Quinine-derived thiourea and squaramide catalyzed conjugate addition of α-nitrophosphonates to enones: Asymmetric synthesis of quaternary α-aminophosphonates

Article abstract of DOI:10.1021/jo502332r

Conjugate addition of α-nitrophosphonates to enones was carried out in the presence of two sets of organocatalysts, viz. a quinine-thiourea and a quinine-squaramide. The quinine-thiourea provided the products possessing an α-quaternary chiral center in high enantioselectivities only in the case of electron rich enones. On the other hand, the quinine-squaramide was more efficient in that a wide variety of electron rich and electron poor enones underwent Michael addition of nitrophosphonates to afford the quaternary α-nitrophosphonates in excellent yields and enantioselectivities. The hydrogen bonding donor ability of the bifunctional catalyst, as shown in the proposed transition states, appears primarily responsible for the observed selectivity. However, a favorable π-stacking between the aryl groups of thiourea/squaramide and aryl vinyl ketone also appeared favorable. The reaction was amenable to scale up, and the enantioenriched quaternary α-nitrophosphonates could be easily transformed to synthetically and biologically useful quaternary α-aminophosphonates and other multifunctional molecules.

Full text of DOI:10.1021/jo502332r

Article
pubs.acs.org/joc
Quinine-Derived Thiourea and Squaramide Catalyzed Conjugate
Addition of α‑Nitrophosphonates to Enones: Asymmetric Synthesis
of Quaternary α‑Aminophosphonates
Kalisankar Bera and Irishi N. N. Namboothiri*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
S
* Supporting Information
ABSTRACT: Conjugate addition of α-nitrophosphonates to enones was carried out in the presence of two sets of
organocatalysts, viz. a quinine-thiourea and a quinine-squaramide. The quinine-thiourea provided the products possessing an α-
quaternary chiral center in high enantioselectivities only in the case of electron rich enones. On the other hand, the quinine-
squaramide was more efficient in that a wide variety of electron rich and electron poor enones underwent Michael addition of
nitrophosphonates to afford the quaternary α-nitrophosphonates in excellent yields and enantioselectivities. The hydrogen
bonding donor ability of the bifunctional catalyst, as shown in the proposed transition states, appears primarily responsible for
the observed selectivity. However, a favorable π-stacking between the aryl groups of thiourea/squaramide and aryl vinyl ketone
also appeared favorable. The reaction was amenable to scale up, and the enantioenriched quaternary α-nitrophosphonates could
be easily transformed to synthetically and biologically useful quaternary α-aminophosphonates and other multifunctional
molecules.
In spite of the above-mentioned studies on the synthesis and
applications of aminophosphonates, in general, and configra-
tionally stable α-aminophosphonates, in particular, quaternary
α-aminophosphonates have received only limited attention.15
This is despite the potential of such α-aminophosphonates as
prospective building blocks in the synthesis of novel protease
inhibitors due to their configurational stability.1
As part of our ongoing research program concerned with the
development of novel methods for the enantioselective
synthesis of nitro- and aminophosphonates, we have reported
the asymmetric synthesis of γ-nitrophosphonates via highly
diastereo- and enantioselective Michael addition of α-lithiated
phosphonates to nitroalkenes using cinchonine as the chiral
catalyst.16 Also β-nitrophosphonates were synthesized by
(S)(−)−Li−Al-BINOL (ALB) catalyzed asymmetric Michael
addition of dialkyl phosphites to nitroalkenes with excellent
enantioselectivity.17 We envisaged that the addition of α-
substituted α-nitrophosphonates to a wide variety of electro-
philes in the presence of suitable chiral catalysts would provide
quaternary α-nitrophosphonates which are immediate precur-
sors of quaternary α-aminophosphonates.18 Very recently, we
INTRODUCTION
■
Aminophosphonic acids are regarded as transition state
analogues of amino acids due to the ability of the phosphonate
moiety to mimic the tetrahedral transition state of peptide bond
hydrolysis.1 The remarkable synthetic and biological profile of
aminophosphonates has stimulated considerable research in
this area.2−4 The role of α-aminophosphonates, in particular, as
various biological agents, viz. antibacterial, antifungal, antiviral,
antitumor and as inhibitors of HIV protease and phosphatase
has been extensively investigated.5,6 α-Aminophosphonates
have been successfully employed as proline surrogates in
asymmetric aldol and Michael reactions.7 The α-amino-
phosphonate moiety is a constituent of bioactive natural
product K-26.8 Since the biological and catalytic activities are
dependent on the absolute configuration at the α-carbon, there
have been many approaches to enantioenriched α-amino-
phosphonates including resolution and auxiliary based
approaches.9 However, catalytic asymmetric approaches have
attracted tremendous attention in recent years.10 These include
hydrophosphonylation of imines,11 nucleophilic addition to α-
iminophosphonates,12 electrophilic amination of α-phospho-
nate carbanion13 and nucleophilic addition of phosphonate
analogues of glycine to various electrophiles.14
Received: October 12, 2014
© XXXX American Chemical Society
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have reported the catalytic enantioselective synthesis of
quaternary α-nitrophosphonates via Michael addition of α-
nitrophosphonates to enones in the presence of a quinine-
thiourea catalyst.19 Similar addition of α-nitrophosphonates to
vinyl sulfones under the catalytic influence of alkaloid-derived
squaramide20 and thiourea21 has been reported. Herein we
report the full version of our preliminary communication on the
addition of α-nitrophosphonates to enones.19 Our report
describes not only the scope and applications of our
methodology but a comparative study on possible hydrogen
bonding and π-stacking interactions between the catalyst and
the substrate by taking two different types of catalysts, viz.
quinine-thiourea and quinine-squaramide. Our investigations
Table 1. Scope of Enones 1
a
b
entry
R, 1
3
time (h) % yield
% ee
1
Ph, 1a
3a
3b
3c
3d
3e
3f
34
34
34
34
34
30
30
32
40
40
32
81
86
85
86
84
75
80
83
78
82
70
45
74
72
87
78
35
69
70
42
43
44
2
4-MeC6H4, 1b
4-MeOC6H4, 1c
3,4-(MeO)2C6H3, 1d
3,4,5-(MeO)3C6H2, 1e
4-NO2C6H4, 1f
4-CF3C6H4, 1g
3-BrC6H4, 1h
3
4
5
6
also unravel the superior catalytic activity of squaramide vis-a-
̀
7
3g
3h
3i
vis thiourea in catalyzing the reaction of a wide range of enones
8
with α-nitrophosphonates.
9
2-furyl, 1i
10
11
2-thienyl, 1j
3j
c-C6H11, 1k
3k
RESULTS AND DISCUSSION
■
a
b
After silica gel column chromatography. ee determined by chiral
At the outset, several thiourea and other catalysts C1−C8 were
screened for the conjugate addition of α-nitrophosphonate 2a
to enone 1b (Figure 1).19 Among these, the quinine-thiourea
catalyst C8 was identified as the best to investigate the scope of
the reaction (Table 1).19 In fact, it was more suited for enones
possessing electron donating aromatic rings 1b−1e (ee 72−
87%, Table 1, entries 2−5) with the exception of 1g−h (ee 69−
70%, entries 7−8). In the case of electroneutral and electron
deficient aryl, heteroaryl and alkyl substituted enones 1a, 1f and
1i−k, respectively, the enantioselectivities were moderate (ee
35−45%, entries 1, 6 and 9−11). Needless to mention, the
chemical yields remained high (70−82%) in these reactions. A
selected electron rich enone 1d was later treated with different
nitrophosphonates 2 to demonstrate the scope of the latter
HPLC.
which led to the synthesis of a variety of nitrophosphonates 4 in
excellent yield and enantioselectivity (Scheme 1). Possible
applications of nitrophosphonates 3 and 4 as potential
precursors for the synthesis of cyclic aminophosphonates 5
and 6 have also been investigated. Thus, nitrophosphonate 3b
has been converted to amidophosphonate 6 via Baeyer−Villiger
oxidation followed by cascade nitro group reduction-lactamiza-
tion. Similarly, nitrophosphonate 4a (R = Et) has been
subjected to cascade nitro group reduction-intramolecular
condensation to afford cyclic iminophosphonate 5 (Scheme
1).19
Subsequent to the above report (Figure 1, Table 1 and
Scheme 1),19 the absolute configuration of nitrophosphonate
4a (R = Et) was unambiguously assigned as R by single crystal
X-ray structure analysis and that of the others by analogy (see
the Supporting Information). The proposed transition state
involving Re-face addition of nitrophosphonate 2 to vinyl
ketone 1 adequately explains the stereochemical outcome (R
configuration) of quaternary α-nitrophosphonates 3−4 (Figure
2). It involves deprotonation of nitrophosphonate 2 by the
quinuclidine moiety of catalyst C8 and activation of enone 1 by
the thiourea moiety. Severe steric interaction between the
phosphonate moiety and the quinuclidine moiety appears to
disfavor the approach of enone 1 to the Si-face of nitro-
Scheme 1. Scope of Nitrophosphonates and Synthetic
Applications of the Michael Adducts
Figure 1. Catalysts screened for the reaction of vinyl ketone 1b with
nitrophosphonate 2a.
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rich aromatic ring in the conjugate addition of nitro-
phosphonate 2a to electron deficient enone 1f under otherwise
identical conditions (mesitylene-xylene, 85:15, −65 °C, Figure
3 and Table 2).22
At the outset, conjugate addition of nitrophosphonate 2a to
enone 1f was performed in the presence of catalyst C9 to afford
the desired adduct 3f in 93% yield and enhanced
enantioselectivity (35% to 44%, Table 2, entry 1, see also
Table 1, entry 6). Later, catalysts C10−C13 bearing aromatic
rings with greater electron donating capabilities were screened
(Table 2, entries 2−5; Figure 3). Surprisingly, catalyst C10 with
a strongly electron donating OMe group at the para-position of
the aromatic ring decreased the enantioselectivity to 22% (entry
2) though it could enhance the π−π interaction between the
electron deficient aromatic ring of enone 1f and the catalyst’s
electron rich aromatic ring. This observation suggested that the
increase in the electron density of the aromatic ring in C10,
though could enhance the π-stacking, caused an undesirable
decrease in the acidity of thiourea moiety and in turn its
hydrogen bonding ability leading to a dramatic drop in the ee of
conjugate adduct 3f.23 This observation was further supported
by employing catalysts C11−C13 with electron donating
groups at unhindered meta- and/or para-positions (entries 3−
5). Thus, two Me groups at the 3 and 5 positions of the
aromatic ring of catalyst C11 increased the selectivity to 49%
(entry 3). The ee was substantially higher with catalyst C12
possessing a meta-OMe group as compared to C10 (Table 2,
entry 4) clearly indicating a direct correlation between the H-
bonding ability of the thiourea moiety and the substitution on
the aromatic ring. As expected, a 3,4-dimethoxyphenyl group
attached to thiourea moiety as in catalyst C13 decreased the ee
to below 20% confirming the remarkable dependence of
enantioselectivity on the electronic character of the aromatic
ring attached to the thiourea moiety (Table 2, entry 5). These
observations also unambiguously established that the primary
factor that controls the enantioselectivity is H-bonding and not
π-stacking, but when circumstances do permit, π-stacking offers
an additional point of interaction that stabilizes the transition
state and improves the enantioselectivity.
Figure 2. Proposed transition states for the thiourea catalyzed Michael
addition of nitrophosphonates 2 to enones 1.
phosphonate 2. Absence of such steric interaction along with
possible existence of a favorable π−π interaction between the
aryl group of enone 1 and the aryl group of catalyst C8, favored
the approach of enone 1 to the Re-face of nitrophosphonate 2
and afforded nitrophosphonates 3 and 4 with R configuration
(Figure 2).
We reasoned that as catalyst C8 has an electron deficient
aromatic ring attached to the thiourea moiety, the high
enantioselectivities observed, in general, for electron rich
enones could be due to excellent π-stacking between the
electron deficient aromatic ring of the catalyst C8 and the
electron rich aromatic ring of the enones (e.g., 1b−e, Table 1,
entries 2−5). Similarly, the poor selectivities observed for
electroneutral, electron deficient, and heteroaromatic enones as
well as alkyl enones could be due to poor π-stacking between
the two aromatic rings as a result of the electron poor nature
(mismatch in electron density) of both aromatic rings (e.g., 1a,
1f and 1i−j, respectively) or due to the absence of an aromatic
ring in the enone (e.g., 1k, Table 1, entries 1, 6 and 9−11).
In order to circumvent the poor enantioselectivities observed
for enones possessing electron poor aromatic rings, it was
anticipated that a catalyst possessing an electron rich aromatic
ring attached to the thiourea moiety would offer better π-
stacking and in turn improve the enantioselectivity of the
conjugate adduct. Armed with this rationale, we employed
several cinchona derived thiourea catalysts with a key electron
Figure 3. Thiourea and squaramide catalysts screened.
