Enantioselective synthesis of both enantiomers of tert-butylphenylphosphine oxide from (S)-prolinol

Article abstract of DOI:10.1016/j.tetlet.2005.10.058

Both enantiomers of tert-butylphenylphosphine oxide can be easily synthesised starting from (S)-prolinol-based oxazaphospholidine.

Full text of DOI:10.1016/j.tetlet.2005.10.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8677–8680
Enantioselective synthesis of both enantiomers of
tert-butylphenylphosphine oxide from (S)-prolinol
*
´
Adeline Leyris, Didier Nuel, Laurent Giordano, Mathieu Achard and Gerard Buono
ˆ
Universite´ Paul Ce´zanne Aix-Marseille III, UMR-CNRS-6180, Faculte´ Saint-Je´rome—EGIM Sud, Case A62-Avenue
Escadrille Normandie-Niemen 13397, Marseille cedex 20, France
Received 9 September 2005; revised 11 October 2005; accepted 14 October 2005
Abstract—Both enantiomers of tert-butylphenylphosphine oxide can be easily synthesised starting from (S)-prolinol-based
oxazaphospholidine.
ꢀ 2005 Elsevier Ltd. All rights reserved.
OH
P
O
P
OH
P
Secondary phosphine oxides (SPOs) are effective inter-
mediates for the preparation of tertiary phosphines
and phosphine oxides,1 and enantiopure SPOs have
been used to obtain chiral tertiary mono- and diphos-
phine oxides.2,3
[M]
R2
R2
R2
H
[M]
R1
R1
R1
Scheme 1. Coordination behaviours of SPOs.
In the last decade, achiral SPOs have proved to be effi-
cient ligands in a number of transition metal reactions.
For instance, platinum complexes coordinated by SPOs
are able to catalyse hydration of nitriles to amides4 while
palladium/SPOs complexes are effective in cross-cou-
pling reactions of aryl chlorides.5 We have recently
reported that these ligands are suitable for an unusual
palladium catalysed [2+1] cycloaddition of terminal
alkynes with norbornene derivatives.6 However, the
use of chiral SPOs in enantioselective catalysis is much
less developed and it is expected that new asymmetric
applications will emerge.7 Indeed, in very recent letters,
their activity has been tested successfully in iridium- or
rhodium-catalysed asymmetric hydrogenation of imi-
nes8 or of functionalised olefins9 and in palladium-catal-
ysed asymmetric allylic alkylation.10
Among the chiral SPOs ligands tested in metal catalysed
transformations, tert-butylphenylphosphine oxide
1
appears to be the most promising. In contrast to the
racemic SPOs which are readily available, enantiomeri-
cally pure SPOs requires chemical resolution2a or sepa-
ration by chiral chromatography.8 To the best of our
knowledge, only one report describes the enantioselec-
tive synthesis of 1 in a four step sequence including a
crystallisation to obtain an highly pure diastereomer.12
Hence, the development of an efficient strategy to pre-
pare tert-butylphenylphosphine oxide 1 in an optically
pure form is in high demand. In this letter, we report
the first direct (one-pot, two-steps) enantioselective syn-
thesis of tert-butylphenylphosphine oxide 1 (Scheme 2).
When enantiomerically pure oxazaphospholidine (RP)-
2, easily prepared from PhP(NMe2)2 and S-(+)-pro-
linol,13 was treated with tert-butyllithium in THF at
low temperature, alcoholate 3, resulting from the cleavage
In these reactions, the coordination of chiral SPOs to
the metal through the tautomer displaying a trivalent
phosphorus atom proceeds without racemisation
(Scheme 1).6,10a,11
O
P
O
P
H
H
t-Bu
or
Ph
Ph
Keywords: Secondary phosphine oxides; Oxazaphospholidine; Enan-
tioselective synthesis; S-(+)-Prolinol; Tricoordinated organophospho-
rus compound.
