Enantioselective synthesis of secondary phosphine oxides from (RP)-(-)-menthyl hydrogenophenylphosphinate

Article abstract of DOI:10.1016/j.tetlet.2007.05.140

Alkyl- and arylphenylphosphine oxides can easily be synthesized with an excellent enantiomeric excess starting from diastereomerically pure (R_P)-(-)-menthylhydrogenophenylphosphinate and organometallic reagents.

Full text of DOI:10.1016/j.tetlet.2007.05.140

Tetrahedron Letters 48 (2007) 5247–5250
Enantioselective synthesis of secondary phosphine oxides
from (RP)-(ꢀ)-menthyl hydrogenophenylphosphinate
*
*
´
Adeline Leyris, Julie Bigeault, Didier Nuel, Laurent Giordano and Gerard Buono
ˆ
Universite´ Paul Ce´zanne Aix-Marseille III, UMR-CNRS-6180, Faculte´ Saint-Je´rome—Ecole Centrale Marseille,
Case A62-Avenue, Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France
Received 10 April 2007; revised 16 May 2007; accepted 23 May 2007
Available online 26 May 2007
Abstract—Alkyl- and arylphenylphosphine oxides can easily be synthesized with an excellent enantiomeric excess starting from
diastereomerically pure (RP)-(ꢀ)-menthylhydrogenophenylphosphinate and organometallic reagents.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Enantiomerically pure secondary phosphine oxides
(SPOs) have so far mainly been obtained through chem-
ical resolution1 or chromatographic separation2 but
rarely by asymmetric synthesis.3 Such compounds
proved to be promising ligands for not only asymmetric
catalysis,2,4 but also precursors of chiral tertiary mono-
and diphosphine oxides.1,5 In a previous Letter,3a we
described the first synthesis of each enantiomer of tert-
butylphenylphosphine oxide through an oxazaphos-
pholidine precursor (RP)-I based on (S)-prolinol (Scheme
1). However, this method could not be extended to a
wide variety of alkyl and aryl substituents on the phos-
phorus atom. We thus focused on new routes and
precursors for efficient and general access to
enantiomerically pure SPOs.
can be successfully used for the multigram-scale prepa-
ration of diastereomerically pure phosphinates such as
II, which was successfully crystallized as a single diaste-
reoisomer by Mislow and co-workers (Scheme 2).6
Emmick and Letsinger reported that benzylmagnesium
chloride reacts cleanly with (ꢀ)-menthyl phenylphos-
phinate II to afford unsymmetrical SPO, through
substitution of (ꢀ)-menthyloxy group. However, the
diastereomers of II could not be separated to be used
in the enantioselective synthesis of a SPO.7 This method,
combined with the straightforward crystallization proce-
dure of diastereomerically pure (RP)-II appeared to be a
promising route to enantiomerically pure SPOs that we
decided to further explore. In this Letter, we report the
first enantioselective synthesis of SPOs using various
organometallic reagents for nucleophilic substitution
of (ꢀ)-menthyloxy group.
The chiral pool is a precious source of asymmetric
inductors. In particular, alcohols such as (ꢀ)-menthol
We firstly explored the addition of an excess (5 equiv) of
tert-BuMgCl on (RP)-II at ꢀ78 ꢁC (Table 1). Grignard
reagent (1 equiv) is required to abstract the proton
carried by (RP)-II, generating an intermediate species
O
P
O
P
1)
t-BuLi, THF, -78 °C
H
H
-Bu
or
N
Ph
Ph
2) Acidic work-up
t
-Bu
t
P
O
Ph
(RP)-I
(S)-(-)-1
(R)-(+)-1
Scheme 1. Asymmetric synthesis of tert-butylphenylphosphine oxide 1
from oxazaphospholidine (RP)-I.
O
P
O
P
H
H
Ph
O
O
Ph
Keywords: Chiral secondary phosphine oxides; (ꢀ)-Menthol; Enantio-
(
RP)-II
(SP)-II
selective synthesis; Diastereomerically pure phosphinate.
