Enantiodivergent Synthesis of Both PAMPO Enantiomers Using l -Menthyl Chloroacetate and Stereomutation at P in Classical Quaternisation Reactions

Article abstract of DOI:10.1055/s-0039-1691531

A practical protocol for efficient synthesis of both PAMPO enantiomers as well as related functionalised P-stereogenic phosphine oxides in 1-3 steps from effectively resolved (S _P)- l -menthyl o -anisyl-(phenyl)phosphinylacetate has been develo

Full text of DOI:10.1055/s-0039-1691531

SYNTHESIS
0
0
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8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
K. Dziuba et al.
Paper
Synthesis
Enantiodivergent Synthesis of Both PAMPO Enantiomers Using
L-Menthyl Chloroacetate and Stereomutation at P in Classical
Quaternisation Reactions
Kamil Dziuba
0
0
0
0-
0
0
0
2-8
8
3
3-3
1
7
0
O
MeO
O
P
Małgorzata Lubańska
*
O
K. Michał Pietrusiewicz*
SP
89%
88%
Department of Organic Chemistry, Maria Curie-Skłodowska
University, Gliniana 33, 20-614 Lublin, Poland
kazimierz.pietrusiewicz@poczta.umcs.lublin.pl
O
O
P
96%
89%
P*
*
R
Me
OMe
OMe
MeO
O
P
O
P
MeO
*
*
RP
CO2H
Me
(RP)-PAMPO
R = allyl
R = 1E-propenyl
SP
chromatography-free, multigram scale
(SP)-PAMPO
Received: 08.10.2019
Accepted after revision: 19.11.2019
Published online: 04.12.2019
based on stereoselective displacement of various chiral es-
ter, amide and even carbon leaving groups in the resolved
phosphinate,8 phosphonate9 or phosphine oxide10 deriva-
tives by organometallic nucleophiles. Some of these meth-
ods can be very effective but still they are multistep, require
often tedious resolution of the starting phosphinate or
phosphoroamidate precursor, are sensitive to the nature of
the organometallic reagent and the leaving group and, typi-
cally, provide only one enantiomer of PAMPO. Because of
these problems, expeditious synthesis of enantiopure PAMPO
in large quantities and in both enantiomeric forms poses a
considerable challenge even today. We decided then to turn
our attention back to the once readily resolved crystalline
(SP)-L-menthyl o-anisyl(phenyl)phosphinylacetate (1)6 to
elaborate on its potential as a convenient precursor to both
PAMPO enantiomers in multigram quantities. We now wish
to report a successful execution of this project which also
led to the development of a potentially general protocol for
the synthesis of other enantiopure phosphine oxides from
(SP)-1. In addition, the study has brought about an unex-
pected observation of stereomutation of the phosphorus
stereogenic centre in the direct quaternisation of a tertiary
phosphine at room temperature.
DOI: 10.1055/s-0039-1691531; Art ID: ss-2019-t0572-op
Abstract A practical protocol for efficient synthesis of both PAMPO
enantiomers as well as related functionalised P-stereogenic phosphine
oxides in 1–3 steps from effectively resolved (SP)-L-menthyl o-anisyl-
(phenyl)phosphinylacetate has been developed. Examples of non-
stereoselective quaternisation of a tertiary phosphine by alkyl halides
have been revealed.
Key words P-stereogenic phosphine oxides, PAMPO, resolution, phos-
phines, pyramidal inversion, non-stereoselective quaternisation
P-Stereogenic phosphorus compounds play an import-
ant role in modern synthetic chemistry serving as chiral re-
agents, ligands and organocatalysts, as well as components
of biologically active species and new materials.1 In particu-
lar, non-racemic P-stereogenic phosphine ligands have
played an historical role in the development of asymmetric
reactions catalysed by transition-metal complexes.2 Their
importance is commonly associated with the early success-
ful use of PAMP and DIPAMP ligands for rhodium-catalysed
asymmetric hydrogenation that opened up the way to the
first industrial application of the process for the production
of L-DOPA.3 Originally, these two ligands were synthesised
from enantiopure o-anisyl(methyl)phenylphosphine oxide
(PAMPO) by stereoselective reduction (PAMP), and by cou-
pling and reduction (DIPAMP),4 following the methodolo-
gies pioneered by Mislow and Horner.5 The historical and
industrial importance of non-racemic PAMPO aroused keen
interest in its efficient preparation, as reflected by the vari-
ety of different synthetic approaches to its synthesis devel-
oped over the past four decades. These include singular res-
olution of PAMPO bearing an ancillary -L-menthoxycar-
bonyl group6 and oxidative dynamic kinetic resolution of
racemic PAMP,7 but in the vast majority, they have been
We began by modifying our original synthesis of (SP)-16
to further improve its efficiency and reproducibility on a
multigram scale. The modifications included replacement
of the Arbuzov step originally utilised for introduction of
the L-menthyl acetate auxiliary6a,11 with a more practical
and cleaner alkylation of secondary o-anisyl(phenyl)phos-
phine oxide by L-menthyl chloroacetate,12 as well as optimi-
sation and shortening of the crystallisation process
(Scheme 1). Under the optimised conditions, diastereomer-
ically pure (SP)-1 could be reproducibly obtained from an
equimolar mixture of the two P-epimers in remarkable 41%
yield (82% for one epimer).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Dziuba et al.