C
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Table 2. Screening of Catalysts and Reaction Conditions
a
b
entry
1
C
solvent
T (°C)
time (h)
3
% yield
% ee
c
c
c
c
c
c
c
c
c
1
1f
C9
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
mesitylene:xylene
DCM
−65
−65
−65
−65
−65
−65
−65
−65
−65
rt
20
20
20
20
20
10
10
7
3f
93
90
92
90
89
85
87
90
90
88
89
91
92
95
92
88
91
90
44
22
49
40
19
60
70
90
91
67
62
63
78
80
83
74
65
92
2
1f
C10
C11
C12
C13
C14
C15
C16
C16
C16
C16
C16
C16
C16
C16
C16
C16
C17
3f
3
1f
3f
4
1f
3f
5
1f
3f
6
1f
3f
7
1f
3f
8
1f
3f
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
20
2
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
10
11
12
13
14
15
16
17
18
EDC
rt
2
CHCl3
rt
2
toluene
rt
2
xylene
rt
2
mesitylene
rt
2
THF
rt
2
MeCN
rt
2
c
mesitylene:xylene
−65
c
20
a
b
After silica gel column chromatography. ee determined by chiral HPLC. Ratio 85:15.
At this juncture, it became apparent that we needed a catalyst
Table 3. Scope of Enones 1
which could form stronger hydrogen bonding with the
electrophile compared to the thiourea derivative and also
possess an aromatic ring with optimum electron density. The
recent success of chiral squaramides as strong hydrogen bond
donor catalysts in asymmetric catalysis prompted us to employ
a squaramide derivative as catalyst in our reaction.24 Therefore,
we screened the quinine-squaramide catalysts C14−C16 in the
conjugate addition of nitrophosphonate 2a to enone 1f (Table
2, entries 6−8). To our delight, 10 mol % of squaramide C14
provided the quaternary α-nitrophosphonate 3f in good yield
(85%) and with 60% enantioselectivity (Table 2, entry 6). The
enantioselectivity further improved to 70% when squaramide
C15 was employed (Table 2, entry 7). However, the best
enantioselectivity (90%) was obtained with squaramide C16
(Table 2, entry 8). Under the same reaction conditions, enone
1a also provided quaternary nitrophosphonate 3a in 90% yield
and 91% selectivity (Table 2, entry 9). Screening of several
solvents at two different temperatures confirmed the efficacy of
our initially chosen solvent system (mesitylene:xylene, 85:15)
and temperature (−65 °C) to get the best results (Table 2,
entries 9−17). Finally, marginally higher selectivity was
obtained in the presence of dihydroquinine-squaramide C17
(Table 2, entry 18), which was chosen for further studies.
Under the optimized conditions, i.e., 10 mol % of squaramide
C17, in mesitylene and xylene (85:15), at −65 °C, the scope of
the above reaction was investigated by treating α-nitro-
phosphonate 2a with various enones 1a−s (Table 3). Although
the steric and electronic properties and position of substituents
on the aromatic ring of enones 1a-s had no effect on the
chemical yields of the Michael adducts 3a−s (90−98% except
in the case of 3k), such factors influenced the selectivities and
rate of the reaction (Table 3). Enones possessing electron
donating substituents (Me and OMe, entries 2−4) and electron
a
b
entry
R, 1
C6H5, 1a
time (h)
3
% yield
% ee
1
20
18
25
30
7
3a
3b
3c
3d
3f
90
92
98
92
90
96
96
93
70
94
96
95
97
98
95
98
92
97
93
94
92
96
85
93
51
92
88
90
74
15
96
95
90
2
4-MeC6H4, 1b
4-MeOC6H4, 1c
3,4-(MeO)2C6H3, 1d
4-NO2C6H4, 1f
3-BrC6H4, 1h
2-furyl, 1i
3
4
5
6
10
10
13
25
10
8
3h
3i
7
8
2-thienyl, 1j
3j
9
c-C6H11, 1k
3k
3l
10
11
12
13
14
15
16
17
4-ClC6H4, 1l
4-CNC6H4, 1m
4-BrC6H4, 1n
2-ClC6H4, 1o
1-naphthyl, 1p
2-naphthyl, 1q
PhCHCH, 1r
C6H5CHCMe, 1s
3m
3n
3o
3p
3q
3r
3s
10
20
18
12
15
28
91
b
a
Isolated yield after silica gel column chromatography. ee determined
by chiral HPLC.
withdrawing substituents (NO2, Br, Cl, CN, entries 5−6 and
10−12) at unhindered positions of the aromatic ring furnished
the Michael adducts 3b−d, 3f, 3h, 3l−n in excellent yields
(90−98%) and selectivities (88−97%) over a period of 7−30 h.
However, the rate of the reaction was faster for electron
deficient enones (7−10 h, entries 5−6 and 10−12) compared
with their electron rich congeners (18−30 h, entries 2−4).
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Heteroaromatic enones 1i,j reacted with nitrophosphonate 2a
in 10−13 h to provide the products 3i,j in 93−96% yield and
85−93% ee (entries 7−8). Though the ortho-substituted
aromatic enone 1o provided Michael adduct 3o in excellent
yield (97%), the enantioselectivity surprisingly dropped to 74%
(entry 13). Poor selectivity (15% ee) was observed also in case
of 1-naphthyl vinyl ketone 1p (entry 14). However, 2-naphthyl
vinyl ketone 1q furnished the Michael adduct 3q in excellent
yield 95% and selectivity 96% (entry 15). Notably, the
regioselective Michael addition of α-nitrophosphonate 2a to
the β-unsubstituted olefin moiety over the β-substituted olefin
moiety in enone 1r,s was observed under the present reaction
conditions (entries 16−17). An aliphatic enone 1k also
furnished the Michael adduct 3k in moderate yield and
selectivity which suggests that π-stacking interaction may be
important for higher asymmetric induction (entry 9).
Further, we also explored the scope of the reaction with
other sterically and electronically different nitrophosphonates
2b−g (Table 4). Various alkyl, cycloalkyl, ester and benzyl
substituted nitrophosphonates 2b−g were treated with a
representative enone 1h under the optimal reaction conditions
(Table 4). It is noteworthy that regardless of the length of the
alkyl substituents and bulkiness of the nitrophosphonates, the
Michael adducts 7a−f were isolated in excellent yields (94−
98%) and selectivities (91−98% ee) over a period of 10−22 h
(Table 4, entries 1−6). Presumably, due to the bulkiness of the
substituent, the rate of the reaction was very slow at −65 °C in
case of cyclopropyl substituted nitrophosphonate 2d and the
reaction was performed at −40 °C (entry 3).
The absolute configuration of the Michael adduct 3n was
unambiguously assigned as R by single crystal X-ray structure
analysis and that of the others was assigned by analogy (see the
Supporting Information). The observed stereochemistry can be
explained based on the transition state proposed in Figure 4. It
involves deprotonation of nitrophosphonate 2 by the
quinuclidine moiety of catalyst C17 and activation of enone
1 by the squaramide moiety (Figure 4). Because of severe steric
interaction between the phosphonate moiety and the
quinuclidine moiety, approach of enone 1 toward the Si face
of nitrophosphonate 2 to provide the product with S
configuration appears disfavored. However, approach of
enone 1 toward the Re face of nitrophosphonate 2 appears
favored in the absence of such steric interactions affording
nitrophosphonates 3 or 7 with R configuration. More
importantly, the distance between the two N−H hydrogens is
Figure 4. Proposed transition state.
approximately 0.6 Å more in squaramide compared to that in
thiourea and the acidity of squaramide hydrogens is
approximately 2 orders of magnitude higher than that of
thiourea.23,24 This allows squaramide to simultaneously activate
enone and nitrophosphonate via hydrogen bonding more
effectively compared to thiourea and in turn provide better
enantioselectivities.
To demonstrate the practical utility of our method, the
asymmetric Michael addition of nitrophosphonate 2a to enone
1h was carried out on multigram scale (Scheme 2).
Gratifyingly, we observed that 5 mol % of catalyst C17 was
sufficient to catalyze the reaction without any appreciable drop
in the yield or selectivity and the desired Michael adduct 3h was
obtained in 2.8 g (95%) with 94% ee.
Nitrophosphonylketones 3 and 7 in which the carbonyl
group is at the δ-position of the nitro and the phosphonate
groups are excellent precursors for the enantioselective
synthesis of quaternary γ-phosphonylcarboxylic acid 9,
hydroxamic acid 12 and amides 10−11 (Scheme 3). Thus, a
representative nitrophosphonylketone 3b was subjected to
Baeyer−Villiger oxidation using m-CPBA-TFA to afford
nitrophosphonylester 8 in 95% yield. Subsequent lithium
hydroxide mediated ester hydrolysis of 8 provided quaternary
γ-nitro-γ-phosphonyl butaric acid 9 in 84% yield. Further, ester
8 was successfully transformed to hydroxamic acid 12 in 94%
yield by treating with hydroxylamine hydrochloride in the
presence of pyridine. Reaction of benzylamine with ester 8 led
to the formation of amide 11 in 82% yield which was subjected
to Zn-HCl-mediated selective reduction of nitro group to
generate quaternary α-aminophosphonate 10 in 96% yield.
Finally, the effect phosphonate ester moiety on the rate of
reaction and the enantioselectivity as well as the possible
deprotection of the ester to obtain free phosphonic acid were
investigated (Schemes 4 and 5). Surprisingly, the addition of di-
isopropyl ester 2h to vinyl ketone 1f remained incomplete even
after 3 days to afford the product 13 in moderate yield (42%)
and selectivity (74% ee, Scheme 4).
Table 4. Scope of Nitrophosphonates 2
Considering the potential of free phosphonic acids to behave
as Bronsted acids in catalysis and also to exhibit biological
activity due to the presence of additional co-ordinating sites as
compared to phosphonate esters, a representative phosphonate
ester 3f was subjected to acid hydrolysis to afford phosphonic
acid 14 in good yield (75%, Scheme 5).
a
b
entry
R, 2
time (h)
7
% yield
% ee
1
2
Et, 2b
10
17
20
20
22
20
7a
7b
7c
7d
7e
7f
96
97
94
98
95
98
92
96
92
95
91
98
n-Pr, 2c
Scheme 2. Scaled-up Reaction
c
3
c-C3H5, 2d
4
5
6
n-C9H19, 2e
EtO2C(CH2)3, 2f
PhCH2CH2, 2g
a
b
After silica gel column chromatography. ee determined by chiral
c
HPLC. Reaction performed at −40 °C.
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Scheme 3. Synthetic Transformations of α-Nitrophosphonates
and C1730 were prepared by literature methods. Enones 119 and
nitrophosphonates 219,20 were known in the literature and prepared
following the literature procedures.
Scheme 4. Effect of Ester Group on the Rate of Reaction and
Enantioselectivity
General Procedure for the Synthesis of Thiourea Catalysts
C9−C13. To a solution of dihydroquinineamine (500 mg, 1.54 mmol)
in dry THF (5 mL) was slowly added a solution of aryl isothiocyanate
(1.7 mmol) in dry THF (5 mL) at 0 °C. Then the reaction mixture
was brought to rt and stirred for 12 h. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography using EtOAc−MeOH (98:2) as eluent.
Scheme 5. Acid Mediated Hydrolysis of Phosphonate Ester
to Phosphonic Acid
Catalyst C9. Colorless solid; Yield 440 mg, 60%; mp 116−119 °C;
IR (film, cm−1) 3264 (br m), 2955 (m), 2930 (m), 2866 (w), 1622
(m), 1589 (w), 1512 (vs), 1475 (m), 1337 (w), 1314 (w), 1297 (w),
1
1261 (w), 1241 (m), 1229 (m), 1032 (w), 853 (w); H NMR (400
MHz, CDCl3) δ 0.75 (t, J = 7.3 Hz, 3H), 0.92 (dd, J = 13.0, 6.4 Hz,
1H), 1.08−1.28 (m, 3H), 1.36−1.45 (br m, 1H), 1.46−1.56 (br m,
1H), 1.57−1.62 (br m, 1H), 1.62−1.72 (br m, 1H), 2.36 (s, 3H),
2.36−2.43 (m, overlaps with singlet, 1H), 2.58−2.69 (m, 1H), 3.08
(dd, J = 13.5, 10.0 Hz, 1H), 3.12−3.17 (br m, 1H), 3.27−3.38 (br m,
1H), 3.93 (s, 3H), 5.90 (br s, 1H), 7.07, 7.16 (ABq, J = 8.1 Hz, 4H),
7.16 (br s overlap with ABq, 1H), 7.34 (dd, J = 9.2, 2.6 Hz, 1H), 7.78
(br s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.27 (br s, 1H, D2O
exchangeable), 8.44 (s, 1H), 8.98 (br s, 1H, D2O exchangeable); 13C
NMR (100 MHz, CDCl3) δ 12.1, 21.2, 25.2, 25.6, 27.4, 28.4, 37.1,
41.6, 55.8, 57.0, 60.8, 102.6, 119.9, 122.0, 125.6, 128.4, 130.2, 131.7,
135.1, 136.7, 144.8, 145.6, 147.7, 157.9, 180.7; MS (ES+, Ar) m/z (rel
intensity) 477 ([MH + 2]+, 13), 476 ([MH + 1]+, 36), 475 (MH+,
100), 458 (12), 368 (17); HRMS (ES+, Ar) calcd for C28H35N4OS
(MH+) 475.2532, found 475.2523; [α]25D = −224.0° (c = 0.5, CHCl3).
