The PMe3-catalyzed addition of enantiomerically pure (?)-MenthylO(Ph)P(O)H to electron-deficient alkenes: an efficient way for the preparation of P-stereogenic compounds

Article abstract of DOI:10.1016/j.tetasy.2016.11.005

A variety of P-stereogenic organophosphorus compounds can be readily prepared by stereoretentive addition. The PMe₃-catalyzed addition of optically active (?)MenthylO(Ph)P(O)H compounds to electron deficient alkenes occur stereospecifically, to produce the corresponding P-stereogenic adducts in high yields. By simply removing the volatiles under vacuum, spectroscopically pure products can be obtained. The present method provides a salt-free clean process for the preparation of P-chiral organophosphorus compounds.

Full text of DOI:10.1016/j.tetasy.2016.11.005

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The PMe3-catalyzed addition of enantiomerically pure (ꢀ)-MenthylO
(Ph)P(O)H to electron-deficient alkenes: an efficient way for the
preparation of P-stereogenic compounds
Yuta Saga a,b, Yuka Mino b, Shin-ichi Kawaguchi c, Daoqing Han d, Akiya Ogawa a, Li-Biao Han d,
⇑
a Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan
b Katayama Chemical Industries Co., Ltd., 26-22, 3-Chome, Higasinaniwa-cho, Amagasaki, Hyogo 660-0892, Japan
c Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan
d National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1, Higashi, Tsukuba, Ibaraki 305-8565, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of P-stereogenic organophosphorus compounds can be readily prepared by stereoretentive
addition. The PMe3-catalyzed addition of optically active (ꢀ)MenthylO(Ph)P(O)H compounds to electron
deficient alkenes occur stereospecifically, to produce the corresponding P-stereogenic adducts in high
yields. By simply removing the volatiles under vacuum, spectroscopically pure products can be obtained.
The present method provides a salt-free clean process for the preparation of P-chiral organophosphorus
compounds.
Received 15 September 2016
Revised 31 October 2016
Accepted 7 November 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
NH2
N
1. Introduction
O
P
O
O
P
N
O
P-Stereogenic organophosphorus compounds are highly useful
compounds. The chirality of the phosphorus center plays a key role
in asymmetric catalysis.1 The novel effects of the chirality of the
phosphorus centers in biochemistry have also been recognized
long before (Scheme 1). For example, the biological activity
PhO
P
O
Et
O
SPh
OEt
Me
PhS
Et
OEt
NH
H
(RP)
(SP)
OH
F
CO2i-Pr
fonofos oxon
sofosbuvir [(RP,SP)-mixture]
(LD50) of fonofos oxon towards house fly is 4
l
g/g with the (SP)-
enantiomer, but 48
l
g/g with the (RP)-enantiomer under similar
Scheme 1. Example of the crucial rule of the chirality at the phosphorus centers in
the biochemical activities.
conditions.2 A recent example is sofosbuvir, an effective nucleotide
analogue drug used clinically since 2013 for the treatment of hep-
atitis C virus infection.3 Studies have revealed that the (SP)-form is
more active than the corresponding (RP)-form.4
proceeded stereospecifically with retention of configuration at
the phosphorus to produce the corresponding optically-active P-
stereogenic organophosphorus compounds in high yields
(Scheme 2).7 Unfortunately, similar additions with electron-defi-
cient alkenes were hampered by severe polymerization of the ole-
fins. On the other hand, although a base-catalyzed addition of a P
(O)H bond to electron-deficient alkenes can take place easily,1 this
method cannot be generally applied to 1 because of its rapid
racemization under basic conditions.7–9 Therefore, a general stere-
oselective addition of 1 to an electron-deficient alkenes has not
been achieved. It should be noted that compared with a simple ali-
phatic alkene, the adduct with an electron-deficient alkene is a
multiple functionalized molecule, which can be easily transformed
into other functional molecules.
However, the preparation of a pure P-stereogenic organophos-
phorus compound is not easy using traditional methods because
of the tedious synthetic procedures.1 This situation has stimulated
long-continued active studies on the development of new efficient
preparations of P-stereogenic organophosphorus compound.5
Conversely, enantiomerically pure hydrogen phosphoryl com-
pounds 1 are relatively accessible phosphorus compounds.6 There-
fore, the stereospecific addition of these compounds to alkenes
would be a practical and convenient method for the preparation
of P-stereogenic organophosphorus compounds (Scheme 2). It
was recognized that the radical addition of 1 to aliphatic alkenes
Recently, we found that PMe3 can efficiently catalyze the addi-
tion of Z1,Z2P(O)H compounds to vinylphosphoryl compounds to
⇑
Corresponding author. Tel.: +81 29 861 4855; fax: +81 29 861 6344.
E-mail address: libiao-han@aist.go.jp (L.-B. Han).
http://dx.doi.org/10.1016/j.tetasy.2016.11.005
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
Y. Saga et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
anionic addition with a base
radical addition
O
P
H2C CHR
H2C CHR
not applicable
racemization
O
P
(CH2)2R
Z2
Z1
aliphatic alkenes
aliphatic alkenes
H
Z2
Z1
H2C CHEWG
H2C CHEWG
not applicable
cat. PMe3
H2C CHEWG
O
P
(CH2)2EWG
Z2
Z1
stereoretention
Scheme 2. Stereospecific addition of optically active Z1,Z2P(O)H compounds to electron-deficient alkenes.
give the corresponding vic-bisphosphorylethanes in high yields.10
This is a clean salt-free process. By simply removing the volatiles
under vacuum, spectroscopically pure products can be obtained.