Paper
Synthesis
MeO
O
P
MeO
Me
1. PhSiH3
2. MeX
O
O
MeO
O
P
MeO
O
P
1. NaH, THF, rt
P
H
O
O
O
2. ClCH2CO2MenthL
3. Base, RCHO
95%
1
34.8 g
(RP)-PAMPO
(SP)-1
2 diastereomers (1:1) 61.1 g
Scheme 3 Synthetic route designed for conversion of (SP)-1 into (RP)-
PAMPO
O
crystallisation
MeO
O
P
heptane, 5 °C, 6 d
O
41%
conversion of (SP)-1, as expected, but the resulting L-men-
thyl o-anisyl(phenyl)phosphinoacetate (3) was formed as a
ca. 1.1:1 mixture of the two P-epimers (31P NMR). Lowering
the reaction temperature to 80 °C (48 h) resulted in only
partial reduction of (SP)-1 (50%) which was again accompa-
nied by substantial epimerisation at P. This time, the result-
ing phosphine 3 was obtained as a ca. 3.2:1 mixture of the
(RP)-3 and (SP)-3 epimers, respectively (31P NMR). Appar-
ently, unlike other acyclic alkyl(diaryl)phosphines, which
typically are configurationally stable up to 110–130 °C (cf.
ref. 19), phosphine 3 undergoes unexpectedly facile pyra-
midal inversion, even at temperatures as low as 80 °C.15
A search for other reagents and conditions which could
enable fully stereoretentive reduction of (SP)-1 revealed
quickly that changing PhSiH3 to a stronger reductant, like
Cl3SiH or Cl3SiH/pyridine,5d,e,16 allowed the reaction to be
carried out at still lower temperature (65 °C, 6 h),17 with
complete avoidance of P-epimerisation (31P NMR). The ex-
pected absolute configuration (RP) of the phosphine ob-
tained under these conditions was confirmed by its stereo-
retentive oxidation by H2O218 which yielded back (SP)-1 hav-
ing the same specific rotation sign and value as the starting
one.
(SP)-1
>99% de, 26.3 g
Scheme 1 Synthesis of multigram quantities of diastereomerically
pure (SP)-1
Subsequent conversion of diastereomerically pure (SP)-1
into (SP)-PAMPO was based on the previously described
protocols6,12,13 and involved unmasking of the latent acetate
Me group by hydrolysis and decarboxylation of the menthyl
carboxylate moiety to afford enantiopure (SP)-PAMPO in
89.3% overall yield (Scheme 2).
O
O
MeO
O
P
MeO
O
P
KOH
OH
O
MeOH
96%
(SP)-2 13.9 g
(SP)-1 21.4 g
MeO
O
PhBr
P
Me
160 °C
93%
With the reduction obstacle overcome, the stereocon-
trolled conversion of (SP)-1 into (RP)-PAMPO became feasi-
ble and could be successfully completed as planned. Thus,
reduction of (SP)-1 by Cl3SiH/pyridine gave (RP)-3 in >95%
yield (31P NMR). Crude phosphine was then quaternised by
methyl triflate in benzene to afford methyl phosphonium
salt (RP)-4, in practically quantitative yield (31P NMR). Final-
ly, treatment of crude (RP)-4 with potassium carbonate and
benzaldehyde in THF furnished (RP)-PAMPO in 94% yield
(Scheme 4).
As indicated in Scheme 4, due to very high yields of (RP)-
3 and (RP)-4 (31P NMR), as well as their sensitivity or highly
polar nature, respectively, these intermediate products
were not isolated and were used as crude for further steps
to avoid unnecessary loss during their attempted chromato-
graphic purifications. In this way, together with purifica-
tion of the final (RP)-PAMPO by a bulb-to-bulb (Kugelrohr)
distillation, the whole synthesis could be carried out silica-
free with a remarkably high 88.4% overall yield.
(SP)-PAMPO 10.3 g
Scheme 2 Synthesis of (SP)-PAMPO from (SP)-1
In contrast to the straightforward conversion of (SP)-1
into (SP)-PAMPO outlined above, synthesis of (RP)-PAMPO
from (SP)-1 required inversion of configuration at P. For this,
we chose to develop a procedure having the potential for a
more general use. The designed sequence of reactions in-
cluded stereoretentive deoxygenation of (SP)-1 followed by
quaternisation of the resulting phosphine by MeX, and re-
moval of the acetate moiety, in its entirety this time, in the
final Wittig step (Scheme 3). Because all the intervening
steps could be expected to occur with retention of configu-
ration, the overall stereochemical result should be inversion
at P, as visualised in Scheme 3.
According to this outline, (SP)-1 was treated with PhSiH3,
a reagent known to reduce acyclic phosphine oxides with
clean retention of configuration.14 However, heating the re-
action mixture at 110 °C for 24 hours resulted in the full
Importantly, by replacement of MeOTf with other alkyl
electrophiles, the developed protocol has the potential to
serve as a general method for the synthesis of a wider vari-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

C
K. Dziuba et al.
Paper
Synthesis
placing potassium carbonate by a stronger base (e.g., NaH)
to incur in situ isomerisation of the allylic double bond in
the last step (Scheme 5, path b).
O
MeO
MeO
MeO
O
Cl3SiH, Py
P
O
benzene, 65 °C, 6 h
It is important to stress that the choice of triflate and
mesylate as electrophiles in the syntheses of (RP)-PAMPO,
(RP)-6 and (RP)-7 was by no means accidental. Attempted
use of methyl iodide or allyl iodide (or bromide) led to the
formation of the corresponding phosphonium salts with a
partial or even complete P-epimerisation (Table 1). This was
completely unexpected since tertiary phosphines, which
have high barriers to pyramidal inversion, typically higher
than 29 kcal/mol,19 are commonly known to undergo qua-
ternisation by alkyl halides with full retention of configura-
tion at the phosphorus centre.6b,20 It should be noted, how-
ever, that some precedents of loss of stereochemical integ-
rity at P in quaternisation of cyclic phosphoroamidates as
well as in the more closely related one-pot conversions of
tertiary phosphine–boranes into quaternary phosphonium
salts at 60 °C are already on record.9a,21 The data collected in
Table 1 indicate that the stereochemical outcome of the
quaternisation of (RP)-3 shows a pronounced dependence
on solvent polarity as well as on nucleophilicity of the leav-
ing group. It also seems to be associated with the presence
of the menthoxycarbonyl group as the only structural dis-
tinction from the typical alkyl(diaryl)phosphine structure.
