Highly enantioselective Michael addition of α-substituted nitrophosphonates to a vinyl sulfone

Article abstract of DOI:10.1055/s-0033-1338434

Organocatalytic asymmetric Michael reaction of α-substituted nitrophosphonates to phenyl vinyl sulfone catalyzed by cinchona alkaloid-derived tertiary amine-thioureas afforded α,α-disubstituted nitrophosphonates in very good yields and excellent enantiomeric excesses. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338434

1654▌
SPECIAL TOPIC
special topic
Highly Enantioselective Michael Addition of α-Substituted Nitrophosphonates
to a Vinyl Sulfone
α,α-Disubstituted Nitrophosphonates
Guo-Ying Chen, Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Science Drive 3,
Singapore 117543, Republic of Singapore
Fax +65(6779)1691; E-mail: chmlyx@nus.edu.sg
Received: 08.03.2013; Accepted after revision: 02.04.2013
group has recently developed a number of asymmetric or-
Abstract: Organocatalytic asymmetric Michael reaction of α-sub-
ganocatalytic conjugate additions by employing vinyl sul-
stituted nitrophosphonates to phenyl vinyl sulfone catalyzed by cin-
fones as Michael acceptors.8 We envisioned that a
chona alkaloid-derived tertiary amine-thioureas afforded α,α-
conjugate addition of α-substituted α-nitrophosphonates
to vinyl sulfones may provide a straightforward method to
access α,α-dialkyl-substituted aminophosphonic acids,
which are interesting molecules in medicinal chemistry.2
Herein, we document the first organocatalytic asymmetric
Michael addition of α-substituted nitrophosphonates to a
vinyl sulfone.
disubstituted nitrophosphonates in very good yields and excellent
enantiomeric excesses.
Key words: thiourea, Michael Addition, cinchona alkaloid, vinyl
sulfone, nitrophosphonate
α-Aminophosphonic acids, as structural and functional
surrogates of α-amino acids, were first investigated in the
1940s.1 Subsequently, the biological activities and medic-
inal applications of α-aminophosphonic acids were re-
vealed, which made them interesting targets in organic
synthesis.2 The catalytic asymmetric synthesis of α-ami-
nophosphonic acids was mainly focused on the C–C, C–
N, and C–P bond forming reactions.3 However, asymmet-
ric synthesis of α-aminophosphonic acids containing a
quaternary α-carbon center has been explored to a much
less extent.
To promote the projected Michael addition of α-nitro-
phosphonates in an asymmetric manner, chiral bifunction-
al tertiary amines with a suitable Brønsted acid moiety
seem to be excellent choices. The catalysts investigated in
this study are illustrated in Figure 1. We chose the conju-
gate addition of nitrophosphonate 1a to phenyl vinyl sul-
fone (2) in toluene as a model reaction to evaluate the
catalytic effects of different bifunctional tertiary amine
catalysts. All cinchona alkaloid derived tertiary amine-
thiourea catalysts were found to be effective, affording the
desired adducts in excellent yields and very good enantio-
selectivities (Table 1, entries 1–4). While sulfonamide-
containing catalyst C5 afforded the products in excellent
ee and slightly decreased chemical yield (entry 5), catalyst
C6 with a guanidine group9 turned out to be less efficient
(entry 6). Overall, tertiary amine-thiourea catalysts clear-
ly performed best for the Michael reaction investigated.
Solvent screening was then carried out (entries 7–11), and
toluene remained to be the solvent of choice for the reac-
tion. When the reaction of phosphonate 1a and phenyl vi-
nyl sulfone (2) was performed in toluene in the presence
of quinidine-derived C1, adduct 3a was obtained in 98%
yield and with 96% ee.
