Synthesis of geminal bisphosphonates via organocatalyzed enantioselective Michael additions of cyclic ketones and 4-piperidones

Article abstract of DOI:10.1039/c1ob06473h

A Michael addition reaction of cyclic ketones and piperidones to a vinyl phosphonate is described. The reaction, catalyzed by chiral diamines, produced geminal γ-oxobisphosphonates in high yields (up to 92%) and very high ees (up to >99%). Disubstituted ketones gave drs of up to 8:92. The synthesis and characterization of several new compounds with potential biological activity is described.

Full text of DOI:10.1039/c1ob06473h

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PAPER
Synthesis of geminal bisphosphonates via organocatalyzed enantioselective
Michael additions of cyclic ketones and 4-piperidones†
Ana Maria Fa´ısca Phillips* and Maria Teresa Barros*
Received 28th August 2011, Accepted 28th September 2011
DOI: 10.1039/c1ob06473h
A Michael addition reaction of cyclic ketones and piperidones to a vinyl phosphonate is described. The
reaction, catalyzed by chiral diamines, produced geminal g-oxobisphosphonates in high yields (up to
92%) and very high ees (up to >99%). Disubstituted ketones gave drs of up to 8 : 92. The synthesis and
characterization of several new compounds with potential biological activity is described.
Introduction
Millions of doses of bisphosphonates are used annually through-
out the world for the treatment and prevention of bone disorders,
such as osteoporosis, Paget’s disease and bone-related cancers.1
Compounds A–D (Fig. 1) are examples. Bisphosphonates con-
tain P–C–P(O)(OH)2 moieties and they are hydrolysis-resistant
analogues of pyrophosphate, P–O–P(O)(OH)2, a unit found in
many molecules essential for life, such as DNA, RNA, proteins,
enzymes, ATP, phospholipids, and so on. Hence they have a
huge potential as targets for pharmaceutical applications. Recent
studies in vitro and in vivo showed that some are potent inhibitors
of parasitic protozoa responsible for diseases considered by the
Fig. 1 Biologically active geminal bisphosphonates.
World Health Organization as major tropical diseases. These
include Trypanosoma cruzi, the pathogen that causes Chagas’
future, better capable of interacting with the allosteric sites of
proteins. This concept is supported by a recent structure activity
relationship (SAR) study, which showed that the two enantiomers
disease,2 T. brucei, which causes sleeping sickness,3 and Plasmod-
ium falciparum, responsible for malaria.3a,4 Some bisphosphonates
also activate cells known to possess potent antitumour activity, the
of E, a phosphonocarboxylate analogue of minodronate D, had
gd T cells, which means that they could control a broader range of
significantly different activities,9 and that [(+)-E] was the most
tumours.5
potent selective inhibitor known of Rab geranylgeranyltransferase,
Studies to investigate the mode of action of bisphosphonates6
another enzyme in the mevalonate pathway. This was the first
and discover molecular targets for drug design found, as potential
report ever that a change in the configuration of the chiral
candidates, the enzymes farnesyl diphosphate synthase (FPPS)
center resulted in large differences in the activity of this type
and hexokinase. FPPS plays an important role in the meval-
of compounds. Bisphosphonates are known to have few or no
onate/cholesterol biosynthetic pathway, in protein prenylation,
toxic side effects. Their properties are related to the nature of the
and the generation of isoprenoid lipids.6 Hexokinase catalyzes the
functional substituents on the geminal carbon atom. Yet, despite
first step in glycolysis.7 Both enzymes are strongly inhibited by
the fact that they have many applications, there have been very
certain geminal bisphosphonates. X-ray crystallography studies
few reports on the development of methods to synthesize chiral
showed that the binding of risedronate-related compounds to
bisphosphonates.
FPPS is stereospecific,8 which suggests that chiral bisphospho-
nates could become important pharmaceutical targets in the
Department of Chemistry, CQFB-REQUIMTE, Faculdade de Cieˆncias e
Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829-516,
Caparica, Portugal. E-mail: amfp@dq.fct.unl.pt, mtbarros@dq.fct.unl.pt;
Our research interests in the Michael addition reaction10
Fax: +351-212948550; Tel: +351 212948300
† Electronic supplementary information (ESI) available: Experimental
brought our attention to a class of phosphonates reported as
details for the synthesis of new compounds and their characterization
data, copies of 1H and 13C NMR spectra and chromatographic traces. See
DOI: 10.1039/c1ob06473h
having, in their racemic forms, potent anti-arthritic and anti-
inflammatory activity.11 They are 4-oxobisphosphonates, e.g. F
404 | Org. Biomol. Chem., 2012, 10, 404–412
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and G (Fig. 1), and an enantioselective Michael addition reaction
of ketones to vinylbisphosphonate would be one of the obvious
ways to access chiral analogues. Besides the potential to have anti-
arthritic and anti-inflammatory activity, they could be further
transformed into compounds with other useful properties,12 i.e.