>95%
(SP)-1
O
O
MeOTf
P
benzene, rt, 22 h
>99%
(RP)-3
–OTf
MeO
Me
P
1. K2CO3
2. PhCHO
Me
P+
O
O
O
3. THF, rt, 18 h
94%
(RP)-PAMPO
(RP)-4
Scheme 4 Conversion of (SP)-1 into (RP)-PAMPO
ety of enantiopure phosphine oxides of RP configuration
bearing phenyl and o-anisyl substituents at P. This is exem-
plified below by the use of allyl mesylate in lieu of MeOTf in
an equally straightforward synthesis of (RP)-allyl(o-anisyl)-
phenylphosphine oxide (6), via the corresponding allyl-
phosphonium salt (RP)-5, in 89.3% overall yield from (SP)-1
(Scheme 5, path a). Interestingly, an isomeric phosphine ox-
ide (RP)-7 possessing a conjugated E-propenyl substituent at
P could be also directly derived from (RP)-5 by simply re-
Table 1 Quaternisation of (RP)-3 by Alkyl Electrophiles
X–
R
O
O
MeO
MeO
RX
P+
P
O
O
rt, 24 h
(RP)-3
O
MeO
allylOMs
P
O
Conversiona dra
MeCN, rt, 24 h
RX
Solvent
>99%
MeI
benzene
MeCN
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
82:18
(RP)-3
MeI
88:12
100:0
50:50
50:50
100:0
86:14
100:0
–OMs
P+
MeOTf
benzene
benzene
benzene
MeCN
MeO
K2CO3
PhCHO
O
O
MeO
P
allyl bromide
allyl iodide
O
THF, rt, 18 h
95%
allyl iodide
(RP)-5
(RP)-6
path a
allyl mesylate
allyl mesylate
benzene
MeCN
1. NaH
2. PhCHO
3. THF, rt, 18 h
94%
path b
a Determined by 31P NMR.
The observed solvent and counterion dependence
seems to be suggestive of the probable formation of a dis-
crete non-ionic P(V) intermediate that could be responsible
for the observed stereomutation at room temperature. The
actual role of the menthoxycarbonyl group in its possible
formation is at present unclear and requires more detailed
studies.
MeO
P
O
(RP)-7
Scheme 5 Synthesis of enantiopure (RP)-allyl(2-methoxyphenyl)phenyl-
phosphine oxide (6) and (RP)-(2-methoxyphenyl)phenyl-(E)-1-propenyl-
phosphine oxide (7)
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

D
K. Dziuba et al.
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Synthesis
In conclusion, we have developed a convenient resolu-
tion procedure offering access to multigram quantities of
crystalline, enantiomerically pure (SP)-1 in high yield.22 By
the judicious use of its auxiliary acetate function, it can be
efficiently transformed into either enantiomer of PAMPO by
straightforward decarboalkoxylation (SP), or by a reduc-
tion–quaternisation–Wittig sequence (RP). A significant ad-
vantage of the latter is that it can be considered as a general
route for the synthesis of (RP)-alkyl(o-anisyl)phenylphos-
phine oxides, including functionalised ones. The study has
also revealed that phosphine 3 bearing an -menthoxycar-
bonyl group is prone to undergo facile pyramidal inversion
at unexpectedly low temperature. In addition, the study
represents the first report on stereomutation at P in quater-
nisation of a tertiary phosphine by alkyl halides, and high-
lights the importance of structural features of the phos-
phine on the mechanism and stereocontrol. Ongoing efforts
in our laboratory are aimed towards further investigation of
the origin of the non-stereoselectivity observed in this pro-
cess.
13C NMR (126 MHz, CDCl3):  = 133.00 (d, J = 2.8 Hz), 130.79 (d, J =
11.8 Hz), 129.84 (d, J = 131.8 Hz), 128.68 (d, J = 13.7 Hz), 61.94 (d, J =
6.4 Hz), 16.29 (d, J = 6.6 Hz).
31P NMR (202 MHz, CDCl3):  = 24.47 (s).
(2-Methoxyphenyl)phenylphosphine Oxide24
To a stirred solution of 2-methoxyphenylmagnesium bromide in Et2O
(200 mL), prepared from magnesium (9.6 g, 0.4 mol) and 1-bromo-2-
methoxybenzene (75 g, 0.4 mol), was added dropwise ethyl phenyl-
phosphinate (34.03 g, 0.2 mol) dissolved in anhydrous Et2O (70 mL) at
10–15 °C. The resulting mixture was heated to reflux for 1 h, cooled
and mixed with 25% aq sulfuric acid (100 mL). Then, the layers were
separated and the aqueous phase was extracted with CHCl3 (3 × 75
mL). The organic layers were combined, dried over anhydrous MgSO4,
filtered and evaporated. The residue was dissolved in hexane/acetone
and the solution was kept in a refrigerator for 6 h to afford (2-me-
thoxyphenyl)phenylphosphine oxide (32.97 g, 71% yield); white crys-
tals; mp 101–103 °C (Lit.24 101–103 °C).
1H NMR (500 MHz, CDCl3):  = 8.17 (d, J = 499.3 Hz, 1 H), 7.79 (ddd, J =
14.3, 7.5, 1.8 Hz, 1 H), 7.76–7.70 (m, 2 H), 7.55–7.49 (m, 2 H), 7.47–
7.42 (m, 2 H), 7.10 (tdd, J = 7.7, 2.0, 1.0 Hz, 1 H), 6.91 (ddd, J = 8.4, 5.7,
0.9 Hz, 1 H), 3.77 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 160.63 (d, J = 3.7 Hz), 134.46 (d, J = 2.1
Hz), 133.00 (d, J = 7.1 Hz), 132.10 (d, J = 104.5 Hz), 132.05 (d, J = 3.0
Hz), 128.53 (d, J = 13.1 Hz), 121.12 (d, J = 12.1 Hz), 119.32 (d, J = 101.8
Hz), 110.81 (d, J = 6.2 Hz), 55.54 (s).
Reagents were purchased from commercial suppliers and used with-
out further purification. Solvents were dried over molecular sieves
(benzene, toluene, MeCN), sodium ketyl (THF) and sodium (Et2O), and
distilled under argon before use. All reactions involving formation
and further reactions of phosphine 3 were carried out under argon at-
mosphere with attempted complete exclusion of air from the reaction
vessels and solvents, including those used in the workup. NMR spec-
31P NMR (202 MHz, CDCl3):  = 14.41 (s).
