A simple route to chiral phosphinous acid-boranes

Article abstract of DOI:10.1039/b802817f

We report a simple one-pot synthesis of enantiomerically enriched alkyl- and arylphenylphosphinous acid-borane starting from readily available (R _P)-(-)-menthylhydrogenophenylphosphinate and organolithium reagents. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802817f

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A simple route to chiral phosphinous acid–boranesw
´
Delphine Moraleda, David Gatineau, David Martin, Laurent Giordano and Gerard Buono*
Received (in Cambridge, UK) 19th February 2008, Accepted 26th March 2008
First published as an Advance Article on the web 22nd April 2008
DOI: 10.1039/b802817f
We report a simple one-pot synthesis of enantiomerically
enriched alkyl- and arylphenylphosphinous acid–borane starting
from readily available (RP)-(À)-menthylhydrogenophenyl-
phosphinate and organolithium reagents.
meric equilibrium, SPOs do not react with boranes, under mild
conditions. We knew from the report of Pietrusiewicz and co-
workers5b that the reaction could occur at room temperature
when deprotonating the SPO. Recently, our interest in SPOs9
prompted us to design an enantioselective synthesis of such
compounds from (RP)-(À)-menthyl hydrogenophenylphosphi-
nate 1.9c We felt that this approach could be adapted to the
synthesis of phosphinous acid–boranes.
The availability of chiral organophosphorous compounds has
allowed tremendous achievements in chemistry, in particular
in the field of asymmetric metal catalysis.1 However most of
the popular chiral P-ligands, such as the ubiquitous BINAP,
are based on chiral C-backbones. In comparison, the occur-
rence of P-stereogenic ligands in literature is lower because
their synthesis often presents a challenge. As P-chiral com-
pounds could not be found in the natural pool of chirality,
they were initially obtained by the resolution of racemic
mixtures by means of a chiral auxiliary. Nowadays, stereo-
selective syntheses are supplanting this methodology.2 For
instance, one of the most convenient and versatile approach
to chlorophosphine–boranes or phosphinite–boranes, which
are precursors of P-chiral tertiary phosphine–boranes,3 is the
nucleophilic substitution of chiral 1,3,2-oxazaphospholidine–
boranes with organolithium reagents. However, this method,
Initially, we examined the model reaction of enantiopure
(RP)-(À)-110 with MeLi (2.5–3 equiv.) at À78 1C in THF. The
first equivalent of organometallic reagents was required to
abstract the proton carried by (RP)-(À)-1, whereas the second
equivalent was used for the substitution of menthyloxy group.
At this stage, lithium phosphinate species (S)-2a was quenched
with BH3ÁSMe2. The desired methylphenyl phosphinous
acid–borane (S)-(À)-3a was obtained in 78% overall yield
and 95% ee (Table 1, entry 1). Of note, when the reaction
was carried out with MeMgBr instead of MeLi, (S)-(À)-3a was
obtained with poorer yield (64%) and ee (86%).
Then, we briefly explored the scope of this first approach
(method A) using various organolithium reagents in similar
conditions. The phosphinous acid–boranes 3a–g were ob-
tained in good yields (Table 1). Good enantioselectivities
(91–98% ee) were observed with aryllithium reagents (entries
4–6) and n-butyllithium (89% ee, entry 2). Conversely, 3g and
3c were obtained with modest 72 and 60% ee, respectively
(entries 7 and 3). The latter case was particularly enlightening.
Indeed, we knew that the first step of the procedure afforded
2c with at least 84% ee.9c In addition, ee’s remained un-
changed when stirring 2c at room temperature for 3 days,
suggesting that this compound did not racemize under our
conditions. Thus, a significant loss of enantiopurity occurred
upon the addition of BH3ÁSMe2. This statement is in agree-
ment with the recent report of Stankevic et al., who noticed
that the deprotonation of resolved enantiopure tert-butylphe-
nylphosphine oxide, followed by the addition of BH3, afforded
3c with only 74% ee.5a
which was initially described by Juge
´
et al.,4 suffers from
limitations. For instance, the subsequent acidolysis (or metha-
nolysis) step is limited to not sterically hindered substituents.
As recently stated,2d an overall methodology is still lacking.
Recently, Pietrusiewicz and Stankevic demonstrated the
potentiality of chiral phosphinous acid–boranes as key
intermediates for the preparation of various P-stereogenic
compounds, such as bulky tertiary and secondary phosphine–
boranes, phosphinite–boranes or boranatophosphinous–sulfo-
nic anhydrides.5 Some enantiopure phosphinous acid–boranes
are available, but only from racemic resolution.5e,f Despite
promising results, this methodology is at a very early stage of
development. In particular, an efficient and versatile stereo-
selective route to chiral phosphinous acid–boranes remains to
be designed. To our knowledge there are only two reports of
stereoselective syntheses (Scheme 1), and none exceeds 73% of
