A Novel Resolution Procedure for the Preparation of P-Stereogenic Phosphine Oxides

Article abstract of DOI:10.1021/ol991174s

(Matrix Presented) A new general route for preparing enantiomerically pure P-stereogenic phosphine oxides has been developed by exploiting the Staudinger reaction between racemic tertiary phosphines and an enantiomerically pure organoazide. The resulting

Full text of DOI:10.1021/ol991174s

ORGANIC
LETTERS
1999
Vol. 1, No. 12
2009-2011
A Novel Resolution Procedure for the
Preparation of P-Stereogenic Phosphine
Oxides
Neil G. Andersen, Philip D. Ramsden, Daqing Che, Masood Parvez,‡ and
,†
Brian A. Keay*
Department of Chemistry, The UniVersity of Calgary,
Calgary, Alberta, Canada T2N 1N4
keay@ucalgary.ca
Received October 21, 1999
ABSTRACT
A new general route for preparing enantiomerically pure P-stereogenic phosphine oxides has been developed by exploiting the Staudinger
reaction between racemic tertiary phosphines and an enantiomerically pure organoazide. The resulting phosphinimines are easily resolved by
either crystallization or flash chromatography and serve as synthetic intermediates toward enantiomerically pure phosphine oxides.
Asymmetric synthesis mediated by transition metals bearing
enantiomerically pure phosphine ligands has become a
cornerstone of organic chemistry and has allowed for the
preparation of a variety of complex natural products.1 As a
result, much effort has been directed toward the rational
design, synthesis, and testing of new enantiomerically pure
phosphines for various synthetic purposes. A diverse range
of enantiomerically pure phosphines is now commercially
available, and numerous other ligands have been reported
in the literature.2 Among these known phosphines, however,
the vast majority of examples are predicated upon carbon-
based central or axial chirality rather than asymmetry about
a tetrahedral phosphorus atom. The low abundance of
P-stereogenic phosphines for asymmetric transformations is
due, in part, to the relative difficulty of obtaining such
compounds by resolution procedures or diastereoselective
synthesis.3 While there have been several recent advances
in the diastereoselective synthesis of P-stereogenic materials,4
there are still relatively few resolution methods available for
obtaining enantiomerically pure tertiary phosphines. We
herein report a new, simple, and effective method for
obtaining P-stereogenic phosphine oxides using an enantio-
merically pure organoazide resolving agent.
We rationalized that a Staudinger reaction between a
racemic tertiary phosphine and an enantiomerically pure
azide could potentially furnish a 1:1 mixture of diastereo-
meric phosphinimines if the PdN bond rotational barrier was
low enough to prevent geometrical isomerism.5 To our
delight, treatment of racemic phosphine 1a with (1S)-camphor-
sulfonyl azide 26 afforded an equimolar mixture of dia-
† Tel.: (403) 220-5354. Fax: (403) 284-1372.
‡ To whom correspondence regarding crystallographic data should be
addressed.
(1) Stephenson, G. R. AdVanced Asymmetric Synthesis; Chapman &
Hall: New York, 1996 and references therein.
(2) For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley & Sons: New York, 1994; Chapter 2. (b) Ojima, I.
Catalytic Asymmetric Synthesis; VCH Publishers: Weinheim, 1993; Chapter
1. (c) Morrison, J. D. Asymmetric Synthesis; Academic Press: New York,
1985; Vol. 5, Chapter 1.
(3) Pietrusiewicz, K. M.; Zablocka M. Chem. ReV. 1994, 94, 1375.
(4) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279.
(5) The calculated PdN rotational barrier is ca. 2.54 kcal/mol. See:
Koketsu, J.; Ninomiya, Y.; Suzuki, Y.; Koga, N. Inorg. Chem. 1997, 36,
694 and references therein.
10.1021/ol991174s CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/13/1999

