Stereoselective Synthesis of 4-Substituted Cyclic Sulfamidate-5-Phosphonates by Using Rh-Catalyzed, Asymmetric Transfer Hydrogenation with Accompanying Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/acs.joc.5b01434

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation of 4-substituted cyclic sulfamidate imine-5-phosphonates produces the corresponding cyclic sulfamidate-5-phosphonates. The process employs a HCO₂H/Et₃N mixture as the hydrogen source and the chiral Rh catalysts, (R,R)- or (S,S)-Cp?RhCl(TsDPEN), and it takes place at room temperature within 1 h with high yields and high levels of stereoselectivity.

Full text of DOI:10.1021/acs.joc.5b01434

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Note
Stereoselective Synthesis of 4-Substituted Cyclic Sulfamidate-5-
Phosphonates by Using Rh Catalyzed, Asymmetric Transfer
Hydrogenation with Accompanying Dynamic Kinetic Resolution
Yeon Ji Seo, Jin-ah Kim, and Hyeon-Kyu Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01434 • Publication Date (Web): 17 Aug 2015
Downloaded from http://pubs.acs.org on August 21, 2015
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Stereoselective Synthesis of 4-Substituted Cyclic Sulfamidate-5-
Phosphonates by Using Rh Catalyzed, Asymmetric Transfer
Hydrogenation with Accompanying Dynamic Kinetic Resolution.
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a,b+
a+
a,b
Yeon Ji Seo, Jin-ah Kim, and Hyeon-Kyu Lee *
Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong,
Daejeon 305-600, Korea; Department of Medicinal Chemistry and Pharmacology, University of
Science and Technology, 113 Gwahango, Yuseong, Daejeon 305-333, Korea.
leehk@krict.re.kr
O
O
O
O
O
O
Boc
HN
Boc
HN
Ts
N
Rh
0
.5 mol%
(R,R)-1a
S
S
S
Ph
Ph
N
4
O
5
HN
4
O
+
HN
4
O
OH
NH2
1
and
HCO H/Et N
5
5
2
1
2
2
3
o
N
2
R
EA, 25 C
R
P(OMe)2
R
Ph
P(OMe)
2
Ph
P(OMe)
2
Cl
P(OMe)
2
P(OMe)
2
H
O
O
O
O
O
-
racemic 4
(
4S,5R)-
5
(
4R,5S 5
minor
)-
(1S,2S)-
7a
(1S,2S)-
9a
(R,R)-
1
a
major
R =
alkyl
up to >99% & >99% ee, dr
(hetero)aryl,
Abstract: Dynamic kinetic resolution driven, asymmetric transfer hydrogenation of 4-substituted
cyclic sulfamidate imine 5-phosphonates produces the corresponding cyclic sulfamidate 5-
phosphonates. The process employs a HCO H/Et N mixture as the hydrogen source and the
2
3
chiral Rh catalysts, (R,R)- or (S,S)-Cp*RhCl(TsDPEN), and it takes place at room temperature
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within 1 h with high yields and high levels of stereoselectivity.
Enantiomerically enriched β-amino-α-hydroxy phosphonates, which are isoteres of the
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corresponding β-amino-α-hydroxy carboxylates, have attracted great interests because of their
1-5
wide range of biological activities.
These substances are also potentially important
intermediates in the synthesis of renin inhibitors, HIV protease inhibitors and haptens in the
2
,4
development of catalytic antibodies. Although a number of methods have been described for
1,2,6
the preparation of β-amino-α-hydroxy phosphonates,
most procedures targeted at
enantiomerically enriched members of this family require the use of stoichiometric amounts of
7
3
chiral starting materials such as chiral amino acids, amino aldehydes or aziridines. Thus far,
only a few catalytic asymmetric methods have been described to prepare these substances, one of
5
,8
which is Sharpless asymmetric aminohydroxylation (AA) of unsaturated phosphonates.
However Sharpless AA of aryl-substituted unsaturated phosphonates proceeds in low yields (21-
5
5
3%) and with variable levels of stereoselectivity (32-98% ee).
Recently we described a new procedure for asymmetric transfer hydrogenation (ATH) of
prochiral cyclic sulfamidate imines, which uses HCO H/Et N as the hydrogen source and well
2
3
9
-11
defined chiral Rh catalysts (Scheme 1).
In this early effort, we showed that ATH of the 4,5-
disubstituted cyclic sulfamidate imine 2, possessing a configurationally labile stereogenic C-5
centers, is accompanied by dynamic kinetic resolution (DKR). It was also observed that DKR is
caused by rapid racemization at the acidic stereogenic C-5 position under the reaction conditions.
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Scheme 1. Stereoselective synthesis of 4,5-disubstituted cyclic sulfamidates 3 and 5
work)
Previous
(
O
O
O
O
O
O
0.5 mol %
(R,R)-1a
S
S
S
N
4
O
5
HN
4
O
5
+
HN
4
O
5
HCO H/Et N
2
3
o
10
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Ph
CO Me EA, 25 C
-
Ph
CO Me Ph
CO Me
2
2
2
racemic 2
4S,5S)-
major (98%
3
4R,5R
)-
3
minor
(
(
ee)
work)
(This
O
O
O
O
O
O
0
.5 mol %
(R,R)-1a
S
S
S
N
4
O
5
HN
4
O
5
+
HN
4
O
5
HCO H/Et N
2
3
o
R
25 C
R
P(OMe)2
R
P(OMe)
2
P(OMe)
2
O
O
O
racemic-4
4S,5R
)-
major
5
(
4R,5S
5
(
)-
minor
R =
alkyl
(hetero)aryl,
We envisioned that introduction of a phosphonate group at C-5 of the 4,5-disubstituted cyclic
sulfamidate imine framework would enhance the acidity of H-5 and, as a result, would promote
high levels of stereoselectivity in the ATH–DKR reaction. Importantly, the cyclic sulfamidate-5-
phosphonates 5 (Scheme 1) produced in these reactions could be potentially valuable
intermediates in the synthesis of various chiral β-amino-α-hydroxy phosphonic acid derivatives.
Below, we describe the results of a study guided by these proposals, which led to the
development of a highly efficient ATH reaction of cyclic imine-5-phosphonates 4 that is
accompanied by DKR and the application of this process to the preparation of stereochemically
enriched, chiral cyclic sulfamidate-5-phosphonates 5.
Scheme 2. Synthesis of 4-substituted sulfamidate imine-5-phosphonates 4
O
O
O
O
P
O
O
P
S
PIFA
i) NH
ii) PTSA, heat
2
SO
2
Cl
N
4
O
5
OR2
OR2
OR
2
R1
R1
OR2
OH
R1
2 2
P(OR )
O
A
B
4
The racemic cyclic imine-5-phosphonates 4, used in this study were prepared from α-hydroxy-β-
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keto phosphonates (B) and sulfamoyl chloride using a modification of a previously described
1
2
procedure (Scheme 2).
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Table 1. Optimization of chiral catalysts 1 for ATH-DKR reactions of 4a
O
O
O
O
O
O
S
S
S
mol %)
(
R,R)- (0.5
HCO H/Et N
1
N
4
O
5
HN
4
O
5
HN
4
O
5
+
2
3
o
25 C
Ph
Ph
Ph
P(OMe)
2
P(OMe)
2
P(OMe)
2
O
O
O
racemic-4a
5a
(4R,5S)-
5a
(
4S,5R)-
c
Conv
dr
ee
(%)
Entry
1
cat.-1
b
d
(
%)
syn:anti
(R,R)-1a
>99
>99
>99
>99
>99
>99
>25:1
98
97
39
96
92
94
2
3
4
5
6
(S,S)-1a
(R,R)-1b
(R,R)-1c
(R,R)-1d
(R,R)-1e
>25:1
>25:1
>25:1
>25:1
>25:1
a. Reaction conditions: 4a (0.5 mmol), cat-1 (0.5 mol %), HCO H/Et N (F/T = 5:2, 0.5 mL),
2
3
o
1
EtOAc (5 mL), at 25 C. b. Determined by using H NMR analysis of crude product mixture. c.