α-Nitrophosphonates have been used as a precursor of α-
aminophosphonic acids in recent years. In particular, use
of α-substituted α-nitrophosphonates conveniently leads
to the formation of α-aminophosphonic acids with a qua-
ternary α-carbon center. In 2008, Johnston reported highly
diastereoselective and enantioselective additions of α-ni-
trophosphonates to imines catalyzed by a chiral Brønsted
acid, which serves as a concise route to α-substituted α,β-
diaminophosphonic acids.4 Very recently, Namboothiri et
al. disclosed an enantioselective Michael addition of α-
substituted α-nitrophosphonates to enones, and the α-ami-
nophosphonates were prepared for the first time.5 Shortly
after, Mukherjee and co-workers reported an asymmetric
Michael reaction of α-substituted nitrophosphonate and
nitroolefins, generating chiral α,γ-diaminophosphonic
acid precursors with contiguous quaternary and tertiary
stereocenters.6
With the optimized conditions in hand, the substrate scope
was next explored, and the results are summarized in Ta-
ble 2. In general, the reaction tolerated well with different
α-alkyl-substituted α-nitrophosphonates. The reaction
was applicable to the nitrophosphonates with an ethyl, a
propyl, and a pentyl group at the α-position, and the ad-
ducts were obtained in nearly quantitative yields, and ex-
cellent enantiomeric excesses (Table 2, entries 1–4).
When the size of the alkyl substituent at the α-position
was further increased, the enantioselectivity of the reac-
tion was maintained, and chemical yield of the addition
was decreased (entry 5). When α-benzyl-substituted nitro-
phosphonate was employed, the desired Michael addition
product was obtained in moderate yield, and with slightly
Vinyl sulfones are useful acceptors in conjugate additions.
They are particularly valuable in organic synthesis due to
the powerful electron-withdrawing nature of the sulfone
functionality, and a variety of well-established post-syn-
thetic manipulations of the sulfone group.7 Our research
SYNTHESIS 2013, 45, 1654–1658
Advanced online publication: 17.04.2013
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DOI: 10.1055/s-0033-1338434; Art ID: SS-2013-C0190-ST
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
α,α-Disubstituted Nitrophosphonates
1655
Table 1 Conjugate Addition of Phosphonate 1a to Phenyl Vinyl Sul-
fone (2) Catalyzed by Bifunctional Tertiary Aminesa
OMe
OMe
H
N
O
H
N
O
OEt
cat. (10 mol%)
EtO
EtO
P
+
P
SO2Ph
SO2Ph
HN
OEt
solvent, r.t.
NH
N
NO2
1a
O2N
HN
S
N
S
NH
2
3a
Entry
Cat.
Solvent
Yield (%)b
ee (%)c
F3C
CF3
F3C
C2
CF3
1
C1
C2
C3
C4
C5
C6
C1
C1
C1
C1
C1
toluene
toluene
toluene
toluene
toluene
toluene
xylenes
THF
98
87
98
91
81
76
98
99
84
80
91
96
92
89
94
94
65
96
92
92
94
94
C1
2
3
H
N
H
N
4
HN
5
NH
N
HN
S
N
6
S
NH
7
F3C
CF3
8
F3C
C3
CF3
C4
9
Et2O
10
11
CH2Cl2
CHCl3
OMe
H
H
N
N
a Reactions were performed with nitrophosphonate 1a (0.025 mmol),
phenyl vinyl sulfone (2; 0.025 mmol), and the catalyst (0.0025 mmol)
in the solvent specified (0.10 mL) at r.t. for 24 h.
b Isolated yield.
HN
HN
N
F3C
SO2
N
HN
N
c Determined by HPLC analysis on a chiral stationary phase.
Me
C5
C6
CF3
F3C
CF3
Figure 1 Tertiary amine catalysts derived from cinchona alkaloids
decreased enantiomeric excess (entry 6). When branched
alkyl substituent was introduced to the nitrophosphonate,
the reaction had to be run at higher temperature for a lon-
ger reaction time; the corresponding product could still be
obtained in moderate yield and excellent ee (entry 7).
However, the tert-butyl-substituted nitrophosphonate was
unsuitable for the reaction, presumably due to the large
steric hindrance introduced by the tert-butyl group (entry
8). Equally excellent results were obtained when the reac-
tion was performed at a larger scale (entries 9, 10). The
absolute configurations of the products were assigned
based on the X-ray crystallographic structure10 of 3a (Fig-
ure 2).
In conclusion, we have developed the first asymmetric
Michael reaction of α-substituted nitrophosphonates to a
vinyl sulfone catalyzed by tertiary-amine thiourea cata-
lysts derived from cinchona alkaloids. The desired
Michael adducts were prepared in moderate to high chem-
ical yields, and with excellent enantiomeric excesses. The
reported method is simple and efficient, representing a
promising approach to asymmetric synthesis of α-amino-
phosphonic acids.
