Dynamic kinetic resolution based asymmetric transfer hydrogenation of α-alkoxy-β-ketophosphonates. Diastereo- and enantioselective synthesis of monoprotected 1,2-dihydroxyphosphonates

Article abstract of DOI:10.1021/jo500148j

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation reactions of a wide range of 2-substituted α-alkoxy-β- ketophosphonates 3 were observed to proceed efficiently to give the corresponding 2-substituted α-alkoxy-β-hydroxy phosphonates 4 w

Full text of DOI:10.1021/jo500148j

Article
pubs.acs.org/joc
Dynamic Kinetic Resolution Based Asymmetric Transfer
Hydrogenation of α‑Alkoxy-β-Ketophosphonates.
Diastereo- and Enantioselective Synthesis of
Monoprotected 1,2-Dihydroxyphosphonates
Se-Mi Son†,‡ and Hyeon-Kyu Lee*,†,‡
†Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-600, Korea
‡Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 113 Gwahango, Yuseong,
Daejeon 305-333, Korea
S
* Supporting Information
ABSTRACT: Dynamic kinetic resolution driven, asymmetric
transfer hydrogenation reactions of a wide range of 2-substituted
α-alkoxy-β-ketophosphonates 3 were observed to proceed effi-
ciently to give the corresponding 2-substituted α-alkoxy-β-hydroxy
phosphonates 4 with excellent levels of diastereo- and enantio-
selectivity. These processes are promoted by using well-defined,
commercially available, chiral transition metal catalysts and a
0.2:1 mixture of formic acid and triethylamine as the hydrogen source and solvent.
using similar chiral Ru-catalyst systems.30 Recently, Zhang and co-
INTRODUCTION
■
workers uncovered a stereoselective AH reactions of α-alkyl-
Enantiomerically enriched α-substituted-β-hydroxy phospho-
nates have attracted considerable interests because of their wide
β-ketophosphonates2 and α-acylamindo-β-ketophosphonates
employing Ru-SunPhos as the catalyst system,1 which generate
range of biological activities as well as their abilities to serve as
the corresponding α-alkyl-β-hydroxy phosphonates and
α-acylamido-β-hydroxy phosphonates. In addition, enantioselec-
tive syntheses of β-hydroxy-α-aminophosphonate derivatives were
surrogates of the corresponding β-hydroxy carboxylates.1−6
These substances are also key intermediates in the synthesis of
potentially important peptide analogues, enzyme inhibitors,
reported via organocatalytic asymmetric 1,2-addition reactions
phosphonic acid-based antibiotics, and drug candidates.2,7−12
of α-isothiocyanato phosphonates to aldehydes.31,32 However,
Although a number of methods have been described for the
until now, no reports exist describing the efficient synthesis of
enantiomerically enriched α-alkoxy-β-hydroxy phosphonates.
Asymmetric transfer hydrogenation (ATH) reactions, which
employ hydrogen sources other than molecular hydrogen, have
preparation of enantiomerically enriched β-hydroxy phospho-
nates, including enzymatic13−19 and nonenzymatic resolutions
of racemic mixtures,20−22 most suffer from either low levels of
stereoselectivitiy or poor efficiencies. Enantiomerically enriched
α-substituted-β-hydroxy phosphonates have also been prepared
proven to be among the most powerful methods for
asymmetric reductions of ketones to produce chiral alco-
by utilizing asymmetric C−P bond-forming reactions of chiral
hols.33−39 Major reasons for the superior nature of these
α-hydroxy aldehydes with phosphonates.23,24 However, these
reactions lie in their operational simplicity, excellent stereo-
approaches require the use of stoichiometric amounts of chiral
selectivities, the availability of various hydrogen sources, and
starting materials and the observed stereoselectivities of the
formed chiral 1,2-dihydroxy phosphonates are not high.25,26
the ability to use readily accessible and less sensitive catalysts.
In addition, transition metal-catalyzed asymmetric transfer
In some cases, Sharpless asymmetric dihydroxylation of
hydrogenation of configurationally labile carbonyl compounds
α,β-unsaturated phosphonates was used to generate 1,2-dihydroxy
phosphonates with high levels of stereoselectivity.27−29 However,
via dynamic kinetic resolution (DKR) has emerged as an
efficient and powerful technique for controlling the stereo-
in this case the need exists to discriminate between the hydroxyl
groups in the 1,2-dihydroxy phosphonate moiety when selective
transformations to produce α-substituted-β-hydroxy phosphonates
are desired.
In 1995, Noyori and co-workers described asymmetric
hydrogenation (AH) reactions of β-ketophosphonates using a
BINAP-based Ru catalyst system, which generate β-hydroxy
chemistry at two contiguous stereogenic centers formed in the
process. Examples of reactions of this type include ATH of
α-substituted β-ketoesters,40−42 β-ketoamides,43 cyclic α-oxy-
β-ketoamides (e.g., 2-benzoylmorpholin-3-ones),44 β-ketosul-
fones,45 2-substituted-cycloalkanones,46−48 1,3-diketones,49−51
1,2-diketones,52,53 α-ketoesters,54 and α-ketophosphonates.55
phosphonates, and applied this method to the synthesis of the
antibiotic, fosfomycin.10 Later, Genet and co-workers also explored
Received: January 21, 2014
Published: February 26, 2014
AH reactions of β-ketophosphonates and β-ketothiophosphonates
© 2014 American Chemical Society
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Interestingly, ATH-DKR of α-ketophosphonates, forming the
corresponding α-hydroxy phosphonates,55 proceeds by addition
of hydrogen to the carbonyl diastereotopic face that is opposite
to that observed in the analogous reduction of α-ketoesters.
Recently, stereoselective ATH-DKR reactions of α-alkoxy-
β-keto esters have been reported to form the corresponding
α-alkoxy-β-hydroxy esters.40 However, no previous reports exist
describing asymmetric hydrogenation (AH) or asymmetric
transfer hydrogenation (ATH) of α-alkoxy-β-ketophosphonates
using chiral transition metal-catalysts.
In the studies described below, we have developed a highly
efficient and stereoselective method for the synthesis of
α-alkoxy-β-hydroxy phosphonates 4 (monohydroxy-protected
1,2-dihydroxy phosphonates) starting from the corresponding
racemic α-alkoxy-β-ketophosphonates 3 (Scheme 2). The process,
which enables simultaneous stereochemical control of two
contiguous stereogenic centers in a single step, involves DKR
driven, chiral transition metal catalyzed, asymmetric transfer
hydrogenation (ATH).
Table 1. Optimization of Chiral Catalysts 5 in ATH-DKR
Reactions of 3a
a
b
c
d
e
entry
5
conv (%)
dr (syn:anti) ee(syn) (%)
config
1
2
3
4
5
(R,R)-5a
(R,R)-5b
(R,R)-5c
(R,R)-5d
(R,R)-5e
56
74
98:2
97:3
93:7
90:10
99:1
98
98
S,S
S,S
S,S
S,S
S,S
93
98
44
>99
>99
>99
a
Reaction conditions: 3a (1 mmol), 5 (0.5 mol %), F/T (1 mL),
b
1
CH2Cl2 (10 mL), at 35 °C. Determined by using H NMR analysis.
c
syn-4a:anti-4a, determined by using 1H NMR or chiral HPLC analysis
d
of the crude reaction mixture. Determined by using chiral HPLC anal-
ysis. Determined by comparison of the optical rotation of debenzyla-
e
tion product 6 (see Scheme 4 below) with those reported in the literature.
promoted by (R,R)-5a and (R,R)-5b (Table 1, entries 1 and 2).
When Noyori’s Ru-catalyst, (R,R)-5c, is employed,38 the
conversion of the ATH reaction is improved to 93% (Table 1,
entry 3). In contrast, use of the Ru-catalyst (R,R)-5d,43 which
contains an electron-deficient pentafluorophenylsulfonyl group on
the chiral ligand, results in an inefficient (44% conversion) ATH
reaction and a decreased level of diastereoselectivity (90:10 dr)
(Table 1, entry 4). The results of further studies revealed that
ATH reaction of 3a using the Ru catalyst (R,R)-5e,39,40 which
possesses an η6-arene = mesitylene ligand, produces (S,S)-4a in
the highest conversion (>99%) and levels of stereoselectivity
(99:1 dr, 99% ee) (Table 1, entry 5).
RESULTS AND DISCUSSION
■
The racemic α-alkoxy-β-ketophosphonates 3, used in this effort
to explore the ATH-DKR process, were readily prepared
through LDA promoted condensation reactions of the
corresponding carboxylate esters 1 with dialkyl α-alkoxyme-
thylphosphonates 256,57 (Scheme 1).58,59 In initial studies,
Scheme 1. Synthesis of α-Alkoxy-β-ketophosphonates 3
The influence of solvents on ATH-DKR reaction of 3a
promoted by (R,R)-5e was investigated next (Table 2). In most
Table 2. Optimixation of the ATH-DKR of 3a in Various
Solvents
diethyl α-benzoyl-α-benzyloxymethylphosphonate (3a) was
subjected to ATH reaction (methylene chloride at 35 °C for
23 h) using the known chiral transition metal catalysts 5a−5e
(0.5 mol %) and a 5:2 mixture of formic acid and triethylamine
as the hydrogen source (Scheme 2, Table 1).
a
Scheme 2. ATH-DKR Reactions of α-Alkoxy-β-
ketophosphonates 3
b
c
d
entry
solvent
CH2Cl2
convn (%)
dr (syn:anti)
ee (syn) (%)
1
2
3
4
5
6
7
8
9
>99
>99
99
99:1
98:2
98:2
98:2
98:2
97:3
97:3
97:3
99:1
>99
99
Cl(CH2)2Cl
EtOAc
>99
99
CHCl3
98
toluene
DMF
97
>99
99
96
MeOH
THF
92
>99
92
86
2-propanol
99
99
a
Reaction conditions: 3a (0.1 mmol), (R,R)-5e (0.5 mol %), and
HCO2H/Et3N (F/T = 5:2) (0.1 mL) in 1.0 mL of solvent at 35 °C for
b
c
1
1
23 h. Determined by H NMR. dr was determined by H NMR or
d
chiral HPLC. ee was determined by chiral HPLC.
ATH reactions of 3a using the rhodium (R,R)-5a60 or
iridium catalyst (R,R)-5b61 were observed to yield the syn-
diastereomer (S,S)-4a as the major product with high levels of
diastereo- and enantioselectivity. However, the reactions do
not proceed to completion as reflected in the respective
conversions of 56% and 74% for processes (23 h at 35 °C)
of the solvents tested (CH2Cl2, Cl(CH2)2Cl, CHCl3, EtOAc,
Toluene, DMF, MeOH, THF, IPA), reactions (23 h at 35 °C)
of diethyl (1-benzoyl-1-benzyloxy)methylphosphonate (3a,
0.1 M) take place completely to form (S,S)-4a with high levels of
stereoselectivity (dr =97:3−99:1, ee =92−99%). Reaction in THF is
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the exception to this trend in that it takes place more slowly than
those in other solvents (86% conversion, 92% ee, 23 h).
generate the corresponding products 4b and 4c with excellent
levels of stereoselectivity (Table 4, entries 2 and 3). The benzyl
ether group in 3a tolerates the reductive reaction conditions,
but it can be removed using Pd/C-H2 in EtOH/AcOH
(Scheme 4). Various α-benzyloxy-β-ketophosphonates 3
bearing meta- or para-electron-donating and electron-with-
drawing substituted aryl moieties are smoothly converted to the
corresponding monobenzyl protected 2-aryl-1,2-dihydroxy
phosphonates 4 in uniformly excellent yields (94−99%) and
stereoselectivities (98:2−99:1 dr, 98−99% ee) and in short
reaction time periods (2−5 h). The results also show that
substrates with electron-withdrawing aryl groups react slightly
faster (2−3 h) than those containing electron-donating groups
such as methyl or methoxy (4−5 h). However, ATH reaction of
the α-benzyloxy-β-ketophosphonate 3d containing an ortho-Cl
substituted aryl group produces the corresponding reduction
product 4d in high yield (97%) but with poor stereoselectivities
(60:40 dr, 82/47% ee) (Table 4, entry 4). In addition, the
ortho-Me aryl substituted substrate 3g is inert under the
reaction conditions even after 24 h (quantitative recovery
of 3g) (Table 4, entry 7). Although ATH reaction of 3o,
possessing a 2′-naphthyl group, proceeds smoothly in 4 h to
produce 4o with an excellent yield and stereoselectivities, the
1′-naphthyl analogue 3p reacts only reluctantly to generate 4p
in 19% yield in 4 h, and although a >90% conversion is attained
in 30 h, the diastereoselectivity of the process is extremely low
(dr = 43:57) (Table 4, entries 15 and 16). These observations
suggest that both the steric and electronic natures of ortho-
substituents have an effect on the ATH process, perhaps by
inhibiting formation of the catalyst−substrate complex.
Importantly, ATH reaction of 3a under the same conditions,
except employing (S,S)-5e instead of (R,R)-5e as catalyst, produces
(R,R)-4a as the major product with excellent levels of stereo-
selectivity (99:1 dr, 99% ee) (Table 4, entry 30). This observation
demonstrates that the source of dynamic kinetic resolution in this
process is the configurational lability of the stereogenic center in 3a,
which causes rapid racemization of the substrate under the reaction
conditions (Scheme 3). As a result, the absolute stereochemistry
of the major reduction product depends on the chirality of the
Ru-catalysts in a manner such that (S)-3a is preferentially reduced
with (R,R)-5e to afford alcohol (S,S)-4a and (R)-3a is prefer-
entially reduced with (S,S)-5e to give alcohol (R,R)-4a.
α-Benzyloxy-β-ketophosphonates containing heteroaromatic
moieties such as 2-furyl (3q) and 2-thienyl (3r) are also
suitable substrates for the ATH-DKR reaction. These processes
produce the respective reduction products 4q and 4r with
excellent levels of stereoselectivity (Table 4, entries 17 and 18).
Similarly, ATH reactions of β-ketophosphonates bearing
nitrogen-containing heteroaromatic substituents such as 3′-pyridyl
(3t) and 4′-pyridyl (3u) react to form the corresponding products
4t and 4u with excellent stereoselectivities (Table 4, entries
20 and 21). In the cases of ATH of the pyridyl containing
β-ketophosphonates 3t and 3u, excess amounts of formic acid
(16 equiv) are need to promote complete reactions in 3.5 h. In
contrast, the 2′-pyridyl substituted substrate 3s β-ketophosphonate
undergoes the ATH reaction only slowly (31% conversion to 4s in
3.5 h, Table 4, entry 19).