Catalyst C11. Colorless solid; Yield 820 mg, 68%; mp 117−120 °C;
IR (film, cm−1) 3194 (br s), 2930 (vs), 2865 (s), 1622 (s), 1590 (s),
1511 (vs), 1475 (s), 1346 (m), 1313 (m), 1296 (m), 1228 (s), 1136
CONCLUSIONS
■
The quinine-thiourea catalyzed Michael addition of tertiary α-
nitrophosphonates to vinyl ketones proceed with high
enantioselectivity in the case of electron rich aromatic enones
and low to moderate enantioselectivity in the case of electron
poor aromatic enones. On the other hand, both types of enones
undergo the Michael addition with high enantioselectivity in
the presence of a quinine-squaramide catalyst suggesting the
̀
superior catalytic activity of squaramide vis-a-vis thiourea in this
transformation. This is attributed primarily to the ability of
squaramide to form strong H-bonding when compared with
thiourea though the catalyst-substrate interaction via π-stacking
that supplements the former also appears probable. Scale up of
the reaction to multigram scale and synthetic transformations
of the Michael adducts, α-nitro-δ-ketophosphonates, to
carboxylic acid, amide, hydroxamic acid and phosphonic acid
with a key quaternary chiral center have been successfully
carried out.
1
(vw), 1082 (w), 1032 (m), 853 (m), 736 (m); H NMR (400 MHz,
CDCl3) δ 0.74 (t, J = 7.3 Hz, 3H), 0.94 (dd, J = 13.2, 6.7 Hz, 1H),
1.07−1.27 (m, 3H), 1.35−1.44 (br m, 1H), 1.46−1.55 (br m, 1H),
1.57−1.62 (br m, 1H), 1.62−1.72 (br m, 1H), 2.31 (s, 6H), 2.37 (dd, J
= 13.8, 3.0 Hz, 1H), 2.64−2.73 (m, 1H), 2.99−3.08 (m, 1H), 3.10 (dd,
J = 13.5, 10.0 Hz, 1H), 3.25−3.38 (br m, 1H), 3.91 (s, 3H), 5.81 (br s,
1H), 6.81 (s, 2H), 6.91 (s, 1H), 7.12 (br s, 1H), 7.33 (dd, J = 9.2, 2.3
Hz, 1H), 7.75 (br s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.25 (br s, 1H, D2O
exchangeable), 8.47 (s, 1H), 8.76 (br s, 1H, D2O exchangeable); 13C
NMR (100 MHz, CDCl3) δ 12.1, 21.4, 25.2, 25.8, 27.4, 28.6, 37.2,
41.6, 55.7, 57.2, 60.9, 102.5, 119.9, 121.9, 123.1, 128.3, 131.6, 137.3,
139.4, 144.8, 145.8, 147.6, 157.7, 180.3; MS (ES+, Ar) m/z (rel
intensity) 491 ([MH + 2]+, 13), 490 ([MH + 1]+, 38), 489 (MH+,
100), 311 (45), 290 (22); HRMS (ES+, Ar) calcd for C29H37N4OS
(MH+) 489.2688, found 489.2689; [α]25D = −150.1° (c = 0.5, CHCl3).
Catalyst C12. Colorless solid; Yield 870 mg, 72%; mp 109−112 °C;
IR (film, cm−1) 3277 (br m), 2927 (s), 2864 (m), 1621 (m), 1602
(m), 1557 (s), 1509 (vs), 1433 (w), 1302 (m), 1266 (s), 1228 (s),
1034 (m), 854 (w), 739 (m); 1H NMR (400 MHz, CDCl3) δ 0.74 (t, J
= 7.3 Hz, 3H), 0.90 (dd, J = 13.0, 6.5 Hz, 1H), 1.08−1.28 (m, 3H),
1.34−1.44 (br m, 1H), 1.45−1.55 (br m, 1H), 1.56−1.70 (br m, 2H),
2.39 (br d, J = 10.9 Hz, 1H), 2.58−2.69 (m, 1H), 3.05 (dd, J = 13.3,
10.2 Hz, 1H), 3.08 (br s, 1H), 3.27−3.38 (br m, 1H), 3.74 (s, 3H),
EXPERIMENTAL SECTION
■
General Experimental Details. The melting points recorded are
uncorrected. NMR spectra (1H, 1H decoupled 13C and 31P) were
recorded with TMS as the internal standard for 1H and 13C and
phosphoric acid as the external standard for 31P. The coupling
constants (J values) are given in Hz. The J values reported as part of
13C NMR data are only for C−P couplings. High resolution mass
spectra were recorded under ESI Q-TOF conditions. Enantioselectiv-
ities were determined using an HPLC equipped with a PDA detector
and a chiral column. Specific rotations were measured for solutions of
samples of known concentrations in CHCl3 using a polarimeter
equipped with a sodium vapor lamp. X-ray data were collected on a
diffractometer equipped with graphite monochromated Mo Kα
radiation. The structure was solved by direct methods shelxs97 and
refined by full-matrix least-squares against F2 using shelxl97 software.
Catalysts C1−C2 and C4−C5,25 C3,26 C6,27 C7−C8,19 C10,28 C1629
F
DOI: 10.1021/jo502332r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.93 (s, 3H), 5.91 (br s, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.79 (dd, J =
8.2, 2.2 Hz, 1H), 6.84 (s, 1H), 7.15 (br s, 1H), 7.24 (t, J = 8.2 Hz, 1H),
7.34 (dd, J = 9.2, 2.2 Hz, 1H), 7.79 (br s, 1H), 7.96 (d, J = 9.2 Hz,
1H), 8.32 (br s, 1H, D2O exchangeable), 8.46 (br s, 1H), 9.16 (br s,
1H, D2O exchangeable); 13C NMR (100 MHz, CDCl3) δ 12.1, 25.1,
25.7, 27.4, 28.5, 37.2, 41.7, 55.6, 55.8, 57.0, 60.8, 102.5, 110.7, 112.9,
117.4, 119.9, 122.0, 128.4, 130.2, 131.6, 138.8, 144.8, 145.6, 147.7,
157.8, 160.5, 180.3; MS (ES+, Ar) m/z (rel intensity) 493 ([MH + 2]+,
12), 492 ([MH + 1]+, 37), 491 (MH+, 100), 368 (19), 310 (12);
HRMS (ES+, Ar) calcd for C28H35N4O2S (MH+) 491.2481, found
Hz, 1H), 9.64 (br s, 1H, D2O exchangeable); 13C NMR (100 MHz,
DMSO-d6) δ 26.2 (t), 27.3 (t), 27.4 (d), 39.4 (d), 40.1 (t), 53.3 (d),
55.1 (q), 55.7 (t), 55.8 (q), 58.9 (d), 101.6 (d), 103.9 (d), 108.6 (d),
110.3 (d), 114.4 (t), 119.5 (d), 122.0 (d), 127.6 (s), 130.2 (d), 131.6
(d), 140.0 (s), 142.2 (d), 143.3 (s), 144.4 (s), 147.9 (d), 158.0 (s),
160.2 (s), 163.7 (s), 168.1 (s), 179.9 (s), 184.0 (s); MS (ES+, Ar) m/z
(rel intensity) 527 ([MH + 2]+, 34), 526 ([MH + 1]+, 85), 525
([MH]+, 100), 309 (44), 263 (62); HRMS (ES+, Ar) calcd for
C31H33N4O4 (MH+) 525.2502, found 525.2502; [α]25D = −52.45° (c =
0.25, DMSO).
491.2462; [α]25 = −183.0° (c = 0.5, CHCl3).
General Procedure for the Addition of Dialkyl 1-Nitro-
ethylphosphonate 2 to Enones 1. To a solution of dialkyl-1-
nitroethylphosphonate 2 (0.2 mmol) and catalyst C17 (10 mol %, 0.02
mmol) in mesitylene:xylene (85:15, 0.2 mL) was added enone 1 (0.3
mmol, dissolved in mesitylene:xylene (85:15, 0.2 mL) at −65 °C. The
reaction mixture was stirred at the same temperature and monitored
by TLC. The solvent was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography using
EtOAc−pet ether as eluent (30−45% gradient elution).
D
Catalyst C13. Colorless solid; Yield 490 mg, 61%; mp 108−110 °C;
IR (film, cm−1) 3208 (br m), 2999 (w), 2954 (m), 2931 (m), 2870
(w), 1622 (m), 1591 (w), 1512 (vs), 1465 (m), 1348 (w), 1296 (w),
1
1262 (m), 1238 (s), 1135 (w), 1028 (m), 854 (w); H NMR (400
MHz, CDCl3) δ 0.75 (t, J = 7.3 Hz, 3H), 0.89 (dd, J = 14.6, 6.9 Hz,
1H), 1.10−1.28 (m, 3H), 1.35−1.44 (br m, 1H), 1.45−1.55 (br m,
1H), 1.59 (br s, 1H), 1.60−1.70 (br m, 1H), 2.38 (d, J = 11.5 Hz, 1H),
2.58−2.68 (br m, 1H), 3.05, 3.09 (ABq, J = 10.1 Hz, 2H), 3.35 (br s,
1H), 3.78 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 5.91 (br s, 1H), 6.68 (d,
J = 7.7 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H),
7.11 (br s, 1H), 7.35 (dd, J = 9.2, 2.4 Hz, 1H), 7.79 (br s, 1H), 7.96 (d,
J = 9.2 Hz, 1H), 8.10 (br s, 1H, D2O exchangeable), 8.43 (br s, 1H),
8.90 (br s, 1H, D2O exchangeable); 13C NMR (100 MHz, CDCl3) δ
12.1, 25.2, 25.7, 27.5, 28.6, 37.2, 41.8, 55.9, 56.2, 57.3, 60.8, 102.6,
110.1, 111.4, 118.2, 119.6, 122.0, 128.4, 130.6, 131.7, 144.9, 145.8,
147.7, 148.0, 149.6, 157.9, 180.7; MS (ES+, Ar) m/z (rel intensity) 523
([MH + 2]+, 12), 522 ([MH + 1]+, 38), 521 (MH+, 100), 369 (15),
368 (55), 309 (14), 297 (9); HRMS (ES+, Ar) calcd for C29H37N4O3S
Diethyl 2-nitro-5-oxo-5-phenylpentan-2-ylphosphonate (3a).19
Colorless solid; Yield 62 mg, 90%; mp 72−74 °C; [α]25D = −8.40° (c
= 1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH = 95/5,
flow rate 0.5 mL/min, λ = 254 nm), tR (major) = 29.0 min, tR (minor)
= 33.7 min; 92% ee.
Diethyl 2-nitro-5-oxo-5-p-tolylpentan-2-ylphosphonate (3b).19
Light yellow liquid; Yield 66 mg, 92%; [α]25 = −8.0° (c = 0.5,
D
CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH = 95/5, flow rate
0.5 mL/min, λ = 230 nm), tR (major) = 27.6 min, tR (minor) = 30.8
min; 97% ee.
(MH+) 521.2586, found 521.2573; [α]25 = −187.50° (c = 0.25,
Diethyl 5-(4-methoxyphenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3c).19 Colorless liquid; Yield 73 mg, 98%; [α]25D = −10.62° (c =
1.00, CHCl3); HPLC Chiralpak IA (pet ether/i-PrOH = 90/10, flow
rate 1 mL/min, λ = 268 nm), tR (major) = 17.5 min, tR (minor) = 19.9
min; 93% ee.
Diethyl 5-(3,4-dimethoxyphenyl)-2-nitro-5-oxopentan-2-yl-
phosphonate (3d).19 Light yellow solid; Yield 74 mg, 92%; mp
58.5−61 °C; [α]25D = −8.97° (c = 1.00, CHCl3); HPLC Chiralpak IA
(pet ether/i-PrOH = 95/5, flow rate 1 mL/min, λ = 230 nm), tR
(major) = 50.6 min, tR (minor) = 56.5 min; 94% ee.
D
CHCl3).
General Procedure for the Synthesis of Squaramide
Catalysts C14−C15. To a solution of 3-methoxy-4-(arylamino)-
cyclobut-3-ene-1,2-dione (3.09 mmol) in dry DCM (10 mL) was
slowly added a solution of quinineamine (1.0 g, 3.09 mmol) in dry
DCM (10 mL) at rt. The reaction mixture was stirred for 48 h, and the
resulting precipitate was isolated by filtration. The residue was washed
with ether (10 mL) and dried in vacuo to afford catalyst C14 or C15
as white solid.
