[5.5]-P-spirocyclic chiral triaminoiminophosphorane-catalyzed asymmetric hydrophosphonylation of aldehydes and ynones daisuke uraguchi1

Article abstract of DOI:10.1246/bcsj.20170040

Development of highly efficient and enantioselective hydrophosphonylations of aldehydes and ynones mediated by [5.5]- P-spirocyclic chiral triaminoiminophosphoranes as base catalysts is described. The strong basicity of the iminophosphoranes and hydrogen-

Full text of DOI:10.1246/bcsj.20170040

Selected Paper
[5.5]-P-Spirocyclic Chiral Triaminoiminophosphorane-Catalyzed
Asymmetric Hydrophosphonylation of Aldehydes and Ynones
Daisuke Uraguchi,1 Takaki Ito,1 Yuto Kimura,1 Yumiko Nobori,1 Makoto Sato,1,2 and Takashi Ooi*1,2
1Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied Chemistry,
Graduate School of Engineering, Nagoya University, Nagoya, Aichi 464-8601
2CREST, Japan Science and Technology Agency (JST), Nagoya University, Nagoya, Aichi 464-8601
E-mail: tooi@apchem.nagoya-u.ac.jp
Received: January 28, 2017; Accepted: February 8, 2017; Web Released: April 4, 2017
Takashi Ooi
Takashi Ooi received his B.S. in 1989 and his Ph.D. in 1994 from Nagoya University under the guidance of
Prof. H. Yamamoto. After postdoctoral work with Prof. J. Rebek, Jr. (MIT, Cambridge), he joined the group of
Prof. K. Maruoka in Hokkaido University as an assistant professor in 1995, became a lecturer in 1998, and
then moved to Kyoto University as an associate professor in 2001. In 2006, he moved to Nagoya University
as a full professor. Since 2013, he has been a principle investigator at the Institute of Transformative Bio-
Molecules (WPI-ITbM) in Nagoya University.
Abstract
extremely low (³10¹4%), even though it is considered to be a
nucleophilic tautomer. Therefore, the efficiency of the nucle-
ophilic addition of dialkyl phosphonates to carbonyl com-
pounds depends on this unfavorable equilibrium, suggesting
that activation of dialkyl phosphonates would be crucial for
attaining sufficient reactivity. In fact, Wynberg used a basic
organic molecule, quinine, as a sole catalyst capable of acti-
vating dialkyl phosphonates for promoting asymmetric hydro-
phosphonylation for the first time in 1983, though it was only
applicable to a highly reactive aromatic aldehyde, 2-nitro
benzaldehyde.6 A decade lapsed before asymmetric hydro-
phosphonylation was revisited in the arena of Lewis acid
chemistry, leading to the identification of several effective cata-
lysts, but with limited success.7,8 In 1996, Shibasaki developed
the first highly enantioselective and general protocol based on
the use of an aluminum-based chiral heterobimetallic complex
and later introduced a complementarily effective, lanthanide-
derived heterobimetallic catalyst for expanding the aldehyde
scope.8c,8e In most of the reported Lewis acid-catalyzed sys-
tems, the Lewis acidic metal center is engaged in the activation
of a carbonyl electrophile and phosphonate is simultaneously
activated through the formation of a metallophosphite. How-
ever, the generally observed moderate catalytic efficiency
implies that the expected generation of the metallophosphite is
sluggish. The benefit of accelerating the metallophosphite gen-
eration for enhancing the reaction rate was indeed substantiated
by the addition of external inorganic base, and Katsuki signifi-
cantly improved the catalytic activity of an aluminum-salalen
complex by combined use of K2CO3.7h Simultaneous activation
of carbonyl functionality and the phosphonate by a bifunctional
chiral catalyst was also found to be efficacious for facilitating
Development of highly efficient and enantioselective hydro-
phosphonylations of aldehydes and ynones mediated by [5.5]-
P-spirocyclic chiral triaminoiminophosphoranes as base cata-
lysts is described. The strong basicity of the iminophos-
phoranes and hydrogen-bond donating ability of their conjugate
acids, tetraaminophosphonium ions, are critical for the facile
generation of aminophosphonium phosphites with substantial
nucleophilicity as well as for the subsequent selective, yet
productive, P-C bond formation by suppressing undesired side
reactions. The scope and limitations of these catalytic asym-
metric methodologies are also reported.
1. Introduction
Among various enantioselective phosphorus-carbon (P-C)
bond formations, hydrophosphonylation of carbonyl com-
pounds (Pudovik reaction) has garnered particular attention
from the chemical science community, because it provides a
straightforward access to a wide variety of optically active α-
hydroxy phosphonates, a biologically important class of com-
pounds that has structural similarity to α-hydroxy carboxylic
acids and exhibits unique activity.1-3 While dialkyl phos-
phonate (dialkyl phosphite) is commonly employed as a phos-
phorus nucleophile for coupling with carbonyl electrophiles,
effecting facile P-C bond formation is rather difficult due to the
intervention of the phosphonate-phosphite tautomerization.4,5
Specifically, dialkyl phosphonates exist largely, if not entirely,
in the phosphonate form under neutral conditions and the
contribution of the phosphite form to the equilibrium is
546 | Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan

O
P
phosphonate
form
OR
OR
R'
R'
O
OR
H
P-Brook
P
OR
retro-
reaction
O
P
R"
O
O
P
H B
OR
base
(B)
R'
∗
OR
OR
O
P
O
R"
O
OR
H B
∗
OR
OR
OH
P
R'
R"
phosphite
form
R" OH
OR
hydrophosphonylation
OR
Figure 1. Hydrophosphonylation of carbonyl compounds.
smooth P-C bond formation while controlling the absolute
stereochemistry.9-11 Although these contributions clearly indi-
cate the importance of increasing the concentration of the phos-
phite tautomer in the hydrophosphonylation, simple activation
of dialkyl phosphonates via deprotonation with a basic catalyst
remains an inaccessible tactic due to the lack of suitable chiral,
non-racemic molecular entities that exert adequately strong
basicity, thus leaving the intrinsic reactivity of the phosphite
form obscure.12
Ar
Ar
H
N
H
N
1a: Ar = Ph
1b: Ar = 4-CF3C6H4
1c: Ar = 4-ClC6H4
1d: Ar = 4-FC6H4
1e: Ar = 4-MeC6H4
1f: Ar = 4-MeOC6H4
P
Ar
Ar
N
H
N
H
Cl
1·HCl
Figure 2. [5.5]-P-Spirocyclic chiral tetraaminophospho-
nium chlorides 1¢HCl.
Upon considering not only the generation of a reactive
phosphorus nucleophile, but also the inherent features of the
subsequent P-C bond-forming process under basic conditions,
it appears to be associated with the side reactions; those are
retro-hydrophosphonylation (blue arrows) and phospha-Brook
rearrangement (red arrows) (Figure 1).13 These reactions are
particularly problematic in the addition of phosphites to ketone
carbonyls, presumably because of the following reasons: 1)
steric repulsion between ketone substituents (R¤, R¤¤) and the
P(O)(OR)2 moiety in the transiently generated alkoxide inter-
mediate, and 2) the geminal dialkyl effect (Thorpe-Ingold
effect) on the propensity for the rearrangement via three-
membered ring formation.14,15 Since the P-C bond formation is
reversible, the presence of an alkoxide ion at the α-position to a
phosphoryl group assists the cleavage of the P-C bond, which
points out that rapid protonation of the alkoxide ion in the
base-catalyzed hydrophosphonylation is essential to suppress
the undesired retro-reaction. Protonation is also beneficial for
avoiding the intramolecular nucleophilic attack of the oxyanion
to the phosphorus center to cause the subsequent rearrange-
ment. This important requirement for regulating the reaction
pathway could be fulfilled if the conjugate acid of the basic
promoter has high proton-transfer ability.
