Catalytic asymmetric synthesis of α,β-disubstituted α,γ-diaminophosphonic acid precursors by michael addition of α-substituted nitrophosphonates to nitroolefins

Article abstract of DOI:10.1021/ol3012666

Michael additions of α-substituted nitrophosphonates to various nitroolefins are shown to proceed with high diastereo- and enantioselectivity when catalyzed by a quinine-derived thiourea-tertiary amine bifunctional catalyst and generate α,γ-diaminophosphonic acid precursors with contiguous quaternary and tertiary stereocenters.

Full text of DOI:10.1021/ol3012666

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic Asymmetric Synthesis
of r,β-Disubstituted
r,γ-Diaminophosphonic Acid Precursors
by Michael Addition of r-Substituted
Nitrophosphonates to Nitroolefins
Chandra Bhushan Tripathi, Satavisha Kayal, and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India
sm@orgchem.iisc.ernet.in
Received May 8, 2012
ABSTRACT
Michael additions of R-substituted nitrophosphonates to various nitroolefins are shown to proceed with high diastereo- and enantioselectivity
when catalyzed by a quinine-derived thiourea-tertiary amine bifunctional catalyst and generate R,γ-diaminophosphonic acid precursors with
contiguous quaternary and tertiary stereocenters.
Structural resemblance of aminophosphonic acids with
a hydrated tetrahedral intermediate of amino acids has
established aminophosphonic acids as structural and func-
tional surrogates for amino acids.1 Consequently, amino-
phosphonic acids owing to their diverse biological and
medicinal applications2 prompted the development of new
methodologies for their asymmetric synthesis. The past
decade has witnessed substantial progress in this area in
terms of catalytic asymmetric CÀH,3 CÀC,4 CÀP,5 and
CÀN6 bond formation.7
(3) Goulioukina, N. S.; Bondarenko, G. N.; Lyubimov, S. E.;
Davankov, V. A.; Gavrilov, K. N.; Beletskaya, I. P. Adv. Synth. Catal.
2008, 350, 482–492.
(4) For selected examples, see: (a) Rai, V.; Namboothiri, I. N. N.
Tetrahedron: Asymmetry 2008, 19, 767–772. (b) Rai, V.; Mobin, S. M.;
Namboothiri, I. N. N. Tetrahedron: Asymmetry 2007, 18, 2719–2726. (c)
Kiyohara, H.; Matsubara, R.; Kobayashi, S. Org. Lett. 2006, 8, 5333–
5335. (d) Kiyohara, H.; Nakamura, Y.; Matsubara, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2006, 45, 1615–1617. (e) Kobayashi, S.;
Kiyohara, H.; Nakamura, Y.; Matsubara, R. J. Am. Chem. Soc. 2004,
126, 6558–6559. (f) Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1,
837–839.
(5) For selected examples, see: (a) Ohara, M.; Nakamura, S.;
Shibata, N. Adv. Synth. Catal. 2011, 353, 3285–3289. (b) Zhu, Y.;
Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153–
156. (c) Zhao, D.; Wang, Y.; Mao, L.; Wang, R. Chem.;Eur. J. 2009,
15, 10983–10987. (d) Fu, X.; Loh, W.-T.; Zhang, Y.; Chen, T.; Ma, T.;
Liu, H.; Wang, J.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 7387–
7390. (e) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 5079–5081. (f) Rai, V.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2008, 19, 2335–2338. (g) Akiyama, T.; Morita, H.; Itoh, J.;
Fuchibe, K. Org. Lett. 2005, 7, 2583–2585. (h) Joly, G. D.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 4102–4103.
(1) (a) Kudzin, Z. H.; Kudzin, M. H.; Drabowicz, J.; Stevens, C. V.
Curr. Org. Chem. 2011, 15, 2015–2071. (b) Orsini, F.; Sello, G.; Sisti, M.
Curr. Med. Chem. 2010, 17, 264–289. (c) Kukhar, V. P.; Romanenko,
V. D. In Chemistry of Aminophosphonic Acids and Phosphonopeptides;
Hughes, A. B., Ed.; Wiley-VCH: Weinheim, Germany, 2009; pp 189À260.
(d) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879–10888.
(2) (a) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54,
5955–5980. (b) Sienczyk, M.; Oleksyszyn, J. Curr. Med. Chem. 2009, 16,
1673–1687. (c) Alonso, E.; Solis, A.; del Pozo, C. Synlett 2000, 698–700.
(d) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.;
Taylor, S. D.; Yager, K. M.; Sprengler, P. A.; Benkovics, S. J. Science
1994, 265, 234–237. (e) Kaplan, A. P.; Bartlett, P. A. Biochemistry 1991,
30, 8165–8170. (f) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J.
