Synthesis of P-stereogenic phosphorus compounds. Asymmetric oxidation of phosphines under appel conditions

Article abstract of DOI:10.1021/ja072925l

Racemic phosphines are converted into enantioenriched phosphine oxides via a synthetically simple, but theoretically interesting, oxidation procedure in good enantiomeric excess (up to 80%) and excellent yields (>95%). These phosphine oxides can be oxidatively coupled to provide easy access to enantiopure DiPAMPO analogues. Particularly attractive aspects of this procedure are the operational simplicity and the low cost required to synthesize these high value compounds. Copyright

Full text of DOI:10.1021/ja072925l

Published on Web 07/14/2007
Synthesis of P-Stereogenic Phosphorus Compounds. Asymmetric Oxidation
of Phosphines under Appel Conditions
Enda Bergin,†,‡ Cormac T. O’Connor,†,‡ Shane B. Robinson,† Eoghan M. McGarrigle,†
Colm P. O’Mahony,† and Declan G. Gilheany*,†,‡
School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology, Conway Institute,
UniVersity College Dublin, Belfield, Dublin 4, Ireland, and Celtic Catalysts Ltd., NoVa Centre,
Belfield InnoVation Park, Dublin 4, Ireland
Received April 26, 2007; E-mail: declan.gilheany@ucd.ie
Scheme 1. Reduction and Oxidation of P(III)/P(V) Compounds
Chiral nonracemic phosphorus compounds are ubiquitous in
catalytic asymmetric synthesis, both as ligands in metal-based
processes1 and as organocatalysts in their own right.2 However,
although a very large number of such ligands have been tested, the
great majority have their chirality located on the carbon backbone
(C-stereogenic, e.g., BINAP and DuPHOS)1a instead of on the
phosphorus atom (P-stereogenic, e.g., DiPAMP).1c This is despite
the fact that better chiral induction might be expected by incorpora-
tion of chirality as close as possible to the catalytic center.3 Although
P-stereogenic ligands have proven to be effective,4 relatively few
have been studied because they are difficult to synthesize.5 Early
methods were based on resolution and the generation of unequal
mixtures of diastereomers,5a while more recent strategies include
desymmetrization, enzymatic resolution, and catalytic asymmetric
synthesis.5b,6 Some of these methods can be very effective, but most
are limited in scope in some way and there remains a clear need
for a general solution. Herein we report on our efforts to provide
such a methodology.
We have been interested in this difficult problem for some time.7
We felt that there was promise in strategies involving kinetic
resolution (KR) or dynamic kinetic resolution (DKR) in P(III)/P(V)
interconversions (Scheme 1). Our initial approach centered on KR
in asymmetric reduction (Scheme 1a), but this gave uniformly low
selectivity,7a in line with previous reports,8 and we turned our
attention to asymmetric oxidation (Scheme 1b). There have been
very few reported successes at KR/DKR in such systems,5a,9 most
notably by Perlikowska et al.9a who reported up to 39% ee in the
KR of P-stereogenic tertiary phosphines and 70% ee for a single
example of the first DKR of a chlorophosphine. In our early
experiments,7b,c we reacted racemic phosphines with chiral nonra-
cemic epoxides hoping that the high temperature of the reaction
would allow DKR through racemization of the phosphine, but the
selectivity was low (20% at best).
Scheme 2. Racemic Phosphine/Chiral Alcohol in Appel
Conditions
menthol in benzene at reflux gave the phosphine oxide ((R)-
PAMPO) in good yields and up to 24% ee.
Subsequently, we used the more reactive hexachloroacetone
(HCA)12 in place of CCl4, which allows reaction at much lower
temperatures. A wide range of commercially available chiral
nonracemic alcohols were screened at room temperature, and it was
found that terpineols gave the highest selectivity, although certain
diols and amino alcohols were also effective in inducing enanti-
oselectivity in PAMP oxidation.13 We then focused on cyclic
secondary alcohols at -78 °C for studies with a wider range of
tertiary phosphines, with results shown in Table 1 and Chart 1.
Table 1 shows that phosphine oxides can be produced in good
ee (up to 80%, two cases) and excellent yield. In most cases the
highest selectivity was achieved with menthol, an inexpensive,
readily available alcohol. In addition, no stereochemical information
is lost in the reaction, and (-)-menthol is converted into (+)-
neomenthyl chloride with a very high selectivity. The cost of (-)-
menthol, even in stoichiometric quantities, compares favorably with
the cost of typical loadings of a chiral metal-based catalyst.
To show the power of our method, we used it for a simple two-
step synthesis of optically pure bisphosphine oxides from racemic