Figure 2 X-ray crystal structure of 3a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1654–1658

1656
G.-Y. Chen, Y. Lu
SPECIAL TOPIC
Table 2 The Scope of the Reactiona
Michael Addition of Nitrophosphonate 1a to Phenyl Vinyl Sul-
fone (2); Diethyl (R)-[2-Nitro-4-(phenylsulfonyl)butan-2-
yl]phosphonate (3a); Typical Procedure
O
O
P
OEt
EtO
EtO
To a mixture of nitrophosphonate 1a (5.3 mg, 0.025 mmol) and phe-
nyl vinyl sulfone 2 (4.2 mg, 0.025 mmol) in toluene (0.1 mL) at r.t.
was added the catalyst C1 (1.5 mg, 0.0025 mmol). The reaction
mixture was then stirred for 24 h. The solvent was removed, and the
residue was purified by column chromatography on silica gel (n-
hexane–EtOAc, 5:1 to 1:1) to afford product 3a as a colorless solid;
yield: 9.3 mg (98%).
C1 (10 mol%)
R
P
SO2Ph
+
SO2Ph
OEt
toluene, r.t.
NO2
R
O2N
1
2
3
Entry
Product (R)
Yield (%)b
ee (%)c
1
3a (Me)
3b (Et)
98
98
98
98
65
53
50
96
96
94
94
92
86
92
HPLC analysis: Daicel Chiralpak IC, n-hexane–i-PrOH (90:10), 1.0
mL/min, λ = 254 nm, tR (major) = 47.8 min, tR (minor) = 72.3 min;
96% ee.
1H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 7.0 Hz, 6 H), 1.78 (d,
J = 14.5 Hz, 3 H), 2.51–2.69 (m, 2 H), 3.21–3.31 (m, 2 H), 4.15–
4.24 (m, 4 H), 7.58–7.61 (m, 2 H), 7.67–7.71 (m, 1 H), 7.91–7.93
(m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 16.3, 20.9, 29.0, 51.1, 51.2, 64.5,
64.6, 64.7, 64.8, 87.5, 88.7, 128.1, 129.5, 134.1, 138.5.
HRMS (ESI): m/z calcd for C14H23NO7PS [M + H]+: 380.0927;
found: 380.0933.
2
3
3c (n-Pr)
3d (C5H11)
3e (C9H19)
3f (Bn)
4
5
6
7d
8
3g (i-Pr)
3h (t-Bu)
3a (Me)
3b (Et)
e
e
–
–
Diethyl (R)-[3-Nitro-1-(phenylsulfonyl)pentan-3-yl]phospho-
nate (3b)
Yield: 9.3 mg (98%); colorless oil.
9f
10f
11f
98
95
92
96
96
94
HPLC analysis: Daicel Chiralpak IA, n-hexane–i-PrOH (90:10),
1.0 mL/min, λ = 254 nm, tR (major) = 11.1 min, tR (minor) = 13.0
min; 96% ee.
1H NMR (500 MHz, CDCl3): δ = 0.94 (t, J = 7.0 Hz, 3 H), 1.32–1.34
(m, 6 H), 2.04–2.14 (m, 1 H), 2.32–2.45 (m, 2 H), 2.62–2.73 (m, 1
H), 3.37–3.45 (m, 2 H), 4.10–4.24 (m, 4 H), 7.58–7.61 (m, 2 H),
7.66–7.70 (m, 1 H), 7.93–7.94 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 7.86, 7.93, 16.3, 26.2, 29.2, 51.6,
64.1, 64.2, 64.7, 64.8, 91.7, 92.9, 128.1, 129.4, 134.0, 138.7.
HRMS (ESI): m/z calcd for C15H25NO7PS [M + H]+: 394.1084;
found: 394.1088.
