Chiral phosphinyl analogues of 2-C-arylmorpholinols: 2-aryl-3,5-diphenyl-[1,4,2]-oxazaphosphinanes

Article abstract of DOI:10.1016/j.tetasy.2006.05.003

(2R,3R,5R)-2-Aryl-3,5-diphenyl-[1,4,2]-oxazaphosphinanes 6, analogues of C-arylmorpholinol 3, were prepared with diastereomeric excess higher than 94%, via a three step sequence: (i) diastereoselective addition-cyclization reaction from methyl hypophosphi

Full text of DOI:10.1016/j.tetasy.2006.05.003

Tetrahedron: Asymmetry 17 (2006) 1402–1408
Chiral phosphinyl analogues of 2-C-arylmorpholinols:
2-aryl-3,5-diphenyl-[1,4,2]-oxazaphosphinanes
*
´ ˆ
Jean-Noel Volle, David Virieux, Matthieu Starck, Jerome Monbrun,
¨
Ludovic Clarion and Jean-Luc Pirat*
Laboratoire de Chimie Organique, UMR CNRS 5076, Ecole Nationale Supe´rieure de Chimie de Montpellier, 8,
Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
Received 3 April 2006; accepted 8 May 2006
Abstract—(2R,3R,5R)-2-Aryl-3,5-diphenyl-[1,4,2]-oxazaphosphinanes 6, analogues of C-arylmorpholinol 3, were prepared with diaste-
reomeric excess higher than 94%, via a three step sequence: (i) diastereoselective addition–cyclization reaction from methyl hypophosph-
ite and a chiral imine 10, (ii) pallado-catalyzed arylation, and then (iii) a selective inversion of configuration at the phosphorus center.
ꢀ 2006 Elsevier Ltd. All rights reserved.
F
1. Introduction
Bupropion 1 is an active ingredient of Wellbutrinꢁ, which
is marketed in the United States for the treatment of
depression. It mainly metabolizes into hydroxybupropion
2,1 which is twice as selective toward the noradrenergic sys-
tem than bupropion itself.2 Thereafter, a structure–activity
relationship study on the 2-arylmorpholinol core allowed
the discovery of compound 3,3 which possesses a 15-fold
higher in vitro specific affinity than 2 toward the enzymes
responsible for the capture of noradrenaline.4 The strong
activity of 2-arylmorpholinols on the noradrenergic sys-
tems could thus provide a new therapeutic means for the
treatment of depression and attention deficit hyperactivity
disorder (ADHD) (Fig. 1).
OH
OH
O
O
O
Cl
F
Me
Cl
Me
Me
Me
Me
N
H
Me
Me
N
H
Me
N
H
Me
2, Hydroxybupropion
3, 1555U88
1, Bupropion
Figure 1. Antidepressants: bupropion 1 and 2-C-arylmorpholinols 2–3.
A 1H NMR study allowed us to determine both the relative
and absolute configurations of the two newly created stereo-
genic centers in accordance with X-ray diffraction
experiments.
We envisioned oxazaphosphinanes
6
as structural
O
P
O
P
O
P
Ar
Ph
Ph
O
O
analogues of C-arylmorpholinol 3. In continuation of our
previous work on oxazaphosphinanes 4 and 5,5 we herein
report the synthesis of chiral oxazaphosphinanes 6 in both
enantiomeric forms. The preparation of compound 6 re-
quired the creation of two vicinal stereogenic centers. They
were introduced by a three step procedure, a diastereoselec-
tive addition–cyclization reaction, followed by arylation
and then by a selective epimerization at the phosphorus
center under thermodynamic conditions (Fig. 2).
Ph
Ph
O
H
N
H
Ph
Ph
N
H
Ph
N
H
Ph
( )-6
( )-5
( )-4
Figure 2. Structural analogy between P-aryl-1,4,2-oxazaphosphinanes 6
and 2-C-arylmorpholinols 2–3.
2. Results and discussion
*
According to the retrosynthetic analysis shown in Scheme
Corresponding authors. Fax: +33 4 67144319; e-mail addresses: jean-
noel.volle@enscm.fr; pirat@enscm.fr
1, the thermodynamic oxazaphosphinane 6 could be
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.003

J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
1403
O
P
The three-dimensional structure and the configuration
of the two newly created stereogenic centers were deter-
mined by an X-ray experiment on a monocrystal of (+)-8
obtained by crystallization from dichloromethane.8a As
expected, the P–H bond and the 3-phenyl group were in
a cis position relative to the 5-phenyl substituent.5d The
six-membered ring showed a preferred chair conformation,
where the two phenyl groups occupy an equatorial position
O
P
O
P
Ar
Ar
O
N
H
O
N
O
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
6
H
7
H
8
O
P
H
OH
N
OH
OH
OM
Ph
1
(Fig. 3). Interestingly, the H NMR spectra were also use-
NH2
N
Ph
ful for the determination of the absolute configuration of
both phosphorus and carbon atoms. The spectra exhibited
two independent AX and ABCX spin systems. In fact, in
the AX systems involving a (O)PCH linkage, 2JPH coupling
constants are sensitive to the dihedral angles O–P–C–H.