they could be converted by the Strecker or by the Bucherer–
Bergs reaction into chiral a,a-disubstituted amino acids bearing
a 4-bisphosphonyl moiety. These compounds would be structural
analogues of L-2-amino-4-phosphonobutanoic acid (L-AP4)13 H,
a known antagonist of the metabotropic glutamate receptors,
mGlu, end receivers of information from L-glutamate I, the major
excitatory neurotransmitter in the central nervous system.14 mGlu
plays a key role in fundamental processes like neural development,
learning and memory, and is implicated in a variety of acute and
chronic CNS disorders, being a potential target for therapeutic
intervention. Thus a library of these compounds may reveal
important new leads for pharmaceutical development.
The Michael addition reaction is a powerful tool for C–C bond
formation and for the elaboration of complex molecules from
simple substrates. Applications to the synthesis of phosphonates
have been recently reviewed.15 There have been a few reports on
the conjugate addition reaction of carbon nucleophiles to gem-
inal vinyl bisphosphonates: Grignard reagents,16 organolithium
compounds,17 and carbanions generated with sodium ethoxide,18
tertiary amines,11b lithium amide base,11a,19 or inorganic base.18
Catalytic asymmetric methods are still rare.20 To the best of
our knowledge, besides a report on the use of Ni(II)-Schiff
base complexes to promote the addition of nitroacetates to
ethyledenebisphosphonates,21 only organocatalysts were used to
achieve chiral induction.
Scheme 1 The Michael addition of cyclohexanone to bisphosphonate 2.
To explore the possibility of asymmetric induction via enamine
catalysis, the amines shown in Fig. 2 were tried as organocatalysts.
A ten-fold excess of ketone, commonly used in organocatalyzed
addition reactions, and 10 mol% catalyst, were used as starting
conditions for a preliminary screening. Piperazine, a catalyst
we found useful in the Michael addition of aldehydes to b-
nitrostyrenes,10d did not react, neither did its 1-methyl derivative.
There was also no reaction in the presence of catalyst V. Commer-
cially available (S)-(+)-1-(2-pyrrolidinylmethyl) pyrrolidine III, a
proline derivative that has in the past been successfully used in
other organocatalyzed reactions,21,31 gave a single phosphorus-
containing product, as determined by 31P NMR spectroscopy,
which was isolated by chromatography and identified as the desired
Michael addition adduct.
The application of organocatalysis22 in phosphonate chemistry
has been recently reviewed.23 The addition of aldehydes to a
vinylidene bisphosphonate catalysed by a diphenylprolinol silyl
ether was reported to give g-geminal bisphosphonate aldehydes in
high yields and ees of up to 97%.24–26 Dihydroquinine was used
to catalyse the addition of prochiral b-ketoesters to vinylidene
bisphosphonates to provide highly substituted adducts in high
yields and ees of up to 99%.27 We recently communicated the first
examples of the enantioselective addition of ketones to tetraethyl
methylenediphosphonate, catalyzed by chiral diamines.28 In order
to create a library of 4-oxobisphosphonates for SAR studies, we
have now explored this reaction further and applied it to a wide
range of cyclic ketones and piperidones, substances often used
as advanced intermediates in the synthesis of biologically active
piperidines,29 but which may also be active by themselves.30 The
full details of the work are presented here.
Fig. 2 The organocatalysts screened.
Afterwards the reaction conditions were optimized using di-
amine III as catalyst. The nature of the solvent did not have a
large influence on the outcome of the reaction (Table 1), with ees
varying between 30 and 34%, except for the ionic liquid [bmin]PF6,
which gave an improvement of 10%, but a lower yield of product
was obtained. The reaction could also be carried out successfully
in brine, but more than 3 days were needed for complete conversion
of the substrate rather than the typical 17 h necessary in the other
solvents, with no benefits in terms of asymmetric induction. When
the salt was changed to LiCl, the best ee was obtained in CH2Cl2 at
Table 1 Effect of the solvent on the asymmetric Michael addition of
cyclohexanone to tetraethyl vinylidene bisphosphonate catalyzed by IVa
Results and discussion
Entry
Solvent
Time [h]
Conversion [%]
eeb [%]
Prior to our short communication, the organocatalyzed asym-
metric Michael addition reaction of ketones to electron-deficient
olefins had been reported by others21 and by us10c with other
acceptors, i.e. nitroalkenes, enones, vinyl sulfones, alkylidene
malonates, maleimides, a,b-unsaturated aldehydes, imides, a-
substituted vinyl cyanoacetates, acetylenic esters, but not with
vinyl bisphosphonates. We chose as a model reaction for our
studies the addition of cyclohexanone to tetraethyl vinylidene
bisphosphonate (Scheme 1).
