Consecutive dynamic resolutions of phosphine oxides

Article abstract of DOI:10.1039/c3sc52913d

A crystallization-induced asymmetric transformation (CIAT) involving a radical-mediated racemization provides access to enantiopure secondary phosphine oxides. A consecutive CIAT is used to prepare enantio- and diastereo-pure tert-butyl(hydroxyalkyl)phenylphosphine oxides.

Full text of DOI:10.1039/c3sc52913d

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Consecutive dynamic resolutions of phosphine
oxides†
Cite this: DOI: 10.1039/c3sc52913d
a
a
a
b
c
Felix A. Kortmann, Mu-Chieh Chang, Edwin Otten, Erik P. A. Couzijn,* Martin Lutz
and Adriaan J. Minnaard*a
Received 21st October 2013
Accepted 26th November 2013
A crystallization-induced asymmetric transformation (CIAT) involving a radical-mediated racemization
provides access to enantiopure secondary phosphine oxides. A consecutive CIAT is used to prepare
enantio- and diastereo-pure tert-butyl(hydroxyalkyl)phenylphosphine oxides.
DOI: 10.1039/c3sc52913d
www.rsc.org/chemicalscience
approach that very recently has been extended by a research
Introduction
17
group of Boehringer Ingelheim, and the BuLi/spartein-medi-
18,19
Phosphine oxides play an important role as precursors for chiral ated desymmetrization of aryldimethylphosphine-P-borane.
phosphine ligands as well as being powerful ligands them- The latter has been extended to a dynamic thermodynamic
1
,2
20
selves.
Recently, bisphosphine monoxides have caught resolution variant. Both methods are frequently applied but
3
considerable attention due to their hemilabile coordination.
scale-up is not always straightforward since purication by
While asymmetric catalysis with phosphine–transition metal chromatography is oen involved.
complexes initially employed ligands that were stereogenic at
Phosphine oxides, both secondary (SPO) and tertiary (TPO),
phosphorus (P-chiral ligands, such as monodentate CAMP and seem to be for us the ideal precursors to enantiopure tertiary
its dimer DiPAMP), ligands with backbone chirality turned out phosphines. Phosphine oxides are readily prepared on the large
to be more readily accessible and emerged subsequently in scale in racemic form, are air- and moisture-stable and most
4
–6
numerous variations (e.g. DIOP, BINAP, JOSIPHOS).
Currently, however, the use of P-chirality faces a remarkable without racemization is now well established.
revival as illustrated by the advent of catalysts based on, for not surprising that a lot of P-chiral phosphines are prepared via
oen crystalline. The reduction of tertiary phosphine oxides
21–26
It is therefore
7
8
9
2,27
example, the BIBOP, SMS-Phos, and Tangphos ligands. The their phosphine oxides and subsequent reduction. Unfortu-
enantioselectivity and turnover frequency of these catalysts in nately, the bottleneck is the access to enantiopure phosphine
some cases surpass those reached by catalysts based on back- oxides, currently obtained via resolution. Obviously, this is
bone-chiral ligands.
The synthetic accessibility of enantiopure P-chiral separation.
compounds is a fundamental challenge and some of the
We realized that this situation would strongly improve upon
10–12
accompanied by the disadvantages of a diastereomeric
pursued approaches are important contributions to organic replacement of the resolution with a deracemization of a
chemistry. The rst methods to be developed for resolution secondary phosphine oxide followed by a stereoselective
relied on diastereomeric complex formation or a covalently conversion into the tertiary phosphine oxide and subsequent
2
attached chiral auxiliary. In particular, the use of menthol reduction (Scheme 1), here exemplied by starting from PhPCl .
1
3,14
phosphinates has broad scope.
been studied intensively as well,
Asymmetric synthesis has
The choice to prepare racemic secondary phosphine oxides
and two methods stand out: assures straightforward availability of the starting material and
the Jug ´e –Stephan method based on the addition of organo- gives full freedom in the introduction of the third substit-
15,16
10,15,16,28
29–32
33
lithium reagents to N-ephedrinophosphine-P-borane, an uent.
Alkylation, arylation,
alkene addition, and
34
conjugate addition of secondary phosphine oxides have all
been well described and take place without erosion of
enantiopurity. The missing piece in this scheme is the
a
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG
Groningen, The Netherlands. E-mail: A.J.Minnaard@rug.nl; Web: http://www.rug.nl/
research/bio-organic-chemistry
b
Laboratorium f u¨ r Organische Chemie, ETH Z u¨ rich, HCI G 204, CH-8093 Z u¨ rich,
Switzerland. E-mail: couzijn@org.chem.ethz.ch
c
Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht,
The Netherlands
†
Electronic supplementary information (ESI) available: Experimental procedures,
details of the X-ray structures and DFT calculations. CCDC 953762 and 946519.