stereomeric phosphinimines, without complication by po-
in the case of isopropylmethylphenylphosphine (1c) could
the diastereomers not be fully separated since the first
diastereomer to crystallize was always found to contaminate
the mother liquor to a small degree.15 Cleavage of the
isomerically pure phosphinimines via acid hydrolysis was
found to afford stereochemically pure16 phosphine oxides
8a-f (Table 2), which were easily separated from the
sulfonamide byproduct17 via column chromatography.
1
tential bond isomers, as evidenced by H and 31P NMR
analysis. However, conditions could not be found to separate
the resulting mixture by chromatography or crystallization.
This disappointing result led us to screen a variety of other
enantiomerically pure azides7 in hopes of finding an efficient
resolving agent. We were pleased to find that the dia-
stereomeric phosphinimines produced from the reaction of
(1S,2R)-O-(tert-butyldimethylsilyl)isobornyl-10-sulfonyl azide
(3) with various racemic phosphines were easily separable
by fractional crystallization or flash chromatography.
This new, effective resolving agent can easily be prepared
on a large scale by the three-step sequence shown in Scheme
1 from known isoborneol derivative 4.8
Table 2. Hydrolysis of Isomerically Pure Phosphinimines
Scheme 1. Synthesis of the Resolving Agent9 a
SM
R1
R2
R3
yield (%)
6a
7b
6c
6d
6e
7f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
C6H11
C5H9
CH(CH3)2
1-naphthyl
9-phenanthryl
p-PhC6H4
93
93
94
96
>99
93
a Reagents and conditions: (a) TBSCl, Et3N, DMF, rt, 3 h; (b)
SOCl2, C6H6, DMF; reflux 12 h; (c) NaN3, DMA, H2O, 60 °C 12
h, 57% isolated yield from 4.
1-naphthyl
To investigate the stereochemical course of the hydrolysis
step, a single-crystal X-ray structure determination of phos-
phinimine 6c was performed from which the absolute
configuration of the phosphorus center was determined to
have R configuration (Figure 1).
Treatment of racemic phosphines10 1a-f with (1S,2R)-
sulfonyl azide 3 in THF at 60 °C smoothly affords the desired
phosphinimine mixtures11 in high yield (Table 1). Separation
(7) Alkyl azides such as (+)-neomenthyl azide, 3R-azido-5R-cholestane,
and 6-azido-6-deoxy-1,2,3,4-di-O-isopropyliden-R-D-galactopyranose were
found to be unsuitable resolving agents since the resulting phosphinimine
mixtures were generally less stable toward storage or flash chromatography.
(8) Dimmel, D. R.; Fu, W. Y., J. Org. Chem. 1973, 38, 3782.
Table 1. Treatment of Racemic Phosphines with Azide 314
(9) Selected spectral data for azide 3: R20D ) -36.2° (c ) 5.5, CHCl3);
1
IR (KBr) cm-1 2131; H NMR (200 MHz) δ 4.06 (m, 1H), 3.97 (d, J )
14.0, 1H), 3.12 (d, J ) 14.0 Hz, 1H), 2.10-1.88 (m, 1H), 1.86-1.49 (m,
4H), 1.47-1.06 (m, 3H), 1.05 (s, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.11 (s,
3H), 0.08 (s, 3H); 13C NMR (50 MHz) δ 75.8, 54.9, 50.4, 49.3, 44.5, 41.9,
28.6, 27.2, 25.8, 20.6, 20.1, 17.8, -4.1, -5.4; exact mass calcd for
C16H31N3O3SSi - C4H9 316.1151, found 316.1120.
Diastereomer
(10) Racemic phosphines were prepared via known general methods,
see: (a) Payne, N. C.; Stephan, D. W. Can. J. Chem. 1980, 58, 15. (b)
Bestman, H. J.; Lienert, J.; Heid, E. Chem. Ber. 1982, 115, 3875. (c) Wittig,
G.; Braun, H.; Cristau, H. Liebigs Ann. Chem. 1971, 751, 17.
(11) Analytical samples of all new compounds were obtained by
crystallization or flash chromatography. The structure assigned to each
compound was in accord with its spectral (1H, 13C, and 31P NMR, IR, and
MS) characteristics including suitable combustion analysis (C, H) and/or
high-resolution mass spectral analysis.
(12) Entries 1a-1c of Table 1 were separated by fractional crystallization.
(13) Entries 1d-1f of Table 1 were separated by flash chromatography.
(14) Typical Procedure. Azide 3 (0.410 g, 1.10 mmol) in THF (2.5
mL) was added dropwise to the starting phosphine (1.00 mmol) in THF
(2.5 mL). The resulting mixture was then heated (60 °C, 12 h) and
subsequently concentrated in vacuo. The crude phosphinimines thus obtained
were separated by crystallization or flash chromatography. The yield reported
in Table 1 is the combined isolated yield of 6 and 7. In each case, compound
6 was assigned as the first isomer to crystallize or elute from the column.
(15) The phosphinimine purity is easily determined by 1H and 31P NMR
analysis. Compound 7c was obtained as a ca. 7:1 mixture with isomer 6c.
(16) Optical rotation data for the phosphine oxides closely matched the
reported values. See Table 3.
entry
R1
R2
R3
yield (%)
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
C6H11
C5H9
94
90
87
94
89
91
CH(CH3)2
1-naphthyl
9-phenanthryl
p-PhC6H4
1-naphthyl
of the resulting mixtures may be accomplished by fractional
crystallization from petroleum ether or acetonitrile.12 In some
cases, resolution may be obtained by simple flash chroma-
tography using hexane/ethyl acetate eluent mixtures.13 Only
(6) Cremlyn, R.; Burrell, K.; Fish, K.; Hough, I.; Mason, D. Phosphorus
Sulfur 1982, 12, 197.
(17) At present, we have not found a suitable method for recycling the
resolving agent.
2010
Org. Lett., Vol. 1, No. 12, 1999