1
2
3
4
5
6
7
CH2Cl2
CH2ClCH2Cl
CHCl3
EtOH
DMF
[bmin]PF6
Brine
17
17
17
17
17
17
89
100
100
100
100
100
100
100
32
34
30
32
32
46
36
a Conditions: room temperature, bisphosphonate (1 mM) :
ketone : catalyst 1 : 10 : 0.1. b Determined by 13C NMR spectroscopy.
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Table 2 The effect of additives, catalyst load and temperature on the
peak between a multiplet at 2.89–3.01 ppm (H-1¢) and a doublet
at 1.26 ppm (C-5¢–CH3) indicated a close spatial relationship (syn)
between these two protons, which is only possible if the compound
had a trans configuration. When 2-phenylcyclohexanone was used
as substrate, there was no reaction in CH2Cl2. The reaction was
possible in [bmin]PF6, but the conversion was only 80% after 7 days
(entry 3) and 20% of an unknown additional product formed too.
Product 6 was found to be racemic. This suggests that the presence
of the bulky a-substituent hinders enamine formation and the
reaction may even proceed via the formation of an intermediate
enolate instead of an enamine, with the chiral diamine acting
as a base. In this case prochiral enolate faces could have led
to transition states of more comparable energies, and the final
product was racemic.
Michael addition reactiona
Entry Solvent
Additive
Time [h] Conversion [%] eeb [%]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN LiCl
THF
Toluene PhCOOH
CH2Cl2
None
PhCOOH
LiCl
17
17
17
24
17
17
40
17
168
17
17
17
17
100
100
50
100
100
100
50
100
63
100
100
100
100
32
40
48
24
20
36
6
30
26
30
26
30
32
LiCl
CH3COOH
CH3COOH
p-TsOH·H2O
PhCOOH
PhCOOH
8c
9d
10
11
12
13e
PhCOOH
PhCOOH
The monoacetal of 1,4-cyclohexanedione 1f was also used as a
substrate for the reaction, giving product 3f in moderate yield and
a good enantioselectivity of 64%. Enantioselective alkylation of 1f
provides a route to a-alkylated 1,4-cyclohexanedione derivatives,
which are also important building blocks for the synthesis of
natural products.33
a Conditions: r.t., with bisphosphonate (1 mM) : ketone : catalyst : additive
1 : 10 : 0.1 : 0.1. b Determined by 13C NMR spectroscopy. c Reaction with
20 mol% catalyst + additive. d Reaction at 0 ◦C. e Reaction with catalyst
IV.
t1 , but unfortunately it dropped as the reaction proceeded (Table
22, entries 3 and 4).
The enantiomeric excesses of the disubstituted ketones 3b–f and
6 were determined by HPLC. For this purpose, it was necessary to
prepare racemic standards for comparison of retention times, and
this was done via a Michael addition reaction of ketone enolates
formed in the presence of DBU to vinyl bisphosphonate 2, in an
adaptation of the method developed by Schlachter et al.11a and
Nugent et al.11b for the synthesis of geminal bisphosphonates F
and G (Scheme 3). For ketones with no absorption in the UV-
VIS region of the spectrum, a method to convert them into their
hydrazones by reaction with 2,4-dinitrophenylhydrazine (Scheme
4) was used.34 These reactions were selective, giving the products
cleanly in 17 h at r.t. When the hydrazone-forming reactions are
mediated by catalytic amounts of acid, no racemization is found to
occur.34b Presumably the compounds isolated are the more stable
E-isomers.
The effect of catalyst load and the presence of acids as additives
was also investigated, but the results did not vary much. A
higher induction was obtained in [bmin]PF6, but the yield of
product obtained in this reaction was lower than in CH2Cl2.
Finally, a combination of 10 mol% diamine III and PhCOOH
in dichloromethane (Table 2, entry 2) were selected as optimum
conditions for further studies. Two additional diamines, IV and
VI, were tried as potential catalysts with these conditions, but
they gave no additional improvement in the results.
The enantiomeric excess of the product of these reactions was
determined by 13C NMR spectroscopy, from the ratio of the signals
of the diastereoisomeric acetals 4 obtained after reaction of 3a with
(S,S)-2,3-butanediol in the presence of p-TsOH32 (Scheme 2).
Scheme 2 Acetal synthesis for ee determination.
In order to explore further the potentialities of the reaction, the
method developed was then applied to a wide range of ketones.