We envisaged that this PMe3-catalyzed addition might be applica-
ble to the addition of optically active (ꢀ)-MenthylO(Ph)P(O)H 1 to
electron-deficient alkenes. Herein we report that the PMe3-cat-
alyzed addition of 1 to electron-deficient alkenes occurs with the
retention of configuration, producing the corresponding P-chiral
adducts in high yields (Scheme 2). These P-chiral products are
promisingly useful as ligands for asymmetric catalysts.1
bidentate bisphosphorylethanes. Not limited to vinylphosphonate
(entries 1–3), vinylphosphine oxide (entry 4), phosphinate (entries
5 and 7), and cyclic phosphorus compounds (entry 6) could also be
used as the substrates to give the corresponding adducts in good
yields. In addition to (RP)-1a, the enantiomerically pure ben-
zylphosphinate (RP)-1c could also be used as substrate to produce
the corresponding adducts efficiently. Similarly, by using starting
materials with an (S)-configuration at the phosphorus (SP)-1b
and (SP)-1d, the corresponding adducts with (SP)-configurations
were selectively obtained (entries 10 and 13). The stereoselectivity
in the addition of 2m was confirmed by using HPLC with a chiral-
pack IA column (Fig. 1).11 In addition to vinylphosphoryl com-
pounds, other electron-deficient alkenes, such as acrylonitrile and
methyl acrylate, could also be used as substrates in this selective
addition of optically active P(O)H compounds to afford the corre-
sponding adducts selectively (entries 8 and 9). It should be noted
that C2-symmetric bidentate P-stereogenic phosphorus com-
pounds (RP,RP)-2b and (RP,SP)-2k could be easily prepared using
this method (entries 7 and 11).
Since the present method is advantageous due to its easy oper-
ation, a relatively large amount (a few tens of grams) of P-stere-
ogenic organophosphorus compounds could be readily prepared.
For example, to a solution of (RP)-1a (6.3 g, 50 mmol) and PMe3
(2.5 mmol) in THF (50 mL) cooled with an ice water bath, was
slowly added methyl acrylate (4.3 g, 51 mmol). After the mixture
was stirred for 2.0 h, the cooling bath was removed. Stirring was
then continued for 18 h at room temperature. The PMe3 catalyst
and other volatiles were removed under vacuum (1 mmHg) to give
(RP)-2i as a yellow oil, which was NMR spectroscopically pure
(10.3 g, 97% yield) (Eq. 3). Decolorization of the product was easily
achieved by treatment with activated charcoal: by treating the yel-
low oil of (RP)-2i with a small amount of activated charcoals, (RP)-
2i was obtained as a colorless oil successfully.
2. Results and discussion
At 0 °C, PMe3 (0.025 mmol) was added to a mixture of (ꢀ)-Men-
thyl (RP)-phenylphosphinate (RP)-1a (0.5 mmol) and diethyl
vinylphosphonate 3a (0.5 mmol) in THF (0.5 mL). The solution
was stirred at room temperature for 6 h. As confirmed by 1H and
31P NMR spectroscopies of the crude product, the starting materials
were consumed to give (RP)-2a (vide infra for the determination of
the stereochemistry) in 89% yield (Eq. 1). The selectivity is excel-
lent since no other isomers could be detected.
O
P
O
P
5 mol% PMe3
(EtO)2(O)P
+
H
P(O)(OEt)2
(-)MenO
1 M THF, rt, 6 h
(-)MenO
Ph
Ph
ð1Þ
1a
3a
(RP)-
(Men = menthyl)
2a
(RP)- , 89% yield
The product, (RP)-2a, is a known compound.7 Therefore, the
absolute configuration at the stereogenic phosphorus of the addi-
tion product 2a was readily determined to be (RP) by comparing
its NMR spectroscopies with those of the authentic sample. This
result shows that this catalytic addition proceeds via retention of
configuration at the phosphorus. This characteristic stereoreten-
tion was further confirmed by carrying out an addition of (RP)-1a
to an enantiomerically pure vinylphosphorus compound (RP)-3b
under similar conditions. Adduct 2b was isolated in 75% yield
(Eq. 2). The 31P NMR spectroscopy of 2b displays only one signal,
showing that the two phosphorus atoms have the same (RP)-
configuration.
PMe3/THF(2.5 mL)
(RP)-1a
C(O)OMe
4.3 g
+
(RP)-2i
ð3Þ
1. 0 °C, 2.0 h; 25 °C, 18 h
2. vaccum (1 mmHg, 4.0 h)
6.3 g
10.3 g (97% yield)
The observed stereochemistry of the PMe3-catalyzed additions
of R2P(O)H compounds may provide clues to the reaction mecha-
nism.9 The intermediacy of a phosphonium salt,4 generated via
the addition of PMe3 to 3, seems relatively certain as described pre-
viously.10,12 An equilibrium between P(V) 1 and P(III) 5 also
exists.5,13 To explain that the addition of 1 to 3 to give 2 proceeds
with retention of configuration at the phosphorus, one possible
reaction mechanism is shown in Scheme 3. Thus, via an exchange
reaction with PMe3, 5 attacks 4 to give 6, which in turn leads to 2
via a subsequent rearrangement. The stereochemistry at the phos-
phorus during the above reactions remains intact.
