
Pd/C (0.6 equiv. in weight) was added. The mixture was
stirred under H2 (1 atm) until completion of the reaction
(monitored by TLC, 4–6 h), then filtered over Celite᭨,
concentrated under reduced pressure giving rise to
22.8 mmol of (Ϫ)-(Z)-[(6-oxo-5R-phenyl)morpholin-3-
yliden]acetic acid methyl ester 7a as a yellow oil that crys-
tallised.
4-(6-Oxo-5R-phenyl-5,6-dihydro-2H-[1,4]oxazin-3-
yl)butanoic acid methyl ester (7c). Yield 95%. IR (CHBr3)
n cmϪ1 1750, 1740 (CyO); 1675 (CyN). 1H NMR (CDCl3)
d 2.00 (m, 2H, CH2CH2COO); 2.40 (t, 2H, CH2CO2CH3);
2.50 (t, 2H, CH2CN); 3.70 (s, 3H, OCH3); 4.80 (d, 2H,
Jˆ1.5, H-2); 5.40 (s, 1H, H-5); 7.30 (m, 5H, Har). 13C
NMR (CDCl3)
d
20.4 (CH2CH2CH2); 32.9, 34.6
(CH2CO2CH3 and CH2CN); 51.6 (OCH3); 62.8 (C-5); 69.0
(C-2); 127.3, 128.1, 128.7 and 135.5 (Car); 166.1, 167.8
(2×COO); 173.4 (CN).
Preparation of N-benzylated enamine (14)
(Ϫ)-3-Oxo-4-[(R)-(phenyl)((phenylmethoxycarbonyl)-
(phenylmethyl)amino)acetoxy] butanoic acid methyl
ester. Using the same procedure as for 10a, the methyl 4-
chloroacetoacetate 9a was condensed with the potassium
salt of (Ϫ)-(R)-(phenyl)[(phenylmethoxycarbonyl)(phenyl-
methyl)amino]acetic acid to give a colourless oil after
chromatography. Yield 66%. [a]2D0 Ϫ17.9 (c 3.72, CHCl3).
5-Methyl-3R-phenyl-3,6-dihydro-[1,4]oxazin-2-one (7d).
Quantitative yield. IR (neat) n cmϪ1 1735 (CyO), 1670
1
(CyN). H NMR (CDCl3) d 2.20 (s, 3H, CH3); 4.80 (s,
2H, H-6); 5.30 (s, 1H, H-3); 7.30 (m, 5H, Har). 13C NMR
(CDCl3) d 22.6 (CH3); 62.9 (C-3); 69.7 (C-6) 127.4, 128.3,
128.9 and 135.6 (Car); 165.8, 167.5 (CN, COO).
1
IR (neat) n cmϪ1 1750–1690 (CyO). H NMR (CDCl3) d
5-Ethyl-3R-phenyl-3,6-dihydro-[1,4]oxazin-2-one (7e).
Quantitative yield. IR (neat) n cmϪ1 1735 (CyO); 1670
3.47 (s, Ͻ2H, COCH2CO); 3.71 and 3.75 (enol) (2s, 3H,
CH3); 4.23 (d, 1H, Jˆ16.0, PhCHHN); 4.40–4.95 (m, 3H,
OCH2COϩPhCHHN); 5.21 (s, 2H, OCH2Ph); 5.85 (br s,
1H, CHN); 6.91 (br s, 2H, Har); 7.14–7.30 (m, 13H, Har).
13C NMR (CDCl3) d 46.1 (COCH2CO); 49.6 (NCH2Ph);
52.0 (CH3enol); 53.0 (CH3); 63.9 (CHN); 68.4 (OCH2Ph);
69.0 (OCH2CO); 89.7 (CyCHenol); 127.3, 127.6, 128.6,
129.0, 129.1, 129.3 130.3, 133.9, 136.6 and 138.5 (Car);
157.5 (NCOO); 167.2 and 170.4 (2×COO); 197.0 (CO).
Anal. Calcd for C28H27NO7: C, 68.70; H, 5.56; N, 2.86.
Found C, 68.57; H, 5.71; N, 2.80.
1
(CyN). H NMR (CDCl3) d 1.30 (t, 3H, CH3); 2.40 (q,
2H, CH2CH3); 4.75 (s, 2H, H-6); 5.35 (s, 1H, H-3); 7.30
(m, 5H, Har). 13C NMR (CDCl3) d 19.5 (CH3); 28.7
(CH2CH3); 62.4 (C-3); 68.6 (C-6), 127.1, 127.8, 128.4 and
135.5 (Car); 167.9, 169.7 (CN, COO).
5-(Methylethyl)-3R-phenyl-3,6-dihydro-[1,4]oxazin-2-
one (7f). Quantitative yield. IR (neat) n cmϪ1 1740 (CyO);
1665 (CyN). 1H NMR (CDCl3) d 1.20 (d, 6H, 2×CH3); 2.70
(m, 1H, CH(CH3)2); 4.80 (s, 2H, H-6); 5,30 (s, 1H, H-3);
7.30 (m, 5H, Har). 13C NMR (CDCl3) d 19.4 and 19.5
(2×CH3); 35.1 (CH(CH3)2); 62.8 (C-3); 67.7 (C-6); 127.2,
128.2, 128.8 and 135.3 (Car); 168.4 (CN); 173.5 (COO).