t-Bu
(S)-(-)-1
(R)-(+)-1
*
Corresponding author. Tel.: +33 4 91 28 86 81; fax: +33 4 91 28 27
42; e-mail: gerard.buono@univ.u-3mrs.fr
Scheme 2. Structure of tert-butylphenylphosphine oxide 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.058

8678
A. Leyris et al. / Tetrahedron Letters 46 (2005) 8677–8680
only plays an important role in the yield and enantiose-
b or c
a
H3B
Ph
lectivity of the reaction but also allows control of the
enantiomer obtained. By using acids of high acidity
(pKa 6 1) or Amberlyst 15 resin, (+)-(R)-1 was obtained
with fairly good yields and enantioselectivities (Table 1,
entries 2–4). When acids of low acidity (pKa ꢀ 3–5) were
used, (À)-(S)-1 was the preferred enantiomer obtained
with acceptable eeÕs (Table 1, entries 5–8). Using p-tolu-
enesulfonic acid afforded (R)-1 in 88% yield15 and up to
91% ee (Table 1, entry 4). After a single recrystallisation
from petroleum ether/diethyl ether (2/1), compound 1
was determined to be essentially optically pure (>99%)
in 75% yield.16
N
N
N
P
P
P
t-Bu
Ph
t-Bu
O
Ph
LiO
RO
(Rp)-2
(Rp)-3
(Rp)-4 R = H
(Rp)-5 R = C(O)PhpNO2
Scheme 3. Synthesis of compounds 4 and 5. Reagents and conditions:
(a) t-BuLi, THF, À78 ꢁC, 15 min; (b) Me3SiCl, THF,À78 ꢁC, 15 min
then, BH3–Me2S, rt, 12h and KF, MeOH, rt, 24 h, 64% of 4; (c) p-
NO2PhC(O)Cl, THF, À78 ꢁC, 15 min and BH3–Me2S, rt, 12h, 51% of
5.
of the P–O bond, was obtained (see Scheme 3). At this
stage, the reaction mixture was quenched by addition
of Me3SiCl followed by BH3–Me2S. The resulting BH3
protected silylether was converted into the alcool 4 in
the presence of KF in methanol. The diastereomeric ex-
cess detected on the crude derivative 4 was found to be
P91% by 1H and 31P NMR. This NMR analysis shows
clearly that the ring opening of the oxazaphospholidine
2 proceeds with high diastereoselectivity.
In order to get some information on the stereochemical
course of the reaction, it was necessary to determine
whether the ring opening step occurred with inversion
or retention of configuration at the phosphorus atom.
Therefore compound 5 a derivative of intermediate 3
protected with BH3, resulting from the reaction of 3
with p-nitrobenzoyl chloride, was isolated and crystal-
lised from petroleum ether/diethyl ether (Scheme 3).
The structure of 5 determined by X-ray diffraction
(Fig. 1) highlights a p stacking interaction between aro-
matic groups with an interplane distance of 378.7 pm
and reveals that the ring opening of 2 proceeded with
a retention of configuration to afford (RP)-5.17 This is
To date, this powerful synthetic methodology developed
´
by Juge and co-workers was based exclusively on the
regio- and stereoselective nucleophilic substitution of
either 1,3,2-oxazaphospholidine–boranes and from the
analogous phosphine oxides (both derived from the
enantiomers of ephedrine as template) but not on
unprotected tricoordinated (r3k3) compounds.14
´
in agreement with results observed by Juge and co-
workers on the ring opening of an ephedrine based
oxazaphospholidine.14 This implies that in the case of
strong acids the hydrolysis proceeds with retention of
configuration whereas in the case of weak organic acids
inversion of configuration occurs.
Subsequent treatment of 3 by sulfuric acid on silica
(4 equiv) followed by hydrolysis gave compound 1 with
23% yield and 18% ee (Table 1, entry 1).
14
´
Juge and co-workers showed that the ring opening of
This encouraging result prompted us to optimise this
reaction. We tried various acids of different strengths
(Table 1). We were delighted to find that the acid not
the protected ephedrine based oxazaphospholidine by
tert-butyllithium proceeded diastereoselectively with
retention of configuration on the phosphorus atom to
Table 1. Effects of the acid on the hydrolysis
O
P
O
P
1) t-BuLi, THF, -78 oC
N
H
H
t-Bu
or
Ph
Ph
2) Acidic work-up
P
t-Bu
O
Ph
(Rp)-2
(S)-(-)-1
(R)-(+)-1
Entrya
Acid
Yieldb (%)
eec (%)
Enantiomer
1
H2SO4/silica
23
18
(
(R)-(+)
R)-(+)
(R)-(+)
(R)-(+)
(S)-(À)
(S)-(À)
(S)-(À)
S)-(À)
2Amberlyst 15
3
4
5
70
74
Triflic acid
PTSA
Formic acid
Acetic acid
Acetic acid
20
88
77
84
76
7285
87
91
77
71
81
6
7d
8d
p-Nitrobenzoic acid
(
a All reactions were carried out with 1.2mmol of 2 in THF at À78 ꢁC. 2/t-BuLi/acid/H2O = 1/1.05/4/4.6. A 15 min delay between the addition of
t-BuLi and hydrolysis was necessary.
b Isolated yield.
c Enantiomeric excesses were determined by HPLC analysis on a Daicel Chiralcel AD-H column at k = 254 nm; flow rate 1 mL/min; eluent: hexane/
i-PrOH 90/10, t(S) = 9.56 min, t(R) = 13.12min.
d For the hydrolysis dry organic acid is added, 15 min prior to water. PTSA = p-toluenesulfonic acid.

A. Leyris et al. / Tetrahedron Letters 46 (2005) 8677–8680
8679
CNRS, for its financial support. A.L. acknowledges
MENRT for a doctoral fellowship.