*
Corresponding authors. Tel.: +33 4 91 28 86 81; fax: +33 4 91 28 27
42 (G.B.); e-mail addresses: laurent.giordano@univ-cezanne.fr;
gerard.buono@univ-cezanne.fr
Scheme 2. Structure of menthyl hydrogenophenylphosphinate diaste-
reoisomers (RP)-II and (SP)-II.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.140

5248
A. Leyris et al. / Tetrahedron Letters 48 (2007) 5247–5250
The mixture was allowed to slowly come back to room
temperature, and the conversion, checked by 31P
NMR, appeared to be complete (Table 1, entry 1). How-
ever, tert-butylphenylphosphine oxide 1 was obtained as
a racemic mixture. To evaluate the impact of the alkyl
group of the Grignard reagent on the enantioselectivity
of the substitution on the phosphorus centre, we con-
ducted the same experiment using iPrMgBr as the alkyl-
ating agent. The reaction proceeded cleanly and
surprisingly the enantiomeric excess measured on iso-
propylphenylphosphine oxide 2 was 56% (Table 1, entry
2). The best enantiomeric excess (82%) was observed
with primary Grignard reagents such as EtMgBr (Table
1, entry 3). In order to further explore the influence of
the Grignard reagent on these variations of stereoselec-
tivity, a series of arylmagnesium species were also tested
in the same previous conditions. o-TolylMgBr, o-biphen-
ylMgBr and 1-naphthylMgBr addition on (RP)-II,8
respectively, yielded the corresponding SPOs 4–6 with
good to poor ees (Table 1, entries 4–6).
0
Table 1. Asymmetric synthesis of secondary phosphine oxides from
organometallic precursors RM and (RP)-II
O
O
RM
P
H
P
H
R
O
inversion
Ph
Ph
P)-II
(
R
Entry
1
RM
Product
Yielda (%)
86
eeb (%)
MgCl
1
0
2
3
(ꢀ)-2
(ꢀ)-3
89
60
56
82
MgBr
MgBr
4
5
(+)-4
84
88
68
2
MgBr
MgBr
(ꢀ)-5
The loss of enantioselectivity was therefore imputed to
the excess of Grignard reagent involved in the reaction
and most likely to the steric hindrance of the nucleo-
philic fragment. In order to determine whether the
reactant (RP)-II or the SPO product undergoes epimer-
ization on the phosphorus atom, both the compounds
were tested individually. As a proof-of-principle, each
phosphorus substrate (RP)-II and 4 was treated in the
same previous conditions at ꢀ78 ꢁC with 1 equiv of
o-tolylMgBr followed by hydrolysis under acidic condi-
tions. Phosphinate (RP)-II was converted into an equi-
molar mixture of diastereoisomers (RP)-II and (SP)-II,
whereas an enriched mixture of 4 (68% ee) remained
unaffected by the confrontation with the Grignard
reagent. Thus, using 1 equiv of Grignard reagent results
in the epimerization of (RP)-II probably through the
formation of intermediate (RP)-III (Scheme 4).
MgBr
6
7
(ꢀ)-6
91
80
15
(S)-(ꢀ)-1
86 (80)c
Li
8
9
(ꢀ)-7
(ꢀ)-8
81
76
96
97
Li
Me–Li
10
(+)-4
74
98
Li
Li
11
(ꢀ)-5
98
96
a Yields after purification.12
b Enantiomeric excesses were determined by HPLC analysis on chir-
alpak AD-H or chiralcel OD-H column at k = 254 nm; flow rate
1 mL/min; eluent: hexane/i-PrOH mixtures.
c Solution of (RP)-II in dry THF was added dropwise to a stirred and
cooled (ꢀ78 ꢁC) solution of tert-BuLi.
OMgX
OMgX
P Ph
:
P
:
O
O
Ph
(RP)-III (Scheme 3), which then undergoes nucleophilic
substitution with the remaining excess of organometallic
species.
(
RP)-III
(SP)-III
Scheme 4. Epimerization of intermediate species III.