(SP)-L-Menthyl (2-Methoxyphenyl)phenylphosphinylacetate (1)
A solution of L-menthyl chloroacetate25 (37.24 g, 0.16 mol) in anhy-
drous THF (70 mL) was added dropwise to (2-methoxyphenyl)phen-
ylphosphine oxide (34.83 g, 0.15 mol) suspended in anhydrous THF
(200 mL), followed by portionwise addition of a 60% dispersion of
NaH in oil (6.4 g, 0.15 mol), under argon in a Schlenk-type flask. After
addition, the reaction mixture was stirred at rt for 22 h, and then
evaporated and CH2Cl2 (150 mL) was added. The organic phase was
washed with H2O (2 × 75 mL), dried over anhydrous MgSO4, filtered
and evaporated. The resulting yellow oil was dissolved in warm hep-
tane and slowly cooled to rt, and then the solution was kept in a re-
frigerator at 5 °C for 6 d to yield crystalline precipitate. Additional re-
crystallisation from heptane/CHCl3 [to remove remaining traces of
the oily (RP)-1 epimer6] gave diastereomerically pure (>99% de by
NMR) (SP)-1 (26.35 g, 41% yield); white crystals; mp 97–99 °C [Lit.6a
104–105 °C (measured for a high purity, single crystal)].
tra were recorded on a Bruker AV300 (1H 300 MHz, 31P 121.5 MHz, 13
C
NMR 75 MHz) or Bruker AV500 (1H 500 MHz, 31P 202 MHz, 13C NMR
126 MHz) spectrometer. All spectra were obtained in CDCl3 solutions,
unless mentioned otherwise, and the chemical shifts () are ex-
pressed in ppm using internal reference to TMS and external refer-
ence to 85% H3PO4 in D2O for 31P. Coupling constants (J) are given in
Hz. The abbreviations of signal patterns are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; b, broad. Elemental analy-
ses were measured on a Perkin-Elmer CHN 2400 system. Optical rota-
tions were measured on a Perkin-Elmer 341LC digital polarimeter.
TLC was done on silica gel (Kieselgel 60, F254 on aluminum sheets,
Merck). All column chromatographic separations and purifications
were conducted using Merck silica gel 60 (230–400 mesh), unless
noted otherwise.
[]D20 –36.85 (c 1.1, CHCl3).
Ethyl Phenylphosphinate23
1H NMR (500 MHz, CDCl3):  = 7.99 (ddd, J = 13.5, 7.6, 1.8 Hz, 1 H),
7.84 (ddd, J = 12.5, 8.3, 1.4 Hz, 2 H), 7.55–7.48 (m, 2 H), 7.46–7.40 (m,
2 H), 7.11 (tdd, J = 7.5, 2.0, 0.9 Hz, 1 H), 6.93 (ddd, J = 8.4, 5.7, 0.8 Hz, 1
H), 4.58 (td, J = 10.9, 4.4 Hz, 1 H), 3.83 (s, 3 H), 3.69–3.54 (m, 2 H),
1.79–1.68 (m, 2 H), 1.59 (ddt, J = 13.6, 9.6, 2.8 Hz, 2 H), 1.40–1.30 (m,
1 H), 1.20–1.13 (m, 1 H), 0.99–0.89 (m, 1 H), 0.81 (dd, J = 11.0, 6.8 Hz,
6 H), 0.77–0.65 (m, 2 H), 0.63 (d, J = 6.9 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 166.04 (d, J = 6.8 Hz), 159.80 (d, J = 4.2
Hz), 134.57 (d, J = 5.9 Hz), 134.25 (d, J = 2.2 Hz), 133.14 (d, J = 106.5
Hz), 131.72 (d, J = 3.0 Hz), 130.77 (d, J = 10.3 Hz), 128.25 (d, J = 12.5
Hz), 121.17 (d, J = 11.5 Hz), 119.70 (d, J = 102.8 Hz), 110.74 (d, J = 6.9
Hz), 75.39 (s), 55.38 (s), 46.57 (s), 40.29 (s), 38.64 (d, J = 62.9 Hz),
34.09 (s), 31.26 (s), 25.68 (s), 23.03 (s), 21.93 (s), 20.85 (s), 15.96 (s).
A solution of phenylphosphonic dichloride (50 mL, 0.37 mol) in anhy-
drous Et2O (100 mL) was treated dropwise with a solution of EtOH
(21.5 mL, 0.37 mol) and pyridine (30 mL, 0.37 mol) in Et2O (200 mL)
at rt under argon. After stirring for 2 h, a mixture of H2O (7 mL) and
pyridine (30 mL, 0.37 mol) was added slowly. The reaction mixture
was filtered, the precipitate was washed with Et2O and the volatiles
were evaporated to give an oil. The crude oil was distilled at 95–
98 °C/0.1 mbar (Lit.23 102–103 °C/0.2 mbar) to give ethyl phenyl-
phosphinate (44 g, 70% yield).
1H NMR (500 MHz, CDCl3):  = 7.72–7.64 (m, 2 H), 7.52–7.46 (m, 1 H),
7.48 (d, J = 562.4 Hz, 1 H), 7.43–7.37 (m, 2 H), 4.12–3.96 (m, 2 H), 1.26
(t, J = 7.1 Hz, 3 H).
31P NMR (202 MHz, CDCl3):  = 24.97 (s).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

E
K. Dziuba et al.
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Synthesis
Anal. Calcd for C25H33O4P: C, 70.07; H, 7.76. Found: C, 70.22; H, 7.85.
An analogous reduction carried out in benzene at 80 °C for 48 h gave
only 50% conversion and produced a 3.2:1 mixture of the (RP)-3 and
(SP)-3 epimers, respectively.
31P NMR (122 MHz, CDCl3):  = –23.43, –23.36.
So far, all attempts to also isolate pure (RP)-1 epimer from the com-
bined mother liquors [containing the (RP)-1 and (SP)-1 epimers in ca.
4:1 ratio] were unsuccessful.