O(-)Men
O
P
O
Ph
5 mol% PMe3
P
(RP)-1a
+
P
O
(-)MenO
ð2Þ
1 M THF, rt, 6 h
Ph
Ph
(-)MenO
(RP)-3b
(RP,RP)-2b
This PMe3-catalyzed selective addition could be readily applied
to other compounds to produce the corresponding P-chiral com-
pounds in good yield (Table 1). Thus, (RP)-1a was efficiently added
to various vinylphosphorus compounds to produce P-stereogenic
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Y. Saga et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
PMe3-catalyzed addition of optically P(O)-H compounds to vinylphosphoryl compounds
O
O
P
5 mol% PMe3
THF, rt, 6 h
+
P
EWG
H
EWG
R
R
R'
R'
2
1
3
Entry
1
1
3
Product 2
Yield (%)a
89
d.r.C (d.e %)b
>99:1 (>99)
O
P
P(O)(OEt)2
(RP)-1a
(RP)-2a
P(O)(OEt)2
(-)MenO
Ph
O
P
O(-)Men
P
O
Ph
2
(RP, RP)-2b
75
>99:1 (>99)
(-)MenO
P
Ph
O
Ph
(-)MenO
O
P
P(O)(OMe)2
P(O)(OPh)2
P(O)Ph2
3
(RP)-2c
(RP)-2d
(RP)-2e
(RP)-2f
90
93
95
74
>99:1 (>99)
>99:1 (>99)
>99:1 (>99)
>99:1 (>99)
P(O)(OMe)2
P(O)(OPh)2
P(O)Ph2
(-)MenO
(-)MenO
(-)MenO
(-)MenO
Ph
Ph
Ph
Ph
O
P
4c
5
O
P
O
P
P(O)(OEt)Ph
6
P(O)Ph(OEt)
O
O
P
O
P
O
P
(-)MenO
7
(RP)-2g
66
>99:1 (>99)
Ph
O
O
P
CN
8
9
(RP)-2h
(RP)-2i
48
64
>99:1 (>99)
>99:1 (>99)
CN
(-)MenO
Ph
Ph
O
P
C(O)OMe
P(O)(OMe)2
C(O)OMe
(-)MenO
O
O
P
P
H
P(O)(OMe)2
10
11
12
(SP)-2j
87
77
91
>1:99 (>99)
>1:99 (>99)
>99:1 (>99)
Ph
Ph
O(+)Men
O(+)Men
(SP)-1b
O
P
O(-)Men
P
O
Ph
(RP,SP)-2k
(RP)-2l
(-)MenO
P
Ph
O
O(+)Men
Ph
O
O
P
P(O)(OMe)2
P
H
P(O)(OMe)2
(-)MenO
(-)MenO
O
CH2Ph
CH2Ph
(RP)-1c
O
P(O)(OMe)2
P
P
13
(SP)-2m
55
1:99 (98)e
d
H
P(O)(OMe)2
tBu
tBu
Ph
Ph
(SP)-1d
a
b
c
An equimolar mixture of 1 (0.5 mmol) and 3 (0.5 mmol) in THF (0.5 mL) was stirred at room temperature in the presence of PMe3 (5 mol%). Yields refer to isolated yields.
Values of d.r.C was estimated by 31P NMR spectroscopy.
THF (1 mL), 50 °C.
d
e
1d (R/S = 1/99, 0.55 mmol) and PMe3 (10 mol%) were used.
The (RP):(SP) ratio of the adduct was determined by chiral HPLC.11
3. Conclusion
4. Experimental
4.1. General
We have developed a convenient and versatile method for the
addition of optically active R2P(O)H compounds to electron-defi-
cient alkenes with stereoretention. A variety of functionalized
enantiomerically pure organophosphorus compounds can be con-
veniently prepared by this PMe3-catalyzed method. The isolation
of the adducts is simple, since the PMe3 catalyst can be easily
removed from the products under vacuum to give spectroscopi-
cally pure products after the reaction.14
All materials were obtained from commercial supplies and were
used without further purification. 1H NMR spectra were recorded
on JEOL JNM-ECS400 (400 MHz) FT NMR in CDCl3 with Me4Si as
an internal standard. 13C NMR spectra were taken on JEOL JNM-
ECS400 (100 MHz) FT NMR system in CDCl3. 31P NMR spectra were
taken on JEOL JNM-ECX400 (162 MHz) FT NMR system in CDCl3
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4
Y. Saga et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
PMe3 under reduced pressure gave a crude product. The adducts
were isolated by GPC to afford analytically pure samples.
4.2.1. (RP)-(ꢀ)-Menthyl 2-(diethoxyphosphoryl)ethyl(phenyl)
phosphinate (RP)-2a7
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.70–7.63 (m, 2H),
7.48–7.40 (m, 1H), 7.39–7.33 (m, 2H), 4.23–4.12 (m, 1H), 4.00–
3.87 (m, 4H), 2.20–1.45 (m, 8H), 1.28 (td, J = 9.2, 1.0 Hz, 1H),
1.22–1.13 (m, 1H), 1.18 (d, J = 2.8 Hz, 3H), 1.15 (d, J = 2.8 Hz, 3H),
0.95 (d, J = 2.8 Hz, 3H), 0.88 (d, J = 2.8 Hz, 3H), 0.73 (d, J = 2.6 Hz,
3H), 1.08–0.72 (m, 3H); 13C NMR (CDCl3, 100 MHz) d 131.7 (d, JC–
P = 125.9 Hz), 132.1 (d, JC–P = 2.9 Hz), 131.2 (d, JC–P = 9.6 Hz), 128.3
(d, JC–P = 12.4 Hz), 61.64, 61.63 (d, JC–P = 13.4 Hz), 48.5 (d, JC–
P = 5.7 Hz), 42.9, 33.8, 31.2, 25.5, 24.0 (d, JC–P = 5.7 Hz), 22.9 (d, JC–
P = 5.7 Hz), 22.6, 21.6, 20.9, 18.8 (d, JC–P = 3.8 Hz), 17.3 (d, JC–
P = 2.8 Hz), 16.2 (d, JC–P = 4.8 Hz), 15.4; 31P NMR (CDCl3, 162 MHz)
d 40.9 (d, J = 74.8 Hz), 30.8 (d, J = 74.8 Hz); specific rotation of
(RP)-2a: [
a]
25 = ꢀ18.5 (c 0.11, CHCl3).