References and notes
1. (a) Bhattacharya, A. K.; Roy, N. K. Method of Prepa-
ration of Phosphine Chalcogenides. In The Chemistry of
Organophosphorous Compounds; Hartley, F. R., Ed.;
Wiley: Chichester, 1992; Vol. 2, pp 195–285; (b) Edmund-
son, R. S. Chemical Properties and Reactions of
Phosphine Chalcogenides. In The Chemistry of Organo-
phosphorous Compounds; Hartley, F. R., Ed.; Wiley:
Chichester, 1992; Vol. 2, pp 287–407; (c) Pietrusiewicz,
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3205–3216; (c) Haynes, R. K.; Lam, W. W.-L.; Yeung,
L.-L. Tetrahedron Lett. 1996, 37, 4729–4732.
Figure 1. X-ray structure of 5. HÕs omitted for clarity. Selected bond
lengths: P1–N1 1.662(2), P1–C1 1.817(2), P1–C7 1.862(3), P1–B1
1.932(3). Selected bond angles: N1–P1–C1 108.59(10), N1–P1–C7
108.74(13), C1–P1–C7 105.35(11), N1–P1–B1 110.78(15), C1–P1–B1
111.58(13), C7–P1–B1 111.60(14).
4. (a) Cobley, C. J.; van den Heuvel, M.; Abbadi, A.; de
Vries, J. G. Tetrahedron Lett. 2000, 41, 2467–2470; (b)
Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A: Chem. 2000,
160, 249–261; (c) Jiang, X.-B.; Minnaard, A. J.; Feringa,
B. L.; de Vries, J. G. J. Org. Chem. 2004, 69, 2327–2331;
(d) Herzon, S. B.; Myers, A. G. J. Am. Chem. 2005, 127,
5342–5344.
O
1) t-BuLi, THF, -78 oC
2) PTSA/H2O
Me
Me
Ph
P
H
t-Bu
N
Ph
P
O
6
Ph
(R)-(+)-1
40%, ee = 85%
5. (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516;
(b) Wolf, C.; Lerebours, R. Org. Lett. 2004, 6, 1147–1150;
For a recent application of diamino- and dioxophosphine
oxides, see: (c) Ackermann, L.; Born, R. Angew. Chem.,
Int. Ed. 2005, 44, 2444–2447.
Scheme 4. Ring opening of the unprotected ephedrine
oxazaphospholidine by tert-butyllithium.
6 based
give aminophosphine borane. Nevertheless, no reaction
was observed with the latter under acidolysis conditions.
We thus decided to extend our conditions to the unpro-
tected (1R,2S)-(À)-ephedrine derivative 6. Preliminary
results indicate that the ring opening and acidolysis oc-
curred with poorer global yield (40%) but the stereose-
lectivity of the reaction remains the same as with the
prolinol based phosphine (Scheme 4).
6. Bigeault, J.; Giordano, L.; Buono, G. Angew. Chem., Int.
Ed. 2005, 44, 4753–4757.
7. Dubrovina, N. V.; Bo¨rner, A. Angew. Chem., Int. Ed.
2004, 43, 5883–5886.
8. Jiang, X.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.;
de Vries, J. G. Org. Lett. 2003, 5, 1503–1506.
9. Jiang, X.; van den Berg, M.; Minnaard, A. J.; Feringa, B.
L.; de Vries, J. G. Tetrahedron: Asymmetry 2004, 15,
2223–2229.
The enantiomeric excesses observed are similar when
using p-toluenesulfonic acid (+)-(R)-1, (85% ee) but
much lower when using formic acid (À)-(S)-1 (25% ee).
10. (a) Dai, W.-M.; Yeung, K. K. Y.; Leung, W. H.; Haynes,
R. K. Tetrahedron: Asymmetry 2003, 14, 2821–2826; (b)
Nemoto, T.; Matsumoto, T.; Matsuda, T.; Hitomi, T.;
Hatano, K.; Hamada, Y. J. Am. Chem. 2004, 126, 3690–
3691; (c) Nemoto, T.; Matsuda, T.; Matsumoto, T.;
Hamada, Y. J. Org. Chem. 2005, 70, 7172–7178.
11. (a) Chatt, J.; Heaton, B. T. J. Chem. Soc. A 1968, 2745–
2757; (b) Chan, E. Y. Y.; Zhang, Q. F.; Sau, Y.-K.; Lo, S.
M. F.; Sung, H. H. Y.; Williams, I. D.; Haynes, R. K.;
Leung, W.-H. Inorg. Chem. 2004, 43, 4921–4926.
