Experimental and theoretical investigations of the stereoselective synthesis of P-stereogenic phosphine oxides

Article abstract of DOI:10.1002/chem.201501324

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring-opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P-O bond. Interestingly, the use of a P^III phosphine precursor afforded a P-epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides. That's handy: An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides was developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as a chiral auxiliary, whereby enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor.

Full text of DOI:10.1002/chem.201501324

DOI: 10.1002/chem.201501324
Communication
&
Phosphine Oxides
Experimental and Theoretical Investigations of the Stereoselective
Synthesis of P-Stereogenic Phosphine Oxides
Laurent Copey,[a] Ludivine Jean-GØrard,[a] Eric Framery,[a] Guillaume Pilet,[b] Vincent Robert,[c]
and Bruno Andrioletti*[a]
oxides.[5–9] An alternative strategy involves the use of chiral
Abstract: An efficient enantioselective strategy for the
auxiliaries[10–12] and the use of ephedrine represents a break-
synthesis of variously substituted phosphine oxides has
through in this field.[13] The so-called JugØ–Stephan method in-
been developed, incorporating the use of (1S,2S)-2-amino-
volves the stereoselective ring-opening of an oxazaphospholi-
cyclohexanol as the chiral auxiliary. The method relies on
dine incorporating (+)- or (À)-ephedrine by using organome-
three key steps: 1) Highly diastereoselective formation of
tallic reagents. This very reliable method allowed the prepara-
PV oxazaphospholidine, rationalized by a theoretical study;
tion of a large range of borane-protected phosphines in good
2) highly diastereoselective ring-opening of the oxaza-
to excellent yields and enantiomeric excesses. However, as
phospholidine oxide with organometallic reagents that
ephedrine is an acknowledged precursor for methampheta-
takes place with inversion of configuration at the P atom;
mine and Methcathinone,[14] its commercial availability has
3) enantioselective synthesis of phosphine oxides by
become troublesome.
cleavage of the remaining PÀO bond. Interestingly, the
Additional efforts are currently dedicated to developing new
use of a PIII phosphine precursor afforded a P-epimer oxa-
chiral scaffolds and the recent reports by the groups of Verda-
zaphospholidine. Hence, the two enantiomeric phosphine
guer[15] and Han[16] undoubtedly constitute key contributions in
oxides can be synthesized starting from either a PV or a PIII
this area. Inspired by the oxazaphospholidine method,[13] Ver-
phosphine precursor, which constitutes a clear advantage
daguer and co-workers carefully studied the ring opening of
for the stereoselective synthesis of sterically hindered
bulky oxazaphospholidines based on the cis-1-amino-2-inda-
nol.[15] Conversely, Han et al. chose the tosylamide derived
phosphine oxides.
from (R)-2-(1-aminoethyl)-4-chlorophenol that affords a 6-mem-
bered-ring oxazaphospholidine upon reaction with phenyl-
Access to PIII- or PV-stereogenic molecules is currently a subject
phosphonic dichloride. The latter strategy has proven fruitful
of intense research, owing to of their promising use in enantio-
selective metallo- or organocatalysis.[1–3] However, P-stereogen-
ic ligands used in enantioselective catalysis remain scarce due
to the limited enantiostability of chiral arylphosphines and the
difficulty in accessing enantiopure phosphorus compounds.
However, several very elegant methods giving access to
enantioenriched P-stereogenic phosphines or phosphine
oxides have been developed. Among them, the resolution of
racemic mixtures was proposed,[4] as well as the enantioselec-
tive deprotonation of phosphine–boranes and phosphine
as a large range of sterically crowded phosphine oxides was
prepared in good yields and excellent enantioselectivities.