Med. Chem. 1986, 29, 29–40. (g) 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, 56–58.
r
10.1021/ol3012666
XXXX American Chemical Society

to nitroolefins which generates products with contiguous
quaternary and tertiary stereocenters.
Scheme 1. Nitrophosphonates in Asymmetric Catalysis
Our initial focus was to identify the best catalyst
and suitable reaction conditions for the aforementioned
Michael reaction. The addition of diethyl(1-nitroethyl)-
phosphonate 1a to ω-nitrostyrene 2a served as the model
reaction toward this effort (Table 1). Rapid evaluation of
the catalyst structure was facilitated by the lack of any
measurable background reaction at room temperature
(entry 1). The catalysts of interest were confined to thiour-
ea-based bifunctional compounds derived from trans-1,2-
diaminocyclohexane or cinchona alkaloids, considering
their well-established mode of substrate activation.11 Not
surprisingly, the reaction was found to be catalyzed by this
type of bifunctional catalysts. In the presence of 10 mol %
of Takemoto catalyst12 I in CH2Cl2, nearly complete
conversion to the desired product 3a (with modest dr)
was observed within 14 h at rt (entry 2). The relative and
absolute stereochemistry of the product was determined by
X-ray analysis (vide infra). Even though 3a was obtained
only with moderate er of 36:64 at rt, lowering the reaction
temperature to 0 °C led to substantial improvement of
enantioselectivity (entry 3). Replacement of an electron-
deficient aryl moiety of the catalyst with cyclohexyl pro-
duced a more active catalyst (II); however the stereoche-
mical integrity of the resulting product was diminished
(entry 4). Catalyst III with bulkier ethyl substituents at the
Brønstedbasictertiaryamine center promoted the reaction
with much poorer enantioselectivity (entry 5). Cinchona
alkaloid-derivedbifunctionalcompoundsIVÀVIIIproved
to be good catalyst candidates (entries 6À10), particularly
the quinine and cinchonine-derived catalysts IV and VII,
respectively.13 The reaction medium was found to have a
dramatic influence on the diastereoselectivity of the reac-
tion (entries 11À16), with trifluorotoluene emerging as the
optimum solvent (entry 16). Reversibility of the reaction at
0 °C turned out to be a barrier toward complete conversion
as slight erosion of both dr and er was observed during the
course of the reaction.14 Further temperature optimization
provided À10 °C as the optimum reaction temperature,
and the product with a consistent dr and er was obtained
over the complete reaction course (entry 18).14
R-Nitrophosphonates can be regarded as immediate
precursors of R-aminophosphonic acids, the straightfor-
ward synthesis of which can be realized via addition to
a potentially wide variety of electrophiles. The use of
parent R-nitrophosphonates is complicated by postreac-
tion epimerization of the R-center, but the corresponding
R-substituted nitrophosphonates are innocuous in this
regard. However the application of substituted R-nitro-
phosphonates as a nucleophile has remained rather
limited. In 2008, Johnston reported a diastereo- and
enantioselective Mannich-type reaction of R-methyl-R-
nitrophosphonates to imines using a chiral Brønsted acid
catalyst (Scheme 1).8 Very recently, during the course of
our investigation, Namboothiri achieved an enantioselec-
tive Michael addition of R-substituted-R-nitrophospho-
nates to vinyl ketones with the help of a bifunctional
catalyst (Scheme 1).9 While the above methods led to the
generation of quaternary R,β-diaminophosphonic acid
and R-aminophosphonic acid precursors, respectively,
there is no report for the enantioselective synthesis of the
precursor of R-substituted R,γ-diaminophosphonic acids.
As part of our research program,10 we became intrigued
by the possibility of accessing such a class of compounds
via an asymmetric CÀC bond formation. It was reasoned
that Michael addition of R-substituted-R-nitrophospho-
nates to nitroolefins would generate such densely functio-
nalized compounds with an additional β-substituent
(Scheme 1). Herein, wereportthefirstcatalytic asymmetric
Michael addition of R-substituted-R-nitrophosphonates
(11) For selected reviews, see: (a) Stegbauer, L.; Sladojevich, F.;
Dixon, D. J. Chem. Sci. 2012, 3, 942–958. (b) Siau, W.-Y.; Wang J.
Catal. Sci. Technol. 2011, 1, 1298–1310. (c) Marcelli, T.; Hiemstra, H.
Synthesis 2010, 1229–1279. (d) Takemoto, Y. Chem. Pharm. Bull. 2010,
58, 593–601. (e) Connon, S. J. Chem. Commun. 2008, 2499–2510. (f)
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743. (g)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–
1543. (h) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418–5427. (i)
Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299–4306.