Currently, triaminoiminophosphorane, introduced by
Schwesinger as a P1-phosphazene, is recognized as one of the
strongest organic bases.16,17 In 2007, we disclosed the molecular
design and preparation of [5.5]-P-spirocyclic chiral triamino-
iminophosphorane 1 consisting of four primary amino moieties
and uncovered its significant potential as a chiral organic base
catalyst through the development of the 1-catalyzed highly
stereoselective Henry reaction (Figure 2).18 The key to the
prominent catalytic performance of 1 was not only its strong
basicity, but also the double hydrogen-bond donating ability
of its conjugate acid, tetraaminophosphonium ion 1¢H, to
recognize and control nucleophilic anionic species.19,20 We
hypothesized that chiral iminophosphoranes 1 featuring these
characteristics would be suitable for the activation of dialkyl
phosphonate by deprotonation to generate chiral aminophos-
phonium phosphite. This activation allows us to shift the
phosphonate-phosphite equilibrium and evaluate the intrinsic
reactivity of the phosphite ion, leading to highly efficient asym-
metric hydrophosphonylation. In addition, the pKa value of
the intermediary α-phosphonyl alkoxide is expected to be
higher than that of the N-H proton of 1¢H and thus pseudo-
intramolecular proton transfer would effectively suppress the
undesired pathways to liberate the desired product. Herein, we
report the remarkable catalytic activity and stereocontrolling
ability of 1 in the hydrophosphonylation of aldehydes and
ynones via the generation of chiral tetraaminophosphonium
phosphite.21 The effect of chirality at the α-position of aliphatic
aldehydes on the stereochemical outcome is also discussed for
experimentally understanding the transition state of the present
catalysis.
2. Results and Discussion
With the strong basicity of L-valine-derived triaminoimino-
phosphorane 1a (pKa = 25.0 in MeCN) in mind, we anticipated
that 1a could deprotonate from dimethyl phosphonate (pKa =
18.4 in DMSO) to form the corresponding chiral aminophos-
phonium phosphite 1a¢HOP(OMe)2.22 The validity of this
assumption was verified by 31P NMR analysis of a mixture of
1a and HP(O)(OMe)2 at ¹98 °C, where an equilibrium between
the ion pair 1a¢HOP(OMe)2 and the two parent species was
observed.21a This information prompted us to apply 1a, which
was generated in situ from 1a¢HCl and KOtBu at ¹40 °C, to
the addition of dimethyl phosphonate to benzaldehyde (2a) at
¹78 °C (Table 1, Entry 1). As expected, the P-C bond forma-
tion occurred smoothly to produce α-hydroxy phosphonate 3a
almost quantitatively within 1 h. Enantiomeric excess of 3a was
Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan | 547

Table 1. Optimization of reaction conditions for hydro-
phosphonylation of aldehydesa)
Table 2. Substrate scope of hydrophosphonylation of
aldehydesa)
O
O
1·HCl/KOtBu
1e·HCl/KOtBu
OH
OH
(x mol%)
OMe
OMe
OMe
OMe
(1 mol%)
Ph
H
R1
H
O
P
O
P
+
R1
P
+
Ph
P
2a
2
THF
–78 °C
THF
–98 °C
OMe
OMe
O
3a
O
3
H
H
OMe
OMe
Entry
1
x
Time (h)
Yield (%)b) ee (%)c)
Time Yield
(h)
ee
Entry R1 (2)
3
(%)b) (%)c)
1
2
3
4
5
6
7
8d)
1a
1b
1c
1d
1e
1f
5
5
5
5
5
5
1
1
1
4
97
98
93
90
92
99
99
97
85
78
74
76
92
78
91
98
1
2
3
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-FC6H4 (2d)
8
3
4
5.5
6
7
6.5
9
4
3
99
91
97
99
95
99
98
94
98
97
96
90
81
90
98
99
99
99
94 3b
96 3c
97 3d
95 3e
97 3f
95 3g
98 3h
98 3i
96 3j
98 3k
99 3l
98 3m
96 3n
96 3o
89 3p
91 3q
85f) 3r
78f) 3s
2.5
1.5
0.5
0.25
1
4
5
6
7
8
9
10
11
4-ClC6H4 (2e)
4-MeOCOC6H4 (2f)
3-MeOC6H4 (2g)
3-BrC6H4 (2h)
3-CF3C6H4 (2i)
2-MeC6H4 (2j)
2-FC6H4 (2k)
1e
1e
4
a) Unless otherwise noted, the reaction was performed with 1.0
mmol of 2a, 1.05 equiv of dimethyl phosphonate, x.x mol%
of 1¢HCl, and x mol% of KOtBu in THF (5.0 mL) at ¹78 °C.
b) Isolated yield. c) Enantiomeric excesses were analyzed by
HPLC with chiral stationary phase column. Absolute stereo-
chemistry of 3a was assigned by comparison with literature
data.8c d) The reaction was conducted at ¹98 °C.
1-naphthyl (2l)
3
2
12d) 2-furyl (2m)
13e) 2-thienyl (2n)
24
13
15e) (E)-Me(CH2)2CH=CH (2p) 16
14
(E)-PhCH=CH (2o)
16
Ph(CH2)2 (2q)
6
16
9.5
17e) Me(CH2)8 (2r)
18e) cyclohexyl (2s)
determined to be 85% by HPLC with chiral stationary phase
column and its absolute configuration was determined to be R
by comparison of the sign of its optical rotation with the liter-
ature data.8c,23 The correlation between the structure of 1 and
its catalytic activity was reflected in the reaction rate, and the
general tendency was that the more basic iminophosphorane
catalyzed the reaction with higher efficiency (Entries 1-6).
Interestingly, introduction of an electron-withdrawing group to
the 4-position of the geminal aromatic substituents of 1 caused
a slight decrease in enantioselectivity. In consideration of the
enantiocontrolling ability, iminophosphorane 1e bearing 4-tolyl
groups was selected as an optimal catalyst for further inves-
tigations (Entry 5). Importantly, the significantly high cataly-
tic performance allowed us to reduce the catalyst loading to
1 mol% and lower the reaction temperature to ¹98 °C (Entries 7
and 8). Even under these conditions, essentially enantiopure 3a
was obtained in near quantitative yield, again emphasizing the
prominent activity of 1e as an organic base catalyst.
The scope and limitations of the 1e-catalyzed asymmetric
hydrophosphonylation of aldehydes were then evaluated, and
the results are summarized in Table 2. Both electron-rich and
electron-deficient 4-substituted benzaldehydes 2b-2e were
tolerated, and the corresponding α-hydroxy phosphonates 3b-
3e were obtained almost quantitatively with excellent enantio-
selectivity, although the reactivity was variable depending
on the substituent (Entries 1-4). Incorporation of a strongly
electron-withdrawing methoxycarbonyl group at the 4-position
(2f) did not affect the reaction outcome (Entry 5). With 3-
substituted benzaldehydes of different electronic attributes, the
P-C bond formation proceeded with similar levels of efficiency
and stereoselectivity (Entries 6-8). The catalysis of 1e was
insensitive to the steric demand of aromatic aldehydes as it was
applicable to 2-substituted benzaldehydes 2j and 2k without
a) Unless otherwise noted, the reaction was performed with
1.0 mmol of 2, 1.05 equiv of dimethyl phosphonate, 1.1 mol%
of 1e¢HCl, and 1 mol% of KOtBu in THF (5.0 mL) at ¹98 °C.
b) Isolated yield. c) Enantiomeric excesses were analyzed by
HPLC with chiral stationary phase column. Absolute stereo-
chemistry of 3 was assigned or assumed by comparison with
literature data.7,8 d) The reaction was conducted at ¹78 °C.
e) 5.5 mol% of 1e¢HCl and 5 mol% of KOtBu were used.
f) Enantiomeric excess was determined after benzoylation.
any detrimental effect on the reactivity and selectivity profiles
(Entries 9 and 10). Similarly, 1-naphthaldehyde (2l) underwent
smooth hydrophosphonylation with rigorous stereocontrol
(Entry 11). Heteroaromatic aldehydes 2m and 2n also appeared
to be good candidates as electrophilic partners, albeit a slight
decrease in reactivity was observed (Entries 12 and 13).