D
4.2.2. Ethylene bis-[(RP)-(ꢀ)-Menthyl phenylphosphinate] (RP,
RP)-2b7
White solid; mp 201–202 °C; 1H NMR (CDCl3, 400 MHz) d 7.73–
7.65 (m, 4H), 7.53–7.48 (m, 2H), 7.44–7.38 (m, 4H), 4.27–4.21 (m,
2H), 2.25–2.12 (m, 4H), 1.90–1.76 (m, 2H), 1.70–1.55 (m, 6H), 1.37
(td, J = 23.0, 5.6, 2H), 1.32–1.21 (m, 2H), 0.95 (d, J = 6.8 Hz, 6H),
0.86 (d, J = 6.8 Hz, 6H), 0.72 (d, J = 7.2 Hz, 6H), 1.01–0.69 (m, 6H);
13C NMR (CDCl3, 100 MHz) d 132.1 (d, JC–P = 62.9 Hz), 132.0,
131.30 (d, JC–P = 4.7 Hz), 131.26 (d, JC–P = 4.8 Hz), 128.37 (d, JC–
P = 5.7 Hz), 128.31 (d, JC–P = 6.7 Hz), 48.6 (d, JC–P = 2.9 Hz), 42.9,
33.9, 31.3, 25.6, 22.7, 22.5 (tt, JC–P = 87.8, 83.5 Hz), 21.7, 21.0,
15.5; 31P NMR (CDCl3, 162 MHz) d 41.4; specific rotation of (RP,
Figure 1. Determination of the (RP):(SP) ratio of 2m [(RP):(SP) = 2/98] by HPLC (UV)
using a chiralpack IA column (hexane/iPrOH = 8/2, 0.9 ml/min, 25 °C). Retention
time: 6.90 min (SP), 7.44 min (RP).
with 85% H3PO4 solution as an external standard. HPLC (recycle
GPC) method for isolation was performed on Japan Analytical
Industry LC-908 with JAIGEL-1H (polystyrene-based column). High
resolution mass spectra were obtained on JEOL JMS700 at Kyoto-
RP)-2b: [
a
]
D
26 = ꢀ46.3 (c 0.11, CHCl3); HRMS (ESI) Calcd for C34H52
-
O4P2Na [M+Na]+: 609.3239, Found: 609.3234.
Nara Advanced Nanotechnology Network. Optical rotations [a]
D
of the products were measured on a JASCO DIP-1000 at 589 nm
(Na lamp), 100 mm of cell length. Caution: trimethylphosphine
has toxicity and high volatility. When trimethylphosphine is
manipulated, ventilate the bench carefully.
4.2.3. (RP)-(ꢀ)-Menthyl 2-(dimethoxyphosphoryl)ethyl(phenyl)
phosphinate (RP)-2c
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.81–7.74 (m, 2H),
7.58–7.43 (m, 3H), 4.33–4.24 (m, 1H), 3.72 (d, J = 8.0 Hz, 3H),
3.69 (d, J = 8.4 Hz, 3H), 2.30–1.59 (m, 6H), 1.38 (tt, J = 23.0,
5.6 Hz, 1H), 1.33–1.24 (m, 1H), 0.96 (d, J = 7.2 Hz, 3H), 0.86 (d,
J = 6.8 Hz, 3H), 0.74 (d, J = 6.4 Hz, 4H), 1.10–0.70 (m, 4H); 13C
NMR (CDCl3, 100 MHz) d 131.5 (d, JC–P = 124.9 Hz), 132.0, 131.1
(d, JC–P = 9.5 Hz), 128.3 (d, JC–P = 12.4 Hz), 52.2 (d, JC–P = 5.7 Hz),
48.4 (d, JC–P = 5.7 Hz), 42.8, 33.7, 31.1, 25.4, 23.7 (d, JC–P = 5.7 Hz),
22.7 (d, JC–P = 4.8 Hz), 22.5, 21.5, 20.8, 17.6, 16.2, 15.3; 31P NMR
(CDCl3, 162 MHz) d 40.6 (d, J = 78.7 Hz), 33.4 (d, J = 74.8 Hz); speci-
4.2. General procedure for the PMe3-catalyzed addition of P(O)H
compounds to vinylphosphorus compounds
A glass schlenk tube was charged with P(O)H compounds
(0.5 mmol), vinylphosphorus compounds (0.5 mmol), and 0.5 mL
of solvent. After the tube was cooled in an ice bath, PMe3/THF
(1.0 mol/L, 25 lL) was injected into the system with a syringe.
