Catalytic asymmetric synthesis of nitrogen-containing gem-bisphosphonates using a dinuclear Ni2-Schiff base complex

Article abstract of DOI:10.1055/s-0029-1217192

A catalytic asymmetric synthesis of nitrogen-containing gem-bisphoshonates is described. A Lewis acid-Br?nsted base bifunctional homodinuclear Ni₂-Schiff base complex promoted catalytic enantioselective conjugate addition of nitroacetates to et

Full text of DOI:10.1055/s-0029-1217192

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1635
Catalytic Asymmetric Synthesis of Nitrogen-Containing gem-Bisphosphonates
Using a Dinuclear Ni2–Schiff Base Complex
Catalytic
Asymme
u
tric Synthesi
k
s
of
N
itrogen
o
-Containing gem-B
K
isphosphonates ato, Zhihua Chen, Shigeki Matsunaga,* Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56845206; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; E-mail: smatsuna@ mol.f.u-tokyo.ac.jp
Received 30 January 2009
are summarized in Table 1 and Table 2. With a homodi-
Abstract: A catalytic asymmetric synthesis of nitrogen-containing
nuclear Ni2–Schiff base 1 complex,10c,e which was origi-
gem-bisphoshonates is described. A Lewis acid–Brønsted base bi-
functional homodinuclear Ni2–Schiff base complex promoted cata-
lytic enantioselective conjugate addition of nitroacetates to
nally developed for
a Mannich-type reaction of
nitroacetates, the reaction of 2a with 3a proceeded at 0 °C
ethylidenebisphosphonates, giving products in up to 93% ee and in THF, and product 4aa was obtained in quantitative con-
94% yield. Transformation of the product into a chiral a-amino
ester with a gem-bisphosphonate moiety is also described.
version and 38% ee (Table 1, entry 1). With other homo-
dinuclear complexes, such as a Co2-1 complex,10f the
reactivity was good, but the enantioselectivity was worse
than that in entry 1 (entries 2–4: 21–0% ee). The hetero-
dinuclear transition metal/rare earth metal Schiff base
complexes are effective in other reactions.10a,b,d Therefore,
Key words: asymmetric catalysis, asymmetric synthesis, bisphos-
phonates, Michael addition
gem-Bisphosphonates (BP) have high affinity for hy- we also examined heterodinuclear Ni/rare earth metal
droxyapatite bone mineral surfaces and constitute an im- complexes (entries 5–7), but the results were much less
portant class of biologically active compounds.1 Some BP satisfactory. The reaction conditions were further opti-
are used clinically for the prevention and treatment of sev- mized using the Ni2-1 complex (Table 2). By changing the
eral bone disorders, such as Paget’s disease, osteoporosis, ester moiety of the nitroacetate to a bulkier tert-butyl
bone metastasis, myeloma, and rheumatoid arthritis.2 The group, enantioselectivity improved to 58% ee (entry 2,
use of BP as carriers for bone-specific therapeutic agents 3b). Solvent affected the enantioselectivity, and toluene in
has also been intensively studied.1 In addition, BP are ef- entry 5 was the best, giving 4ab in 75% ee. The addition
fective growth inhibitors of several protozoan parasites of 5 Å MS further improved the enantioselectivity to 83%
that cause African sleeping sickness, malaria, and others.3 ee (entry 6). Catalyst loading was successfully reduced to
Because of these important pharmacologic activities, syn- 3 mol% in entry 7, while maintaining good conversion
thetic methods for various BP have been intensively in- and enantioselectivity.
vestigated over the last two decades. Catalytic asymmetric
approaches for the synthesis of optically active BP are,
however, quite limited.4 Highly enantioselective organo-
catalytic 1,4-additions5 of aldehydes,4a b-keto esters,4b
and ketones4c to ethylidenebisphosphonates have been re-
ported, but there are no reports of a catalytic asymmetric
N
N
N
O
N
O
synthesis of nitrogen-containing BP. Because nitrogen-
containing BP are often biologically much more active
than BP without an amino functional group,6 the develop-
ment of a new method for chiral nitrogen-containing BP
is in high demand. Herein, we report catalytic asymmetric
1,4-addition of nitroacetates to ethylidenebisphospho-
nates. A Lewis acid–Brønsted base bifunctional homodi-
nuclear Ni2–Schiff base 1 complex (Figure 1) promoted
the reaction, giving products in up to 93% ee and 94%
yield.
