Turning regioselectivity into stereoselectivity: Efficient dual resolution of P-stereogenic phosphine oxides through bifurcation of the reaction pathway of a common intermediate

Article abstract of DOI:10.1002/anie.201309556

Synthetic routes that provide facile access to either enantiomeric form of a target compound are particularly valuable. The crystallization-free dual resolution of phosphine oxides that gives highly enantioenriched materials (up to 94 % ee) in excellent y

Full text of DOI:10.1002/anie.201309556

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DOI: 10.1002/anie.201309556
Asymmetric Synthesis
Turning Regioselectivity into Stereoselectivity: Efficient Dual
Resolution of P-Stereogenic Phosphine Oxides through Bifurcation of
the Reaction Pathway of a Common Intermediate**
Kirill Nikitin,* Kamalraj V. Rajendran, Helge Mꢀller-Bunz, and Declan G. Gilheany*
1) Inversion of the order of attachment of two groups at
a phosphorus atom that already bears a chiral auxiliary, for
example, ephedrine,[7] which recently culminated in the
development of a very effective route based on 1-phenyl-
ethylamine by Han and co-workers.[8]
2) Use of (À)-menthol as an inexpensive template: Intro-
duced by Mislow and co-workers,[9] it has been used in
a number of ways to synthesize both enantiomers of P-
stereogenic compounds, commonly by classical diastereo-
mer separation and subsequent separate manipulations of
both isomers. Recently, this concept was efficiently
applied by Berger and Montchamp.[10]
Abstract: Synthetic routes that provide facile access to either
enantiomeric form of a target compound are particularly
valuable. The crystallization-free dual resolution of phosphine
oxides that gives highly enantioenriched materials (up to 94%
ee) in excellent yields is reported. Both enantiomeric oxides
have been prepared from a single intermediate, (RP)-alkoxy-
phosphonium chloride, which is formed in the course of
a selective dynamic kinetic resolution using a single enantiomer
of menthol as the chiral auxiliary. The origin of the dual
stereoselectivity lies in bifurcation of the reaction pathway of
this intermediate, which works as a stereochemical railroad
switch. Under controlled conditions, Arbuzov-type collapse of
À
this intermediate proceeds through C O bond fission with
retention of the configuration at the phosphorus center.
À
Conversely, alkaline hydrolysis of the P O bond leads to the
opposite SP enantiomer.
I
n asymmetric synthesis, an ideal scenario is to generate both
enantiomers of the target using only one enantiomer of the
chiral agent. In this way, maximum benefit is extracted from
the source of chirality, and the decision on the configuration
of the product is transferred to the operator.[1] As asymmetric
synthesis has matured, methods for this highly desirable goal
have been developed only slowly, but have become an
emerging topic in synthetic methodology.[2]
In organophosphorus chemistry, the need for flexible
routes to non-racemic P-stereogenic compounds has been
well established,[3,4] with significant applications in catalytic
asymmetric synthesis[5] and for accessing enantiomerically
pure phosphonates and phosphoramidates as nucleotide pro-
drugs.[6] Some progress towards dual stereoselection has been
achieved and two distinct types of approach towards this ideal
scenario for P-stereogenic compounds may be discerned:
Scheme 1. Stereoselective synthesis of P-stereogenic phosphines and
phosphine oxides (racemic forms are shown in gray): a) (COCl)2,
CH2Cl2, RT; b) (À)-menthol, toluene/CH2Cl2, À828C; c) Arbuzov-type
collapse, 50–608C; d) hexachloroacetone or (COCl)2; e) LiAlH4.
Our contributions to the synthesis of P-stereogenic
compounds (Scheme 1) include an asymmetric three-step
one-pot transformation of racemic phosphine oxide rac-1 or
the parent phosphine rac-2 leading to enantioenriched 1 or
2.[11] Our current method involves the chlorination of either
rac-1 or rac-2 to form enantiomeric chlorophosphonium salts
(CPSs) 3,[12] which, according to the present hypothesis,
rapidly interconvert and are dynamically resolved in the
presence of a chiral auxiliary, such as menthol, to give the
[*] Dr. K. Nikitin, Dr. K. V. Rajendran, Dr. H. Mꢀller-Bunz,
Prof. Dr. D. G. Gilheany
Centre for Synthesis and Chemical Biology
School of Chemistry and Chemical Biology
University College Dublin
Belfield, Dublin 4 (Ireland)
E-mail: kirill.nikitin@ucd.ie
diastereomeric alkoxyphosphonium salt (DAPS)
4
(path b).[13] The final ee of scalemic 1 formed by Arbuzov
collapse of 4 (path c) is limited by the diastereomeric purity,
de, of 4.[14] Alternatively, hydride reduction of 4 (path e) leads
to enantioenriched 2.[13,15]
declan.gilheany@ucd.ie
[**] This work was supported by a Science Foundation Ireland Principal
Investigator Award to D.G.G. (09/IN.1/B2627). We are grateful to
the UCD School of Chemistry and Chemical Biology for access to
their analysis facilities.
We have recently been working on the two principal
limitations of this approach. First, the desirable stereochem-
ical outcome of at least 90% ee for the product oxides had not
been attained in auxiliary screening.[11] Second, as the
Supporting information for this article, including experimental
procedures and details of the measurements, is available on the
WWW under http://dx.doi.org/10.1002/anie.201309556.
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Table 1: Thermal collapse of (RP)-4a–d into scalemic (RP)-1a–d.[a]
stereochemical configuration of product 1 is set by the
configuration of the chiral auxiliary, preparation of the
opposite enantiomer required a change of auxiliary.[11]
Herein, we report two important breakthroughs: the synthesis
of enantioenriched 1 with > 90% ee and the preparation of
both enantiomers of 1 using the same chiral auxiliary.
Entry DAPS Additive[b]
de of 4 [%][c] ee of 1 [%][d] Preservation of
selectivity [%][e]
1
2
3
4
4a
4b
4c
4d
–
87
73
84
84.5
84
92
tert-butanol 87
CH(OMe)3 87
pyridine
98.5
98.5
98.5
We have recently described[13] an NMR-based method for
the determination of the de of the crucial DAPS intermedi-
ates 4, and we have now correlated this value with the
ultimate ee value. Thus, racemic oxides 1a–d were reacted
with oxalyl chloride to give salts 3a–d, which were then
treated with a solution of (À)-menthol at À828C (Scheme 2).
87
5
6
7
8
–
96
87
92
92.5
92
95.5
98
98
tert-butanol 96
CH(OMe)3 96
pyridine
96
98
9
–
95
79
92
91
92
91.5
98.5
98
10
11
12
tert-butanol 95
CH(OMe)3 95
pyridine
95
98.5
13
14
15
16
–
97
84
91
93
93
93
97
98
98
tert-butanol 97
CH(OMe)3 97
pyridine
97
[a] Mixture of CH2Cl2 and toluene (1:3 v/v), 608C, 3 h; quantitative
conversion into 1 determined by 31P NMR spectroscopy. [b] Added before
heating: tert-butanol or orthoformate (10% v/v); pyridine (4% v/v).
[c] Determined by 31P NMR spectroscopy, error Æ1%. [d] Determined by
HPLC analysis on a chiral stationary phase error Æ0.5%. [e] 50(de+ee)/
de; see the Supporting Information for details.
Scheme 2. One-pot chiral resolution of phosphine oxides 1. a) (COCl)2,
CH2Cl2, RT; b) (À)-menthol, toluene/CH2Cl2, À828C; c) Arbuzov-type
collapse, 50–608C.
After three hours, the reaction mixture was typically allowed
to warm up to 08C, and a sample of it was used to determine
the diastereomeric purity of the resulting DAPS 4 by
31P NMR spectroscopy in CDCl3. The reaction mixture was
then heated at 608C, and the Arbuzov-type collapse of 4
leading to (RP)-1 in quantitative yield was monitored by
HPLC analysis on a chiral stationary phase selected results
are given in Table 1 (for details, see the Supporting Informa-
tion). It can be seen that in the absence of any other
intervention, there is significant erosion of selectivity during
the Arbuzov collapse (Table 1, entries 1, 5, 9, 13). We found
that a major factor contributing to this erosion was the acidity
of the reaction, as HCl is formed during this process, which
may induce racemization of 1. Indeed, removal of HCl by
addition of weak bases or acid-scavenging reagents was found
to be very beneficial for the stereochemical outcome, allowing
almost complete preservation of the selectivity achieved in
the formation of DAPS 4 (Table 1, entries 2–4, 6–8, 15, and
16). A plausible mechanism for the stereochemical erosion
involves the equilibrium maintenance of a small concentra-
tion of CPS 3, which then reversibly interacts with scalemic 1
to reduce its ee value (for details, see the Supporting
Information).
the process, namely the de value of 4. The key finding is that
the introduction of additional CH2 fragments in the linear
alkyl chain leads to a significant increase in selectivity
(Table 1; for the Et, nPr, and nBu derivatives 4b–d,
> 95% de). We have previously shown[11] that 1a and other
À
phosphine oxides that containing a P CH3 fragment are
formed in the RP form with (À)-menthol as the source of
chirality. This was also confirmed for the scalemic oxides (RP)-
1b–d (Figure 1), which shows that the introduction of an
The nature of the solvent also has a significant effect on
the erosion of the selectivity. For 4a (initially 87% de), the
loss of stereochemical information was significant in ether
and hydrocarbon solvents, but much lower in acetonitrile,
CH2Cl2, chloroform, and in the more basic dimethyl sulfoxide
(DMSO; see the Supporting Information, Table S1).
Having established the set of conditions that enables the
preservation of stereochemistry during the collapse of 4, we
are now in a position to comment on the intrinsic selectivity of
Figure 1. Bifurcation of reactivity: controlled transformation of 4d into
1d and stereochemical spectrum showing intermediate and ultimate
attained ee values. R=(À)-menthyl.
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extended n-alkyl chain resulted in true amplification of
stereoselectivity without a change of its sign, and it is
therefore likely that the same selection mechanism is
responsible for the stereochemical differentiation.
shown in Figure 1 for (RP)-4d. Thus, by carefully adjusting the
reaction conditions, a highly R- or S-selective stereochemical
outcome can be achieved with this chiral-resolution method.
The process can be conveniently run on a gram scale with high
selectivity; for example, the R and S enantiomers of the oxide
1d were obtained in 94 and 90% ee, respectively, and the pure
oxides 1a–d can be isolated in 91–96% yield (for details, see
the Supporting Information). Furthermore, the chiral auxil-
iary (À)-menthol can be recovered after the inversion process.
In conclusion, we have achieved a critical leap in the
stereoselectivity of dynamic resolution reactions of tertiary
phosphine oxides, owing to three factors. First, an extension of
the alkyl chain attached to the phosphorus atom led to
significantly increased intrinsic diastereoselectivity. Second,
an enantioselectivity of greater than 98% was attained for the
following step by rigorously controlling stereochemical ero-
sion. Finally, the inversion of the stereochemical outcome
using the same chiral auxiliary makes this approach very
powerful for the practical preparation of various P-stereo-
genic compounds from the same reaction mixture. We believe
that this is the first example in chemistry where dual chiral
resolution of a racemic substrate (rather than a prochiral
entity) was achieved via an intermediate whose bifurcated
reactivity leads to the two opposite enantiomers because of
two different mechanistic paths.
With the RP selectivity improved, we then focused on the
preparation of the opposite SP enantiomer of 1. Although this
process would normally require (+)-menthol as the chiral
auxiliary, one can evoke an alternative reaction pathway that
involves a nucleophilic attack on the intermediate 4,[10,16]
because the hydrolysis of (RP)-4 should in principle occur
with inversion. On treatment with an excess of aqueous
NaOH at 08C in acetonitrile for 30 min, salt (RP)-4a (87% de)
gave the oxide (SP)-1a (opposite configuration) in 76% ee
and 100% yield, which corresponds to inversion of the
configuration at the phosphorus center in 93.5% of cases
during the hydrolysis of (RP)-4a. This experiment was
repeated with 18O-labeled reagents; (SP)-1a was furnished
with an 18O incorporation of 93%, whereas thermal collapse
of (RP)-4a in the presence of H218O in acetonitrile gave only
unlabeled (RP)-1a in 80% ee, which is in agreement with the
proposed mechanism (Scheme 3).
Received: November 3, 2013
Keywords: chirality · chiral resolution · enantioselectivity ·
.
phosphine oxides · regioselectivity
Scheme 3. Translating regioselectivity into stereoselectivity: Retention
of configuration is observed when (RP)-4a collapses through nucleo-
[1] A multiplicity of names for the concept has arisen. We prefer
“dual stereoselection” or “resolution”, as suggested by a recent
review (see Ref. [2a]).
À
philic attack of a chloride anion (C O bond cleavage, going left);
however, inversion acccompanies alkaline hydrolysis of (RP)-4a leading
À
to (SP)-1a (P O bond cleavage, going right).
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Further improvement of the selectivity could be attained
by using aqueous Bu4NOH in acetonitrile. When these
conditions were applied to (RP)-4a–d, scalemic (SP)-1a–d
were prepared in 84–90% ee and quantitative yields
(Scheme 4). Other nucleophiles, for example, alkali metal
alkoxides, yielded 1 with a lower final ee value or in the
presence of sodium ethoxide even in its racemic form.
As the reactions for the synthesis of enantioenriched
phosphine oxides proceed with either retention or inversion,
they can be viewed as a “stereochemical spectrum”, which is
Scheme 4. Alkaline hydrolysis of the alkoxyphosphonium salts
(RP)-4a–d accompanied by inversion of the configuration at the
phosphorus center (initial de of 4 given in Table 1, quantitative
conversion into 1a–d determined by 31P NMR spectroscopy).
R=(À)-menthyl.
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