Simultaneously with Han’s work, we investigated the possi-
bility of using a new chiral auxiliary that would allow easy
access to sophisticated P-stereogenic systems. We chose the
readily available (1S,2S)-2-aminocyclohexanol, a chiral scaffold
found in a large number of catalytic systems.[17] It was expect-
ed that the relatively rigid and bulky cyclohexyl backbone
would lead to highly diastereoselective transformations, even
in the case of sterically crowded phosphines.[18] Moreover, the
four stereoisomers of 2-aminocyclohexanol are either commer-
cially available or can be readily prepared.[17a] Within the frame
of our study, we decided to use the trans stereoisomer, which
was seldom used in related studies and would afford a fairly
reactive 5-membered oxazaphospholidine ring. During our in-
vestigations, only the (S,S) enantiomer was used when enantio-
selective reactions were carried out. Tolylsulfonamide afforded
good results in the case of Han’s (R)-2-(1-aminoethyl)-4-chloro-
phenol strategy. Hence, we decided to first investigate the
effect of the tolylsulfonamide substituent on the outcomes of
the reaction.
[a] L. Copey, Dr. L. Jean-GØrard, Dr. E. Framery, Prof. B. Andrioletti
Institut de Chimie et Biochimie MolØculaires et SupramolØculaires (ICBMS-
UMR CNRS 5246), UniversitØ Claude Bernard Lyon 1, Bâtiment Curien (CPE)
43, Bd du 11 Novembre 1918, 69622 Villeurbanne cedex (France)
Fax: (+33)472-44-6264
E-mail: bruno.andrioletti@univ-lyon1.fr
Homepage: http://www.icbms.fr/casyen/45-casyen-andrioletti/23-andrioletti
[b] Dr. G. Pilet
Laboratoire des MultimatØriaux et Interfaces (UMR 5615)
UniversitØ Claude Bernard Lyon 1
43, Bd du 11 Novembre 1918, 69622 Villeurbanne cedex (France)
[c] Prof. V. Robert
The reaction of tosyl-protected (+/-)-trans-1,2-aminocyclo-
hexanol (Æ)-1 with phenylphosphonic dichloride in the pres-
ence of N-methylimidazole (N-MeIm) in dichloromethane at
258C afforded the expected oxazaphospholidine oxide 4 with
Laboratoire de Chimie Quantique—UMR 7177, Institut de Chimie 1
rue Blaise Pascal 67081 Strasbourg (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501324.
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As oxazaphospholidine 4 appeared rather unstable during
purifications, the activated PÀN bond was next selectively
cleaved[15] upon treatment of the crude oxazaphospholidine
with 3.3 equivalents of ethylmagnesium bromide at À788C in
dichloromethane (Scheme 1). At this temperature, only one
diastereoisomer (Æ)-7 was detected and was isolated by silica
gel flash chromatography in 98% yield over two steps.
Table 1. Diastereoselective formation of oxazaphospholidine.
Entry
R
Amino al-
cohol
T
d.r. of the crude
Oxazaphospholidine
[8C] (yield [%])[a]
1
2
3
4
5
Tol
(Æ)-1
(Æ)-2
(Æ)-3
(Æ)-1
(Æ)-1
25 91:9
25 80:20
25 87:13
4
5
6
4
4
Me
Mes
Tol
À20 94:6 (100)
Tol
À78 99:1 (100)
[a] Determined by 31P NMR spectroscopy (see the Supporting Informa-
tion).