M1
M2
OH HO
OH
HO
O
O
dinucleating Schiff base 1
M1 = M2 = Ni: (R)-Ni2–1 complex
M1 = M2 = Co(OAc): (R)-Co2–1 complex
Figure 1 Structures of dinucleaing Schiff base 1 and homodinuclear
Schiff base complexes
Because the Ni2–1 complex is bench-stable and storable,
the substrate scope of the reaction (Table 3) was investi-
gated using a catalyst stored for more than 3 months.12
Various a-substituted nitroacetates were applicable under
the optimized reaction conditions in toluene with the 5 Å
MS additive. In addition to methyl-substituted nitroace-
tate 3b (entry 1), ethyl, n-propyl, and benzyl-substituted
nitroacetates 3c–e gave products in good isolated yields
and 84–82% ee (entries 2–4). It is noteworthy that the
reaction proceeded nicely using functionalized nitro-
Initially, we screened catalysts for the reaction of ethyl-
idenebisphosphonate 2a with nitroacetate 3a. Among var-
ious Lewis acid/Brønsted base cooperative catalysts,7–9
dinuclear Schiff base complexes10,11 showed promising
results for the present reaction. The optimization studies
SYNLETT 2009, No. 10, pp 1635–1638
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217192; Art ID: Y00609ST
© Georg Thieme Verlag Stuttgart · New York

1636
Y. Kato et al.
CLUSTER
not yet clear, we speculate that a Lewis acid/Brønsted
base cooperative mechanism might be involved, as in oth-
er reactions promoted by dinuclear Schiff base complex-
es.10 A Ni-aryloxide moiety would function as a Brønsted
base to deprotonate the a-proton of nitroacetate 3 or b-
keto ester 5 to generate a Ni-enolate. The other Ni Lewis
acidic metal center would interact with ethylidenebispho-
sphonate 2. Mechanistic studies are required to determine
the origin of the stereoselectivity.
Table 1 Catalyst Screening for the Reaction of Ethylidenebisphos-
phonate 2a with Nitroacetate 3a
O
P
O
P
M1/M2/Schiff
base 1
(10 mol%)
EtO
EtO
OEt
O
P
O
P
CO2Et
NO2
OEt
EtO
EtO
OEt
OEt
+
Me
CO2Et
THF, 0 °C
Me NO2
3a
(1.1 equiv)
2a
4aa
Entry M1
M2
Ni
CoIIIOAc CoIIIOAc
Time (h) Conv. (%)a ee (%)
O
P
O
P
EtO
EtO
OEt
OEt
O
P
O
P
1
2
3
4
5
6
7
Ni
41
41
83
83
41
41
41
>95
>95
>95
>95
>95
>95
>95
38
21
0
EtO
EtO
OEt
OEt
cat. Ni2–1
(10 mol%)
2a
+
CO2t-Bu
O
toluene
5 Å MS, 0 °C
42 h
Cu
Pd
Ni
Ni
Ni
Cu
O
Pd
0
CO2t-Bu
MeO
6 99% yield, 80% ee
La(Oi-Pr)
Sm(Oi-Pr)
Gd(Oi-Pr)
3
MeO
5
5
(1.1 equiv)
7
Scheme 1 Catalytic asymmetric 1,4-addition of b-keto ester 5 to
vinylidenebisphosphonate 2a
a Conversion yield determined by 1H NMR analysis of crude reaction
mixture.