These generally have a minimal value (ꢀ14 to ꢀ18 Hz)
for a gauche conformation and a maximum value (ꢀ5 to
0 Hz) for a 180ꢂ dihedral angle.9 In the same way, the dihe-
dral angular dependence for 3JPH in the six-membered het-
erocyclic ring system –POCH2– indirectly allowed the
determination of the configuration of the phosphorus atom
H
9
11
10
Scheme 1. Retrosynthetic analysis for compound 6.
obtained from compound 7 by inversion of configuration
at the phosphorus center leading to the more stable trans
isomer. This epimerization could be carried out under
acidic conditions, as mentioned for a cyclic phosphonate.6
As for obtention of compound 5, 7 could be easily accessi-
ble from oxazaphosphinane 8, by palladium catalyzed cou-
pling of the corresponding aryl halide. The main point of
interest for this reaction is the complete retention of config-
uration observed at the phosphorus center.5c The other
retrosynthetic steps are based on previously described
diastereoselective nucleophilic addition followed by cycli-
zation of methyl hypophosphite to a chiral imino alcohol.
3
3
by attribution of the cis JHaHc and trans JHbHc coupling
constants.
Thereafter, the complete determination of the coupling
2
3
3
constants JPH for Hd proton and JPH, JHH for Ha, Hb
and Hc for compound 8 was undertaken in deuterated ace-
tone (Fig. 3).10 Thus, coupling constant values were:
3
(R)-Imino alcohol 10 was prepared via condensation of
(R)-glycinol 11 with benzaldehyde in dichloromethane in
the presence of sodium sulfate as the drying agent. Methyl
hypophosphite was obtained according to a methodology
already developed in the laboratory by mixing hypophos-
phorous acid and trimethyl-orthoformate in toluene/THF
(1:1).7 Contrary to the synthesis of compound 4, acyclic
intermediates 9 could not be identified by 31P NMR after
dilution of the reaction mixture with THF and addition
of imine (R)-10. However at this stage, the main signal at
32.6 ppm (formation rate 20%) was assigned to the cyclic
compound (ꢀ)-8. The addition of a 40% molar solution
of potassium tert-butoxide in THF allowed us to obtain
40–50% yield of compound (ꢀ)-8.
2JPHd = ꢀ15.4 Hz for the AX system and JPHa = 21.5 Hz
3
and JPHb = 3.6 Hz. The Karplus relationships between
Hc and Ha or Hc and Hb were also determined to be
3JHaHc = 2.1 Hz and 3JHbHc = 10.5 Hz. These were in good
agreement with those described for the gauche and the anti
conformation of morpholines.11 These different coupling
constants allowed us to conclude that compound 8, in solu-
tion, has the same conformation as observed for the solid
state (Fig. 3).
3JP,Hb= 3.6 Hz
Hb
H
H
N
Ph
Ha
Ph
3JHb,Hc = 10.5 Hz
3JHa,Hc = 2.1 Hz
P
O
O
All these observations showed that the cyclization partially
occurred before the basic treatment. The differences in the
reactivity noticed between acyclic intermediates 9 and those
observed for the preparation of 4, can be attributed to the
stronger nucleophilicity of the primary hydroxyl group in
intermediate 9 in comparison with the secondary alcohol
involved in the formation of 4.5a After work-up and col-
umn chromatography on silica gel, oxazaphosphinane
(ꢀ)-8 was isolated in 30% yield. Enantiomer (+)-8 was pre-
pared from (S)-10 in identical yield using the same proce-
dure (Scheme 2).
Hc
Hd
2JP,Hd = 15.4Hz
3JP,Ha = 21.5 Hz
Figure 3. X-ray structure and 1H NMR analysis of (+)-8.
Pallado-catalyzed arylation of (ꢀ)-oxazaphosphinane 8
took place using conditions previously developed and
depicted (Scheme 3). 2-Aryl-[1,4,2]-oxazaphosphinanes
(+)-7 were prepared in 64–75% yields as a single diastereo-
mer. Similarly, the same reactions were carried out with
enantiomer (+)-8, whose results are given in Table 1.
O
P
O
P
H
OMe
OH
H
O
OH
N
The retention of configuration previously observed during
the arylation process was also confirmed for compound
(ꢀ)-7b, after an X-ray experiment on a monocrystal
obtained from ethyl acetate/chloroform.8b Structure 7b
adopted a chair conformation where the cis P-aryl group
was in an axial position (Fig. 4).
H2P(O)OMe
THF/toluene
Ph
t
-BuOK
30%
Ph
N
H
9
Ph
Ph
N
H
Ph
Ph
(-)-8
(R)-10
Scheme 2. Preparation of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinane 8.

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J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
O
P
O
P
O
P
O
P
Ph
Ph
Ar
O
Ph
Ph
O
O
H
O
(a)
(b)
ArX (1eq.), Pd(PPh3)4 (10%)
HCl (12M), 70 ºC, 72 h
Et3N (3 eq.), PhMe, 90 ºC, 4 h
Propylene oxide
Ph
N
H
Ph
Ph
N
H
Ph
N
H
Ph
N
H
Ph
(+)-7a
(-)-6a
(+)-7
(-)-8
(b)
(a)
Scheme 3. Arylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinane (ꢀ)-
8.
Ph
Ph
Ph
O
O
O
H2N
Ph
H2N
Ph
O
OH
Ph
H2N
Ph
HO
13
Ph
P
P
P
Table 1. Arylation of 2-H-2-oxo-1,4,2-oxazaphosphinane 8
O
Ph
12
14
Compound Ar–X
Yield (%)a
Scheme 4. Inversion of configuration at the phosphorus of 2-aryl-2-oxo-
1,4,2-oxazaphosphinanes 7.
(+)-Enantiomer (ꢀ)-Enantiomer
7a
7b
7c
7d
7e
Ph–I
74
73
68
73
70
75
69
72
64
p-MeO–C6H4–I
p-Br–C6H4–I
m-Cl–C6H4–I
Table 3. Configuration inversion of 2-aryl-1,4,2-oxazaphosphinanes 7
Reagent compound
Final product compound
Yield (%)a
3,5-F2–C6H3–Br 69
(+)-7a
(ꢀ)-7a
(+)-7e
(ꢀ)-6a
(+)-6a
(ꢀ)-6eb
80
88
64
a Yield after purification by column chromatography.
a After treatment with propylene oxide.
b 48 h to 90 ꢂC.