(SP)-(2-Methoxyphenyl)phenylphosphinylacetic Acid (2)
(RP,SP)-L-Menthyl (2-Methoxyphenyl)phenylphosphinoacetate (3)
To a solution of (SP)-1 (21.43 g, 0.05 mol) in MeOH (150 mL) was add-
ed KOH (4 g, 0.1 mol). The reaction mixture was stirred at rt for 24 h,
and then evaporated and CHCl3 (150 mL) was added. The phases were
separated, and the organic phase was washed with H2O (2 × 50 mL),
dried over anhydrous MgSO4, filtered and evaporated. The crude
product was purified by crystallisation (MeCN) to give (SP)-2 (13.93 g,
96% yield); colorless crystals; mp 177–179 °C.
[]D20 –26.27 (c 1.0, MeOH) [Lit.26 []D –5.4 (c 0.65, MeOH), measured
for a sample of estimated 45% ee (uncrystallised)].
1H NMR (500 MHz, CDCl3):  = 7.75 (ddd, J = 13.6, 7.6, 1.7 Hz, 1 H),
7.67 (ddt, J = 12.8, 7.0, 1.5 Hz, 2 H), 7.43 (dddd, J = 16.6, 9.2, 5.2, 1.3
Hz, 2 H), 7.38–7.31 (m, 2 H), 7.03–6.98 (m, 1 H), 6.85 (dd, J = 8.3, 5.7
Hz, 1 H), 4.61 (bs, OH), 3.68 (s, 3 H), 3.50 (d, J = 14.7 Hz, 2 H).
To a solution of (SP)-1 (0.94 g, 0.0022 mol) in anhydrous toluene (50
mL) was added dropwise Cl3SiH (1.11 mL, 0.011 mol). The mixture
was heated under argon at 110 °C for 24 h. After cooling to rt, 30% aq
NaOH (100 mL) was added carefully to the opaque mixture, until the
organic and aqueous layers became clear. After separation, the aque-
ous layer was washed with benzene (2 × 45 mL). The combined or-
ganic layers were washed with H2O (45 mL), dried over anhydrous
MgSO4, filtered and evaporated under vacuum to give a ca. 1:1 mix-
ture of the (RP)-3 and (SP)-3 epimers (31P NMR).
31P NMR (202 MHz, CDCl3):  = –23.57, –23.50.
An analogous reduction at 80 °C for 24 h gave a 6.4:1 mixture of the
(RP)-3 and (SP)-3 epimers, respectively.
31P NMR (202 MHz, CDCl3):  = –23.55, –23.49.
13C NMR (126 MHz, CDCl3):  = 171.98 (d, J = 6.3 Hz), 163.87 (d, J = 4.5
Hz), 138.71 (d, J = 2.2 Hz), 137.79 (d, J = 6.0 Hz), 136.04 (d, J = 2.9 Hz),
136.01 (d, J = 107.9 Hz), 134.49 (d, J = 10.6 Hz), 132.38 (d, J = 12.8 Hz),
125.19 (d, J = 11.6 Hz), 122.34 (d, J = 104.7 Hz), 115.02 (d, J = 7.1 Hz),
59.28 (s), 41.67 (d, J = 64.5 Hz).
However, reduction of (SP)-1 carried out at 65 °C for 12 h produced
the desired (RP)-3 without any concomitant epimerisation at P [31
P
NMR (202 MHz, CDCl3):  = –23.66]. The same fully stereoretentive
reduction was achieved by reduction of (SP)-1 at 65 °C with
Cl3SiH/pyridine (vide infra).
31P NMR (202 MHz, CDCl3):  = 33.00 (s).
(RP)-L-Menthyl (2-Methoxyphenyl)phenylphosphinoacetate (3)
Anal. Calcd for C15H15O4P: C, 62.07; H, 5.21. Found: C, 62.12; H, 5.25.
To a solution of (SP)-1 (1.07 g, 0.0025 mol) in anhydrous benzene (50
mL) was added pyridine (1.0 mL, 0.0125 mol) followed by dropwise
addition of Cl3SiH (1.0 mL, 0.01 mol). The mixture was heated under
argon at 65 °C for 6 h. After cooling to rt, 30% aq NaOH (100 mL) was
added carefully to the opaque mixture, until the organic and aqueous
layers became clear. After separation, the aqueous layer was washed
with benzene (2 × 45 mL), and the combined organic layers were
washed with H2O (2 × 45 mL), dried over anhydrous MgSO4, filtered
and evaporated under vacuum to give (RP)-3 as the pure epimer in
>95% yield. This product was used for the next step without further
purification.
(SP)-(2-Methoxyphenyl)methylphenylphosphine Oxide [(SP)-
PAMPO]
A solution of (SP)-2 (13.06 g, 0.045 mol) in bromobenzene (100 mL)
was stirred at reflux temperature for 8 h. The reaction mixture was
evaporated under vacuum and the crude product was purified by
Kugelrohr distillation (0.1 mbar, 195–199 °C) to give optically pure
(SP)-PAMPO (10.31 g, 93% yield); white solid; mp 75–78 °C.
[]D20 –25.95 (c 1.0, MeOH) [Lit.8 []D –26 (c 1.2, MeOH).
1H NMR (500 MHz, CDCl3):  = 7.95 (ddd, J = 13.1, 7.5, 1.8 Hz, 1 H),
7.77–7.68 (m, 2 H), 7.50–7.42 (m, 2 H), 7.42–7.37 (m, 2 H), 7.08 (tdd,
J = 7.5, 1.8, 0.9 Hz, 1 H), 6.87 (ddd, J = 8.4, 5.4, 0.9 Hz, 1 H), 3.70 (s, 3
H), 2.06 (d, J = 14.0 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 159.87 (d, J = 4.2 Hz), 134.90 (d, J =
103.9 Hz), 133.93 (d, J = 2.0 Hz), 133.86 (d, J = 5.9 Hz), 131.27 (d, J =
2.8 Hz), 130.21 (d, J = 10.2 Hz), 128.20 (d, J = 12.2 Hz), 121.32 (d, J =
99.9 Hz), 121.00 (d, J = 11.2 Hz), 110.89 (d, J = 6.7 Hz), 55.29, 16.12 (d,
J = 75.2 Hz).
31P NMR (122 MHz, CDCl3):  = –23.94 (s).