a diastereoisomeric ratio (d.r.) of 91:9 (Table 1, entry 1). Switch-
ing from a tolyl to a methyl or mesityl sulfonamide (Table 1,
entries 2 and 3) afforded a lower d.r. of 80/20 and 87/13, re-
spectively. Hence, we decided to optimize the reaction condi-
tions with the tosyl amide and screened various bases, sol-
vents, and reaction temperatures (see the Supporting Informa-
tion). The study revealed that the d.r. increased when the tem-
perature decreased and the highest d.r. (99:1) was obtained at
À788C, without altering the chemical yield (100%; Table 1,
entry 5). It is also important to note that the concentration of
the starting N-tosylamido alcohol (Æ)-1 must be kept below
0.5m to avoid the formation of a dimeric species.[19,23]
The configuration at the phosphorus atom of the major dia-
stereoisomer was assigned unambiguously by using NMR spec-
troscopy. For example, structural determination of oxazaphos-
pholidine 4 was determined by NOESY experiments (see the
Supporting Information). As 1H NMR spectroscopy indicated
that the bicyclic structure of oxazaphospholidine 4 is rigid, it
was anticipated that the phenyl group would display NOE sig-
nals with either H1 or H2, depending on the absolute configu-
ration of the phosphorus atom. The NOESY spectrum exhibited
only one NOE signal between H2 and Ph. No cross-peak with
H1 was observed, and the cis position of H2 and the phenyl
group was unequivocally established (Figure 1). X-Ray crystal
structure analysis of single crystals obtained from vapor diffu-
sion of pentane into a solution of oxazaphospholidine 4 in
chloroform confirmed the assignment unambiguously
(Figure 1, right).[23] Computational studies were also performed
to rationalize the high diastereoselectivity observed (see
below).
Scheme 1. Synthesis of phosphine oxide (Æ)-8 by sequential cleavage of PÀ
N and PÀO bonds.
Cleavage of the PÀO bond appeared more difficult and
harsh conditions were needed. Indeed, addition of 6 equiva-
lents of Grignard reagents and heating of the reaction mixture
at reflux for 2 h were required to ensure the conversion of
phosphinate (Æ)-7 to phosphine oxide (Æ)-8 in 85% yield. It
should also be noted that the chiral auxiliary (Æ)-1 could be re-
covered in 95% yield. When 4 equivalents of Grignard were
used under reflux, the desired phosphine oxide (Æ)-8 was
formed in 58% yield. Switching to organolithium reagents re-
sulted in the degradation of the phosphinate at elevated tem-
perature, and did not afford (Æ)-8 in more than 15% yield at
258C. X-Ray diffraction analysis of the obtained single crystals
of (Æ)-7 proved that, as expected,[16] ring opening occurred
with inversion of configuration at the P atom.[20,23]
The method was then applied to the enantiomerically pure
tosylamido-protected trans-1,2-aminocyclohexanol (+)-1.[21] By
using the previously optimized conditions, oxazaphospholidine
RP-4 was formed by treatment of (+)-1 with N-MeIm and phe-
nylphosphonic dichloride in dichloromethane at À788C. After
2 h of reaction at this temperature and 1 hour at 258C,
31P NMR spectroscopy confirmed the quantitative and highly
diastereoselective conversion of the starting amino alcohol to
the oxazaphospholidine (see the Supporting Information).
Next, we turned our attention to the in situ ring opening of
oxazaphospholidine RP-4 with various Grignard reagents. To
this end, the reaction mixture was cooled to À788C and
3.3 equivalents of Grignard reagent were added (Table 2).
Different alkyl and aryl Grignard reagents were investigated.
Primary alkylmagnesium reagents afforded the corresponding
phosphinates (+)-RP-7 and (+)-RP-9 in very good yields and ex-
cellent diastereoselectivities (Table 2, entries 1 and 2). Secon-
dary alkylmagnesium reagents could also be employed as nu-
cleophiles, albeit with diminished diastereoselectivity (Table 2,
entries 3 and 4). The reactions of sterically hindered Grignard
reagents, such as tBuMgBr and FcMgBr, were more challeng-
Figure 1. P configuration of oxazaphospholidine 4 determined by using
NOESY (1H–1H) experiment and X-Ray crystal structure determination.
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nates and small nucleophiles were used
(Table 3, entries 6 and 7). Interestingly, a biphen-
yl-based phosphine oxide ligand (À)-SP-20
could be synthesized in 78% yield and good
enantioselectivity (e.r.=96:4; Table 3, entry 5).