Transition metal catalyzed-ATH reactions of ketones are
most often performed in 2-propanol (IPA) or a 5:2 mixture of
formic acid and triethylamine, with the latter being preferred
because in this case reactions are nearly irreversible. Recently it
has been shown that ratio of formic acid and triethylamine has a
significant effect on both the rates and enantioselectivities of
ATH reactions of ketones.44,62 In the current effort, we also
observed that the formic acid and triethylamine ratio
dramatically affects the time required for completion of the
ATH reaction of 3a catalyzed by 5e (Table 3). Specifically,
Table 3. ATH-DKR Reaction of 3a with Varying HCO2H/
a
Et3N (F/T) Ratio
c
F/T
ratio
FA
(equiv)
time
(h)
dr
ee (syn)
d
b
entry
conv. (%)
(syn:anti)
(%)
1
2
3
4
5
5:2
10.7
5.6
24
6
>99 (97)
>99
99:1
99:1
99:1
99:1
99:1
99:1
>99
>99
>99
>99
>99
>99
1:1
e
0.2:1
13.6
13.6
4.1
5
>99
f
0.2:1
0.2:1
0.2:1
2
>99
g
g
2
>99
h
,h
6
4.1
7
>99
a
Reaction conditions: 3a (0.1 mmol), (R,R)-5e (0.5 mol %), and
HCO2H/Et3N (F/T = 5:2 or 1:1) (0.1 mL) in 1.0 mL of CH2Cl2.
b
Determined by using 1H NMR analysis of the crude reaction mixture
c
(isolated yields in parentheses). dr was determined by using 1H NMR or
d
e
chiral HPLC. ee was determined by using chiral HPLC. HCO2H/
Et3N (F/T = 0.2:1, 1 mL) was used as hydrogen source and solvent
with addition of small amount of CH2Cl2 (∼0.2 mL) to make the solu-
f
tion a single phase. Only HCO2H/Et3N (F/T = 0.2:1, 1 mL) was used
g
(0.1 M) with no added solvent. Amount of HCO2H/Et3N (F/T =
0.2:1) was reduced to 0.3 mL (0.3 M). 0.1 mol % (S/C = 1000) of
h
(R,R)-5e was used. FA (equiv): equivalent amount of formic acid to 3a.
reduction of the ratio of formic acid and triethylamine from 5:2
to 1:1 and to 0.2:1 affects a dramatic reduction in the time
required for completion of the ATH reaction from 24 to 6 and
to 2 h without causing a deterioration of the dr or % ee. In
addition, we observed that slow addition of formic acid
(4 equiv) to a Et3N (20 equiv) solution of 3a and (R,R)-5e
(0.5 mol %) promoted the most efficient process in terms of
stereoselectivity and reaction time (2 h). Moreover, the amount
of catalyst loading can be reduced to 0.1 mol % (S/C = 1000)
with longer reaction time to complete the reaction without loss
of the optical purity (Table 3, entry 6).
The scope and limitations of AHT-DKR process were
explored next using a variety of α-alkoxy-β-ketophosphonates
(3, 0.3 M) and the optimized reaction conditions (35 °C)
involving 5e (0.5 mol %) as the catalyst and a 0.2:1 molar ratio of
formic acid and triethylamine as both the hydrogen source and
solvent. The results of this survey are summarized in Table 4.
The results show that ATH reactions of both the
α-benzyloxy- and α-methyloxy-substituted phosphonates 3a
and 3b produce the corresponding products 4a and 4b with
excellent efficiencies and stereoselectivities (Table 4, entries 1
and 2). In a similar manner, ATH reactions of both the diethyl
(3b) and dimethyl (3c) esters of ketophosphonate take place to
The results of continuing studies revealed that Rh-containing
5a is a better catalyst than Ru-5e for the ATH reaction of
2′-pyridyl β-ketophosphonates 3s. Specifically, 3s reacts in the
presence of 5a in 1:1 formic acid and triethylamine in 6 h to
produce 4s completely but with a low level of stereoselectivity
(96:4 dr, 44% ee, Table 4, entry 22). In addition, ATH
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a
Table 4. ATH-DKR Reactions of 2-Substituted α-Alkoxy-β-ketophosphonates 3
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Table 4. continued
a
Reaction conditions: 3 (1 mmol) and (R,R)-5 (0.5 mol %) in Et3N (2.85 mL, 20 equiv) with slow addition of formic acid (0.15 mL, 4 equiv) at
b
c
35 °C. Conversion was determined by using 1H NMR analysis of the crude reaction mixture (isolated yields in the parentheses) dr was determined
by using H NMR or chiral HPLC. ee was determined by using chiral HPLC. Determined by analogy to 4a, 4n, 4u, 4v, or 4y. Determined by
comparison of the optical rotation of debenzylation product with that reported in the literature (see Scheme 4). No reaction. Determined by using
d
e
f
1
g
h
i
X-ray crystallography. Reaction conditions for entries 19−21: 3 (1 mmol) and Ru-catalyst (R,R)-5e (0.5 mol %) in Et3N (80 equiv) with slow
j
addition of formic acid (16 equiv) at 35 °C. Same reaction conditions for entries 19−21 (Table 4) except that Rh-catalyst (R,R)-5a instead of Ru-
catalyst (R,R)-5e in 1:1 mixture of formic acid and triethylamine was employed.
reactions of the 3′-pyridyl- and 4′-pyridyl-phosphonates 3t and
3u using Rh-catalyst 5a in 1:1 formic acid and triethylamine
form the corresponding products 4t (99:1 dr, 91% ee) and 4u
(98:2 dr, 98% ee) with varying degrees of stereoselectivity
(Table 4, entries 23 and 24).
The application of the ATH reaction to stereoselective
reductions of 2-alkyl substituted α-alkoxy-β-ketophosphonates
was explored next. The results demonstrate that ATH reactions
of 2-methyl or 2-ethyl substituted α-benzyloxy-β-ketophosph-
onates 3v and 3w using Ru-catalyst 5e occur to produce the
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In order to determine the absolute and relative stereo-
chemistries of the ATH-DKR reaction products, 4a, 4v, and 4y
were converted to the respective 1,2-dihydroxy-substituted
phosphonates 6,27,28 7,28,66 and 8 by using Pd/C-catalyzed
hydrogenolysis (Scheme 4). The absolute stereochemistries of
Scheme 3. Dynamic Kinetic Resolution in ATH Reaction of
Racemic-3a Catalyzed by (R,R)-5e
Scheme 4. Determination of the Absolute Stereochemistry of
a
ATH-DKR Product 4
a
corresponding products 4v and 4w in high yields but with
slightly lower diastereoselectivities than those that attend
ATH of 2-(hetero)aryl substituted β-ketophosphonates
(Table 4, entries 25 and 26). ATH of 2-phenethyl substituted
β-ketophosphonates bearing α-benzyloxy (3y) and α-methoxy
(3z) groups also proceed to completion in 4−5 h and also take
place with slightly lower levels of diastereoselectivity (Table 4,
entries 28 and 29). However, the efficiencies of ATH reactions
of 2-alkyl substituted α-benzyloxy-β-ketophosphonates are
sensitive to the steric bulkiness of the 2-alkyl group, as is
exemplified by the 2-cyclohexyl analogue 3x, which is inert
under the reaction conditions even over an extended time
period of 24 h (Table 4, entry 27).
(a) Pd/C, H2, EtOH/AcOH (100:1), rt; (b) AD-mix-α, MeSO2NH2,
t-BuOH/H2O, 0 °C.
6, 7, and 8 were then determined on the basis of comparisons
of their properties with those of known (6 and 7) or
independently synthesized phosphonate 8 using Sharpless
asymmetric dihydroxylation of the corresponding α,β-unsatu-
rated phosphonate67 employing AD-mix-α. Additionally, the
absolute stereochemistries of 4n and 4u were unambiguously
assigned by using single-crystal X-ray crystallographic analysis
(deposited, CCDC-982444 for (S,S)-4n and CCDC-982443 for
(S,S)-4u, see Supporting Information).
Finally, the scope of the process was explored employing the
2-cinnamoyl substituted α-benzyloxy-β-ketophosphonate 3ab
(Table 5). Reaction of this substrate promoted by the Ru-
catalyst 5e takes place to generate 4ab as the expected major
product (66%) with good stereoselectivities (99:1 dr, 98% ee)
(Table 5, entry 3) along with the CC reduction products 3y
(22%) and 4y (12%). Because it is well-known that transfer
hydrogenations promoted by Noyori-type diamine−transition
metal (Ru, Rh, Ir) complexes are highly chemoselective, with
CO reduction being favored over CC reduction,39,63 the
present result is interesting. However, it was reported recently
that the use of Ru- or Rh-amido catalysts causes reversal of the
typical CO over CC selectivities in ATH reactions of α,β-
unsaturated carbonyl compounds when the CC double bond
is activated by electron-withdrawing substituents or the reaction
is performed in an aqueous medium.64,65 In line with this
finding, we observed that the chemoselectivity of reaction of
3ab can be changed to favor CC reduction by replacing
catalyst 5e with Rh(III)-5a or Ir(III)-5b (Table 5, entries 3−5).
In summary, the investigation described above has led to
the development of a convenient and general protocol for
asymmetric transfer hydrogenation (ATH) reactions of readily
available, racemic 2-substituted α-alkoxy-β-ketophosphonates 3
that generate 2-substituted α-alkoxy-β-hydroxyphosphonates 4.
This process, which employs a 0.2:1 molar ratio mixture of
HCO2H and Et3N as the hydrogen source and solvent, along
with the well-defined chiral RuCl(TsDPEN)mesitylene cata-
lysts (S,S)- and (R,R)-5e, efficiently produces the correspond-
ing monobenzyl protected 2-aryl-, 2-heteroaryl-, 2-alkyl-, and 2-
alkenyl-substituted 1,2-dihydroxy phosphonates with excellent
levels of diastereo- and enantioselectivity in short reaction
times. ATH reactions, carried out under the conditions outlined
above, are accompanied by dynamic kinetic resolution (DKR)
which leads to simultaneous control of the stereochemistry
at two contiguous stereogenic centers. Finally, the observa-
tions show that the chemoselectivity of the ATH reaction of
1-cinnamoyl-1-benzyloxy-methylphosphonate (3ab) can be
switched from favoring CO reduction to favoring CC
a
Table 5. ATH-DKR Reactions of 1-Cinnamoyl-1-benzyloxy-methylphosphonate (3ab)
b
c
c
c
entry
cat-5
solvent
F/T ratio
conv (%)
4ab
3y
4y
1
2
3
4
5
(R,R)-5e (Ru)
(R,R)-5e (Ru)
(R,R)-5e (Ru)
(R,R)-5a (Rh)
(R,R)-5b (Ir)
CH2Cl2
CH2Cl2
5:2
1:1
>99
>99
>99
>99
>99
56(>99:1)
63(>99:1)
13
−
22
87
76
31(64:36)
37(57:43)
d
neat
0.2:1
0.2:1
0.2:1
66(99:1, 98%ee)
12
9
d
neat
4
d
neat
14
10
a
Reaction conditions: 3 (0.1 mmol) in 1.0 mL of solvent with 0.1 mL of HCO2H/Et3N (F/T = 5:2 or 1:1), cat-5 (0.5 mol %) at 35 °C for 24 h.
b
c
d
Determined by using 1H NMR. Ratio by 1H NMR, dr and ee (in parentheses) by chiral HPLC. HCO2H/Et3N (0.2:1) was used (0.1 M) as the
hydrogen source and solvent.
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2. General Procedure for the Synthesis of α-Benzyloxy
β-Ketophosphonates (3). To the ester (1.15 equiv) and diethyl
benzyloxymethylphosphonate (2a, 1 equiv) in THF at −5 °C was
added dropwise with stirring a 1.5 M solution of LDA (2.1 equiv)
maintaining the internal temperature below 0 °C. The reaction
mixture was stirred at 0 °C until complete consumption of diethyl
benzyloxymethylphosphonate (2a) as determined by TLC (typically
less than 45 min.). The reaction mixture was then carefully quenched
with 5 N HCl to adjust the pH to ∼4 and diluted with EtOAc. The
aqueous layer was separated and extracted with EtOAc. The combined
organic layers were washed with water and brine, dried over MgSO4,
filtered, and concentrated to yield α-benzyloxy β-ketophosphonate 3.
Purification by column chromatography afforded pure 3.
reduction by changing the catalyst from Ru(II)-5e to Rh(III)-
5a or Ir(III)-5b.
EXPERIMENTAL SECTION
■
General Methods. All commercial reagents were used as obtained
unless otherwise noted. Reactions were performed using oven-dried
glassware under an atmosphere of nitrogen. Dichloromethane (DCM),
ether, THF were dried and purified using a solvent purification system.
Flash column chromatography was carried out using silica gel (38−75 μm).
Analytical thin layer chromatography (TLC) was performed using silica
gel 60 F254 plates. Preparative thin layer chromatography (PLC) was
performed using silica gel 60 F254 2 mm plates. Visualization of the
developed chromatograms was accomplished with UV light and by staining
with ethanolic phosphomolybdic acid (PMA) solution or ninhydrin
solution followed by heating. Nuclear magnetic resonance (NMR) spectra
were recorded using a 500 MHz (1H NMR at 500 MHz and 13C NMR at
125 MHz) or 300 MHz instrument (1H NMR at 300 MHz and 13C NMR
at 75 MHz). 1H NMR data are reported as follows: chemical shift
(δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad), integration, coupling constants (Hz). 13C NMR
data are reported in terms of chemical shifts (δ, ppm). High performance
liquid chromatography (HPLC) was carried out on a system equipped with
a Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralpak ID, or Chiralpak
AD-H column. HR-MS were measured using electron impact (EI) ioniza-
tion via double focusing mass analyzer (magnetic and electric fields) or
electrospray ionization (ESI) via a time of flight (TOF) analyzer. Formic
acid/triethylamine mixtures (molar ratio = 5:2 or 1:1) are commercially
available. The formic acid/triethylamine mixture (molar ratio = 0.2:1) was
prepared by slow addition of formic acid to triethylamine with stirring at
room temperature according to the literature procedure.62 Chiral catalysts,
(R,R)-5c, (R,R)-5d, and (R,R)-5e are commercially available. (R,R)-5a60
and (R,R)-5b61 were prepared according to the literature procedures.