enantiomeric excess (ee).6 Herein we report a simple one-pot
and stereoselective synthesis of phosphinous acid–boranes,
with up to 99% ee.
The phosphinous acid-secondary phosphine oxide (SPO)
tautomerism is well known.7 Usually, only the latter, which
is the more stable, is observed.8 Curiously, despite the tauto-
´
´
Universite Aix-Marseille, Institut des Sciences Moleculaires de
Marseille, ECM, CNRS, UMR 6263, Av. Escadrille Normandie
Niemen, Marseille Cedex 20, 13397. E-mail: gerard.buono@
univ-cezanne.fr
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic analyses. See DOI: 10.1039/b802817f
Scheme 1 Previously reported stereoselective routes to chiral phos-
phinous acid–boranes.
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Table
(method A)
1
One-pot synthesis of phosphinous acid–boranes 3a–g
Table
(method B)
2
One-pot synthesis of phosphinous acid–boranes 3a–g
Entry
1
R
4a–g
(d31P/
ppm)
Product
Yielda
(%)
eeb
(%)
Entry
R
Product
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
Me
n-Bu
t-Bu
2-MeC6H4
2-PhC6H4
1-Naphthyl
1-Furyl
S-(À)-3a
(À)-3b
78
84
82
93
84
88
92
95
89
60
98
93
91c
72
Me
100
S-(À)-
3a
(À)-3b
S-(À)-
3c
78
95
S-(À)-3c
(+)-3d
(À)-3e
2
3
n-Bu
t-Bu
106
115
70
70
89
84
R-(À)-3f
(+)-3g
4
2-
97
(+)-3d
75
97
a
b
Yields after purification. Enantiomeric excesses were determined
Me(C6H4)
2-Ph(C6H4)
1-Naphthyl
by HPLC analysis on Chiralpak AS-H (l = 254 nm; 1 mL minÀ1
eluent: hexane–i-PrOH mixtures). Enantiomeric excess was deter-
mined by HPLC analysis on Chiralpak OD-H (l = 254 nm;
1 mL minÀ1; eluent: hexane–EtOH) (8 : 2).
;
5
6
99
92
(À)-3e
R-(À)-
3f
85
75
95
99c
c
7
1-Furyl
75
(+)-3g
72
80
a
b
Yields after purification. Enantiomeric excesses were determined by HPLC
analysis on Chiralpak AS-H (l = 254 nm; 1 mL minÀ1; eluent: hexane–i-PrOH
c
mixtures). Enantiomeric excess was determined by HPLC analysis on
Chiralpak OD-H (l = 254 nm; 1 mL minÀ1; eluent: hexane–EtOH) (8 : 2).
Unsatisfied with these results we decided to explore a new
approach (method B). After the addition of (RP)-(À)-1 to
organolithium reagents,11 lithium phosphinate species 2a–g
were trapped by addition of Me3SiCl. The resulting O-silylated
product 4 was then protected using BH3ÁSMe2 and desilylated
by treatment with aqueous HCl. All steps were conveniently
monitored by 31P NMR. This one-pot procedure afforded the
desired phosphinous acid–borane 3a–g in 70–85% yields after
purification. All results are summarised in Table 2.
Scheme 2 Two-step stereoselective synthesis of enantiopure 3c.
Using this method almost all enantioselectivities have been
improved (Table 2, entries 3, 5, 6 and 7). Of note, when the
reaction was performed with t-BuLi, S-(À)-3c was obtained
with 84% ee. This value, which corresponds to the enantios-
electivity of the first step, seemed to indicate that the three last
steps occurred without significant racemization. To verify this
point, we synthesized tert-butylphenylphosphine oxide 5 by
adding (RP)-(À)-1 to tert-butyllithium.9c A single crystallisa-
tion afforded (S)-(À)-5 with 99.6% ee.9b Addition of Me3SiCl
and the subsequent addition of BH3ÁSMe2 afforded (S)-(À)-3c
with 499% ee, as indicated by HPLC analysis (Scheme 2).
In conclusion, we reported simple diastereoselective one-pot
syntheses of enantioenriched chiral phosphinous acid–boranes
starting from cheap and readily available (RP)-(À)-menthylhy-
drogenophenylphosphinate and organolithium reagents.
Although direct trapping of the resulting lithium phosphinate
species with BH3ÁSMe2 afforded the desired products with up
to 98% ee, it generally resulted in partial racemization. Such
loss could be avoided by using Me3SiCl as trapping agent. This
general approach affords an unprecedented versatile diastereo-
selective entry to chiral phosphinous acid–boranes, and there-
fore, to a broad range of P-chiral compounds.
Notes and references
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A
Pfaltz and H Yamamoto, Springer, Heidelberg, 1999;
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4. (a) S. Juge
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´
, M. Stephan, J. A. Laffitte and J. P. Genet, Tetrahedron
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552–556.
We are grateful to CNRS and ANR project ‘‘SPOs Preli-
gands’’ (Contract No. BLAN07-1_190839) for funding. D. G.
thanks MENRT for the doctoral fellowship. We also think Dr
N. Vanthuyne (CNRS, UMR 6263) for HPLC analyses.
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6. (a) J. Uziel, M. Stephan, E. B. Kaloun, J. P. Genet and S. Juge
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8. A recently isolated stable phosphinous acid stands as an exception
to this rule: (a) B. Hoge, S. Neufeind, S. Hettel, W. Wiebe and
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11. ‘Inverse’ addition of methyllithium or butyllithium on
(RP)-(À)-1 was also performed: similar enantioselectivities were
observed.
¨
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Chem. Commun., 2008, 3031–3033 | 3033