1
Only 4,5-cis products were detected by using H NMR analysis of crude product mixtures. d.
Determined by using chiral HPLC analysis.
R
R
Ts
N
O S O
O S O
Ph
Ph
Ph
Ph
Ph
Ph
N
N
M
Ru
Ru
N
N
N
Cl
: M=Rh
M=Ir
Cl
Cl
H
H
H
2
2
2
R,R)-1a
R,R)-1b
(R,R)-
(R,R)-
1c: R= p-Tolyl (R,R)-1e: R= p-Tolyl
1d: R= F Ph
(
(
:
5
In initial studies aimed at identifying ideal catalyst systems for the ATH of these substrates,
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reaction of racemic 4-phenyl-cyclic imine-5-phosphonate dimethyl ester (4a) was carried out at
rt using known chiral transition metal catalysts 1a-e (0.5 mol %), HCO H/Et N (F/T = 5:2), as
2
3
the hydrogen source and EtOAc as solvent. The results (Table 1) show that ATH reactions of 4a
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promoted by most of the chiral transition metal catalysts, except Ir-complex 1b, proceed
1
4
rapidly and with high stereoselectivities. Based on the observation that the Rh-catalyst (R,R)-1a
displayed the highest stereoselectivity (98% ee), it was used in further exploratory reactions. The
influence of solvent on the ATH reaction of 4a promoted by (R,R)-1a was investigated next (see
SI). In most of the solvents tested (EtOAc, CH Cl , Cl(CH ) Cl, CHCl , toluene, DMF, MeOH,
2
2
2 2
3
THF and 2-propanol), ATH of 4a takes place completely to form (4S,5R)-5a with high levels of
stereoselectivity (>25:1 dr, 89-98% ee). For experimental convenience all further ATH reactions
were carried out in EtOAc as solvent.
a
Table 2. ATH reactions of 4-substituted-cyclic sulfamidate imine-5-phosphonates 4
O
O
O
O
O
O
S
R,R) (0.5
-1a
mol
S
S
(
%)
N
4
O
5
HN
4
O
5
HN
4
O
5
+
HCO H/Et
2
3
N(5:2)
EtOAc(0.1M), 25 C
o
R1
2
2
R1
P(OR
)
R1
P(OR
)
2
2
2 2
P(OR )
O
O
O
racemic-4
5
(4R,5S)-
5
(4S,5R)-
substrate
time
h)
conv
(%)
ee(syn)
(%)
d
entry
b
c
conf.
(
4
,5
R
1
R
2
1
2
3
4
5
a
Me
Et
0.5
0.5
0.5
0.5
1.0
>99(99)
>99(96)
>99(94)
>99(99)
>99(95)
98
4S,5R
e
f
b
c
98
4S,5R
4S,5R
4S,5R
4S,5R
Me
g
Me
Me
Me
96
d
e
97
96
Me
MeO
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h
6
7
f
Me
Me
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Me
1.5
1.0
1.0
0.5
>99(91)
>99(96)
>99(97)
>99(94)
94
4S,5R
4S,5R
g
g
h
97
Cl
Cl
F
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i
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98
97
4R,5S
4S,5R
F
F
1
0
i
Me
24
50
42
81
-
-
j
j
11
i
Me
Me
1.0
>99(95)
1
2
j
0.5
>99(95)
>99 4S,5R
NC
f
13
14
k
Me
0.5
>99(93)
99
97
4S,5R
MeO C
2
l
m
m
n
n
o
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
0.5
1.5
>99(97)
>99(90)
4S,5R
4S,5R
4S,5R
4S,5R
4S,5R
O
k
1
5
93
97
O
S
S
j
j
k
16
1.0
>99(90)
1
7
2.0
>99(94)
97
i
j
j
18
1.0
>99(90)
99
97
f
1
2
2
2
2
9
0.5
>99(99)
4S,5R
Ph
j
j
l
m
0
1
2
3
p
q
r
12
>99(50)
75
-
ND
j
j
m
24
39
ND
j
j
m
30
35
-
ND
j
j
m
s
24
35
-
ND
a
Reaction conditions: 4 (0.5 mmol), (R,R)-1a (0.5 mol %), HCO H/Et N (5:2, 0.5 mL), EtOAc (5
2
3
b
1
mL), rt. Determined by H NMR analysis of the crude products (isolated yields in parentheses).
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c
1
Determined by using chiral HPLC. Only 4,5-cis products were detected in H NMR of crude
d
products. Absolute configurations of N-Boc-5b, 5k and 5o were determined by using X-ray
crystallographic analysis and absolute configurations of the other products were determined by
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e
f
analogy to N-Boc-5b, 5k and 5o. ee of N-Boc-5b. Determined by using X-ray crystallographic
g
h
i
analysis (see, SI). ee of N-Boc-5c. ee of N-Boc-5f. (S,S)-1a (0.5 mol %) was used as catalyst.
j
k
l
1
:1 mixture of HCO H/Et N was used as the hydrogen source. ee of N-Boc-5m. ee of ring-
2 3
m
opened derivative derived from 5p (see, Supplementary Information-1). ND: Not Determined.
The scope and limitations of the ATH-DKR reaction were explored using a variety of cyclic
sulfamidate imine 5-phosphonates 4 and optimized conditions involving (R,R)-1a (0.5 mol %) as
o
the catalyst, a 5:2 mixture of HCO H/Et N as the hydrogen source, EtOAc (25 C) as the solvent.
2
3
The results (Table 2) show that ATH reactions of 4a catalysed by (R,R)-1a under the optimized
reaction conditions produces a mixture of stereoisomeric 4,5-cis sulfamidate 5-phosphonates, in
which the (4S,5R)-5a isomer predominates (98% ee, 99% yield, Table 2, entry 1). In a manner
9
that is similar to our previous findings, ATH of 4-substituted cyclic sulfamidate imine-5-
1
carboxylates (2, Scheme 1), 4,5-trans sulfamidate 5-phosphonates are not detected (by using H
NMR analysis) in reactions of 4a. ATH of 4-phenyl cyclic imines 5-phosphonate diethyl ester
(
4b) also produces the corresponding cyclic sulfamidates 5b with excellent efficiency and
stereoselectivity. The results also show that most of the ATH reactions of 4-aryl-5-phosphonate
cyclic imine dimethyl esters take place completely at rt in short time periods. For example, ATH-
DKR of cyclic sulfamidate imines possessing either electron-withdrawing or electron-donating
groups at the meta- or para-position on the phenyl ring afford the corresponding sulfamidates in
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uniformly high yields and stereoselectivites. However, ATH reaction of the cyclic imine 4i
containing an ortho-substituted phenyl group occurs slowly (50% conversion, 24 h). Because the
HCO H/Et N (F/T) ratio is known to have a significant effect on both rates and
2
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5,16
enantioselectivities of ATH reactions,
a 1:1 instead of 5:2 mixture of F/T was employed as
the hydrogen source. Under these conditions, ATH of 4i is complete in 1 h (81% ee) (Table 2,
entries 10 and 11). That cyclic imines containing heteroaromatic moieties are also suitable
substrates for the ATH-DKR reaction was demonstrated by the finding that with respective furan
and thiophene 4n and 4m derivatives participate in the process (Table 2, entries 15,17). As in the
reaction of 4i, employing a 1:1 instead of 5:2 mixture of F/T as the hydrogen source led to ATH
reactions of 4m and 4n that are complete within 1 h and that take place with improved
stereoselectivities (93 to 97% ee for 5m and 97 to 99% ee for 5n, Table 2, entries 15-18).