Diethyl 2-nitro-5-(4-nitrophenyl)-5-oxopentan-2-ylphosphonate
Catalyst C14. Colorless solid; Yield 1.325 g, 80%; mp 256−258 °C;
IR (film, cm−1) 3244 (br s), 2945 (br s), 1793 (m), 1678 (s), 1583
(vs), 1472 (vs), 1230 (m), 1172 (w), 1029 (w), 915 (w), 842 (m), 689
(w);1H NMR (400 MHz, DMSO-d6) δ 0.62 (br s, 1H), 1.45−1.55 (br
m, 4H), 2.18 (s, 6H), 2.25 (br s, 1H), 2.57−2.64 (m, 1H), 2.65−2.73
(m, 1H), 3.17 (dd, J = 13.4, 10.2 Hz, 1H), 3.25−3.37 (br m, 1H), 3.46
(q, J = 8.9 Hz, 1H), 3.94 (s, 3H), 4.97 (d, J = 10.7 Hz, 1H), 5.01 (d, J
= 17.3 Hz, 1H), 5.97 (td, J = 17.3, 10.7 Hz, 1H), 6.04 (br s, 1H), 6.63
(s, 1H), 6.94 (s, 2H), 7.44 (dd, J = 9.2, 2.5 Hz, 1H), 7.66 (d, J = 4.6
Hz, 1H), 7.78 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.10 (br s, 1H, D2O
exchangeable), 8.81 (d, J = 4.6 Hz, 1H), 9.58 (br s, 1H, D2O
exchangeable); 13C NMR (100 MHz, DMSO-d6) δ 21.1 (q), 26.2 (t),
27.3 (t), 27.4 (d), 39.4 (d), 40.1 (t), 53.3 (d), 55.7 (t), 55.7 (q), 58.8
(d), 101.5 (d), 114.3 (t), 116.0 (d), 119.6 (d), 122.0 (d), 124.5 (d),
127.5 (s), 131.6 (d), 138.5 (s), 142.3 (d), 143.3 (s), 144.3 (s), 147.8
(d), 157.9 (s), 163.7 (s), 167.9 (s), 180.0 (s), 184.0 (s); MS (ES+, Ar)
m/z (rel intensity) 525 ([MH + 2]+, 8), 524 ([MH + 1]+, 38), 523
(MH+, 100), 309 (10), 192 (14); HRMS (ES+, Ar) calcd for
C32H35N4O3 (MH+) 523.2709, found 523.2707; [α]25D = −69.07° (c =
0.25, DMSO).
Catalyst C15. Colorless solid; Yield 1.240 g, 75%; mp 167−169 °C;
IR (film, cm−1) 3265 (br m), 2927 (m), 1672 (m), 1627 (m), 1606
(m), 1547 (m), 1435 (s), 1224 (w), 1027 (w), 923 (w), 823 (w), 684
(w); 1H NMR (400 MHz, DMSO-d6) δ 0.63 (br s, 1H), 1.46−1.59 (br
m, 4H), 2.25 (br s, 1H), 2.56−2.73 (m, 2H), 3.17 (t, J = 11.4 Hz, 1H),
3.25−3.35 (br m, 1H), 3.47 (q, J = 9.3 Hz, 1H), 3.70 (s, 3H), 3.94 (s,
3H), 4.97 (d, J = 9.5 Hz, 1H), 5.02 (d, J = 17.2 Hz, 1H), 5.98 (td, J =
17.2, 9.5 Hz, 1H), 6.01 (br s, overlaps with td, 1H), 6.56 (d, J = 8.1 Hz,
1H), 6.85 (d, J = 7.9 Hz, 1H), 7.14 (br s, 1H), 7.18 (t, J = 8.1 Hz, 1H),
7.44 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 4.6 Hz, 1H), 7.77 (br s, 1H), 7.96
(d, J = 9.2 Hz, 1H), 8.19 (br s, 1H, D2O exchangeable), 8.82 (d, J = 4.6
(3f).19 Light yellow solid; Yield 70 mg, 90%; mp 79−82 °C; [α]25
=
D
−10.67° (c = 1.00, CHCl3); HPLC Chiralpak IC (pet ether/i-PrOH =
60/40, flow rate 1 mL/min, λ = 216 nm), tR (major) = 32.7 min, tR
(minor) = 50.1 min; 92% ee.
Diethyl 5-(3-bromophenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3h).19 Light yellow oil; Yield 81 mg, 96%; [α]25 = −6.03° (c
D
= 1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH = 95/5,
flow rate 0.5 mL/min, λ = 230 nm), tR (major) = 30.4 min, tR (minor)
= 33.9 min; 96% ee.
Diethyl 5-(furan-2-yl)-2-nitro-5-oxopentan-2-ylphosphonate
(3i).19 Light yellow oil; Yield 63 mg, 95%; [α]25 = −8.25° (c =
D
1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH = 95/5, flow
rate 1 mL/min, λ = 268 nm), tR (major) = 24.9 min, tR (minor) = 29.1
min; 85% ee.
Diethyl 2-nitro-5-oxo-5-(thiophen-2-yl)pentan-2-ylphosphonate
(3j).19 Colorless solid; Yield 65 mg, 93%; mp 60−61 °C; [α]25
=
D
−6.92° (c = 1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH
= 95/5, flow rate 0.5 mL/min, λ = 260 nm), tR (major) = 44.2 min, tR
(minor) = 49.5 min; 93% ee.
Diethyl 5-cyclohexyl-2-nitro-5-oxopentan-2-ylphosphonate
(3k).19 Colorless liquid; Yield 49 mg, 70%; [α]25 = −1.08 (c =
D
1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH = 95/5, flow
rate 0.5 mL/min, λ = 254 nm), tR (major) = 18.5 min, tR (minor) =
20.3 min; 51% ee.
Diethyl 5-(4-chlorophenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3l). Colorless solid; Yield 71 mg, 94%; mp 56−58 °C; IR
(film, cm−1) 2984 (m), 2925 (m), 2854 (m), 1689 (s), 1590 (m),
1572 (m), 1547 (s), 1488 (w), 1445 (w), 1400 (w), 1370 (w), 1336
(w), 1258 (s), 1213 (m), 1177 (w), 1163 (w), 1092 (m), 1048 (vs),
1
1021 (vs), 979 (s), 863 (w), 790 (w), 761 (w); H NMR (400 MHz,
CDCl3) δ 1.35 (t, J = 7.0 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H), 1.84 (d, J =
G
DOI: 10.1021/jo502332r
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14.2 Hz, 3H), 2.57 (dtd, J = 15.2, 10.2, 5.0 Hz, 1H), 2.75 (dtd, J =
15.2, 10.2, 5.0 Hz, 1H), 3.05, 3.13 (ABqdd, J = 17.7, 10.2, 5.0 Hz, 2H),
4.19−4.31 (m, 4H), 7.43 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 16.5, 16.6, 20.8, 30.2, 33.1 (d, J = 7.0
Hz), 64.4 (d, J = 7.0 Hz), 64.7 (d, J = 8.0 Hz), 89.4 (d, J = 151.0 Hz),
129.2, 129.6, 134.7, 140.1, 196.7; 31P NMR (162 MHz, CDCl3) δ 16.4;
MS (ES+, Ar) m/z (rel intensity) 380 ([MH + 2]+, 43), 379 ([MH +
1]+, 20), 378 (MH+, 100), 333 (20), 332 (15), 331 (54), 201 (19), 179
(15); HRMS (ES+, Ar) calcd for C15H22NO6PCl (MH+) 378.0873,
found 378.0878; [α]25D = −10.38° (c = 0.50, CHCl3); HPLC Chiralcel
OD-H (pet ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ = 230 nm),
tR (major) = 32.9 min, tR (minor) = 35.6 min; 92% ee.
PrOH = 80/20, flow rate 1.0 mL/min, λ = 216 nm), tR (major) = 35.3
min, tR (minor) = 37.7 min; 74% ee.
Diethyl 5-(naphthalen-1-yl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3p). Colorless oil; Yield 77 mg, 98%; IR (neat, cm−1) 3051
(w), 2985 (s), 2934 (m), 1683 (s), 1545 (s), 1509 (m), 1443 (m),
1388 (m), 1368 (w), 1336 (m), 1258 (s), 1176 (m), 1164 (m), 1100
(m), 1044 (s), 975 (s), 861 (m), 803 (s), 780 (s), 681 (w), 588 (w),
570 (w); 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J = 7.1 Hz, 3H), 1.37
(t, J = 7.1 Hz, 3H), 1.85 (d, J = 14.3 Hz, 3H), 2.65 (dddd, J = 15.4,
12.7, 9.7, 5.8 Hz, 1H), 2.87 (dtd, J = 15.4, 9.7, 5.8 Hz, 1H), 3.16, 3.23
(ABqdd, J = 17.4, 9.7, 5.8 Hz, 2H), 4.18−4.33 (m, 4H), 7.47 (t, J = 8.3
Hz, 1H), 7.52 (td, J = 8.2, 1.2 Hz, 1H), 7.58 (td, J = 8.2, 1.2 Hz, 1H),
7.85 (dd, J = 8.2, 1.2 Hz, 1H), 7.87 (dd, J = 8.2, 1.2 Hz, 1H), 7.98 (d, J
= 8.3 Hz, 1H), 8.60 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 16.5, 16.5, 20.5 (d, J = 1.0 Hz), 30.5, 36.1 (d, J = 8.0 Hz), 64.5 (d, J =
7.0 Hz), 64.5 (d, J = 7.0 Hz), 89.5 (d, J = 150.0 Hz), 124.5, 125.7,
126.6, 128.1, 128.2, 128.6, 130.2, 133.3, 134.1, 135.0, 201.5; 31P NMR
(162 MHz, CDCl3) δ 16.6; MS (ES+, Ar) m/z (rel intensity) 396
([MH + 2]+, 4), 395 ([MH + 1]+, 23), 394 (MH+, 100), 370 (6), 369
(15), 348 (14), 347 (51), 209 (25), 201 (34), 179 (9); HRMS (ES+,
Diethyl 5-(4-cyanophenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3m). Colorless solid; Yield 71 mg, 96%; mp 103−105 °C; IR
(film, cm−1) 3097 (w), 2988 (w), 2934 (w), 2228 (m), 1693 (s), 1546
(s), 1439 (w), 1388 (w), 1334 (w), 1300 (w), 1256 (m), 1213 (m),
1164 (w), 1048 (s), 1018 (s), 967 (m), 864 (m), 838 (w), 792 (w),
741 (w), 589 (w), 575 (w); 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J =
7.0 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H), 1.83 (d, J = 14.2 Hz, 3H), 2.57
(dtd, J = 15.2, 10.2, 5.1 Hz, 1H), 2.74 (dtd, J = 15.2, 10.2, 5.1 Hz, 1H),
3.10, 3.20 (ABqdd, J = 17.8, 10.2, 5.1 Hz, 2H), 4.17−4.31 (m, 4H),
7.76, 8.02 (ABq, J = 8.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ
16.5, 16.6, 21.1, 30.0, 33.6 (d, J = 7.0 Hz), 64.4 (d, J = 8.0 Hz), 64.8 (d,
J = 7.0 Hz), 89.2 (d, J = 151.0 Hz), 116.8, 118.0, 128.6, 132.7, 139.3,
196.6; 31P NMR (162 MHz, CDCl3) δ 16.2; MS (ES+, Ar) m/z (rel
intensity) 371 ([MH + 2]+, 4), 370 ([MH + 1]+, 20), 369 (MH+, 100),
323 (12), 322 (35); HRMS (ES+, Ar) calcd for C16H22N2O6P (MH+)
369.1216, found 369.1224; [α]25D = −9.42° (c = 0.50, CHCl3); HPLC
Chiralpack IC (pet ether/i-PrOH = 60/40, flow rate 1.0 mL/min, λ =
216 nm), tR (major) = 35.3 min, tR (minor) = 56.4 min; 88% ee.
Diethyl 5-(4-bromophenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3n). Colorless solid; Yield 80 mg, 95%; mp 74−75 °C; IR
(film, cm−1) 2985 (w), 1689 (m), 1586 (w), 1545 (s), 1443 (w), 1397
(w), 1337 (w), 1257 (m), 1210 (w), 1163 (w), 1019 (vs), 983 (m),
863 (w); 1H NMR (500 MHz, CDCl3) δ 1.36 (t, J = 7.0 Hz, 3H), 1.37
(t, J = 6.5 Hz, 3H), 1.84 (d, J = 14.3 Hz, 3H), 2.57 (dtd, J = 15.0, 10.2,
5.0 Hz, 1H), 2.76 (dtd, J = 15.0, 10.2, 5.0 Hz, 1H), 3.05, 3.14 (ABqdd,
J = 17.4, 10.2, 5.0 Hz, 2H), 4.20−4.32 (m, 4H), 7.60 (d, J = 8.3 Hz,
2H), 7.80 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 16.5,
16.5, 20.8, 30.2, 33.0 (d, J = 7.5 Hz), 64.4 (d, J = 5.0 Hz), 64.6 (d, J =
6.3 Hz), 89.4 (d, J = 152.2 Hz), 128.8, 129.7, 132.1, 135.1, 196.8; 31P
NMR (202 MHz, CDCl3) δ 16.4; LRMS (ES+, Ar) 446 (M+2]+, 100),
444 (M+, 98); HRMS (ES+, Ar) calcd for C15H21BrNO6PNa (MNa+)
444.0182, found 444.0181; [α]25D = −9.42° (c = 1.00, CHCl3); HPLC
Chiralpack IA (pet ether/i-PrOH = 90/10, flow rate 0.5 mL/min, λ =
216 nm), tR (major) = 100.3 min, tR (minor) = 112.6 min; 90% ee.
Selected X-ray data: C15H21BrNO6P, M = 422.21, Monoclinic, space
group P2(1), a = 10.158(5) Å, b = 6.593(5) Å, c = 13.228(5) Å, α =
90.000(4)°, β = 98.716(5)°, γ = 90.000(5)°, V = 875.7(9) Å3, Z = 2,
ρcald = 1.601 Mg/m3, F(000) = 432, λ = 0.71073 Å, μ = 2.469 mm−1,
total/unique reflections = 12316/4035. Final R [I > 2σ(I)]: R1 =
0.0533, wR2 = 0.1002. R (all data): R1 = 0.0657, wR2 = 0.1094.
Absolute structure parameter 0.011(9).