To demonstrate the utility of the present reaction, trans-
formations of the Michael adduct 4ab were investigated
(Scheme 2). Conversion of the bisphosphonate moiety
into a biologically active bisphosphonic acid was success-
fully performed with TMSBr at 50 °C. The tert-butyl ester
moiety remained unchanged when the reaction was per-
formed in the presence of N,O-bis(trimethylsilyl)acet-
amide,4b and bisphosphonic acid 7ab was obtained in
quantitative yield. The nitro group in 4ab was reduced us-
ing NiCl2 and NaBH4 to afford bisphosphonate 8ab with
an a-amino ester group in 92% yield. Because BP with
both a-hydroxy and g-amino moieties have higher biolog-
ical activities,6,14 we investigated the introduction of a-
hydroxy group to 4ab. By treatment of 4ab with KOt-Bu
and dimethyldioxirane at –78 °C for 10 minutes, desired
9ab was obtained in 48% isolated yield. The isolated yield
Table 2 Optimization of Reaction Conditions
O
P
O
P
EtO
EtO
OEt
O
P
O
P
cat. Ni2–1
CO2R
NO2
OEt
EtO
EtO
OEt
OEt
(x mol%)
+
Me
CO2R
solvent, 0 °C
Me NO2
2a
3a R = Et
3b R = t-Bu
4aa R = Et
4ab R = t-Bu
(1.1 equiv)
Entry Nitro- Solvent
acetate
Additive Catalyst Time Conv. ee
(x mol%) (h)
(%)a (%)
>95 38
>95 58
1
2
3
4
5
6
7
3a
3b
3b
3b
3b
3b
3b
THF
none
10
10
10
10
10
10
3
41
45
45
45
45
45
48
THF
none
EtOH
none
>95
3
O
P
O
P
O
P
O
P
CH2Cl2
toluene
toluene
toluene
none
>95 20
>95 75
>95 83
95 84
EtO
EtO
OEt
HO
HO
OH
OEt
OH
none
a
b
4ab
CO2t-Bu
CO2t-Bu
5 Å MS
5 Å MS
Me NH2
8ab
c
Me NO2
7ab
a Conversion yield determined by 1H NMR analysis of crude reaction
mixture.
O
P
O
P
O
P
EtO
EtO
OEt
OEt
OEt
EtO
O
P
OEt
+
HO
EtO
CO2t-Bu
O
CO2t-Bu
acetate 3f with a phthalimide moiety. Product 4af was ob-
tained in 81% yield and 93% ee (entry 5). Benzyl and allyl
groups were also applicable as protecting groups of bis-
phosphonic acid (entries 6 and 7), although the reactivity
was somewhat decreased, possibly due to steric hin-
drance. As a donor, not only nitroacetates, but also b-keto
ester 5 was applicable, giving product 6 in 80% ee
(Scheme 1).13 Although the precise reaction mechanism is
Me NO2
9ab
Me NO2
10ab
Scheme 2 Transformation of product 4ab. Reagents and conditi-
ons: a) TMSBr, N,O-bis(trimethylsilyl)acetamide, 50 °C, 14 h; then
MeOH, r.t., 2 h, quant.; b) NaBH4, NiCl2·6H2O, MeOH, 0 °C to r.t.,
12 h, 92% yield; c) KOt-Bu, dimethyldioxirane, THF–acetone,
–78 °C, 10 min, 48% (9ab), 26% (10ab).
Synlett 2009, No. 10, 1635–1638 © Thieme Stuttgart · New York

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Catalytic Asymmetric Synthesis of Nitrogen-Containing gem-Bisphosphonates
1637
Table 3 Catalytic Asymmetric 1,4-Addition of Nitroacetates 3b–f to Vinylidenebisphosphonate 2a–c
O
P
O
P
R1O
R1O
OR1
OR1
O
P
O
P
cat. Ni2-1
R1O
R1O
OR1
OR1
CO2t-Bu
NO2
(10 mol%)
+ R2
CO2t-Bu
toluene
5 Å MS, 0 °C
R2 NO2
4
2a-c
3b-f
(1.1 equiv)
Entry
Bisphosphonate 2, R1 Nitroacetate 3, R2
4
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
2a, Et
2a, Et
2a, Et
2a, Et
3b, Me
3c, Et
4ab
4ac
4ad
4ae
24
24
24
24
83
94
81
88
82
82
84
82
3d, n-Pr
3e, Bn
O
N
5
2a, Et
4af
24
81
93
O
3f
6
7
2b, Bn
3b, Me
4bb
4cb
24
24
69
65
81
76
2c, allyl
3b, Me
a Isolated yield of analytically pure compound after silica gel column chromatography.
b Determined by chiral HPLC analysis using DAICEL CHIRALPAK AD-H (entries 1, 3–7) or CHIRALCEL OD-H (entry 2).
Phillips, A. M. F. Eur. J. Org. Chem. 2008, 2525.
(5) A general review on organocatalytic asymmetric 1,4-
additions:Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(6) (a) Zhang, Y.; Leon, A.; Song, Y.; Studer, D.; Haase, C.;
Koscielski, L. A.; Oldfield, E. J. Med. Chem. 2006, 49,
5804. (b) Dunford, J. E.; Kwaasi, A. A.; Rogers, M. J.;
Barnett, B. L.; Ebetino, F. H.; Russell, R. G. G.; Oppermann,
U.; Kavanagh, K. L. J. Med. Chem. 2008, 51, 2187.
(c) Kavanagh, K. L.; Guo, K.; Dunford, J. E.; Wu, X.;
Knapp, S.; Ebetino, F. H.; Rogers, M. J.; Russell, R. G.;
Oppermann, U. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
7829.
(7) Recent reviews on bifunctional asymmetric catalysis:
(a) Shibasaki, M.; Matsunaga, S.; Kumagai, N. Synlett 2008,
1583. (b) Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc.
Jpn. 2008, 81, 60. (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520. (e) Yamamoto, H.; Futatsugi, K. Angew.
Chem. Int. Ed. 2005, 44, 1924.
of 9ab was moderate due to the formation of byproducts,
such as rearranged adduct 10ab.14b,c
In summary, we developed catalytic asymmetric access to
optically active nitrogen-containing bisphosphonates. A
homodinuclear Ni2–Schiff base 1 complex promoted cat-
alytic asymmetric 1,4-additions of a-substituted nitroace-
tates 3 to ethylidenebisphosphonates 2, giving products in
up to 94% yield and 93% ee.15
Acknowledgment
This work was partially supported by Grant-in-Aid for Scientific
Research (S) (for MS), and Grant-in-Aid for Young Scientists (A)
(for SM) from JSPS and MEXT.
References
(1) For a recent review, see: Zhang, S.; Gangal, G.; Uludag, H.
Chem. Soc. Rev. 2007, 36, 507.
(8) General review on metal-catalyzed asymmetric 1,4-
additions: Christoffers, J.; Koripelly, G.; Rosiak, A.;
Rössle, M. Synthesis 2007, 1279.
(2) Reviews focused on the anticancer activity: (a) Guise, T. A.
Cancer Treat. Rev. 2008, 34, S19. (b) Lipton, A. Cancer
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A.; Concepción, J. L.; Yardley, V.; Croft, S. L.; Urbina, J.
A.; Oldfield, E. J. Med. Chem. 2006, 49, 215; and references
therein.
(9) For selected recent examples of bifunctional Lewis acid–
Brønsted base catalysts developed in our group for
asymmetric 1,4-additions, see: La catalyst: (a) Park, S.-Y.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. Tetrahedron
Lett. 2007, 48, 2815; and references therein. Y-Li catalyst:
(b) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13419. Zn catalyst:
(c) Harada, S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2582.
(4) (a) Sulzer-Mossé, S.; Tissot, M.; Alexakis, A. Org. Lett.
2007, 9, 3749. (b) Capuzzi, M.; Perdicchia, D.; Jørgensen,
K. A. Chem. Eur. J. 2008, 14, 128. (c) Barros, M. T.;
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(10) (a) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2007, 129, 4900. (b) Handa, S.;
Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
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Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 2170. (d) Sohtome, Y.; Kato, Y.; Handa, S.;
Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki, M.
Org. Lett. 2008, 10, 2231. (e) Chen, Z.; Yakura, K.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 3239.
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(g) Xu, Y.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew.
Chem. Int. Ed. 2009, 48, 3353.
(11) For selected examples of related bifunctional bimetallic
Schiff base complexes in asymmetric catalysis, see
(a) Annamalai, V.; DiMauro, E. F.; Carroll, P. J.; Kozlowski,
M. C. J. Org. Chem. 2003, 68, 1973; and references therein.
(b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem.
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analogy based on the enantiofacial selectivity of nitroacetate
3b in the asymmetric Mannich-type reactions.
(14) A review on the synthesis of a-hydroxy-bisphosphonates:
(a) Lecouvey, M.; Leroux, Y. Heteroatom Chem. 2000, 11,
556. For the rearrangement of a-hydroxy-bisphosphonate,
see: (b) Szajnman, S. H.; García Liñares, G.; Moro, P.;
Rodriguez, J. B. Eur. J. Org. Chem. 2005, 3687.
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(15) General Procedure
5 Å MS (Fluka, powder, 20 mg) in a test tube was flame-
dried prior to use under vacuum for 5 min. After cooling
down to r.t., argon gas was refilled, and the Ni2–Schiff base
1 catalyst (6.4 mg, 0.01 mmol) and toluene (333 mL) were
added. The mixture was cooled down to 0 °C, and nitro-
acetate 3b (15.9 mL, 0.11 mmol) was added to the mixture.
After stirring for 15 min at 0 °C, ethylidenebisphosphonate
2a (27.5 mL, 0.1 mmol) was added. The reaction mixture was
stirred for 24 h at 0 °C. The mixture was filtered through a
short pad of SiO2 (eluent: hexane–acetone = 1:3). The
combined filtrate was concentrated under reduced pressure,
and the residue was purified by SiO2 column chromatography
(hexane–acetone = 4:1 to 2:1) to afford 4ab (39.7 mg, 0.083
mmol, 83% yield) as a colorless oil.
(12) To demonstrate the stability of the Ni2–Schiff base 1
complex, the catalyst stored for 3 months was used in this
study. Freshly prepared Ni2–Schiff base 1 complex showed
comparable reactivity and enantioselectivity. For more
detailed information of the Ni2–Schiff base 1 complex, see
ref. 10c.
(13) The absolute configuration of 6 was determined by
comparing the sign of optical rotation with the literature data
in ref. 4b. The enantiofacial selectivity of b-keto ester was
same as that observed in the asymmetric Mannich-type
reaction of b-keto ester using the Ni2–Schiff base 1 complex.
The absolute configurations of 4 were tentatively assigned in
Compound 4ab: colorless oil. IR(neat): n = 3473, 2982,
1746, 1555, 1251, 1023 cm–1. 1H NMR (500 MHz, CDCl3):
d = 1.29–1.40 (m, 12 H), 1.46 (s, 9 H), 1.76 (s, 3 H), 2.36–
2.50 (m, 1 H), 2.77–3.01 (m, 2 H), 4.06–4.26 (m, 8 H).
13C NMR (125 MHz, CDCl3): d =14.8, 16.1–16.4 (m), 19.0,
29.4, 30.3 (t, J = 154.0 Hz), 62.9–63.1 (m), 82.8, 90.6,
164.2. 31P NMR (202 MHz, CDCl3): d = 20.4, 21.4. ESI-MS:
m/z = 498 [M + Na]+. HRMS: m/z calcd for C17H36NO10P2
[M + H]+: 475.1814; found: 476.1811; [a]D22.5 –19.8 (c 0.80,
CHCl3). HPLC [DAICEL CHIRALPAK AD-H, hexane–
2-PrOH (95:5), flow 1 mL/min, detection at 210 nm]: tR =
21.8 min (major)and 20.2 min (minor).
Synlett 2009, No. 10, 1635–1638 © Thieme Stuttgart · New York

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