Importantly, ATH reaction of 4g under the optimized conditions, except using the (S,S)-1a as the
catalyst, produces the antipodal sulfamidate (4R,5S)-5g with an efficiency and stereoselectivity
(98% ee, 97% yield) that match those associated with the reaction promoted by (R,R)-1a (Table
2
, entry 8). We also observed that the catalyst loading can be reduced to 0.1 mol % (S/C = 1,000)
in the ATH-DKR reaction of 4a which requires a longer time (3 h) for completion but has a high
efficiency and product enantiomeric purity (95% yield, 96% ee).
ATH reactions of 4-alkyl substituted cyclic sulfamidate imine 5-phosphonates were explored.
The results show that the efficiencies and stereoselectivities of the ATH-DKR reactions of these
substrates are sensitive to the steric bulkiness of the 4-alkyl group. For example, ATH reaction of
less hindered 4-phenethyl cyclic imine 4o under the optimized conditions is completed in 0.5 h
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with an excellent level of stereoselectivity (97% ee, Table 2, entry 19) but that of the 4-isobutyl-
cyclic imine 4p requires 12 h for completion and occurs with a decreased level of
stereoselectivity (75% ee, Table 2, entry 20). However, ATH reaction of sterically more
demanding 4-alkyl cyclic imines such as 4-isopropyl 4q, 4-cyclohexyl 4r, and 4-t-butyl 4s is
more sluggish resulting in only 35~39% conversions even after 24 h (Table 2, entries 21~23).
Since it is known that an attractive interaction between arene ligand of the catalyst and aryl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
7
substrate is of great importance in the favored transition state, low reactivity of 4-alkyl
substrates which are absent from such attractive interaction in the transition state is not surprising.
Scheme 3. ATH of 4-styryl cyclic imine-5-phosphonate 4t
O
O
O
O
O
O
S
0.5 mol %
S
S
N
4
O
5
(R,R)-
1a
HN
4
O
5
HN
4
O
5
+
F/T=5:2
o
EA, 25 C
Ph
P(OMe)
2
Ph
P(OMe)
2
Ph
P(OMe)
2
O
98%
O
O
4t
(4S,5R)-5t
(1:1)
(4S,5R)-5o
99% ee
94% ee
Next, the scope of the process was explored by employing the 4-styryl substituted cyclic imine-
-phosphonate dimethyl ester 4t as the substrate (Scheme 3). ATH reaction of 4t under the
5
optimized reaction conditions using (R,R)-1a as the catalyst generates 5t as the expected C=N
reduction product with high enantiomeric purity (99% ee) along with the both C=N and C=C
reduction product (4S,5R)-5o (94% ee), (5t:5o=1:1). When 5t is subjected to the same ATH
reaction conditions, the unconjugated C=C bond does not undergo reduction. It is well-known
that transfer hydrogenations promoted by Noyori type diamine-transition metal complexes are
18,19
highly chemoselective, with C=O reduction being favoured over C=C reduction.
However, it
was reported recently that the use of Ru- or Rh-amido catalysts causes reversal of the typical
C=O over C=C reduction selectivities in ATH reactions of α,β-unsaturated carbonyl compounds
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
when the C=C double bond is activated by electron-withdrawing substituents or the reaction is
2
0,21
performed in an aqueous medium.
Similar to the known transfer hydrogenation of substrates
2
0
containing a C=C bond conjugated to C=O group with the Rh-amido catalysts, the C=C bond
conjugated to C=N group in 4t is reduced under the ATH reaction conditions to produce 4o,
which is rapidly reduced to form 5o (see entry 19 in Table 2 and Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The cyclic sulfamidate-5-phosphonates 5 produced in these ATH reactions are valuable
2
2
intermediates in the synthesis of various chiral β-amino-α-hydroxy phosphonic acid derivatives
and 1,2-functionalized amino-phosphonic acid derivatives. In order to demonstrate the utility of
the methodology developed in this study, the 4-phenyl cyclic sulfamidate-5-phosphonate 5a was
transformed to the corresponding 2-amino-1-hydroxy phosphonate 7a and mono-protected 1,2-
diamino phosphonate 9a (Scheme 4). Treatment of N-Boc-5a with PhCO H in the presence of
2
CsF leads to smooth formation of the ring-opened product, O-benzoyl-N-Boc-6a, with inversion
23
12
of configuration at C-1. Selective removal of the O-benzoyl group in 6a using KCN in MeOH
produces 2-(N-Boc-amino)-1-hydroxy-phosphonate 7a. Similarly, ring opening of N-Boc-5a with
NaN produces 8a, which upon subsequent hydrogenation forms the mono-protected 1,2-
3
diamino-phosphonate 9a. (Scheme 4)
Scheme 4. Conversion of cyclic sulfamidate 5a to 1,2-functionalized phosphonates 7a and 9a
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O
O
O
O
Boc
HN
Boc
S
S
Boc
HN
4
O
5
N
4
O
5
OBz
1
HN
2
OH
a
b
c
2
1
Ph
Ph
N-Boc-(
5a
4S,5R)-
Ph
Ph
P(OMe)
2
P(OMe)
2
P(OMe)
2
P(OMe)
2
O
O
O
O
4S,5R)-
5a
(1S,2S)-6a
(1S,2S)-7a
(
Boc
Boc
d
10
11
12
13
14
15
16
17
18
19
20
21
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23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HN
2
N3
1
HN
2
NH2
1
e
Ph
Ph
P(OMe)
2
P(OMe)
2
O
O
1S,2S)-
8a
1S,2S 9a
( )-
(
Reaction conditions: (a) (Boc) O, Et N, cat. DMAP, CH Cl , 71%; (b) PhCO H, CsF, DMF, 60
2
3
2
2
2
o
C, 3 h, 89%; (c) KCN, MeOH, rt, 3 h, 64%; (d) NaN , DMF, rt, 70%; (e) H , Pd/C, MeOH, rt,
3
2
1
2 h, 60%
In summary, a convenient and highly stereoselective methodology for the preparation of 4-
substituted cyclic sulfamidate 5-phosphonate esters 5 has been developed. This process,
involving asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution (ATH–
DKR), uses HCO H/Et N as the hydrogen source and the well-defined chiral Rh catalysts (S,S)-
2
3
or (R,R)-Cp*RhCl(TsDPEN). Most of the 4-substituted cyclic sulfamidate imine 5-phosphonate
esters 4 probed in the effort undergo efficient and highly stereoselective ATH–DKR reactions
rapidly (within 1 h) under mild and experimentally convenient conditions (room temperature,
without the need for solvent degassing or an inert atmosphere).
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
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
DCM), ether, THF were dried and purified using a solvent purification system. Flash column
chromatography was carried out on silica gel (38-75 μm). Analytical thin layer chromatography
TLC) was performed on silica gel 60 F254 plates. Preparative thin layer chromatography (PLC)
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was performed on silica gel 60 F254 2 mm plates. Visualization of the developed chromatogram
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
1
13
were recorded using 500 MHz NMR instrument ( H NMR at 500 MHz and C NMR at 125
1
13
1
MHz) or 300 MHz NMR instrument ( H NMR at 300 MHz and C NMR at 75 MHz). H NMR
data are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =
1
3
triplet, q = quartet, m = multiplet, br = broad), integration, coupling constants (Hz). Data for C
NMR are reported in terms of chemical shift (δ, ppm). High performance liquid chromatography
(HPLC) was carried out on a HPLC system equipped with a Chiralpak IA, Chiralpak IB,
Chiralpak IC, Chiralpak ID, Chiralpak AD-H, or Chiralpak OD-H column. HR-MS were
measured with electron impact (EI) ionization via double focusing mass analyzer (magnetic and
electric fields) or electrospray ionization (ESI) via Time of flight (TOF) analyzer. The formic
1
4
acid/triethylamine mixtures (molar ratio = 5:2 or 1:1) are commercially available. (R,R)-1a and
13
(R,R)-1b were prepared according to the literature procedures. Chiral catalysts, (R,R)-1c, (R,R)-
1
d, and (R,R)-1e are commercially available.