By using a less sterically hindered phosphinate,
such as methylphenyl phosphinate (+)-RP-9,
a larger range of nucleophiles could be intro-
duced, affording the desired phosphine oxides
(+)-RP-19, (À)-SP-8, and (À)-SP-21 with excellent
enantioselectivities, albeit with limited yields
when the steric hindrance of the Grignard nu-
cleophiles increased.
Table 2. Diastereoselective ring opening of oxazaphospholidine.
Entry
R1ÀM
d.r. of the crude[a]
Yield [%] (d.r.)[a]
Phosphinate
1
2
3
4
5
6
7
8
9
EtMgBr
99:1
95:5
90:10
76:24
82:18
99:1
99:1
99:1
99:1
80:20
98 (>99:1)
81 (>99:1)
60 (96:4)
50 (>99:1)
31 (97:3)
60 (>99:1)
67 (>99:1)
97 (>99:1)
65 (>99:1)
35 (>99:1)
(+)-RP-7
(+)-RP-9
MeMgCl
iPrMgCl
CyMgBr
tBuLi[b]
(+)-RP-10
(À)-RP-11
(+)-RP-12
(À)-SP-13
(À)-RP-14
(À)-SP-15
(À)-SP-16
(À)-SP-17
FcLi[b]
vinylMgBr
oAnMgBr
oBiPhMgBr
MesMgBr
The first cyclization step to form oxazaphos-
pholidine was critical because of the trans dis-
position of the two nucleophilic groups. As far
as we know, such rigid trans oxazaphospholi-
dine species have not been reported to date
and, contrary to the PÀN and PÀO bond cleav-
age, the formation of the major diastereoiso-
10
[a] Yield of isolated product; d.r. determined by 31P NMR spectroscopy; [b] the corresponding
Grignard reagent did not afford any desired phosphinate. Dichloromethane was thus re-
moved by evaporation and replaced with anhydrous THF.
Table 3. Synthesis of P-stereogenic phosphine oxides.
ing. The use of the less basic but more nucleophilic organo-
lithium reagents was required to afford the expected phosphi-
nates, although in a lower yield (Table 2, entries 5 and 6). The
addition of arylmagnesium reagents (o-anisyle and 2-biphenyl)
resulted in the formation of the corresponding phosphinates
(À)-SP-15 and (À)-SP-16 in good to excellent yields (97% and
65% respectively) and excellent diastereoselectivities (99/1)
(Table 2, entries 8 and 9). In contrast, the addition of a bulky
mesitylmagnesium reagent took place with a moderate selec-
tivity of 60% (Table 2, entry 10).
Entry R1
R2ÀM
EtMgBr
T [8C] Yield [%] (e.r.)[a] Phosphine oxide
1[b]
2
oAn
66
40
61 (86:14)
60 (97:3)
(À)-SP-18
(À)-SP-18
(À)-SP-19
–
oAn
oAn
oAn
oBiPh
tBu
Fc
EtMgBr
3[c]
4
MeMgCl 40
iPrMgCl 40[d]
MeMgCl 40
MeMgCl 40
MeMgCl 40
oAnMgBr 40
95 (90:10)
No reaction
78 (96:4)
No reaction
No reaction
60 (93:7)
5
6
7
(À)-SP-20
X-Ray crystal structure analysis of (À)-SP-15 confirmed the in-
version of stereochemistry previously observed (Scheme 1; see
the Supporting Information).[23] Interestingly, the reaction could
be easily scaled up to allow the preparation of phosphinates
(+)-RP-9, (À)-SP-15, and (À)-SP-16 on a gram scale (81, 54, and
64% yield, respectively) with excellent diastereoselectivities
(d.r.>99:1).
–
–
8
Me
(+)-RP-19
(À)-SP-8
(À)-SP-21
–
9
10
11
Me
Me
Me
EtMgBr
iPrMgCl 40
CyMgCl 40[d]
40
82 (>99:1)
50 (>99:1)
No reaction
[a] Yield of isolated product; e.r. determined by HPLC; [b] EtMgBr (3m in
Et2O) was added to a solution of phosphinate (À)-RP-14 in THF (1m);
[c] the optically pure chiral auxiliary was recovered in 81% yield; [d] heat-
ing the reaction mixture under reflux only led to decomposition of the
starting phosphinate.