OMgX
O
P
RMgX, THF, -78 °C
P
H
O
O
Ph
P)-III
Ph
P)-II
(
R
(R
OMgX
RMgX, THF, -78 °C
inversion or retention
O
P
O
P
or
H
Ph
P
H
Ph
R
R
O
Ph
(
RP)-III
SPOs
Scheme 3. A possible pathway for the enantioselective synthesis of SPOs using Grignard reagents.

A. Leyris et al. / Tetrahedron Letters 48 (2007) 5247–5250
5249
a
b
(R)-1
or
t
-BuLi, THF, -78 °C
N
N
P
P
-Bu
retention
Ph
O
(S)-1
Ph
LiO
RP
t
(
)
(
R
P)-I
Li
O
P
O
P
O
P
t-BuLi, THF, -78 °C
H2O
H
O
H
inversion
Ph
Ph
Ph
(S)-1
(S)
(
RP)-II
Scheme 5. Compared stereoselectivity for the asymmetric synthesis of (S)-1 as a major product. Nucleophilic attack of tert-BuLi proceeds with (a)
retention of configuration on oxazaphospholidine (RP)-I, (b) inversion of configuration on phosphinate (RP)-II.
Such an observation is in agreement with previous
results indicating that phosphinate species epimerizes
in the presence of bases.6
These results led us to the conclusion that sterically
hindered Grignard reagent used for the substitution
reaction of the menthyloxy group on the deprotonated
phosphinate II proceeds slower than its epimerization.
We therefore tested other organometallic species and
naturally turned to commercially available or readily
accessible organolithium species to generate enantio-
merically enriched SPOs. Comparatively to the Grignard
analogue, tert-butyllithium (2 equiv) in THF at ꢀ78 ꢁC
reacted as cleanly but yielded the corresponding SPO
(S)-(ꢀ) 19 with a significant increase in enantiomeric
excess (86%) (Table 1, entry 7). Interestingly, whereas the
nucleophilic attack on oxazaphospholidine precursor
(RP)-I proceeds with retention of configuration at the
phosphorus centre,3a in the case of phosphinate species
Scheme 6. HPLC chromatograms of SPO mixtures 4 obtained from
o-TolylMgBr (left) and o-TolylLi (right).
derived from menthol (RP)-II the substitution of the
menthyloxy fragment occurs with inversion of configu-
ration (Scheme 5).
sor. The use of an organolithium reagent offers a
straightforward access to phosphorus species with excel-
lent optical purities. Interestingly, whereas oxazaphosp-
Similarly, n-BuLi and MeLi reacted stereoselectively on
(RP)-II yielding n-butylphenylphosphine oxide 7 and
methylphenylphosphine oxide 8 with 96% and 97% ee,
holidines react with the retention of configuration with
respectively (Table 1, entries 8 and 9). This method
organolithium species, the phosphinate precursors
was extended to aromatic nucleophiles using the corre-
afford the same products with inversion of configuration.
sponding lithiated species. o-Tolyl- and 2-biphenyl- were
prepared by the treatment of the corresponding bromide
Organolithium reagents of various natures, combined
with diastereomerically pure phosphinates, should
therefore prove to be a valuable method providing an
easy entry to chiral SPOs and subsequent related ligands
precursors at ꢀ30 ꢁC in THF with 2 equiv of tert-butyl-
lithium.10 This general procedure afforded the desired
SPOs 4 and 5 with excellent enantiomeric excess (Table
such as tertiary mono- and diphosphine oxides. Further
1, entries 10 and 11). HPLC chromatograms reported in
investigations of these optically active SPOs ligands in
Scheme 6 illustrate the contrasted enantioselectivities
enantioselective catalytic carbon–carbon bond forming
depending on the nature of the metal on the tolyl
reactions will be reported in due course.
derivative 4, which could be obtained from o-TolylLi
almost as a single enantiomer without recrystallization.11
In addition this procedure allows recovery of the (ꢀ)-
menthol chiral auxiliary without any loss of optical
activity.