1
. Synthesis of α-hydroxy-β-keto phosphonates
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A)
(
Method
O
O
O
O
O
O
Ts-N3
Rh2
(OAC)
4
P OMe
OMe
P OMe
OMe
P OMe
OMe
OH
R1
R1
H O/THF
R1
K CO
2
2
3
N2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B)
(
Method
O
O
O
O
PhI(OCOCF
H O
3
)
2
P OMe
OMe
OH
P OMe
OMe
R1
R1
2
1
-1. Synthesis of α-diazo-β-keto phosphonates
24
α-Diazo-β-keto phosphonates were prepared from the corresponding β-keto phosphonates
25
following the reported procedures.
(
1-Diazo-2-oxo-2-m-tolyl-ethyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc,
O
O
1:2 to 1:3)
Me
P(OMe)2
1
yield: 79% (0.87 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
N2
13
7.42-7.44 (m, 2H), 7.31-7.32 (m, 2H), 3.81 (s, 3H), 3.79(s, 3H), 2.37(s, 3H).; C NMR (75 MHz,
CDCl ) δ 187.5 (d, J = 8.8 Hz), 138.7, 136.7 (d, J = 3.2 Hz), 133.2, 128.5, 127.9, 124.3, 62.7
3
cp
cp
(
d, J = 217.2 Hz), 54.1, 54.0, 21.3.; HRMS (EI): m/z calcd for C H N O P 268.0613, found
cp 11 13 2 4
268.0602.
(
1-Diazo-2-oxo-2-p-tolyl-ethyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:2)
1
yield: 71.6% (3.17 g as a yellow oil); H NMR (300 MHz, CDCl ) δ 7.57-7.60 (m, 2H), 7.27-
3
O
O
13
P(OMe)2
N2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
7
.28 (m, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 2.41(s, 3H).; C NMR (75 MHz, CDCl ) δ 187.0 (d, J
3
cp
= 8.9 Hz), 143.3, 134.0 (d, J = 3.5 Hz), 129.3, 127.5, 64.2 (d, J = 217.0 Hz), 54.0, 53.9, 21.6.;
cp
cp
HRMS (EI): m/z calcd for C H N O P 268.0613, found 268.0611.
11
13
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
1-Diazo-2-(4-methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
yield: 92% (0.92 g as a yellow oil), H NMR (300 MHz, CDCl ) δ
3
O
O
P(OMe)2
7.58 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H, J = 8.6 Hz), 3.73 (s, 6H), 3.70
N2
13
MeO
(s, 3H).; C NMR (75 MHz, CDCl ) δ 185.7 (d, J = 9.2 Hz), 163.0,
3
cp
1
29.7, 129.1 (d, J = 2.8 Hz), 113.8, 62.0 (d, J = 216.5 Hz), 55.4, 54.0, 53.8.; HRMS (EI): m/z
cp cp
calcd for C H N O P 284.0562, found 284.0554.
11
13
2
5
[
2-(3-Chloro-phenyl)-1-diazo-2-oxo-ethyl]-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:3)
1
yield: 73% (1.6 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
Cl
P(OMe)2 7.646-7.653 (m, 1H), 7.50-7.55 (m, 2H), 7.37-7.41 (m, 1H), 3.82 (s,
N2
13
3H), 3.80 (s, 3H).; C NMR (125 MHz, CDCl ) δ 185.9 (d, J =
3
cp
1
0.0 Hz), 138.3, 134.8, 132.4, 129.9, 127.6, 125.4, 63.8 (d, J = 217.9 Hz), 54.1, 54.0.; HRMS
cp
(EI): m/z calcd for C H ClN O P 288.0067, found 288.0064.
1
0
10
2
4
[
2-(4-Chloro-phenyl)-1-diazo-2-oxo-ethyl]-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:3)
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9
1
yield: 69.2% (3.03 g as a yellow oil); H NMR (300 MHz, CDCl ) δ
3
O
O
P(OMe)2
13
7.62-7.66 (m, 2H), 7.42-7.46 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H).; C
N2
Cl
NMR (75 MHz, CDCl ) δ 186.0 (d, J = 9.9 Hz), 138.8, 135.06,
3
cp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
135.04, 128.9, 63.5 (d, J = 217.0 Hz), 54.0, 53.9.; HRMS (EI): m/z calcd for C H ClN O P
cp
10 10
2
4
2
88.0067, found 288.0065.
[1-Diazo-2-(4-fluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:3)
1
yield: 74% (0.81 g as a yellow oil); H NMR (300 MHz, CDCl ) δ
3
O
O
P(OMe)2
13
7
.71-7.76 (m, 2H), 7.12-7.18 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H).; C
N2
F
NMR (75 MHz, CDCl ) δ 185.9 (d, J = 9.8 Hz), 165.1 (d, J =
3
cp
cf
2
2
52.5 Hz), 133.0 (d, J = 5.6 Hz), 130.1 (d, J = 9.0 Hz), 115.8 (d, J = 21.9 Hz), 63.3 (d, J =
cf cf cf cp
18.6 Hz), 54.0, 54.0.; HRMS (EI): m/z calcd for C H FN O P 272.0362, found 272.0361.
10
10
2
4
[2-(4-Cyano-phenyl)-1-diazo-2-oxo-ethyl]-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:2)
1
O
O
yield: 50% (1.0 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
P(OMe)2
7
.77-7.78 (m, 4H), 3.82 (d, 3H, J= 1.9 Hz), 3.79 (d, 3H, J= 1.9 Hz).;
N2
NC
3
1
C NMR (75 MHz, CDCl ) δ 185.8 (d, J = 10.8 Hz), 140.4, 132.3, 128.0, 117.7, 115.8, 64.8 (d,
3
cp
J = 217.6 Hz), 54.1, 54.0.; HRMS (EI): m/z calcd for C H N O P 279.0409, found 279.0410.
cp
11 10
3
4
[1-Diazo-2-(4-methoxycarbonyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Purified by column chromatography on silica gel (CH Cl /MeOH, 10:1)
2
2
1
yield: 67% (1.83 g as a yellow oil), H NMR (500 MHz, CDCl )
3
O
O
P(OMe)2
δ 8.13 (d, 2H, J= 8.5 Hz), 7.72 (d, 2H, J= 8.4 Hz), 3.95(s, 3H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N2
MeO C
13
2
3.82 (s, 3H), 3.80 (s, 3H).; C NMR (125 MHz, CDCl ) δ 186.8
3
(
d, J = 9.9 Hz), 166.0, 140.5, 133.4, 129.8, 127.3, 62.5(d, J = 188.6 Hz), 54.1, 54.0, 52.5.;
c
p
c
p
HRMS (EI): m/z calcd for C H N O P 312.0511, found 312.0506.
1
2
13
2
6
(1-Diazo-2-furan-2-yl-2-oxo-ethyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:3 to 1:4)
1
yield: 84.2% (1.9 g as a dark-brown oil), H NMR (300 MHz, CDCl ) δ
3
O
O
7
.56-7.57 (m, 1H), 7.26-7.28 (m, 1H), 6.58-6.60 (dd, 1H, J= 1.74, 3.63
P(OMe)2
O
N2
13
Hz), 3.91 (s, 3H), 3.87 (s, 3H).; C NMR (125 MHz, CDCl ) δ 172.5 (d,
3
J = 8.2 Hz), 151.5, 145.3, 117.4, 112.6, 61.0 (d, J = 236.4 Hz), 54.3, 54.2.; HRMS (EI): m/z
cp
cp
calcd for C H N O P 244.0249, found 244.0258.