Ar) calcd for C19H25NO6P (MH+) 394.1420, found 394.1433; [α]25
D
= −0.70° (c = 1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-
PrOH = 95/5, flow rate 0.5 mL/min, λ = 230 nm), tR (major) = 53.3
min, tR (minor) = 66.7 min; 15% ee.
Diethyl 5-(naphthalen-2-yl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3q). Colorless solid; Yield 75 mg, 95%; mp 63−65 °C; IR
(film, cm−1) 3053 (w), 2985 (m), 2931 (w), 1685 (m), 1546 (s), 1509
(w), 1443 (w), 1388 (w), 1336 (w), 1258 (s), 1176 (w), 1164 (w),
1100 (w), 1049 (s), 1021 (s), 975 (w), 861 (w), 803 (m), 780 (m),
588 (w), 570 (w); 1H NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.0 Hz,
3H), 1.39 (t, J = 7.0 Hz, 3H), 1.89 (d, J = 14.2 Hz, 3H), 2.65 (dddd, J
= 15.2, 10.5, 13.5, 5.2 Hz, 1H), 2.86 (dtd, J = 15.2, 10.0, 5.1 Hz, 1H),
3.22 (ddd, J = 17.4, 10.0, 5.2, Hz, 1H), 3.31 (ddd, J = 17.4, 10.5, 5.1
Hz, 1H), 4.22−4.36 (m, 4H), 7.56 (dt, J = 8.4, 1.4 Hz, 1H), 7.61 (dt, J
= 8.4, 1.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.4, 1.4 Hz,
1H), 7.97 (d, J = 8.0 Hz, 1H), 8.01 (dd, J = 8.4, 1.4 Hz, 1H), 8.46 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 16.4, 16.4, 20.4, 30.2, 32.9 (d, J
= 8.0 Hz), 64.3 (d, J = 7.0 Hz), 64.4 (d, J = 8.0 Hz), 89.4 (d, J = 150.0
Hz), 123.6, 126.9, 127.7, 128.5, 128.6, 129.6, 129.8, 132.4, 133.6,
135.6, 197.5; 31P NMR (162 MHz, CDCl3) δ 16.6; MS (ES+, Ar) m/z
(rel intensity) 395 ([MH + 1]+, 23), 394 (MH+, 100), 370 (14), 369
(24), 348 (32), 347 (92), 209 (28), 201 (52), 179 (17); HRMS (ES+,
Ar) calcd for C19H25NO6P (MH+) 394.1420, found 394.1423; [α]25
D
= −15.92° (c = 0.50, CHCl3); HPLC Chiralpack IC (pet ether/i-
PrOH = 60/40, flow rate 1.0 mL/min, λ = 216 nm), tR (major) = 20.3
min, tR (minor) = 22.9 min; 96% ee.
(E)-Diethyl 2-nitro-5-oxo-7-phenylhept-6-en-2-ylphosphonate
(3r). Colorless oil; Yield 72 mg, 98%; IR (neat, cm−1) 3058 (w),
2986 (m), 2934 (w), 2913 (w), 1692 (m), 1665 (m), 1613 (m), 1577
(w), 1546 (s), 1496 (w), 1450 (m), 1388 (w), 1370 (w), 1335 (w),
1258 (s), 1185 (m), 1163 (w), 1097 (m), 1048 (vs), 1022 (vs), 977
1
(s), 857 (w), 793 (w), 752 (m), 692 (m), 587 (w); H NMR (400
MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.79
(d, J = 14.3 Hz, 3H), 2.41−2.55 (m, 1H), 2.63−2.74 (m, 1H), 2.74−
2.86 (m, 2H), 4.16−4.30 (m, 4H), 6.69 (d, J = 16.3 Hz, 1H), 7.31−
7.42 (m, 3H), 7.47−7.54 (m, 2H), 7.53 (d, J = 16.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 16.4, 16.5, 20.4, 30.0, 34.9 (d, J = 8.0 Hz),
64.4 (d, J = 7.0 Hz), 64.5 (d, J = 7.0 Hz), 89.5 (d, J = 150.0 Hz), 125.7,
128.4, 129.1, 130.8, 134.3, 143.4, 197.6; 31P NMR (162 MHz, CDCl3)
δ 16.5; MS (ES+, Ar) m/z (rel intensity) 372 ([MH + 2]+, 4), 371
([MH + 1]+, 20), 370 (MH+, 100), 324 (5), 323 (9), 266 (18), 228
(6), 214 (14), 158 (7); HRMS (ES+, Ar) calcd for C17H25NO6P
Diethyl 5-(2-chlorophenyl)-2-nitro-5-oxopentan-2-ylphospho-
nate (3o). Colorless oil; Yield 73 mg, 97%; IR (neat, cm−1) 3064
(w), 2986 (s), 2934 (s), 2914 (s), 1704 (s), 1590 (m), 1547 (s), 1471
(m), 1435 (m), 1388 (w), 1338 (w), 1290 (w), 1259 (s), 1210 (w),
1163 (m), 1096 (w), 1049 (s), 1025 (s), 975 (m), 861 (m), 791 (w),
758 (s), 588 (m), 567 (w); 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J =
7.1 Hz, 6H), 1.79 (d, JC−P = 14.3 Hz, 3H), 2.46−2.60 (m, 1H), 2.69−
2.82 (m, 1H), 3.04 (t, J = 7.9 Hz, 2H), 4.15−4.29 (m, 4H), 7.25−7.32
(m, 1H), 7.34−7.40 (m, 2H), 7.41−7.45 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 16.4, 16.5, 20.3, 30.0, 37.2 (d, J = 8.0 Hz), 64.4 (d, J =
7.0 Hz), 64.5 (d, J = 7.0 Hz), 89.2 (d, J = 150.0 Hz), 127.1, 129.1,
130.7, 131.0, 132.2, 138.6, 200.7; 31P NMR (162 MHz, CDCl3) δ 16.4;
MS (ES+, Ar) m/z (rel intensity) 380 ([MH + 2]+, 41), 379 ([MH +
1]+, 19), 378 (MH+, 100), 333 (7), 332 (6), 331 (20); HRMS (ES+,
Ar) calcd for C15H22NO6PCl (MH+) 378.0873, found 378.0886;
[α]25D = −4.07° (c = 1.00, CHCl3); HPLC Chiralpack IC (pet ether/i-
(MH+) 370.1420, found 370.1431; [α]25 = −10.92° (c = 1.00,
D
CHCl3); HPLC Chiralpack IC (pet ether/i-PrOH = 60/40, flow rate
1.0 mL/min, λ = 260 nm), tR (major) = 24.3 min, tR (minor) = 41.2
min; 95% ee.
(E)-Diethyl 6-methyl-2-nitro-5-oxo-7-phenylhept-6-en-2-yl-
phosphonate (3s). Colorless oil; Yield 70 mg, 91%; IR (neat, cm−1)
3055 (m), 2871 (m), 2986 (s), 2932 (s), 1668 (s), 1627 (m), 1546
(s), 1491 (w), 1444 (s), 1388 (m), 1369 (m), 1335 (w), 1259 (s),
H
DOI: 10.1021/jo502332r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1204 (w), 1162 (w), 1049 (s), 1025 (s), 974 (m), 925 (w), 861 (m),
793 (m), 754 (s), 700 (m), 679 (w), 588 (m), 511 (w); 1H NMR (400
MHz, CDCl3) δ 1.37 (t, J = 7.0 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H), 1.84
(d, J = 14.3 Hz, 3H), 2.06 (d, J = 1.1 Hz, 3H), 2.50 (dddd, J = 15.2,
12.7, 10.5, 5.0 Hz, 1H), 2.74 (ddt, J = 15.2, 10.0, 5.3 Hz, 1H), 2.89
(ddd, J = 16.7, 10.0, 5.0 Hz, 1H), 2.97 (ddd, J = 16.7, 10.5, 5.3 Hz,
1H), 4.20−4.32 (m, 4H), 7.31−7.38 (m, 1H), 7.39−7.44 (m, 4H),
7.50 (q, J = 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1, 16.3,
16.4, 20.2, 30.6, 31.7 (d, J = 8.0 Hz), 64.3, 64.3, 89.4 (d, J = 149.0 Hz),
128.4, 128.7, 129.7, 135.5, 136.6, 139.3, 199.5; 31P NMR (162 MHz,
CDCl3) δ 16.6; MS (ES+, Ar) m/z (rel intensity) 386 ([MH + 2]+, 4),
385 ([MH + 1]+, 22), 384 (MH+, 100), 359 (13), 338 (12), 337 (36),
266 (30), 238 (12), 201 (25), 200 (11), 199 (50), 179 (14); HRMS
(ES+, Ar) calcd for C18H27NO6P (MH+) 384.1576, found 384.1557;
1H), 3.48 (ddd, J = 18.2, 11.2, 4.4 Hz, 1H), 4.16−4.28 (m, 2H), 4.31−
4.41 (m, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.67 (ddd, J = 7.9, 1.8, 1.0 Hz,
1H), 7.86 (ddd collapsed to dt, J = 7.9, 1.0 Hz, 1H), 8.06 (dd
collapsed to t, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 2.9 (d,
J = 6.0 Hz), 3.9 (d, J = 3.0 Hz), 16.5 (d, J = 6.0 Hz), 16.6 (d, J = 6.0
Hz), 18.2, 25.8, 33.8 (d, J = 2.0 Hz), 63.7 (d, J = 8.0 Hz), 64.8 (d, J =
6.0 Hz), 92.9 (d, J = 156.0 Hz), 123.1, 126.8, 130.4, 131.1, 136.3,
138.3, 197.1; 31P NMR (162 MHz, CDCl3) δ 15.8; MS (ES+, Ar) m/z
(rel intensity) 451 ([MH + 3]+, 24), 450 ([MH + 2]+, 88), 449 ([MH
+ 1]+, 25), 448 (MH+, 100), 404 (22), 403 (93), 402 (27), 401 (81),
265 (30), 263 (40); HRMS (ES+, Ar) calcd for C17H24NO6PBr (MH+)
448.0525, found 448.0523; [α]25D = −2.10° (c = 1.00, CHCl3); HPLC
Chiralcel OD-H (pet ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ =
230 nm), tR (major) = 24.1 min, tR (minor) = 31.8 min; 92% ee.
Diethyl 1-(3-bromophenyl)-4-nitro-1-oxotridecan-4-ylphospho-
nate (7d). Colorless oil; Yield 105 mg, 98%; IR (neat, cm−1) 3064
(m), 2930 (vs), 2860 (vs), 1692 (vs), 1548 (vs), 1467 (s), 1444 (s),
1393 (w), 1369 (w), 1340 (w), 1263 (m), 1207 (m), 1163 (m), 1096
(m), 1067 (s), 951 (m), 904 (w), 864 (w), 790 (s), 761 (s), 739 (s),
700 (m), 682 (m), 566 (m); 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J
= 6.9 Hz, 3H), 1.18−1.32 (m, 13H), 1.35 (t, J = 7.1 Hz, 3H), 1.37 (t, J
= 7.1 Hz, 3H), 1.41−1.54 (m, 1H), 2.05−2.20 (m, 1H), 2.23−2.37 (m,
1H), 2.46 (dtd, J = 15.4, 10.0, 5.4 Hz, 1H), 2.72 (dtd, J = 15.4, 10.0,
5.4 Hz, 1H), 3.26 (ABqdd, J = 17.9, 10.0, 5.4 Hz, 2H), 4.11−4.35 (m,
4H), 7.34 (t, J = 7.9 Hz, 1H), 7.69 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.89
(ddd collapsed to dt, J = 7.9, 1.0 Hz, 1H) 8.08 (dd collapsed to dt, J =
1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 16.5 (d, J = 5.0
Hz), 16.6 (d, J = 5.0 Hz), 22.8, 23.6, 23.7, 28.1, 29.3 (d, J = 3.0 Hz),
29.6, 29.6, 32.0, 34.0 (d, J = 4.0 Hz), 36.4, 64.0 (d, J = 7.0 Hz), 64.7 (d,
J = 7.0 Hz), 93.2 (d, J = 150.0 Hz), 123.2, 126.8, 130.4, 131.2, 136.3,
138.4, 197.1; 31P NMR (162 MHz, CDCl3) δ 16.2; MS (ES+, Ar) m/z
(rel intensity) 559 ([MNa + 3]+, 27), 558 ([MNa + 2]+, 100), 557
([MNa + 1]+, 28), 556 (MNa+, 100); HRMS (ES+, Ar) calcd for
[α]25 = −19.79° (c = 1.00, CHCl3); HPLC Chiralcel OD-H (pet
D
ether/i-PrOH = 95/5, flow rate 1.0 mL/min, λ = 280 nm), tR (major)
= 18.0 min, tR (minor) = 21.2 min; 90% ee.