3JP,Hb= 2.1 Hz
Hb
P
-MeO-Ph
Ph
H
N
Ph
Ha
ents were in equatorial positions. Neutralization of ammo-
nium salt 14 by treatment with propylene oxide gave after
filtration, pure oxazaphosphinane 6a. Similarly, the other
enantiomer (+)-7a gave the same results. Compound 7e re-
quired more drastic conditions and the inversion of config-
uration took place at 90 ꢂC leading to (2R,3R,5R)-(ꢀ)-
oxazaphosphinane 6e. This is consistent with the proposed
mechanism, where the initial protonation of the phos-
phoryl group was slowed down by the electron withdraw-
ing and negative inductive effects caused by the two
fluorine atoms on the aromatic substituent. This would
prevent the formation of phosphorane 13 and therefore
the inversion process (Table 4).
3JHb,Hc = 10.5 Hz
P
O
O
Hc
Hd
2JP,Hd = 19.0 Hz
3JP,Ha = 18.6 Hz
3JHa,Hc = 3.3 Hz
Figure 4. X-ray structure and 1H NMR analysis of (+)-7b.
For compound 8, proton NMR spectra allowed us to con-
firm the configuration of the two stereogenic centers. All
the coupling constants were compatible with the conforma-
tion issued from X-ray data analysis.
Similar values were found for the others structures 7a–e,
and are listed in Table 2.
Table 4. Coupling constants of 2-aryl-[1,4,2]-oxazaphosphinanes 6a and
6e
2JPHd
3JPHa
3JPHb
3JHaHc
3JHbHc
Table 2. Coupling constants of 2-aryl-1,4,2-oxazaphosphinanes 7a–e
Compound
Compound
6a
6e
0.0
0.0
18.8
18.8
2.8
3.0
2.6
2.5
10.9
10.9
7a
7b
7c
7d
7e
2JPHd
3JPHa
3JPHb
3JHaHc
3JHbHc
ꢀ19.0
18.5
2.0
3.0
10.7
ꢀ19.0
18.6
2.1
3.3
10.5
ꢀ19.0
19.5
1.3
3.7
10.2
ꢀ19.0
18.2
2.5
3.4
10.5
ꢀ19.2
19.8
0.5
3.6
10.2
Suitable crystals for X-ray analysis were obtained from
dimethylsulfoxide–methanol solution for compound (+)-
6a, the absolute configuration of which is shown in Figure
5.8c
The final step involved the treatment of compound (+)-7a
with hydrochloric acid solution (35%), which was carried
out at 70 ꢂC leading to a clean inversion of configuration
at the phosphorus atom (Scheme 4). The reaction was com-
plete after 72 h. Oxazaphosphinane 14 was formed in more
than 97% and less than 3% of the starting material 7a (Ta-
ble 3). This mechanism probably involved the formation of
unstable dihydroxyphosphorane 13 showing two hydroxyl
groups in an apical position (Scheme 4). The dynamic equi-
librium between the two isomers 12 and 14 favored the
thermodynamic product 14, where all the phenyl substitu-
3JP,Hb = 2.6 Hz
Hb
O
P
H
N
Ph
Ha
Ph
3JHb,Hc = 10.9 Hz
O
Ph
Hc
Hd
2JP,Hd = 0 Hz
3JHa,Hc = 2.8 Hz
3JP,Ha = 18.8 Hz
Figure 5. X-ray structure and 1H NMR analysis of (+)-6a.

J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
1405
2
3
3
In solution, JPHd coupling constants were deeply affected
O), 4.40 (1H, dd, JHH = 8.6 Hz, JHH = 4.3 Hz, CH2–
CH–N), 7.1–7.7 (9H, m, CHar), 8.23 (1H, s, N–CH–Ph).
by the inversion of configuration at the phosphorus atom
changing from ꢀ19 to 0.0 Hz while other coupling con-
stants did not change.
Minor (isoxazoline form 13%, two diastereoisomers
60:40) d 2.7 (1H, s broad, NH), 3.71 (0.4H, dd, JHH
3
=
=
2
3
8.1 Hz, JHH = 6.8 Hz, CH2–O), 3.77 (0.6H, dd, JHH
7.7 Hz, 2JHH = 7.6 Hz, CH2–O), 4.22 (0.6H, dd,
2
3. Conclusion
3JHH = 7.7 Hz, JHH = 7.6 Hz, CH2–O), 4.31 (0.4H, dd,
3JHH = 8.3 Hz, JHH = 6.8 Hz, CH2–O), 4.42 (0.4H,
2
3
3
In conclusion, a sequence involving an arylation reaction
and a selective inversion of configuration at the phospho-
rus atom was shown to be synthetically useful for obtaining
phosphinyl analogues of hydroxybupropion with various
substituents on aryl directly linked to the phosphorus.