Acknowledgements
In conclusion, we have explored the influence of the
metal and of the alkyl fragment of various organometallic
species on the obtention of chiral SPOs from a readily
accessible diastereomerically pure phosphinate precur-
We thank Drs. Julien Leclaire, David Martin and
Alphonse Tenaglia for the useful suggestions. We are
grateful to CNRS for its financial support. A.L. and
J.B. acknowledge MENRT for a doctoral fellowship.

5250
A. Leyris et al. / Tetrahedron Letters 48 (2007) 5247–5250
light petroleum/MeOH mixtures to afford compounds
References and notes
1–6.
9. Retention times on identical conditions were related to
absolute configuration. See Ref. 5c.
1. Drabowicz, J.; Lyzwa, P.; Omelanczuk, J.; Pietrusiewicz,
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3. (a) Leyris, A.; Nuel, D.; Giordano, L.; Achard, M.;
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Kolodiazhnyi, O. I.; Grishkun, E. V. Tetrahedron: Asym-
metry 1996, 7, 967–970; (c) Kolodiazhnyi, O. I.; Gry-
shkun, E. V.; Andrushko, N. V.; Freytag, M.; Jones, P.
G.; Schmutzler, R. Tetrahedron: Asymmetry 2003, 14,
181–183.
10. When n-BuLi was used to generate aryllithium,
(ꢀ)-menthyl n-butylphenylphosphinate was obtained as a
major product. Such species is likely to be generated by the
attack of II, after deprotonation, on 1-bromobutane. In
comparison, tert-BuLi produces tert-butylbromide as a
side product which undergoes elimination upon reaction
the excess of tert-BuLi, being hence converted to isobutene
which is cleanly expelled from the reaction mixture. If the
reaction is conducted above ꢀ30 ꢁC, the alkyllithium
reagents react slowly with THF.
11. Typical procedure for the preparation of (+)-phenyl-o-
tolylphosphine oxide (+)-4: tert-BuLi (2.6 mL of 1.7 M
solution in pentane, 4.4 mmol) was added slowly to a
stirred and cooled (ꢀ30 ꢁC) solution of 2-bromotoluene
(377 mg, 2.2 mmol) in dry THF (2 mL) and stirring was
continued for 1 h. The former solution is then added at
once at ꢀ78 ꢁC to a solution of phosphinate (RP)-II
(n = 1 mmol, 280 mg, c 0.5 M in THF) and the solution
was allowed to come back to room temperature. The
reaction mixture is then diluted with Et2O (5 mL) and
NH4Cl saturated aqueous solution (5 mL). The organic
phase was separated off, and the aqueous phase was
extracted with AcOEt (2 · 5 mL). The combined organic
layers were dried (MgSO4), filtered, concentrated under
vacuum and 118 mg of (ꢀ)-menthol was removed by
means of bulb to bulb distillation (60 ꢁC, 10ꢀ1 mm Hg).
Purification of the crude by chromatography on a short
plug of deactivated silica gel (10% H2O) using Et2O/light
petroleum/MeOH 4/1/0.05 as eluent, afforded 74% of (+)-
4 (98% ee) as a white solid. Enantiomeric excess was
determined by HPLC analysis on a Chiralpak AD-H
column at k = 254 nm; flow rate 1 mL/min; eluent: hex-
ane/i-PrOH 90/10, Rt: (ꢀ) = 18.7 min, (+) = 20.1 min
4. (a) Jiang, X.; van den Berg, M.; Minnaard, A. J.;
Feringa, B. L.; de Vries, J. G. Tetrahedron: Asymmetry
2004, 15, 2223–2229; (b) Dai, W.-M.; Yeung, K. K. Y.;
Leung, W. H.; Haynes, R. K. Tetrahedron: Asymmetry
2003, 14, 2821–2826; (c) Nemoto, T.; Matsumoto, T.;
Masuda, T.; Hitomi, T.; Hatano, K.; Hamada, Y. J. Am.
Chem. Soc. 2004, 126, 3690–3691; (d) Nemoto, T.;
Masuda, T.; Matsumoto, T.; Hamada, Y. J. Org. Chem.