Reoxidation of (RP)-L-Menthyl (2-Methoxyphenyl)phenylphosphi-
noacetate (3) to (SP)-L-Menthyl (2-Methoxyphenyl)phenylphosphi-
nylacetate (1)
To a solution (RP)-3 (0.825 g, 0.002 mol) in CH2Cl2 (50 mL) was added
30% aq H2O2 (10 mL). The mixture was stirred at rt for 24 h. The
phases were separated, and the organic phase was washed twice with
H2O (25 mL), dried over anhydrous MgSO4, filtered and evaporated.
The crude product was purified by column chromatography (CH2Cl2/
EtOAc, 25:1) to give (SP)-1 (0.815 g, 95% yield) of >99% optical purity;
mp 96–98 °C.
31P NMR (202 MHz, CDCl3):  = 28.63 (s).
Anal. Calcd for C14H15O2P: C, 68.29; H, 6.14. Found: C, 68.21; H, 6.00.
(RP,SP)-L-Menthyl (2-Methoxyphenyl)phenylphosphinoacetate (3)
[]D20 –36.84 (c 1.2, CHCl3).
To a solution of (SP)-1 (0.86 g, 0.002 mol) in anhydrous toluene (50
mL) was added dropwise PhSiH3 (1.2 mL, 0.01 mol). The mixture was
heated under argon at 110 °C for 48 h. After cooling to rt, 30% aq
NaOH (100 mL) was added carefully to the opaque mixture, until the
organic and aqueous layers became clear. After separation, the aque-
ous layer was washed with benzene (2 × 45 mL). The combined or-
ganic layers were washed with H2O (45 mL), dried over anhydrous
MgSO4, filtered and evaporated under vacuum to give a ca. 1:1:1 mix-
ture of the (RP)- and (SP)-3 epimers (31P NMR).
1H NMR (500 MHz, CDCl3):  = 7.99 (ddd, J = 13.5, 7.6, 1.8 Hz, 1 H),
7.84 (ddd, J = 12.5, 8.3, 1.4 Hz, 2 H), 7.55–7.48 (m, 2 H), 7.46–7.40 (m,
2 H), 7.11 (tdd, J = 7.5, 2.0, 0.9 Hz, 1 H), 6.93 (ddd, J = 8.4, 5.7, 0.8 Hz, 1
H), 4.58 (td, J = 10.9, 4.4 Hz, 1 H), 3.83 (s, 3 H), 3.69–3.54 (m, 2 H),
1.79–1.68 (m, 2 H), 1.59 (ddt, J = 13.6, 9.6, 2.8 Hz, 2 H), 1.40–1.30 (m,
1 H), 1.20–1.13 (m, 1 H), 0.99–0.89 (m, 1 H), 0.81 (dd, J = 11.0, 6.8 Hz,
6 H), 0.77–0.65 (m, 2 H), 0.63 (d, J = 6.9 Hz, 3 H).
31P NMR (202 MHz, CDCl3):  = 25.01 (s).
31P NMR (122 MHz, CDCl3):  = –23.64, –23.62.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

F
K. Dziuba et al.
Paper
Synthesis
(RP)-L-Menthoxycarbonylmethyl(2-methoxyphenyl)methylphen-
ylphosphonium Triflate (4)
mL), dried over anhydrous MgSO4, filtered and evaporated. The result-
ing crude product was purified by column chromatography (CH2Cl2/
EtOAc, 25:1; Rf = 0.29) and dried in vacuum to give pure (RP)-6 (0.49 g,
95% yield); white solid; mp 167–169 °C.
A solution of methyl trifluoromethanesulfonate (0.27 mL, 0.0025
mol) in anhydrous bezene (5 mL) was added dropwise to (RP)-3 (0.825
g, 0.002 mol) suspended in anhydrous benzene (25 mL) under argon
in a Schlenk-type flask. After addition, the reaction mixture was
stirred at rt for a further 22 h. Then, the reaction mixture was evapo-
rated and CH2Cl2 (50 mL) was added. The organic phase was washed
with H2O (2 × 50 mL), dried over anhydrous MgSO4, filtered, evaporat-
ed and dried in vacuum to give diastereomerically pure (>99% de by
31P NMR) (RP)-4 (1.14 g, 99% yield) as a thick oil. This product was
used for the next step without further purification.
[]D20 +21.67 (c 1.14, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.97 (ddd, J = 12.8, 7.5, 1.8 Hz, 1 H),
7.83–7.75 (m, 2 H), 7.57–7.46 (m, 2 H), 7.45–7.38 (m, 2 H), 7.11 (tdd,
J = 7.5, 1.8, 0.8 Hz, 1 H), 6.92 (ddd, J = 8.4, 5.4, 0.8 Hz, 1 H), 5.90–5.76
(m, 1 H), 5.21–5.08 (m, 2 H), 3.81 (s, 3 H), 3.38–3.22 (m, 2 H).
13C NMR (126 MHz, CDCl3):  = 159.63 (d, J = 4.5 Hz), 134.72 (d, J = 5.4
Hz), 134.04 (d, J = 2.2 Hz), 133.55 (d, J = 100.8 Hz), 131.45 (d, J = 2.7
Hz), 130.72 (d, J = 9.6 Hz), 128.22 (d, J = 12.1 Hz), 127.69 (d, J = 9.9 Hz),
121.22 (d, J = 10.9 Hz), 120.37 (d, J = 12.3 Hz), 119.77 (d, J = 98.0 Hz),
110.69 (d, J = 6.8 Hz), 55.29, 35.53 (d, J = 70.1 Hz).
31P NMR (122 MHz, CDCl3):  = 19.76 (s).
(RP)-(2-Methoxyphenyl)methylphenylphosphine Oxide [(RP)-PAMPO]
31P NMR (202 MHz, CDCl3):  = 29.86 (s).
To a solution of crude (RP)-4 (1.14 g, 0.0019 mol) in anhydrous THF
(25 mL) were added K2CO3 (1.382 g, 0.01 mol) and benzaldehyde (1.02
mL, 0.01 mol) under argon in a Schlenk-type flask. After stirring for
18 h, the reaction mixture was evaporated and CH2Cl2 (50 mL) was
added. The organic phase was washed with H2O (2 × 50 mL), dried
over anhydrous MgSO4, filtered and evaporated. The resulting crude
product was purified by Kugelrohr distillation (0.1 bar, 194–199 °C) to
give (RP)-PAMPO (0.463 g, 94% yield) of >99% optical purity; white
solid; mp 74–77 °C (Lit.27 70–75 °C).
Anal. Calcd for C16H17O2P: C, 70.58; H, 6.29. Found: C, 70.55; H, 6.47.
(RP)-(2-Methoxyphenyl)phenyl-(E)-1-propenylphosphine Oxide
(7)
A 60% dispersion of NaH in oil (0.1 g, 0.0025 mol) was added portion-
wise to a solution of crude (RP)-5 (1.09 g, 0.0019 mol) in anhydrous
THF (25 mL) under argon in a Schlenk-type flask. After completion of
the addition, to the reaction solution was added dropwise benzalde-
hyde (1.02 mL, 0.01 mol). After a stirring period of 18 h, the reaction
mixture was evaporated, CH2Cl2 (50 mL) was added, and the organic
phase was washed with H2O (2 × 50 mL), dried over anhydrous
MgSO4, filtered and evaporated. The resulting crude product was pu-
rified by column chromatography (CH2Cl2/EtOAc, 25:1; Rf = 0.27) and
dried in vacuum to give pure (RP)-7 (0.48 g, 94% yield); white solid;
mp 150–151 °C.
[]D20 +25.9 (c 1.2, MeOH) [Lit.27 []D +25.9 (c 1.0, MeOH)].
1H NMR (300 MHz, CDCl3):  = 7.98 (ddd, J = 13.1, 7.5, 1.8 Hz, 1 H),
7.76 (ddt, J = 12.3, 6.5, 1.7 Hz, 2 H), 7.56–7.36 (m, 4 H), 7.11 (tdd, J =
7.5, 1.8, 0.9 Hz, 1 H), 6.95–6.85 (m, 1 H), 3.74 (s, 3 H), 2.09 (d, J = 14.0
Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 159.87 (d, J = 4.2 Hz), 134.90 (d, J =
103.9 Hz), 133.93 (d, J = 2.0 Hz), 133.86 (d, J = 5.9 Hz), 131.27 (d, J =
2.8 Hz), 130.21 (d, J = 10.2 Hz), 128.20 (d, J = 12.2 Hz), 121.32 (d, J =
99.9 Hz), 121.00 (d, J = 11.2 Hz), 110.89 (d, J = 6.7 Hz), 55.29, 16.12 (d,
J = 75.2 Hz).
[]D20 –32.70 (c 1.02, CHCl3).
1H NMR (500 MHz, CDCl3):  = 8.03 (ddd, J = 13.0, 7.5, 1.8 Hz, 1 H),
7.70–7.62 (m, 2 H), 7.52 (tdd, J = 7.3, 1.8, 0.7 Hz, 1 H), 7.49–7.43 (m, 1
H), 7.43–7.36 (m, 2 H), 7.13 (tdd, J = 7.6, 1.9, 0.9 Hz, 1 H), 7.01–6.87
(m, 2 H), 6.46 (ddq, J = 27.2, 17.0, 1.7 Hz, 1 H), 3.66 (s, 3 H), 2.00 (dt, J =
6.6, 1.9 Hz, 3 H).
31P NMR (122 MHz, CDCl3):  = 28.98 (s).
Anal. Calcd for C14H15O2P: C, 68.29; H, 6.14. Found: C, 68.21; H, 6.05.
13C NMR (126 MHz, CDCl3):  = 160.05 (d, J = 4.1 Hz), 147.27 (d, J = 1.7
Hz), 134.88 (d, J = 108.1 Hz), 133.89 (d, J = 7.8 Hz), 133.86 (d, J = 4.0
Hz), 131.13 (d, J = 2.7 Hz), 130.60 (d, J = 10.5 Hz), 128.11 (d, J = 12.6
Hz), 122.87 (d, J = 105.2 Hz), 121.09 (d, J = 11.1 Hz), 120.79 (d, J =
103.9 Hz), 110.97 (d, J = 6.7 Hz), 55.30, 20.43 (d, J = 19.0 Hz).
(RP)-Allyl(L-menthoxycarbonylmethyl)(2-methoxyphenyl)phenyl-
phosphonium Mesylate (5)
A solution of allyl methanesulfonate (0.28 mL, 0.0025 mol) in anhy-
drous MeCN (5 mL) was added dropwise to (RP)-3 (0.825 g, 0.002 mol)
suspended in anhydrous MeCN (25 mL) under argon in a Schlenk-type
flask. After addition, the reaction mixture was stirred at rt for 24 h.
Then, the reaction mixture was evaporated and CH2Cl2 (50 mL) was
added. The organic phase was washed with H2O (2 × 50 mL), dried
over anhydrous MgSO4, filtered, evaporated and dried in vacuum to
give diastereomerically pure (31P NMR) (RP)-5 (1.09 g, 99% yield) as a
thick oil. This product was used for the next step without further pu-
rification.
31P NMR (202 MHz, CDCl3):  = 20.69 (s).
Anal. Calcd for C16H17O2P: C, 70.58; H, 6.29. Found: C, 70.52; H, 6.45.
Quaternisation of (RP)-L-Menthyl (2-Methoxyphenyl)phenylphos-
phinoacetate (3); General Procedure
A solution of an electrophile RX (0.0013 mol) in anhydrous solvent (5
mL) was added dropwise to (RP)-3 (0.413 g, 0.001 mol) dissolved (or
partly dissolved) in the same solvent (25 mL) under argon in a
Schlenk-type flask. After addition, the reaction mixture was stirred at
rt for 24 h. Then, the reaction mixture was evaporated and CH2Cl2 (50
mL) was added. The organic phase was washed with H2O (2 × 50 mL),
dried over anhydrous MgSO4, filtered, evaporated and dried in vacu-
um to give the crude phosphonium salt. Diastereomeric ratios and
conversions were determined by 31P NMR.
31P NMR (122 MHz, CDCl3):  = 18.37 (s).