monophospine, via dimerization of the enantioenriched monooxide
(Scheme 3). In the example shown, chiral dimer (R,R)-6 was
produced in 98% ee and the minor amount of meso compound
formed was easily removed by recrystallization from benzene, which
yielded enantiopure (>99.9% ee) bisphosphine oxide in an isolated
yield of 73% from the racemic phosphine.
Scheme 4 shows some of the known or likely reaction intermedi-
ates under Appel conditions.11a Analysis of our reaction mixtures
by 31P NMR shows three signals: one corresponding to phosphine
oxide, which increases as the reaction progresses, and a transient
narrowly spaced unequal pair at ∼65-70 ppm. We propose that
these are diastereomeric alkoxyphosphonium salts (a and b).
Stereoselection could occur at several points in Scheme 4. Perhaps
most likely is in equilibration between the diastereomeric phos-
phoranes, which then collapse to produce unequal amounts of salts
a and b, and hence unequal amounts of oxide. This would constitute
dynamic thermodynamic resolution.14 However, if the phosphonium
A way to achieve facile interconversion of stereogenic phos-
phorus centers at low temperatures is via pseudorotation of
pentavalent pentacoordinate phosphorus compounds (10P5).10 We
therefore explored a variety of processes that could involve 10P5,
and we report now our preliminary results on an asymmetric version
of the oxidation/reduction/dehydration system known as the Appel
conditions.11 Typically, these conditions involve use of PPh3/CCl4
to convert an alcohol to an alkyl chloride in high yield. From our
perspective, these conditions are an oxidation of a phosphine
involving a potentially chiral reagent (Scheme 2). Therefore, we
were encouraged when our first experiments with this system gave
some selectivity. Treatment of racemic phenyl-ortho-anisylmeth-
ylphosphine (PAMP, the precursor of DiPAMP) with CCl4 and (-)-
† University College Dublin.
‡ Celtic Catalysts Ltd.
9
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J. AM. CHEM. SOC. 2007, 129, 9566-9567
10.1021/ja072925l CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantiomeric Excessesa Obtained in the DKR of
P-stereogenic phosphine oxides in excellent yields and opens up a
new, facile route for the synthesis of enantiopure bisphosphine
oxides. The latter is especially important because many methods
exist for their conversion into phosphines with stereocontrol (both
retention and inversion),15 and the resulting bisphosphines have high
utility in asymmetric catalysis. We are investigating the reaction
mechanism and the use of the products in catalytic asymmetric
synthesis, which will be the subject of future reports.
Phosphines According to Scheme 2 (using HCA)b
#
R1
alcohol
% ee
config
1c
2c
3c
4c
5c
6
7
8
9
10
11
12
13
14
15
16
17
18
o-anisyl
o-anisyl
o-anisyl
o-anisyl
o-anisyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-iPrPh
o-iPrPh
o-iPrPh
o-ClPh
tBu
(-)-menthol 1a
50
64
42
77
75
80
59
71
58
80
41
20
71
48
6
(R)
(S)
(S)
(R)
(S)
(R)
(S)
(S)
(S)
(R)d
(S)d
(R)d
nde
(S)
(R)
(S)
(R)
(S)
(+)-neomenthol 3
(+)-isomenthol 2
(-)-8-phenylmenthol 1b
(+)-trans-2-tert-butylcyclohexanol 4
(-)-menthol 1a
(+)-neomenthol 3
(+)-isomenthol 2
Acknowledgment. We thank Dr. Gary King for determining
the absolute configuration of 6. For financial support, we thank
Enterprise Ireland (Grants SC/96/429 (S.B.R.), ST/00/040), the Irish
Research Council for Science Engineering and Technology (Schol-
arship for E.B.), and University College Dublin (Demonstratorships
for C.T.O., C.P.O., E.M.M.).
(+)-trans-2-tert-butylcyclohexanol 4
(-)-menthol 1a
(+)-neomenthol 3
(-)-8-phenylmenthol 1b
(-)-menthol 1a
(-)-menthol 1a
tBu
(+)-neomenthol 3
Supporting Information Available: Procedures for the asymmetric
oxidation reactions, phosphine syntheses, and a listing of results of
oxidations at room temperature with other chiral alcohols are available.
This material is available free of charge via the Internet at http://
pubs.acs.org.
tBu
(+)-isomenthol 2
42
8
7
tBu
(-)-8-phenylmenthol 1b
(+)-trans-2-tert-butylcyclohexanol 4
tBu
a Determined by CSP HPLC (see SI). b Phosphine (0.11 mmol), alcohol
(1.2 equiv), HCA (1 equiv), yields >95% (not isolated). c No 4 Å MS used,
due to decreased yield by product absorption; see SI for details. d Assigned
by analogy with o-anisyl and o-tolyl cases. e Not determined.
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Scheme 3
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In summary, the results presented here represent a completely
unprecedented method for the synthesis of highly enantioenriched
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