The reactions proceeded smoothly at room temperature to give
the desired 2,4-disubstituted Michael adducts in high yields (Table
Scheme 3 The Michael addition to vinylidene bisphosphonate catalyzed
by DBU. The relative configuration observed for the major product is
opposite to that obtained with the chiral catalyst.
1
3). No condensation products formed, as indicated by H NMR
spectroscopy.
As shown in the table, the reactivity of 4-substituted cyclo-
hexanones was similar, with 4-phenycyclohexanone reacting the
fastest (entry 2). Diastereoselectivities, determined from the ratio
of signals in 31P NMR spectra of the crude products, were
moderate, varying from 12 to 1 to 2.5 to 1. The enantiomeric
excesses were high, going up to 88% with the bulkiest substituent,
tert-butyl, providing the greatest enantiocontrol (entry 5).
The diastereoselectivity of the major product was found to be
trans from a NOESY spectrum of 3c. The presence of a cross
The Michael addition reaction was also applied to the alkylation
of cyclopentanone and some derivatives, but they showed different
reaction patterns from the cyclohexanones. Cyclopentanone was
very reactive. When the ketone and the bisphosphonate were
reacted in the usual 10 : 1 ratio, there was complete conversion
to products within 1.5 h. However, a 6 : 94 mixture of 2-
monosubstituted to 2,5-disubstituted cyclopentanone was ob-
tained (Scheme 5). With a 1 : 1 ratio of ketone to bisphosphonate,
after 1 h there was already 60% conversion, but the same product
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Table 3 Asymmetric Michael addition of cyclohexanones to tetraethyl vinylidene bisphosphonatea
Entry
1
Ketone
Product
Time
17 h
Yieldb [%]
61
drc [cis/trans]
eed [cis/trans]
—
40
2
7 h
78
8 : 92
62 : 76
3e
7 d
80
86
14 : 86
18 : 82
0
4
17 h
83 : 71
5
17 h
92
30 : 70
88 : 78
6
17 h
25 h
72
62
30 : 70
86 : 77
7f
—
64
a Conditions: r.t., bisphosphonate (1 mM) : ketone : catalyst : PhCOOH = 1 : 10 : 0.1 : 0.1. b After isolation by column chromatography. c Determined by 31
P
NMR spectroscopy. d Determined by 13C NMR spectroscopy (entry 1), or by chiral HPLC neat, or after conv. into 2,4-dinitrophenylhydrazones (entries
4–7). e Reaction in [bmin]PF6, conv. shown. f A ratio of bisphosphonate (1 mM) : ketone = 1 : 4 was used.
distribution was obtained. Thus, either the 2-monosubstituted
cyclopentanone is much more reactive towards the catalyst than
the unsubstituted ketone, or an enamine intermediate reacts with
the vinyl phosphonate to produce an iminium salt that is so
reactive, that after protonation it is deprotonated again to form a
new enamine, before hydrolysis takes place. Hence there is a second
addition, and the disubstituted product is preferentially obtained.
Disubstituted cyclopentanone 9 is chiral and has a high optical
rotation ([a]2D2 -30.2, c = 0.69) in CHCl3. This indicates that the
compound is trans disubstituted, with C2 symmetry, since a cis-
disubstituted compound would be meso and optically inactive.
Bisphosphonate 9 has to be chromatographed fast on silica gel,
else it decomposes partially via a retro-Michael reaction. In
contrast to this reaction, when the preparation of a racemic sample
was attempted with the DBU-promoted addition, the product
obtained was primarily mono-substituted, even when the reaction
was allowed to proceed for 17 h, with a 4 : 1 bisphosphonate to
ketone ratio, and a 3-fold excess of DBU. In order to obtain
a racemic substrate for HPLC analysis, bisphosphonate 9 was
refluxed in ethanolic KOH for 17 h, which resulted in full
racemization, as evidenced by the optical rotation of the product.
DNPH derivatives were subsequently prepared.
1-Indanone
showed
a
similar
behaviour
to
2-
phenylcyclohexanone. When the reaction was attempted with a
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Scheme 4 The synthesis of DNPH adducts for ee determination by
HPLC.
Scheme 6 The Michael addition reaction of 1-indanone and 2-indanone.
Very small amounts of other products also formed, which made
product isolation difficult. In addition, some decomposition was
also observed during chromatography. Although this product
could be isolated pure enough for spectroscopic identification,
it was never pure enough to allow an unambiguous determination
of the enantiomeric excess, and hence this was abandoned.