After the mixture was stirred for 30 min, the ice bath was removed.
Stirring was then continued for 20 h at room temperature. The
reaction was monitored by 31P NMR. Removal of the solvent and
fic rotation of (RP)-2c: [a]
25 = –16.7 (c 0.11, CHCl3); HRMS (ESI)
D
Calcd for C20H34O5P2Na [M+Na]+: 439.1779, Found: 439.1775.
PH(O)R2
3
PMe3
O
P
OH
Me3P
RO
Ph
P
P(O)R2
RO
Ph
P(O)R2
P(O)R2
4
P
2
Ph
OH
6
RO
O
P
5
H
Ph
RO
1
Scheme 3. A proposed reaction mechanism for the PMe3-catalyzed addition with retention of configuration at the phosphorus.
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Y. Saga et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.2.4. (RP)-(ꢀ)-Menthyl 2-(diphenoxyphosphoryl)ethyl(phenyl)
phosphinate (RP)-2d
(d, JC–P = 11.5 Hz), 128.4 (d, JC–P = 12.4 Hz), 128.3 (d, JC–
P = 13.3 Hz), 128.3 (d, JC–P = 12.4 Hz), 125.1, 124.6 (d, JC–
P = 3.8 Hz), 123.9 (d, JC–P = 5.7 Hz), 123.9 (d, JC–P = 5.7 Hz), 123.8
(d, JC–P = 4.8 Hz), 123.8 (d, JC–P = 4.8 Hz), 122.8, 121.9 (d, JC–
P = 11.4 Hz), 121.9 (d, JC–P = 11.5 Hz), 120.1 (d, JC–P = 6.7 Hz), 48.5
(d, JC–P = 2.8 Hz), 48.4 (d, JC–P = 2.8 Hz), 42.9 (d, JC–P = 3.8 Hz), 33.8,
31.2, 25.6, 22.51 (dd, JC–P = 99.6, 10.5 Hz), 22.47 (dd, JC–P = 99.6,
10.5 Hz), 21.7, 21.03 (dd, JC–P = 96.8, 4.8 Hz), 20.09 (d, JC–P = 96.3,
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.82–7.76 (m, 2H),
7.58–7.53 (m, 1H), 7.52–7.44 (m, 2H), 7.32–7.25 (m, 4H), 7.18–
7.09 (m, 6H), 4.36–4.26 (m, 1H), 2.42–2.12 (m, 5H), 1.79–1.57
(m, 3H), 1.40 (tt, J = 22.6, 6.2 Hz, 1H), 1.35–1.23 (m, 1H), 0.94 (d,
J = 7.2 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.4 Hz, 3H),
1.05–0.71 (m, 3H); 13C NMR (CDCl3, 100 MHz) d 150.0 (dd, JC–
P = 8.6, 5.7 Hz), 132.3 (d, JC–P = 2.8 Hz), 131.6 (d, JC–P = 125.8 Hz),
129.7, 128.5 (d, JC–P = 12.4 Hz), 125.2, 120.3 (d, JC–P = 3.9 Hz), 48.6
(d, JC–P = 5.7 Hz), 42.3, 33.5, 31.3, 25.7, 24.0 (d, JC–P = 5.7 Hz), 23.0
(d, JC–P = 6.7 Hz), 22.3, 21.7, 20.9, 18.7 (dd, JC–P = 18.7, 2.8 Hz),
15.5; 31P NMR (CDCl3, 162 MHz) d 40.1 (d, J = 78.6 Hz), 24.2 (d,
4.8 Hz), 20.9, 15.4; 31P NMR (CDCl3, 162 MHz)
d 40.5 (d,
J = 41.6 Hz), 37.4 (d, J = 41.6 Hz); specific rotation of (RP)-2g:
[a
]
D
26 = ꢀ25.9 (c 0.10, CHCl3); HRMS (ESI) Calcd for C30H36O4P2Na
[M+Na]+: 545.1987; Found: 545.1984.
J = 78.6 Hz); specific rotation of (RP)-2d: [
a
]
26 = –16.6 (c 0.12,
4.2.8. (RP)-Menthyl 2-cyanoethyl(phenyl)phosphinate (RP)-2h7
White solid; mp 76–77 °C; 1H NMR (CDCl3, 400 MHz) d 7.82–
7.75 (m, 2H), 7.63–7.56 (m, 1H), 7.54–7.47 (m, 2H), 4.36–4.25
(m, 1H), 2.70–2.42 (m, 2H), 2.36–2.22 (m, 1H), 2.22–2.09 (m,
2H), 1.83–1.57 (m, 3H), 1.41 (td, J = 23.2, 6.4 Hz, 1H), 1.36–1.23
(m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.75 (d,
J = 6.4 Hz, 3H), 1.06–0.70 (m, 3H); 13C NMR (CDCl3, 100 MHz) d
132.6 (d, JC–P = 2.8 Hz), 131.2 (d, JC–P = 9.5 Hz), 130.6 (d, JC–
P = 127.7 Hz), 128.6 (d, JC–P = 12.4 Hz), 118.3 (d, JC–P = 19.1 Hz),
48.4 (d, JC–P = 5.8 Hz), 42.8, 33.7, 31.2, 26.5 (d, JC-P = 100.1 Hz),
25.7, 22.6, 21.7, 20.8, 15.4, 10.6; 31P NMR (CDCl3, 162 MHz) d
D
CHCl3); HRMS (ESI) Calcd for C30H38O5P2Na [M+Na]+: 563.2092;
Found: 563.2095.