3d (C5H11)
a Reactions were performed with nitrophosphonate 1 (0.025 mmol),
phenyl vinyl sulfone (2; 0.025 mmol), and C1 (0.0025 mmol) in tol-
uene (0.10 mL) at r.t. for 24 h.
b Isolated yield.
c Determined by HPLC analysis on a chiral stationary phase.
d The reaction was performed at 50 °C for 48 h.
e No reaction was observed.
f Reactions were performed with nitrophosphonate 1 (0.1 mmol), phe-
nyl vinyl sulfone (2; 0.1 mmol), and C1 (0.01 mmol) in toluene (0.2
mL) at r.t. for 24 h.
Diethyl(R)-[3-Nitro-1-(phenylsulfonyl)hexan-3-yl]phosphonate
(3c)
Yield: 9.9 mg (98%); colorless oil.
HPLC analysis: Daicel Chiralpak IA, n-hexane–i-PrOH (90:10),
1.0 mL/min, λ = 254 nm, tR (major) = 10.3 min, tR (minor) = 12.1
min; 94% ee.
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.22–1.43
(m, 8 H), 1.93–2.08 (m, 1 H), 2.20–2.30 (m, 1 H), 2.40–2.45 (m, 1
H), 2.62–2.72 (m, 1 H), 3.40–3.43 (m, 2 H), 4.15–4.22 (m, 4 H),
7.58–7.61 (m, 2 H), 7.67–7.70 (m, 1 H), 7.92–7.93 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 13.8, 16.3, 16.7, 16.8, 26.6, 37.7,
51.7, 64.2, 64.7, 64.8, 91.3, 92.5, 128.1, 129.4, 134.0, 138.7.
HRMS (ESI): m/z calcd for C16H27NO7PS [M + H]+: 408.1240;
found: 408.1240.
All the starting materials were obtained from commercial sources
and used without further purification, unless otherwise stated. Tol-
uene, THF, and Et2O were dried and distilled from sodium benzo-
phenone ketyl prior to use. CHCl3 and CH2Cl2 were distilled from
1
CaH2 prior to use. H and 13C NMR spectra were recorded on a
Bruker ACF 300 or AMX 500 (500 MHz) spectrometer. Chemical
shifts were reported in parts per million (ppm), and the residual sol-
vent peak was used as an internal reference: proton (CHCl3, δ =
7.26), carbon (CHCl3, δ = 77.0). Standard abbreviations for multi-
plicities were used in the 1H NMR assignments. Coupling constants
were reported in Hertz (Hz). Low-resolution mass spectra were ob-
tained on a Finnigan/MAT LCQ spectrometer in ESI mode, and a
Finnigan/MAT 95XL-T mass spectrometer in FAB mode. All high-
resolution mass spectra were obtained on a Finnigan/MAT 95XL-T
spectrometer. For TLC, Merck precoated TLC plates (Merck 60
F254) were used, and compounds were visualized with a UV light
at 254 nm. Flash chromatographic separations were performed on
Merck 60 (0.040–0.063 mm mesh) silica gel. The enantiomeric ex-
cesses of products were determined by HPLC analysis on a chiral
stationary phase. The nitrophosphonates utilized in the study were
synthesized according to the literature procedure,4 and the thiourea
catalysts were also prepared following the literature procedures.11
Diethyl (R)-[3-Nitro-1-(phenylsulfonyl)octan-3-yl]phosphonate
(3d)
Yield: 10.7 mg (98%); colorless oil.
HPLC analysis: Daicel Chiralpak IA, n-hexane–i-PrOH (90:10),
1.0 mL/min, λ = 254 nm, tR (major) = 9.2 min, tR (minor) = 10.7
min; 94% ee.
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.13–1.42
(m, 12 H), 1.97–2.05 (m, 1 H), 2.19–2.45 (m, 2 H), 2.63–2.73 (m, 1
H), 3.38–3.45 (m, 2 H), 4.12–4.22 (m, 4 H), 7.58–7.61 (m, 2 H),
7.67–7.70 (m, 1 H), 7.92–7.93 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 13.8, 16.3, 22.1, 22.8, 26.5, 31.4,
35.6, 51.6, 51.7, 64.2, 64.7, 64.8, 91.3, 92.5, 128.1, 129.4, 134.0,
138.7.
Synthesis 2013, 45, 1654–1658
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
α,α-Disubstituted Nitrophosphonates
1657
HRMS (ESI): m/z calcd for C18H31NO7PS [M + H]+: 436.1533;
found: 436.1547.