Oxazaphosphinanes (+)-6a and (ꢀ)-6a and 6e were ob-
tained stereoselectively under thermodynamic control,
which was consistent with the active hemiketal configura-
tion of hydroxybupropion. We plan to use this methodol-
ogy in order to prepare the exact phosphorus analogue of
C-arylmorpholinol 3.
dd, JHH = 8.3 Hz, JHH = 8.1 Hz, CH2–CH–N), 4.44
3
3
(0.6H, dd, JHH = 7.7 Hz, JHH = 7.6 Hz, CH2–CH–N),
5.50 (0.6H, s, N–CH–Ph), 5.56 (0.4H, s, N–CH–Ph), 7.1–
7.7 (10H, m, CHar). 13C NMR (CDCl3): Major d 67.81
(s, CH2–O), 76.27 (s, Ph–CH–N), 126.14–131.03 (m,
CHar), 135.88 (s, Car), 140.68 (s, Car). Minor (isoxazoline
form, two diastereoisomers) d 60.80 (s, CH2–CH–N), 63.01
(s, CH2–CH–N), 72.16 (s, CH2–O), 76.67 (s, CH2–O), 92.62
(s, O–CH–N), 93.43 (s, O–CH–N), 126–150 (Car and
CHar). IR (m/cmꢀ1) 3255, 3077, 3063, 3028, 2944, 2885,
1637, 1600, 1578, 1490, 1453, 1385, 1352, 1306, 1215,
1156, 1134, 1094, 1071, 1055, 1045, 1027.
4. Experimental
4.2. Preparation of (2R,3S,5S)-(+)- and (2S,3R,5R)-(ꢀ)-3,5-
diphenyl-2-hydrogeno-2-oxo-[1,4,2]-oxazaphosphinane (8)
All reactions involving air or moisture sensitive reagents or
intermediates were carried out under dry nitrogen in flame-
dried glassware. Reagents, such as benzaldehyde or aryl
iodides were all purified by distillation or sublimation. Sol-
vents were all dried by distillation and stored under nitro-
gen atmosphere before use, tetrahydrofuran and toluene
over sodium wires/benzophenone and dichloromethane
over phosphorus pentoxide. Commercially available re-
agents were used without further purification. Merck silica
gel (35–70 lm) was used for column chromatography.
In a 50 mL flask containing the reaction mixture of methyl
hypophosphite8 freshly prepared (55 mmol) under nitrogen
were added dry THF (12.5 mL) and (S)- or (R)-2-benzyl-
idene-amino-2-phenylethanol (12.8 g, 57 mmol). After 24 h
at room temperature, sublimed t-BuOK (0.7 g, 7 mmol)
was added at ꢀ5 ꢂC. The reaction mixture was then stirred
for 2 h and allowed to stand at room temperature over-
night. The solution was evaporated and the residue purified
by column chromatography on silica gel with dichloro-
methane/ethyl acetate (100/0 to 20/80) as eluent, leading
to a white solid obtained in 28% yield (4.4 g).
Melting points were measured on a Buchi B-540 apparatus
¨
and are uncorrected. 31P and 19F spectrums were per-
formed on a Bruker AC 200 MHz spectrometer operating,
20
(2R,3S,5S)-8: mp = 143–144 ꢂC, ½aꢁD ¼ þ19:5 (c 1.04,
20
1
respectively, at 81 and 188 MHz. H and 13C experiments
were recorded on Bruker DRX 400 MHz spectrometers
with frequency of 101 MHz for 13C. Infrared spectra were
recorded on a FT-NICOLET 210 spectrometer. High reso-
lution mass spectra were measured on JEOL JMS-SX 102A
spectrometer with m-nitrobenzyl alcohol as matrix (NBA)
and optical rotation values, with Perkin–Elmer model 241
polarimeter.
CHCl3); (2S,3R,5R)-8: mp = 143–144 ꢂC, ½aꢁD ¼ ꢀ19:0 (c
1
1.04, CHCl3). 31P NMR (CDCl3): d 33.1 (s); H NMR
3
(CDCl3): d 2.14 (1H, d broad, JPH = 35.6 Hz, NH), 4.1–
4.4 (4H, m), 6.75 (1H, dd, 1JPH = 553.9 Hz, 3JHH = 5.0 Hz,
P(O)H), 7.21–7.37 (6H, m, CHar), 7.38–7.53 (4H, m, CHar).
1H NMR (CD3COCD3):
d
2.14 (1H,
d
broad,
3
3JPH = 35.6 Hz, NH), 4.28 (1H, ddd, JPH = 21.7 Hz,
3
2JHH = 10.8 Hz, JHH = 2.1 Hz, CH2–O), 4.34 (1H, dd,
3
4.1. Preparation of (R)-(+)- and (S)-(ꢀ)-2-(benzylidene-
2JPH = 15.4 Hz, JHH = 5.0 Hz, N–CH–Ph), 4.36 (1H,
2
3
3
amino)-2-phenylethanol (10)
ddd, JHH = 10.8 Hz, JHH = 10.5 Hz, JPH = 3.6 Hz,
3
3
CH2–O), 4.42 (1H, ddd, JHH = 10.5 Hz, JPH = 2.3 Hz,
In a 1.0 L flask and under nitrogen, was charged (S)- or
(R)-2-amino-1-phenylethanol (25.0 g, 0.18 mol), followed
by dichloromethane (400 mL), benzaldehyde (20.4 mL,
0.2 mol), and sodium sulfate (250 g). After 24 h of strong
stirring at ambient temperature, the mixture was filtered
on a coarse fritted filter and the residue washed with
dichloromethane (200 mL). The solution was concentrated
under reduced pressure to afford a pale yellow oil, which
solidifies on standing, 34.0 g (83%).