1. Synthesis of 1-Alkyloxymethylphosphonate Dialkyl Ester (2).56,57
A mixture of triethyl phosphite (0.1 mmol) and benzyl chloromethyl
2.1. Diethyl (1-benzyloxy-2-oxo-2-phenylethyl)phosphonate, 3a:
1
yield: 95.6% (4.8 g as a coloress oil); H NMR (500 MHz, CDCl3) δ
8.04 (d, 2H, J = 8.2 Hz), 7.60−7.58 (m, 1H), 7.47−7.44 (m, 2H),
7.32−7.29 (m, 5H), 5.14 (d, 1H, Jcp = 20 Hz), 4.78 (d, 1H, J = 11.8
Hz), 4.56 (d, 1H, J = 11.8 Hz), 4.21−4.10 (m, 4H), 1.29 (t, 3H, J = 7.0
Hz), 1.21 (t, 3H, J = 7.0 Hz).; 13C NMR (75 MHz, CDCl3) δ 195.0,
136.2, 135.7, 133.7, 129.5, 128.6, 128.6, 128.5, 128.4, 80.0 (d, Jcp
151.1 Hz), 74.0 (d, Jcp = 12.6 Hz), 63.8 (d, Jcp = 6.8 Hz), 63.6 (d, Jcp
=
=
6.8 Hz), 16.4 (d, Jcp = 6.5 Hz), 16.3 (d, Jcp = 6.5 Hz).; HRMS (EI):
m/z calcd for C19H23O5P 362.1283, found 362.1279.
2.2. Diethyl (1-methoxy-2-oxo-2-phenylethyl)phosphonate, 3b.
1
yield: 73.0% (1.6 g as a coloress oil); H NMR (500 MHz, CDCl3) δ
8.12 (d, 2H, J = 7.7 Hz), 7.61 (t, 1H, J = 7.5 Hz), 7.49 (t, 2H, J = 7.6
Hz), 5.01 (d, 1H, Jcp = 19.4 Hz), 4.24−4.13 (m, 4H), 3.51 (s, 3H),
1.32 (t, 3H, J = 7.1 Hz), 1.23 (t, 3H, J = 7.1 Hz).; 13C NMR (125
MHz, CDCl3) δ 194.6, 135.5, 133.7, 129.3, 128.4, 83.4 (d, Jcp = 151.1
Hz), 63.8 (d, Jcp = 7.0 Hz), 63.5 (d, Jcp = 7.0 Hz), 60.4 (d, Jcp = 12.9
Hz), 16.3 (d, Jcp = 5.9 Hz), 16.1 (d, Jcp = 6.1 Hz).; HRMS (EI): m/z
calcd for C13H19O5P 286.0970, found 286.0960.
ether (0.11 mmol) was heated to 130 °C with stirring for 3 h. After
completion of reaction, the reaction mixture was cooled to room
temperature and purified by flash chromatograph (SiO2, hexane/
EtOAc 1:2) to give diethyl benzyloxymethylphosphonate (2a, 23.6 g,
87%) as a pale-yellow oil.
2.3. Dimethyl (1-methoxy-2-oxo-2-phenylethyl)phosphonate, 3c:
1
yield: 76.0% (1.7 g as a coloress oil); H NMR (500 MHz, CDCl3) δ
1.1. Diethyl Benzyloxymethylphosphonate (2a): yield: 87%
1
(23.6 g as a pale-yellow oil); H NMR (500 MHz, CDCl3): δ 7.40−
8.13 (d, 2H, J = 7.7 Hz), 7.63 (t, 1H, J = 7.4 Hz), 7.51 (t, 2H, J = 7.6
Hz), 5.04 (d, 1H, Jcp = 19.4 Hz), 3.85 (d, 3H, J = 10.9 Hz), 3.78 (d,
3H, J = 10.9 Hz), 3.51 (s, 3H).; 13C NMR (125 MHz, CDCl3) δ 194.5,
135.3, 133.9, 129.3, 128.5, 83.0 (d, Jcp = 151.5 Hz), 60.4 (d, Jcp = 13.2
Hz), 54.2 (d, Jcp = 6.6 Hz), 54.0 (d, Jcp = 6.6 Hz).; HRMS (EI): m/z
calcd for C11H15O5P 258.0657, found 258.0654.
7.29 (m, 5H), 4.67 (s, 1H), 4.22−4.17 (m, 4H), 3.78 (d, 1H, J = 8.7 Hz),
1.37 (t, 6H, J = 7.0 Hz).
1.2. Dimethyl methyloxymethylphosphonate (2b): yield: 72%
(5.6 g as a colorless oil); 1H NMR (500 MHz, CDCl3): δ 3.83 (d, 6H,
J = 10.6 Hz), 3.79 (d, 2H, J = 8.6 Hz), 3.49 (s, 3H).
2.4. Diethyl [1-benzyloxy-2-(2-chloro-phenyl)-2-oxo-ethyl]-
phosphonate, 3d: yield: 86.7% (1.4 g as a pale-yellow oil); 1H
1.3. Diethyl methyloxymethylphosphonate (2c): yield: 57% (5.7 g
1
NMR (500 MHz, CDCl3) δ 7.54 (d, 1H, J = 7.6 Hz), 7.41−7.40 (m,
2H), 7.36−7.29 (m, 6H), 5.24 (d, 1H, Jcp = 21.4 Hz), 4.87 (d, 1H, J =
11.8 Hz), 4.72 (d, 1H, J = 11.8 Hz), 4.21−4.11 (m, 4H), 1.29 (t, 3H,
J = 7.1 Hz), 1.18 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ
197.3 (d, Jcp = 1.9 Hz), 137.4, 136.5, 132.1, 131.2, 130.3, 130.3, 128.6,
128.5, 128.4, 126.7, 81.3 (d, Jcp = 151.7 Hz), 74.1 (d, Jcp = 10.5 Hz),
63.8 (d, Jcp = 6.7 Hz), 63.5 (d, Jcp = 6.7 Hz), 16.4 (d, Jcp = 5.9 Hz), 16.2
as a colorless oil); bp 69−73 °C/2 mmHg; H NMR (500 MHz,
CDCl3): δ 4.23−4.17 (m, 4H), 3.76 (d, 2H, J = 8.4 Hz), 3.50 (s, 3H),
1.38 (t, 6H, J = 7.0 Hz).
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(d, Jcp = 6.2 Hz).; HRMS (EI): m/z calcd for C19H22ClO5P 396.0893,
found 396.0892.
2.5. Diethyl [1-benzyloxy-2-(3-chloro-phenyl)-2-oxo-ethyl]-
phosphonate, 3e: yield: 93.0% (2.5 g as a pale-yellow oil); 1H
(d, 1H, J = 11.9 Hz), 4.22−4.09 (m, 4H), 2.42 (s, 3H), 1.29 (t, 3H, J =
7.1 Hz), 1.22 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ
194.3, 144.8, 136.3, 133.2, 129.6, 129.2, 128.6, 128.5, 128.4, 79.9 (d,
Jcp = 150.9 Hz), 73.8 (d, Jcp = 12.7 Hz), 63.8 (d, Jcp = 6.7 Hz), 63.6 (d,
Jcp = 6.8 Hz), 21.8, 16.4 (d, Jcp = 5.6 Hz), 16.3 (d, Jcp = 5.6 Hz).;
HRMS (EI): m/z calcd for C20H25O5P 376.1440, found 376.1441.
2.10. Diethyl [1-benzyloxy-2-(4-methoxy-phenyl)-2-oxo-ethyl]-
phosphonate, 3j: yield: 92.8% (2.3 g as a pale-yellow oil); 1H
NMR (500 MHz, CDCl3) δ 8.02 (s,1H), 7.95 (d, 1H, J = 7.9 Hz),
7.56−7.54 (m, 1H), 7.41−7.38 (m, 1H), 7.33−7.28 (m, 5H), 5.03 (d,
1H, Jcp = 20.3 Hz), 4.74 (d, 1H, J = 11.8 Hz), 4.59 (d, 1H, J = 11.8
Hz), 4.21−4.14 (m, 4H), 1.30 (t, 3H, J = 7.0 Hz), 1.24 (t, 3H, J = 7.1
Hz).; 13C NMR (75 MHz, CDCl3) δ 194.2 (d, Jcp = 1.0 Hz) 137.1,
136.0, 134.8, 133.7, 129.8, 129.5, 128.8, 128.7, 128.6, 127.9, 80.7(d, Jcp
= 151.1 Hz), 74.4 (d, Jcp = 12.4 Hz), 64.0 (d, Jcp = 6.8 Hz), 63.8 (d, Jcp
= 6.8 Hz), 16.5 (d, Jcp = 5.6 Hz), 16.4 (d, Jcp = 5.1 Hz).; HRMS (EI):
m/z calcd for C19H22ClO5P 396.0893, found 396.0896.
2.6. Diethyl [1-benzyloxy-2-(4-chloro-phenyl)-2-oxo-ethyl]-
NMR (500 MHz, CDCl3) δ 8.11 (d, 2H, J = 9.0 Hz), 7.33−7.29 (m,
5H), 6.93 (d, 2H, J = 9.0 Hz), 5.06 (d, 1H, Jcp = 19.8 Hz), 4.77 (d, 1H,
J = 11.8 Hz), 4.53 (d, 1H, J = 11.8 Hz), 4.22−4.11 (m, 4H), 3.88 (s,
3H), 1.29 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz).; 13C NMR (75
MHz, CDCl3) δ 193.0 (d, Jcp = 1.2 Hz), 164.1, 136.4, 132.1, 128.6,
128.6, 128.6, 128.4, 113.7, 80.2 (d, Jcp = 150.8 Hz), 73.9 (d, Jcp = 13.0
Hz), 63.7 (d, Jcp = 7.2 Hz), 63.7 (d, 1H, Jcp = 7.4 Hz), 55.6, 16.4 (d,
Jcp = 6.0 Hz), 16.3 (d, Jcp = 5.9 Hz).; HRMS (EI): m/z calcd for
C20H25O6P 392.1389, found 392.1386.
phosphonate, 3f: yield: 88.5% (1.3 g as a pale-yellow oil); 1H
NMR (500 MHz, CDCl3) δ 8.04 (d, 2H, J = 8.6 Hz), 7.43 (d, 2H, J =
8.6 Hz), 7.34−7.27 (m, 5H), 5.02 (d, 1H, Jcp = 20.2 Hz), 4.74 (d, 1H,
J = 11.8 Hz), 4.56 (d, 1H, J = 11.8 Hz), 4.21−4.12 (m, 4H), 1.30 (t,
3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz,
CDCl3) δ 194.0, 140.3, 136.0, 133.8, 131.1, 128.8, 128.7, 128.7, 128.6,
80.7 (d, Jcp = 151.0 Hz), 74.3 (d, Jcp = 12.6 Hz), 63.9 (d, Jcp = 6.8 Hz),
63.8 (d, Jcp = 6.8 Hz), 16.4 (d, Jcp = 5.9 Hz).; HRMS (EI): m/z calcd
for C19H22ClO5P 396.0893, found 396.0898.
2.11. Diethyl [1-benzyloxy-2-(4-fluoro-phenyl)-2-oxo-ethyl]-
phosphonate, 3k: yield: 96.7% (1.3 g as a pale-yellow oil); 1H
2.7. Diethyl [1-benzyloxy-2-oxo-2-(o-tolyl)-ethyl]phosphonate,
1
3g: Yield: 89.7% (930 mg as a pale-yellow oil); H NMR (500 MHz,
NMR (500 MHz, CDCl3) δ 8.16−8.13 (m, 2H), 7.33−7.28 (m, 5H),
7.14−7.11 (m, 2H), 5.02 (d, 1H, Jcp = 20.2 Hz), 4.74 (d, 1H, J = 11.8
Hz), 4.56 (d, 1H, J = 11.8 Hz), 4.22−4.11 (m, 4H), 1.30 (t, 3H, J = 7.0
Hz), 1.25 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 193.6
(d, Jcp = 1.4 Hz), 166.2 (d, Jcf = 254.4 Hz), 136.1, 132.5 (d, Jcf = 9.4
Hz), 131.9 (d, Jcf = 2.9 Hz), 128.7, 128.6, 128.5, 115.6 (d, Jcf = 21.7
Hz), 80.7 (d, Jcp = 150.9 Hz), 74.2 (d, Jcp = 12.6 Hz), 63.9 (d, Jcp = 5.4
Hz), 63.8 (d, Jcp = 6.6 Hz), 16.4 (d, Jcp = 5.4 Hz).; HRMS (EI): m/z
calcd for C19H22FO5P 380.1189, found 380.1184.
CDCl3) δ 7.45 (d, 1H, J = 7.8 Hz), 7.37−7.29 (m, 6H), 7.23 (d, 1H,
J = 7.5 Hz), 7.18 (t, 1H, J = 7.5 Hz), 5.06 (d, 1H, Jcp = 21.0 Hz), 4.80
(d, 1H, J = 12.0 Hz), 4.65 (d, 1H, J = 11.9 Hz), 4.19−4.00 (m, 4H),
2.43 (s, 3H), 1.26 (t, 3H, J = 7.1 Hz), 1.12 (t, 3H, J = 7.1 Hz).; 13C
NMR (75 MHz, CDCl3) δ 197.9 (d, Jcp = 1.3 Hz), 138.4, 136.7, 136.3,
131.6, 131.6, 128.9, 128.6, 128.5, 128.4, 125.3, 80.8 (d, Jcp = 151.6 Hz),
73.7 (d, Jcp = 11.6 Hz), 63.6 (d, Jcp = 6.6 Hz), 63.3 (d, Jcp = 6.9 Hz),
20.4, 16.3 (2, Jcp = 6.0 Hz), 16.1 (d, Jcp = 6.3 Hz).; HRMS (EI): m/z
calcd for C20H25O5P 376.1440, found 376.1442.
2.12. Diethyl[1-benzyloxy-2-(4-nitro-phenyl)-2-oxo-ethyl]-
phosphonate, 3l: yield: 26.6% (330 mg as a pale-yellow oil); 1H
2.8. Diethyl [1-benzyloxy-2-oxo-2-(m-tolyl)-ethyl]phosphonate,
1
3h: Yield: 93.5% (1.3 g as a pale-yellow oil); H NMR (500 MHz,
NMR (500 MHz, CDCl3) δ 8.32−8.21 (m, 5H), 7.32−7.24 (m, 4H),
5.04 (d, 1H, Jcp = 20.8 Hz), 4.71 (d, 1H, J = 11.8 Hz), 4.63 (d, 1H, J =
11.8 Hz), 4.23−4.17 (m, 4H), 1.31 (t, 3H, J = 7.0 Hz), 1.28 (t, 3H, J =
7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 194.5 (d, Jcp = 1.6 Hz), 150.5,
139.9, 135.6, 130.8, 128.8, 128.8, 123.5, 81.3 (d, Jcp = 151.0 Hz), 74.7
(d, Jcp = 12.0 Hz), 64.1 (d, Jcp = 7.1 Hz), 16.4 (d, Jcp = 5.9 Hz).; HRMS
(EI): m/z calcd for C19H22 NO7P 407.1134, found 407.1130.
CDCl3) δ 7.83−7.81 (d, 2H, J = 8.6 Hz), 7.39−7.29 (m, 7H), 5.14 (d,
1H, Jcp = 19.9 Hz), 4.76 (d, 1H, J = 11.8 Hz), 4.55 (d, 1H, J = 11.8
Hz), 4.22−4.08 (m, 4H), 2.39 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz), 1.20
(t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 195.0 (d, Jcp = 0.9
Hz) 138.2, 136.3, 135.8, 134.5, 129.7, 128.5, 128.5, 128.3, 128.3, 126.7,
79.8 (d, Jcp = 151.1 Hz), 73.8 (d, Jcp = 12.6 Hz), 63.7 (d, Jcp = 6.8 Hz),
2.13. Diethyl [1-benzyloxy-2-(4-cyano-phenyl)-2-oxo-ethyl]-
phosphonate, 3m: yield: 86.1% (1.3 g as a pale-yellow oil); 1H
63.5 (d, Jcp = 6.8 Hz), 21.3, 16.3 (d, Jcp = 6.3 Hz), 16.2 (d, Jcp
=
7.5 Hz).; HRMS (EI): m/z calcd for C20H25O5P 376.1440, found
376.1439.
NMR (500 MHz, CDCl3) δ 8.15(d, 2H, J = 8.3 Hz), 7.74 (d, 2H, J =
8.3 Hz), 7.32−7.23 (m, 5H), 4.98 (d, 1H, Jcp = 20.6 Hz), 4.70 (d, 1H,
J = 11.8 Hz), 4.61 (d, 1H, J = 11.8 Hz), 4.22−4.12 (m, 4H), 1.30 (t,
3H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.0 Hz).; 13C NMR (75 MHz,
2.9. Diethyl [1-benzyloxy-2-oxo-2-(p-tolyl)-ethyl]phosphonate,
1
3i: Yield; 92.5% (1.0 g as a pale-yellow oil); H NMR (500 MHz,
CDCl3) δ 7.97 (d, 2H, J = 8.2 Hz), 7.34−7.29 (m, 5H), 7.25 (d, 2H,
J = 8.1 Hz), 5.12 (d, 1H, Jcp = 19.8 Hz), 4.78 (d, 1H, J = 11.9 Hz), 4.54
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CDCl3) δ 194.5 (d, Jcp = 1.6 Hz), 138.4, 135.7, 132.1, 130.1, 128.7,
118.0, 116.7, 81.2 (d, J cp = 150.9 Hz), 74.6 (d, Jcp = 12.1 Hz), 64.0 (d,
Jcp = 6.9 Hz), 16.4 (d, Jcp = 5.9 Hz).; HRMS (EI): m/z calcd for
C20H22NO5P 387.1236, found 387.1237.
6.7 Hz), 63.7 (d, Jcp = 6.8 Hz), 16.5 (d, Jcp = 5.9 Hz) 16.4 (d, Jcp = 6.1
Hz).; HRMS (EI): m/z calcd for C17H21O6P 352.1076, found 352.1074.
2.18. Diethyl [1-benzyloxy-2-oxo-2-(thiophen-2-yl)-ethyl]-
1
phosphonate, 3r: yield: 90.9% (2.5 g as a light-green oil); H NMR
2.14. Diethyl [1-benzyloxy-2-(4-carbomethoxy-phenyl)-2-oxo-
ethyl]phosphonate, 3n: yield: 90.7% (2.8 g as a pale-yellow oil);
(500 MHz, CDCl3) δ 8.11 (d, 1H, J = 3.4 Hz), 7.73 (d, 1H, J = 4.4
Hz), 7.35−7.33 (m, 5H), 7.17−7.15 (m, 1H), 4.86 (d, 1H, Jcp = 19.2
Hz), 4.83 (d, 1H, J = 11.4 Hz), 4.60 (d, 1H, J = 11.8 Hz), 4.23−4.13
(m, 4H), 1.30 (t, 3H, J = 7.3 Hz), 1.27 (t, 3H, J = 7.3 Hz).; 13C NMR
(75 MHz, CDCl3) δ 187.5, 141.4, 136.1, 135.3, 135.3, 128.7, 128.6,
128.5, 128.3, 81.2 (d, Jcp = 151.5 Hz), 74.4 (d, Jcp = 12.7 Hz), 63.9 (d,
Jcp = 6.7 Hz), 63.8 (d, Jcp = 6.8 Hz), 16.4 (d, Jcp = 6.2 Hz).; HRMS
(EI): m/z calcd for C17H21O5PS 368.0847, found 368.0842.
1H NMR (500 MHz, CDCl3) δ 8.12−8.10 (m, 4H), 7.33−7.27 (m,
5H), 5.09 (d, 1H, Jcp = 20.3 Hz), 4.75 (d, 1H, J = 11.8 Hz), 4.60 (d,
1H, J = 11.8 Hz), 4.23−4.16 (m, 4H), 3.97 (s, 1H), 1.28 (t, 3H, J = 7.1
Hz), 1.23 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 194.9,
166.2, 138.8, 135.9, 134.1, 129.5, 129.3, 128.6, 128.6, 128.5, 80.5 (d, Jcp
= 151.1 Hz), 74.2 (d, Jcp = 12.3 Hz), 63.9 (d, Jcp = 6.8 Hz), 63.6 (d, Jcp
= 6.9 Hz), 52.5, 16.3 (d, Jcp = 5.4 Hz), 16.2 (d, Jcp = 5.3 Hz).; HRMS
(EI): m/z calcd for C21H25O7P 420.1338, found 420.1333.
2.19. Diethyl [1-benzyloxy-2-oxo-2-(pyridin-2-yl)-ethyl]-
phosphonate, 3s: yield: 89.0% (1.3 g as a pale-yellow oil); 1H
2.15. Diethyl [1-benzyloxy-2-(naphthalen-2-yl)-2-oxo-ethyl]-
phosphonate, 3o: yield: 94.0% (1.1 g as a pale-yellow oil); 1H
NMR (500 MHz, CDCl3) δ 8.67 (d, 1H, J = 3.8 Hz), 8.04 (d, 1H, J =
8.1 Hz), 7.87−7.84 (m, 1H), 7.51−7.49 (m, 1H), 7.42−7.40 (m, 2H),
7.35−7.31 (m, 1H), 6.40 (d, 1H, Jcp = 19.7 Hz), 4.81 (d, 1H, J = 11.6
Hz), 4.71 (d, 1H, J = 11.9 Hz), 4.25−4.19 (m, 2H), 4.11−4.07 (m,
2H), 1.30 (t, 3H, J = 7.1 Hz), 1.10 (t, 3H, J = 7.1 Hz).; 13C NMR (75
MHz, CDCl3) δ 195.5, 153.0, 148.8, 137.0, 128.5, 128.2, 127.6, 122.5,
76.9 (d, Jcp = 149.7 Hz), 74.2 (d, Jcp = 11.0 Hz), 63.8 (d, Jcp = 6.7 Hz),
63.3 (d, Jcp = 6.5 Hz), 16.4 (d, Jcp = 6.1 Hz), 16.2 (d, Jcp = 6.4 Hz).;
HRMS (EI): m/z calcd for C18H22NO5P 363.1236, found 363.1234.
2.20. Diethyl [1-benzyloxy-2-oxo-2-(pyridin-3-yl)-ethyl]-
phosphonate, 3t: yield: 95.9% (1.1 g as a pale-yellow oil); 1H
NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.08 (d, 1H, J = 8.6 Hz),
7.97 (d, 1H, J = 8.1 Hz), 7.91−7.89 (m, 2H), 7.64 (t, 1H, J = 7.6 Hz),
7.59 (t, 1H, J = 7.6 Hz), 7.33 (s, 5H), 5.26 (d, 1H, Jcp = 19.9 Hz), 4.83
(d, 1H, Jcp = 11.9 Hz), 4.62 (d, 1H, Jcp = 11.9 Hz), 4.22−4.13 (m, 4H),
1.30 (t, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz,
CDCl3) δ 194.7, 136.2, 135.8, 132.9, 132.3, 131.8, 130.0, 128.8, 128.5,
128.4, 128.2, 127.7, 126.7, 124.6, 80.2 (d, Jcp = 151.3 Hz), 74.0 (d, Jcp =
12.5 Hz), 63.8(d, Jcp = 7.0 Hz), 63.5 (d, Jcp = 7.1 Hz), 16.3 (d, Jcp = 6.1
Hz), 16.2 (d, Jcp = 6.1 Hz).; HRMS (EI): m/z calcd for C23H25O5P
412.1440, found 412.1430.
2.16. Diethyl [1-benzyloxy-2-(naphthalen-1-yl)-2-oxo-ethyl]-
phosphonate, 3p: yield: 81.0% (930 mg as a pale-yellow solid);
NMR (500 MHz, CDCl3) δ 9.19 (d, 1H, J = 1.4 Hz), 8.79 (dd, 1H, J =
1.8 Hz, J = 8.0 Hz), 7.41−7.39 (m, 1H), 7.32−7.27 (m, 5H), 4.99 (d,
1H, Jcp = 20.4 Hz), 4.74 (d, 1H, J = 11.8 Hz), 4.64 (d, 1H, J = 11.8
Hz), 4.22−4.15 (m, 4H), 1.31 (t, 3H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.1
Hz).; 13C NMR (75 MHz, CDCl3) δ 194.6 (d, Jcp = 1.4 Hz), 153.7,
150.7, 137.1, 135.8, 131.0, 128.7, 128.7, 123.3, 81.2 (d, Jcp = 150.9 Hz),
74.5 (d, Jcp = 12.0 Hz), 64.0 (d, Jcp = 6.8 Hz), 63.9 (d, Jcp = 6.9 Hz),
16.4 (d, Jcp = 5.9 Hz), 16.3 (d, Jcp = 6.0 Hz).; HRMS (EI): m/z calcd
for C18H22NO5P 363.1236, found 363.1236.
1
mp: 76−79 °C; H NMR (500 MHz, CDCl3) δ 8.39 (d, 1H, J = 8.4
Hz), 8.01 (d, 1H, J = 8.2 Hz), 7.88 (d, 1H, J = 8.0 Hz), 7.76 (d, 1H,
J = 7.2 Hz), 7.59−7.55 (m, 2H), 7.48 (t, 1H, J = 7.8 Hz), 7.35 (s, 5H),
5.22 (d, 1H, Jcp = 21.2 Hz), 4.87 (d, 1H, Jcp = 12.0 Hz), 4.73 (d, 1H,
Jcp = 12.0 Hz), 4.18−4.15 (m, 2H), 4.01−3.98 (m, 2H), 1.26 (t, 3H,
J = 7.0 Hz), 0.99 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ
197.7, 136.3, 134.4, 133.8, 132.9, 130.3, 128.6, 128.6, 128.4, 128.4,
128.3, 128.0, 126.5, 125.4, 124.1, 80.9 (d, Jcp = 151.9 Hz), 73.8 (d, Jcp =
11.7 Hz), 63.8 (d, Jcp = 6.6 Hz), 63.2 (d, Jcp = 7.2 Hz), 16.3 (d, Jcp = 5.7
Hz), 15.9 (d, Jcp = 6.2 Hz).; HRMS (EI): m/z calcd for C23H25O5P
412.1440, found 412.1427.
2.21. Diethyl [1-benzyloxy-2-oxo-2-(pyridin-4-yl)-ethyl]-
phosphonate, 3u: yield: 93.6% (1.2 g as a pale yellow oil); 1H
NMR (500 MHz, CDCl3) δ 8.80 (d, 2H, J = 6.0 Hz), 7.81 (dd, 2H, J =
1.5 Hz, J = 4.5 Hz), 7.34−7.26 (m, 5H), 5.00 (d, 1H, Jcp = 20.5 Hz), 4.72
(d, 1H, J = 11.8 Hz), 4.63 (d, 1H, J = 11.8 Hz), 4.22−4.14 (m, 4H), 1.31
(t, 3H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz,
CDCl3) δ 195.4 (d, Jcp = 1.1 Hz), 150.7, 141.4, 135.7, 128.7, 122.2, 80.8
(d, Jcp = 151.1 Hz), 74.5 (d, Jcp = 11.8 Hz), 64.0 (d, Jcp = 7.1 Hz), 63.9 (d,
Jcp = 8.2 Hz), 16.4 (d, Jcp = 5.8 Hz), 16.3 (d, Jcp = 5.9 Hz).; HRMS (EI):
m/z calcd for C18H22NO5P 363.1236, found 363.1236.
2.17. Diethyl [1-benzyloxy-2-(furan-2-yl)-2-oxo-ethyl]-
1
phosphonate, 3q: yield: 76.2% (2.5 g as a light-pink oil); H NMR
2.22. Diethyl [1-(benzyloxy)-2-oxopropyl]phosphonate, 3v: yield:
(500 MHz, CDCl3) δ 7.66 (s, 1H), 7.51 (d, 1H, J = 3.5 Hz), 7.35−
7.29 (m, 5H), 6.58 (d, 1H, J = 2.0 Hz), 4.96 (d, 1H, Jcp = 19.2 Hz),
4.81 (d, 1H, J = 11.8 Hz), 4.61 (d, 1H, J = 11.8 Hz), 4.22−4.15 (m,
4H), 1.31 (t, 3H, J = 7.0 Hz), 1.27 (t, 3H, J = 7.0 Hz).; 13C NMR (75
MHz, CDCl3) δ 182.7, 151.1, 147.5, 136.2, 128.6, 128.6, 128.5, 121.0,
78.0% (1.6 g as a coloress oil); 1H NMR (500 MHz, CDCl3) δ
112.7, 79.6 (d, Jcp = 152.1 Hz), 74.2 (d, Jcp = 12.2 Hz), 63.9 (d, Jcp
=
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7.40−7.29 (m, 5H), 4.76 (d, 1H, J = 11.8 Hz), 4.67 (d, 1H, J = 11.8
Hz), 4.32 (d, 1H, Jcp = 19.4 Hz), 4.24−4.17 (m, 4H), 1.35 (t, 3H, J =
7.1 Hz).; 13C NMR (125 MHz, CDCl3) δ 203.1, 135.8, 128.1, 127.8,
NMR (500 MHz, CDCl3) δ 7.78 (d, 1H, J = 16.0 Hz), 7.62−7.61 (m,
2H), 7.44−7.33 (m, 8H), 7.26 (d, 1H, J = 16.0 Hz), 4.82 (d, 1H, J =
11.9 Hz), 4.66 (d, 1H, J = 11.8 Hz), 4.52 (d, 1H, Jcp = 19.4 Hz), 4.25−
4.18 (m, 4H), 1.35 (m, 6H).; 13C NMR (75 MHz, CDCl3) δ 194.1,
144.3, 136.2, 134.4, 130.9, 128.9, 128.8, 128.6, 128.5, 128.4, 121.6, 81.8
(d, Jcp = 150.0 Hz), 74.2 (d, Jcp = 11.9 Hz), 63.6 (d, Jcp = 6.6 Hz), 63.5
(d, Jcp = 6.6 Hz), 16.4 (d, Jcp = 5.9 Hz).; HRMS (EI): m/z calcd for
C21H25O5P 388.1440, found 388.1419.