(E)-[(6-Oxo-5R-phenyl-4-phenylmethyl)morpholin-3-
yliden]acetic acid methyl ester (14). The (Ϫ)-3-oxo-4-
[(R)-(phenyl)((phenylmethoxycarbonyl)(phenylmethyl)-
amino) acetoxy]butanoic acid methyl ester was cyclised to
enaminoester 14 using the same procedure as for 7a. Crude
yield 96%. IR (CHBr3) n cmϪ1 1750 (CyO); 1680 (CyC);
1600 (CyCar). 1H NMR (CDCl3) d 3.66 (s, 3H, CH3); 4.23
(d, 1H, Jˆ15.9, PhCHHN); 4.77 (d, 1H, Jˆ15.9, CHHO);
4.83 (d, 1H, Jˆ15.9, PhCHHN); 5.08 (s, 1H, CyCH); 5.22
(s, 1H, H-5); 6.53 (d, 1H, Jˆ15.9, CHHO); 7.15–7.50 (m,
10H, Har). 13C NMR (CDCl3) d 51.4 (CH3); 54.2 (PhCH2N);
64.2 (C-5); 65.0 (C-2); 86.6 (CyCH); 126.3, 127.6, 128.9,
129.7, 129.8, 130.2, 133.2 and 134.5 (Car); 153.4 (CyCH);
167.8 and 168.8 (2×COO).
5-Butyl-3R-phenyl-3,6-dihydro-[1,4]oxazin-2-one (7g).
Quantitative yield. IR (neat) n cmϪ1 1740 (CyO); 1660
1
(CyN). H NMR (CDCl3) d 1.00 (t, 3H, CH3); 1.10–1.80
(m, 4H, CH2CH3 and CH2CH2CH2); 2.40 (t, 2H, CH2CN);
4.80 (s, 2H, H-6); 5.40 (s, 1H, H-3); 7.30 (m, 5H, Har). 13
C
NMR (CDCl3) d 13.5 (CH3); 22.1 and 27.5 (CH2CH3 and
CH2CH2CH2); 35.6 (CH2CN); 62.6 (C-3); 68.7 (C-6); 127.2,
127.8, 128.4 and 135.5 (Car); 167.8, 169.1 (COO and CN).
5-(2-Methylpropyl)-3R-phenyl-3,6-dihydro-[1,4]oxazin-
2-one (7h). Quantitative yield. IR (neat) n cmϪ1 1740
1
(CyO), 1665 (CyN). H NMR (CDCl3) d 1.00 (d, 6H,
2×CH3); 2.10 (m, 1H, CH(CH3)2); 2.30 (d, 2H, CH2CH);
Morpholinones (17)
4.80 (s, 2H, H-6); 5.40 (s, 1H, H-3); 7.30 (m, 5H, Har). 13
C
NMR (CDCl3) d 22.5 (2×CH3); 26.0 (CH(CH3)2); 44.9
(CH2CH); 62.9 (C-3); 69.1 (H-6); 127.3, 128.0, 128.6 and
135.7 (Car); 167.9, 168.7 (COO and CN).
Method A: To a stirred solution of freshly prepared oxa-
zinone 7 (10 mmol) in methanol (30 mL), 0.4 mmol of
platinum oxide (hydrate) (0.04 equiv.) was added. The
suspension was stirred under H2 (1 atm.) at room tempera-
ture until completion of the reaction (monitored by TLC, 4–
6 h). The mixture was then filtered through Celite᭨ and the
5-(1,1-Dimethylethyl)-3R-phenyl-3,6-dihydro-[1,4]oxazin-
2-one (7i). Quantitative yield. IR (neat) n cmϪ1 1735

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
243
1
filtrate was concentrated under reduced pressure. The major
cis morpholinone 17 was isolated after chromatography on
silica gel (chloroform/acetone) as a yellow oil (for yields see
Table 1).
(neat) n cmϪ1 1735 (CyO). H NMR (CDCl3) d 1.10 (d,
3H, CH3); 1.90 (br s, 1H, NH); 3.40 (m, 1H, H-5); 4.10 (t,
1H, Jˆ10.5, H-6); 4.25 (dd, 1H, Jˆ3.7 and 10.5, H-6); 4.70
(s, 1H, H-3); 7.25–7.45 (m, 5H, Har). 13C NMR (CDCl3) d
16.6 (CH3); 48.0 (C-5); 64.0 (C-3); 75.4 (C-6); 128.3, 128.5
and 138.3 (Car); 168.6 (CO). Anal. Calcd for C11H13NO2: C,
69.11; H, 6.81; N, 7.30. Found C, 69.08; H, 6.84; N, 7.30.
Method B. To a stirred mixture of freshly prepared oxa-
zinone 7 (5 mmol) in acetonitrile (35 mL) and sodium
triacetoxyborohydride (8 mmol, 1.70 g, 1.6 equiv.), chloro-
trimethylsilane (6 mmol) was added. The suspension was
stirred at room temperature until completion of the reaction
(monitored by TLC, about 4 h). The mixture was then
filtered through Celite᭨ and the filtrate was concentrated.
The crude oily residue was diluted with 30 mL of dichloro-
methane, washed with a saturated aqueous solution of
sodium hydrogenocarbonate (2×30 mL) and then with
brine (30 mL). The organic layer was dried over anhydrous
sodium sulphate. The major cis diasteroisomer was isolated
after chromatography on silica gel (chloroform/acetone) as
a yellow oil (for yields see Table 1).
(Ϫ)-(3R,5S)-5-Ethyl-3-phenylmorpholin-2-one
(17e).
Yield 90% (method C). [a]2D01 Ϫ66.1 (c 3.75, CHCl3). IR
(neat) n cmϪ1 1735 (CyO). H NMR (CDCl3) d 0.95 (t,
3H, CH3); 1.50 (m, 2H, CH2CH3); 2.05 (br s, 1H, NH);
3.10 (m, 1H, H-5); 4.10 (t, 1H, Jˆ10.7, H-6); 4.20 (dd,
1H, Jˆ3.4 and 10.7, H-6); 4.70 (s, 1H, H-3); 7.25-7.50
(m, 5H, Har). 13C NMR (CDCl3) d 9.9 (CH3); 24.9
(CH2CH3); 53.7 (C-5); 63.7 (C-3); 74.1 (C-6); 128.4,
128.5, 128.7 and 136.4 (Car); 169.1 (CO). Anal. Calcd for
C12H15NO2: C, 70.24; H, 7.32; N, 6.83. Found C, 70.24; H,
7.29; N, 6.88.