(RP)-Allyl(2-methoxyphenyl)phenylphosphine Oxide (6)
To a solution of crude (RP)-5 (1.09 g, 0.0019 mol) in anhydrous THF
(25 mL) were added K2CO3 (1.382 g, 0.01 mol) and benzaldehyde (1.02
mL, 0.01 mol) under argon in a Schlenk-type flask. After a stirring pe-
riod of 18 h, the reaction mixture was filtered, evaporated and CH2Cl2
(50 mL) was added. The organic phase was washed with H2O (2 × 50
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

G
K. Dziuba et al.
Paper
Synthesis
Thermally Induced Inversion at P in (RP)-L-Menthyl (2-Methoxy-
phenyl)phenylphosphinoacetate (3)
(9) (a) Jugé, S.; Genet, J. P. Tetrahedron Lett. 1989, 30, 2783.
(b) Brown, J. M.; Carey, J. V.; Russell, M. J. H. Tetrahedron 1990,
46, 4877. (c) Carey, J. V.; Barker, M. D.; Brown, J. M.; Russell, M. J.
H. J. Chem. Soc., Perkin Trans. 1 1993, 831. (d) Corey, E. J.; Chen,
Z.; Tanoury, G. J. J. Am. Chem. Soc. 1993, 115, 11000. (e) Adams,
H.; Collins, R. C.; Jones, S.; Warner, J. A. Org. Lett. 2011, 13, 6576.
(f) Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu,
Y.; Li, Z.; Reeves, J. T.; Desrosiers, J.-N.; Ma, S.; Grinberg, N.; Lee,
H.; Mangunuru, H. P. R.; Zhang, Y.; Krishnamurthy, D.; Lu, B. Z.;
Song, J. J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013,
135, 2474. (g) D’Onofrio, A.; Copey, L.; Jean-Gérard, L.; Goux-
Henry, C.; Pilet, G.; Andrioletti, B.; Framery, E. Org. Biomol.
Chem. 2015, 13, 9029. (h) Copey, L.; Jean-Gérard, L.; Framery, E.;
Pilet, G.; Robert, V.; Andrioletti, B. Chem. Eur. J. 2015, 21, 9057.
(10) Cardellicchio, C.; Fiandanese, V.; Naso, F.; Pacifico, S.;
Koprowski, M.; Pietrusiewicz, K. M. Tetrahedron Lett. 1994, 35,
6343.
A solution of (RP)-3 (0.05 g, 0.125 mmol) in anhydrous toluene (0.5
mL) was heated under argon at 110 °C for 6 h to give a ca. 1:1:1 mix-
ture of the (RP)-3 and (SP)-3 epimers (31P NMR).
31P NMR (202 MHz, CDCl3):  = –23.93, –23.86.
An analogous experiment at 80 °C for 12 h gave a 1.7:1 mixture of the
(RP)-3 and (SP)-3 epimers, respectively.
31P NMR (202 MHz, CDCl3):  = –23.95, –23.89.
However, heating (RP)-3 at 65 °C for 12 h did not incur any detectable
epimerisation at P and left the starting (RP)-3 epimer unchanged.
31P NMR (202 MHz, CDCl3):  = –23.99.
Funding Information
(11) Bodalski, R.; Rutkowska-Olma, E.; Pietrusiewicz, K. M. Tetrahe-
dron 1980, 36, 2353.
(12) Imamoto, T.; Sato, K.; Johnson, C. R. Tetrahedron Lett. 1985, 26,
783.
We thank Narodowe Centrum Nauki (National Science Centre,
Poland) for partly funding this work through grant NN204 265 238.
N
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o
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e
C
e
ntur
m
N
a
u
k
i(N
N
2
0
4
2
6
5
2
3
8)
(13) Pietrusiewicz, K. M.; Zabłocka, M.; Monkiewicz, J. J. Org. Chem.
1984, 49, 1522.
Acknowledgment
(14) (a) Marsi, K. L. J. Org. Chem. 1974, 39, 265. (b) Demchuk, O. M.;
Jasiński, R.; Pietrusiewicz, K. M. Heteroat. Chem. 2015, 26, 441.
(c) Herault, D.; Nguyen, D. H.; Nuel, D.; Buono, G. Chem. Soc. Rev.
2015, 44, 2508. (d) Kovacs, T.; Keglevich, G. Curr. Org. Chem.
2017, 21, 569.
(15) Separate experiments involving heating of enantiopure (RP)-3
in toluene under argon in the absence of PhSiH3 at 110 °C for 6
h, and at 80 °C for 12 h, resulted in nearly complete (ca. 1.1:1)
and partial (ca. 1.7:1) epimerisation, respectively, as revealed by
31P NMR. No epimerisation of (RP)-3 was observed at 65 °C (12
h), but at this temperature an attempted reduction of (SP)-1 by
PhSiH3 did not take place even after prolonged heating (48 h).
(16) (a) Quin, L. D.; Caster, K. C.; Kislaus, J. C.; Mesch, K. A. J. Am.
Chem. Soc. 1984, 106, 7021. (b) Krenske, E. H. J. Org. Chem. 2012,
77, 3969.
We thank Mr. Witold Wiśniewski for carrying out preliminary experi-
ments.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691531.
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References
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(17) Similarly to reductions with PhSiH3, treatment of (SP)-1 with
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configuration at P observed in an intramolecular SN2 reaction
involving
a
secondary phosphine as nucleophile, see:
(b) Muldoon, J. A.; Varga, B. Z.; Deegan, M. M.; Chapp, T. W.;
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(22) Economy of the presented synthesis of (SP)-1 can be further
improved by the possibility of recycling the difficult-to-purify
oily (RP)-1 epimer left behind in the original mother liquor. This
can be achieved by epimerisation through reduction at 110 °C
either by PhSiH3, or by Cl3SiH (preferred for larger scale), fol-
lowed by oxidation with H2O2 to restore the starting 1:1
mixture of (RP)-1 and (SP)-1 for repeated resolution.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

H
K. Dziuba et al.
Paper
Synthesis
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J. Am. Chem. Soc. 1975, 97, 2567.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H