Sulfonyl as a Traceless Activation Group for Enantioselective Mannich Reaction Catalyzed by Thiourea to Access Chiral β-Aminophosphonates

Article abstract of DOI:10.1055/s-0036-1589156

An efficient enantioselective Mannich reaction of N -protected α-sulfones with β-benzenesulfonyl phosphonates was developed by using a chiral cinchona alkaloid-derived thiourea as a catalyst. This method was used to obtain a series of chiral α-sulfonyl-β-aminophosphonates in yields of up to 96% with 89:11 dr and 88% ee. These compounds were further transformed into β-aminophosphonates or chiral azetidines with various functional groups by a Horner-Wadsworth-Emmons/aza-Michael addition reaction sequence.

Full text of DOI:10.1055/s-0036-1589156

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
Y. Peng et al.
Letter
Synlett
Sulfonyl as a Traceless Activation Group for Enantioselective
Mannich Reaction Catalyzed by Thiourea to Access Chiral β-Amino-
phosphonates
Yungui Peng◊*
Yanqiang Ning◊
Songlin Tan◊
Dezhong Li
O
O
O
O
R1OCNH
O
O
R1OCNH
R1OCNH
P(OEt)2
Cat., LiOH·H2O
Mg, MeOH
(BrCH2)2
P(OEt)2
P(OEt)2
+
Ar
Ar
Tol, –20 °C, 72 h
Ar
SO2Ph
SO2Ph
R'
SO2Ph
Cat:
up to 96% yield
N
H
up to 96% yield
NHR
89:11 dr
Na Liao
87% ee
N
H
O
88% ee
S
Key Laboratory of Applied Chemistry of Chongqing Municipality,
School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, P. R. of China
pengyungui@hotmail.com
N
R' = 3,5-(F3C)2C6H3; R = 4-CF3C6H4
pyg@swu.edu.cn
◊ These authors contributed equally
Received: 15.10.2017
Accepted after revision: 27.11.2017
Published online: 19.01.2018
group3f reported that the introduction of an electron-with-
drawing group (NO2) at the α-position of a phosphonate en-
hances the acidity of its α-hydrogen, permitting asymmet-
ric Mannich reactions with imines to give a series of chiral
α,β-diaminophosphonic acid derivatives. The sulfone group
is an efficient electron-withdrawing group, and we hypo-
thesized that it might be used to activate the α-hydrogen
atom of a phosphonate by enhancing its acidity, permitting
an asymmetric Mannich reaction to occur under moderate
basic conditions.
DOI: 10.1055/s-0036-1589156; Art ID: st-2017-w0765-l
Abstract An efficient enantioselective Mannich reaction of N-protect-
ed α-sulfones with β-benzenesulfonyl phosphonates was developed by
using a chiral cinchona alkaloid-derived thiourea as a catalyst. This
method was used to obtain a series of chiral α-sulfonyl-β-aminophos-
phonates in yields of up to 96% with 89:11 dr and 88% ee. These com-
pounds were further transformed into β-aminophosphonates or chiral
azetidines with various functional groups by a Horner–Wadsworth–Em-
mons/aza-Michael addition reaction sequence.
In continuation of our longstanding research efforts in
phosphonate chemistry,4 we developed a complementary
method for the synthesis of chiral β-aminophosphonic acid
derivatives. We investigated the asymmetric Mannich reac-
tions of sulfonyl phosphonates with N-protected α-sul-
fones, through formation of imines in situ in the presence of
a base and a chiral thiourea catalyst.5 A series of chiral α-
sulfone β-aminophosphonates were obtained, from which
the sulfonyl moiety could be removed smoothly by reduc-
tion.6 These compounds were further transformed to fur-
nish chiral azetidines with various functional groups
through sequential Horner–Wadsworth–Emmons reaction
and aza-Michael addition. Here, we report our alternative
strategy in which a sulfonyl group is used as a traceless
activation group to obtain chiral β-aminophosphonates
with good enantioselectivities and diastereoselectivities.
After conducting initial trials, we examined the reaction
of the N-protected α-amidosulfone 1a with the β-benzene-
sulfonyl phosphate 2 as a model reaction. In the presence of
LiOH·H2O as a base, the chiral thioureas 3a–e were screened
as catalysts at a 10 mol% loading in toluene at –20 °C (Table
1). Catalysis with chiral thiourea 3a gave the desired prod-
uct 4a smoothly in 83% yield with 79:21 dr and 74% ee (Ta-
ble 1, entry 1). On the basis of this result, we modified the
catalyst structure by introducing a phenyl group at the 11-
position to give catalyst 3b, which gave the same stereocon-
Key words amidosulfones, aminophosphonates, asymmetric synthe-
sis, Mannich Reaction, thioureas, organocatalysis
β-Aminophosphonates are isosteres of carboxylates that
have a high resistance to enzymatic hydrolysis and show
good bioactivity in biological and pharmaceutical chemis-
try.1 β-Aminophosphonates are widely present in natural
products,2 and they have potential applications in the syn-
thesis of inhibitors of human renin and calpain I, and as
anti-HIV agents. The development of methods for the syn-
thesis of chiral β-aminophosphonic acid and its derivatives
is therefore of interest to synthetic chemists, and many effi-
cient approaches to the construction of these compounds
have been established.3
Developed methods include synthesis from natural amino
acids, asymmetric Michael addition of phosphites to nitro-
olefins, and asymmetric hydrogenation of β-amidophos-
phonates. There are no reports of asymmetric Mannich
reactions of methyl phosphonate with imines or their pre-
cursors as efficient methods for producing chiral β-amino-
phosphonic acid derivatives, especially those that cannot be
obtained from proteinogenic amino acids. This may be be-
cause the low acidity of the α-hydrogen atom of a phospho-
nate means that a strong base is needed for deprotonation,
which can make asymmetric synthesis difficult. Johnston’s
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Y. Peng et al.
Letter
Synlett
trol and maintained the enantioselectivity and diastereo-
selectivity of the product (entry 2). When the substituent at
the 11-position was enlarged to naphthyl (3c), the enantio-
selectivity of the product increased slightly to 80% ee (entry
3). The results obtained by using catalysts 3d and 3e
showed that the electronic effect of the substituents on the
phenyl at the 11-position markedly affected the perfor-
mance of the catalyst. The presence of an electron-donating
methoxy substituent on the phenyl group (3d) resulted in a
low product yield (27%) and low enantioselectivity (68% ee)
(entry 4). An electron-withdrawing CF3 substituent on the
phenyl group at the 11-position (3e) gave the best results,
providing a 93% yield and 83% ee (entry 5). Catalyst 3e was
therefore used to further optimize the solvent (entries 5–
10) and the reaction temperature (entries 11 and 12). The
results showed that toluene was the best solvent and –20 °C
was the optimal temperature.
N-protecting groups, gave only moderate enantioselectivi-
ties of 63% and 45% ee, respectively (Table 2, entries 4 and
6). When the size of R1 was decreased from t-Bu in Boc to
i-Pr (1e), the enantioselectivity of the product decreased
from 63% to 46% ee (entry 5). In contrast, when the steric
hindrance of R1 was increased by changing R1 from t-Bu to
C(Me)2Et (1c), the product enantioselectivity increased sig-
nificantly to 78% ee (entry 3). The best result was achieved
when R1 was further increased in size by changing it to
C(Me)2-i-Pr (1b; entry 2). The novel CO2C(Me)2-i-Pr group
was therefore the best N-protecting group and this was
used for further substrate development.
Table 2 Effect of Various N-Protecting Groups on the Enantioselective
Mannich Reaction Catalyzed by 3ea
O
O
O
R1OCNH
O
R1OCNH
P(OEt)2
3e (10 mol%)
P(OEt)2
+
Ph
Table 1 Catalytic Enantioselective Mannich Reaction under Various
Tol, LiOH·H2O,
Ph
SO2Ph
SO2Ph
SO2Ph
Conditionsa
–20 °C
1
2
4
Entry
Substrate R1
Product Yieldb (%) drc
eed (%)
O
O
O
tBu COCNH
O
tBu COCNH
P(OEt)2
Cat. (10 mol%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
C(Me)2-t-Bu
4a
4b
4c
4d
4e
4f
93
91
98
93
95
98
80:20
83
85
78
63
46
45
+
P(OEt)2
solv. LiOH·H2O,
Ph
C(Me)2-iPr
C(Me)2Et
t-Bu
85:15
88:12
90:10
92:8
Ph
SO2Ph SO2Ph
–20 °C
SO2Ph
4a
1a
2
R2
N
H
Cat: R = 3,5-(F3C)2C6H3
N
NHR
3a: R' = H; 3b: R' = Ph; 3c: R' = 1-naphthyl
3d: R' = 4-MeOC6H4; 3e: R' = 4-F3CC6H4
H
O
i-Pr
S
Bn
87:13
N
a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), 3e (10 mol%), LiOH·H2O
(0.14 mmol), toluene (1.0 mL), –20 °C, 48 h.
b Isolated yield.
Entry
Catalyst
Solvent
Yieldb (%)
drc
79:21
eed (%)
c Determined by 1H NMR spectroscopy.
d Determined by chiral HPLC.
1
2
3a
3b
3c
3d
3e
3e
3e
3e
3e
3e
3e
3e
toluene
toluene
toluene
toluene
toluene
PhEt
83
74
78
27
93
91
76
35
37
67
98
28
74
74
80
68
83
83
67
4
78:22
79:21
79:21
80:20
79:21
78:22
78:22
79:21
79:21
79:21
79:21
3
Once we had optimized the reaction conditions, we in-
vestigated the substrate scope. Various α-amidosulfones 1
were used in the catalytic asymmetric Mannich reaction
(Table 3).7 The reaction proceeded smoothly irrespective of
whether there was an electron-withdrawing or an electron-
donating group on the phenyl ring of the α-amidosulfone
(Table 3, entries 1–11), and it gave the corresponding chiral
α-sulfonyl-β-aminophosphonates in good to excellent
yields with moderate to good stereoselectivities. The effect
of the substituent pattern on the phenyl ring was then ex-
amined. A substituent at the meta-position decreased the
enantioselectivity (entries 3, 5, and 10). Disubstituted α-
amidosulfones with two substituents on the phenyl ring
were suitable for this reaction (entries 12–14). α-Amidosul-
fones derived from 2-naphthyl and piperonyl aldehydes
also gave good yields and high enantioselectivities (entries
15 and 16). It was difficult to separate the diastereomers of
4 by silica gel chromatography; consequently, therefore the
diastereomeric ratios of 4 were determined by means of
1H NMR spectroscopy. Because we intended to use the sul-
fonyl group as a traceless activation group, the mixtures of
4
5
6
7
PhCl
8
THF
9
CH2Cl2
MeCN
toluene
toluene
16
0
10
11e
12f
79
86
a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), catalyst (10 mol%),
LiOH·H2O (0.14 mmol), solvent (1.0 mL), –20 °C, 48 h.
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d Determined by chiral HPLC.
e Reaction at –10 °C.
f Reaction at –30 °C.
The effect of substituent R1 as part of the N-protecting
group of the α-sulfone was then explored. Boc (R1 = t-Bu,
1d) and Cbz (R1 = Bn, 1f), which are typical and widely used
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
Y. Peng et al.
Letter
Synlett
Table 3 Asymmetric Mannich Reactions of Various α-Amidosulfones Catalyzed by 3ea and Subsequent Desulfonylation Reactionsb
O
R1OCNH
O
Ar
SO2Ph
O
R1OCNH
O
1
R1OCNH
Mg, MeOH
(BrCH2)2
O
3e, LiOH·H2O
P(OEt)2
+
P(OEt)2
Ar
Tol, –20 °C, 72 h
Ar
O
SO2Ph
4
5
P(OEt)2
SO2Ph
2
b: R1 = iPrC(Me)2
Entry
Ar
Ph
Product
Yieldc (%)
drd (%)
eee (%)
Product
Yieldc (%)
eee (%)
1
2
4ba
4bb
4bc
4bd
4be
4bf
91
94
96
92
86
93
83
93
94
94
95
82
88
87
92
88
85:15
82:18
85:15
83:17
84:16
76:24
78:22
83:17
88:12
85:15
86:14
68:32
89:11
79:21
85:15
84:16
85
83
64
83
59
77
76
86
87
81
87
48
88
73
80
87
5ba
5bb
5bc
5bd
5be
5bf
81
96
84
80
57
60
96
87
69
67
94
77
87
83
93
82
84
83
65
82
61
76
75
85
86
81
86
49
87
72
80
86
2-FC6H4
3
3-FC6H4
4
4-FC6H4
5
3-ClC6H4
6
4-ClC6H4
7
2-F3CC6H4
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(Cl)2C6H3
3,4-(Me)2C6H3
2-Cl-4-MeC6H3
2-naphthyl
piperonyl
4bg
4bh
4bi
5bg
5bh
5bi
8
9
10
11
12
13
14
15
16
4bj
5bj
4bk
4bl
5bk
5bl
4bm
4bn
4bo
4bp
5bm
5bn
5bo
5bp
a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), 3e (10 mol%), LiOH·H2O (0.14 mmol), toluene (1.0 mL), –20 °C, 72 h.
b Reaction conditions: Mg turnings (30 equiv), 1,2-dibromoethane (50 μL), anhyd MeOH (0.1 mmol/mL).
c Isolated yield.
d Determined by 1H NMR spectroscopy.
e Determined by chiral HPLC.
products 4 were treated with magnesium filings and 1,2-
dibromoethane in anhydrous methanol to achieve smooth
reductive desulfonylation7 and transformation into the cor-
responding β-aminophosphonates 5 with retention of the
optical purity.
To further demonstrate the potential use of the β-amino-
phosphonate products 4 (Scheme 1), 4ba was treated
sequentially with LiHMDS and (CH2O)n. The Horner–
Wadsworth–Emmons reaction proceeded smoothly to give
the asymmetric aza-Morita–Baylis–Hillman (aza-MBH)-
equivalent product 6 of the α,β-unsaturated sulfone. Com-
pound 6 was further transformed into the chiral azetidine 7
by an aza-Michael reaction in the presence of LiOH·H2O
(Scheme 1).8
Scheme 1 Derivatization of chiral α-sulfone β-aminophosphonates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
Y. Peng et al.
Letter
Synlett
The sulfonyl moiety can be used as a potential function-
al group in the production of various azetidines containing
fluorine, allyl, or olefin substituents.9 In addition, the N-
protecting group CO2C(Me)2-i-Pr in 5 was removed smooth-
ly in a similar manner to that used for removing Boc, to give
8 in good yield without racemization (Scheme 2).
addition was also established. A novel N-protecting group
was also developed. Further exploration of the use of azeti-
dines in organic synthesis is currently ongoing in our labo-
ratory.
Funding Information
O
We are grateful for financial support from the National Science Foun-
dation of China (21172180).
iPr
COCNH
NH2
O
O
CH2Cl2–TFA (10:1)
)(
P(OEt)2
P(OEt)2
Ph
(91% yield, 84% ee)
Ph
0 °C to r.t.
5ba
8
Supporting Information
Supporting information for this article is available online at
Scheme 2 Removal of the novel N-protecting group
https://doi.org/10.1055/s-0036-1589156.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
The absolute configuration of 4ba was unambiguously
determined to be S,S by means of X-ray crystal analysis,10
and the configurations of the other products were deduced
accordingly. Based on the stereochemical outcome, we pro-
pose the possible transition-state model shown in Figure 1.
The thiourea activates the imine by two hydrogen-bonding
interactions with the nitrogen atom and the oxygen atom of
the carbonate, respectively. The deprotonated anion of the
β-benzenesulfonyl phosphate is directed by coordination
with the tertiary nitrogen atom through its counterion, i.e.,
lithium. Nucleophilic addition from the Si face of the imine
then leads to the observed favored product. The definite
reason why substituents at the 11-position of the catalysts
affect the catalytic performance is unclear. The absolute
configuration of the new stereogenic center in 7 was con-
firmed by using NOESY, which showed a correlation be-
tween the benzyl proton and the hydroxy proton.
References and Notes
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S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978,
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Thibodeaux, C. J.; Li, S.; Metzger, E.; Fudala, J.; Su, J.; Zhang, J.-K.;
Lee, J.; Cioni, J. P.; Evans, B. S.; Hirota, R.; Labeda, D. P.; van der
Donk, W. A.; Metcalf, W. W. Proc. Natl. Acad. Sci. U. S. A. 2015,
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Microbiol. Mol. Biol. Rev. 2014, 78, 176. (d) Horsman, G. P.;
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W.; Xie, M.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2013, 52, 3473.
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Chem. Commun. 2007, 5058. (e) Hashimoto, T.; Maruoka, K. J. Am.
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Si-face attack
O
F3C
SO2Ph
H
(EtO)2P
(4) (a) Zhang, H.; Wen, X.; Gan, L.; Peng, Y. Org. Lett. 2012, 14, 2126.
(b) Chen, J.; Wen, X.; Wang, Y.; Du, F.; Cai, L.; Peng, Y. Org. Lett.
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iPr
O
O
Li
N
Ph
N
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H
H
N
S
O
N
CF3
N
F3C
Figure 1 Proposed transition-state model
In conclusion, we have developed a highly efficient meth-
od for synthesizing β-aminophosphonates by an enantio-
selective Mannich reaction catalyzed by a chiral thiourea,
combined with the use of a sulfonyl as a traceless group for
activating the α-hydrogen atom of a phosphonate.11 An
alternative method for obtaining aza-MBH products of α,β-
unsaturated sulfones and azetidines through a Horner–
Wadsworth–Emmons reaction and sequential aza-Michael
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
Y. Peng et al.
Letter
Synlett
(7) When optimizing the reaction conditions, a retro-Mannich and
a Horner–Wadsworth–Emmons reaction were observed if the
reaction time was too long, so the reaction time was set at 72 h
for further investigations of the substrates.
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Gnanaprakasam, B. Org. Lett. 2017, 19, 3628. (b) Yang, Y.;
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reduced pressure. The crude product 4 was purified by chroma-
tography [silica gel, EtOAc–PE].
1,2-Dibromoethane (50 μL) was added to a mixture of product 4
and Mg turnings (30 equiv) in anhyd MeOH (0.1 mmol/mL) at
0 °C, and the mixture was stirred at r.t. for 11 h. The reaction
was then quenched with sat. aq NH4Cl and the mixture was fil-
tered. The aqueous layer was extracted with EtOAc. The organic
phases were combined, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The crude product was then
purified by chromatography [silica gel, EtOAc–PE].
Diethyl ((2S)-2-Phenyl-2-{[(1,1,2-trimethylpropoxy)carbonyl]-
amino}ethyl)phosphonate (5ba)
(10) CCDC 1548198 contains the supplementary crystallographic
data for compound 4ba. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(11) Mannich Products 4 and Aminophosphonates 5; General
Procedure
Prepared from 4ba (32 mg, 0.060 mmol), Mg turnings (44 mg,
1.80 mmol), and 1,2-dibromoethane (50 μL), as described above,
as a colorless oil; yield: 19 mg (81%), [α]D25 + 13.7 (c = 0.38, CH2-
Cl2). HPLC: Chiralpak ID column [hexane–i-PrOH (80:20), flow
rate: 0.5 mL/min, λ = 254 nm]: tminor = 25.6 min, tmajor = 29.8 min.
1H NMR (600 MHz, CDCl3): δ = 7.31 (s, 4 H), 7.24 (s, 1 H), 5.81 (s,
1 H), 5.03 (s, 1 H), 4.03 (s, 2 H), 3.85 (d, J = 54.0 Hz, 2 H), 2.42–
2.13 (m, 3 H), 1.35 (s, 6 H), 1.28 (t, J = 6.0 Hz, 3 H), 1.14 (s, 3 H),
0.93–0.73 (m, 6 H). 13C NMR (151 MHz, CDCl3): δ = 154.9, 142.3,
128.5, 127.3, 126.0, 84.8, 61.8 (d, J = 7.5 Hz), 61.6 (d, J = 6.0 Hz),
50.3, 36.2, 33.2 (d, J = 140.4 Hz), 23.1, 23.0, 17.3, 16.3 (d, J = 6.0
Hz), 16.2 (d, J = 6.0 Hz). HRMS (ESI): m/z [M + Na]+ Calcd for
The N-protected α-amido sulfone 1 (0.12 mmol, 1.2 equiv), 3e
(10 mol%), and LiOH·H2O (0.14 mmol, 1.4 equiv) were dissolved
in toluene (1.0 mL) at –20 °C, and the mixture was stirred for 5
min. β-Benzenesulfonyl phosphate 2 (0.1 mmol, 1.0 equiv) was
added at –20 °C, and the mixture was stirred for 72 h. The reac-
tion was quenched with sat. aq NH4Cl, and the aqueous layer
was extracted with EtOAc (3 × 30 mL). The organic phases were
combined, dried (Na2SO4), filtered, and concentrated under
C
19H32NNaO5P: 408.1916; found: 408.1918.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E