4.2.5. (RP)-(ꢀ)-Menthyl 2-(diphenylphosphoryl)ethyl(phenyl)
phosphinate (RP)-2e7
White solid; mp 150–151 °C; 1H NMR (CDCl3, 400 MHz) d 7.79–
7.61 (m, 6H), 7.56–7.39 (m, 9H), 4.29–4.19 (m, 1H), 2.62–2.25 (m,
2H), 2.25–1.93 (m, 4H), 1.70–1.48 (m, 2H), 1.35 (tt, J = 22.8, 6.0 Hz,
1H), 1.31–1.21 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H), 0.78 (d, J = 7.2 Hz,
3H), 0.73 (d, J = 6.4 Hz, 3H), 1.25–0.70 (m, 3H); 13C NMR (CDCl3,
100 MHz) d 132.3 (d, JC–P = 1.9 Hz), 132.2 (d, JC–P = 99.2 Hz), 132.0
(d, JC–P = 96.3 Hz), 131.9, 131.3 (d, JC–P = 9.6 Hz), 131.2 (d, JC–
P = 2.8 Hz), 130.8 (d, JC–P = 5.7 Hz), 130.7 (d, JC–P = 5.7 Hz), 128.8
(d, JC–P = 1.9 Hz), 128.7 (d, JC–P = 1.9 Hz), 128.6, 128.4, 48.7 (d, JC–
P = 5.7 Hz), 43.0, 33.9, 31.4, 25.6, 22.8, 22.6 (dd, JC–P = 36.7,
3.8 Hz), 21.8, 21.7, 21.1 (dd, JC–P = 120.1, 4.7 Hz), 21.0, 15.5; 31P
37.8; specific rotation of (RP)-2h: [
a]
D
24 = ꢀ4.9 (c 0.53, CHCl3).
4.2.9. (RP)-(ꢀ)-Menthyl 2-(methoxycarbonyl)ethyl(phenyl)
phosphinate (RP)-2i7
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.83–7.75 (m, 2H),
7.58–7.51 (m, 1H), 7.51–7.44 (m, 2H), 4.34–4.24 (m, 1H), 3.62 (s,
3H), 2.67–2.39 (m, 2H), 2.33–2.07 (m, 3H), 1.78–1.56 (m, 3H),
1.38 (td, J = 23.2, 6.0 Hz, 1H), 1.34–1.23 (m, 1H), 1.07–0.77 (m,
3H), 0.96 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H) 0.74 (d,
NMR (CDCl3, 162 MHz)
J = 37.0 Hz); specific rotation of (RP)-2e: [a]
d
41.6 (d, J = 37.0 Hz), 33.1 (d,
26 = –29.3 (c 0.58,
D
CHCl3).
J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 172.4 (d, JC–
4.2.6. (1RP)-(ꢀ)-Menthyl 2-[ethoxy(phenyl)-(2racemic)-phos-
phoryl]ethyl(phenyl)phosphinate (RP)-2f
P = 18.1 Hz), 132.1 (d, JC–P = 124.9 Hz), 132.0 (d, JC–P = 1.9 Hz),
131.2 (d, JC–P = 10.5 Hz), 128.3 (d, JC–P = 12.4 Hz), 51.7, 48.6 (d, JC–
P = 5.7 Hz), 42.9, 33.8, 31.2, 26.4, 25.5, 25.5 (d, JC–P = 102.1 Hz),
22.6, 21.7, 20.9, 15.4; 31P NMR (CDCl3, 162 MHz) d 40.8; specific
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.80–7.65 (m, 4H),
7.60–7.40 (m, 6H), 4.32–4.16 (m, 1H), 4.12–3.78 (m, 2H), 2.28–
1.81 (m, 4H), 1.76–1.54 (m, 4H), 1.42–1.21 (m, 5H), 1.02–0.70
(m, 12H); 13C NMR (CDCl3, 100 MHz) d 132.3, 132.1, 131.6 (d, JC–
P = 124.9 Hz), 131.5 (d, JC–P = 124.6 Hz), 131.4 (d, JC–P = 10.5 Hz),
131.2 (d, JC–P = 9.6 Hz), 130.2 (d, JC–P = 6.7 Hz), 129.0 (d, JC–
P = 5.7 Hz), 128.52 (d, JC–P = 12.4 Hz), 128.49 (d, JC–P = 12.4 Hz),
128.33 (d, JC–P = 12.4 Hz), 128.30 (d, JC–P = 12.4 Hz), 60.7 (d, JC–
P = 6.7 Hz), 48.50 (d, JC–P = 5.3 Hz), 48.45 (d, JC–P = 5.2 Hz), 42.9,
33.8, 31.2, 25.5 (d, JC–P = 7.7 Hz), 22.6 (d, JC–P = 3.8 Hz), 22.49 (dd,
JC–P = 99.7, 7.2 Hz), 22.46 (dd, JC–P = 99.7, 7.2 Hz), 22.0 (dd, JC–
P = 101.1, 9.5 Hz), 22.0 (dd, JC–P = 101.1, 9.5 Hz), 20.8 (d, JC–
P = 6.6 Hz), 16.21 (d, JC–P = 6.1 Hz), 16.19 (d, JC–P = 5.7 Hz), 15.4 (d,
JC–P = 10.5 Hz); 31P NMR (CDCl3, 162 MHz) d 43.9 (d, J = 67.4),
43.8 (J = 67.4), 41.3 (d, J = 71.1); specific rotation of (RP)-2f:
rotation of (RP)-2i: [
a]
24 = ꢀ11.5 (c 0.50, CHCl3).
D
4.2.10. (SP)-(+)-Menthyl 2-(diethoxyphosphoryl)ethyl(phenyl)
phosphinate (SP)-2j
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.73–7.65 (m, 2H),
7.75–7.68 (m, 8H), 7.53–7.46 (m, 1H), 7.43–7.38 (m, 2H), 4.28–
4.13 (m, 1H), 3.74–3.51 (m, 6H), 2.20–1.70 (m, 5H), 1.69–1.51
(m, 3H), 1.38–1.17 (m, 2H), 1.11–0.64 (m, 12H); 13C NMR (CDCl3,
100 MHz) d 132.4 (d, JC–P = 1.9 Hz), 131.8 (d, JC–P = 124.9 Hz),
131.4 (d, JC–P = 9.6 Hz), 128.6 (d, JC–P = 12.4 Hz), 52.6 (dd, JC–
P = 6.7, 2.0 Hz), 48.8 (d, JC–P = 5.8 Hz), 43.1, 34.0, 31.4, 25.8, 23.5
(dd, JC–P = 101.1, 5.7 Hz), 22.8, 21.9, 21.1, 17.2 (dd, JC–P = 144.0,
2.9 Hz), 15.6; 31P NMR (CDCl3, 162 MHz) d 40.7 (d, J = 46.2 Hz),
[
a]
D
26 = ꢀ23.5 (c 0.10, CHCl3); HRMS (ESI) Calcd for C26H38O4P2Na
33.5 (d, J = 46.2 Hz); specific rotation of (SP)-2j: [a]
26 = +10.1 (c
D
[M+Na]+: 499.2143; Found: 499.2148.
0.41, CHCl3); Calcd for C20H34O5P2Na [M+Na]+: 439.1779, Found:
439.1780.
4.2.7. 2-[(ꢀ)-Menthoxy(phenyl)-(1RP)-phosphoryl]ethyl-9,10-
dihydro-9-oxa-10-(2racemic)-phosphaphenanthrene-10-oxide
(RP)-2g
4.2.11. (1SP)-(+)-Menthyl 2-[(-)-menthoxy(phenyl)-(2RP)-phos-
phoryl]ethyl(phenyl)phosphinate (RP,SP)-2k7
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.89–7.78 (m, 2H),
7.75–7.57 (m, 4H), 7.50–7.33 (m, 4H), 7.33–7.06 (m, 3H), 4.22–
4.11 (m, 1H), 2.35–1.88 (m, 5H), 1.69–1.65 (m, 3H), 1.33–1.12
(m, 2H), 0.95–0.60 (m, 12H); 13C NMR (CDCl3, 100 MHz) d 148.83
(d, JC–P = 8.6 Hz), 148.75 (d, JC–P = 8.6 Hz), 135.7 (d, JC–P = 3.8 Hz),
135.6 (d, JC–P = 3.8 Hz), 133.3 (d, JC–P = 1.9 Hz), 132.2 (d, JC–
P = 1.9 Hz), 131.6 (d, JC–P = 129.4 Hz), 131.4 (d, JC–P = 129.4 Hz),
132.1 (d, JC–P = 10.5 Hz), 131.2 (d, JC–P = 10.5 Hz), 131.1 (d, JC–
P = 9.5 Hz), 130.5 (d, JC–P = 4.7 Hz), 129.9 (d, JC–P = 11.4 Hz), 129.8
White solid; mp 201–202 °C; 1H NMR (CDCl3, 400 MHz) d 7.78–
7.68 (m, 4H), 7.58–7.51 (m, 2H), 7.50–7.42 (m, 4H), 4.27–4.15 (m,
2H), 2.23–1.94 (m, 6H), 1.78–1.71 (m, 2H), 1.68–1.54 (m, 14H),
1.38–1.22 (m, 4H), 0.89 (d, J = 7.2 Hz, 6H), 0.75 (d, J = 6.8 Hz, 6H),
0.73 (d, J = 6.8 Hz, 6H), 0.99–0.71 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 132.4 (d, JC–P = 92.5 Hz), 131.4 (d, JC–P = 93.4 Hz),
132.1, 131.3 (d, JC–P = 4.7 Hz), 131.2 (d, JC–P = 4.8 Hz), 127.5 (d, JC–
P = 5.7 Hz), 127.4 (d, JC–P = 6.6 Hz), 48.69 (d, JC–P = 2.9 Hz), 48.66
(d, JC–P = 2.9 Hz), 42.1, 33.0, 30.2, 24.7, 22.4, 21.9 (tt, JC–P = 86.8,
Please cite this article in press as: Saga, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.005

6
Y. Saga et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
86.3 Hz), 21.8, 20.8, 20.0, 14.6; 31P NMR (CDCl3, 162 MHz) d 41.5;
specific rotation of (RP, SP)-2k: [
26 = –6.8 (c 0.11, CHCl3).
A. Supplementary data
a]
D
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.11.
005.