Method C. To a stirred solution of freshly prepared oxa-
zinone 7 (10 mmol) in acetonitrile (40 mL), 14 mL of a
1 mol LϪ1 solution of borane–tetrahydrofuran complex
(BH3–THF) (14 mmol, 1.4 equiv.) were added. The solu-
tion was stirred at room temperature until completion of
the reaction (monitored by TLC, about 3 h). The reaction
was quenched with methanol (5 mL) and concentrated
under reduced pressure. The crude residue was diluted
with 50 mL of dichloromethane, washed with brine
(2×50 mL) then dried over anhydrous sodium sulphate.
The major cis diastereoisomer was isolated after chromato-
graphy on silica gel (chloroform/acetone) as a yellow oil
(for yields see Table 1).
(Ϫ)-(3R,5S)-5-Methylethyl-3-phenylmorpholin-2-one
(17f). Yield 93% (method C). [a]2D0 Ϫ38.4 (c 3.15, CHCl3).
IR (neat) n cmϪ1 1740 (CyO). 1H NMR (CDCl3) d 0.97 (d,
3H, Jˆ6.8 CH3); 1.00 (d, 3H, Jˆ6.8 CH3); 1.70 (m, 1H,
CH(CH3)2); 1.90 (br s, 1H, NH); 3.00 (m, 1H, H-5); 4.20
(t, 1H, Jˆ10.7, H-6); 4.40 (dd, 1H, Jˆ3.9 and 10.7, H-
6); 4.70 (s, 1H, H-3); 7.25–7.50 (m, 5H, Har). 13C NMR
(CDCl3) d 18.7, 18.9 (2×CH3); 30.2 (CH(CH3)2); 58.0
(C-5); 63.5 (C-3); 72.8 (C-6); 128.2, 128.3, 128.6
and 138.5 (Car); 169.3 (CO). Anal. Calcd for
C13H17NO2: C, 71.23; H, 6.85; N, 6.39. Found C, 71.26;
H, 6.84; N, 6.50.
(Ϫ)-(3R,5S)-5-Butyl-3-phenylmorpholin-2-one
(17g).
(Ϫ)-3-[(3S,5R)-6-Oxo-5-phenylmorpholin-3-yl]propanoic
acid methyl ester (17b). Yield 80% (method C). [a]2D0 Ϫ1.4
(c 3.20, CHCl3). IR (neat) n cmϪ1 3320 (NH); 1730 (CyO).
1H NMR (CDCl3) d 1.60–2.00 (m, 2H, CH2CH2CO2CH3);
1.90 (br s, 1H, NH); 2.45 (t, 2H, CH2CO2CH3); 3.35 (m, 1H,
H-3); 3.70 (s, 3H, OCH3); 4.15 (t, 1H, Jˆ10.7, H-2); 4.35
(dd, 1H, Jˆ3.6 and 10.7, H-2); 4.75 (s, 1H, H-5); 7.20–7.50
(m, 5H, Har). 13C NMR (CDCl3) d 26.5 (CH2CH2CO2CH3);
29.8 (CH2CO2CH3); 51.1, 51.5 (CH3 and C-3); 62.7 (C-5);
73.1 (C-2); 127.9, 128.3 and 138.1, (Car); 168.9 and 173.1
(2×COO). Anal. Calcd for C14H17NO4:C, 63.89; H, 6.46; N,
5.32. Found C, 64.05; H, 6.38; N, 5.45.
Yield 87% (method C). [a]2D01 Ϫ15.2 (c 3.00, CHCl3). IR
(neat) n cmϪ1 1735 (CyO). H NMR (CDCl3) d 0.90 (t,
3H, CH3); 1.10–1.55 (m, 6H, 3×CH2); 1.90 (br s, 1H,
NH); 3.30 (m, 1H, H-5); 4.20 (t, 1H, Jˆ10.7, H-6); 4.40
(dd, 1H, Jˆ3.5 and 10.7, H-6); 4.70 (s, 1H, H-3); 7.30–7.50
(m, 5H, Har). 13C NMR (CDCl3) d 13.9 (CH3); 22.7, 22.8,
31.4 (3×CH2); 52.6 (C-5); 64.0 (C-3); 74.5 (C-6); 128.4,
128.6, 129.5, 129.6, 130.6 and 138.4 (Car); 170.5 (CO).
Anal. Calcd for C14H19NO2: C, 72.10; H, 8.15; N, 6.01.
Found C, 72.18; H, 8.17; N, 6.12.
(Ϫ)-(3R,5S)-5-(2-Methylpropyl)-3-phenylmorpholin-2-
one (17h). Yield 92% (method C). [a]2D0 Ϫ1.2 (c 3.70,
1
(Ϫ)-4-[(3S,5R)-6-Oxo-5-phenylmorpholin-3-yl]butanoic
acid methyl ester (17c). Yield 76% (method C). [a]2D0 Ϫ1.8
(c 3.00, CHCl3). IR (neat) n cmϪ1 3330 (NH); 1740, 1725
CHCl3). IR (neat) n cmϪ1 1735 (CyO). H NMR (CDCl3)
d 0.94 (d, 3H, Jˆ4.0, CH3); 0.95 (d, 3H, Jˆ4.0, CH3); 1.30
(m, 2H, CH2CH(CH3)2); 1.70 (m, 1H, CH(CH3)2); 1.90 (br s,
1H, NH); 3.30 (m, 1H, H-5); 4.10 (t, 1H, Jˆ10.2, H-6); 4.30
(dd, 1H, Jˆ3.5 and 10.2, H-6); 4.70 (s, 1H, H-3); 7.30–7.50
(m, 5H, Har). 13C NMR (CDCl3) d 22.4, 23.1 (2×CH3); 24.5
(CH2CH(CH3)2); 40.5 (CH(CH3)2); 50.4 (C-5); 63.9 (C-3);
74.7 (C-6); 128.3, 128.6 and 138.4 (Car); 169.0 (CO). Anal.
Calcd for C14H19NO2: C, 72.10; H, 8.15; N, 6.01. Found C,
72.10; H, 8.15; N, 6.11.