The DBU promoted reaction gave, under standard conditions,
a complex mixture of products. After optimization, it was possible
to obtain one product selectively by running the reaction for
2 h in an ice bath. However, only disubstituted product was
obtained. This product was identical to the disubstituted product
obtained in the enamine-catalyzed reaction. Unlike the reaction
with cyclopentanone, with 2-indanone the second alkylation took
place on the same carbon atom, showing the large preferential
formation of the trisubstituted enolate over the disubstituted one
for the second addition. The presence of two substituents could be
confirmed by the integration in the 1H NMR spectrum and by mass
spectrometry. Disubstitution on the same carbon atom could be
unambiguously confirmed by a DEPT experiment, which showed,
besides the presence of signals corresponding to CH2 groups of
the POEt moieties and the methylene groups b to phosphorus, the
presence of an additional CH2 signal at 42.85 ppm.
In order to further examine the potentialities of the enam-
ine promoted reaction, it was decided to extend the substrate
range to 4-tetrahydropyranone and 4-piperidones. The results are
presented in Table 4. There was smooth addition in all cases
to give the desired bisphosphonates as single reaction products.
The 4-piperidones obtained had high enantioselectivities of up
to 90%. However, it was found that these compounds racemized
partially during chromatography on silica gel, and hence the
enantiomeric excesses shown in Table 4 were determined prior
to chromatographic purification.
Scheme 5 The Michael addition reaction of cyclopentanone to vinyl
bisphosphonate 2.
5 : 1 ratio of ketone to bisphosphonate, after 17 h there were only
traces of product. Bisphosphonate 12 could eventually be prepared
in 81% yield after a 46 h reflux. Unfortunately this product was
racemic. Dialkylated indanone 13 was also obtained in low
amount (Scheme 6). The synthesis of bisphosphonate 12 had
been previously described, in a DBU catalyzed reaction.11 Under
our standard conditions, a 34 : 66 mixture of monosubstituted to
disubstituted indanone was obtained.
The alkylation of 2-indanone was also attempted. This substrate
was very reactive, and under standard conditions the enamine-
catalyzed reaction was complete in just over 1.5 h. However, a
mixture of approx. 70 : 30 of monosubstituted 15 to disubstituted
ketone 16 was obtained, plus small amounts of non-phosphorus-
containing condensation products. When the ratio of the reagents
was lowered to 3 : 1 2-indanone to bisphosphonate, there was
complete conversion in 17 h, with a similar product distribution.
The reaction with 4-tetrahydropyranone gave the product in a
high yield of 88%, but with a lower asymmetric induction, similar
to that obtained in the reaction of unsubstituted cyclohexanone.
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Table 4 Asymmetric Michael addition of 4-piperidones and 4-
The absolute configuration determined is consistent with the
preferential formation of an anti enamine (Fig. 4) in which the
double bond is oriented away from the bulky substituent at
position 2 of the pyrrolidine ring. Reaction can then take place
at the Re face as in K, or the Si face as in L. When the catalyst
is protonated, phosphonate approach to the Re face gives a tight
acyclic synclinal transition state K, which can be stabilized by
electrostatic interactions between a) the partially positive nitrogen
atom of the enamine, b) the partially negatively charged oxygen
atom of the phosphonate group and c) the protonated nitrogen
atom on the second pyrrolidine ring. If attack were to occur
on the Si face, the nitrogen atom of the second ring would
be too far away from the reaction centre and the stabilization
brought about by factor c) would not take place. This reaction
model proposed is in agreement with Seebach’s model for Michael
addition reactions with pre-formed enamines from pyrrolidines.36
In our reactions in aprotic media the products also had a 2S
configuration. Presumably under these conditions the nitrogen
atom on the second ring stabilizes the partially positively charged
phosphorus atom in transition state M.
tetrahydropyranone to tetraethyl vinylidene bisphosphonatea
Entry Ketone
1
Product
Time [%] Yieldb [%] eec [%]
5
58
61
88
90
65
40
2
3
6
17
The relative configuration, which was established to be trans for
3c, can be explained by an axial approach of the electrophilic vinyl
bisphosphonate to an enamine in which the 6-membered ring is
in the more stable chair-like conformation, and both the bulky
pyrrolidine ring and the 4-methyl group occupy an equatorial
position as in O. In this way 1,3-allylic strain as well as 1,3-diaxial
interactions are minimized (Fig. 5). This is in general agreement
with existing knowledge on reactions of pyrrolidine enamines of
1,4-disubstituted cyclohexanones.37
a Conditions: r.t., bisphosphonate (1 mM) : ketone : catalyst : PhCOOH =
1 : 10 : 0.1 : 0.1. b After isolation by column chromatography. c Determined
by 13C NMR spectroscopy (entry 3), or by chiral HPLC.
These results show that this new method of synthesis of geminal
4-oxobisphosphonates has wide applicability and may be used
for target oriented synthesis with substrates containing other
functional groups.
Overall the results provide further evidence supporting the
current wave of thought that in organocatalytic reactions mediated
by chiral amines, enamines are involved as intermediate species.
In these reactions, the absolute configuration of the major enan-
tiomer produced was determined by 13C NMR spectroscopy. The
spectra of the diastereomeric acetals 4 was used and the empirical
method of Le`miere et al.35 As a consequence of the Cahn–Ingold–
Prelog sequence rules, acetals of 2-substituted cyclohexanone 3a
fitted the model derived for 2-benzylcyclohexanone (Fig. 3). The
configuration of 3a was found to be 2S. A similar result was
obtained for bisphosphonate 20. The absolute configuration is
believed to be the same for the other products obtained, assuming
that they were formed by enamine catalysis and similar reaction
pathways.
Conclusion
We have developed a method for the diastereo- and enantioselec-
tive synthesis of functionalized geminal bisphosphonates, which
are chiral structural analogues of biologically active compounds.
The organocatalyzed Michael addition reaction protocol devel-
oped could be successfully applied to 4-substituted cyclohex-
anones, piperidones and cyclopentanones, and it gave several new
geminal 4-oxobisphosphonates in high yields, good diastereoselec-
tivities and very high enantioselectivities. Aromatic substitution
at position 2 of the ring retarded the reaction considerably, and
although products could be obtained, they were racemic. Studies
to evaluate the biological activity of these compounds are under
way.
Experimental
Synthesis of substrates
Tetraethyl vinylbisphosphonate (2). This compound was pre-
pared from paraformaldehyde and commercially available
tetraethyl methylenebis(phosphonate) according to a literature
procedure.38
1,4-Cyclohexanedione monoethylene acetal (1f). This monoac-
etal used as a substrate in Michael addition reactions was prepared
Fig. 3 Determination of the absolute configuration of 3a and 20.35
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Fig. 4 Proposed facial selectivity for the transition state.
Tetraethyl
[2-(5¢-tert-butyl-2¢-oxocyclohexyl)ethylidene]bis-
phosphonate (3d). Prepared from ethylidene bisphosphonate
2 and 4-tert-butylcyclohexanone, according to the general
procedure. The product was obtained as a 70 : 30 (trans/cis)
mixture of diastereoisomers, as determined by 31P NMR
spectroscopy. The crude product was purified by column
chromatography on silica gel with 1 : 1 acetone/CHCl3 to
give product 3d as a mixture of two diastereoisomers, in
the form of a colourless viscous liquid (78 mg, 92%). The
diastereoisomers separate partially during chromatography, but
complete separation requires several chromatographies. Major
diastereoisomer: dH (400 MHz; CDCl3) 0.89 (s, 9 H, 3 ¥ CH3 of
t-Bu), 1.33 (m, 12 H, OCCH3), 1.45–1.60 (m, 2 H, 2 ¥ 3¢-H),
1.63–1.84 (m, 2 H, 2 ¥ 4¢-H), 1.87–2.04 (m, 2 H, PCCH2),
2.24–2.56 (m, 4 H, PCHP + 1¢-H + 2 ¥ 6¢-H), 2.75–2.86 (m, 1 H,
1¢-H), 4.03–4.26 (m, 8 H, OCH2) ppm; dC (100 MHz; CDCl3)
16.37 (4 ¥ OCCH3), 25.71 (CH2, PCCH2), 27.27 (3 ¥ CH3 of
t-Bu), 29.67 (Cq, t-Bu), 31.50 (CH2, C-4¢), 32.52 (CH2, C-5¢),
33.78 (CH, t, JCP 133.4 Hz, PCHP), 38.62 (CH2, C-6¢), 41.72
(CH2, C-3¢), 46.70 (CH2, C-1¢), 62.64 (m, CH2, 4 ¥ OCH2), 215.0
(Cq, C O); dP (162 MHz; CDCl3) 23.67, 24.06; m/z 455 (M+1,
3), 454 (M+, 12), 397 (16), 351 (7), 317 (24), 301 (22), 289 (10),
288 (100), 273 (5), 271 (5), 261 (29), 244 (6), 233 (14), 205 (6), 187
(8), 177 (6), 171 (5), 165 (6), 159 (8), 152 (21), 136 (5), 122 (7), 112
(5), 110 (7), 109 (7), 98 (7), 97 (8), 96 (5), 95 (7), 83 (10), 82 (6), 81
(8), 79 (5), 72 (23), 70 (5), 69 (12), 67 (9), 59 (32), 57 (18), 55 (20),
54 (5); minor diastereoisomer: dH 0.84 (s, 9 H, 3 ¥ CH3 of t-Bu),