Notably, catalytically generated chiral aminophosphonium
phosphite, a key reactive species, reacted with α,β-unsaturated
aldehydes such as 2o and 2p preferentially in a 1,2-fashion to
give enantiomerically enriched α-hydroxy allylic phosphonates
3o and 3p, respectively, without any detectable formation of
the 1,4-adducts (Entries 14 and 15). While linear aliphatic
aldehydes were accommodated with a comparable degree of
reactivity and selectivity, α-branched aliphatic aldehydes were
found to be challenging substrates and a considerable decrease
in the enantioselectivity seemed inevitable (Entries 16-18).
The observed erosion of stereoselectivity in the hydro-
phosphonylation of α-branched aliphatic aldehydes led us to
examine the reaction with α-chiral aldehyde 2t to figure out the
effect of the α-stereocenter on the facial discrimination of the
aldehyde carbonyl by the catalyst (Figure 3). When 2t was treat-
548 | Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan

1e·HCl/KOtBu
(5 mol%)
HP(O)(OMe)2
(0.5 equiv)
O
OH
OMe
OMe
Ar'
H
Ar'
P
a
THF
–98 °C, 2 h
Me
2t
Me
3t
O
b
50%, dr = 1:1.7
76% ee/82% ee
c
-
O
OMe
Figure 3. Effect of chirality at α-position of aldehyde on
stereoselectivity of hydrophosphonylation catalyzed by
chiral iminophosphorane 1e (Ar¤ = 4-tBuC6H4).
MeO
P
a:
b:
c:
1.59 Å
1.63 Å
2.46 Å
H
Ph
H
O
ed with 0.5 equiv of dimethyl phosphonate under the influence
of 5 mol% of in situ-generated 1e at ¹98 °C, a diastereomeric
mixture of α-hydroxy phosphonate 3t was obtained in 50%
yield (Figure 3). Enantiomeric excess of each diastereomer was
determined to be 76% and 82%, respectively. Although a certain
difference in enantioselectivity between the two diastereomers
and a detectable degree of kinetic resolution were observed,
this result suggested that essentially the catalyst-controlled
hydrophosphonylation took place.
Me
TS-SR
(ΔG = 0.0 kcal mol-1)
In order to understand the origin of poor kinetic resolution in
the 1e-catalyzed addition of dimethyl phosphonate to α-chiral
aldehyde 2t, we conducted a density functional theory (DFT)
calculation using a model structure of 2t, where a 4-tert-
butylphenyl group was replaced with a simple phenyl group.24
According to the elegant computational studies reported by
Simón and Paton (using benzaldehyde as an electrophile),25
transition states (TS) of P-C bond formation, giving rise to anti-
and syn-adducts (TS-SR and TS-RR), were located at B3LYP/
6-31G** (Figure 4).26 Thermodynamic parameters (175.15 K
and 1 atm) estimated at the same level and single point energies
at SMD(THF)-ωB97XD/6-31++G(d,p) were used to calcu-
late Gibbs free energies. The Gibbs free energy difference of
these TSs was 0.2 kcal¢mol¹1, which consistently reproduced
the experimental finding that almost no kinetic resolution was
observed in the reaction with 2t. As shown in Figure 4, 1e¢H
donates two N-H protons to interact with oxygen atoms of the
phosphite and carbonyl groups concomitantly, and the nucle-
ophilic phosphorus approaches the carbonyl carbon from the
open side, as indicated by the Felkin-Anh model. The α-
stereocenter of the aldehyde was directed away from the chiral
space created by 1e¢H in both diastereomeric TSs; therefore, its
direct influence on the chiral environment was unlikely. Since
the phenyl group of α-chiral aldehyde could be oriented anti
with respect to the Cα-CHO bond, the steric demand of the
benzyl moiety in the carbonyl addition would be very similar to
that of the methyl group. Consequently, 1e could not distin-
guish the benzyl and methyl groups on 2t, resulting in the lack
of kinetic resolution.
a
b
c
-
O
OMe
MeO
P
a:
b:
c:
1.56 Å
1.65 Å
2.52 Å
H
Me
O
H
Ph
TS-RR
(ΔG = +0.2 kcal mol-1)
Figure 4. Optimized TS structures, TS-SR and TS-RR, of
the P-C bond formation (unimportant hydrogen atoms are
omitted from the structures for clarity).
demonstrate the power of the present iminophosphorane catal-
ysis.14,15 Although the possible side reactions (retro-reaction
and phospha-Brook rearrangement) would likely become more
critical, we expected that the N-H moieties of the conjugate
acid of 1 would be capable of rapidly protonating the inter-
mediary alkoxide, thereby minimizing the intervention of those
undesired pathways.
As an initial attempt, acetophenone was selected as a repre-
sentative substrate and reacted with dimethyl phosphonate
(1.05 equiv) in the presence of 5 mol% of 1a¢HCl/KOtBu in
THF at ¹78 °C. The hydrophosphonylation did proceed and the
desired adduct was isolated in 59% yield after 34 h of stirring
(Figure 5). However, its enantiomeric excess was unfortunately
very low. Since an additional trial with 1¤-acetonaphthone
resulted in only a slight improvement of the reaction outcome,
we turned our attention from aromatic ketones to ynones with
Having seen the uniquely high catalytic activity of imino-
phosphorane 1, we were intrigued with its application to
hydrophosphonylation of ketones. Because ketones are far less
reactive than aldehydes and existing catalytic systems are not
effective enough to promote P-C bond formation, the hydro-
phosphonylation of ketones could offer a vital platform to
Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan | 549

Table 4. Substrate scope for hydrophosphonylation of
O
1a·HCl/KOtBu
ynonesa)
Me OH
OMe
OMe
(5 mol%)
Ar
Me
1d·HCl/KOtBu
+
H
Ar
P
OMe
OMe
THF
–78 °C
(5 mol%)
O
O
Me OH
P
HP(O)(OMe)2
OMe
OMe
O
Ar = Ph: 34 h, 59%, 11% ee
1-naph: 40 h, 73%, 30% ee
P
Me
THF
–78 °C
R2
R2
O
4
5
Figure 5. Attempt of hydrophosphonylation of aromatic
ketones under the catalysis of iminophosphorane 1a.
Time Yield
(h)
ee
Entry R2 (4)
5
(%)b) (%)c)
Table 3. Optimization of catalyst structure for hydrophos-
phonylation of ynonesa)
1
2
3
4
5
6
7
8
Et (4b)
Me(CH2)8 (4c)
76
22
17
16
17
19
19
17
73
98
96
97
97
96
96
96
90
88
90
79
81
87
5b
5c
5d
5e
5f
1·HCl/KOtBu
cyclohexyl (4d)
Me2CHCH2 (4e)
BnOCH2 (4f)
tBuMe2SiO(CH2)2 (4g)
Me3SiO(Me)2C (4h)
Me3Si (4i)
(5 mol%)
O
Me OH
OMe
OMe
HP(O)(OMe)2
5g
88d) 5h
91e) 5i
P
Me
THF
–78 °C
nHex
O
nHex
4a
5a
a) The reaction was performed with 0.2 mmol of 4, 0.4 mmol
of dimethyl phosphonate, 5.5 mol% of 1d¢HCl, and 5 mol%
of KOtBu in THF (2.0 mL) at ¹78 °C. b) Isolated yield.
c) Enantiomeric excesses were analyzed by HPLC with chiral
stationary phase column. Absolute stereochemistry was as-
signed as analogy of 5i. d) Enantiomeric excess was deter-
mined after desilylation. e) Absolute stereochemistry was
determined by X-ray diffraction analysis (CCDC 772834).
Entry
1
Time (h)
Yield (%)b)
ee (%)c)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
24
68
24
19
21
21
99
53
87
99
99
94
83
76
83
88
71
81
a) The reaction was performed with 0.2 mmol of 4a, 0.4 mmol
of dimethyl phosphonate, 5.5 mol% of 1¢HCl, and 5 mol%
of KOtBu in THF (2.0 mL) at ¹78 °C. b) Isolated yield.
c) Enantiomeric excesses were analyzed by HPLC with chiral
stationary phase column. Absolute stereochemistry was as-
signed as analogy of 5i (see Table 4, Entry 8).
fluorophenyl substituents was identified as an optimal catalyst
(Entries 3-6).
Substrate generality was then explored with regard to the
terminal substituent of ynone 4 using iminophosphorane 1d as a
catalyst (Table 4). The reactions with ynones possessing linear
alkyl groups such as ethyl (4b) and n-octyl (4c) showed a simi-
lar profile to that observed with 4a (Entries 1 and 2). Although
4d with sterically hindered cyclohexyl substituent was smoothly
converted to the corresponding adduct 5d with high enantio-
selectivity, β-branching from the alkyne terminus (4e) caused a
slight decrease in the level of stereocontrol (Entries 3 and 4).
The substrates incorporating benzyl and tert-butyldimethylsilyl
ethers were also amenable to the present system (Entries 5
and 6). Furthermore, the presence of 2-silyloxy-2-propyl and
trimethylsilyl groups, which are often used as protective groups
of terminal alkynes, were well tolerated (Entries 7 and 8), and
thus, products 5h and 5i could be readily transformed to the
corresponding terminal alkynes, enhancing the synthetic utility
of this asymmetric hydrophosphonylation protocol.
anticipation that their keto-carbonyls would be more reactive
because of the electronegativity of the sp-hybridized carbon
atom and less bulkiness of the alkyne component. In addition,
we considered the synthetic utility of the products, optically
active propargylic alcohols, which are versatile building blocks
for the asymmetric synthesis of various biologically important
molecules owing to the rich chemistry of carbon-carbon triple
bonds that can be derivatized into numerous other functional
groups.27,28 As expected, dec-3-yn-2-one (4a) was converted
into the corresponding α-tetrasubstituted α-hydroxy propargylic
phosphate 5a quantitatively within 24 h under similar reaction
conditions to those of the reactions with aromatic ketones
except for using 2 equiv of dimethyl phosphonate (Table 3,
Entry 1).29 The enantiomeric excess of 5a was determined to be
83%; this result encouraged us to investigate the relationship
between the steric/electronic properties of 1, particularly with
respect to the geminal aromatic substituents, and enantioselec-
tivity. Introduction of the strongly electron-withdrawing and
relatively bulky trifluoromethyl group to the 4-position of the
aromatic appendages (1b) diminished the catalytic activity with
a slight deterioration of enantioselectivity (Entry 2). While
the attachment of electron-releasing groups (1e and 1f) caused
a negative impact, the installation of 4-halogenated aromatic
groups was revealed to be beneficial, and 1d with 4-
3. Conclusion
Establishment of the [5.5]-P-spirocyclic chiral iminophos-
phorane-catalyzed highly efficient and enantioselective hydro-
phosphonylations of aldehydes and ynones was fully described.
These catalytic asymmetric methods relied on the following
distinct features of the iminophosphoranes as organic base
catalysts: 1) their strong basicity that enabled the facile and
substantial generation of reactive chiral aminophosphonium
phosphite, and 2) the hydrogen-bond donating ability of their
conjugate acids, the aminophosphonium ions, that was crucial
550 | Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan

not only for rigorously controlling the absolute stereochemistry
in the addition of the phosphite ion to the carbonyls, but also
for suppressing the undesired side reactions by rapid pro-
tonation of the alkoxide intermediates. This study experimen-
tally proves the inherently high nucleophilicity of phosphite
ions, and it provides a tactic for accelerating P-C bond for-
mation with dialkyl phosphonates. We believe that the clear
advantages of utilizing strongly basic organic molecules for the
activation of dialkyl phosphonates will stimulate further
research efforts for the development of chiral catalysts that
are effective for improving and inventing various phosphony-
lation reactions.
salt 1¢HCl (0.011 equiv, 11 ¯mol) under Ar atmosphere and
THF (5.0 mL) was introduced. Then, a 1.0 M THF solution of
potassium tert-butoxide (10.0 ¯L, 0.010 equiv, 10.0 ¯mol) was
added to the suspension at ¹78 °C and the resulting mixture
was stirred for 30 min at ¹40 °C. Aldehyde 2 (1.0 equiv, 1.0
mmol) and dimethyl phosphonate (96.3 ¯L, 1.05 equiv, 1.05
mmol) were introduced dropwise slowly at ¹98 °C and the
stirring was continued for the reaction time given in Tables 1
and 2 of the manuscript. A solution of trifluoroacetic acid in
toluene (0.5 M, 100 ¯L) was added to the reaction mixture
and it was poured into ice-cooled water. The aqueous phase
was extracted with ethyl acetate (EA). The combined organic
extracts were dried over Na2SO4 and filtered. All volatiles were
removed by evaporation and the purification of the residue
by column chromatography on silica gel gave the correspond-
ing α-hydroxy phosphonate 3, whose enantiomeric excess was
determined by chiral stationary phase HPLC analysis. Absolute
configurations of 3a and 3s were determined to be R by com-
parison of their optical rotations and/or HPLC retention times
to the literature data7e,7h,8c,31 and that of 3b-3r were assigned
by analogy.23 Compounds 3a-3e, 3g-3i, 3l-3m, and 3o-3s
were identified by comparison with their reported spectral
data.7,8,21a
4. Experimental
General Information. Infrared spectra were recorded on a
JASCO FT/IR-300E or Shimadzu IRAffinity-1 spectrometer.
1H NMR spectra were recorded on a Varian INOVA-500 (500
MHz), JEOL JNM-ECA600II (600 MHz), or JEOL JNM-
ECS400 (400 MHz) spectrometer. Chemical shifts are report-
ed in ppm from tetramethylsilane (0.0 ppm) resonance as the
internal standard (CDCl3). Data are reported as follows: chemi-
cal shift, integration, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, quin = quintet, sept = septet, m =
multiplet, br = broad) and coupling constants (Hz). 13C NMR
spectra were recorded on a Varian INOVA-500 (126 MHz),
JEOL JNM-ECA600II (151 MHz), or JEOL JNM-ECS400
(101 MHz) spectrometer with complete proton decoupling.
Chemical shifts are reported in ppm from the solvent resonance
as the internal standard (CDCl3; 77.16 ppm). 31P NMR spectra
were recorded on a Varian INOVA-500 (202 MHz), Varian
Mercury-300BB (121 MHz), or JEOL ECA500II (202 MHz)
spectrometer with complete proton decoupling. Chemical shifts
are reported in ppm from H3PO4 (0.0 ppm) resonance as the
external standard. The high-resolution mass spectra (HRMS)
were measured on a BRUKER DALTONICS microTOF focus-
KR (ESI-TOF), JEOL JMS-700 (MStation) (FAB), or Thermo
Fisher Scientific Exactive (ESI) spectrometer. Optical rota-
tions were measured on a HORIBA SEPA-500 polarimeter.
Analytical thin layer chromatography (TLC) was performed on
Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm).
Flash column chromatography was performed on silica gel 60
(spherical, 40-50 ¯m; Kanto Chemical Co., Inc.). Enantiomeric
excesses were determined by HPLC analysis using chiral
columns [º 4.6 mm © 250 mm, DAICEL CHIRALPAK AD-H
(ADH), CHIRALCEL OD-H (ODH), CHIRALCEL OD-3
(OD3), CHIRALPAK IA (IA), CHIRALPAK AS-H (ASH),
CHIRALPAK AS-3 (AS3), CHIRALPAK IF-3 (IF3), or
CHIRALCEL OJ-H (OJH)].
Characterization of α-Hydroxy Phosphonate 3. Methyl
4-((Dimethoxyphosphoryl)(hydroxy)methyl)benzoate (3f):
HPLC OD3, hexane (H)/Ethanol (EtOH) = 19:1, flow rate =
1.0 mL/min, λ = 210 nm, 15.4 min (minor enantiomer), 18.9
1
min (major enantiomer); H NMR (600 MHz, CDCl3) ¤ 8.04
(2H, d, J = 8.4 Hz), 7.57 (2H, dd, JH-H = 7.8 Hz, JP-H = 1.8
Hz), 5.14 (1H, dd, JP-H = 12.6 Hz, JH-H = 5.2 Hz), 4.13 (1H,
dd, JP-H = 8.4 Hz, JH-H = 5.2 Hz), 3.92 (3H, s), 3.72 (3H, d,
J
P-H = 10.2 Hz), 3.71 (3H, d, JP-H = 10.2 Hz); 13C NMR (151
MHz, CDCl3) ¤ 166.9, 141.5, 130.1 (d, JP-C = 2.9 Hz), 129.8,
127.0 (d, JP-C = 5.9 Hz), 70.6 (d, JP-C = 159.0 Hz), 39.3 (d,
J
P-C = 7.1 Hz), 53.9 (d, JP-C = 7.2 Hz), 52.3; 31P NMR (202
MHz, CDCl3) ¤ 23.2; IR (film): 3227, 2957, 1719, 1611, 1435,
1414, 1283, 1236, 1190, 1113, 1034, 837 cm¹1; HRMS (ESI)
+
Calcd for C11H15Na1O6P1 ([M+Na]+) 297.0498. Found
23
297.0495; ½ꢀꢀD +58.020° (c = 1.00, CHCl3).
Dimethyl (Hydroxy(o-tolyl)methyl)phosphonate (3j):
HPLC ASH, H/2-propanol (IPA) = 5:1, flow rate = 0.5
mL/min, λ = 210 nm, 18.6 min (major enantiomer), 31.4 min
(minor enantiomer); 1H NMR (500 MHz, CDCl3) ¤ 7.64 (1H, d,
J = 7.5 Hz), 7.27 (1H, t, J = 7.5 Hz), 7.23 (1H, tt, J = 7.5,
1.5 Hz), 7.17 (1H, d, J = 7.5 Hz), 5.30 (1H, dd, JP-H = 10.8 Hz,
J
J
H-H = 4.3 Hz), 3.72 (3H, d, JP-H = 10.5 Hz), 3.65 (3H, d,
P-H = 10.5 Hz), 3.17 (1H, br), 2.39 (3H, s); 13C NMR (126
MHz, CDCl3) ¤ 135.9 (d, JP-C = 7.2 Hz), 134.9 (d, JP-C = 1.9
Hz), 130.5 (d, JP-C = 1.1 Hz), 128.3 (d, JP-C = 3.3 Hz), 127.3
All reactions were carried out under an Argon (Ar) atmos-
phere in dried glassware. All substrates were purified by column
chromatography, recrystallization, or distillation prior to use.
Tetrahydrofuran (THF) was supplied from Kanto Chemical Co.,
Inc. as “Dehydrated solvent system”. Chiral aminophospho-
nium salts 118a and ynones 430 were prepared by following the
literature procedure. Other simple chemicals were purchased
and used as such.
(d, JP-C = 4.4 Hz), 126.4 (d, JP-C = 3.3 Hz), 67.2 (d, JP-C
=
160.7 Hz), 54.0 (d, JP-C = 6.7 Hz), 53.7 (d, JP-C = 7.7 Hz), 19.6;
31P NMR (121 MHz, CDCl3) ¤ 24.9; IR (film): 3269, 2958,
¹1
2854, 1588, 1490, 1457, 1228, 1052, 837, 818, 858 cm
;
+
HRMS (ESI-TOF) Calcd for C10H15Na1O4P1 ([M+Na]+)
253.0600. Found 253.0609.
Dimethyl
((2-Fluorophenyl)(hydroxy)methyl)phos-
General Procedure for Chiral Triaminoiminophos-
phorane-Catalyzed Asymmetric Hydrophosphonylation of
Aldehydes. To a dried test tube was weighted phosphonium
phonate (3k): HPLC ASH, H/IPA = 3:1, flow rate = 0.5
mL/min, λ = 210 nm, 14.2 min (major enantiomer), 22.1 min
(minor enantiomer); 1H NMR (500 MHz, CDCl3) ¤ 7.69 (1H, t,
Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan | 551

J = 8.0 Hz), 7.33-7.28 (1H, m), 7.20 (1H, t, J = 8.0 Hz), 7.05
(1H, t, J = 8.0 Hz), 5.44 (1H, d, JP-H = 11.5 Hz), 4.69 (1H, br),
3.79 (3H, d, JP-H = 10.5 Hz), 3.71 (3H, d, JP-H = 10.5 Hz);
13C NMR (126 MHz, CDCl3) ¤ 159.8 (dd, JF-C = 247.7 Hz,
tion of potassium tert-butoxide (10.0 ¯L, 0.050 equiv, 10 ¯mol)
at ¹78 °C under Ar atmosphere. The resulting mixture was
stirred for 30 min at ¹40 °C. Ynone 4 (1.0 equiv, 0.2 mmol) and
dimethyl phosphonate (36.7 ¯L, 2.0 equiv, 0.4 mmol) were
introduced dropwise slowly at ¹78 °C and the stirring was
continued for the reaction time given in Tables 3 and 4 of the
manuscript. After addition of a solution of trifluoroacetic acid
in toluene (0.5 M, 100 ¯L), the reaction mixture was poured
into ice-cooled water. The aqueous phase was extracted with
EA three times and the combined organic extracts were dried
over Na2SO4. Filtration and concentration were performed to
afford the crude residue. The residue was purified by column
chromatography on silica gel to give the α-tetrasubstituted α-
hydroxy phosphonate 5, whose enantiomeric excess was deter-
mined by HPLC analysis. Absolute configuration of 5i was
determined by X-ray crystallographic analysis (CCDC 772834)
and that of other 5 was estimated as analogy.
J
P-C = 6.8 Hz), 129.9 (dd, JF-C = 8.3 Hz, JP-C = 3.0 Hz), 129.0
(t, JP-C = 3.6 Hz, JF-C = 3.6 Hz), 124.5 (t, JP-C = 3.1 Hz, JF-C
3.1 Hz), 124.4 (dd, JF-C = 13.5 Hz, JP-C = 1.5 Hz), 115.2 (dd,
=
J
J
F-C = 21.9 Hz, JP-C = 2.1 Hz), 63.7 (dd, JP-C = 163.8 Hz,
F-C = 3.7 Hz), 54.3 (d, JP-C = 6.7 Hz), 53.8 (d, JP-C = 7.2
Hz); 31P NMR (121 MHz, CDCl3) ¤ 23.8 (d, JF-P = 5.9 Hz); IR
¹1
(film): 3270, 2955, 2852, 1488, 1463, 1235, 1041, 834 cm
HRMS (ESI-TOF) Calcd for C9H12F1Na1O4P1 ([M+Na]+)
;
+
257.0349. Found 257.0354.
Dimethyl (Hydroxy(thiophen-2-yl)methyl)phosphonate
(3n):
HPLC AS3, H/IPA = 5:1, flow rate = 1.0 mL/min,
λ = 210 nm, 10.4 min (major enantiomer), 13.6 min (minor
enantiomer); 1H NMR (500 MHz, CDCl3) ¤ 7.32 (1H, dd,
J
J
J
H-H = 4.0 Hz, JP-H = 1.5 Hz), 7.21 (1H, t, JH-H = 3.5 Hz,
P-H = 3.5 Hz), 7.01 (1H, dd, J = 4.0, 3.5 Hz), 5.27 (1H, d,
P-H = 10.5 Hz), 4.41 (1H, br), 3.78 (3H, d, JP-H = 11.0 Hz),
Characterization of Ynone 4. Tridec-3-yn-2-one (4c):
1H NMR (400 MHz, CDCl3) ¤ 2.35 (2H, t, J = 7.3 Hz), 2.32
(3H, s), 1.57 (2H, quin, J = 7.3 Hz), 1.39 (2H, quin, J = 7.3
Hz), 1.27 (10H, br), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (101
MHz, CDCl3) ¤ 185.2, 94.4, 81.5, 32.9, 32.0, 29.5, 29.4, 29.2,
29.0, 27.8, 22.8, 19.1, 14.3; IR (film) 2925, 2855, 2209, 1679,
1466, 1421, 1358, 1227, 960, 722 cm¹1; HRMS (FAB) Calcd
3.74 (3H, d, JP-H = 10.0 Hz); 13C NMR (101 MHz, CDCl3)
¤ 139.5 (d, JP-C = 4.8 Hz), 127.0 (d, JP-C = 1.9 Hz), 126.3 (d,
J
J
P-C = 7.7 Hz), 125.9, 66.7 (d, JP-C = 169.4 Hz), 54.2 (d,
P-C = 6.8 Hz), 53.9 (d, JP-C = 7.7 Hz); 31P NMR (121 MHz,
+
CDCl3) ¤ 22.5; IR (film): 3235, 2957, 1449, 1202, 1121,
for C13H23O1 ([M+H]+) 195.1749. Found 195.1752.
+
1038, 845 cm¹1; HRMS (ESI) Calcd for C7H11Na1O4P1S1
6-((tert-Butyldimethylsilyl)oxy)hex-3-yn-2-one
(4g):
22
([M+Na]+) 245.0008. Found 245.0007; ½ꢀꢀD +26.143° (c =
1H NMR (400 MHz, CDCl3) ¤ 3.78 (2H, t, J = 6.9 Hz), 2.58
(2H, t, J = 6.9 Hz), 2.32 (3H, s), 0.90 (9H, s), 0.09 (6H, s);
13C NMR (101 MHz, CDCl3) ¤ 184.9, 91.1, 82.2, 60.9, 32.9,
26.0, 23.5, 18.4, ¹5.2; IR (film) 2929, 2857, 2213, 1681, 1471,
1360, 1227, 1110, 838, 778 cm¹1; HRMS (FAB) Calcd for
1.03, CHCl3).
Dimethyl (3-(4-(tert-Butyl)phenyl)-1-hydroxy-2-methyl-
propyl)phosphonate (3t):
HPLC minor-isomer OD3, H/
EtOH = 97:3, flow rate = 0.5 mL/min, λ = 210 nm, 17.6 min
(major enantiomer), 23.2 min (minor enantiomer); major-
isomer IF3, H/EtOH = 97:3, flow rate = 0.5 mL/min, λ =
210 nm, 27.5 min (major enantiomer), 29.7 min (minor enan-
tiomer); 1H NMR (400 MHz, CDCl3) minor-isomer ¤ 7.29 (2H,
C12H23O2Si1 ([M+H]+) 227.1467. Found 227.1477.
+
5-Methyl-5-((trimethylsilyl)oxy)hex-3-yn-2-one
(4h):
1H NMR (400 MHz, CDCl3) ¤ 2.35 (3H, s), 1.53 (6H, s),
0.21 (9H, s); 13C NMR (101 MHz, CDCl3) ¤ 184.4, 96.0, 82.6,
66.5, 32.6, 32.3, 1.9; IR (film) 2987, 2213, 1683, 1418, 1361,
1250, 1167, 1038, 843, 756 cm¹1; HRMS (ESI-TOF) Calcd for
d, J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz), 3.83 (6H, d, JP-H
=
10.4 Hz), 3.80 (1H, td, JP-H = 12.1 Hz, JH-H = 12.1, 6.0 Hz),
3.44 (1H, br), 3.10 (4H, dd, J = 13.4, 3.6 Hz), 2.45 (1H, dd,
J = 13.4, 9.2 Hz), 2.30-2.12 (1H, m), 1.30 (9H, s), 0.98 (3H,
d, J = 6.8 Hz); major-isomer ¤ 7.30 (2H, d, J = 8.0 Hz), 7.11
(2H, d, J = 8.0 Hz), 3.89 (1H, ddd, JP-H = 8.4 Hz, JH-H = 7.4,
3.2 Hz), 3.773 (3H, d, J = 10.4 Hz), 3.770 (3H, d, J = 10.4 Hz),
2.90 (1H, br), 2.79 (1H, dd, J = 13.4, 7.4 Hz), 2.57 (1H, ddd,
J = 13.4, 7.4, 2.8 Hz), 2.22 (1H, sept-d, J = 7.4, 3.2 Hz), 1.30
(9H, s), 1.08 (3H, d, J = 7.4 Hz); 13C NMR (151 MHz, CDCl3)
+
C10H18Na1O2Si1 ([M+Na]+) 221.0974. Found 221.0982.
Characterization of α-Tetrasubstituted α-Hydroxy
Phosphonate 5. Dimethyl (1-Hydroxynon-2-yn-1-yl)phos-
phonate (5a): HPLC ODH, H/IPA = 100:1, flow rate = 0.5
mL/min, λ = 210 nm, 30.2 min (major enantiomer), 33.2 min
(minor enantiomer); 1H NMR (400 MHz, CDCl3) ¤ 3.89 (3H, d,
J
P-H = 10.1 Hz), 3.88 (3H, d, JP-H = 10.5 Hz), 3.50 (1H, br),
2.24 (1H, t, J = 7.3 Hz), 2.23 (1H, t, J = 7.3 Hz), 1.66 (3H, d,
minor-isomer ¤ 148.9, 137.1, 129.2, 125.2, 7.20 (d, JP-C
156.1 Hz), 53.3 (d, JP-C = 7.2 Hz), 53.2 (d, JP-C = 7.2 Hz), 37.8
(d, JP-C = 8.6 Hz), 37.5, 34.5, 31.6, 16.0 (d, JP-C = 7.2 Hz);
=
JP-H = 15.6 Hz), 1.52 (2H, quin, J = 7.3 Hz), 1.41-1.34 (2H,
m), 1.33-1.24 (4H, m), 0.89 (3H, t, J = 7.1 Hz); 13C NMR
(101 MHz, CDCl3) ¤ 88.2 (d, JP-C = 8.7 Hz), 78.5, 65.9 (d,
major-isomer ¤ 149.1, 137.1, 129.0, 125.4, 69.7 (d, JP-C
=
J
P-C = 176.1 Hz), 54.73 (d, JP-C = 6.8 Hz), 54.66 (d, JP-C
6.8 Hz), 31.4, 28.6, 28.4 (d, JP-C = 2.9 Hz), 25.4, 22.6, 19.0 (d,
P-C = 1.9 Hz), 14.1; 31P NMR (162 MHz, CDCl3) ¤ 23.3; IR
=
157.6 Hz), 53.2 (d, JP-C = 7.2 Hz), 39.7 (d, JP-C = 14.5 Hz),
36.7, 34.5, 31.5, 14.4, one carbon atom was not found probably
due to overlapping; 31P NMR (202 MHz, CDCl3) monor-isomer
¤ 28.1; major-isomer ¤ 28.0; IR (film): 3294, 2957, 2866,
1512, 1460, 1364, 1219, 1034, 829 cm¹1; HRMS (ESI) Calcd
J
(film): 3284, 2932, 2857, 2242, 1455, 1365, 1238, 1185, 1034,
834 cm¹1; HRMS (ESI-TOF) Calcd for C12H23Na1O4P1
+
25
([M+Na]+) 285.1226. Found 285.1240; ½ꢀꢀD +25.0° (c =
for C16H27Na1O4P1 ([M+Na]+) 337.1539. Found 337.1531.
0.58, MeOH).
+
General Procedure for Chiral Triaminoiminophos-
phorane-Catalyzed Asymmetric Hydrophosphonylation of
Ynones. To a suspension of phosphonium salt 1¢HCl (0.055
equiv, 11 ¯mol) in THF (2.0 mL) was added a 1.0 M THF solu-
Dimethyl (1-Hydroxypent-2-yn-1-yl)phosphonate (5b):
HPLC OJH, H/IPA = 50:1, flow rate = 0.5 mL/min, λ = 210
nm, 20.2 min (major enantiomer), 23.2 min (minor enantiomer);
1H NMR (400 MHz, CDCl3) ¤ 3.89 (6H, d, JP-H = 10.1 Hz),
552 | Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan

3.23 (1H, br), 2.27 (2H, qd, JH-H = 7.5 Hz, JP-H = 4.0 Hz) 1.65
(3H, d, JP-H = 15.6 Hz), 1.15 (3H, t, J = 7.5 Hz); 13C NMR
(101 MHz, CDCl3) ¤ 89.6 (d, JP-C = 8.7 Hz), 77.8, 65.9 (d,
(4H, m) 7.33-7.27 (1H, m), 4.60 (2H, s), 4.22 (2H, d, JP-H =
4.1 Hz), 3.89 (3H, d, JP-H = 10.5 Hz), 3.88 (3H, d, JP-H = 10.6
Hz), 1.70 (3H, d, JP-H = 15.6 Hz), O-H proton was not found
probably due to broadening; 13C NMR (101 MHz, CDCl3) ¤
137.3, 128.6, 128.3, 128.1, 84.9, 83.2 (d, JP-C = 9.7 Hz), 71.6,
65.8 (d, JP-C = 176.1 Hz), 57.4, 54.9 (d, JP-C = 7.7 Hz), 54.8
(d, JP-C = 7.7 Hz), 25.1; 31P NMR (162 MHz, CDCl3) ¤ 22.9;
IR (film) 3270, 2957, 2855, 1714, 1454, 1355, 1235, 1034,
J
P-C = 176.1 Hz), 54.8 (d, JP-C = 7.7 Hz), 54.7 (d, JP-C = 6.8
Hz), 25.3, 13.6, 12.7; 31P NMR (162 MHz, CDCl3) ¤ 23.3;
IR (film) 3290, 2958, 2243, 1645, 1456, 1366, 1237, 1031,
835, 754 cm¹1; HRMS (ESI-TOF) Calcd for C8H15Na1O4P1
+
25
([M+Na]+) 229.0600. Found 229.0595; ½ꢀꢀD +26.2° (c =
+
0.75, MeOH).
838, 753 cm¹1; HRMS (ESI-TOF) Calcd for C14H19Na1O5P1
25
Dimethyl (1-Hydroxydodec-2-yn-1-yl)phosphonate (5c):
HPLC ODH, H/IPA = 100:1, flow rate = 0.5 mL/min, λ =
210 nm, 26.5 min (major enantiomer), 30.8 min (minor enan-
tiomer); 1H NMR (400 MHz, CDCl3) ¤ 3.89 (3H, d, JP-H = 10.1
Hz), 3.88 (3H, d, JP-H = 10.5 Hz), 2.51 (1H, d, JP-H = 4.1
Hz), 2.25 (2H, qd, JH-H = 7.2 Hz, JP-H = 4.0 Hz), 1.65 (3H, d,
([M+Na]+) 321.0862. Found 321.0856; ½ꢀꢀD +20.3° (c =
1.04, MeOH).
Dimethyl
pent-2-yn-1-yl)phosphonate (5g):
(5-((tert-Butyldimethylsilyl)oxy)-1-hydroxy-
HPLC ASH, H/IPA =
10:1, flow rate = 0.5 mL/min, λ = 210 nm, 9.1 min (minor
enantiomer), 11.3 min (major enantiomer); 1H NMR (400 MHz,
J
P-H = 15.6 Hz), 1.53 (1H, q, J = 7.3 Hz), 1.51 (1H, q, J =
CDCl3) ¤ 3.88 (3H, d, JP-H = 10.5 Hz), 3.87 (3H, d, JP-H
10.1 Hz), 3.72 (2H, t, J = 7.1 Hz), 2.46 (2H, td, JH-H = 7.1 Hz,
P-H = 4.6 Hz), 1.65 (3H, d, JP-H = 15.6 Hz), 0.89 (9H, s), 0.07
=
7.3 Hz), 1.37 (2H, quin, J = 7.3 Hz), 1.32-1.23 (10H, br), 0.88
(3H, t, J = 6.9 Hz); 13C NMR (101 MHz, CDCl3) ¤ 88.0 (d,
J
J
P-C = 9.7 Hz), 78.6, 65.8 (d, JP-C = 175.1 Hz), 54.7 (d, JP-C
=
(6H, s), O-H proton was not found probably due to broadening;
13C NMR (101 MHz, CDCl3) ¤ 84.9 (d, JP-C = 9.7 Hz), 79.6,
65.8 (d, JP-C = 175.1 Hz), 61.6, 54.8 (d, JP-C = 7.7 Hz), 54.7
(d, JP-C = 7.7 Hz), 25.9, 25.4, 23.3, 18.4, ¹5.2; 31P NMR
(162 MHz, CDCl3) ¤ 23.2; IR (KBr) 3278, 2957, 2240, 1471,
1360, 1240, 1101, 1028, 836, 773 cm¹1; HRMS (ESI-TOF)
7.7 Hz), 54.6 (d, JP-C = 6.8 Hz), 31.9, 29.5, 29.3, 29.2, 28.9,
28.5, 25.4, 22.7, 18.9, 14.2; 31P NMR (162 MHz, CDCl3) ¤
23.2; IR (film) 3282, 2926, 2854, 2242, 1462, 1238, 1185, 1033,
834, 764 cm¹1; HRMS (ESI-TOF) Calcd for C15H29Na1O4P1
+
25
([M+Na]+) 327.1696. Found 327.1683; ½ꢀꢀD +21.1° (c =
+
1.79, MeOH).
Calcd for C14H29Na1O5P1Si1 ([M+Na]+) 359.1414. Found
25
Dimethyl
(3-Cyclohexyl-1-hydroxyprop-2-yn-1-yl)-
359.1413; ½ꢀꢀD +19.8° (c = 1.23, MeOH).
phosphonate (5d): HPLC IA, H/IPA = 100:1, flow rate =
0.5 mL/min, λ = 210 nm, 58.0 min (minor enantiomer), 61.2
min (major enantiomer); H NMR (400 MHz, CDCl3) ¤ 3.89
Dimethyl
(1,4-Dihydroxy-4-methylpent-2-yn-1-yl)-
phosphonate (desilylated 5h): HPLC ASH, H/IPA = 10:1,
flow rate = 0.5 mL/min, λ = 210 nm, 10.3 min (minor enan-
tiomer), 11.3 min (major enantiomer); 1H NMR (400 MHz,
CDCl3) ¤ 5.09 (1H, brd, JP-H = 1.4 Hz), 4.62 (1H, br), 3.90
(6H, d, JP-H = 10.1 Hz), 1.61 (3H, d, JP-H = 15.1 Hz), 1.53 (3H,
s), 1.50 (3H, s); 13C NMR (101 MHz, CDCl3) ¤ 92.7 (d,
1
(3H, d, JP-H = 10.0 Hz), 3.88 (3H, d, JP-H = 10.1 Hz), 3.55 (1H,
br), 2.48-2.38 (1H, m), 1.84-1.75 (2H, m), 1.74-1.65 (2H, m),
1.65 (3H, d, JP-H = 15.1 Hz), 1.56-1.38 (3H, m), 1.37-1.24
(3H, m); 13C NMR (101 MHz, CDCl3) ¤ 92.0 (d, JP-C = 9.7
Hz), 78.6, 65.9 (d, J = 174.6 Hz), 54.8 (d, JP-C = 8.7 Hz), 54.7
(d, JP-C = 7.7 Hz), 32.4, 29.1, 25.9, 25.5, 24.8, two carbon
atoms were not found due to overlapping; 31P NMR (162 MHz,
CDCl3) ¤ 23.3; IR (film) 3283, 2931, 2853, 2233, 1448, 1237,
1185, 1033, 835, 757 cm¹1; HRMS (ESI-TOF) Calcd for
J
J
P-C = 9.7 Hz), 80.2, 65.3 (d, JP-C = 176.1 Hz), 64.7, 54.99 (d,
P-C = 7.7 Hz), 54.96 (d, JP-C = 7.7 Hz), 31.3, 30.8, 24.7;
31P NMR (162 MHz, CDCl3) ¤ 23.5; IR (film) 3305, 2983,
2243, 1647, 1455, 1365, 1236, 1171, 1035, 787 cm¹1; HRMS
(ESI-TOF) Calcd for C9H17Na1O5P1 ([M+Na]+) 259.0706.
+
25
25
C12H21Na1O4P1+ ([M+Na]+) 283.1070. Found 283.1083; ½ꢀꢀD
Found 259.0696; ½ꢀꢀD +21.0° (c = 1.73, MeOH).
+20.0° (c = 3.28, MeOH).
Dimethyl (1-Hydroxy-3-(trimethylsilyl)prop-2-yn-1-yl)-
phosphonate (5i): HPLC ADH, H/IPA = 50:1, flow rate =
0.5 mL/min, λ = 210 nm, 15.3 min (minor enantiomer), 16.6
Dimethyl
(1-Hydroxy-5-methylhex-2-yn-1-yl)phos-
phonate (5e): HPLC ADH, H/IPA = 20:1, flow rate = 0.5
mL/min, λ = 210 nm, 15.1 min (minor enantiomer), 16.0 min
(major enantiomer); H NMR (400 MHz, CDCl3) ¤ 3.89 (3H,
1
min (major enantiomer); H NMR (400 MHz, CDCl3) ¤ 3.90
1
(3H, d, JP-H = 10.6 Hz), 3.88 (3H, d, JP-H = 10.5 Hz), 3.62 (1H,
br), 1.67 (3H, d, J = 15.6 Hz), 0.18 (9H,s); 13C NMR (101 MHz,
CDCl3) ¤ 103.4, 92.2 (d, JP-C = 7.7 Hz), 66.1 (d, JP-C = 174.2
Hz), 55.1 (d, JP-C = 7.7 Hz), 54.9 (d, JP-C = 7.7 Hz), 25.2, ¹0.2;
31P NMR (162 MHz, CDCl3) ¤ 22.3; IR (KBr) 3287, 2963,
2160, 1252, 1238, 1160, 1054, 1028, 841, 783 cm¹1; HRMS
(ESI-TOF) Calcd for C9H19Na1O4P1Si1+ ([M+Na]+) 273.0682.
d, JP-H = 10.5 Hz), 3.88 (3H, d, JP-H = 10.1 Hz), 2.55 (1H, br),
2.15 (2H, dd, JH-H = 6.6 Hz, JP-H = 4.0 Hz), 2.14 (1H, d, J =
6.6 Hz), 1.83 (1H, sept, J = 6.6 Hz), 1.66 (3H, d, JP-H = 15.6
Hz), 0.98 (6H, d, J = 6.6 Hz); 13C NMR (101 MHz, CDCl3)
¤ 87.1 (d, JP-C = 8.7 Hz), 79.5, 66.0 (d, JP-C = 176.1 Hz), 54.7
(d, JP-C = 6.8 Hz), 54.6 (d, JP-C = 6.8 Hz), 28.0, 25.4, 22.0, two
carbon atoms were not found probably due to overlapping;
31P NMR (162 MHz, CDCl3) ¤ 23.2; IR (film) 3288, 2958,
2242, 1464, 1368, 1238, 1186, 1034, 832, 762 cm¹1; HRMS
25
Found 273.0688; ½ꢀꢀD +21.4° (c = 1.03, MeOH). Crystal data
for 5i (CCDC 772834): C9H19O4PSi (MW 250.30), Monoclinic,
P21, a = 9.5228(13), b = 7.4316(11), c = 9.7945(14) ¡,
¢ = 103.092(3)°, V = 675.14(17) ¡3, Z = 2, T = 153(2) K,
Independent reflections 3033 [Rint = 0.0248], Flack parameter
0.17(10), R1(Rw) = 0.0388 (0.0968) (I > 2σ(I)), GOF = 1.071.
+
(ESI-TOF) Calcd for C10H19Na1O4P1 ([M+Na]+) 257.0913.
25
Found 257.0910; ½ꢀꢀD +23.6° (c = 1.98, MeOH).
Dimethyl (4-(Benzyloxy)-1-hydroxybut-2-yn-1-yl)phos-
phonate (5f): HPLC OJH, H/IPA = 10:1, flow rate = 0.5
mL/min, λ = 210 nm, 31.4 min (major enantiomer), 33.2 min
Financial support was provided by CREST-JST, Program
for Leading Graduate Schools “Integrative Graduate Education
1
(minor enantiomer); H NMR (400 MHz, CDCl3) ¤ 7.42-7.33
Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan | 553

2008, 64, 2864.
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R-isomer.7e,7h,8c
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4 under the influence of a catalytic amount of KOtBu gave the
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Bull. Chem. Soc. Jpn. 2017, 90, 546–555 | doi:10.1246/bcsj.20170040
© 2017 The Chemical Society of Japan | 555