Enantioselective preparation of P-chiral phosphine oxides

Article abstract of DOI:10.1021/ol202916j

A highly efficient chiral auxiliary-based strategy for the asymmetric synthesis of P-chiral phosphine oxides in >98:2 er has been developed. The methodology involves the highly stereoselective formation of P-chiral oxazolidinones that then undergo displacement with a variety of Grignard reagents to prepare the desired phosphine oxides.

Full text of DOI:10.1021/ol202916j

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6576–6579
Enantioselective Preparation of P-Chiral
Phosphine Oxides
Harry Adams, Rebecca C. Collins, Simon Jones,* and Christopher J. A. Warner
Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill,
Sheffield, S3 7HF, U. K.
simon.jones@sheffield.ac.uk
Received October 28, 2011
ABSTRACT
A highly efficient chiral auxiliary-based strategy for the asymmetric synthesis of P-chiral phosphine oxides in >98:2 er has been developed.
The methodology involves the highly stereoselective formation of P-chiral oxazolidinones that then undergo displacement with a variety of
Grignard reagents to prepare the desired phosphine oxides.
Nonsymmetrically substituted phosphorus compounds
are commonplace in asymmetric synthesis, both as chiral
ligands1 and more recently as organocatalysts.2 Despite
their frequent use, the synthesis of such species still remains
a challenge. Commonly employed methods often involve
the formation and separation of diastereomeric mixtures of
menthyl phosphinates and cyclic phosphoramidates, strate-
methods including enantioselective deprotonation of
phosphine-boranes and sulfides,7 enzymatic resolution,8
organometallic mediated transformations,9 and most re-
cently through an asymmetric oxidation of racemic phos-
phines under Appel conditions.10
As part of the need to synthesize a series of chiral
phosphine oxides, the compatibility of Mislow’s menthyl
phosphinate with a range of Grignard reagents was
3
4
ꢀ
gies originally developed by Mislow, and Juge and Genet,
respectively. More recently, such a methodology has facil-
tated the synthesis of P-chiral phosphine boranes and
phosphine sulfides.5 Further strategies toward introduction
of P-chirality have been reviewed,6 with representative
(7) (a) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 9075–9076. (b) Ohashi, A.; Kikuchi, S.-I.; Yasutake, M.;
Imamoto, T. Eur. J. Org. Chem. 2002, 2002, 2535–2546. (c) McGrath,
M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378–16379. (d) Genet,
C.; Canipa, S. J.; O’Brien, P.; Taylor, S. J. Am. Chem. Soc. 2006, 128,
9336–9337. (e) Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.;
Taylor, S. Chem. Commun.2008, 3750–3752. (f) Canipa, S. J.; O’Brien, P.;
Taylor, S. Tetrahedron: Asymmetry 2009, 20, 2407–2412. (g) Gammon,
J. J.; O’Brien, P.; Kelly, B. Org. Lett. 2009, 11, 5022–5025. (h) Gammon,
J. J.; Gessner, V. H.; Barker, G. R.; Granander, J.; Whitwood, A. C.;
Strohmann, C.;O’Brien, P.; Kelly, B. J. Am. Chem. Soc. 2010, 132, 13922–
13927. (i) Granander, J.; Secci, F.; Canipa, S. J.; O’Brien, P.; Kelly, B.
J. Org. Chem. 2011, 76, 4794–4799.
(8) (a) Serreqi, A. N.; Kazlauskas, R. J. J. Org. Chem. 1994, 59, 7609–
7615. (b) Shioji, K.; Ueno, Y.; Kurauchi, Y.; Okuma, K. Tetrahedron
Lett. 2001, 42, 6569–6571. (c) Wiktelius, D.; Johansson, M. J.; Luthman,
K.; Kann, N. Org. Lett. 2005, 7, 4991–4994.
(9) (a) Blank, N. F.; McBroom, K. C.; Glueck, D. S.; Kassel, W. S.;
Rheingold, A. L. Organometallics 2006, 25, 1742–1748. (b) Harvey, J. S.;
Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.; Thompson, A. L.;
Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V. Angew. Chem., Int.
Ed. 2009, 48, 762–766. (c) Chan, V. S.; Chiu, M.; Bergman, R. G.; Toste,
F. D. J. Am. Chem. Soc. 2009, 131, 6021–6032.
(1) For a preface to a special issue on chiral phosphorus ligands, see:
Zhang, X. Tetrahedron: Asymmetry 2004, 15, 2099–2100.
(2) For reviews, see: (a) Methot, J. L.; Roush, W. R. Adv. Synth.
Catal. 2004, 346, 1035–1050. (b) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719–724. (c) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909–3912. (d) Benaglia, M.; Rossi, S. Org. Biomol. Chem. 2010, 8,
3824–3830. (e) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005–1018.
(3) (a) Korpiun, O.; Mislow, K. J. Am. Chem. Soc. 1967, 89, 4784–
4786. (b) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4842–4846.
(4) Juge, S.; Genet, J. P. Tetrahedron Lett. 1989, 30, 2783–2786.
(5) For selected examples, see: (a) Imamoto, T.; Oshiki, T.; Onozawa,
T.; Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244–5252.
(b) Corey, E. J.; Chen, Z.; Tanoury, G. J. J. Am. Chem. Soc. 1993, 115,
ꢀ
11000–11001. (c) Moulin, D.; Bago, S.; Bauduin, C.; Darcel, C.; Juge, S.
Tetrahedron: Asymmetry 2000, 11, 3939–3956. (d) Miura, T.; Yamada,
H.; Kikuchi, S.; Imamoto, T. J. Org. Chem. 2000, 65, 1877–1880.
ꢀ
(e) Bauduin, C.; Moulin, D.; Kaloun, E. B.; Darcel, C.; Juge, S. J. Org.
Chem. 2003, 68, 4293–4301.
(6) (a) Glueck, D. S. Chem.;Eur. J. 2008, 14, 7108–7117. (b) Harvey,
J. S.; Gouverneur, V. Chem. Commun. 2010, 46, 7477–7485.
(10) (a) Bergin, E.; O’Connor, C. T.; Robinson, S. B.; McGarrigle,
E. M.; O’Mahony, C. P.; Gilheany, D. G. J. Am. Chem. Soc. 2007, 129,
9566–9567. (b) Rajendran, K. V.; Kennedy, L.; Gilheany, D. G. Eur. J.
Org. Chem. 2010, 5642–5649.
r
10.1021/ol202916j
Published on Web 11/22/2011
2011 American Chemical Society