8
9
2
5
(1-Diazo-2-oxo-2-thiophen-2-yl-ethyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:4)
1
yield: 62.8% (1.08 g as a yellow oil), H NMR (300 MHz, CDCl ) δ
3
O
O
7.75-7.76 (m, 1H), 7.66-7.67 (m, 1H), 7.12-7.14 (m, 1H), 3.88 (s, 3H),
P(OMe)2
S
N2
13
3
.86 (s, 3H).; C NMR (125 MHz, CDCl ) δ 177.2 (d, J = 9.7 Hz),
3
cp
1
41.5(d, J = 2.3 Hz), 133.5, 131.1, 128.0, 62.5 (d, J = 216.6 Hz), 54.1, 54.1.; HRMS (EI): m/z
cp cp
calcd for C H N O PS 260.0021, found 260.0019.
8
9
2
4
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8
9
(1-Diazo-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 2:1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yield: 63% (0.73 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2
7
2
.26-7.29 (m, 2H), 7.18-7.20 (m, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 2.94-
N2
1
3
.97 (m, 2H), 2.83-2.76 (m, 2H).; C NMR (125 MHz, CDCl ) δ
3
191.7 (d, J = 13.1 Hz), 140.5, 128.5, 128.4, 126.3, 63.5 (d, J = 220.1 Hz), 53.56, 53.52, 40.9,
cp
cp
3
0.3.; HRMS (EI): m/z calcd for C H N O P 282.0769, found 282.0792.
12 15 2 4
(
1-Diazo-2-oxo-4-phenyl-but-3-enyl)-phosphonic acid dimethyl ester
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1)
1
yield: 68.8% (2.27 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2 7.76 (d, 1H, J = 15.5 Hz), 7.58-7.60 (m, 2H), 7.41-7.42 (m, 3H),
N2
13
7
.12-7.15 (d, 1H, J = 15.5 Hz), 3.90 (s, 3H), 3.87 (s, 3H).; C NMR
(
125 MHz, CDCl ) δ 181.8 (d, J = 13.0 Hz), 143.2, 134.2, 130.8, 129.0, 128.6, 120.8, 64.2 (d,
3
cp
J = 213.9 Hz), 53.6, 53.6.; HRMS (EI): m/z calcd for C H N O P 280.0613, found 280.0614.
cp
12 13
2
4
1
-2. Synthesis of α-hydroxy-β-keto phosphonates
2
5
[
Method A]
O
O
O
O
Rh2
4
P OR2
OR2
(OAc)
P OR2
OR2
OH
R1
R1
THF/H2
O(2:1)
N2
reflux
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6
A solution of the diazo compound (1.0 eq) in THF and H O (2:1 ratio) was refluxed with
2
Rh (OAc) (0.03 eq) for over-night and allowed to cool to room temperature. The mixture was
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
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7
8
9
0
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2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
concentrated in vacuo and the aqueous residue was extracted with EtOAc (x3). The combined
organic layers were washed with water and brine, dried over MgSO , filtered, and evaporated to
4
dryness. The residue was purified chromatography to give the α-hydroxy-β-ketophosphonates.
2
6
[Method B]
O
O
O
O
PhI(OCOCF
3
)
2
P OR2
OR2
OH
P OR2
OR2
R1
R1
H O
2
To a suspension of β-ketophosphonate in H O was added PIFA (2.0 eq) portionwise within 10
2
minutes. The reaction mixture was stirred at room temperature until TLC indicated the total
consumption of the β-ketophosphonate. The reaction mixture was treated with saturated
NaHCO (aq) and extracted with EtOAc (x3). The combined organic layers were washed with
3
water and brine, dried over MgSO . The solvent was removed under vaccum and the residue was
4
purified by chromatography to give a desired product.
(1-Hydroxy-2-oxo-2-phenyl-ethyl)-phosphonic acid diethyl ester [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:4)
1
O
O
yield: 59% (1.30 g as a yellow oil); H NMR (500 MHz, CDCl ) δ 8.02-
3
P(OMe)2
8.03 (d, 2H, J = 7.35 Hz), 7.61-7.64 (m, 1H), 7.47-7.50 (m, 2H), 5.52-5.56
OH
13
(
d, 1H, J = 16.15 Hz), 3.69-3.73 (m, 6H).; C NMR (125 MHz, CDCl ) δ 195.0, 134.7, 133.5,
3
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29.5, 128.6, 72.6 (d, J = 149.8 Hz), 54.3 (d, J = 7.1 Hz), 54.0 (d, J = 7.1 Hz).; HRMS(EI):
cp
cp
cp
m/z calcd for C H O P 244.0501, found 244.0489
1
0
13
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
1-Hydroxy-2-oxo-2-phenyl-ethyl)-phosphonic acid diethyl ester [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:3)
1
yield: 37% (40 mg as a yellow oil); H NMR (300 MHz, CDCl ) δ 8.03-
3
O
O
P(OEt)2
8.06 (m, 2H), 7.61-7.64 (m, 1H), 7.48-7.53 (m, 2H), 5.53 (d, 1H, J = 16.2
OH
13
Hz), 4.03-4.19 (m, 4H), 1.17-1.27 (m, 6H).; C NMR (75 MHz, CDCl ) δ
3
1
6
95.2 (d, J = 2.0 Hz), 134.6, 133.8, 129.5, 128.5, 72.7 (d, J = 149.8 Hz), 63.8 ( d, J = 7.1 Hz),
cp cp cp
3.6 (d, J = 7.2 Hz), 16.2 (d, J = 6.0 Hz).; HRMS (EI): m/z calcd for C H O P 272.0814,
cp
cp
12 17
5
found 272.0813.
(1-Hydroxy-2-oxo-2-m-tolyl-ethyl)-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:3)
1
yield: 57% (0.47 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
Me
P(OMe)2
7
.83-7.86 (m, 2H), 7.45-7.46 (m, 1H), 7.38-7.41 (m, 1H), 5.55 (d, 1H,
J = 16.1 Hz), 3.75 (d, 3H, J = 9.2 Hz), 3.73 (d, 3H, J = 9.1 Hz), 2.43
s, 3H).; C NMR (75 MHz, CDCl ) δ 195.1 (d, J = 2.2 Hz), 138.7, 135.6, 133.6, 129.9, 128.6,
OH
1
3
(
3
cp
1
26.9, 72.6 (d, J = 150.1 Hz), 54.4 (d, J = 7.1 Hz), 54.2 (d, J = 7.1 Hz), 21.4.; HRMS (EI):
cp cp cp
m/z calcd for C H O P 258.0657, found 258.0655.
11
15
5
(1-Hydroxy-2-oxo-2-p-tolyl-ethyl)-phosphonic acid dimethyl ester [Method A]
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2
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5
5
5
5
6
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:3)
1
yield: 67% (0.75 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
.98 (d, 2H, J = 8.3 Hz), 7.33 (d, 2H, J = 8.12 Hz), 5.56 (d, 1H, J =
5.7 Hz), 3.79 (d, 3H, J = 10.8 Hz), 3.74 (d, 3H, J = 10.8 Hz), 2.46 (s,
O
O
P(OMe)2
7
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
Me
1
3
3
1
H).; C NMR (75 MHz, CDCl ) δ 197.5 (d, J = 2.4 Hz) , 139.4, 134.1, 132.8, 131.9, 129.5,
3
cp
25.5, 74.0 (d, J = 152.7 Hz), 54.2 (d, J = 7.0 Hz), 53.6 (d, J = 7.0 Hz), 20.7.; HRMS (EI):
cp
cp
cp
m/z calcd for C H O P 258.0657, found 258.0646.
11
15
5
[2-(4-Methoxyphenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:3)
1
yield: 44% (0.3 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
8.02 (d, 2H, J = 9.0 Hz), 6.93 (d, 2H, J = 9.0 Hz), 5.48 (d, 1H, J =
15.2 Hz), 3.84 (s, 3H), 3.75 (d, 3H, J = 10.8 Hz), 3.67 (d, 3H, J =
O
O
P(OMe)2
OH
MeO
13
10.7 Hz).; C NMR (75 MHz, CDCl ) δ 192.7 (d, J = 2.1 Hz), 164.8, 132.5, 126.2, 114.1, 72.0
3
cp
(
d, J = 149.5 Hz), 55.6, 54.2 (d, J = 7.1 Hz), 54.0 (d, J = 7.1 Hz).; HRMS (EI): m/z calcd for
cp cp cp
C H O P 274.0606, found 274.0602.
11
15
6
[2-(3-Chlorophenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
yield: 99.2% (1.34 g as a yellow oil), H NMR (300 MHz, CDCl ) δ
3
8.03-8.04 (m, 1H), 7.93-7.96 (m, 1H), 7.60-7.64 (m, 1H), 7.44-7.49
(m, 1H), 5.51 (d, 1H, J = 16.5 Hz), 3.79 (d, 3H, J = 11.0 Hz), 3.75 (d,
O
O
Cl
P(OMe)2
OH
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H, J = 9.8 Hz).; C NMR (75 MHz, CDCl ) δ 194.0 (d, J = 2.1 Hz), 135.1, 135.0, 134.6,
3
cp
129.9, 129.3, 127.7, 72.8 (d, J = 150.0 Hz), 54.4 (d, J = 7.1 Hz), 54.2 (d, J = 7.0 Hz).;
cp
cp
cp
HRMS (EI): m/z calcd for C H ClO P 278.0111, found 278.0100.
1
0
12
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[
2-(4-Chlorophenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
yield: 62% (1.2 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2
8.02 (d, 2H, J = 8.7 Hz), 7.49 (d, 2H, J = 8.7 Hz), 5.51 (d, 1H, J =
OH
1
3
Cl
1
6.2 Hz), 3.80 (d, 3H, J = 10.9 Hz), 3.73 (d, 3H, J = 10.8 Hz).; C
NMR (75 MHz, CDCl ) δ 193.8, 141.5, 131.7, 130.9, 129.1, 72.6 (d, J = 149.6 Hz), 54.3 (d, J
3
cp
cp
=
7.2 Hz), 54.2 (d, J = 7.2 Hz).; HRMS (EI): m/z calcd for C H ClO P 278.0111, found
cp 10 12 5
278.0130.
[
2-(4-Fluoro-phenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
yield: 91% (0.7 g as a yellow solid), mp = 101.4-102.9 C; H NMR
P(OMe)2 (500 MHz, CDCl ) δ 8.10-8.12 (m, 2H), 7.16-7.19 (m, 2H), 5.48-5.52
o
1
O
O
3
OH
F
(dd, 1H, J = 5.4, 16.0 Hz), 4.15-4.16 (brs, 1H), 3.79 (d, 3H, J = 10.8
13
Hz), 3.71 (d, 3H, J = 10.8 Hz).; C NMR (75 MHz, CDCl ) δ 193.3 (d, J = 2.1 Hz), 166.7 (d,
3
cp
J = 256.2 Hz), 132.4 (d, J = 9.7 Hz), 129.8 (d, J = 2.9 Hz), 115.9 (d, J = 22.0 Hz), 72.5 (d,
cf
cf
cf
cf
J = 149.5 Hz), 54.3 (d, J = 7.1 Hz), 54.1 (d, J = 7.1 Hz).; HRMS (EI): m/z calcd for
cp
cp
cp
C H FO P 262.0406, found 262.0396.
10
12
5
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2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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[2-(2-Fluorophenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method B]
Purified by column chromatography on silica gel (CH Cl /MeOH, 20:1)
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield: 42% (0.42 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
F
O
O
P(OMe)2
7
.90-7.93 (m, 1H), 7.60-7.94 (m, 1H), 7.28-7.31 (m, 1H), 7.18-7.21 (m,
OH
1
H), 5.65 (d, 1H, J = 18.7 Hz), 3.88-3.92 (brs, 1H), 3.77 (d, 3H, J = 10.7
1
3
Hz), 3.72 (d, 3H, J = 11.0 Hz).; C NMR (125 MHz, CDCl ) δ 193.5, 162.0 (d, J = 254.4 Hz),
3
cf
1
36.1 (d, J = 9.5 Hz), 131.0 (d, J = 1.9 Hz), 124.7 (d, J = 3.2 Hz), 122.9 (d, J = 12.3 Hz),
cf cf cf cf
1
16.6 (d, J = 23.4 Hz), 75.8 (dd, J = 10.7, 148.7 Hz), 54.4 (d, J = 7.3 Hz), 53.9 (d, J = 7.3
cf cp cp cp
Hz) ; HRMS (EI): m/z calcd for C H FO P 262.0406, found 262.0405.
1
0
12
5
[2-(4-Cyano-phenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:3)
1
yield: 56% (0.53 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2
8.15 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H, J = 8.0 Hz), 5.54 (d, 1H, J =
OH
13
NC
1
7.2 Hz), 3.79 (d, 3H, J = 10.9 Hz), 3.73 (d, 3H, J = 10.8 Hz).; C
NMR (125 MHz, CDCl ) δ 194.3 (d, J = 2.0 Hz), 136.6, 132.4, 129.9, 117.7, 117.6, 73.2 (d,
3
cp
J = 149.4 Hz), 54.4 (d, J = 7.3 Hz), 54.2 (d, J = 7.1 Hz).; HRMS (EI): m/z calcd for
cp
cp
cp
C H NO P 269.0453, found 269.0441.
11 12
5
[2-(4-Methoxycarbonyl-phenyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester
[Method A]
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2
3
4
5
6
7
8
9
Purified by column chromatography on silica gel (CH Cl only)
2
2
1
yield: 42% (0.71 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2
8
.15-8.17 (m, 2H), 8.09-8.11 (m, 2H), 5.73 (brs, 1H), 5.62 (d, 1H,
J = 16.9 Hz), 3.96 (s, 3H), 3.77 (d, 3H, J = 7.5 Hz), 3.75 (d, 3H, J
7.5 Hz).; C NMR (125 MHz, CDCl ) δ194.8, 165.9, 136.7, 135.2, 129.7, 129.4, 73.0 (d, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
MeO C
2
13
=
3
cp
1
50 Hz), 54.4 (d, J = 7.2 Hz), 54.2 (d, J = 7.2 Hz), 52.62.; HRMS (EI): m/z calcd for
cp cp
C H O P 302.0555, found 302.0551.
12
15
7
[2-(2-Naphthyl)-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
yield: 88.9% (1.28 g as a yellow oil), H NMR (500 MHz, CDCl )
3
O
O
P(OMe)
2
δ 8.62 (s, 1H), 8.05-8.07 (m, 1H), 7.99-8.01 (d, 1H, J = 8.15 Hz),
OH
7
.86-7.92 (m, 2H), 7.55-7.64 (m, 2H), 5.68-5.72 ( m, 1H), 4.26-
1
3
4.28 (m, 1H), 3.70-3.75 (m, 6H).; C NMR (125 MHz, CDCl ) δ 194.72-194.74 (d, J = 2.2 Hz),
3
cp
1
36.3, 132.2, 132.2, 130.7, 130.0, 129.4, 128.6, 127.9, 127.1, 124.25, 72.1-73.3 (d, J = 149.9
cp
Hz), 54.26-54.32 (d, J = 7.15Hz), 54.08-54.13 (d, J = 7.18 Hz).; HRMS (EI): m/z calcd for
cp
cp
C H O P 294.0657, found 294,0649
14
15
5
(2-Furan-2-yl-1-hydroxy-2-oxo-ethyl)-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:4)
1
yield: 42% (0.76 g as a dark-brown oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)2
7.64 (d, 1H, J = 1.2 Hz), 7.44 (d, 1H, J = 3.7 Hz), 6.54 (dd, 1H, J = 1.7,
O
OH
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
.7 Hz), 5.27 (d, 1H, J = 16.2 Hz), 4.29 (brs, 1H), 3.74 (d, 3H, J = 10.8 Hz), 3.69 (d, 3H, J =
1
3
10.8 Hz).; C NMR (75 MHz, CDCl ) δ 182.6 (d, J = 1.6 Hz), 149.8, 148.1, 121.3, 112.9, 72.3
3
cp
(d, J = 149.4 Hz), 54.2 (d, J = 7.0 Hz), 54.1 (d, J = 7.0 Hz).; HRMS (EI): m/z calcd for
cp cp cp
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C H O P 234.0293, found 234.0293.
8
11
6
(1-Hydroxy-2-oxo-2-thiophen-2-yl-ethyl)-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:3)
1
yield: 93.3% (0.7 g as a dark-brown oil), H NMR (300 MHz, CDCl ) δ
3
O
O
8
.01 (d, 1H, J = 3.6 Hz), 7.81 (d, 1H, J = 5.1 Hz), 7.21 (t, 1H, J = 4.8
P(OMe)2
S
OH
Hz), 5.35 (d, 1H, J = 15.0 Hz), 3.86 (d, 3H, J = 10.8 Hz), 3.77 (d, 3H, J
1
3
=
10.8 Hz), 2.05-2.54 (brs, 1H).; C NMR (75 MHz, CDCl ) δ 187.0 (d, J = 1.8 Hz), 139.6,
3
cp
136.1, 135.6, 128.6, 73.1 (d, J = 149.8 Hz), 54.3 (d, J = 6.7 Hz), 54.2 (d, J = 6.6 Hz).; HRMS
cp
cp
cp
(EI): m/z calcd for C H O PS 250.0065, found 250.0063.
8 11 5
(1-Hydroxy-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1 to 1:3)
1
yield: 87.6% (1.86 g as a pale yellow oil), H NMR (500 MHz,
O
O
P(OMe)2
CDCl ) δ 7.26-7.29 (m, 2H), 7.17-7.21 (m, 3H), 4.65 (d, 1H, J = 18.4
3
OH
Hz), 3.83 (d, 3H, J = 10.9 Hz), 3.73 (d, 3H, J = 10.7 Hz), 3.21-3.26
1
3
(m, 1H), 2.90-2.99 (m, 3H).; C NMR (125 MHz, CDCl ) δ 204.5, 140.2, 128.5, 128.4, 126.3,
3
7
5.5 (d, J = 150.6 Hz), 54.2 (d, J = 7.3 Hz), 54.0 (d, J = 7.3 Hz), 40.9, 29.4.; HRMS (EI): m/z
cp cp cp
calcd for C H O P 272.0814, found 272.0821.
1
2
17
5
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Dimethyl (1-hydroxy-4-methyl-2-oxopentyl)phosphonate [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yield: 70.6% (756 mg as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)
2
4
.64 (d, 1H, J = 18 Hz), 3.88 (d, 3H, J = 10.9 Hz), 3.8 (d, 3H, J = 10.65
OH
Hz), 2.70-2.75 (m, 1H), 2.54-2.59 (m, 1H), 2.22-2.26 (m, 1H), 0.95 (d,
6H, J = 6.75 Hz).; C NMR (125 MHz, CDCl ) δ 204.7 (d, J = 1.5 Hz), 128.1, 75.7 (d, J = 125
1
3
3
cp
cp
Hz), 54.2 (d, J = 7.3 Hz), 54.0 (d, J = 7.0 Hz), 48.2, 24.7, 22.4 (d, J = 30 Hz).; HRMS (EI):
cp
cp
cp
m/z calcd for C H O P 224.0814, found 224.0808
8
17
5
Dimethyl (1-hydroxy-3-methyl-2-oxobutyl)phosphonate [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
yield: 52.2% (1.18 g as a yellow oil), H NMR (500 MHz, CDCl ) δ 4.84
O
O
3
P(OMe)
2
(
d, 1H, J = 18.15 Hz), 3.88 (d, 3H, J = 10.85 Hz), 3.8 (d, 3H, J = 10.65
OH
1
3
Hz), 3.20-3.25 (m, 1H), 1.16-1.2 (m, 6H).; C NMR (125 MHz, CDCl )
3
δ 209.6 (d, J = 2.1 Hz), 73.9 (d, J = 151 Hz), 54.2 (d, J = 7.25Hz), 54.0 (d, J = 6.95 Hz), 37.5,
cp
cp
cp
cp
19.7, 17.3.; HRMS (EI): m/z calcd for C H O P 210.0657, found 210.0617
7
15
5
[
2-cyclohexyl-1-hydroxy-2-oxo-ethyl]-phosphonic acid dimethyl ester [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2 to 1:4)
1
yield: 74.3% (288.1 g as a yellow oil), H NMR (500 MHz, CDCl ) δ
3
O
O
P(OMe)
2
4.78-4.82(d, 1H, J = 17.95 Hz), 3.86-3.88 (d, 3H, J = 10.85 Hz), 3.77-
OH
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
.79(d, 3H, J = 10.8 Hz), 2.93-2.98 (m, 1H), 1.32-1.89 (m, 10H), 5.68-5.72 ( m, 1H), 4.26-4.28
1
3
(m, 1H), 3.70-3.75 (m, 6H).; C NMR (125 MHz, CDCl ) δ 208.37, 73.35-74.56 (d, J = 151.1
3
cp
Hz), 54.16-54.22 (d, J = 7.3 Hz), 53.93-53.98 (d, J = 6.91 Hz), 47.2, 30.1, 27.2, 25.8, 25.6,
cp
cp
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4.9.; HRMS (EI): m/z calcd for C H O P 250.0970, found 250.0961.
10 19 5
Dimethyl (1-hydroxy-3,3-dimethyl-2-oxobutyl)phosphonate [Method B]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:2)
1
O
O
yield: 40.1% (771 mg as a yellow oil), H NMR (500 MHz, CDCl ) δ 5.01
3
P(OMe)
2
(d, 1H, J = 15.4 Hz), 3.87 (d, 3H, J = 10.9 Hz), 3.8 (d, 3H, J = 10.85 Hz),
OH
1
3
1
.29 (s, 9H).; C NMR (125 MHz, CDCl ) δ 212.2, 71.6 (d, J = 147.1 Hz), 54.2 (d, J = 7.4 Hz),
3
cp
cp
5
3.9 (d, J = 7.0 Hz), 43.8, 26.7.; HRMS (EI): m/z calcd for C H O P 224.0814, found
cp 8 17 5
224.0801
(1-Hydroxy-2-oxo-4-phenyl-but-3-enyl)-phosphonic acid dimethyl ester [Method A]
Purified by column chromatography on silica gel (n-Hexane/EtOAc, 1:1)
1
yield: 66.2% (1.27 g as a yellow oil), H NMR (500 MHz, CDCl )
3
O
O
δ 7.82 (d, 1H, J = 15.9 Hz), 7.58 (d, 2H, J = 7.3 Hz), 7.35-7.40 (m,
P(OMe)2
OH
3
H), 7.18 (d, 1H, J = 15.9 Hz), 4.92 (d, 1H, J = 17.7 Hz), 4.26 (brs,
13
1
H), 3.86 (d, 3H, J = 10.8 Hz), 3.76 (d, 3H, J = 10.8 Hz).; C NMR (125 MHz, CDCl ) δ 192.9
3
(d, J = 1.9 Hz), 145.6, 133.9, 131.4, 129.0, 120.6, 75.1 (d, J = 150.7 Hz), 54.3 (d, J = 7.3 Hz),
cp cp cp
5
4.1 (d, J = 6.6 Hz).; HRMS (EI): m/z calcd for C H O P 270.0657, found 270.0659.