4.2.12. (RP)-(ꢀ)-Menthyl benzyl[2-(diethoxyphosphoryl)ethyl]
phosphinate (RP)-2l
White solid; mp 96–97 °C; 1H NMR (CDCl3, 400 MHz) d 7.35–
7.22 (m, 5H), 4.27–4.16 (m, 1H), 3.69 (dd, J = 2.7, 1.0 Hz, 6H),
3.15 (dd, J = 13.2, 6.4 Hz, 2H), 2.05–1.77 (m, 6H), 1.72–1.61 (m,
4H), 1.49–1.23 (m, 2H), 1.15–0.70 (m, 3H), 0.90 (d, J = 7.2 Hz,
3H), 0.86 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 131.5 (d, JC–P = 7.6 Hz), 129.7 (d, JC–P = 6.7 Hz), 128.7 (d,
JC–P = 1.9 Hz), 126.7 (d, JC–P = 11.6 Hz), 52.5 (d, JC–P = 2.9 Hz), 48.6
(d, JC–P = 5.7 Hz), 43.6, 37.3 (d, JC–P = 85.8 Hz), 33.9, 31.4, 25.5,
22.7, 21.9, 21.1 (dd, JC–P = 92.5, 5.7 Hz), 21.0, 17.2 (dd, JC–
P = 143.0, 4.8 Hz), 15.4; 31P NMR (CDCl3, 162 MHz) d 49.8 (d,
J = 71.1 Hz), 33.2 (d, J = 67.4 Hz); specific rotation of (RP)-2l:
References
1. (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-Interscience: New
York, 2000; (b) Kagan, H. B.; Sasaki, M. Chemistry of Organophosphorus
Compounds; Wiley & Sons: New York, 1990; (c) Imamoto, T. In Handbook of
Organophosphorus Chemistry; Engel, R., Ed.; Marcel Dekker: New York, 1992.
Chapter 1.
2. Lee, P. W.; Allahyari, R.; Fukuto, T. R. Pestic. Biochem. Physiol. 1978, 8, 146–157.
3. Ross, B. S.; Rwddy, P. G.; Zhang, H.-R.; Rachakoonda, S.; Sofia, M. J. J. Org. Chem.
2011, 76, 8311–8319.
4. Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.;
Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J. J. Biol. Chem. 2010, 285,
34337–34347.
5. (a) Chen, T.; Han, L.-B. Synlett 2015, 1153–1163; (b) Nemoto, T.; Hamada, Y.
Tetrahedron 2011, 67, 667–687.
[a]
26 = –33.9 (c 0.10, CHCl3); HRMS (ESI) Calcd for C21H36O5P2Na
D
[M+Na]+: 453.1936; Found: 453.1934.
6. (a) Han, L.-B.; Xu, Q. Japanese Patent JP2006-137710A (filed, 12 November
2004; opened, 1 June 2006).; (b) Xu, Q.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc.
2008, 130, 12648–12655; (c) Han, L.-B.; Xu, Q. Japanese Patent JP2008-69103A
(filed, 25 August 2006; opened, 3 March 2008).
4.2.13. (SP)-t-Butyl-[2-(dimethoxyphosphoryl)]phenylphosphine
oxide (SP)-2m
Colorless oil; 1H NMR (CDCl3, 400 MHz) d 7.74–7.66 (m, 2H),
7.59–7.45 (m, 3H), 3.74 (d, J = 16.0, 10.0 Hz, 3H), 3.71 (d,
J = 16.4 Hz, 3H), 2.37–2.07 (m, 3H), 1.69–1.52 (m, 1H), 1.15 (d,
J = 15.2 Hz, 9H); 13C NMR (CDCl3, 100 MHz) d 131.8, 131.7, 128.5
(d, JC–P = 86.7 Hz), 128.3 (d, JC–P = 10.4 Hz), 52.4 (d, JC–P = 4.8 Hz),
32.6 (d, JC–P = 67.7 Hz), 24.2, 16.6 (dd, JC–P = 143.1, 3.9 Hz), 16.0
(dd, JC–P = 61.5, 5.2 Hz); 31P NMR (CDCl3, 162 MHz) d 50.8 (d,
J = 56.2 Hz), 34.3 (d, J = 56.2 Hz); specific rotation of (RP)-2m:
7. Han, L.-B.; Zhao, C.-Q. J. Org. Chem. 2005, 70, 10121–10123.
8. Farnham, W. B.; Murray, R. K.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 5809–5810.
9. A few additions have been achieved by using (-)-MenOMgCl as a catalyst (ref7).
10. Saga, Y.; Han, D.; Kawaguchi, S.-i.; Ogawa, A.; Han, L.-B. Tetrahedron Lett. 2015,
56, 5303–5305.
11. The RP/SP ratio of adduct 2m was estimated to be ca. 2/98.
12. Wang, X.-B.; Saga, Y.; Shen, R.; Fujino, H.; Goto, M.; Han, L.-B. RSC Adv. 2012, 2,
5935–5937.
13. (a) Wang, X.-B.; Goto, M.; Han, L.-B. Chem. Eur. J. 2014, 20, 3631–3635; (b) Li, G.
Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516.
14. Mislow et al. have shown that the MenO group in the enantiomerically pure
phosphinates can be stereospecifically replaced with RLi or RMgX. (a) Ref. 8;
(b) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem. Soc. 1968, 90,
4842–4846; (c) Lewis, R. A.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7009–7012.
[a]
26 = –11.0 (c 0.50, CHCl3); HPLC analysis (UV 254 nm) on chiral-
D
pack IA column using hexane/iPrOH (8/2) as eluent (0.9 ml/min) at
25 °C. Retention time of enantiomers: 6.90 min (SP), 7.44 min (RP).
Racemic 2m was known.10
Please cite this article in press as: Saga, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.005