examined. Application of the reported conditions gave
essentially no diastereoselectivity in the addition of methyl
phenyl phosphinoyl chloride to menthol, followed by time-
consuming and low-yielding separation of these isomers by
iterative fractional crystallization. Subsequent nucleophi-
lic displacement with an organometallic reagent required
long reaction times at elevated temperatures and led to
poor overall yields of the desired target (<10% over two
steps). Application of a similar strategy noted by Hii and
co-workers using 1,2:5,6-di-O-cyclohexylidene-D-gluco-
furanose (DCG)11 gave an improvement in the diastereos-
electivity (93:7 dr) in reasonable yield (84% of a single
isolated diastereoisomer), but essentially no reactivity with
organometallic reagents other than vinyl magnesium bro-
mide as reported in their work.
Recent studies from our laboratories exploring the
chemistry of N-phosphoryl oxazolidinones highlighted the
reaction of an oxazolidinone with racemic ethyl(methyl)-
chloro phosphate, albeit with poor diastereoselectivity,
and the subsequent displacement with a magnesium alk-
oxide.12 Although no chemistry has been reported on the
reactions of oxazolidinones with phosphinoyl chlorides or
their subsequent reaction with organometallic reagents, we
investigated this as a possible route to access the desired
P-chiral phosphine oxides.
Deprotonation of the oxazolidinone 1 with n-BuLi
at À78 °C followed by addition of methylphenylphosphi-
noyl chloride gave limited conversion to a diastereomeric
mixture of the desired N-phosphinoyl oxazolidinones 2 and
3, withthemajorproductidentified asn-butylmethylphenyl
phosphine oxide, derived from attack of unreacted n-BuLi
with the phosphinic chloride (Table 1, entry 1). Warming
the reaction to 0 °C still gave low conversion; however,
changing the base to the less nucleophilic LiHMDS resulted
in complete conversion of the oxazolidinone 1, providing
products 2 and 3 in a diastereomeric ratio of 83:17 in favor
of 2 (Table 1, entry 3). The use of MeMgBr increased the
diastereoselectivity further but with a significant drop in
the conversion to product (Table 1, entry 4). However, use
of lithium chloride and triethylamine originally reported
by Ho and Mathre13 gave complete conversion to the N-
phosphinoyl oxazolidinone in excellent diastereoselectivity
and good yield after isolation of the major diastereoisomer
by column chromatography (Table 1, entry 5). This process
can be been conducted on a 2 g scale with no significant loss
in yield or selectivity. No formation of the N-phosphinoyl
oxazolidinones was observed using either LiCl or Et3N in
isolation, confirming the synergistic nature of these re-
agents. The absolute configuration of the major diastereoi-
somer 2 was established by X-ray crystallography.
Table 1. Optimisation of the Diastereoselectivity for the For-
mation of N-Phosphinoyl Oxazolidinones 2 and 3
conv
(%)b
ratio
2:3b
yield
(%)c
entry
conditionsa
1
2
3
4
5
1.1 equiv n-BuLi, À78 °C to rt
1.1 equiv n-BuLi, 0 °C
1.1 equiv LiHMDS, 0 °C
1.1 equiv MeMgBr, 0 °C
<10 ND
<10 ND
100
64
83:17
89:11
54
62
74
1.1 equiv LiCl, 1.3 equiv NEt3, 0 °C 100 >95:5
a All reactions performed on a 1 mmol scale in THF (5 mL) and
stirred for 18 h. b Determined by integration of appropriate signals in
the 1H NMR spectrum of the crude reaction material. c Refers to isolated
diastereoisomer 2.
possibility of the reaction proceeding by dynamic kinetic
resolution of the phosphinoyl chloride was also ruled out,
as no change in selectivity was observed when the stoichio-
metry of the phosphinoyl chloride and auxiliary were
altered. Thus it is highly likely that the reaction proceeds
by apical attack of the oxazolidinone opposite the electro-
negative chlorine atom to generate two diastereomeric
trigonal pyramidal intermediates (Scheme 1).15 These in-
termediates undergo pseudorotation in order to avoid the
steric interaction of the phenyl group with the stereodir-
ecting group of the auxiliary. This converts the higher
energy diastereoisomer into the more favored trigonal
pyramidal intermediate that delivers the observed product.
Experimental and computational studies to substantiate
this proposal are currently in progress.
Scheme 1. Proposed Model for the Diastereoselective Forma-
tion of Oxazolidinone 2
The isolation of the major diastereoisomer in greater
than 50% yield rules out the reaction proceeding by kinetic
resolution, analogous to recent reports of the synthesis of
chiral sulfoxides using an Evans derived auxiliary.14 The
(11) Oliana, M.; King, F.; Horton, P. N.; Hursthouse, M. B.; Hii,
K. K. J. Org. Chem. 2006, 71, 2472–2479.
(12) Jones, S.; Selitsianos, D. Tetrahedron: Asymmetry 2005, 16,
3128–3138.
(14) Liu, L.-J.; Chen, L.-J.; Li, P.; Li, X.-B.; Liu, J.-T. J. Org. Chem.
2011, 76, 4675–4681.
(15) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279–
(13) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–2273.
1332.
Org. Lett., Vol. 13, No. 24, 2011
6577