1.00–1.18 (m, 1 H, 6¢-H), 1.18–1.44 (m, 1 H, 4¢-H), 1.24–1.31 (m,
12 H, OCCH3), 1.49–1.69 (m, 2 H, PCCH + 5¢-H), 1.97–2.13 (m,
2 H, 4¢-H + 6¢-H), 2.19–2.37 (m, 3 H, PCCH + 2 ¥ 3¢-H), 2.71
(tq, 1 H, J 4.9, 9.0, 23.7 Hz, PCHP), 2.81–2.95 (m, 1 H, 1¢-H),
4.00–4.22 (m, 8 H, OCH2) ppm; dC 16.44 (4 ¥ OCCH3), 26.35
(CH2, PCCH2), 27.67 (3 ¥ CH3 of t-Bu), 29.03 (CH2, C-4¢), 29.72
(Cq, t-Bu), 32.47 (CH, t, JCP 164.7 Hz, PCHP), 35.98 (CH2, C-6¢),
41.74 (CH2, C-3¢), 47.00 (CH, C-5¢), 47.52 (CH, m, C-1¢), 62.60
(m, 4 ¥ OCH2), 213.3 (Cq, C O); dP (162 MHz; CDCl3) 23.62,
24.28; m/z 456 (M+2, 0.2), 455 (M+1, 2), 454 (M+, 10), 397 (10),
317 (20), 301 (22), 289 (14), 288 (80), 261 (28), 260 (10), 233 (15),
204 (32), 202 (100), 187 (11), 171 (11), 167 (31), 152 (22), 149 (33),
144 (25), 133 (16), 132 (12), 118 (12), 117 (34), 116 (20), 115 (37),
109 (17), 105 (18), 104 (28), 99 (10), 98 (11), 93 (10), 91 (17), 89
(13), 79 (10), 77 (17), 76 (19), 74 (12), 69 (10), 67 (10), 63 (11), 57
(34), 58 (10), 55 (18), 51 (12), 50 (13), 46 (12), 45 (26) (Found C,
Fig. 5 The preferred conformation for the addition reaction.
from 1,4-cyclohexanedione and ethylene glycol according to a
literature procedure.39
General procedure for the asymmetric Michael addition reaction.
To vinyl gem-bisphosphonate (1.0 mmol) in dry dichloromethane
(1.0 mL) was added the ketone (10.0 mmol), (S)-(+)-1-(2-
pyrrolidinylmethyl)pyrrolidine (0.1 mmol) and benzoic acid
(0.1 mmol). The solution was stirred at room temperature, under
argon, for the times specified. The reaction was then quenched with
a concentrated solution of ammonium chloride, and the products
were extracted with dichloromethane. The combined extracts
were dried with anhydrous sodium sulfate, and the solvent was
evaporated off on a rotary evaporator to give the crude product,
which was purified by column chromatography on silica gel. In
some cases, as specified for each compound in the supporting
information,† the presence of benzoic acid in the crude product
interfered with product isolation during chromatography. The
work-up procedure was then modified to resolve this problem
as follows: when the reaction was complete, water was added, the
mixture was treated with a saturated solution of NaHCO3 and the
product was extracted with dichloromethane. The organic phase
was then washed successively with a 1 M HCl solution and with
water, filtered through anhydrous Na2SO4, and the solvent was
evaporated off on a rotary evaporator to give the crude product,
which was purified by column chromatography on silica gel.
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50.62; H, 9.05 (major + minor). Calcd for C20H40O7P2: C, 52.86;
H, 8.87). The enantiomeric excesses were determined by HPLC
on a chiral column after conversion of the diastereoisomers
into their 2,4-dinitrophenylhydrazones,34 (Chiralpak AD-H, 16%
i-PrOH in hexane, 1.0 mL min-1, 365 nm): tR = 14.5 (cis, major),
25.6 (trans, major), 40.1 (cis, minor), 45.8 (trans, minor) min,
relative to the racemic sample prepared with DBU as base.
PCH), 36.68 (CH2, C-6¢), 42.00 (Cq, t-Bu), 42.44–42.60 (m, CH,
PCCCH), 47.27 (CH, C-5¢), 62.20–62.77 (m, CH2, 4¥OCH2), 116.7
(CH, C-6¢¢, Ar), 123.5 (CH, C-3¢¢, Ar), 128.9 (Cq, C-2¢¢, Ar), 130.0
(CH, C-5¢¢, Ar), 137.6 (Cq, C-4¢¢, Ar), 145.5 (Cq, C-1¢¢, Ar), 162.4
(C N); dP (162 MHz; CDCl3) 24.36, 24.61; m/z 634 (M+, 2),
599 (13), 515 (16), 487 (10), 452 (31), 435 (22), 407 (13), 379 (11),
377 (20), 351 (14), 317 (19), 301 (52), 289 (22), 288 (100), 273
(16), 267 (13), 261 (46), 260 (12), 245 (13), 233 (31), 217 (13), 205
(21), 200 (11), 189 (20), 187 (19), 177 (30), 165 (26), 158 (22), 152
(34), 137 (17), 135 (10), 125 (14), 110 (11), 109 (49), 108 (10), 93
(12), 57 (47), 46 (10) (Found C, 48.80; N, 8.55; H, 7.11. Calcd for
C26H44N4O10P2: C, 49.10; N, 8.83; H, 6.99).