(CyO). 1H NMR (CDCl3)
d
1.50–2.00 (m, 4H,
CH2CH2CH2CO2CH3); 2.00 (br s, 1H, NH); 2.40 (t, 2H,
CH2CO2CH3); 3.20–3.40 (m, 1H, H-3); 3.70 (s, 3H,
OCH3); 4.20 (t, 1H, Jˆ10.6, H-2); 4.40 (dd, 1H, Jˆ3.6
and 10.6, H-2); 4.75 (s, 1H, H-5); 7.20–7.50 (m, 5H, Har).
13C NMR (CDCl3) d 20.6 (CH2CH2CO2CH3); 30.6, 33.4
(CH2CH2CH2CO2CH3); 51.7 (C-3); 51.8 (OCH3); 63.6
(C-5); 74.0 (C-2); 128.2, 128.5 and 137.9 (Car); 169.2 and
173.5 (2×COO). Anal. Calcd for C15H19NO4: C, 64.28; H,
6.86; N, 5.05. Found C, 64.63; H, 6.70; N, 5.23.
(Ϫ)-(3R,5S)-5-(1,1-Dimethylethyl)-3-phenylmorpholin-
2-one (17i). Yield 89% (method A). [a]2D0 Ϫ5.7 (c 3.00,
1
CHCl3). IR (neat) n cmϪ1 1735 (CyO). H NMR (CDCl3)
(Ϫ)-(3R,5S)-5-Methyl-3-phenylmorpholin-2-one (17d).
Yield 89% (method C). [a]2D0 Ϫ9.5 (c 3.00, CHCl3). IR
d 1.00 (s, 9H, 3×CH3); 1.90 (br s, 1H, NH); 3.00 (m, 1H, H-
5); 4.30 (t, 1H, Jˆ10.2, H-6); 4.40 (dd, 1H, Jˆ3.5 and 10.2,

244
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
H-6); 4.70 (s, 1H, H-3); 7.25-7.50 (m, 5H, Har). 13C NMR
(CDCl3) d 26.4 (3×CH3); 32.7 (C(CH3)3); 61.1, 63.6 (C-3
and C-5); 71.2 (C-6); 128.3, 128.6 and 138.7 (Car); 169.4
(CO). Anal. Calcd for C14H19NO2: C, 72.10; H, 8.15; N,
6.01. Found C, 72.02 H, 8.21; N, 6.05.
(Ϫ)-2-[(3S,5R)-6-Oxo-5-phenylmorpholin-3-yl]acetic
acid methyl ester (17a). To a stirred solution of 0.14 g of 19
(0.413 mmol) in 4.5 mL of methylacetate was added 0.14 g
of 10% Pd/C (1 equiv. in weight). The mixture was stirred at
room temperature under H2 (1 atm) until completion of the
reaction (monitored by TLC, about 20 h). The mixture was
then filtered through Celite᭨ and the filtrate was concen-
trated under reduced pressure. The crude product was
chromatographed on silica gel (cyclohexane/ethylacetate
1/1) to lead to 0.065 g (0.26 mmol) of (Ϫ)-2-[(3S,5R)-6-
oxo-5-phenylmorpholin-3-yl]acetic acid methyl ester 17a.
Yield 64%.
Preparation of (17a) from (7a). (Ϫ)-2-[(3S,5R)-6-Oxo-5-
phenylmorpholin-3-yl]acetic acid methyl ester (17a). To
a stirred solution of 4.98 g of (Ϫ)-(Z)-[(6-oxo-5R-phenyl)-
morpholin-3-yliden]acetic acid methyl ester 7a (20.2 mmol)
in 60 mL of dry tetrahydrofuran was added 1.50 g of 10%
Pt/C (0.3 equiv. in weight). The mixture was stirred at room
temperature under H2 (1 atm) until completion of the reac-
tion (monitored by TLC, about 18 h). The mixture was then
filtered through Celite᭨ and the filtrate was concentrated
under reduced pressure. The crude product was chromato-
graphed on silica gel (cyclohexane/ethylacetate 8/2) to lead
to 0.91 g (3.65 mmol) of (Ϫ)-2-[(3S,5R)-6-oxo-5-phenyl-
morpholin-3-yl]acetic acid methyl ester 17a as a white
solid. Yield 18%. [a]2D0 Ϫ96.9 (c 1.50, CHCl3). IR (Nujol)
n cmϪ1 3330 (NH); 1720 (CyO). 1H NMR (CDCl3) d 2.48–
2.51 (m, 2H, CH2CO2CH3); 2,63 (br s, 1H, NH); 3.69–3.80
(m, 4H, CH3 and H-3); 4.21 (t, 1H, Jˆ10.6, H-2); 4.37 (dd,
1H, Jˆ3.7 and 10.6, H-2); 4.81 (s, 1H, H-5); 7.35–7.51 (m,
5H, Har). 13C NMR (CDCl3) d 36.4 (CH2CO2CH3); 49.3,
52.5 (CH3 and C-3); 63.4 (C-5); 73.0 (C-2); 127.8, 128.6,
128.8, 129.0 and 138.6 (Car); 169.3 and 171.7 (2×COO).
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62.
Found C, 62.61; H, 6.06; N, 5.54.
Aminoalcohols (20d–i)
General procedure for preparation of aminoalcohols
(20d–i) from morpholinones (17): To a stirred solution
of 4 mmol of morpholinone 17 in methanol (20 mL),
0.6 equiv. in weight of palladium (10% Pd/C) was added.
The mixture was stirred under 150 atm of H2 for 72 h. The
catalyst was then removed by filtration through Celite᭨. The
filtrate was concentrated under reduced pressure and the oily
residue was dissolved in chloroform (20 mL). The solution
was extracted with an aqueous solution of 3 mol LϪ1 hydro-
chloric acid (3×20 mL). Solid sodium carbonate was added
to the combined aqueous extracts until saturation and the
solution was then extracted with chloroform (5×20 mL).