Cleavage of the PÀO bond to afford the desired phosphine
oxides was next assayed. The previously developed conditions
were applied to phosphinate (À)-SP-15, but the enantioselec-
tivity was moderate (e.r.=86:14; Table 3, entry 1). Higher ee
values were obtained when the temperature was decreased to
408C and the Grignard reagent reacted with the neat phosphi-
nate. These precautions led to a significant increase in the
enantioselectivity (e.r.=97:3) after 10 h of reaction without al-
tering the reaction yield (Table 3, entry 2). As expected,[16] the
PÀO bond cleavage occurred with inversion of configuration at
the phosphorus atom (see the Supporting Information). The
scope of this PÀO bond cleavage was next evaluated using
various Grignard reagents.[22]
mer was thus not predictable. To gain insights into the high
stereoselectivity obtained and the underlying mechanism of
the reaction, we carried out complementary density functional
theory (DFT) calculations (see the Supporting Information). Pre-
liminary investigations revealed that the reaction proceeds
under kinetic control (see the Supporting Information). Accord-
ingly, different reaction paths were considered to clarify the R
kinetic preference in the cyclization reaction. Assuming that
the reaction is a two-step process, first involving the PÀO
bond formation between the alcohol and PhPOCl2 followed by
the PÀN bond formation, activation energies calculations favor
a base-assisted SN2 mechanism for the initial PÀO bond forma-
Methylmagnesium chloride reacted successfully with phos-
phinate (À)-SP-15 with a satisfying enantioselectivity (Table 3,
entry 3). Unfortunately, bulkier Grignard reagents such as
iPrMgCl failed to provide the desired phosphine oxide (Table 3,
entry 4). Similar results were obtained when bulky phosphi-
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limiting and suggests that the
second step discriminates be-
tween the R and S products. In-
terestingly, the DG value is com-
patible with our experimental
findings. The overall reaction is
diastereoselective at room tem-
perature with a 10:1 ratio in
favor of the least thermodynami-
cally stable adduct.
Given the different reactivity
of PV and PIII derivatives, it was
appealing to apply the method-
ology previously developed to
the synthesis of chiral phos-
phines. Accordingly, dichloro-
phenylphosphine was treated
with N-tosyl-protected trans-1,2-
aminocyclohexanol (+)-1. After
30 min at room temperature, the
formation of the desired oxaza-
phospholidine 22 could be de-
tected with the apparition of
Figure 2. Free energy profile with corresponding activation energies (kcalmolÀ1). The energy difference between
the second-step transition states DG=1.0 kcalmolÀ1
.
a single peak at d=137.6 ppm
on the 31P NMR spectrum. Due
tion, ruling out the addition–elimination pathway. In light of
this model inspection, the activation barriers to forming the R
and S compounds were evaluated in dichloromethane as sol-
vent and using a chlorine anion (Figure 2). From our calcula-
tions, the S adduct is kinetically favored over the R adduct, the
energy barriers being 33.8 and 34.5 kcalmolÀ1, respectively. Let
us stress that the R intermediate is less stable than the S
(2.1 kcalmolÀ1) and the interconversion energy barrier is
26.4 kcalmolÀ1, a much smaller value than previously calculat-
ed energy barriers. Starting from the identified intermediates,
the second reaction step leading to the cyclic adduct was then
considered. Two different sets of transition states were identi-
to its low stability, the product could not be isolated, but
NOESY experiments measured on the crude mixture evidenced
the formation of only one diastereoisomer SP-22, epimer at the
P atom of oxazaphospholidine oxide RP-4 (see the Supporting
Information).