127.8, 81.6 (d, Jcp = 150.0 Hz), 73.7 (d, Jcp = 10.0 Hz), 63.0 (d, Jcp
=
6.3 Hz), 27.0, 15.8 (d, Jcp = 5.0 Hz).; HRMS (EI): m/z calcd for
C14H21O5P 300.1127, found 300.1103.
2.23. Diethyl [1-(benzyloxy)-2-oxobutyl]phosphonate, 3w: yield:
54.0% (1.1 g as a coloress oil); 1H NMR (500 MHz, CDCl3) δ 7.40−
3. General Procedure for the ATH-DKR of α-Alkoxy β-
Ketophosphonates (3) to the α-Alkoxy β-Hydroxy Phosphonates
(4). The solution of α-alkoxy-β-ketophosphonate (3, 1 mmol, 1 equiv)
and (R,R)-5e catalyst (3.1 mg, 0.005 mmol, 0.005 equiv) in Et3N (2.85
mL, 20 equiv) was stirred for 10 min at room temperature. The formic
acid (0.15 mL, 4 equiv) was slowly added by syringe and the resulting
mixture was then purged with nitrogen. The mixture was allowed to
react at 35 °C. After complete consumption of β-ketophosphonate, the
reaction mixture was diluted with EtOAc (50 mL) and washed with
water (10 mL), saturated aqueous NaHCO3 and brine. The solution
was dried over anhydrous MgSO4, and concentrated under reduced
pressure to afford the product. The product was subjected to short
path column of SiO2 to remove colored impurity.
7.33 (m, 5H), 4.74 (d, 1H, J = 11.8 Hz), 4.66 (d, 1H, J = 11.8 Hz),
4.35 (d, 1H, Jcp = 19.3 Hz), 4.25−4.18 (m, 4H), 2.79−2.71 (m, 1H),
2.66−2.58 (m, 1H), 1.35 (t, 6H, J = 7.0 Hz), 1.06 (t, 3H, J = 7.2 Hz).;
13C NMR (125 MHz, CDCl3) δ 206.2 (d, Jcp = 3.8 Hz), 136.0, 128.3
(d, Jcp = 1.3 Hz), 128.1, 128.1 (d, Jcp = 1.3 Hz), 81.4 (d, Jcp = 150.0
Hz), 63.3 (d, Jcp = 3.8 Hz), 63.3 (d, Jcp = 1.3 Hz), 33.1 (d, Jcp = 16.3
Hz), 33.0 (d, Jcp = 1.3 Hz), 16.1 (d, Jcp = 6.3 Hz), 6.98.; HRMS (EI):
m/z calcd for C15H23O5P 314.1283, found 314.1277.
3.1. Diethyl (1S,2S)-(1-benzyloxy-2-hydroxy-2-phenyl-ethyl)-
phosphonate, (1S,2S)-4a: yield: 99.5% (362 mg as coloress oil);
2.24. Diethyl [1-(benzyloxy)-2-cyclohexyl-2-oxo-ethyl]-
1
phosphonate, 3x: yield: 94.1% (1.1 g as a coloress oil); H NMR
(500 MHz, CDCl3) δ 7.38−7.34 (m, 5H), 4.76 (d, 1H, J = 12.0 Hz),
4.59 (d, 1H, J = 12.0 Hz), 4.51 (d, 1H, Jcp = 20.1 Hz), 4.24−4.15 (m,
4H), 2.89−2.85 (m, 1H), 1.80−1.73 (m, 4H), 1.69−1.65 (m, 1H),
1.50−1.45 (m, 1H), 1.34 (q, 6H, J = 7.1 Hz), 1.30−1.19 (m, 4H).; 13C
NMR (125 MHz, CDCl3) δ 208.1 (d, Jcp = 1.7 Hz), 136.4, 128.5,
dr = >99:1; >99% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm tR (minor) = 7.9 min, tR (major) = 10.9 min.);
1
[α]24 = +67.1 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.43
D
(d, 2H, J = 7.3 Hz), 7.37−7.28 (m, 6H), 7.18−7.15 (m, 2H), 5.11 (dd,
1H, J = 4.4 Hz, J = 10.4 Hz), 4.70 (d, 1H, J = 11.1 Hz), 4.37 (d, 1H,
J = 11.1 Hz), 4.21−4.02 (m, 4H), 3.91 (dd, 1H, J = 7.9 Hz, J = 3.8
Hz), 1.33 (t, 3H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz).; 13C NMR (125
MHz, CDCl3) δ 140.4, 140.3, 136.7, 128.4, 128.4, 128.2, 128.1, 127.8,
128.3, 80.3 (d, Jcp = 149.0 Hz), 73.8 (d, Jcp = 10.2 Hz), 63.5 (d, Jcp
=
6.7 Hz), 63.4 (d, Jcp =6.9 Hz), 47.7, 29.2, 27.5, 25.8, 25.7, 25.1, 16.4 (d,
Jcp = 4.3 Hz).; HRMS (EI): m/z calcd for C19H29O5P 368.1753, found
368.1754.
126.7, 79.1 (d, Jcp = 160.2 Hz), 75.1 (d, Jcp = 12.5 Hz), 72.4 (d, Jcp
=
2.25. Diethyl (1-benzyloxy-2-oxo-4-phenyl-butyl)phosphonate,
4.0 Hz), 62.9 (d, Jcp = 7.1 Hz), 62.4 (d, Jcp = 6.8 Hz), 16.5 (d, Jcp = 6.0
Hz), 16.3 (d, Jcp = 5.6 Hz).; HRMS (ESI-TOF): m/z [M + Na]+ calcd
for C19H25O5NaP 387.1337, found 387.1336.
1
3y: yield: 92.3% (2.5 g as a pale yellow oil); H NMR (500 MHz,
3.2. Diethyl (1R,2R)-(1-benzyloxy-2-hydroxy-2-phenyl-ethyl)-
phosphonate, (1R,2R)-4a: yield: 98.4% (359 mg as coloress oil);
CDCl3) δ 7.36−7.28 (m, 7H), 7.22−7.19 (m, 3H), 4.67 (d, 1H, J = 11.9
Hz), 4.57 (d, 1H, J = 11.9 Hz), 4.30 (d, 1H, Jcp = 19.4 Hz), 4.22−4.11
(m, 4H), 3.09−3.03 (m, 1H), 2.97−2.90 (m, 3H), 1.32 (t, 6H, J = 7.1
Hz).; 13C NMR (75 MHz, CDCl3) δ 205.0, 140.8, 136.2, 128.6, 128.5,
128.4, 128.4, 126.1, 81.9 (d, Jcp = 149.0 Hz), 74.2 (d, Jcp = 10.0 Hz), 63.6
(d, Jcp = 6.7 Hz), 63.5 (d, Jcp = 6.7 Hz), 41.3, 29.2, 16.4(d, Jcp = 5.8 Hz).;
HRMS (EI): m/z calcd for C21H27O5P 390.1596, found 390.1601.
2.-26. Dimethyl (1-methoxy-2-oxo-4-phenyl-butyl)phosphonate,
dr = >99:1; >99% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm tR (major) = 7.9 min, tR (minor) = 10.9 min.);
1
[α]23 = −66.6 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.43
D
(d, 2H, J = 7.4 Hz), 7.38−7.29 (m, 6H), 7.17 (bs, 2H), 5.11 (bs, 1H),
4.70 (d, 1H, J = 11.1 Hz), 4.37 (d, 1H, J = 11.1 Hz), 4.12−4.04 (m,
4H), 3.92−3.90 (m, 1H), 1.34 (t, 3H, J = 7.0 Hz), 1.27 (t, 3H, J = 7.2 Hz).
3.3. Diethyl (1S,2S)-(1-methoxy-2-hydroxy-2-phenyl-ethyl)-
phosphonate, (1S,2S)-4b: yield: 98.2% (383 mg as coloress oil); dr =
1
3z: yield: 54.0% (1.2 g as a pale yellow oil); H NMR (500 MHz,
CDCl3) δ 7.31−7.29 (m, 2H), 7.24−7.19 (m, 3H), 4.15 (d, 1H, J =
19.4 Hz), 3.82 (d, 3H, J = 11.1 Hz), 3.80 (d, 3H, Jcp = 11.1 Hz), 3.46
(s, 3H), 3.08−2.95 (m, 4H).; 13C NMR (125 MHz, CDCl3) δ 205.0,
140.7, 128.5, 128.5, 126.2, 85.0 (d, Jcp = 149.5 Hz), 60.7 (d, Jcp = 10.6
Hz), 54.0 (d, Jcp = 6.6 Hz), 63.8 (d, Jcp= 7.1 Hz), 41.1, 29.2.; HRMS
(EI): m/z calcd for C13H19O5P 286.0970, found 286.0963.
>99:1; 99.4% ee: Chiralpak IC, 30% isopropanol/n-hexane, 1.0 mL/min,
215 nm tR (major) = 15.9 min, tR (minor) = 17.9 min.); [α]24
=
D
+40.5 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 2H, J =
7.6 Hz), 7.38 (t, 2H, J = 7.4 Hz), 7.33−7.32 (m, 1H), 5.07 (d, 1H, J =
4.3 Hz), 4.18−4.07 (m, 4H), 3.65 (dd, 1H, J = 3.8 Hz, J = 8.4 Hz),
3.52 (d, 1H, J = 4.1 Hz), 3.41 (s, 3H), 1.34 (t, 3H, J = 7.1 Hz), 1.28 (t,
3H, J = 7.0 Hz).; 13C NMR (125 MHz, CDCl3) δ 140.2 (d, Jcp = 10.0
Hz), 128.2, 127.8, 126.7, 81.9 (d, Jcp = 160.9 Hz), 72.4 (d, Jcp = 5.1
Hz), 63.0 (d, Jcp = 6.6 Hz), 62.3 (d, Jcp = 7.3 Hz), 61.7 (d, Jcp = 3.6 Hz),
2.27. Diethyl (1-benzyloxy-2-oxo-4-phenyl-but-3-enyl)-
phosphonate, 3ab: Yield: 75.3% (1.1 g as a pale yellow oil); 1H
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16.4 (d, Jcp = 5.3 Hz), 16.4 (d, Jcp = 5.4 Hz).; HRMS (EI): m/z calcd
for C13H21O5P 288.1127, found 288.1119.
3.4. Dimethyl (1S,2S)-(1-methoxy-2-hydroxy-2-phenyl-methyl)-
phosphonate, (1S,2S)-4c: yield: 98.0% (255 mg as coloress oil);
[α]26D = +78.6 (c 1.0, CHCl3).; 1H NMR (500 MHz, CDCl3) δ 7.34−
7.28 (m, 7H), 7.14−7.13 (m, 2H), 5.07−5.05 (m, 1H), 4.72 (d, 1H,
J = 11.2 Hz), 4.39 (d, 1H, J = 11.3 Hz), 4.19−4.07 (m, 4H), 3.84 (dd,
1H, J = 3.6 Hz, J = 7.5 Hz), 3.66 (t, 1H, J = 4.4 Hz), 1.35 (t, 3H, J =
7.0 Hz), 1.28 (t, 3H, J = 7.0 Hz).; 13C NMR (75 MHz, CDCl3) δ
138.9 (d, Jcp = 10.5 Hz), 136.5, 133.6, 128.6, 128.5, 128.4, 128.3, 128.2,
78.6 (d, Jcp = 158.5 Hz), 75.0 (d, Jcp = 2.7 Hz), 72.0 (d, Jcp = 4.0 Hz),
63.2 (d, Jcp = 7.0 Hz), 62.6 (d, Jcp = 7.1 Hz), 16.6 (d, Jcp = 5.6 Hz), 16.5
(d, Jcp = 5.6 Hz).; HRMS (EI): m/z calcd for C19H24ClO5P 398.1050,
found 398.1053.
dr = >99:1; 99.5% ee: Chiralpak IC, 30% isopropanol/n-hexane,
1.0 mL/min, 215 nm tR (major) = 16.9 min, tR (minor) = 20.5 min;
3.8. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(m-tolyl)-ethyl]-
phosphonate, (1S,2S)-4h: yield: 98.2% (372 mg as a pale-yellow
1
[α]24 = +42.8 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3) δ 7.47
D
(d, 2H, J = 7.6 Hz), 7.39 (t, 2H, J = 7.4 Hz), 7.34−7.32 (m, 1H), 5.09
(bs, 1H), 3.76 (d, 6H, J = 10.6 Hz), 3.69 (dd, 1H, J = 3.3 Hz, J = 8.5
Hz), 3.42 (bs, 1H), 3.39 (s, 3H).; 13C NMR (125 MHz, CDCl3) δ
140.1 (d, Jcp = 10.4 Hz), 128.3, 127.9, 126.6, 81.9 (d, Jcp = 160.7 Hz),
72.3 (d, Jcp = 4.9 Hz), 61.6 (d, Jcp = 6.5 Hz), 53.5 (d, Jcp = 6.5 Hz), 52.6
(d, Jcp = 7.3 Hz).; HRMS (EI): m/z calcd for C11H17O5P 260.0814,
found 260.0834.
oil); dr =99:1; >99% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 6.9 min, tR (major) = 8.5 min;
[α]25D = +67.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.30−
7.12 (m, 9H), 5.09−5.07 (m, 1H), 4.70 (d, 1H, J = 11.1 Hz), 4.35 (d,
1H, J = 11.1 Hz), 4.21−4.07 (m, 4H), 3.91−3.89 (m, 1H), 3.48 (d,
1H, J = 4.7 Hz), 2.36 (s, 1H), 1.35 (t, 3H, J = 7.1 Hz), 1.29 (t, 3H, J =
7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 140.4, 140.3, 137.9, 136.9,
128.6, 128.4, 128.2, 128.2, 127.5, 123.8, 79.2 (d, Jcp = 160.2 Hz), 75.3
(d, Jcp = 3.2 Hz), 72.5 (d, Jcp = 4.0 Hz), 63.1 (d, Jcp = 6.8 Hz), 62.5 (d,
Jcp = 7.1 Hz), 21.6, 16.7 (d, Jcp = 2.4 Hz), 16.5 (d, Jcp = 3.2 Hz).;
HRMS (EI): m/z calcd for C20H27O5P 378.1596, found 378.1602.
3.9. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(p-tolyl)-ethyl]-
phosphonate, (1S,2S)-4i: yield: 98.6% (373 mg as a pale-yellow
3.5. Diethyl [1-benzyloxy-2-(2-chloro-phenyl)-2-hydroxy-ethyl]-
phosphonate, 4d: yield: 97.0% (387 mg as white solid); dr =
60:40; diastereomers are inseparable by silica gel chromatography.
major isomer (60%); 82% ee: Chiralpak AD-H, 30% isopropanol/
n-hexane, 0.5 mL/min, 254 nm, tR (minor) = 10.5 min, tR (major) =
13.2 min; 1H NMR (500 MHz, CDCl3) δ 7.67 (dd, 1H, J = 1.6 Hz, J =
7.7 Hz), 7.34−7.19 (m, 8H), 5,48 (br s, 1H), 4.63 (d, 1H, J = 11.5
Hz), 4.50 (d, 1H, J = 11.5 Hz), 4.44 (d, 1H, J = 4.2 Hz), 4.32−4.21
(m, 2H), 4.05−3.94 (m, 3H), 1.35 (t, 3H, J = 7.0 Hz), 1.16 (d, 3H,
J = 7.0 Hz). minor isomer (40%); 47% ee: Chiralpak AD-H, 30%
isopropanol/n-hexane, 0.5 mL/min, 254 nm, tR (minor) = 9.6 min, tR
1
(major) = 14.2 min; H NMR (500 MHz, CDCl3) δ 7.74 (d, 1H, J =
7.7 Hz), 7.34−7.19 (m, 6H), 6.98 (d, 2H, J = 6.6 Hz), 5,51 (br s, 1H),
4.53 (d, 1H, J = 11.1 Hz), 4.32−4.21 (m, 4H), 4.17 (d, 1H, J = 11.1
Hz), 4.12 (dd, 1H, J = 1.8 Hz, J = 9.4 Hz), 3.84 (br s, 1H), 1.43−1.33
(m, 6H).; HRMS (EI): m/z calcd for C19H24ClO5P 398.1050, found
398.1036.
oil); dr = 99:1; 99.5% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 8.9 min, tR (major) = 12.3 min;
[α]23D = +68.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.32−
7.29 (m, 5H), 7.18−7.15 (m, 4H), 5.08 (br, 1H), 4.70 (d, 1H, J = 11.1
Hz), 4.38 (d, 1H, J = 11.1 Hz), 4.18−4.04 (m, 4H), 3.90−3.88 (m,
1H), 3.49 (br, 1H), 2.37 (s, 1H), 1.33 (t, 3H, J = 7.0 Hz), 1.26 (t, 3H,
J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 137.5, 137.3, 136.9, 128.9,
128.5, 128.4, 128.1, 126.7, 79.3 (d, Jcp = 159.9 Hz), 75.2 (d, Jcp = 3.2
Hz), 72.4 (d, Jcp = 4.3 Hz), 63.0 (d, Jcp = 6.9 Hz), 62.4 (d, Jcp = 7.1 Hz),
21.2, 16.6 (d, Jcp = 5.7 Hz), 16.5 (d, Jcp = 5.7 Hz).; HRMS (EI): m/z
calcd for C20H27O5P 378.1596, found 378.1592.
3.6. Diethyl (1S,2S)-[1-benzyloxy-2-(3-chloro-phenyl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4e: yield: 96.4% (384 mg as a pale-yellow
3.10. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(4-methoxy-phenyl)-
ethyl]phosphonate, (1S,2S)-4j: yield: 94.6% (373 mg as a pale-yellow
oil); dr = 99:1; >99% ee: Chiralpak AD-H, 10%isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 6.9 min, tR (major) = 8.5 min;
1
[α]24 = +61.3 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.42
D
(s, 1H), 7.29−7.26 (m, 6H), 5.06 (br, 1H), 4.71 (d, 1H, J = 11.1 Hz),
4.36 (d, 1H, J = 11.1 Hz), 4.21−4.10 (m, 4H), 3.84 (dd, 1H, J = 3.4
Hz, J = 7.7 Hz), 3.74 (br, 1H), 1.35 (t, 3H, J = 7.1 Hz), 1.29 (t, 3H, J =
7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 142.6 (d, Jcp = 10.9 Hz),
136.4, 134.2, 129.5, 128.6, 128.5, 128.3, 127.9, 127.1, 124.9, 78.5 (d,
Jcp = 166.9 Hz), 75.1 (d, Jcp = 2.8 Hz), 72.0 (d, Jcp = 3.8 Hz), 63.2 (d,
Jcp = 6.8 Hz), 62.6 (d, Jcp = 7.1 Hz), 16.6 (d, Jcp = 5.7 Hz), 16.5 (d, Jcp =
5.6 Hz).; HRMS (EI): m/z calcd for C19H24ClO5P 398.1050, found
398.1043.
oil); dr = 99:1; 98.7% ee: Chiralpak AD-H, 10% isopropanol/n-
hexane, 1.5 mL/min, 254 nm, tR (minor) = 14.5 min, tR (major) = 17.2
1
min; [α]25 = +73.6 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.34 (d, 2H, J = 8.6 Hz), 7.30−7.29 (m, 3H), 7.21−7.20 (m, 2H), 6.88
(d, 2H, J = 8.6 Hz), 5.06−5.03 (m, 1H), 4.72 (d, 1H, J = 11.1 Hz),
4.40 (d, 1H, J = 11.1 Hz), 4.17−4.03 (m, 4H), 3.87−3.84 (m, 1H),
3.83 (s, 1H), 3.51−3.50 (m, 1H), 1.32 (t, 3H, J = 7.1 Hz), 1.26 (t, 3H,
J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 159.4, 136.9, 132.4 (d, Jcp
= 9.7 Hz), 128.5, 128.4, 128.1, 128.0, 113.7, 79.3 (d, Jcp = 159.5 Hz),
75.2 (d, Jcp = 3.1 Hz), 72.2 (d, Jcp = 4.6 Hz), 63.0 (d, Jcp = 6.8 Hz), 62.4
(d, Jcp = 7.0 Hz), 55.4, 16.6 (d, Jcp = 5.7 Hz), 16.5 (d, Jcp = 5.7 Hz).;
HRMS (EI): m/z calcd for C20H27O6P 394.1545, found 394.1547.
3.11. Diethyl (1S,2S)-[1-benzyloxy-2-(4-fluoro-phenyl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4k: yield: 94.1% (360 mg as a pale-yellow
oil); dr = 99:1; 99.5% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
3.7. Diethyl (1S,2S)-[1-benzyloxy-2-(4-chloro-phenyl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4f: yield: 99.5% (397 mg as a pale-yellow
oil); dr = 99:1; 99.6% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 8.4 min, tR (major) = 10.6 min;
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4H), 3.95 (s, 3H), 3.90 (dd, 1H, J = 3.4 Hz, J = 8.0 Hz), 3.74 (d, 1H,
J = 4.6 Hz), 1.36 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz).; 13C
NMR (75 MHz, CDCl3) δ 167.0, 145.6 (d, Jcp = 11.0 Hz), 136.3,
129.5, 129.4, 128.4, 128.2, 126.6, 78.4 (d, Jcp = 160.6 Hz), 75.0 (d, Jcp =
3.0 Hz), 72.2 (d, Jcp = 3.7 Hz), 63.2 (d, Jcp = 6.8 Hz), 62.6 (d, Jcp = 7.1
Hz), 52.1, 16.5 (d, Jcp = 5.6 Hz), 16.5 (d, Jcp = 5.6 Hz).; HRMS (EI):
m/z calcd for C21H27O7P 422.1494, found 422.1478.
1.5 mL/min, 254 nm, tR (minor) = 6.8 min, tR (major) = 9.8 min;
1
[α]26D= +86.5 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) δ 7.40−
7.37 (d, 2H), 7.31−7.29 (m, 3H), 7.18−7.17 (m, 2H), 7.03 (t, 2H, J =
8.7 Hz), 5.09−5.06 (m, 1H), 4.75 (d, 1H, J = 11.2 Hz), 4.40 (d, 1H,
J = 11.2 Hz), 4.21−4.05 (m, 4H), 3.86−3.83 (m, 1H), 3.60 (d, 1H, J =
4.4 Hz), 1.35 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz).; 13C NMR
(75 MHz, CDCl3) δ 162.5 (d, Jcf = 244.1 Hz), 136.7, 136.0, 128.5 (d,
Jcf = 8.0 Hz), 128.5, 128.5, 128.3, 115.1 (d, Jcf = 21.3 Hz), 78.9 (d, Jcp =
3.15. Diethyl (1S,2S)-[1-benzyloxy-2-(naphthalen-2-yl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4o: yield: 99.5% (412 mg as a pale-yellow
159.8 Hz), 75.1 (d, Jcp = 2.7 Hz), 72.1 (d, Jcp = 4.4 Hz), 63.1 (d, Jcp
=
7.0 Hz), 62.6 (d, Jcp = 7.3 Hz), 16.6 (d, Jcp = 5.6 Hz), 16.6 (d, Jcp = 5.6
Hz).; HRMS (EI): m/z calcd for C19H24FO5P 382.1345, found
382.1347.
3.12. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(4-nitro-phenyl)-
ethyl]phosphonate, (1S,2S)-4l: yield: 97.8% (400 mg as a pale-yellow
solid); mp: 68−72 °C; dr = 99:1; >99% ee: Chiralpak AD-H, 10%
isopropanol/n-hexane, 1.0 mL/min, 254 nm, tR (minor) = 19.0 min, tR
1
(major) = 23.4 min; [α]21 = +23.9 (c 0.4, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.92 (s, 1H), 7.86−7.80 (m, 3H), 7.51−7.48 (m, 3H),
7.23−7.20 (m, 1H), 7.16 (t, 2H, J = 7.3 Hz), 7.06 (d, 2H, J = 7.4 Hz),
5.28 (d, 1H, J = 3.0 Hz), 4.67 (d, 1H, J = 11.1 Hz), 4.33 (d, 1H, J =
11.1 Hz), 4.20−4.09 (m, 4H), 4.00 (dd, 1H, J = 6.0 Hz, J = 1.8 Hz),
3.70 (br, 1H), 1.34 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz).; 13C
NMR (125 MHz, CDCl3) δ 137.8 (d, Jcp = 11.2 Hz), 136.5, 133.2,
133.1, 128.5 128.2, 128.1, 128.0, 127.8, 127.6, 126.1, 125.9, 125.7,
124.5, 78.8 (d, Jcp = 160.4 Hz), 75.1 (d, Jcp = 3.0 Hz), 72.5 (d, Jcp = 4.0
Hz), 63.1 (d, Jcp = 6.6 Hz), 62.5 (d, Jcp = 7.1 Hz), 16.5 (d, Jcp = 5.9 Hz),
16.4 (d, Jcp = 6.0 Hz).; HRMS (EI): m/z calcd for C23H27O5P
414.1596, found 414.1591.
oil); dr =98:2; 98.0% ee: Chiralpak AD-H, 20% isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 6.8 min, tR (major) = 8.8 min;
[α]25D = +71.6 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.13(d,
2H, J = 8.5 Hz), 7.52 (d, 2H, J = 8.5 Hz), 7.29−7.22 (m, 3H), 7.06 (d,
2H, J = 7.0 Hz), 5.18−5.16 (m, 1H), 4.72 (d, 1H, J = 11.0 Hz), 4.36
(d, 1H, J = 11.0 Hz), 4.24−4.14 (m, 4H), 3.92 (d, 1H, J = 4.5 Hz),
3.89 (dd, 1H, J = 3.0 Hz, J = 7.5 Hz), 1.39 (t, 3H, J = 7.0 Hz), 1.31 (t,
3H, J = 7.0 Hz).; 13C NMR (75 MHz, CDCl3) δ 147.8, 147.4, 135.9,
128.6, 128.4, 128.3, 127.4, 123.2, 77.7 (d, Jcp = 159.4 Hz), 74.7 (d, Jcp =
2.3 Hz), 71.9 (d, Jcp = 3.4 Hz), 63.4 (d, Jcp = 6.9 Hz), 62.7 (d, Jcp = 7.1
Hz), 16.5 (d, Jcp = 5.5 Hz), 16.5 (d, Jcp = 5.5 Hz).; HRMS (ESI): m/z
calcd for C19H24NO7NaP 432.1188, found 432.1183.
3.16. Diethyl [1-benzyloxy-2-hydroxy-2-(naphthalen-1-yl)-ethyl)-
phosphonate, 4p: dr = 57:43; diastereomers are inseparable by silica
gel chromatography.
3.13. Diethyl (1S,2S)-[1-benzyloxy-2-(4-cyano-phenyl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4m: yield: 99.8% (389 mg as a pale-
major isomer (57%); 53% ee: Chiralpak IC, 20% isopropanol/
n-hexane, 1.5 mL/min, 254 nm, tR (minor) = 18.0 min, tR (major) =
20.0 min. minor isomer (43%); 47% ee: Chiralpak IC, 20%
isopropanol/n-hexane, 1.5 mL/min, 254 nm, tR (minor) = 11.8 min,
tR (major) = 14.9 min. HRMS (EI): m/z calcd for C23H27O5P
414.1596, found 414.1583.
3.17. Diethyl (1S,2S)-[1-benzyloxy-2-(furan-2-yl)-2-hydroxy-
ethyl]phosphonate, (1S,2S)-4q: yield: 98.4% (349 mg as a pale-
yellow oil); dr = 99:1; 99.3% ee: Chiralpak AD-H, 0.8% isopropanol/
n-hexane, 1.6 mL/min, 254 nm, tR (minor) = 14.7 min, tR (major) =
17.7 min; [α]27 = +63.3 (c 0.3, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 7.59 (d, 2H, J = 7.6 Hz), 7.48 (d, 2H, J = 8.1 Hz), 7.31−7.26
(m, 4H), 7.08 (d, 2H, J = 6.9 Hz), 5.13−5.10 (m, 1H), 4.72 (d, 1H, J =
11.3 Hz), 4.37 (d, 1H, J = 11.4 Hz), 4.24−4.10 (m, 4H), 3.87 (dd, 1H,
J = 7.4 Hz, J = 3.2 Hz), 3.81 (d, 1H, J = 4.8 Hz), 1.38 (t, 3H, J = 7.1
Hz), 1.30 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 146.0,
yellow oil); dr = 99:1; >99% ee: Chiralpak AD-H, 20% isopropanol/
n-hexane, 1.0 mL/min, 254 nm, tR (minor) = 6.9 min, tR (major) = 8.1
1
min; [α]21 = +48.5 (c 0.4 CHCl3); H NMR (500 MHz, CDCl3) δ
136.1, 132.0, 128.6, 128.6, 128.4, 127.5, 119.0, 111.5, 77.9 (d, Jcp
=
D
167.9 Hz), 74.9, 72.1 (d, Jcp = 3.4 Hz), 63.4 (d, Jcp = 7.0 Hz), 62.8 (d,
Jcp = 7.4 Hz), 16.6 (d, Jcp = 3.1 Hz).; HRMS (EI): m/z calcd for
C20H24NO5P 389.1392, found 389.1376.
3.14. Diethyl (1S,2S)-[1-benzyloxy-2-(4-carbomethoxy-phenyl)-2-
hydroxy-ethyl]phosphonate, (1S,2S)-4n: yield: 98.6% (416 mg as a
7.39−7.26 (m, 6H), 6.42−6.39 (m, 2H), 5.12−5.10 (m, 1H), 4.77 (d,
1H, J = 11.1 Hz), 4.52 (d, 1H, J = 11.1 Hz), 4.22−4.13 (m, 5H), 3.35
(d, 1H, J = 5.9 Hz), 1.35 (t, 3H, J = 6.6 Hz), 1.31 (t, 3H, J = 7.1 Hz).;
13C NMR (75 MHz, CDCl3) δ 153.0 (d, Jcp = 11.0 Hz), 153.0, 142.1,
137.0, 128.6, 128.3, 110.7, 108.0, 76.8 (d, Jcp = 162.8 Hz), 75.1 (d, Jcp =
3.5 Hz), 67.5 (d, Jcp = 4.6 Hz), 63.1 (d, Jcp = 7.1 Hz), 62.7 (d, Jcp = 6.9
Hz), 16.6 (d, Jcp = 4.1 Hz).; HRMS (EI): m/z calcd for C17H23O6P
354.1232, found 354.1229.
3.18. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(thiophen-2-yl)-ethyl]-
phosphonate, (1S,2S)-4r: yield: 97.1% (360 mg as a pale-yellow oil);
pale-yellow oil); dr = 99:1; >99% ee: Chiralpak IB, 10% isopropanol/
n-hexane, 1.5 mL/min, 254 nm, tR (major) = 13.5 min, tR (minor) =
18.3 min; [α]21 = +72.5 (c 0.4, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 8.01 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.3 Hz), 7.29−7.24
(m, 3H), 7.10 (dd, 2H, J = 1.4 Hz, J = 7.4 Hz), 5.16−5.14 (m, 1H),
4.67 (d, 1H, J = 11.2 Hz), 4.33 (d, 1H, J = 11.2 Hz), 4.21−4.07 (m,
dr = 99:1; >99% ee: Chiralpak AD-H, 10% isopropanol/n-hexane,
1.5 mL/min, 254 nm, tR (minor) = 8.0 min, tR (major) = 12.2 min;
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[α]25D = +47.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.36−
7.29 (m, 6H), 7.07 (d, 2H, J = 3.4 Hz), 7.00−6.99 (m, 1H), 5.39−5.35
(m, 1H), 4.83 (d, 1H, J = 11.0 Hz), 4.56 (d, 1H, J = 11.0 Hz), 4.21−
4.07 (m, 3H), 4.05−3.96 (m, 1H), 3.69 (d, 1H, J = 6.0 Hz), 1.35 (t,
3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz,
CDCl3) δ 144.1 (d, Jcp = 11.7 Hz), 136.9, 128.5, 128.5, 128.3, 126.6,
125.3, 124.9, 79.1 (d, Jcp = 159.9 Hz), 75.2 (d, Jcp = 3.0 Hz), 69.4 (d,
Jcp = 4.3 Hz), 63.1 (d, Jcp = 6.8 Hz), 62.6 (d, Jcp = 7.0 Hz), 16.6 (d,
Jcp = 5.7 Hz), 16.6 (d, Jcp = 5.7 Hz).; HRMS (EI): m/z calcd for
C17H23O5PS 370.1004, found 370.1003.
ID, 30% isopropanol/n-hexane, 1.0 mL/min, 254 nm, tR (minor) =
1
8.6 min, tR(major) = 10.1 min; [α]17 = +74.8 (c 0.9, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 8.53 (d, 2H, J = 6.0 Hz), 7.30−7.25 (m,
5H), 7.07−7.06 (m, 2H), 5.07 (dd, 1H, J = 3.0 Hz, J = 7.8 Hz), 4.70
(d, 1H, J = 11.4 Hz), 4.37 (d, 1H, J = 11.3 Hz), 4.23−4.09 (m, 5H),
3.91 (dd, 1H, J = 3.0 Hz, J = 7.7 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.30 (t,
3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ 149.6(d, Jcp = 14.0
Hz), 149.5, 136.0, 128.5, 128.4, 128.3, 121.5, 77.6 (d, Jcp = 161.1 Hz),
74.7 (d, Jcp = 2.6 Hz), 71.3 (d, Jcp = 3.1 Hz), 63.3 (d, Jc p= 6.8 Hz), 62.6
(d, Jcp = 7.0 Hz), 16.5 (d, Jcp = 5.5 Hz), 16.4 (d, Jcp = 4.1 Hz).; HRMS
(EI): m/z calcd for C18H24NO5P 365.1392, found 365.1382.
3-19. Diethyl [1-benzyloxy-2-hydroxy-2-(pyridin-2-yl)-ethyl]-
phosphonate, 4s: With (R,R)-5e catalyst and HCO2H/Et3N
3.22. Diethyl (1S,2S)-(1-benzyloxy-2-hydroxy-propyl)-
phosphonate, (1S,2S)-4v: yield: 99.3% (300 mg as a coloress oil);
(0.2:1): 31% conversion after 3.5 h; dr = 92:8; 81.7% ee; Chiralpak
IC, Hx/EtOH/DEA= 90:10:0.1, 1.5 mL/min, 215 nm, tR (minor) =
22.8 min, tR (major) = 26.0 min.
dr =96:4; 97.8% ee: Chiralpak IC, 20% isopropanol/n-hexane, 1.5 mL/
min, 215 nm, tR(minor) = 10.1 min, tR(major) = 13.2 min.); [α]17
=
D
1
+53.3 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3) δ 7.40−7.36 (m,
5H), 4.96 (d, 1H, J = 11.4 Hz), 4.63 (d, 1H, J = 11.3 Hz), 4.26−4.19
(m, 4H), 4.10 (bs, 1H), 3.59 (t, 1H, J = 5.2 Hz), 2.94 (d, 1H, J = 3.6
Hz), 1.38 (t, 6H, J = 7.1 Hz), 1.29 (d, 3H, J = 6.4 Hz).; 13C NMR (125
MHz, CDCl3) δ 137.1, 128.5, 128.5, 128.2, 79.0 (d, Jcp = 158.6 Hz),
74.8, 66.8 (d, Jcp = 4.4 Hz), 62.8 (d, J = 7.2 Hz), 62.4 (d, J = 7.1 Hz),
19.3 (d, J = 7.3 Hz), 16.5 (d, Jcp = 6.7 Hz).; HRMS (EI): m/z calcd for
C14H23O5P 302.1283, found 302.1263.
With (R,R)-5a catalyst and HCO2H/Et3N (1:1): yield: 98.0% (358
mg as a white solid); mp 59−65 °C; dr = 96:4; 44% ee; Chiralpak IC,
Hx/EtOH/DEA = 90:10:0.1, 1.5 mL/min, 254 nm, tR (minor) = 20.1
min, tR (major) = 22.7 min; [α]16D = +87.0 (c 0.4, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 8.51 (d, 1H, J = 4.6 Hz), 7.68 (td, 1H, J = 7.7
Hz, J = 1.7 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.23−7.18 (m, 4H), 6.97 (d,
2H, J = 6.6 Hz), 5.20−5.17 (m, 1H), 4.60 (d, 1H, J = 11.3 Hz), 4.36
(dd, 1H, J = 2.2 Hz, J = 8.3 Hz), 4.31−4.21 (m, 6H), 1.39 (t, 3H, J =
7.1 Hz), 1.36 (t, 3H, J = 7.1 Hz).; 13C NMR (75 MHz, CDCl3) δ
159.3 (d, Jcp = 14.0 Hz), 148.4, 136.8, 136.5, 128.3, 128.2, 127.8, 122.4,
121.3, 77.5 (d, Jcp = 162.6 Hz), 74.7 (d, Jcp = 3.0 Hz), 72.9, 63.1 (d,
Jcp = 6.6 Hz), 62.4 (d, Jcp = 7.0 Hz), 16.6 (d, Jcp = 5.9 Hz).; HRMS
(EI): m/z calcd for C18H24NO5P 365.1392, found 365.1395.
3.20. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(pyridin-3-yl)-
ethyl]phosphonate, (1S,2S)-4t: With (R,R)-5e catalyst and
3.23. Diethyl (1-benzyloxy-2-hydroxy-butyl)phosphonate, 4w:
yield: 98% (310 mg as a coloress oil); dr of crude product = 83:17
(diastereomers are difficult to separate by silica gel chromatography);
dr of purified product = 90:10; major isomer (90%); 97% ee: Chiralpak
ID, 20% isopropanol/n-hexane, 1.0 mL/min, 215 nm, tR(minor) =
1
8.7 min, tR(major) = 9.6 min; H NMR (500 MHz, CDCl3) δ 7.39−
7.29 (m, 5H), 4.93 (d, 1H, J = 11.3 Hz), 4.63 (d, 1H, J = 11.2 Hz),
4.28−4.19 (m, 4H), 3.83 (bs, 1H), 3.69 (t, 1H, J = 4.6 Hz), 2.81 (d,
1H, J = 5.9 Hz), 1.64−1.59 (m, 2H), 1.39−1.37 (m, 6H), 0.91 (t, 3H,
HCO2H/Et3N (0.2:1): >99% conversion after 3.5 h; dr = >99:1;
>99% ee; Chiralpak IC, 20% EtOH/n-hexane, 1.5 mL/min, 215 nm, tR
(minor) = 11.5 min, tR (major) = 18.3 min.
1
J = 7.4 Hz). minor isomer (10%); H NMR (500 MHz, CDCl3) δ
7.39−7.29 (m, 5H), 4.83 (d, 1H, J = 11.3 Hz), 4.60 (d, 1H, J = 11.3
Hz), 4.28−4.19 (m, 4H), 3.82 (bs, 1H), 3.63 (t, 1H, J = 5.8 Hz), 3.34
(bs, 1H), 1.54−1.48 (m, 2H), 1.39−1.37 (m, 6H), 0.98 (t, 3H, J = 7.4 Hz).
3.24. Diethyl (1S,2S)-(1-benzyloxy-2-hydroxy-4-phenyl-butyl)-
phosphonate, (1S,2S)-4y: yield: 96.0% (377 mg as a coloress oil);
With (R,R)-5a catalyst and HCO2H/Et3N (1:1): Yield: 96.2%
(343 mg as a pale-yellow oil); dr = 99:1; >99% ee: Chiralpak IC, 20%
EtOH/n-hexane, 1.5 mL/min, 254 nm, tR(minor) = 10.9 min,
tR(major) = 17.3 min; [α]15D = +75.1 (c 0.6, CHCl3).; 1H NMR (500
MHz, CDCl3) δ 8.62 (d, 1H, J = 1.5 Hz), 8.55 (dd, 1H, J = 1.5 Hz, J =
4.8 Hz), 7.75 (td, 1H, J = 1.5 Hz, J = 7.5 Hz), 7.31−7.25 (m, 4H),
7.18−7.16 (m, 2H), 5.12−5.10 (m, 1H), 4.78 (d, 1H, J = 11.0 Hz),
4.42 (d, 1H, J = 11.0 Hz), 4.23−4.05 (m, 4H), 3.87−3.84 (m, 2H),
1.36 (t, 3H, J = 7.0 Hz), 1.25 (t, 3H, J = 7.0 Hz).; 13C NMR (75 MHz,
CDCl3) δ 149.0, 148.5, 136.3, 135.7 (d, Jcp = 9.8 Hz), 134.6, 128.5,
128.5, 128.3, 123.0, 78.3 (d, Jcp = 160.2 Hz), 74.9 (d, Jcp = 2.3 Hz),
70.8 (d, Jcp = 4.1 Hz), 63.1 (d, Jcp = 7.0 Hz), 62.6 (d, Jcp = 7.1 Hz), 16.5
(d, Jcp = 5.9 Hz), 16.4 (d, Jcp = 7.1 Hz).; HRMS (EI): m/z calcd for
C18H24NO5P 365.1392, found 365.1389.
dr = 85:15; major = 97.8% ee, minor = 99% ee: Chiralpak IC, 10%
ethanol/n-hexane, 0.5 mL/min, 215 nm, tR(major) = 27.4 min,
tR(minor) = 30.2 min; major isomer; 1H NMR (500 MHz, CDCl3) δ
7.37−7.28 (m, 7H), 7.21−7.18 (m, 3H), 4.91 (d, 1H, J = 11.3 Hz),
4.61 (d, 1H, J = 11.3 Hz), 4.26−4.17 (m, 4H), 3.92 (bs, 1H), 3.68 (t,
1H, J = 5.2 Hz), 2.94 (bs, 1H), 2.83−2.78 (m, 1H), 2.67−2.60 (m,
1H), 1.96−1.87 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz).; 13C NMR (125
MHz, CDCl3) δ 141.7, 137.0, 128.5, 128.5, 128.3, 128.3, 128.3, 125.8,
77.4 (d, Jcp = 156.0 Hz), 74.6 (d, Jcp = 1.7 Hz), 69.8 (d, Jcp = 3.3 Hz),
62.8 (d, J = 7.1 Hz), 62.4 (d, J = 6.9 Hz), 34.9 (d, Jcp = 8.3 Hz), 31.8,
16.5 (d, J = 5.3 Hz), 16.5 (d, Jcp = 5.4 Hz).; HRMS (EI): m/z calcd for
C21H29O5P 392.1753, found 392.1747.
3.21. Diethyl (1S,2S)-[1-benzyloxy-2-hydroxy-2-(pyridin-4-yl)-ethyl]-
phosphonate, (1S,2S)-4u: With (R,R)-5e catalyst and HCO2H/Et3N
(0.2:1): >99% conversion after 3.5 h; dr = 98:2; 99.6% ee; Chiralpak
ID, 30% isopropanol/n-hexane, 1.0 mL/min, 215 nm, tR (minor) = 9.0
min, tR (major) = 10.5 min.
With (R,R)-5a catalyst and HCO2H/Et3N (1:1): Yield: 96.9%
(354 mg as a white solid); mp: 64−66 °C dr = 98:2; 97.8% ee, Chiralpak
3.25. Dmiethyl (1S,2S)-(2-hydroxy-1-methoxy-4-phenyl-butyl)-
phosphonate, (1S,2S)-4z: dr = 88:12 by chiral HPLC (diastereomers
are inseparable by silica gel chromatography) major isomer (88%);
95% ee: Chiralpak IA, 5% isopropanol/n-hexane, 1.0 mL/min, 215 nm,
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lit.28 [α]20D = +33.7 (c 1.0, MeOH) for a material of 91% ee; 1H NMR
(500 MHz, CDCl3); δ 7.46−7.29 (m, 5H), 5.14 (br s, 1H), 4.22−4.18
(m, 4H), 4.06 (d, 1H, J = 8.0 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.31 (t, 3H,
J = 7.0 Hz).; 13C NMR (125 MHz, CDCl3): δ 140.2 (d, Jcp = 10.8 Hz),
128.2, 127.8, 126.6, 72.7 (d, Jcp = 158.2 Hz), 72.5 (d, Jcp = 4.1 Hz),
63.4 (d, Jcp = 7.1 Hz), 62.8 (d, Jcp = 7.3 Hz), 16.4 (d, Jcp = 5.9 Hz), 16.3
(d, Jcp = 5.9 Hz).
1
tR (major) = 22.7 min, tR (minor) = 25.0 min; H NMR (500 MHz,
CDCl3) δ 7.32−7.19 (m, 5H), 3.94 (br s, 1H), 3.84 (t, 6H, J = 9.9
Hz), 3.58 (s, 3H), 3.45 (t, 1H, J = 5.6 Hz), 2.94−2.88 (m, 2H), 2.75−
2.69 (m, 1H), 2.01−1.90 (m, 1H), 1.90−1.82 (br s, 1H).; 13C NMR
(125 MHz, CDCl3) δ 141.8, 128.5, 128.4, 125.9, 80.6 (d, Jcp = 158.9
Hz), 69.8 (d, Jcp = 3.5 Hz), 61.3 (d, Jcp = 2.4 Hz), 53.4 (d, Jcp = 6.7 Hz),
52.6 (d, Jcp = 7.2 Hz), 35.0 (d, Jcp = 8.6 Hz), 32.0.; HRMS (EI): m/z
calcd for C13H21O5P 288.1127, found 288.1125. minor isomer (12%);
98% ee: Chiralpak AD-H, 5% isopropanol/n-hexane, 1.5 mL/min,
215 nm, tR (major) = 9.6 min, tR (minor) = 10.5 min
4.2. Debenzylation of 4v to 1,2-Dihydroxy Phosphonate 7. (S,S)-
4v (150 mg, 0.50 mmol, 98% ee), which was obtained from the
3.26. Diethyl (1S,2S,E)-(1-benzyloxy-2-hydroxy-4-phenylbut-3-en-1-yl)-
phosphonate, (1S,2S)-4ab: With (R,R)-5e catalyst and HCO2H/Et3N
ATH-DKR of 3v with (R,R)-5e catalyst, was dissolved in a mixed
solvent of EtOH/AcOH (20:0.1) (20.1 mL), and 10% Pd/C (15 mg)
was added. The suspension was stirred under hydrogen atmosphere
(balloon) for 15 h. After completion of the reaction the catalyst was
removed by filtration through a layer of Celite, the solution was
concentrated, and the residue was purified by a silica gel column
chromatography to give diol 7 (95 mg, 90.4%) as a colorless oil. The
sense and magnitude of optical rotation of the debenzylated product 7
were matched with the known diol compound (S,S)-7.66,28
(F/T = 5:2) at 35 °C for 24 h. 4ab:3y:4y = 56(>99:1 dr):13:31
1
(64:36 dr); ratio was determined by using H NMR, dr and ee (in
parentheses) were determined by using chiral HPLC; Chiralpak ID,
30% isopropanol/n-hexane, 0.8 mL/min, 254 nm, tR(major) = 16.8
min, tR(minor) = 24.4 min. (Stereoisomers are inseparable by silica gel
chromatography.)
With (R,R)-5e(Ru) catalyst and HCO2H/Et3N (F/T = 1:1) at
35 °C for 24 h. 4ab:3y:4y = 63 (>99:1 dr):0:37(57:43 dr).
With (R,R)-5e(Ru) and HCO2H/Et3N (F/T=0.2:1) at 35 °C for
24 h. 4ab:3y:4y = 66(>99:1 dr, 98% ee):22:37(57:43 dr).
With (R,R)-5a(Rh) and HCO2H/Et3N (F/T=0.2:1) at 35 °C for
24 h. 4ab:3y:4y = 4:87:9.
yield: 90.4%; [α]29 = +9.1 (c 0.7, CHCl3), [α]29 = +11.5 (c 2.0,
D
D
MeOH), lit.66 [α]20 = +10.3 (c 1.4, CHCl3), lit.28 [α]20 = +3.7 (c
D
D
1.0, MeOH) for a material of 33% ee; 1H NMR (500 MHz, CDCl3); δ
4.26−4.16 (m, 5H), 4.07 (br s, 1H), 3.70 (td, 1H, J = 8.2 Hz, J = 3.0
Hz), 3.64 (br s, 1H), 1.38−1.34 (m, 6H), 1.32 (d, 3H, J = 6.5 Hz).;
13C NMR (125 MHz, CDCl3): δ 72.1 (d, Jcp = 158.2 Hz), 66.7 (d, Jcp =
3.3 Hz), 63.1 (d, Jcp = 6.6 Hz), 62.6 (d, Jcp = 7.4 Hz), 19.2 (d, Jcp = 9.5
Hz), 16.4 (d, Jcp = 5.4 Hz), 16.3 (d, Jcp = 5.2 Hz).
With (R,R)-5b(Ir) and HCO2H/Et3N (F/T=0.2:1) at 35 °C for
24 h. 4ab:3y:4y = 14:76:10.
4ab: 1H NMR (500 MHz, CDCl3) δ 7.40−7.25 (m, 10H), 6.74 (d,
1H, J = 16.0 Hz), 6.26(dd, 1H, J = 10.0 Hz, J = 5.6 Hz), 4.91 (d, 1H,
J = 11.5 Hz), 4.69 (d, 1H, J = 11.5 Hz), 4.68−4.64 (m, 1H), 4.27−4.16
(m, 4H), 3.84 (dd, 1H, J = 6.5 Hz, J = 4.4 Hz), 3.35 (br s, 1H), 1.39−
1.29 (m, 6H).
4.3. Debenzylation of 4y to 1,2-Dihydroxy Phosphonate 8. (S,S)-
4y (100 mg, 0.25 mmol, syn:anti = 85(95% ee):15(99% ee), which was
4. Determination of the Absolute Configuration of 4a, 4v, 4y by
Comparing with the Known Compound 6, 7, and 8 respectively.
obtained from the ATH-DKR of 3y with (R,R)-5e catalyst, was
dissolved in a mixed solvent of EtOH/AcOH (10:0.1) (10.1 mL), and
10% Pd/C (10 mg) was added. The suspension was stirred under
hydrogen atmosphere (balloon) for 24 h. After completion of the
reaction the catalyst was removed by filtration through a layer of
Celite, and the solution was concentrated to give 8 (72 mg, 93.5%).
The residue was cautiously separated by silica gel column
chromatography to give syn-diol 8 as colorless oil. The sense and
magnitude of optical rotation of the debenzylated product syn-diol 8
were matched with the syn-diol compound (S,S)-8 which was
independently prepared from Sharpless asymmetric dihydroxylation
of diethyl (E)-(4-phenylbut-1-en-1-yl)phosphonate (9)67 with
AD-mix-α68 (see, exp. 4.4 below and chiral HPLC analysis in Supporting
Information for comparison).
4.1. Debenzylation of 4a to 1,2-Dihydroxy Phosphonate 6. (S,S)-4a
(120 mg, 0.33 mmol, 99% ee), which was obtained from the ATH-
DKR of 3a with (R,R)-5e catalyst, was dissolved in a mixed solvent of
EtOH/AcOH (20:0.2) (20.2 mL), and 10% Pd/C (12 mg) was added.
The suspension was stirred under hydrogen atmosphere (balloon) for
30 h. After completion of the reaction the catalyst was removed by
filtration through a layer of Celite, the solution was concentrated, and
the residue was purified by a silica gel column chromatography to give
diol 6 (88 mg, 97.5%) as a colorless oil. The sense and magnitude of
optical rotation of the debenzylated product 6 were matched with the
known diol compound (S,S)-627,28 which was prepared from Sharpless
asymmetric dihydroxylation of diethyl (E)-styrylphosphonate with
AD-mix-α.
96.7% ee: Chiralpak IC, 10% ethanol/n-hexane, 0.8 mL/min,
215 nm, tR (major) = 17.4 min, tR (minor) = 21.9 min; [α]21D = −6.9
yield: 97.5%; [α]30D = +30.7 (c 0.4, CHCl3), [α]30D = +34.3 (c 0.3,
MeOH), lit.27 [α]20D = +24.7 (c 1.0, CHCl3) for a material of 100% ee,
1
(c 0.5, CHCl3); H NMR (500 MHz, CDCl3): δ 7.32−7.20 (m, 5H),
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4.26−4.15 (m, 4H), 4.00 (br s, 1H), 3.79 (t, 1H, J = 9.0 Hz), 3.41 (d,
1H, J = 3.4 Hz, OH), 3.33 (d, 1H, J = 9.4 Hz, OH), 2.86−2.81 (m,
1H), 2.77−2.70 (m, 1H), 2.09−2.05 (m, 1H), 1.91−1.88 (m, 1H),
1.38 (t, 3H, J = 7.1 Hz), 1.33 (t, 3H, J = 7.1 Hz).; 13C NMR (125
MHz, CDCl3): δ 141.8, 128.4, 128.2, 125.7, 71.0 (d, Jcp =158.7 Hz),
69.8 (d, Jcp = 1.6 Hz), 63.0 (d, Jcp = 6.8 Hz), 62.8 (d, Jcp = 7.2 Hz), 34.7
(d, Jcp = 10.7 Hz), 31.8, 16.3 (d, Jcp = 5.6 Hz), 16.3 (d, Jcp = 5.6 Hz).;
HRMS (EI): m/z calcd for C14H23O5P 302.1283, found 302.1270.
4.4. Synthesis of (S,S)-8 from Diethyl (E)-(4-phenylbut-1-en-1-yl)-
phosphonate (9) by Sharpless Asymmetric Dihydroxylation with
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AD-mix-α. To a stirred solution of tert-butyl alcohol (18 mL) and
water (18 mL) were added AD-mix-α (5.0 g) and methanesulfonamide
(0.34 g, 3.54 mmol) at room temperature. The mixture was vigorously
stirred at room temperature until both phases were clear and then
was cooled to 0 °C. A solution of the diethyl (E)-(4-phenylbut-1-
enyl)phosphonate (9)67 (0.95 g, 3.54 mmol) in tert-butyl alcohol (5 mL)
was added at 0 °C. The reaction mixture was stirred at the same
temperature for 48 h. The reaction was quenched at 0 °C by the addition
of sodium sulfite (5.1 g), warmed to room temperature, and further
stirred for 1 h. The reaction mixture was then extracted with EtOAc
(3 × 50 mL). The combined organic layer was washed with aqueous
2 N KOH (50 mL), water (50 mL), and brine (50 mL). The organic
layer was dried over MgSO4, filtered, and then concentrated under
reduced pessure. Purification of the crude product by silica gel column
chromatography afforded (S,S)-8 (925 mg, 86.4%) as a colorless oil.
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yield: 86.4%; 84.2% ee: Chiralpak IC, 10% ethanol/n-hexane,
0.8 mL/min, 215 nm, tR (major) = 17.4 min, tR (minor) = 21.9 min;
[α]21D = −6.0 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.31−
7.19 (m, 5H), 4.25−4.16 (m, 4H), 3.99 (s, 1H), 3.80 (d, 1H, J = 8.6
Hz), 3.69 (br s, 1H), 2.86−2.81 (m, 1H), 2.77−2.71 (m, 1H), 2.10−
2.03 (m, 1H), 1.93−1.86 (m, 1H), 1.74 (br s, 1H), 1.37 (t, 3H, J = 7.0
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Cordero, R.; Fernan
14, 1775.
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́
̃
̃
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142.
ASSOCIATED CONTENT
(23) Bongini, A.; Camerini, R.; Panunzio, M.; Bandini, E.; Martelli,
G.; Spunta, G. Tetrahedron: Asymmetry 1996, 7, 3485.
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Asymmetry 1995, 6, 2127.
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■
S
* Supporting Information
Copies of 1H-, 13C NMR spectra, chiral HPLC chromatograms
of all new chiral compounds and X-ray crystallography data of
(S,S)-4n and (S,S)-4u in CIF format (CCDC-982444 for (S,S)-
4n and CCDC-982443 for (S,S)-4u). This material is available
free of charge via the Internet at http://pubs.acs.org.
(26) Yokomatsu, T.; Suemune, K.; Yamagishi, T.; Shibuya, S. Synlett
1995, 1995, 847.
(27) Maly, A.; Lejczak, B.; Kafarski, P. Tetrahedron: Asymmetry 2003,
14, 1019.
(28) Yokomatsu, T.; Yamagishi, T.; Suemune, K.; Yoshida, Y.;
Shibuya, S. Tetrahedron 1998, 54, 767.
AUTHOR INFORMATION
Corresponding Author
*leehk@krict.re.kr
■
(29) Yokomatsu, T.; Yoshida, Y.; Suemune, K.; Yamagishi, T.;
Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 365.
Notes
The authors declare no competing financial interest.
(30) Gautier, I.; Ratovelomanana-Vidal, V.; Savignac, P.; Genet
̂
, J.-P.
Tetrahedron Lett. 1996, 37, 7721.
ACKNOWLEDGMENTS
■
(31) Cao, Y.-M.; Shen, F.-F.; Zhang, F.-T.; Zhang, J.-L.; Wang, R.
Angew. Chem., Int. Ed. 2014, 53, 1862.
(32) Han, W.-Y.; Zhao, J.-Q.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. J.
This investigation was supported by the Ministry of Strategy
and Finance of Korea, the Ministry of Science, ICT & Future
Planning of Korea, and the Korea Research Institute of
Chemical Technology.
Org. Chem. 2013, 78, 10541.
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