The combined organic extracts were dried over anhydrous
sodium sulphate and concentrated. The oily residue thus
obtained was distilled under reduced pressure with a Kugel-
rohr apparatus.
Preparation of (17a) from (19). (Ϫ)-2-[(3S,5R)-6-Oxo-5-
phenyl-4-phenylmethylmorpholin-3-yl]acetic acid methyl
ester (19). 0.80 g of sodium borohydride (21.0 mmol) was
added portionwise to 12 mL of stirred and cooled glacial
acetic acid (210 mmol; 60 equiv.). The mixture was then
diluted with 3 mL of anhydrous acetonitrile. A solution of
1.18 g of (E)-[(6-oxo-5R-phenyl-4-phenylmethyl)morpho-
lin-3-yliden]acetic acid methyl ester 14 (3.50 mmol) in
acetonitrile (3 mL) was added to the previously prepared
reductive solution. The mixture was stirred at 10ЊC until
complete consumption of 14 (monitored by TLC, 4–6 h).
After addition of 30 mL of water and 20 mL of dichloro-
methane, the reaction mixture was neutralised with solid
sodium carbonate. The aqueous layer was extracted with
dichloromethane (3×30 mL). The combined organic
extracts were dried over anhydrous sodium sulphate and
then concentrated under reduced pressure giving rise to an
oil that crystallised. The major cis morpholine 19 (d.e. 94%)
was isolated as a white solid after chromatography on silica
gel (cyclohexane/ethylacetate: 9/1). Mp 94–96ЊC. Yield
71%. [a]2D0 Ϫ58.5 (c 3.05; CHCl3). IR (Nujol) n cmϪ1
(ϩ)-(2S)-Aminopropan-1-ol (20d). Yield 89%. [a]D20
ϩ18.2 (neat). Lit.33 [a]2D0 ϩ15.2 (neat).
(ϩ)-(2S)-Aminobutan-1-ol (20e). Yield 84%. [a]2D0 ϩ10.2
(neat). Lit.33 [a]2D0 ϩ9.8 (neat).
(ϩ)-(2S)-Amino-3-methylbutan-1-ol (20f). Yield 88%.
[a]2D0 ϩ17.1 (c 11.00, C2H5OH). Lit.34 [a]2D5 ϩ17.0 (c
11.53, C2H5OH).
(ϩ)-(2S)-Aminohexan-1-ol (20g). Yield 78%. [a]2D0 ϩ12.2
(c 1.00, CHCl3). Lit.8a [a]D22 ϩ12.3 (c 0.60, CHCl3).
(ϩ)-(2S)-Amino-4-methylpentan-1-ol (20h). Yield 86%.
[a]2D0 ϩ1.2 (neat). Lit.35 [a]2D0 ϩ1.2 (neat).
(ϩ)-(2S)-Amino-3,3-dimethylbutan-1-ol (20i). Yield
82%. [a]2D0 ϩ37.2 (c 3.00, C2H5OH). Lit.36 [a]2D2 ϩ35.3 (c
3.00, C2H5OH).
1
1770 and 1740 (CyO). H NMR (CDCl3) d 2.37 (dd, 1H,
Jˆ7.8 and 15.8, CHHCOO); 2.53 (dd, 1H, Jˆ5.7 and 15.8,
CHHCOO); 3.45–3.56 (m, 1H, H-3); 3.60 (s, 3H, CH3);
3.77 (d, 1H, Jˆ13.5, NCHHPh); 3.87 (d, 1H, Jˆ13.5,
NCHHPh); 3.91 (dd, 1H, Jˆ9.1 and 11.8, CHHO); 4.25
(dd, 1H, Jˆ4.6 and 11.8, CHHO); 4.49 (s, 1H, H-5);
7.19–7.36 (m, 10H, Har). 13C NMR (CDCl3) d 38.1
(CH2COOCH3); 52.3 (CH3); 55.7 (C-3); 60.9 (NCH2Ph);
65.0 (C-5); 68.1 (C-2); 127.4, 128.3, 128.6, 128.8, 129.1,
129.3, 129.7, 137.5 and 136.7 (Car); 171.0 and 171.6
(2×COO). Anal. Calcd for C20H21NO4:C, 70.78; H, 6.24;
N, 4.13. Found C, 70.88; H, 6.25; N, 4.25.
Cyclic aminoalcohols (26)
Lactamisation of oxazinones (17b) and (17c): Oxazinone
17b or 17c (2.5 mmol) was dissolved in toluene (20 mL).
The mixture was stirred at reflux for 10–20 h (reaction
monitored by TLC). Toluene was evaporated and the
residue obtained was chromatographed on silica gel (ethyl-
acetate/chloroform: 4/1).
(Ϫ)-(4R,8aS)-4-Phenyltetrahydropyrrolo-[2,1-c][1,4]-
oxazin-3,6-dione (23b). The oily product was crystallised

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
245
in ethylacetate/n-hexane (2/1). Mp 124ЊC. Yield 85%. [a]D20
Ϫ14.9 (c 0.70, CHCl3). IR (CHBr3) n cmϪ1 1730 (OCyO);
1680 (NCyO). 1H NMR (CDCl3) d 1.80–2.00 (m, 1H, H-8);
2.25–2.40 (m, 1H, H-8); 2.50–2.60 (m, 2H, H-7); 4.00–
4.15 (m, 1H, H-8a); 4.40 (d, 1H, Jˆ10.6, H-1); 4.50 (dd,
1H, Jˆ3.6 and 10.6, H-1); 5.6 (s, 1H, H-4); 7.30–7.45 (m,
5H, Har). 13C NMR (CDCl3) d 22.6 (C-8); 31.6 (C-7); 54.1
(C-8a); 59.8 (C-4); 70.9 (C-1); 126.6, 128.8, 129.1 and
134.4 (Car); 166.8 (COO); 173.1 (CON). Anal. Calcd for
C13H13NO3: C, 67.53; H, 5.63; N, 6.06. Found: C, 67.52;
H, 5.71; N, 6.02.