oxides 8a, 8c-d, and 8f. In addition, we found that the
phosphine oxide obtained from the hydrolysis of 6b or 6e
exhibited a rotation equal in magnitude but opposite in sign
to the hydrolysis product of 7b or 7e, respectively.
Since reliable methods have been developed to stereo-
specifically reduce phosphine oxides to the corresponding
phosphines with either retention or inversion of configuration
at phosphorus,20 our new resolution protocol also serves as
a route to enantiomerically pure tertiary phosphines. We are
currently investigating the direct reduction of phosphinimines
6a-f and 7a-f to give enantiomerically pure phosphines.
The results of these studies will be disclosed elsewhere.
In summary, we have developed a novel, facile method
for the resolution of P-stereogenic phosphine oxides using a
Staudinger reaction with enantiomerically pure organoazide
3. The resulting phosphinimine diastereomers may be
separated by crystallization or flash chromatography and used
as synthetic intermediates toward enantiomerically pure
phosphine oxides and phosphines.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
financial support. N.G.A. gratefully acknowledges receipt
of an NSERC postgraduate scholarship, a Ralph Steinhauer
Award of Distinction, and an Honorary Killam fellowship.
P.D.R. gratefully acknowledges the receipt of an NSERC
summer studentship.
Figure 1. ORTEP drawing of phosphinimine 6c18 drawn with 30%
probability ellipsoids, except for the hydrogen atoms which are
represented as spheres of arbitrary size.
Treatment of phosphinimine 6c with 3 M H2SO4 in
refluxing 1,4-dioxane for 12 h furnished (-)-phosphine oxide
8c known to be of S configuration.19 Hence the phosphin-
imine hydrolysis proceeds stereospecifically with inversion
of configuration. Moreover, this relationship, in conjunction
with literature data, may be used to unambiguously assign
some of the phosphinimine absolute configurations (Table
3). Although the stereochemical configuration and optical
Supporting Information Available: Experimental pro-
cedure for the preparation of 3, characterization data for
compounds 3, 6a-f, 7a-b, 7d-f, and 8b, and X-ray data
for compound 6c. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL991174S
(18) Compound 6c: orthorhombic P212121 (No. 19); a ) 12.337(4) Å,
b ) 12.833(3) Å, c ) 18.751(2) Å; V ) 2969(1) Å3; Z ) 4; R ) 0.0459;
wR ) 0.1208; Flack parameter [Flack, H. D. Acta Crystallogr. 1983, A39,
876] ) -0.03(2). Bijvoet analysis was performed. A refinement of the
inverted structure was carried out and converged with R ) 0.0543, wR )
0.1427 with Flack parameter ) 1.03(3) and was therefore rejected as the
absolute configuration present in the crystal.
Table 3. Assignment of Phosphinimine Absolute Configuration
from Hydrolysis Product Optical Rotation Data
configuration
(19) Farnham, W. B.; Lewis R. A.; Murray, R. K.; Mislow, K. J. Am.
Chem. Soc. 1970, 92, 5809.
SM
yield (%)
product R20 (c, solvent)
product 8
SM
D
(20) See: (a) Horner, L.; Balzer W.-D., Tetrahedron Lett. 1965, 1157.
(b) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7012.
(c) Marsi, K. L. J. Org. Chem. 1974, 39, 265. (d) Naumann, K.; Zon, G.;
Mislow, K. J. Am. Chem. Soc. 1969, 91, 2788.
6a
7b
6c
6d
6e
7f
93
93
94
96
>99
93
+19.2 (0.93, MeOH)21
+33.3 (1.62, MeOH)
-22.6 (1.00, MeOH)22
+19.8 (2.92, MeOH)23
+71.4 (1.14, MeOH)24
+26.9 (0.62,CHCl3)25
RP
SP
(21) R20D +19.0° in MeOH; (+)-R. Korpium, O.; Lewis, R. A.; Chickos,
J.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4842.
SP
SP
RP
RP
(22) R20 -21.2° in MeOH; (+)-R. Byrne, L. T.; Engelhardt, L. M.;
D
Jacobsen, G. E.; Leung, W.-P.; Papasergio, R. I.; Raston, C. L.; Skelton,
RP
SP
B. W.; Twiss, P.; White, A. H. J. Chem. Soc., Dalton Trans. 1989, 105.
(23) R20 -19.8° in MeOH; (+)-S. Luckenbach, R. Phosphorus 1972,
D
5, 223.
(24) Although methyl-9-phenanthrylphenylphosphine oxide has appeared
numerous times in the literature, to our knowledge no optical rotation data
has been reported for this compound.
rotation data have not been reported for phosphine oxides
8b and 8e, we are confident that we have obtained these
compounds in optically pure form on the basis of the good
agreement observed in the optical rotation data for known
(25) R32 -27.0° in MeOH. Tani, K.; Brown, L. D.; Ahmed, J.; Ibers,
D
J. A.; Yokota. M.; Nakamura, A.; Otsuka, S. J. Am. Chem. Soc. 1977, 99,
7876.
Org. Lett., Vol. 1, No. 12, 1999
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