Diethyl 6-(3-bromophenyl)-3-nitro-6-oxohexan-3-ylphosphonate
(7a). Colorless oil; Yield 84 mg, 96%; IR (neat, cm−1) 2984 (m), 2942
(w), 1692 (s), 1546 (vs), 1442 (w), 1421 (w), 1257 (s), 1207 (w),
1163 (w), 1049 (vs), 1023 (vs), 976 (m), 791 (m), 757 (m), 681 (m);
1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.4 Hz, 3H), 1.29 (t, J =
7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.16 (ddq, J = 14.8, 11.8, 7.4 Hz,
1H), 2.31 (ddq, J = 14.8, 12.2, 7.4 Hz, 1H), 2.41 (dtd, J = 15.5, 10.8,
4.9 Hz, 1H), 2.65 (dtd, J = 15.5, 10.8, 4.9 Hz, 1H), 3.17, 3.25 (ABqdd,
J = 15.9, 10.9, 4.9 Hz, 2H), 4.10−4.28 (m, 4H), 7.28 (t, J = 7.9 Hz,
1H), 7.62 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.83 (ddd collapsed to dt, J =
7.9, 1.4 Hz, 1H), 8.02 (dd collapsed to t, J = 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 8.4 (d, J = 7.0 Hz), 16.5 (d, J = 5.0 Hz), 16.5 (d,
J = 5.0 Hz), 27.7, 29.7, 33.9 (d, J = 4.0 Hz), 63.9 (d, J = 7.0 Hz), 64.7
(d, J = 7.0 Hz), 93.5 (d, J = 150.0 Hz), 123.2, 126.8, 130.4, 131.2,
136.3, 138.3, 197.0; 31P NMR (162 MHz, CDCl3) δ 16.2; MS (ES+,
Ar) m/z (rel intensity) 439 ([MH + 3]+, 20), 438 ([MH + 2]+, 97),
437 ([MH + 1]+, 20), 436 (MH+, 100), 391 (35), 390 (34), 253 (19),
251 (18), 193 (23); HRMS (ES+, Ar) calcd for C16H24NO6BrP (MH+)
436.0525, found 436.0532; [α]25D = −9.06° (c = 1.00, CHCl3); HPLC
Chiralcel OD-H (pet ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ =
216 nm), tR (major) = 24.6 min, tR (minor) = 26.3 min; 92% ee.
Diethyl 1-(3-bromophenyl)-4-nitro-1-oxoheptan-4-ylphospho-
nate (7b). Colorless oil; Yield 87 mg, 97%; IR (neat, cm−1) 2973
(s), 2934 (m), 2876 (w), 1692 (s), 1547 (s), 1468 (w), 1443 (w),
1422 (w), 1338 (vw), 1295 (w), 1255 (s), 1208 (m), 1163 (w), 1096
C23H37NO6PBrNa (MNa+) 556.1434, found 556.1434; [α]25
=
D
−6.72° (c = 1.00, CHCl3); HPLC Chiralcel OD-H (pet ether/i-PrOH
=95/5, flow rate 0.5 mL/min, λ = 230 nm), tR (major) = 15.3 min, tR
(minor) = 18.3 min; 95% ee.
Ethyl 8-(3-bromophenyl)-5-(diethoxyphosphoryl)-5-nitro-8-ox-
ooctanoate (7e). Colorless oil; Yield 99 mg, 95%; IR (neat, cm−1)
3062 (m), 2983 (vs), 2939 (vs), 1727 (vs), 1697 (vs), 1548 (vs), 1477
(w), 1445 (w), 1420 (w), 1338 (vw), 1296 (w), 1261 (m), 1184 (m),
1163 (m), 1096 (m), 1047 (s), 1028 (s), 976 (w), 788 (s), 739 (vs),
703 (s), 684 (m), 563 (m); 1H NMR (400 MHz, CDCl3) δ 1.19 (t, J =
7.1 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H), 1.31 (t, J = 7.3 Hz, 3H), 1.52−
1.65 (m, 1H), 1.68−1.82 (m, 1H), 2.12−2.34 (m, 2H), 2.29 (t, J = 7.0
Hz, 2H), 2.42−2.54 (m, 1H), 2.59−2.73 (m, 1H), 3.22 (ABqdd, J =
9.3, 5.9, 3.0 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 4.12−4.27 (m, 4H),
7.28 (t, J = 7.9 Hz, 1H), 7.63 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.83 (ddd
collapsed to dt, J = 7.9, 1.0 Hz, 1H), 8.04 (dd collapsed to t, J = 1.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.4, 16.5 (d, J = 5.0 Hz),
16.6 (d, J = 5.0 Hz), 19.2, 19.3, 27.9, 33.7, 34.9, 60.8, 64.2 (d, J = 8.0
Hz), 64.8 (d, J = 6.0 Hz), 92.8 (d, J = 149.0 Hz), 123.2, 126.8, 130.4,
131.3, 136.3, 138.3, 172.7, 196.3; 31P NMR (162 MHz, CDCl3) δ 15.7;
MS (ES+, Ar) m/z (rel intensity) 525 ([MH + 3]+, 25), 524 ([MH +
2]+, 100), 523 ([MH + 1]+, 25), 522 (MH+, 100), 478 (40), 477 (36),
476 (40), 475 (30), 431 (20), 429 (20), 301 (31); HRMS (ES+, Ar)
1
(w), 1048 (vs), 1026 (vs), 976 (s), 855 (vw), 790 (m), 765 (m); H
NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H), 1.35 (t, J = 7.1
Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.42−1.58 (m, 1H), 2.09−2.22 (m,
1H), 2.21−2.34 (m, 1H), 2.47 (dtd, J = 15.5, 10.2, 5.2 Hz, 1H), 2.71
(dtd, J = 15.5, 10.2, 5.2 Hz, 1H), 3.22, 3.29 (ABqdd, J = 17.9, 10.2, 5.2
Hz, 2H), 4.16−4.35 (m, 4H), 7.34 (t, J = 7.9 Hz, 1H), 7.68 (ddd, J =
7.9, 1.7, 0.9 Hz, 1H), 7.88 (ddd collapsed to dt, J = 7.9, 1.3 Hz, 1H),
8.08 (dd collapsed to t, J = 1.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.1, 16.5 (d, J = 5.0 Hz), 16.6 (d, J = 5.0 Hz), 17.2 (d, J = 7.0 Hz),
28.1, 34.0 (d, J = 4.0 Hz), 38.3, 64.0 (d, J = 7.0 Hz), 64.7 (d, J = 7.0
Hz), 93.2 (d, J = 150.0 Hz), 123.2, 126.8, 130.4, 131.2, 136.3, 138.3,
197.0; 31P NMR (162 MHz, CDCl3) δ 16.1; MS (ES+, Ar) m/z (rel
intensity) 453 ([MH + 3]+, 21), 452 ([MH + 2]+, 99), 451 ([MH +
1]+, 22), 450 (MH+, 100), 406 (11), 405 (49), 404 (11), 403 (54), 377
(9), 375 (9), 359 (10), 357 (11), 267 (22), 265 (22), 207 (23);
HRMS (ES+, Ar) calcd for C17H26NO6PBr (MH+) 450.0681, found
450.0684; [α]25D = −9.70° (c = 1.00, CHCl3); HPLC Chiralcel OD-H
(pet ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ = 216 nm), tR
(major) = 20.2 min, tR (minor) = 23.0 min; 96% ee.
Diethyl 4-(3-bromophenyl)-1-cyclopropyl-1-nitro-4-oxobutyl-
phosphonate (7c). Colorless oil; Yield 84 mg, 94%; IR (neat,
cm−1) 3065 (m), 2983 (vs), 2931 (s), 2913 (s), 2871 (m), 1691 (vs),
1547 (vs), 1474 (m), 1441 (s), 1335 (w), 1256 (s), 1210 (m), 1163
(m), 1097 (m), 1047 (s), 974 (m), 842 (w), 788 (s), 758 (s), 737 (m),
603 (m), 567 (s); 1H NMR (400 MHz, CDCl3) δ 0.62−0.71 (m, 2H),
0.72−0.82 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H),
1.74 (sextet, J = 7.1 Hz, 1H), 2.23 (ddt, J = 15.4, 11.1, 4.4 Hz, 1H),
2.41 (dtd, J = 15.4, 11.2, 4.4 Hz, 1H), 3.10 (ddd, J = 18.2, 11.1, 4.4 Hz,
calcd for C20H30NO8PBr (MH+) 522.0892, found 522.0872; [α]25
=
D
−4.30° (c = 1.00, CHCl3); HPLC Chiralpack IA (pet ether/i-PrOH =
80/20, flow rate 1.0 mL/min, λ = 250 nm), tR (major) = 10.1 min, tR
(minor) = 8.4 min; 91% ee.
Diethyl 6-(3-bromophenyl)-3-nitro-6-oxo-1-phenylhexan-3-yl-
phosphonate (7f). Colorless oil; Yield 100 mg, 98%; IR (neat,
cm−1) 3063 (w), 3027 (w), 2982 (s), 2934 (m), 2870 (w), 1691 (vs),
1548 (vs), 1497 (w), 1442 (m), 1421 (m), 1393 (w), 1338 (w), 1257
(vs), 1209 (s), 1163 (w), 1096 (w), 1044 (vs), 974 (s), 791 (m), 756
1
(s), 738 (s), 701 (s); H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.1
Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 2.32−2.45 (m, 1H), 2.46−2.64 (m,
3H), 2.65−2.79 (m, 2H), 3.22 (ABqdd, J = 18.0, 10.4, 5.0 Hz, 2H),
4.12−4.30 (m, 4H), 7.12 (dd, J = 7.7, 1.3 Hz, 2H), 7.16 (dt, J = 7.7,
1.3 Hz, 1H), 7.23 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.9 Hz, 1H), 7.62
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(ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.82 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H),
8.01 (dd collapsed to t, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 16.5 (d, J = 6.0 Hz), 16.6 (d, J = 5.0 Hz), 28.6, 30.3 (d, J = 6.0 Hz),
33.9 (d, J = 4.0 Hz), 38.3, 64.1 (d, J = 7.0 Hz), 64.9 (d, J = 7.0 Hz),
93.0 (d, J = 150.0 Hz), 123.3, 126.7, 126.8, 128.6, 128.9, 130.4, 131.2,
136.4, 138.3, 140.1, 196.8; 31P NMR (162 MHz, CDCl3) δ 15.7; MS
(ES+, Ar) m/z (rel intensity) 515 ([MH + 3]+, 25), 514 ([MH + 2]+,
85), 513 ([MH + 1]+, 20), 512 (MH+, 100), 468 (18), 467 (61), 466
(20), 465 (66), 377 (13), 375 (14), 329 (15), 327 (19); HRMS (ES+,
Ar) calcd for C22H28NO6PBr (MH+) 512.0838, found 512.0831;
and pyridine (131 μL, 1.62 mmol) at rt and the mixture was stirred at
rt for 12 h. The mixture was concentrated in vacuo, and the residue
was purified by silica gel column chromatography using EtOAc−
MeOH (5%) as eluent to afford the hydroxamic acid 12. Reddish oil;
Yield 150 mg, 94%; IR (neat, cm−1) 3226 (br vs), 2987 (s), 2929 (s),
1664 (s), 1550 (s), 1445 (m), 1389 (m), 1336 (m), 1243 (s), 1163
(m), 1092 (m), 1048 (s), 1024 (s), 980 (m), 912 (s), 861 (m), 795
1
(w), 735 (s), 647 (w), 587 (w); H NMR (400 MHz, CDCl3) δ 1.37
(t, J = 7.0 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 1.80 (d, J = 14.4 Hz, 3H),
2.19−2.38 (m, 2H), 2.39−2.54 (m, 1H), 2.58−2.72 (m, 1H), 4.17−
4.32 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 16.3 (d, J = 5.0 Hz),
16.3 (d, J = 6.3 Hz), 19.8, 27.1 (d, J = 8.8 Hz), 31.1, 64.6 (d, J = 7.5
Hz), 65.0 (d, J = 7.5 Hz), 89.8 (d, J = 152.2 Hz), 169.4; 31P NMR
(202 MHz, CDCl3) δ 16.4; MS (ES+, Ar) m/z (rel intensity) 322
([MNa + 1]+, 10), 321 (MNa+, 100); HRMS (ES+, Ar) calcd for
[α]25 = −7.58° (c = 1.00, CHCl3); HPLC Chiralcel OD-H (pet
D
ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ = 230 nm), tR (major)
= 37.6 min, tR (minor) = 47.8 min; 98% ee.
(R)-Diisopropyl 2-nitro-5-(4-nitrophenyl)-5-oxopentan-2-yl-
phosphonate (13). Yellow oil; Yield 35 mg, 42%; IR (neat, cm−1)
2983 (m), 2941 (w), 1696 (m), 1603 (w), 1546 (s), 1531 (s), 1463
(w), 1454 (w), 1386 (w), 1376 (w), 1347 (s), 1320 (w), 1255 (m),
1208 (w), 1179 (w), 1143 (w), 1103 (m), 996 (vs), 856 (m), 740 (w);
1H NMR (400 MHz, CDCl3) δ 1.34−1.41 (m, 12H), 1.84 (d, J = 14.2
C9H19N2O7PNa (MNa+) 321.0822, found 321.0826; [α]25 = −4.64°
D
(c = 0.56, CHCl3).
Diethyl 5-(benzylamino)-2-nitro-5-oxopentan-2-ylphosphonate
(11). To a solution of ester 8 (205 mg, 0.55 mmol) in THF (5 mL)
was added benzylamine (120 μL, 1.10 mmol) and the mixture was
refluxed for 24 h. The mixture was concentrated in vacuo, and the
residue was dissolved in EtOAc (15 mL), the organic layer was washed
with 1 N HCl (2 × 5 mL), dried over anhyd sodium sulfate and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography using EtOAc−Pet ether
(50−90%) as eluent to afford the amide 11. Colorless oil; Yield 168
mg, 82%; IR (neat, cm−1) 3431 (br vs), 3302 (br vs), 2988 (w), 2923
(w), 1654 (s), 1546 (vs), 1454 (w), 1389 (w), 1336 (w), 1245 (s),
Hz, 3H), 2.58 (dtd, J = 15.1, 10.2, 5.1 Hz, 1H), 2.78 (dtd, J = 15.1,
10.2, 5.1 Hz, 1H), 3.15, 3.25 (ABqdd, J = 17.8, 10.2, 5.1 Hz, 2H),
4.75−4.92 (m, 2H), 8.10 (d, J = 8.9 Hz, 2H), 8.31 (d, J = 8.9 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 21.1, 23.7 (d, J = 6.0 Hz), 23.8 (d, J =
6.0 Hz), 24.3 (d, J = 3.0 Hz), 24.4 (d, J = 3.0 Hz), 30.1, 34.0 (d, J = 7.0
Hz), 73.5 (d, J = 7.0 Hz), 73.9 (d, J = 7.0 Hz), 89.4 (d, J = 150.0 Hz),
124.1, 129.3, 140.9, 150.7, 196.5; 31P NMR (162 MHz, CDCl3) δ
14.14; MS (ES+, Ar) m/z (rel intensity) 441 ([MNa + 2]+, 4), 440
([MNa + 1]+, 18), 439 (MNa+, 100), 417 (4), 397 (13); HRMS (ES+,
Ar) calcd for C17H25N2O8PNa (MNa+, 100) 439.1241, found
1
1162 (w), 1020 (vs), 977 (w), 860 (w), 751 (w), 701 (w); H NMR
439.1246; [α]25 = −5.38° (c = 1.00, CHCl3); HPLC Chiralpack IC
(400 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 6H), 1.78 (d, J = 14.3 Hz,
3H), 2.22−2.39 (m, 2H), 2.45−2.59 (m, 1H), 2.62−2.76 (m, 1H),
4.15−4.27 (m, 4H), 4.41 (d, J = 5.4 Hz, 2H), 6.03 (t, J = 5.4 Hz, 1H),
7.23−7.30 (m, 3H), 7.30−7.36 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 16.4 (d, J = 6.0 Hz), 16.5 (d, J = 6.0 Hz), 20.1, 30.5 (d, J =
9.0 Hz), 31.5, 43.8, 64.4 (d, J = 7.0 Hz), 64.5 (d, J = 8.0 Hz), 89.6 (d, J
= 152.2 Hz), 127.6, 127.9, 128.8, 138.2, 170.9; 31P NMR (202 MHz,
CDCl3) δ 16.4; MS (ES+, Ar) m/z (rel intensity) 396 ([MNa + 1]+,
13), 395 (MNa+, 100), 373 (45), 367 (13), 350 (26), 328 (19);
HRMS (ES+, Ar) calcd for C16H25N2O6PNa (MNa+) 395.1342, found
395.1344; [α]25D = −5.68° (c = 1.00, CHCl3); HPLC Chiralcel AD-H
(pet ether/i-PrOH = 95/5, flow rate 0.5 mL/min, λ = 204 nm), tR
(major) = 20.3 min, tR (minor) = 26.0 min; 95% ee.
D
(pet ether/i-PrOH = 70/30, flow rate 1.0 mL/min, λ = 230 nm), tR
(major) = 22.3 min, tR (minor) = 30.6 min; 74% ee.
Synthetic Applications of Nitrophosphonates 3b. p-Tolyl 4-
(diethoxyphosphoryl)-4-nitropentanoate (8).19 TFA (2.7 mmol, 200
μL) was added to a stirred solution of m-chloroperbenzoic acid (55−
75%, 4 mmol, 1.0 g) in dichloromethane (3 mL) at rt and the stirring
was continued for 6 h. A solution of 3b (0.5 mmol, 179 mg) in
dichloromethane (1 mL) was added to the reaction mixture and
stirring was continued for another 14 h at rt. The reaction mixture was
diluted with ether (15 mL), washed with a 1 N NaOH solution (10
mL), brine (10 mL) and dried over anhyd sodium sulfate. The organic
layer was concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography using EtOAc−pet ether
(35%) as eluent to afford the ester 8. Light yellow oil; Yield 63 mg,
Diethyl 2-amino-5-(benzylamino)-5-oxopentan-2-ylphospho-
nate (10). Activated Zn (440 mg, 6.71 mmol) was added to a
solution of 10 (100 mg, 0.27 mmol, 95% ee) in EtOH (5 mL) and 2 N
HCl (2 mL) at 0 °C. The reaction mixture was stirred for 2 h at rt.
Then the crude residue was filtered through Celite and concentrated
under reduced pressure. The resulting residue was dissolved in EtOAc
(15 mL), the organic layer was washed with water (2 × 5 mL) and
dried over anhyd sodium sulfate. The solvent was evaporated under
reduced pressure to afford 10. Colorless oil; Yield 89 mg, 96%; IR
(neat, cm−1) 3290 (br s), 3066 (w), 2981 (m), 2933 (w), 1651 (vs),
1552 (m), 1497 (w), 1455 (m), 1391 (w), 1223 (vs), 1163 (w), 1129
93%; [α]25 = 2.77° (c = 1.00, CHCl3); HPLC Chiralpack IA (pet
D
ether/i-PrOH = 98/2, flow rate 1 mL/min, λ = 216 nm), tR (major) =
38.5 min, tR (minor) = 41.9 min; 95% ee.
4-(Diethoxyphosphoryl)-4-nitropentanoic acid (9). To a solution
of 8 (149 mg, 0.40 mmol) in THF (5.0 mL) and H2O (3.0 mL) was
added LiOH·H2O (33 mg, 0.80 mmol) and the mixture was stirred at
room temperature for 30 min. The mixture was acidified with 1 N HCl
and extracted with Et2O (3 × 15 mL). The combined extract was dried
over anhyd sodium sulfate. The organic layer was concentrated under
reduced pressure, and the residue was purified by silica gel column
chromatography using EtOAc−pet ether (90%) as eluent to afford the
acid 9. Colorless oil; Yield 95 mg, 84%; IR (neat, cm−1) 3459 (br w),
2990 (m), 1733 (s), 1549 (s), 1446 (w), 1390 (w), 1337 (w), 1243
1
(w), 1026 (vs), 964 (vs), 791 (w), 753 (m), 701 (m); H NMR (500
MHz, CDCl3) δ 1.25 (d, J = 15.9 Hz, 3H), 1.30 (t, J = 7.1 Hz, 6H),
1.92−2.08 (m, 2H), 2.20 (brs, 2H), 2.38, 2.46 (ABqdd, J = 15.0, 9.6,
6.5 Hz, 2H), 4.06−4.16 (m, 4H), 4.39 (d, J = 5.0 Hz, 2H), 6.50 (t, J =
5.0 Hz, 1H), 7.21−7.26 (m, 3H), 7.27−7.32 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 16.6, 16.6, 22.1, 30.4 (d, J = 7.5 Hz), 32.8 (d, J = 5.0
Hz), 43.6, 51.7 (d, J = 148.4 Hz), 62.7 (d, J = 7.5 Hz), 62.8 (d, J = 7.5
Hz), 127.4, 127.8, 128.7, 138.5, 173.0; 31P NMR (202 MHz, CDCl3) δ
30.4; MS (ES+, Ar) m/z (rel intensity) 366 ([MNa + 1]+, 18), 365
(MNa+, 100), 343 (13); HRMS (ES+, Ar) calcd for C16H27N2O4PNa
(MNa+) 365.1601, found 365.1600; [α]25D = 1.80° (c = 1.00, MeOH);
HPLC Lux Amylose-2 (pet ether/i-PrOH = 80/20, flow rate 0.5 mL/
min, λ = 204 nm), tR (major) = 46.6 min, tR (minor) = 34.3 min; 95%
ee.
1
(m), 1021 (vs), 980 (m), 860 (w), 740 (w); H NMR (400 MHz,
CDCl3) δ 1.31 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H), 1.75 (d, J =
14.6 Hz, 3H), 2.29−2.50 (m, 3H), 2.53−2.73 (m, 1H), 4.13−4.26 (m,
4H), 9.92 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.3 (d, J = 1.0
Hz), 16.4 (d, J = 1.0 Hz), 19.7, 28.5 (d, J = 9.0 Hz), 30.6, 64.8 (d, J =
7.0 Hz), 65.0 (d, J = 7.0 Hz), 89.0 (d, J = 151.0 Hz), 175.7; 31P NMR
(162 MHz, CDCl3) δ 16.4; MS (ES+, Ar) m/z (rel intensity) 307
([MNa + 1]+, 10), 306 (MNa+, 100), 284 (19), 266 (31), 242 (8), 234
(12); HRMS (ES+, Ar) calcd for C9H18NO7PNa (MNa+) 306.0713,
found 306.0713; [α]25 = −1.38° (c = 1.00, CHCl3).
D
Diethyl 5-(hydroxyamino)-2-nitro-5-oxopentan-2-ylphospho-
nate (12). To a solution of 8 (149 mg, 0.40 mmol) in EtOH-DCM
(7:3, 7.0 mL) was added HONH2·HCl (112 mg, 1.62 mmol, 4 equiv)
(R)-2-Nitro-5-(4-nitrophenyl)-5-oxopentan-2-ylphosphonic acid
(14). A solution of nitrophosphonate 3f (100 mg, 0.26 mmol) in 8
N HCl (10 mL) was refluxed for 6 h. The reaction mixture was washed
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with EtOAc (3 × 15 mL), the combined organic layer was dried over
anhyd sodium sulfate. Evaporation of organic layer under reduced
pressure afforded the phosphonic acid 13. Gray solid; Yield 65 mg,
75%; mp 150−152 °C; IR (film, cm−1) 3577 (m), 3110 (m), 3077
(w), 2913 (w), 2868 (w), 1697 (vs), 1602 (m), 1532 (vs), 1465 (w),
1444 (w), 1409 (m), 1388 (m), 1347 (vs), 1321 (s), 1207 (vs), 1110
(w), 1085 (w), 1011 (vs), 990 (vs), 940 (vs), 857 (vs), 832 (m), 784
(w), 736 (s), 685 (m); 1H NMR (500 MHz, DMSO-d6) δ 1.72 (d, J =
13.4 Hz, 3H), 2.30−2.40 (m, 1H), 2.76 (dtd, J = 14.7, 10.6, 4.6 Hz,
1H), 2.99 (ddd, J = 18.1, 10.6, 4.6 Hz, 1H), 3.34 (ddd, J = 18.1, 10.6,
4.6 Hz, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.32 (d, J = 8.9 Hz, 2H); 13C
NMR (125 MHz, DMSO-d6) δ 18.8, 29.0, 33.4 (d, J = 8.8 Hz), 89.5
(d, J = 133.8 Hz), 123.8, 129.4, 141.0, 150.0, 197.8; 31P NMR (162
MHz, DMSO-d6) δ 12.12; MS (ES+, Ar) m/z (rel intensity) 334
([MH + 1]+, 14), 333 (MH+, 100), 315 (13), 308 (9); HRMS (ES+,
(5) Selected recent reviews: (a) Mucha, A.; Kafarski, P.; Berlicki, Y. J.
Med. Chem. 2011, 54, 5955. (b) Sienczyk, M.; Oleksyszyn, J. Curr.
Med. Chem. 2009, 16, 1673.
(6) Antibacterial: (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall,
C. H.; Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S.
Nature 1978, 272, 56. (b) Pratt, R. F. Science 1989, 246, 917.
Antifungal: (c) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat.
́
Elem. 1991, 57, 57. Antitumor: (d) Clezardin, P. Bone 2011, 48, 71.
(e) Gu, L.; Jin, C. Org. Biomol. Chem. 2012, 10, 7098. (f) Huang, X.-
C.; Wang, M.; Pan, Y.-M.; Tian, X.-Y.; Wang, H.-S.; Zhang, Y. Bioorg.
Med. Chem. Lett. 2013, 23, 5283. Antiviral: (g) Zhang, P.; Tang, C.;
Chen, Z.; Wang, B.; Wang, X.; Jin, L.; Yang, S.; Hu, D. Phosphorus,
Sulfur Silicon Relat. Elem. 2014, 189, 530. (h) Chen, M.-H.; Chen, Z.;
Song, B.-A.; Bhadury, P. S.; Yang, S.; Cai, X.-J.; Hu, D.-Y.; Xue, W.;
Zeng, S. J. Agric. Food Chem. 2009, 57, 1383. HIV protease:
(i) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D.
Tetrahedron Lett. 1992, 33, 6625. (j) Senten, K.; Daniels, L.; Var der
Veken, P.; De Meester, I.; Lambeir, A.-M.; Scharpe, S.; Haemers, A.;
Augustyns, K. J. Comb. Chem. 2003, 5, 336. Phosphatase inhibitory
activities: (k) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy,
E.; Demarest, K.; Jordan, J. Bioorg. Med. Chem. 1996, 4, 1693.
(7) Aldol reaction: (a) Diner, P.; Amedjkouh, M. Org. Biomol. Chem.
2006, 4, 2091. Michael additions: (b) Tao, Q.; Tang, G.; Lin, K.;
Zhao, Y.-F. Chirality 2008, 20, 833. (c) Malmgren, M.; Granander, J.;
Amedjkouh, M. Tetrahedron: Asymmetry 2008, 19, 1934.
Ar) calcd for C11H14N2O8P (MH+) 333.0482, found 333.0484; [α]25
D
= +8.73° (c = 0.33, DMSO).
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra and HPLC for all the new/relevant
compounds as well as CIF for representative compounds 3n
and 4a. This material is available free of charge via the Internet
at http://pubs.acs.org.
(8) (a) Ntai, I.; Manier, M. L.; Hachey, D. L.; Bachmann, B. O. Org.
Lett. 2005, 7, 2763. (b) Ntai, I.; Phelan, V. V.; Bachmann, B. O. Chem.
Commun. 2006, 4518.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: irishi@iitb.ac.in.
(9) Recent reviews: (a) Alfonsov, V. A. Phosphorus, Sulfur Silicon
Relat. Elem. 2008, 183, 2637. (b) Kolodiazhnyi, O. I. Tetrahedron:
Asymmetry 1998, 9, 1279. Chiral auxiliary approaches: (c) Lyzwa, P.;
Mikolajczyk, M. Phosphorus, Sulfur Silicon Relat. Elem. 2014, 189, 1174.
(d) Kaur, P.; Wever, W.; Rajale, T.; Li, G. Chem. Biol. Drug. Des. 2010,
76, 314. (e) Lyzwa, P.; Mikolajczyk, M. Pure Appl. Chem. 2010, 82,
577. (f) Palacios, F.; Olszewski, T. K.; Vicario, J. Org. Biomol. Chem.
2010, 8, 4255. (g) Metlushka, K. E.; Sadkova, D. N.; Shaimardanova,
L. N.; Kataeva, O. N.; Alfonsov, V. A. Phosphorus, Sulfur Silicon Relat.
Elem. 2011, 186, 712. (h) Alfonsov, V. A.; McKenna, C. E.; Bayandina,
E. V.; Kashemirov, B.; Yarmieva, L. N.; Kataeva, O. N.; Punegova, L.
N. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2647.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
INNN thanks DAE/BRNS India for financial assistance. KB
thanks CSIR India for a senior research fellowship.
DEDICATION
■
This paper is dedicated to Prof. S. M. Khopkar on account of
his pioneering contributions to analytical chemistry.
́ ̌
(10) For reviews: (a) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17. (b) Ref 3a. (c) Groeger, H.; Hammer, B.
Chem.Eur. J. 2000, 6, 943. (d) Bhadury, P. S.; Li, H. Synlett 2012,
23, 1108. (e) Ordonez, M.; Viveros-Ceballos, J. L.; Cativiela, C.;
Arizpe, A. Curr. Org. Synth. 2012, 9, 310. See also for racemic
synthesis of α-aminophosphonates: (f) Ali, T. E. ARKIVOC 2014, 1,
21. (g) Kuznik, A.; Mazurkiewicz, R.; Kuznik, N. Curr. Org. Synth.
2013, 10, 411. (h) Hudson, H. R.; Volckman, J. F. Period. Polytech.,
Chem. Eng. 2010, 54, 9.
REFERENCES
■
(1) Selected recent books/reviews: (a) Orsini, F.; Sello, G.; Sisti, M.
Curr. Med. Chem. 2010, 17, 264. (b) Lejczak, B.; Kafarski, P. Top.
Heterocycl. Chem. 2009, 20, 31. (c) Kafarski, P.; Lejczak, B. Curr. Med.
Chem.: Anti-Cancer Agents 2001, 1, 301. (d) Kukhar, P.; Hudson, H. R.
Aminophosphonic and Aminophosphinic Acids; John Wiley: Chichester,
U.K., 2000; p 111.
(2) α-Aminophosphonates, selected recent reviews: (a) Liu, B. J.;
Cen, C. C.; Wu, M. S.; Kong, D. L. Asian J. Chem. 2011, 23, 1417.
(b) Kudzin, Z. H.; Kudzin, M. H.; Drabowicz, J.; Stevens, C. V. Curr.
Org. Chem. 2011, 15, 2015. (c) Naydenova, E. D.; Todorov, P. T.;
Troev, K. D. Amino Acids 2010, 38, 23. (d) Sienczyk, M.; Oleksyszyn,
J. Curr. Med. Chem. 2009, 16, 1673. (e) Lewkowski, J. Focus
Organomet. Chem. Res. 2005, 167. (f) Syamala, M. Org. Prep. Proced.
Int. 2005, 37, 103. (g) Turcheniuk, K. V.; Kukhar, V. P.;
Roeschenthaler, G.-V.; Acena, J. L.; Soloshonok, V. A.; Sorochinsky,
A. E. RSC Adv. 2013, 3, 6693.
(11) (a) For a recent review: Merino, P.; Marques-Lopez, E.;
Herrera, R. P. Adv. Synth. Catal. 2008, 350, 1195. For selected recent
articles: (b) Schlemminge, I.; Saida, Y.; Groeger, H.; Maison, W.;
Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65,
4818 and references therein. (c) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102. (d) Akiyama, T.; Morita, H.; Itoh, J.;
Fuchibe, K. Org. Lett. 2005, 7, 2583. (e) Saito, B.; Egami, H.; Katsuki,
T. J. Am. Chem. Soc. 2007, 129, 1978. (f) Pettersen, D.; Marcolini, M.;
Bernardi, L.; Fini, F.; Herrera, R. P.; Sgarzani, V.; Ricci, A. J. Org.
Chem. 2006, 71, 6269. (g) Zhao, D.; Wang, Y.; Mao, L.; Wang, R.
Chem.Eur. J. 2009, 15, 10983. (h) Nakamura, S.; Nakashima, H.;
Yamamura, A.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2008, 350,
1209. (i) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 5079. (j) Nakamura, S.; Hayashi, M.; Hiramatsu, Y.;
Shibata, N.; Funahashi, Y.; Toru, T. J. Am. Chem. Soc. 2009, 131,
18240. (k) Yin, L.; Bao, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2013, 135, 10338. (l) Xie, H.; Song, A.; Zhang, X.; Chen, X.; Li,
H.; Sheng, C.; Wang, W. Chem. Commun. 2013, 49, 928. For
computational, see: (m) Akiyama, T.; Morita, H.; Bachu, P.; Mori, K.;
(3) β-Aminophosphonates, selected recent reviews: (a) Ma, J.-A.
Chem. Soc. Rev. 2006, 35, 630. (b) Palacios, F.; Alonso, C.; De los
Santos, J. M. Chem. Rev. 2005, 105, 899. (c) Mikołajczyk, M. J.
Organomet. Chem. 2005, 690, 2488.
(4) γ-Aminophosphonates, reviews: (a) Bera, K.; Nadkarni, D.;
Namboothiri, I. N. N. J. Chem. Sci. 2013, 125, 443. (b) Ordonez, M.;
́
̃
Labastida-Galvan
21, 129.
́
, V.; Lagunas-Rivera, S. Tetrahedron: Asymmetry 2010,
K
DOI: 10.1021/jo502332r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Yamanaka, M.; Hirata, T. Tetrahedron 2009, 65, 4950. (n) Shi, F.-Q.;
Song, B.-A. Org. Biomol. Chem. 2009, 7, 1292.
therein. For studies on the H-bonding ability of various squaramide
catalysts: (c) Ni, X.; Li, X.; Wang, Z.; Xi, J.-P. Org. Lett. 2014, 16, 1786.
(d) The pKa in DMSO of squaramide C16 is 10.54 (ref 24c), whereas
the corresponding thiourea derivative C4 has a pKa of 12.4 (ref 23c).
The pKa’s reported for C4 in refs 23b and 23c are slightly different
(13.2 and 12.4, respectively).
(25) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7,
1967.
(26) Cao, C. L.; Ye, M. C.; Sun, X. L.; Tang, Y. Org. Lett. 2006, 8,
2901.
(12) For selected recent articles: (a) Goulioukina, N. S.; Bondarenko,
G. N.; Lyubimov, S. E.; Davankov, V. A.; Gavrilov, K. N.; Beletskaya, I.
P. Adv. Synth. Catal. 2008, 350, 482. (b) Kobayashi, S.; Kiyohara, H.;
Nakamura, Y.; Matsubara, R. J. Am. Chem. Soc. 2004, 126, 6558.
(c) Kiyohara, H.; Matsubara, R.; Kobayashi, S. Org. Lett. 2006, 8, 5333.
(d) Kiyohara, H.; Nakamura, Y.; Matsubara, R.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 1615. (e) Dodda, R.; Zhao, C.-G. Tetrahedron
Lett. 2007, 48, 4339. (f) Vicario, J.; Ezpeleta, J. M.; Palacios, F. Adv.
Synth. Catal. 2012, 354, 2641.
(27) Chen, R. J.; Cao, J. Y.; Zou, Q. Y.; Tan, F.; Zhu, Y. X.; Xiao, J.
W. Org. Biomol. Chem. 2010, 8, 1275.
(28) Xu, J.; Hu, Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T. Adv.
Synth. Catal. 2012, 354, 515.
(13) (a) Bernardi, L.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 5772. (b) Kim, M. S.; Hye, R. K.; Kim, Y. D. Org. Lett.
2005, 7, 2309.
(29) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450.
(30) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.;
Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196.
(14) For selected recent articles: (a) Kuwano, R.; Nishio, R.; Ito, Y.
Org. Lett. 1999, 1, 837. (b) Momo, R. D.; Fini, F.; Bernardi, L.; Ricci,
A. Adv. Synth. Catal. 2009, 351, 2283. (c) Cao, Y.-M.; Shen, F.-F.;
Zhang, F.-T.; Zhang, J.-L.; Wang, R. Angew. Chem., Int. Ed. 2014, 53,
1862. (d) Han, W.-Y.; Zhao, J.-Q.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-
C. J. Org. Chem. 2013, 78, 10541.
(15) Reviews covering quaternary α-aminophosphonates: (a) Ordo-
́
nez, M.; Sayago, F. J.; Cativiela, C. Tetrahedron 2012, 68, 6369.
̃
(b) Bera, K.; Namboothiri, I. N. N. Asian J. Org. Chem. 2014, 3, 1234.
(16) (a) Rai, V.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2007, 18, 2719. (b) Rai, V.; Namboothiri, I. N. N.
Tetrahedron: Asymmetry 2008, 19, 767.
(17) Rai, V.; Namboothiri, I. N. N. Tetrahedron: Asymmetry 2008, 19,
2335.
(18) (a) Wilt, J. C.; Pink, M.; Johnston, J. N. Chem. Commun. 2008,
4177. (b) Tripathi, C. B.; Kayal, S.; Mukherjee, S. Org. Lett. 2012, 14,
3296. (c) Pham, T. S.; Gonczi, K.; Kardos, G.; Sule, K.; Hegedus, L.;
Kallay, M.; Kubinyi, M.; Szabo, P.; Petnehazy, I.; Toke, L.; Jaszay, Z.
Tetrahedron: Asymmetry 2013, 24, 1605.
(19) Bera, K.; Namboothiri, I. N. N. Org. Lett. 2012, 14, 980.
(20) Bera, K.; Namboothiri, I. N. N. Adv. Synth. Catal. 2013, 355,
1265.
(21) Ying, G.; Lu, Y. Synthesis 2013, 45, 1654.
(22) Selected books/reviews on bifunctional organocatalysis:
(a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, Germany, 2005. (b) Dalko, P. I., Ed.; Enantioselective
Organocatalysis: Reactions and Experimental Procedures; Wiley-VCH:
Weinheim, Germany, 2007. (c) Pellissier, H. Recent Developments in
Asymmetric Organocatalysis; Royal Society of Chemistry: Cambridge,
U.K., 2010. (d) Connon, S. J. Chem. Commun. 2008, 2499. (e) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (f) Miyabe, H.;
Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785. (g) Aleman, J.; Parra,
A.; Jiang, H.; Jørgensen, K. A. Chem.Eur. J. 2011, 17, 6890. (h) List,
B. Top. Curr. Chem. 2010, 291. (i) Carreira, E. M., Ed.; Synthesis;
Thieme: Stuttgart, Germany, 2011; Issue 12 (Special Issue on
Organocatalysis). (j) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
For pioneering work on chiral thiourea catalysed asymmetric reactions:
(k) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
(l) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. For first use of bis-trifluoromethylphenyl in racemic thiourea
catalyst: (m) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
For thiourea-Bronsted acid co-operative catalysis: (n) Zhang, Z.;
Lippert, K. M.; Hausmann, H.; Kotke, M.; Schreiner, P. R. J. Org.
Chem. 2011, 76, 9764.
(23) For studies on the H-bonding ability of various thiourea
catalysts: (a) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann,
H.; Guenther, S.; Schreiner, P. R. Eur. J. Org. Chem. 2012, 5919. (b) Li,
X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P.
Chem.Eur. J. 2010, 16, 450. (c) Jakab, G.; Tancon, C.; Zhang, Z.;
Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724. (d) The pKa
in DMSO of the vinyl (instead of ethyl) analogue of thiourea C9 is
reported to be 16.2, whereas that of C4 is reported to be 13.2 (ref
23b).
(24) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416. (b) Review: ref 22g and the references cited
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