127.6, 128.2, 128.9 and 136.3 (Car). Anal. Calcd for
C14H21NO2: C, 71.49; H, 8.93; N, 5.96. Found: C, 71.86;
H, 8.75; N, 5.77.
General procedure for debenzylation of aminodiols
(25b) and (25c): To a stirred solution of aminodiol 25b or
25c (4.52 mmol) in methanol (25 mL), 1 equiv. in weight of
palladium (10% Pd/C) was added. The mixture was stirred
under 1 atm of H2 at room temperature for about 2 h (moni-
tored by TLC). The catalyst was removed by filtration
through Celite᭨ and the filtrate was concentrated. The oily
residue was dissolved in chloroform (20 mL) and then
extracted with a solution of hydrochloric acid, 3 mol LϪ1
(3×20 mL). The combined aqueous extracts were neutra-
lised by addition of solid sodium carbonate and then
extracted with chloroform (5×20 mL). The latter organic
extracts were combined, dried over anhydrous sodium
sulphate, concentrated and the residue was distilled with a
Kugelrohr apparatus.
(Ϫ)-(4R,9aS)-4-Phenyltetrahydropyrido-[2,1-c][1,4]-
oxazin-3,6-dione (23c). The oily product was crystallised in
ethylacetate/n-hexane (1/1). Mp 137–139ЊC. Yield 92%.
[a]2D0 Ϫ0.5 (c 2.80, CHCl3). IR (CHBr3) n cmϪ1 1740
1
(OCyO); 1640 (NCyO). H NMR (CDCl3) d 1.70 (m,
1H, H-8); 1.95 (m, 1H, H-8); 2.05 (m, 1H, H-9); 2.15 (m,
1H, H-9); 2.55–2.65 (m, 2H, H-7); 3.80–3.95 (m, 1H,
H-9a); 4.20 (d, 2H, Jˆ6.8, H-1); 6.10 (s, 1H, H-4); 7.25–
7.40 (m, 5H, Har). 13C NMR (CDCl3) d 19.8 and 24.7 (C-8
and C-9); 31.4 (C-7); 54.3 (C-9a); 58.7 (C-4); 68.9 (C-1);
125.8, 128.4, 129.1 and 134.9 (Car); 167.7, 169.4 (COO and
CON). Anal. Calcd for C14H15NO3: C, 68.57; H, 6.12; N,
5.71. Found: C, 68.54; H, 6.17; N, 5.66.
(ϩ)-(2S)-Hydroxymethylpyrrolidine (26b). Yield 90%.
[a]2D1 ϩ30.4 (c 1.00, PhCH3). Lit.37 [a]2D3 ϩ30.9 (c 1.10,
PhH).
(ϩ)-(2S)-Hydroxymethylpiperidine (26c). Yield 90%.
[a]2D1 ϩ15.9 (c 2.50, C2H5OH). Lit.38 [a]2D1 ϩ16.0 (c 2.34,
C2H5OH).
Cyclic aminodiols (25): To a stirred 1 mol LϪ1 solution of
borane–tetrahydrofuran complex (10 mmol, 2.5 equiv.) in
tetrahydrofuran (10 mL), a solution of lactolactam 23b or
23c (4 mmol) in 30 mL of tetrahydrofuran was added. The
mixture was stirred at room temperature for 3 h (monitored
by TLC) and then concentrated under reduced pressure. The
oily residue was dissolved in chloroform (30 mL), washed
with brine (30 mL), dried over anhydrous sodium sulphate
and then concentrated. The crude residue was purified by
chromatography on silica gel (ethylacetate then ethyl-
acetate/methanol: 1/1) to provide the corresponding cyclic
aminodiol as an oily product.
Aminodiols (20a–c)
Aminotriols (24): To a cooled (0ЊC) and stirred solution of
morpholinone 17a, 17b or 17c (4 mmol) in tetrahydrofuran
(50 mL), 20 mmol (760 mg) of lithium aluminium hydride
were added portionwise. The mixture was stirred at room
temperature until completion of the reaction (monitored by
TLC, about 2 h). After successive dropwise additions, via
syringe, of 0.76 mL of water, 0.76 mL of an aqueous solu-
tion of sodium hydroxide (15%) and again 2.28 mL of
water, the mixture was stirred until formation of a white
solid that was removed by filtration through Celite᭨. The
solid was washed several times with tetrahydrofuran. The
organic solution was concentrated under reduced pressure.
The oily residue was then purified by chromatography on
silica gel (chloroform then chloroform/methanol: 8/2).
(Ϫ)-(2R)-[(2S)-Hydroxymethyl)pyrrolidin-1-yl]-2-
phenylethanol (25b). Yield 88%. [a]2D0 Ϫ8.5 (c 4.00,
CHCl3). IR (neat) n cmϪ1 3350. 1H NMR (CDCl3) d
1.45–1.80 (m, 4H, 2×CH2pyr); 2.35 (m, 1H, CHHN); 2.75
(br s, 2H, 2×OH); 2.95 (m, 1H, CHHN); 3.05 (m, 1H,
NCHCH2O); 3.50 (dd, 1H, Jˆ4.5 and 11.5, CHHO);
3.70–3.90 (m, 2H, 2×CHHO); 4.00 (m, 2H, CHHO and
CHPh); 7.15–7.45 (m, 5H, Har). 13C NMR (CDCl3) d
23.4, 27.5 (2×CH2pyr); 47.4 (CH2N); 60.3 (NCHCH2OH);
62.7, 63.4 (2×CH2OH); 64.7 (PhCHN); 127.7, 128.2,
129.1 and 136.4 (Car). Anal. Calcd for C13H19NO2: C,
70.59; H, 8.60; N, 6.33. Found: C, 70.41; H, 8.52; N,
6.42.