2005, 70, 7172–7178; (e) Bigeault, J.; Giordano, L.;
Buono, G. Angew. Chem., Int. Ed. 2005, 44, 4753–
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Vonwiller, S. C. J. Org. Chem. 1994, 59, 2919–2921; (b)
Freeman, R. N.; Haynes, R. K.; Loughlin, W. A.;
Mitchell, C. R.; Strokes, J. V. Pure Appl. Chem. 1993,
65, 647–654; (c) Haynes, R. K.; Au-Yeung, T.-L.; Chan,
W.-K.; Lam, Z.-L.; Yeung, L.-L.; Chan, A. S. C.; Li, P.;
Koen, M.; Mitchell, C. R.; Vonwiller, S. C. Eur. J. Org.
Chem. 2000, 3205–3216; (d) Haynes, R. K.; Lam,
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7. Emmick, T. L.; Letsinger, R. L. J. Am. Chem. Soc. 1968,
90, 3459–3465.
20
½aꢁD (CHCl3, c 1.6) = +2.0. Mp 157–158 ꢁC. Rf (Et2O)
0.14; IR (KBr) m 3352, 3059, 2954, 2922, 2869, 1708, 1594,
1454, 1439, 1178 cmꢀ1
;
31P {1H} NMR (81 MHz, CDCl3):
1
d 22.84 (s). H NMR (CDCl3, 200 MHz): d 2.33 (s, 3H),
8. General procedure: To a suspension of Mg (6 mmol,
m = 146 mg) activated by 1% of 1,2-dibromoethane in dry
THF (1 mL) was added dropwise a solution of the
halogenoalkane (5 mmol, c 1.25 M) at room temperature
followed by heating up at reflux for 15 min. The former
solution is then added at once at ꢀ78 ꢁC to a solution of
phosphinate (RP)-II (n = 1 mmol, 280 mg, c 1 M in THF).
After stirring at room temperature, the reaction mixture is
then diluted with Et2O (5 mL) and the organic phase
is washed with a solution of H2SO4 (0.02 M, 4 mL).
After separation, the aqueous phase is re-extracted twice
with AcOEt (2 · 5 mL). The combined organic phases are
dried over MgSO4, concentrated under vacuum and a
large part of the (ꢀ)-menthol was removed by means of
bulb to bulb distillation (60 ꢁC, 10ꢀ1 mm Hg). The crude
material obtained is then purified by chromatography on a
short plug of deactivated silica gel (10% H20) using Et2O/
1
8.07 (d, JP-H = 480.2 Hz, 1H), 7.15–7.36 (m, 2H), 7.38–
7.75 (m, 4H), 7.77–7.85 (m, 3H). 13C {1H} NMR (CDCl3,
3
50 MHz): d 20.2 (d, JP-C = 6.7 Hz), 126.0 (d, JP-C = 13.5
1
Hz), 128.7 (d, JP-C = 26.0 Hz), 128.9 (d, JP-C = 12.7 Hz,
2
2C), 130.5 (d, JP-C = 4.7 Hz), 130.8 (d, JP-C = 11.4 Hz,
2C), 131.4 (d, JP-C = 10.3 Hz), 132.2 (d, JP-C = 11.1 Hz),
1
132.4 (s, 2C), 132.8 (d, JP-C = 2.5 Hz), 141.4 (d, JP-C
=
9.0 Hz).
12. (a) For the synthesis of unsymmetrical SPOs involving
displacement of alkoxide by a Grignard reagent see: Ref.
7; (b) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.;
Haddad, N.; Hrapchak, M.; Latli, B.; Lee, H.; Sabila, P.;
Saha, A.; Sarvestani, M.; Shen, S.; Varsolona, R.; Wei, X.;
Senanayake, C. H. Org. Lett. 2005, 7, 4277–4280; (c)
Olszewski, T. K.; Boduszek, B.; Sobek, S.; Kozlowski, H.
Tetrahedron 2006, 62, 2183–2189.