References
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Yield: 12.0 mg (98%); colorless oil.
HPLC analysis: Daicel Chiralpak IA, n-hexane–i-PrOH (90:10),
1.0 mL/min, λ = 254 nm, tR (major) = 9.7 min, tR (minor) = 11.9
min; 92% ee.
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1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.13–1.41
(m, 20 H), 1.99–2.02 (m, 1 H), 2.25–2.29 (m, 1 H), 2.38–2.43 (m, 1
H), 2.64–2.70 (m, 1 H), 3.40–3.41 (m, 2 H), 4.12–4.22 (m, 4 H),
7.58–7.61 (m, 2 H), 7.67–7.70 (m, 1 H), 7.92–7.93 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 14.1, 16.3, 22.6, 23.1, 23.2, 26.5,
29.1, 29.3, 31.8, 35.7, 51.6, 64.2, 64.7, 64.8, 91.3, 92.5, 128.1,
129.4, 134.0, 138.6.
HRMS (ESI): m/z calcd for C22H39NO7PS [M + H]+: 492.2179;
found: 492.2183.
Diethyl (R)-[2-Nitro-1-phenyl-4-(phenylsulfonyl)butan-2-
yl]phosphonate (3f)
Yield: 6.3 mg (53%); colorless oil.
HPLC analysis: Daicel Chiralpak IA, n-hexane–i-PrOH (90:10),
1.0 mL/min, λ = 254 nm, tR (major) = 13.6 min, tR (minor) = 14.6
min; 92% ee.
1H NMR (500 MHz, CDCl3): δ = 1.30–1.34 (m, 6 H), 2.23–2.41 (m,
2 H), 3.16–3.20 (m, 1 H), 3.27–3.34 (m, 1 H), 3.50–3.56 (m, 1 H),
3.72–3.77 (m, 1 H), 4.17–4.27 (m, 4 H), 6.98–6.70 (m, 2 H), 7.23–
7.27 (m, 3 H), 7.47–7.50 (m, 2 H), 7.58–7.60 (m, 1 H), 7.78–7.80
(m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 16.1, 26.7, 42.5, 51.5, 64.1, 65.0,
92.3, 92.5, 127.9, 128.1, 128.6, 129.1, 129.7, 131.7, 131.8, 133.7,
138.2.
HRMS (ESI): m/z calcd for C20H26NO7PS + Na [M + Na]+:
478.1060; found: 478.1057.
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1.0 mL/min, λ = 254 nm, tR (major) = 17.8 min, tR (minor) = 21.3
min; 92% ee.
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Int. Ed. 2010, 49, 7753.
1H NMR (500 MHz, CDCl3): δ = 0.86 (d, J = 7.0 Hz, 3 H), 1.11 (d,
J = 6.9 Hz, 3 H), 1.29–1.35 (m, 6 H), 1.78 (d, J = 14.5 Hz, 3 H),
2.28–2.35 (m, 1 H), 2.44–2.56 (m, 1 H), 2.82–2.90 (m, 1 H), 3.41–
3.54 (m, 2 H), 4.10–4.27 (m, 4 H), 7.58–7.61 (m, 2 H), 7.67–7.70
(m, 1 H), 7.93–7.95 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 16.3, 17.2, 17.3, 18.2, 36.6, 51.8,
64.2, 64.4, 128.0, 129.4, 133.9.
HRMS (ESI): m/z calcd for C16H27NO7PS [M + H]+: 408.1240;
found: 408.1240.
Acknowledgment
We thank the National University of Singapore (R-143-000-469-
112) and the Ministry of Education (MOE) of Singapore (R-143-
000-494-112), and GSK-EDB (R-143-000-491-592) for generous
financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1654–1658

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G.-Y. Chen, Y. Lu
SPECIAL TOPIC
(9) Han, X.; Zhong, F.; Lu, Y. Adv. Synth. Catal. 2010, 352,
2778.
(10) CCDC 926461 contains the supplementary crystallographic
data for 3a, which can be obtained free of charge from the
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or by writing to the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
(11) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett.
2005, 7, 1976.
Synthesis 2013, 45, 1654–1658
© Georg Thieme Verlag Stuttgart · New York