To probe the effect of the substituents upon the diaster-
eoselectivity of the reaction, a series of 4- and 5-substituted
oxazolidinones was prepared16 and screened under the
optimized conditions (Table 2). The optimum reaction
time was found to be 18 h, with lower conversion being
observed when left for shorter reaction times. The diaster-
eoselectivity was good toexcellent, butnonesurpassed that
obtained with the original valine derived auxiliary.
Table 3. Scope of the Reaction of N-Phosphinoyl Oxazolidinone
2 with Grignard Reagentsa
Table 2. Effect of Varying the Oxazolidinone Substituents on
the Diastereoselectivity of the N-Phosphinoyl Oxazolidinone
Formed
entry
R1
R2
conv (%)a
drb
1
2
3
4
5
H
i-Pr
Me
Me
Bn
Bn
100
100
100
100
100
88:12
90:10
81:19
82:18
81:19
Me
H
Me
H
a All reactions performed on a 1 mmol scale in THF (5 mL) and
stirred for 18 h. b Determined by integration of appropriate signals in the
1H NMR spectrum of the crude reaction product.
Functionalized oxazolidinones are known to undergo
nucleophilic attack and subsequent cleavage of the N-acyl
bond with a multitude of oxygen,17 sulfur,18 nitrogen,19
and hydride derived nucleophiles17 but never appear to
have been evaluated in reactions with carbon-based nu-
cleophiles. Treatment of N-phosphinoyl oxazolidinone 2
with 2 equiv of o-tolyl magnesium bromide at 0 °C resulted
in complete formation of the phosphine oxide after 45 min,
which was then isolated in 83% yield. Use of fewer
equivalents of Grignard reagent led to significantly lower
yields. Analysis of the enantioselectivity of the phosphine
oxide showed an er of 98:2 in favor of the (S)-enantiomer,
with the identity being confirmed by comparison with the
literature.20 The apparent leakage in enantioselectivity was
established to be due to trace quantities of minor diaster-
eoisomer 3 by HPLC analysis in the starting material and
confirms thatthereaction proceedsbySN2 (P) attackatthe
stereogenic phosphorus center with inversion of stereo-
chemistry. Oxazolidinone 1 could easily be recovered from
a All reactions performed on a 1 mmol scale in THF (5 mL) and
stirred for 45 min. b Refers to isolated product. c Determined by chiral
phase HPLC analysis. d Reaction performed by dropwise addition of a
solution of N-phosphinoyl oxazolidinone 2 to Grignard reagent.
the reaction because of the significant polarity difference
between it and the phosphine oxide. This represents
the most efficient stereoselective method reported to
date for this type of displacement. Screening of a range
of aryl Grignard reagents showed that both ortho- and
para-substituted aromatics were well-tolerated by the re-
action, and the resulting phosphine oxides were isolated in
good yield and an er of over 98:2 in favor of the major
isomer (Table 3, entries 2À7). Attempts at expanding the
(16) Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E. C.; Shyam
Prasad, R.; Sanganee, H. J. Synlett 1998, 519–521.
(17) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737–1739.
(18) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31,
2849–2852.
(19) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc.
1992, 114, 9434–9453.
(20) Chodkiewicz, W.; Jore, D.; Pierrat, A.; Wodzki, W. J. Organo-
met. Chem. 1979, 174, C21–C23.
6578
Org. Lett., Vol. 13, No. 24, 2011