(12) (a) Sakamoto, S.; Inokuma, T.; Takemoto, Y. Org. Lett. 2011,
13, 6374–6377. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672–12673.
(13) For seminal works on bifunctional cinchona alkaloid-based
thiourea derivatives, see: (a) Bernardi, L.; Fini, F.; Herrera, R. P.;
Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375–380. (b) McCooey,
S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367–6370. (c) Ye,
J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481–4483. (d)
(6) For selected examples, see: (a) Bernardi, L.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772–5773. (b) Kim,
M. S.; Hye, R. K.; Kim, Y. D. Org. Lett. 2005, 7, 2309–2311.
(7) For reviews, see: (a) Bhaduri, P. S.; Li, H. Synlett 2012, 23, 1108–
1131. (b) Albrecht, Ł.; Albrecht, A.; Krawczyk, H.; Jørgensen, K. A.
Chem.;Eur. J. 2010, 16, 28–48. (c) Bhadury, P. S.; Song, B.-A.; Yang,
S.; Zhang, Y.; Zhang, S. Curr. Org. Synth. 2008, 5, 134–150. (d) Ma,
J.-A. Chem. Soc. Rev. 2006, 35, 630–636.
(8) Wilt, J. C.; Pink, M.; Johnston, J. N. Chem. Commun. 2008, 4177–
4179.
(9) Bera, K.; Namboothiri, I. N. N. Org. Lett. 2012, 14, 980–983.
(10) Manna, M. S.; Kumar, V.; Mukherjee, S. Chem. Commun. 2012,
48, 5193–5195.
ꢀ
ꢀ
Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–
1969. (e) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
Synlett 2005, 603–606.
(14) See Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

temperature and the product was obtained with a slightly
diminished dr and er (entry 11). Our reaction conditions
are especially suitable for aliphatic nitroolefins as the
products were obtained in very good yield with excellent
diastereo- and enantioselectivity (entries 13À15). Particu-
larly noteworthy is the high enantioselectivity (er = 97:3)
observed for the small methyl substituent (entry 13). The
reaction can also be carried out with a lower catalyst
loading without much influence on the selectivity, albeit
at the expense of the reaction rate.15
Table 1. Catalyst Evaluation and Reaction Conditions Opti-
mization for Asymmetric Michael Addition of Nitrophospho-
nate 1a to ω-Nitrostyrene 2aa
Table 2. Substrate Scope of the Asymmetric Michael Addition
of R-Methyl-nitrophosphonate 1a to Various Nitroolefinsa
T, °C
(t, h)
yield
(%)b
R (2)
Ph (2a)
3
drc
erd
1
2
3
4
5
6
7
8
9
À10 (45) 3a
À10 (62) 3b
À10 (26) 3c
À10 (70) 3d
À10 (36) 3e
À10 (80) 3f
75
64
64
64
70
60
65
82
38
70
76
70
80
79
82
12:1 96.5:3.5
10:1 96.5:3.5
10:1 96:4
T, °C
(t, h)
conv
(%)b
4-ClC6H4 (2b)
3-ClC6H4 (2c)
3-NO2C6H4 (2d)
4-CF3C6H4 (2e)
4-FC6H4 (2f)
cat.
solvent
drb
erc
d
1
À
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
25 (48)
25 (14)
0 (16)
0 (16)
0 (16)
0 (16)
0 (24)
0 (24)
0 (24)
0 (24)
0 (30)
0 (30)
0 (30)
0 (30)
0 (30)
0 (30)
0 (40)
À10 (45)
À
À
10:1 94.5:5.5
12:1 96:4
2
I
>90
50
72
50
40
63
63
55
50
80
94
80
90
90
87
90
>95
3:1
36:64
8:92
3
I
4:1
10:1 97:3
4
II
1.6:1
1.5:1
2:1
18:82
33:67
95:5
4-OMeC6H4 (2g) 0 (32)
3g
10:1 96:4
5
III
IV
V
4-MeC6H4 (2h)
2-Naphthyl (2i)
À10 (90) 3h
0 (32) 3i
À10 (70) 3j
0 (26) 3k
10:1 96.5:3.5
10:1 93:7
6
7
6:1
93:7
10 2-Furyl (2j)
11:1 96.5:3.5
8
VI
VII
VIII
IV
IV
IV
IV
IV
IV
VII
IV
4:1
87:13
5:95
11 2-Thienyl (2k)
5:1
6:1
94.5:5.5
95.5:4.5
9
10:1
4:1
12 PhCHdCH2 (2l) À10 (88) 3l
10
11
12
13
14
15
16
17
18
9:91
13 Me (2m)
14 n-Pent (2n)
15 i-Bu (2o)
À10 (60) 3m
À10 (40) 3n
À10 (60) 3o
12:1 97:3
20:1 >99:1
13:1 99:1
7:1
96:4
CHCl3
THF
15:1
2:1
94.5:5.5
96:4
a Reactions were carried out using 1.0 equiv of 1a and 1.5 equiv of 2.
b Isolated yield of the products after column chromatographic purifica-
tion. c Determined by 1H NMR analysis of the crude reaction mixture.
d Determined by HPLC analysis using a stationary phase chiral column
(see Supporting Information).