For ESI and crystallographic data in CIF or other electronic format see DOI:
Scheme
1 A synthetic route towards enantiopure P-chiral tert-
1
0.1039/c3sc52913d
butylphenylphosphines.
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deracemization of the secondary phosphine oxide and,
surprisingly, this has not been reported.
We report here the crystallization-induced deracemization of
secondary phosphine oxides and provide solid evidence that
this is a radical-mediated process. A consecutive novel crystal- Scheme 3 LiAlH -induced epimerization as described by Mislow et al.
4
lization-induced asymmetric transformation (CIAT) provides
access to enantio- and diastereo-pure tert-butyl(hydroxyalkyl)-
phenylphosphine oxides (Scheme 2).
scalable crystallization-induced dynamic resolution (deracemi-
42
zation) the secondary phosphine oxide 1 can be obtained in
excellent yield and ee. As both enantiomers of DBTA are
commercially available, both enantiomers of 1 are accessible.
An oen undervalued characteristic of crystallization-
induced dynamic resolutions, based on thermodynamic product
formation, is that the efficiency of the underlying resolution is
less important, in contrast to dynamic kinetic resolutions. Even
a small solubility difference for the two crystalline diastereo-
meric complexes should lead to an effective deracemization as
the equilibrium in solution is shied to the less soluble dia-
stereomer. To illustrate this principle we carried out the
dynamic resolution with (S)-BINOL as the resolving agent.
BINOL is known to form diastereomeric complexes with 1, but
the solubility difference is insufficient for an effective resolu-
Results and discussion
Our study is based on tert-butylphenylphosphine oxide 1, the
most used secondary phosphine oxide in catalysis, which is
prepared from dichlorophenylphosphine and tert-butylmagne-
sium chloride in 96% yield. Recently, we reported an efficient
35
resolution for 1 using dibenzoyltartaric acid. In contrast to
36
suggestions in the literature, 1 proved to be congurationally
very stable. Racemization attempts under Brønsted/Lewis acidic
or strongly basic conditions were unsuccessful, except for
heating in concentrated hydrochloric acid, which led to race-
mization but also to degradation (see ESI for details†).
37
Inspired by work of Mislow et al. comprising a hydride-
induced epimerization (Scheme 3), we observed that 1 does
43
tion. Applied in the crystallization-induced dynamic resolu-
tion, however, BINOL provided a rewarding 81% yield and 91%
racemize with LiAlH
4
, too. This mechanism proceeds by hydride
44
ee. Provided that diastereomeric complexes are formed with a
addition–elimination via an achiral pentacoordinate dihydrido
species II.
given secondary phosphine oxide using either DBTA or another
agent, this CIAT will produce highly enantioenriched products
that can be easily recrystallized to yield a single enantiomer. We
did not attempt to expand the method in this way, as the third
substituent in the tertiary phosphine can be freely chosen (vide
supra) in this strategy. This provides already considerable scope.
Iodine is known to readily convert 1 into its corresponding
As LiAlH
addition led to partial reduction of 1, other strong nucleophiles
4,5-dicyanoimidazole, imidazolium triate) were studied that
might generate pentacoordinate intermediate, stereo-
mutation of which would eventually lead to racemization.
4
was not compatible with our resolution and in
(
a
38–40
All attempts failed, however, until an example of an iodine-
catalyzed diastereomeric resolution by Vedejs and Donde for a
tertiary phosphine was taken into consideration. To our great
delight, 1 racemized by heating with only catalytic amounts of
iodine.
This racemization protocol was at least in principle
compatible with our resolution via diastereomeric complex
formation. Aer extensive optimization, the combination of 1%
iodine and stoichiometric (À)-L-dibenzoyltartaric acid (DBTA) as
the resolving agent in reuxing diisopropyl ether, followed by
hot ltration of the crystalline mass, provided the complex in an
excellent 92% yield and 96% ee (Scheme 4). Aer recrystalliza-
tion from toluene/diisopropyl ether the SPO was obtained as a
single enantiomer. The free phosphine oxide 1 is readily
obtained from the complex in quantitative yield by washing
with aqueous base. Thus, via an unprecedented and readily
45
phosphinyl iodide B and HI (Scheme 5), as was conrmed by
the observation of B by NMR spectroscopy (see ESI†), an
increase in acidity, and bleaching of the solution within
minutes. We distrusted, however, racemization mechanisms in
which the formed iodide acts as a nucleophile, as has been
reported for phosphine epimerization. Other strong nucleo-
philes were not able to bring about racemization and also
41
4
iodide added in the form of n-Bu NI had no inuence on the
reaction. Moreover, all attempts to detect pentavalent phos-
phorus species, intermediates in such a racemization mecha-
nism, by NMR spectroscopy failed.
Therefore, Density-Functional Theory (DFT) calculations
47
were performed using Gaussian 09; see the ESI for details.†
Scheme 2 Crystallization-induced asymmetric transformations.
Scheme 4 SPO synthesis via CIAT 1.
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This reaction has been reported with aromatic aldehydes
34
applying a stoichiometric amount of a strong base (LDA). We
realized that viewing hydroxy phosphine oxides as phospha-
benzoins, this would imply that catalytic base should be suffi-
cient and moreover that the reaction should be reversible. Given
the observation that the addition products are invariably crys-
talline solids, this provoked the development of a second crys-
tallization-induced dynamic resolution.
Upon exposure of an equimolar mixture of 1 and benzalde-
hyde to 0.05 M aq. sodium hydroxide, the corresponding tert-
butyl(hydroxybenzyl)phenylphosphine oxide was formed within
minutes as a white precipitate consisting of a nearly 1 : 1
mixture of diastereomers. When this suspension was heated to
ꢀ
8
0 C, dynamic resolution occurred readily to afford a single
Scheme 5 Radical mechanism for racemization of 1 with calculated
À1
Gibbs free energy barriers at 343 K in kcal mol
.
diastereomer in 89% isolated yield (Scheme 7).
The reaction turned out to have a remarkably broad scope,
53
both aromatic and enolizable aliphatic aldehydes being suit-
Structures were fully optimized at the B3LYP/6- able substrates. For the latter there is a preference for one
1G(d),I:LanL2DZ(d) level of theory with the SMD solvation diastereomer already at room temperature, and a single repre-
3
46
model for diisopropyl ether (DIPE). Frequency analyses affor- cipitation afforded the diastereomerically pure products. The
ꢀ
ded Gibbs free energy corrections at 70 C, which were quantitative addition to formaldehyde (Table 1, entry 11)
combined with B3LYP/6-311+G(2d,p),:6-311G(2d)/SMD(DIPE) afforded
enantiopure
tert-butyl(hydroxymethyl)phenyl-
single-point energies to determine the reaction energetics.
phosphine oxide, which until now was only accessible via
54
We initially considered SPO racemization to occur through enzymatic resolution.
38–40
ꢀ
the stereomutation
of pentacoordinate phosphorane inter-
For electron-poor aromatic aldehydes, above 50 C a phos-
mediates. However, none of the possible stereoisomeric pha-Brook rearrangement to the corresponding benzyl phos-
À
55
adducts of SPO with HI, I , or Ic could be located at the used phinate occurred as a competing reaction (Scheme 8).
level of theory. Instead, the optimized structures corresponded Therefore diastereomerically pure products could be obtained
t
+
ꢀ
to ( Bu)(Ph)PH(OH) (for HI) or SPO having a weak interaction at 80 C, but only in low yields.
with I or Ic, respectively. Thus, a stereomutational mechanism
À
The stereochemistry of the newly formed stereocenter was
established by H NMR spectroscopy using the method of Ver-
1
can be excluded.
2
56
We were triggered, though, by the observed erosion of enan- kade, relating JP,H to the relative stereochemistry. As shown
33
tiopurity by Han and Zhao in the radical addition of secondary before (vide supra, see ESI†) the P stereocenter is conguration-
phosphine oxides to alkenes, and in their oxidative dimerization ally stable under the applied reaction conditions. This determi-
48
by Haynes et al. Our DFT calculations indicate that the P–I bond nation was underpinned by X-ray crystallography (Scheme 9).
À1
in B is weak (43.88 kcal mol at the used level of theory) and can
As in the rst dynamic resolution, the stereochemical
which was outcome of the second CIAT is solely determined by the product
49,50
be cleaved, providing a phosphinyl radical D,
indeed detected by trapping experiments with norbornadiene solubilities and the conguration of the starting SPO; e.g. the
51
and 3,4-dihydro-2-H-pyran. The racemization barrier of D was asymmetric transformation of (R)-1 and (S)-1 with benzaldehyde
À1
calculated to be only 11.59 kcal mol , whereas the barriers for affords only the R,R- and S,S-stereoisomers, respectively, and
hydrogen transfer between 1 and D with either opposite or the not their diastereomers. We were therefore delighted to observe
À1
same absolute stereochemistry (21.70 and 22.45 kcal mol
,
that the corresponding reaction of (R)-1 and (S)-1 with p-tol-
ꢀ
respectively) are also surmountable at 70 C. Taken together, this ualdehyde afforded the R,S- and S,R-stereoisomers. As in the
establishes a very effective racemization mechanism via a radical well-known quinine–quinidine example, 2 and 3 can be
58
chain process that explains all observations in this study.
Remarkably, the use of a radical-mediated racemization in a
dynamic resolution has very limited precedent. Both the resolutions based on thermodynamic product formation: the
synthesis of the racemate and the dynamic resolution scale
regarded as quasi-diastereomers.
This again points at the important characteristic of dynamic
52
readily, and do not require low-temperature conditions or
chromatography. Combined with the well worked-out conver-
sion of the product to enantiopure phosphines, this provides an
approach that is comparable in efficiency to the recently dis-
17c
closed Boehringer Ingelheim procedure.
With enantiopure 1 in hand, its addition to aldehydes was
studied in order to transfer chirality to carbon and obtain
straightforward access to tert-butyl(hydroxyalkyl)phenyl-
phosphine oxides (Scheme 6).
Scheme 6 TPO synthesis via CIAT 2.
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Scheme 7 CIAT 2.
Scheme
8
Reaction outcome of tert-butyl(hydroxyalkyl)phenyl-
phosphine oxide synthesis for electron-poor aldehydes.
Table 1 Substrate scope of tert-butyl(hydroxyalkyl)phenylphosphine
oxide synthesis via CIAT 2
a
Entry Substrate
1
Product
d.r.
Yield (%)
89
>20 : 1 (R
p
,R)
,S)
2
3
>1 : 20 (R
p
94
94
>1 : 20 (R
p
,S)
,R)
4
5
>20 : 1 (R
>20 : 1 (R
p
96
Scheme 9 Formation of pseudo-diastereomers (see ESI† for experi-
57
mental details of the X-ray structures).
p
,R)
96
90
efficiency of the underlying resolution (in casu the magnitude of
the solubility difference of the diastereomers) is less important.
6
7
p
1 : 20 (R ,S)
Conclusion
b
b
1 : 3.5
90
In conclusion, a novel strategy for the synthesis of enantiopure
P-chiral phosphine oxides has been developed based on an
unprecedented radical-mediated dynamic resolution. It
provides the nal piece for a practical and scalable approach to
the preparation of P-chiral phosphines. In a subsequent asym-
b
b
8
9
1 : 4.4
93
c
c
metric
transformation,
tert-butyl(hydroxyalkyl)phenyl-
>1 : 20 (R
p
,S) 95
phosphine oxides are prepared in high yield and excellent
stereoselectivity. Containing both P- and C-chirality, these are
promising ligands and organocatalysts, all the more so because
all four (quasi)-diastereomers were shown to be accessible.
c
c
1
1
0
1
>1 : 20 (R
p
,S) 89
n.a.
Quant.
56
Experimental
Dynamic resolution 1
1
2
>1 : 20
(À)-(R,R)-Dibenzoyltartaric acid (590 mg, 1.65 mmol) and tert-
butyl(phenyl)phosphine oxide (250 mg, 1.37 mmol) were
ꢀ
dissolved at 50 C in diisopropyl ether (DIPE, 20 mL). Subse-
a
1
31
b
Determined by H and P NMR spectroscopy. Reaction conducted at
C; at higher temperatures the product rearranges to the
corresponding phosphinate. Reaction conducted at 20
quently, iodine (5 mg, 0.020 mmol) was added. The initially pale
yellow mixture bleached within min and a white precipitate was
ꢀ
5
0
c
ꢀ
C
and
ꢀ
product reprecipitated once from MeOH/H
2
O.
formed. The mixture was stirred for 16 h at 69 C, aer which
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the hot suspension was ltered. The white solid was dissolved
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9
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Acknowledgements
We thank P. van der Meulen for NMR support. Financial
support from the Netherlands Research School for Chemistry
and Catalysis program is acknowledged.
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1
3
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52 A dynamic resolution of diastereomeric titanocene and
3
4
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4
4
a
of the Second Kind. The sometimes applied term 53 The use of acetaldehyde led to aldol condensation products.
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3 J. Drabowicz, P. Ły ˙z wa, J. Omela n´ czuk, K. M. Pietrusiewicz 55 See: T. T.-L. Au-Yeung, PhD thesis, Hong Kong University of
“
4
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57 CCDC numbers 953762 and 946519.
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4
4
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