(2S)-[(2-Hydroxy-(1R)-phenyl)ethylamino]butan-1,4-
1
diol (24a). Yield 38%. IR (neat) n cmϪ1 3500–3000. H
NMR (CDCl3) d 1.51–1.97 (m, 2H, H-3); 2.67–2.80 (m,
1H, H-2); 3.00–4.10 (m, 11H, 3×CH2O, CHPh, 3×OH and
NH); 7.27–7.37 (m, 5H, Har). 13C NMR (CDCl3) d 34.7
(C-3); 56.5 (C-2); 62.1 and 62.5 (2×CH2O); 62.2 (CHPh);
67.9 (CH2O); 128.1, 128.3, 128.6, 129.5, 130.1 and 140.1
(Car).
(Ϫ)-(2R)-[(2S)-Hydroxymethyl)piperidin-1-yl]-2-phenyl-
ethanol (25c). Yield 90%. [a]2D0 Ϫ13.6 (c 2.10, CHCl3). IR
(neat) n cmϪ1 3350. 1H NMR (CDCl3) d 1.10–1.70 (m, 6H,
3×CH2pip); 1.85 (t, 1H, CHHN); 2.50 (br s, 2H, 2×OH); 2.60
(m, 1H, NCHCH2OH); 2.90 (m, 1H, CHHN); 3.65 (m, 1H,
CHHO); 3.70 (m, 1H, CHHO); 4.05 (d, 1H, Jˆ10.2,
CHHO); 4.10 (dd, 1H, Jˆ3.6 and 10.2, CHHO); 4.40 (dd,
(2S)-[(2-Hydroxy-(1R)-phenyl)ethylamino]pentan-1,5-
1
diol (24b). Yield 69%. IR (neat) n cmϪ1 3500–3000. H
NMR (CDCl3) d 1.45–1.80 (m, 4H, H-3 and H-4); 2.50 (m,
1H, H-2); 3.30–3.80 (m, 6H, 3×CH2O); 4.00 (m, 1H,
CHPh); 4.35 (br s, 4H, 3×OH and NH); 7.10–7.40 (m,
5H, Har). 13C NMR (CDCl3) d 29.3, 29.9 (C-3, C-4); 55.6
(C-2); 61.2, 62.3 (2×CH2O); 61.8 (CHPh); 66.6 (CH2O);
127.7, 127.8, 128.6 and 139.5 (Car).
1H, Jˆ4.9 and 10.2, NCHPh); 7.15–7.50 (m, 5H, Har). 13
C
NMR (CDCl3) d 23.6, 25.6, 29.5 (3×CH2pip); 45.2 (CH2N);
58.7, 61.2 (2×CH2O); 60.4 (NCHCH2OH); 63.6 (PhCHN);

246
F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
(2S)-[(2-Hydroxy-(1R)-phenyl)ethylamino]hexan-1,6-
and 9.5, CHHO); 4.36 (dd, 1H, Jˆ5.8 and 9.5, CHHO); 4.40
(s, 1H, NCHPh); 7.35–7.38 (m, 5H, Har). 13C NMR (CDCl3)
d 36.4 (CH2CO); 52.7 (NCHCH2O); 53.2 (CH3); 63.8
(NCHPh); 73.6 (CH2O); 128.0, 129.2, 129.6 and 137.8
(Car); 173.4 and 176.3 (2×CO). Anal. Calcd for
C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found C, 62.30;
H, 6.10; N, 5.57.
1
diol (24c). Yield 74%. IR (neat) n cmϪ1 3500–3000. H
NMR (CDCl3) d 1.20–1.60 (m, 6H, H-3, H-4, H-5); 2.45
(br s, 4H, 3×OH and NH); 2.60 (m, 1H, H-2); 3.25–3.65 (m,
6H, 3×CH2O); 3.90 (m, 1H, CHPh); 7.25–7.45 (m, 5H, Har).
13C NMR (CDCl3) d 22.0, 29.9, 31.8 (C-3, C-4, C-5); 55.8
(C-2); 61.4, 61.6 (2×CH2O); 61.8 (CHPh); 66.9 (CH2O);
127.3, 127.5, 128.5 and 140.7 (Car).
[(2-Methyl-5-oxo-4-phenyl-2,5-dihydrooxazol-2-yl]acetic
acid methyl ester (15). To a stirred solution of (Z)-[(6-oxo-
5R-phenyl)morpholin-3-yliden]acetic acid methyl ester 7a
(6.09 mmol) in toluene (40 mL), 0.16 g (6.67 mmol,
1.1 equiv.) of sodium hydride was added portionwise. The
mixture was refluxed for 4 h. After cooling to room
temperature, water (50 mL) and dichloromethane
(100 mL) were added. The mixture was then neutralised
by addition of an aqueous solution of hydrochloric acid.
The aqueous layer was extracted with dichloromethane.
The combined organic extracts were dried over anhydrous
sodium sulphate and the oily residue was chromatographed
on silica gel (cyclohexane/ethylacetate: 3/1) to give 0.54 g
of 15 as a colourless oil. Yield 36%. IR (neat) n cmϪ1
General procedure for debenzylation of aminotriols (24):
A mixture of aminotriol 24a, 24b or 24c (4 mmol) and
catalyst (10% Pd/C, 0.6 equiv. in weight) in methanol
(20 mL) was stirred at 50–60ЊC under dihydrogen (1 atm)
until completion of the reaction (monitored by TLC, about
1 h) The catalyst was then removed by filtration through
Celite᭨. The filtrate was concentrated and the oily residue
was chromatographed on silica gel (methanol, then metha-
nol/aqueous ammonia solution: 100/3).
(2S)-Aminobutan-1,4-diol (20a). The product could be
obtained pure by distillation with a Kugelrohr apparatus.
Bp 180–200ЊC (1 mmHg). Yield 71%. [a]2D0 ϩ4.1 (c 1.85,
CH3CO2H).39 Lit.40a [a]D22 Ϫ2.1 (c 2, H2O),40b [a]2D2 ϩ6.6 (c
1.2, CH3CO2H).