Similarly to the strategy developed for the phosphine oxide
synthesis, the reaction of Grignard reagents with the crude ox-
azaphospholidine 22 at low temperature afforded the ring-
opened phosphinate, which was trapped as a borane adduct
(+)-RP-23. Purification issues only permitted the isolation of the
o-anisylphenylphosphinite–borane complex, albeit in a good
76% yield and with a diastereoselectivity over 99/1 (Scheme 2).
fied. They differ by the relative orientations of the P=O and NÀ Unfortunately, the desired chiral phosphine–borane SP-24 was
not obtained with satisfying yield or enantioselectivity when
H bonds. For the sake of simplicity, these will be referred to as
parallel and antiparallel transi-
tion states. The calculated
energy barriers are very similar
(ca. 30 kcalmolÀ1). Nevertheless,
the antiparallel transition state
generated from the preferred S
intermediate is the lowest in
energy and leads to the R cyclic
adduct. The competing route
that produces the S stereoisomer
goes through a transition state
lying DG=1.0 kcalmolÀ1 higher
in energy. At this stage, one
should remember that the inter-
conversion barrier between the
R and S reaction intermediates is
26.7 kcalmolÀ1
particular reaction is not rate- Scheme 2. PIII strategy.
. Therefore, this
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phosphinite (+)-RP-23 was treated with 6.0 equivalents of
methylmagnesium chloride. Further optimization, such as the
use of the more nucleophilic methyllithium, failed to provide
the desired phosphine SP-24. Nevertheless, the phosphinites
could be oxidized in situ to the corresponding phosphinates
upon treatment with hydrogen peroxide (Scheme 2) and react-
ed with the appropriate Grignard reagents to afford the final
phosphine oxides (+)-RP-19 and (+)-RP-20, respectively, in very
good yields and enantioselectivities.
In conclusion, we have reported the efficient synthesis of
a large range of enantioenriched phosphine oxides using the
readily available chiral 2-aminocyclohexanol scaffold. We have
also demonstrated that the PV and PIII strategies afford the P-
epimeric oxazaphospholidines. Hence, if the order of addition
of the 2 Grignard reagents is maintained, the two enantiomeric
phosphine oxides are obtained. This constitutes a clear advant-
age for the synthesis of sterically hindered phosphine oxides,
knowing the difficulty to introduce a bulky substituent at the
last step. Thorough theoretical investigations revealed the R ki-
netic preference for the cyclization step and a preference for
the S enantiomer with a DG=1.0 kcalmolÀ1 in agreement with
the experimental observations.
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[18] Using 1-amino-2-indanol (ref. [15]), Verdaguer et al. demonstrated that
bulky P-stereogenic amino phosphines could be efficiently prepared.
Hence a phenol motif is a not a pre-requisite for the preparation of
bulky phosphines.
Acknowledgements
This work was supported by the French Ministry of Higher Edu-
cation (MESR), UniversitØ Claude Bernard, Lyon 1, and the
CNRS.
[19] When the concentration of the reac-
tion mixture exceeds 0.5m, the dimer
was formed in variable amounts. Its
structure was elucidated thanks to X-
Ray analysis and NOESY experiments
(see the Supporting Information).
[20] Oxazaphospholidine oxide RP-4 and
Keywords: asymmetric synthesis
computational studies · phosphanes · stereochemistry
·
chiral auxiliaries
·
phosphinate (Æ)-RP-7 possess the same RP configuration descriptor but
the spatial arrangement around the phosphorus atom differs.
[21] J. Huang, P. O’Brien, Synthesis 2006, 425–434.
[22] The optical purities and the inversion of configuration at the P atom
were confirmed by comparing the specific rotation measured for the
obtained phosphine oxides with the known values reported in the liter-
ature (see the Supporting Information).
[23] CCDC 1052841, 1052842, 1052843 and 1052844 contain the supple-
mentary crystallographic data for complexes RP-4, (Æ)-RP-7, (À)-SP-15,
and dimeric phosphonate, respectively. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Received: April 3, 2015
Published online on May 15, 2015
Chem. Eur. J. 2015, 21, 9057 – 9061
www.chemeurj.org
9061
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