methodology toward aliphatic Grignard reagents initially
proved troublesome with a noticeable decrease in er, for
example, in the addition of pent-4-enylmagnesium bro-
mide (Table 3, entry 8). With aliphatic Grignard reagents,
it was envisaged that the N-phosphinoyl oxazolidinone 2
may undergo nucleophilic substitution by the metalated
oxazolidinone byproduct, resulting in inversion of stereo-
chemistry at the phosphorus center, analogous to that
proposed by Liu.14 Subsequent nucleophilic attack of the
Grignard reagent would resultin formation of the opposite
enantiomer of phosphine oxide (Scheme 2).
A control experiment involving reaction of a 5,5 di-n-
butyl oxazolidinone with N-phosphinoyl oxazolidinone 2
in the presence of methylmagnesium bromide gave the
expected crossover products by LCÀMS, confirming this
reaction pathway. This unwanted process could be mini-
mized by introduction of the N-phosphinoyl oxazolidi-
none 2 dropwise to a solution of excess Grignard reagent
(Table 3, entry 9). Gratifyingly, under these conditions no
racemisation was observed, and the resulting phosphine
oxide was obtained with an excellent er.
In conclusion, a range of diaryl-methyl and alkyl-methyl-
phenyl chiral phosphine oxides have been synthesized
quickly under mild conditions in good yield and excellent
enantioselectivity using the N-phosphinoyl oxazolidinone
derived from L-valine and methylphenyl phosphinic chlor-
ide. Further studies into the origin of the stereoselectivity,
expanding the methodology to encompass the synthesis of
phosphine sulfides and boranes and diversifying the scope
of both the Grignard reagent and phosphinic chloride used
are in progress and will be reported in due course.
Scheme 2. Proposed Racemisation Pathway for Reaction with
Alkyl Grignard Reagents
Acknowledgment. We thank the EPSRC and the Uni-
versity of Sheffield for support.
Supporting Information Available. Experimental proce-
dures, characterization data and spectra for all new com-
pounds, and X-ray data for compound 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
6579