1
1780 and 1740 (CyO); 1620 (CyN). H NMR (CDCl3)
d 1.77 (s, 3H, CH3); 3.00 (d, 1H, Jˆ16.3, CHHCO);
3.08 (d, 1H, Jˆ16.3, CHHCO); 3.64 (s, 3H, CH3O);
7.50–7.56 (m, 3H, Har); 8.36–8.40 (m, 2H, Har). 13C
NMR (CDCl3) d 26.1 (CH3); 41.6 (CH2CO); 52.4
(CH3O); 102.3 (C-2); 129.0, 129.2, 129.3 and 133.1
(Car); 157.8, 164.8 and 168.6 (2×CO and C-4). Anal.
Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found
C, 63.25; H, 5.32; N, 5.52.
(2S)-Aminopentan-1,5-diol (20b). The product could be
obtained pure by distillation with a Kugelrohr apparatus.
Bp 160ЊC (0.1 mmHg). Lit.41 125–135ЊC (0.05 mmHg).
Yield 71%. [a]2D1 Ϫ1.9 (c 1.97, CH3OH).39
(2S)-Aminohexan-1,6-diol (20c). The product could be
obtained pure by distillation with a Kugelrohr apparatus.
Bp 165ЊC (0.1 mmHg). Lit.42 135–145ЊC (0.1 mmHg).
Yield 88%. [a]2D0 ϩ14.7 (c 1.00, C2H5OH). IR (neat) n
cmϪ1 3300. 1H NMR (CDCl3) d 1.20–1.70 (m, 6H,
3×CH2); 2.85 (m, 1H, H-2); 3.40 (m, 1H, H-1); 3.55–3.65
(m, 3H, H-1, H-6). 13C NMR (CDCl3) d 23.4 (C-4); 33.6,
34.3 (C-3, C-5); 53.8 (C-2); 62.7, 67.3 (C-1, C-6).
2-(R,S)-Methyl-3-oxo-4-[(R)-(phenyl)(phenylmethoxy-
carbonylamino)acetoxy]butyric acid methyl ester (16).
To a stirred solution of 5 mmol of 3-oxo-4-[(R)-(phenyl)-
(phenylmethoxycarbonylamino)acetoxy]butyric
acid
methyl ester 10a in 20 mL of freshly distilled acetone,
1.38 g of anhydrous solid potassium carbonate (10 mmol;
2.0 equiv.) were added. The mixture was stirred for 30 min
at room temperature (a reddish colour appeared) and
0.35 mL of iodomethane (5.6 mmol; 1.1 equiv.) was then
added. The mixture was stirred at room temperature until
complete consumption of starting material (monitored by
TLC, about 1 day) then concentrated under reduced pres-
sure. The dark residue was dissolved in 40 mL of dichloro-
methane. The solution was washed with water until
neutrality. The organic layer was dried over anhydrous
sodium sulphate, concentrated and the residue was chroma-
tographed on silica gel (cyclohexane/ethylacetate: 8/2) to
give 0.37 g of 16 (as an equimolecular mixture of diastereo-
isomers) as a colourless oil. Yield 18%. IR (CHBr3) n cmϪ1
3420–3320 (NH); 1750–1720 (CyO). 1H NMR (CDCl3) d
1.32 and 1.33 (2d, 3H, Jˆ7.1, CH3); 3.48–3.61 (m, 1H,
H-2); 3.67 and 3.71 (2s, 3H, CH3O); 4.85 (d, 2H,
Jˆ17.3, OCH2CO); 5.12 (d, 2H, Jˆ12.5, OCH2Ph);
5.50 (br d, 1H, Jˆ7.4, CHN); 5.75 and 5.80 (2 br d,
1H, Jˆ7.4, NH); 7.35–7.41 (m, 10H, Har). 13C NMR
(CDCl3) d 12.8 (CH3); 49.8 (C-2); 53.3 (CH3O); 58.6
(NCHPh); 67.9 (OCH2Ph); 68.7 (OCH2CO); 128.1,
128.8, 129.2, 129.7 and 136.7 (Car); 156.1 (NCOO); 170.7
(2×COO); 199.4 (CO). Anal. Calcd for C22H23NO7: C,
63.91; H, 5.61; N, 3.39. Found C, 63.91; H, 5.74; N,
3.40.
Side-products and other products
Compounds 21 and 22 are obtained when the morpholinone
17a is subjected to the general procedure used for 17d–i
reduction (H2, 150 atm, 10% Pd/C, CH3OH).
4-Hydroxy-3-[((R)-methoxycarbonylphenylmethyl)amino]-
butanoic acid methyl ester (21). IR (Nujol) n cmϪ1 3600–
1
3200 (OH, NH); 1740 (CyO). H NMR (CDCl3) d 2.48
(d, 2H, Jˆ6.4, H-2); 3.02–3.10 (m, 1H, H-3); 3.35–3.45
(m, 1H, H-4); 3.53–3.74 (m, 7H, 2×CH3 and H-4); 4.51
(s, 1H, CHPh); 7.26–7.31 (m, 5H, Har). 13C NMR
(CDCl3) d 37.4 (C-2); 52.0, 52.8 (2×CH3); 54.6 (C-3);
63.5 (CHPh); 63.7 (C-4); 128.0, 128.7, 129.2 and 138.5
(Car); 172.9 and 174.2 (2×CO). Anal. Calcd for
C14H19NO5: C, 59.77; H, 6.81; N, 4.98. Found C,
59.71; H, 6.77; N, 4.94.
(R)-[(5-Oxo-tetrahydrofuran-3S-yl)amino]phenylacetic
acid methyl ester (22). IR (neat) n cmϪ1 3310 (NH); 1770
(CyO lactone); 1730 (CyO ester). 1H NMR (CDCl3) d 2.33
(dd, 1H, Jˆ5.1 and 17.3, CHHCO); 2.26–2.34 (br s, 1H,
NH); 2.57 (dd, 1H, Jˆ7.1 and 17.3, CHHCO); 3.53–3.67
(m, 1H, NCHCH2O); 3.72 (s, 3H, CH3); 4.13 (dd, 1H, Jˆ4.3

F. Segat-Dioury et al. / Tetrahedron 56 (2000) 233–248
247
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