3JHH = 2.1 Hz,
CH2–CH–NH),
6.77
(1H,
dd,
1JPH = 553.9 Hz, JHH = 5.0 Hz, P(O)H), 7.3–7.5 (6H, m,
3
CHar), 7.5–7.7 (4H, m, CHar). 13C NMR (CDCl3): d
1
61.12 (s, CH2–CH–N), 62.69 (d, JPC = 95.9 Hz, N–CH–
2
Ph), 74.92 (d, JPC = 8.0 Hz, O–CH2), 127.32 (s, CHar),
3
5
127.58 (d, JPC = 5.9 Hz, CHar), 128.85 (d, JPC = 3.7 Hz,
CHar), 128.97 (s, CHar), 129.04 (s, CHar), 129.13 (d,
4JPC = 2.9 Hz, CHar), 133.37 (d, JPC = 5.9 Hz, Car),
2
136.98 (s, Car). IR (m/cmꢀ1) 3481, 3267, 3087, 3057, 3029,
2989, 2919, 2871, 2829, 2788, 2339, 1602, 1584, 1492, 1451,
1358, 1318, 1250, 1204, 1183, 1134, 1084, 1055, 1010. HRMS
(FAB+) MH+ calcd for (2R,3S,5S)-C15H17NO2P: 274.0997;
found 274.0992. HRMS (FAB+) MH+ calcd for
(2S,3R,5R)-C15H17NO2P: 274.0997; found 274.1002.
(R)- and (S)-10: mp = 70–71 ꢂC (lit.12 mp = 78 ꢂC). 1H
NMR (CDCl3): Major (open form 87%) d 2.7 (1H, s broad,
2
3
NH), 3.80 (1H, dd, JHH = 11.3 Hz, JHH = 4.1 Hz, CH2–
2
3
O), 3.91 (1H, dd, JHH = 11.3 Hz, JHH = 8.7 Hz, CH2–

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J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
4.3. General procedure for the preparation of 2-aryl-3,5-
diphenyl-2-oxo-[1,4,2]-oxazaphosphinane (7a–e)
2836, 2808, 1599, 1568, 1502, 1494, 1455, 1436, 1294,
1235, 1182, 1119, 1084, 1053, 1028, 1016. HRMS (FAB+)
MH+ calcd for (2R,3S,5S)-C22H23NO3P: 380.1416; found
380.1428; HRMS (FAB+) MH+ calcd for (2S,3R,5R)-
C22H23NO3P: 380.1416; found 380.1414.
In a 25 mL Schlenk tube containing (2R,3S,5S)-(+)-
or (2S,3R,5R)-(ꢀ)-2-hydrogeno-2-oxo-[1,4,2]-oxazaphosph-
inane 8 (1.0 g, 3.6 mmol) under N2 and at room tempera-
ture were successively added, toluene (8 mL),
triethylamine (1.1 g, 1.6 mL, 10.8 mmol), aryl iodide, or
bromide (3.6 mmol) and palladium tetrakis(triphenyl)phos-
phine (0.42 g, 0.36 mmol). The reaction mixture was stirred
and heated at 90 ꢂC for 4 h. After cooling, the mixture was
concentrated under vacuum and the crude residue purified
by a column chromatography on silica gel with dichloro-
methane/ethyl acetate as eluent (gradient 90/10 to 70/30).
A white solid was obtained.
4.3.3. 2-p-Bromophenyl-3,5-diphenyl-2-oxo-[1,4,2]-oxaza-
phosphinane ((2R,3S,5S)-7c). 69%, mp = 169–170 ꢂC,
20
½aꢁD ¼ ꢀ160:4 (c 0.51, CHCl3); (2S,3R,5R)-7c: 68%,
20
mp = 169–170 ꢂC, ½aꢁD ¼ þ160:8 (c 0.51, CHCl3). 31P
NMR (CDCl3): d 28.0 (s). 1H NMR (CDCl3): d 2.36
3
(1H, d broad, JPH = 23.1 Hz, NH), 4.42 (1H, ddd,
2
3
3JPH = 19.5 Hz, JHH = 11.2 Hz, JHH = 3.7 Hz, CH2–O),
4.44 (1H, ddd, 2JHH = 11.2 Hz, 3JHH = 10.2 Hz,
3JPH = 1.3 Hz, CH2–O), 4.57 (1H, dd, JHH = 10.2 Hz,
3
3JHH = 3.7 Hz, CH2–CH–N), 4.79 (1H, d, JPH = 19.0 Hz,
2
4.3.1. 2,3,5-Triphenyl-2-oxo-[1,4,2]-oxazaphosphinane ((2R,
N–CH–Ph), 7.2–7.3 (3H, m, CHar), 7.3–7.6 (9H, m,
CHar), 7.6–7.8 (2H, m, CHar). 13C NMR (CDCl3): d
62.39 (d, 3JPC = 1.5 Hz, CH2–CH–N), 64.86 (d,
20
3S,5S)-7a). 70%, mp = 131–133 ꢂC, ½aꢁD ¼ ꢀ138:5 (c
0.52, CHCl3); (2S,3R,5R)-7a: 74%, mp = 132–134 ꢂC,
20
½aꢁD ¼ þ140:3 (c 0.52, CHCl3). 31P NMR (CDCl3): d 28.7
1JPC = 99.5 Hz, N–CH–Ph), 75.20 (d, JPC = 8.0 Hz,
2
(s). 1H NMR (CDCl3):
d
2.32 (1H,
d
broad,
CH2–O), 127.11 (d, JPC = 5.1 Hz, CHar), 127.16 (d,
3
3
3JPH = 30.9 Hz, NH), 4.42 (1H, ddd, JPH = 18.5 Hz,
1JPC = 126.6 Hz, Car), 127.30 (s, CHar), 127.65 (d,
3
5
2JHH = 10.9 Hz, JHH = 3.0 Hz, CH2–O), 4.50 (1H, ddd,
4JPC = 3.7 Hz, Car), 128.06 (d, JPC = 2.9 Hz, CHar),
3
3
4
2JHH = 10.9 Hz, JHH = 10.7 Hz, JPH = 2.0 Hz, CH2–O),
128.59 (d, JPC = 2.9 Hz, CHar), 128.99 (s, CHar), 129.11
3
3
3
4.57 (1H, dd, JHH = 10.7 Hz, JHH = 3.0 Hz, CH2–CH–
(s, CHar), 131.32 (d, JPC = 13.2 Hz, CHar), 133.73 (d,
2
2
N), 4.80 (1H, d, JPH = 19.0 Hz, N–CH–Ph), 7.1–7.6
2JPC = 9.5 Hz, CHar), 134.19 (d, JPC = 5.1 Hz, Car),
(13H, m, CHar), 7.8–7.9 (2H, m, CHar). 13C NMR
137.44 (s, Car). IR (m/cmꢀ1) 3436, 3264, 3087, 3063,
3028, 2976, 2897, 1602, 1576, 1502, 1497, 1479, 1455,
1228, 1210, 1174, 1119, 1120, 1053, 1068, 1019, 1008.