12. (a) Kolodiazhnyi, O. I.; Grishkun, E. V. Tetrahedron:
Asymmetry 1996, 7, 967–970; (b) Kolodiazhnyi, O. I.;
Gryshkun, E. V.; Andrushko, N. V.; Freytag, M.; Jones,
P. O.; Schmutzler, R. Tetrahedron: Asymmetry 2003, 14,
181–183.
In conclusion, we have developed a convenient, enantio-
selective synthesis of tert-butylphenylphosphine oxide.
Most of all, this method allows the stereochemistry con-
trol of the final product. Efforts are underway to eluci-
date the mechanism details of the hydrolysis reaction,
particularly the influence of the strength of the acid
and to define the scope and limitations of this reaction.
Acknowledgements
13. (a) Cros, P.; Buono, G.; Peiffer, G.; Denis, D.; Mortreux,
A.; Petit, F. New J. Chem. 1987, 11, 573–579; (b) Richter,
W. J. Chem. Ber. 1984, 117, 2328–2336.
We thank Dr. Michel Giorgi, for his kind assistance
with X-ray analysis of compound 5. We are grateful to

8680
A. Leyris et al. / Tetrahedron Letters 46 (2005) 8677–8680
14. (a) Bauduin, C.; Moulin, D.; Kaloun, E. B.; Darcel, C.;
23–88 % of (S)-(À)-1 or (R)-(+)-1 as a white solid. After
recrystallisation from Et2O/light petroleum (1/2), (S)-(À)-
1 or (R)-(+)-1 were obtained as single enantiomer with
ee >99%. White crystals, mp: 75–77 ꢁC. For NMR data,
see: Haynes, R. K. et al. Eur. J. Org. Chem. 2000, 3205–
3216, in Ref. 3. The reaction was carried out on a gram
scale: treatment with p-toluenesulfonic acid under the
same conditions confirmed a similar result (Table 1, entry
4).
´
´
Juge, S. J. Org. Chem. 2003, 68, 4293–4301; (b) Juge, S.;
`
Stephan, M.; Merdes, R.; Genet, J. P.; Halut-Desportes,
D. J. Chem. Soc., Chem. Commun. 1993, 531–533; (c)
´
Moulin, D.; Bago, S.; Bauduin, C.; Darcel, C.; Juge, S.
´
Tetrahedron: Asymmetry 2000, 11, 3939–3956; (d) Juge, S.;
´
ˆ
Stephane, M.; Lafitte, J. A.; Genet, J. P. Tetrahedron. Lett.
1990, 31, 6357–6360.
15. A brief study of the reaction with p-toluene sulfonic acid
showed that a 5 min delay between the addition of t-BuLi
and the hydrolysis (acid and water) decreased the yield to
67% but did not alter the eeÕs.
17. Crystal data for compound 5: Mw = 428.26, orthorhombic,
3
˚
3
colourless crystal (0.4 · 0.25 · 0.25 mm ), a = 8.0310(1) A,
˚
˚
˚
b = 11.1670(2) A, c = 25.9190(5) A, V = 2324.47(7) A ,
space group P212121, Z = 4, q = 1.22 g cmÀ3, l(MoKa) =
1.48 cmÀ1, 15,230 reflections measured at 293 K (Nonius
Kappa CCD diffractometer) in the 0.79–28.27ꢁ h range,
5390 unique (Rint = 0.029), 271 parameters refined on
F2 using 4865 reflections (Shelxl [Sheldrick, G. M.
SHELXL97. Program for the refinement of crystal struc-
tures. Univ. of Go¨ttingen, Germany; 1997]) to final indices
R[F2 > 4rF2] = 0.052, wR = 0.1460 [w = 1/[r2(Fo2) +
16. Preparation of tert-butylphenylphosphine oxide 1: t-BuLi
(0.75 mL of 1.7 M solution in pentane, 1.27 mmol) was
added slowly to a stirred and cooled (À78 ꢁC) solution of
(RP)-oxazaphospholidine 2 (248 mg, 1.2 mmol) in dry
THF (5 mL). After 15 min, dry acid (4.8 mmol) and water
(0.1 mL, 5.5 mmol) were added successively and the
reaction mixture was stirred at room temperature for
12h. After evaporation of THF, the crude mixture was
diluted with Et2O (10 mL), water (2mL) and potassium
carbonate (248 mg, 1.8 mmol) was added. The organic
phase was separated off, and the aqueous phase was
extracted with Et2O (3 · 5 mL) and CH2Cl2 (3 · 5 mL).
The combined organic layers were dried (Na2SO4), filtered
and concentrated under vacuum. Purification by chroma-
tography (silica gel, Et2O/light petroleum 4/1), afforded
(0.0947P)2 + 0.3371P] where P = (Fo2 + 2 Fc)/3]. The last
2
residual Fourier positive and negative peaks were equal
0.311 and À0.389, respectively.CCDC 277820 (compound
5) contains the supplementary crystallographic data for
this letter. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.