cp 12 15 5
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2
. Typical procedure for the synthesis of 4-substituted cyclic imine-5-phosphonates 4 from
9
α-hydroxy-β-keto phosphonates
O
O
O
O
10
11
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13
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59
60
S
1
. ClSO NH /DMA
2 2
N
4
O
5
P(OMe)
2
2. TsOH, Toluene, reflux
OH
P(OMe)
O
2
B
4a
To the solution of 2-phenyl-1-hydroxy-2-oxo-ethyl-phosphonic acid dimethyl ester (B, 1.3 g,
1
2
5
1
.32 mmol) in DMA (N,N-dimethyl acetamide, 20 mL) was added chlorosulfamide (1.3 g,
0.64 mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction
mixture was diluted with EtOAc (30 mL) and washed with brine. The organic layer was dried
over anhydrous MgSO and the solvent was removed. The residue was re-dissolved in toluene
4
(10 mL) and catalytic amount of PTSA (p-toluenesulfonic acid) was added. The reaction mixture
was heated to reflux for 2 h and cooled to room temperature. The solvent was removed and the
reaction mixture was diluted with EtOAc (30 mL) and washed brine. The organics were dried
over MgSO , and evaporated. The residue was recrystallized from EtOAc/n-Hexane, to give the
4
desired imine, as white crystals 4a (0.85 g, 54% yield).
Dimethyl 4-phenyl-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4a
Recrystallized from EtOAc/n-Hexane
o
1
yield: 54% (0.86 g as a white solid), mp = 160.5-162.7 C; H NMR (500
O
N
O
O
S
MHz, CDCl ) δ 8.14-8.16 (m, 2H), 7.74-7.76 (m, 1H), 7.59-7.62 (m, 2H),
3
P(OMe)2
6.19 (d, 1H, J = 10.8 Hz), 3.95 (d, 3H, J = 11.1 Hz), 3.71 (d, 3H, J = 11.1
O
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
Hz).; C NMR (75 MHz, CDCl ) δ 173.5, 136.0, 130.7, 129.2, 126.9, 82.7 (d, J = 155.3 Hz),
3
cp
55.4 (d, J = 7.0 Hz), 55.3 (d, J = 6.1 Hz).; HRMS (EI): m/z calcd for C H NO PS 305.0123,
cp
cp
10 12
6
found 305.0096.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
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0
1
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9
0
1
2
3
4
5
6
7
8
9
0
Diethyl 4-phenyl-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4b
Recrystallized from EtOAc/n-Hexane
o
1
yield: 57% (0.41 g as a white solid), mp = 146.8-147.6 C; H NMR (500
O
N
O
O
S
MHz, CDCl ) δ 8.01-8.12 (m, 2H), 7.69-7.72 (m, 1H), 7.53-7.56 (m, 2H),
3
P(OEt)2 6.10 (d, 1H, J = 10.7 Hz), 4.16-4.25 (m, 2H), 3.88-4.09 (m, 2H), 1.37 (t, 3H,
O
13
J = 7.2 Hz), 1.16 (t, 3H, J = 7.1 Hz).; C NMR (75 MHz, CDCl ) δ 173.8,
3
1
35.8, 130.7, 129.1, 127.1, 83.2 (d, J = 154.5 Hz), 65.4 (d, J = 7.1 Hz), 65.2 (d, J = 7.3 Hz),
cp cp cp
16.3 (d, J = 5.7 Hz), 16.0 (d, J = 5.8 Hz).; HRMS (EI): m/z calcd for C H NO PS 333.0436,
cp
cp
12 16
6
found 333.0434.
Dimethyl 4-(3-methyl-phenyl)-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4c
Recrystallized from EtOAc/n-Hexane
o
1
O
N
O
O
yield: 55% (0.66 g as a white solid); mp = 155.4-157.5 C; H NMR
S
(
500 MHz, CDCl ) δ 7.95 (s, 1H), 7.89 (d, 1H, J = 7.9 Hz), 7.52 (d, 1H,
3
P(OMe)2
O
Me
J = 7.7 Hz), 7.45 (t, 1H, J = 7.8 Hz), 6.12 (d, 1H, J = 10.7 Hz), 3.91 (d,
1
3
3
H, J = 11.1 Hz), 3.71 (d, 3H, J = 11.1 Hz), 2.45 (s, 3H).; C NMR (75 MHz, CDCl ) δ 173.8,
3
1
39.3, 136.9, 130.9, 129.0, 128.0, 126.8, 82.8 (d, J = 155.4 Hz), 55.3 (d, J = 7.0 Hz), 55.2 (d,
cp
cp
J = 7.3 Hz), 21.3.; HRMS (EI): m/z calcd for C H NO PS 319.0279, found 319.0284.
cp
11 14
6
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Dimethyl 4-(4-methyl-phenyl)-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4d
Recrystallized from EtOAc/n-Hexane
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
yield: 73% (0.42 g as a white solid); mp = 208.8-211.5 C; H NMR
O
N
O
O
S
(300 MHz, acetone-d ) δ 8.10 (d, 2H, J = 7.8 Hz), 7.48 (d, 2H, J = 7.9
6
P(OMe)2
O
Hz), 6.97 (d, 1H, J = 11.3 Hz), 3.87 (d, 3H, J = 11.1 Hz), 3.73 (d, 3H, J =
Me
13
11.1 Hz), 2.49 (s, 3H).; C NMR (75 MHz, , acetone-d ) δ 175.4, 147.3,
6
1
30.7, 129.7, 123.9, 83.7 (d, J = 151.1 Hz), 54.7 (d, J = 6.9 Hz), 54.6 (d, J = 6.6 Hz), 21.5.;
cp cp cp
HRMS (EI): m/z calcd for C H NO PS 319.0279, found 319.0300.
11 14
6
Dimethyl 4-(4-methoxy-phenyl)-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4e
Recrystallized from EtOAc/n-Hexane
o
1
O
N
O
O
yield: 75% (1.185 g as a white solid); mp = 178.8-180.3 C; H NMR
S
(
500 MHz, CDCl ) δ 8.17 (d, 2H, J = 9.0 Hz), 7.06 (d, 2H, J = 9.0 Hz),
3
P(OMe)2
O
6.12 (d, 1H, J = 10.1 Hz), 3.98 (d, 3H, J = 11.1 Hz), 3.95 (s, 3H), 3.74
MeO
1
3
(
d, 3H, J = 11.0 Hz).; C NMR (75 MHz, DMSO-d ) δ 174.2, 165.6,
6
133.4, 118.7, 114.7, 83.4 (d, J = 151.0 Hz), 56.0, 54.7 (d, J = 7.0 Hz), 54.6 (d, J = 6.8 Hz).;
cp
cp
cp
HRMS (EI): m/z calcd for C H NO PS 335.0229, found 335.0234.
11
14
7
Dimethyl 4-(3-chloro-phenyl)-5H-1,2,3-oxathiazole-5-phosphonate 2,2-dioxide, 4f
Recrystallized from EtOAc/n-Hexane
o
1
yield: 78% (0.94 g as a white solid); mp = 176.7-180.8 C; H NMR
O
N
O
O
S
29
P(OMe)2
Cl
O
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