3
(CDCl3): d 62.44 (d, JPC = 2.2 Hz, CH2–CH–NH), 65.07
1
2
(d, JPC = 98.1 Hz, N–CH–Ph), 75.07 (d, JPC = 8.0 Hz,
3
CH2–O), 127.25 (d, JPC = 5.1 Hz, CHar), 127.37 (s,
HRMS
(FAB+)
MH+
calcd
for
(2R,3S,5S)-
CHar), 127.8–128.0 (m, CHar), 127.8–128.1 (m, CHar),
C21H2079BrNO2P: 428.0415; found 428.0392; HRMS
(FAB+) MH+ calcd for (2S,3R,5R)-C21H2079BrNO2P:
428.0415; found 428.0424.
1
128.10 (d, JPC = 125.9 Hz, Car), 128.4–129.1 (m, CHar),
2
132.2–132.4 (m, CHar), 134.53 (d, JPC = 5.8 Hz, Car),
137.62 (s, Car). IR (m/cmꢀ1) 3449, 3279, 3061, 3029,
2981, 2919, 2942, 2878, 2812, 1601, 1591, 1491, 1452,
1436, 1242, 1204, 1192, 1120, 1083, 1055, 1017. HRMS
(FAB+) MH+ calcd for (2R,3S,5S)-C21H21NO2P:
350.1310; found 350.1311; HRMS (FAB+) MH+ calcd
for (2S,3R,5R)-C21H21NO2P: 350.1310; found 350.1320.
4.3.4. 2-m-Chlorophenyl-3,5-diphenyl-2-oxo-[1,4,2]-oxaza-
phosphinane ((2R,3S,5S)-7d). 72%, mp = 128–130 ꢂC,
20
½aꢁD ¼ ꢀ152:8 (c 0.55, CHCl3); (2S,3R,5R)-7d: 73%,
20
mp = 128–130 ꢂC, ½aꢁD ¼ þ152:7 (c 0.55, CHCl3). 31P
NMR (CDCl3): d 26.9 (s). 1H NMR (CDCl3): d 2.48
3
(1H, s broad, NH), 4.44 (1H, ddd, JPH = 18.2 Hz,
3
4.3.2. 2-p-Methoxyphenyl-3,5-diphenyl-2-oxo-[1,4,2]-oxaza-
phosphinane ((2R,3S,5S)-7b). 75%, mp = 200–201 ꢂC,
2JHH = 11.0 Hz, JHH = 3.4 Hz, CH2–O), 4.50 (1H, ddd,
3
3
2JHH = 11.0 Hz, JHH = 10.5 Hz, JPH = 2.5 Hz, CH2–O),
20
3
3
½aꢁD ¼ ꢀ145:0 (c 0.51, CHCl3); (2S,3R,5R)-7b: 73%,
4.57 (1H, dd, JHH = 10.5 Hz, JHH = 3.4 Hz, CH2–CH–
N), 4.80 (1H, d, JPH = 19.0 Hz, N–CH–Ph), 7.2–7.5
20
mp = 200–201 ꢂC, ½aꢁD ¼ þ145:6 (c 0.51, CHCl3). 31P
2
NMR (CDCl3): d 29.17 (s). 1H NMR (CDCl3): d 2.29
(10H, m, CHar), 7.5–7.6 (2H, m, CHar), 7.6–7.9 (2H,
3
3
(1H, d broad, JPH = 30.3 Hz, NH), 4.38 (1H, ddd,
m, CHar). 13C NMR (CDCl3): d 62.39 (d, JPC = 2.2 Hz,
2
3
1
3JPH = 18.6 Hz, JHH = 11.1 Hz, JHH = 3.3 Hz, CH2–O),
CH2–CH–N), 64.96 (d, JPC = 99.5 Hz, N–CH–Ph), 75.19
4.46 (1H, ddd, 2JHH = 11.1 Hz, 3JHH = 10.5 Hz,
(d, JPC = 8.0 Hz, CH2–O), 127.17 (d, JPC = 5.1 Hz,
2
3
3JPH = 2.1 Hz, CH2–O), 4.54 (1H, dd, JHH = 10.5 Hz,
CHar), 127.35 (s, CHar), 128.14 (d, JPC = 3.7 Hz, CHar),
128.59 (d, JPC = 2.9 Hz, CHar), 129.02 (s, CHar), 129.13
3
5
3JHH = 3.3 Hz, CH2–CH–N), 4.75 (1H, d, JPH = 19.0 Hz,
2
3
3
N–CH–Ph), 6.8–6.9 (2H, m, CHar), 7.1–7.3 (3H, m,
CHar), 7.3–7.5 (5H, m, CHar), 7.5–7.6 (2H, m, CHar),
7.7–7.9 (2H, m, CHar). 13C NMR (CDCl3): d 55.23 (s,
(s, CHar), 129.40 (d, JPC = 14.6 Hz, CHar), 130.23 (d,
1JPC = 123.7 Hz, Car), 133.30 (d, JPC = 8.8 Hz, CHar),
2
2
4
132.24 (d, JPC = 9.5 Hz, Car), 132.48 (d, JPC = 2.9 Hz,
3
2
O–CH3), 62.42 (d, JPC = 1.5 Hz, CH2–CH–N), 65.06 (d,
CHar), 134.00 (d, JPC = 5.1 Hz, Car), 134.28 (d,
2
1JPC = 98.8 Hz, N–CH–Ph), 74.87 (d, JPC = 6.6 Hz,
3JPC = 16.8 Hz, Car), 137.27 (s, Car). IR (m/cmꢀ1) 3444,
3278, 3056, 3029, 2981, 2944, 2882, 2816, 1601, 1563,
1494, 1470, 1453, 1431, 1395, 1373, 1320, 1241,
1210, 1192, 1131, 1082, 1055, 1028, 1016. HRMS
(FAB+) MH+ calcd for (2R,3S,5S)-C21H2035ClNO2P:
384.0920; found 384.0929; HRMS (FAB+) MH+ calcd
3
CH2–O), 113.56 (d, JPC = 13.9 Hz, CHar), 119.34 (d,
3
1JPC = 131.7 Hz, Car), 127.24 (d, JPC = 5.1 Hz, CHar),
5
127.33 (s, CHar), 127.79 (d, JPC = 2.9 Hz, CHar), 128.40
4
(d, JPC = 2.9 Hz, CHar), 128.82 (s, CHar), 129.02 (s,
2
CHar), 134.20 (d, JPC = 10.3 Hz, CHar), 134.84 (d,
2JPC = 5.9 Hz, Car), 137.83 (s, Car), 162.71 (s, Car). IR
(m/cmꢀ1) 3453, 3283, 3087, 3059, 3032, 2971, 2939, 2884,
for
384.0919.
(2S,3R,5R)-C21H2035ClNO2P:
384.0920;
found

J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
1407
4.3.5.
2-(3,5-Difluorophenyl)-3,5-diphenyl-2-oxo-[1,4,2]-
(2S,3S,5S)-C21H21NO2P: 350.1310; found 350.1317;
HRMS (FAB+) MH+ calcd for (2R,3R,5R)-C21H21NO2P:
350.1310; found 350.1313.
oxazaphosphinane ((2R,3S,5S)-7e). 64%, mp = 138–
20
140 ꢂC, ½aꢁD ¼ ꢀ122:2 (c 0.54, CHCl3); (2S,3R,5R)-7e:
20
69%, mp = 138–140 ꢂC, ½aꢁD ¼ þ122:2 (c 0.54, CHCl3).
31P NMR (CDCl3): d 25.2 (t, JPF = 7.1 Hz). 19F NMR
4.4.2.
2-(3,5-Difluoro)phenyl-3,5-diphenyl-2-oxo-[1,4,2]-
4
(CDCl3): d 25.2 (t, JPF = 7.2 Hz). 1H NMR (CDCl3):
oxazaphosphinane ((2R,3R,5R)-6e). 64%, mp = 196–197
4
20
3
d 2.46 (1H, d broad, NH), 4.44 (1H, ddd, JPH = 19.8 Hz,
ꢂC, ½aꢁD ¼ ꢀ80:0 (c 0.50, acetone). 31P NMR (CDCl3): d
2JHH = 11.3 Hz, JHH = 3.6 Hz, CH2–O), 4.46 (1H, ddd,
26.29 (s). H NMR (CD3COCD3): d 2.86 (1H, s broad,
3
1
2JHH = 11.3 Hz, JHH = 10.2 Hz, JPH = 0.5 Hz, CH2–O),
NH), 4.21 (1H, ddd, JHH = 10.9 Hz, JHH = 3.0 Hz,
3
3
2
3
3
3
3
4.56 (1H, dd, JHH = 10.2 Hz, JHH = 3.6 Hz, CH2–CH–
N), 4.81 (1H, d, JPH = 19.2 Hz, N–CH–Ph), 6.8–6.9 (1H,
3JPH = 18.7 Hz, CH2–O), 4.42 (1H, td, JHH = 10.9 Hz,
2
3
3JHH = 2.5 Hz, CH2–O), 4.59 (1H, dd, JHH = 10.9 Hz,
m, CHar), 7.2–7.3 (3H, m, CHar), 7.4–7.5 (7H, m, CHar),
3JHH = 3.0 Hz, CH2–CH–N), 4.60 (1H, s, N–CH–Ph),
7.1–7.3 (11H, m, CHar), 7.4–7.5 (2H, m, CHar). 13C
NMR (CD3COCD3): d 62.66 (s, CH2–CH–N), 64.10 (d,
7.5–7.6 (2H, m, CHar). 13C NMR (CDCl3): d 62.42 (d,
3JPC = 2.2 Hz, CH2–CH–N), 64.76 (d, JPC = 101.0 Hz,
1
2
2
N–CH–Ph), 75.35 (d, JPC = 8.8 Hz, CH2–O), 108.02 (td,
1JPC = 99.5 Hz, N–CH–Ph), 72.43 (d, JPC = 5.9 Hz,
2JFC = 24.9 Hz, JPC = 1.5 Hz), 115.24 (m, CHar), 127.04
CH2–O), 109.08 (td, JFC = 25.6 Hz, JPC = 1.5 Hz),
116.13 (m, CHar), 128.0–130 (m, CHar and Car), 134.83
4
2
4
3
(d, JPC = 4.4 Hz, CHar), 127.32 (s, CHar), 128.28 (d,
5JPC = 3.7 Hz, CHar), 128.69 (d, JPC = 3.7 Hz, CHar),
(dt, JPC = 130.3 Hz, JFC = 7.3 Hz, Car), 136.77 (d,
2JPC = 5.1 Hz, Car), 139.58 (s, Car), 163.53 (ddd,
4
1
3
129.13 (s, CHar), 129.20 (s, CHar), 131.97 (dt,
1JPC = 124.4 Hz, 3JFC = 7.3 Hz, Car), 133.64 (d,
2JPC = 5.9 Hz, Car), 137.04 (s, Car), 162.49 (ddd,
1JFC = 251.4 Hz, JFC = 20.5 Hz, JPC = 11.0 Hz). IR (m/
cmꢀ1) 3310, 3072, 3034, 2936, 2863, 1610, 1590, 1493,
1456, 1426, 1304, 1234, 1219, 1128, 1104, 1082. HRMS
(FAB+) MH+ calcd for (2R,3R,5R)-C21H19F2NO2P:
386.1141; found 386.1141.
3
3
1JFC = 252.5 Hz, JFC = 21.2 Hz, JPC = 11.0 Hz). IR (m/
cmꢀ1) 3280, 3092, 3060, 3038, 2985, 2949, 2886, 2824,
1613, 1596, 1495, 1454, 1422, 1298, 1122, 1106, 1056,
1081, 1019. HRMS (FAB+) MH+ calcd for (2R,3S,5S)-
C21H19F2NO2P: 384.1121; found 386.1130; HRMS
(FAB+) MH+ calcd for (2S,3R,5R)-C21H19F2NO2P:
386.1121; found 386.1114.
4
4
Acknowledgements
Arie Van der Lee is warmly acknowledged for X-ray ana-
lyses and M. Maria Luisa Cuadrado for her practical work
during a 6-month scholarship.
4.4. General procedure for the inversion of configuration
reaction
In a 50 mL Schlenk tube, 2-aryl-[1,4,2]-oxazaphosphinane
(0.75 g) (ꢀ)-7a, (+)-7a, or (+)-7e was mixed with a concen-
trated solution of hydrochloric acid (25 mL, 12 M) at 70 ꢂC
(90 ꢂC for 7e). After 72 h (48 h for 7e), the reaction mixture
was cooled at room temperature, and diluted with a satu-
rated brine solution (25 mL), filtered on a coarse fritted fil-
ter and the cake washed with brine (2 · 25 mL). After
drying, the amorphous solid was treated with propylene
oxide (100 mL) for 24 h. The crude mixture was filtered
and the solution evaporated, with a white solid being
obtained.
References
1. Welch, R. M.; Allen, A. A.; Schroeder, D. H. Xenobiotica
1987, 17, 287–298.
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J.-L. Tetrahedron Lett. 2001, 42, 4491–4494.
8. Crystal structures were deposited at the Cambridge Crystal-
lographic Data Centre and referenced with following num-
ber’s: (a) CCDC 603689 for 8; (b) CCDC 603690 for 7b and
(c) CCDC 603691for 6a.
9. Phosphorus-31 NMR Spectroscopy in Stereochemical Analy-
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chaft: Weiheim (Germany), 1987; pp 365–385.
4.4.1. 2,3,5-Triphenyl-2-oxo-[1,4,2]-oxazaphosphinane ((2S,
20
3S,5S)-6a). 88%, mp >250 ꢂC, ½aꢁD ¼ þ91:1 (c 0.48,
20
CHCl3); (2R,3R,5R)-6a: 80%, mp >250 ꢂC, ½aꢁD ¼ ꢀ91:7
1
(c 0.48, CHCl3). 31P NMR (CDCl3): d 29.0 (s). H NMR
(CDCl3): d 2.35 (1H, s broad, NH), 4.29 (1H, ddd,
3
3
2JHH = 11.1 Hz, JHH = 2.8 Hz, JPH = 18.8 Hz, CH2–O),
3
4.46 (1H, s, N–CH–Ph), 4.57 (1H, dd, JHH = 10.9 Hz,
3JHH = 2.8 Hz,
CH2–CH–N),
4.80
(1H,
ddd,
3
3
2JHH = 11.1 Hz, JHH = 10.9 Hz, JPH = 2.6 Hz, CH2–O),
7.2–7.5 (10H, m, CHar), 7.5–7.6 (3H, m, CHar), 7.7–7.9
(2H, m, CHar). 13C NMR (CDCl3): d 62.83 (s, CH2–
1
CH–N), 64.28 (d, JPC = 97.3 Hz, N–CH–Ph), 71.07 (d,
2JPC = 5.9 Hz, CH2–O), 129–127 (m, CHar and Car),
2
4
132.25 (d, JPC = 9.5 Hz, CHar), 132.93 (d, JPC = 2.2 Hz,
2
CHar), 135.23 (d, JPC = 4.4 Hz, Car), 137.94 (s, Car). IR
(m/cmꢀ1) 3444, 3306, 3061, 3083, 3065, 3031, 2938, 2886,
2859, 1601, 1591, 1491, 1454, 1439, 1233, 1216, 1125,
1080, 1043, 1027. HRMS (FAB+) MH+ calcd for

1408
J.-N. Volle et al. / Tetrahedron: Asymmetry 17 (2006) 1402–1408
10. All simulations were performed using gNMR 3.65 by
IvorySoft, published by Cherwell Scientific, Oxford, UK,
1998.
11. Sprag, R. A. J. Chem. Soc. (Sec. B) 1968, 1128–1132.
12. Higashiyama, K.; Inoue, H.; Yamauchi, T.; Takahashi, H. J.
Chem. Soc., Perkin Trans. 1 1995, 111–115.