General procedure for the Michael addition reaction catalyzed
by DBU. This procedure, used for the preparation of racemic
standards, is a modification of the method described by Nugent
et al.11 for analogous compounds. To vinyl gem-bisphosphonate
(1.0 mmol) in dry dichloromethane (1.0 mL) was added the ketone
(1.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mmol).
The solution was stirred at room temperature, under argon, for
one hour. Water was then added, and the products were extracted
with dichloromethane. The combined organic extracts were dried
with anhydrous sodium sulfate, and the solvent was evaporated
off on a rotary evaporator to give the crude product, which was
purified by column chromatography on silica gel.
Acknowledgements
A. M. Fa´ısca Phillips thanks the financial support of Fundac¸a˜o
para a Cieˆncia e a Tecnologia (MCTES).
Notes and references
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rac-Tetraethyl [2-(5¢-tert-butyl-2¢-oxocyclohexyl)ethylidene]bis-
phosphonate. Prepared from ethylidene bisphosphonate 2 and
4-tert-butylcyclohexanone, according to the general procedure.
The product was obtained as a 25 : 75 (trans/cis) mixture of
diastereoisomers as determined by 31P NMR spectroscopy. The
crude product was purified by column chromatography on silica
gel with 3 : 2 acetone/CHCl3 to give the product as a mixture
of two diastereoisomers, in the form of a colourless viscous
liquid (39 mg, 41%). The diastereoisomers separate partially
during chromatography, but complete separation requires several
chromatographies. The spectroscopic data of the product agrees
with that of the product obtained in the asymmetric reaction.
General procedure for the synthesis of 2,4-dinitrophenylhydrazine
adducts34. The bisphosphonate (0.20 mmol) was dissolved in
ethanol (1.0 mL) and 2,4-dinitrophenylhydrazine (0.20 mmol) was
added, followed by a catalytic amount of para-toluenesulfonic
acid. The mixture was stirred at room temperature for 17 h. An
aqueous saturated solution of sodium bicarbonate was added, and
the compound was extracted with dichloromethane. The com-
bined organic extracts were washed with water, filtered through
anhydrous sodium sulfate, and the solvent was then removed in a
rotary evaporator, to give a yellow-orange solid.
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Dinitrophenylhydrazine adduct of tetraethyl [2-(5¢-tert-butyl-2¢-
oxocyclohexyl)ethylidene]bisphosphonate (7a). Prepared from 3f
(from the major diastereoisomer of the DBU-catalyzed reaction)
and dinitrophenylhydrazine according to the general procedure.
The crude product was purified by preparative TLC on silica
gel with EtOAc/acetone 3 : 2 as eluent to give 7a as an orange
hygroscopic solid (34 mg, 77%). dH (400 MHz; CDCl3) 0.89 (s, 9
H, 3 ¥ CH3, t-Bu), 1.06 (q, 1 H, J 13 Hz), 1.24–1.40 (superimp.
m, 1 H), 1.26–1.40 (m, 12 H, 4 ¥ OCCH3), 1.44–1.56 (m, 1 H),
1.80–1.94 (m, 1 H), 2.00 (td, J 2.0, 4.8 Hz, 1 H), 2.04–2.16 (m, 2
H), 2.60–2.80 (m, 1 H), 2.82–3.06 (m, 3 H), 4.08–4.32 (m, 8 H, 4
¥ OCH2), 8.19 (d, 1 H, J = 9.2 Hz, H-6¢¢), 8.28 (dd, 1 H, J 2.4,
9.2 Hz, H-5¢¢), 9.12 (d, 1 H, J 2.4 Hz, H-3¢¢), 11.28 (s, 1 H, N-
NH); dC (100 MHz; CDCl3) 16.40–16.54 (m, CH3, 4 ¥ OCCH3),
25.03 (d, CH2, JCP 6 Hz, PCCH2), 27.18 (CH2, C-4¢), 27.52 (CH3,
3 ¥ CH3 of t-Bu), 28.02 (CH2, C-3¢), 34.48 (d, CH, JCP 134 Hz,
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412 | Org. Biomol. Chem., 2012, 10, 404–412
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The Royal Society of Chemistry 2012
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