TBME
EtOAc
PhCF3
PhCF3
PhCF3
10:1
10:1
12:1
7:1
95:5
94:6
96.5:3.5
6:94
12:1
96.5:3.5
a Reactions were carried out using 1.0 equiv of 1a and 1.5 equiv of 2a.
To check the viability of a larger R-substitution on
nitrophosphonate, we applied R-ethyl-dimethylphospo-
nate 1b, with aliphatic nitroolefins 2nÀo under our stan-
dard reaction conditions (Scheme 2). The corresponding
Michael adducts 4aÀb were obtained as a single diaster-
eomer in good yield with high enantioselectivity.
b Conversion and diastereomeric ratio (dr) were determined by 1H NMR
analysis of the crude reaction mixture. c Enantiomeric ratio (er) deter-
mined by HPLC analysis using a stationary phase chiral column (see
Supporting Information). d No conversion after 48 h. TBME: tert-Butyl
methyl ether.
The relative and absolute configuration of the Michael
adduct 3o was determined by X-ray structure analysis and
found to be (2S, 3R) (Figure 1). It is expected that the
absolute configuration for the remaining examples can be
assigned by analogy as the same.
The synthetic potential of the Michael adduct was
demonstrated by the reduction of 3a (Scheme 3). When
treated with NaBH4 and NiCl2 for 30 min at À35 to
0 °C, the product pyrazolidinyl phosphonate 5, generated
via reductive NÀN bond formation, was obtained in
The optimized catalyst (IV) and reaction conditions
(Table 1, entry 18) were then applied for the evaluation
of the scope of this reaction. The results are summarized
in Table 2. We were pleased to find that a wide range of
nitroolefins with a diverse steric and electronic environ-
ment reacted smoothly with R-methyl-nitrophosphonate
1a. Different substituents on aromatic nitroolefins furn-
ished the Michael adducts 3aÀh in moderate to good yields
with uniform dr and er, regardless of their position and
electronic properties (entries 1À8). Heteroaromatic sub-
stituted nitroolefins were also tolerated (entries 10À11),
although 2-thienylnitroolefin required a somewhat higher
(15) Using 5 mol % of IV, the Michael adduct 3c was obtained in
59% yield with dr 10:1 and er = 95.5:4.5 after 48 h at À10 °C.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Substrate Scope with Respect to R-Ethyl-nitropho-
sphonate 1b
Scheme 3. Synthetic Utility of Michael Adduct 3a
In summary, we have developed a highly diastereo- and
enantioselective catalytic Michael addition of R-substi-
tuted nitrophosphonates to nitroolefins using a quinine-
derived bifunctional catalyst. The products of this reaction,
consisting of adjacent quaternary and tertiary stereo-
centers, were obtained in good to high yields and represent
immediate precursors of R,β-disubstituted R,γ-diamino-
phosphonic acids.
Acknowledgment. A generous start-up grant from In-
dian Institute of Science, Bangalore, is gratefully acknowl-
edged. This work is supported by DST, New Delhi (Grant
No. SR/FT/CS-90/2010) and CSIR, New Delhi (Grant
No. 01(2505)/11/EMR-II). We thank Prof. T. N. Guru
Row and Mr. Pavan M.S. (Solid State and Structural
Chemistry Unit, IISc, Bangalore) for their help with the
X-ray diffraction analysis. C.B.T. and S.V.K. acknowl-
edge CSIR and IISc, respectively for doctoral fellowships.
Figure 1. Relative and absolute configuration of 3o and its X-ray
structure.
60% yield. Aminophosphonates and aminophospho-
nic acids of this type have already been tested as
potential organocatalysts for asymmetric aldol and
Michael reactions.16
Supporting Information Available. Detailed experimen-
tal procedures, spectral and analysis data for all new
compounds together with HPLC chromatograms of the
relevant compounds (PDF), and X-ray data of 3o (CIF
file). This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) (a) Malmgren, M.; Granander, J.; Amedjkouh, M. Tetrahedron:
Asymmetry 2008, 19, 1934–1940. (b) Tao, Q.; Tang, G.; Lin, K.; Zhao,
ꢀ
Y.-F. Chirality 2008, 20, 833–838. (c) Diner, P.; Amedjkouh, M. Org.
Biomol. Chem. 2006, 4, 2091–2096.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX