Highly enantioselective approach to geminal bisphosphonates by organocatalyzed michael-type addition of β-ketoesters

Article abstract of DOI:10.1002/chem.200701317

A valuable organocatalyzed protocol has been developed for the asymmetric synthesis of bisphosphonate derivatives, a class of pharmaceutically important molecules. Cheap and commercially available dihydroquinine effectively catalyzed conjugate additions o

Full text of DOI:10.1002/chem.200701317

DOI: 10.1002/chem.200701317
Highly Enantioselective Approach to Geminal Bisphosphonates by
Organocatalyzed Michael-Type Addition of b-Ketoesters
Marinella Capuzzi, Dario Perdicchia, and Karl Anker Jørgensen*[a]
Abstract: A valuable organocatalyzed
protocol has been developed for the
asymmetric synthesis of bisphospho-
nate derivatives, a class of pharmaceut-
ically important molecules. Cheap and
commercially available dihydroquinine
effectively catalyzed conjugate addi-
tions of cyclic b-ketoesters to ethylide-
nebisphosphonate esters, leading to op-
tically active geminal bisphosphonates,
bearing an all-carbon substituted qua-
ternary stereocenter, in high yields and
enantioselectivities of up to 99% ee.
Further elaborations of Michael ad-
ducts to the corresponding bisphos-
phonic acids or vinyl phosphonates
have also been successfully performed,
with conservation of optical purity.
Keywords: asymmetric catalysis
bisphosphonates ketoesters
Michael addition · organocatalysis
·
·
·
Introduction
Michael-type addition to ethylidene bisphosphonate esters is
a common and effective procedure affording methylene bi-
sphosphonate derivatives. Carbon nucleophiles,[10] as well as
nitrogen,[3,11] oxygen,[11,12] sulphur[11,13] and phosphorus[14] nu-
cleophiles undergo the Michael reaction in good yields. Sur-
prisingly, despite the importance of enantiomerically pure
compounds in the pharmaceutical industry, to our knowl-
edge, only the report of Alexakis and co-workers presenting
the conjugate addition of aldehydes to vinyl phosphonates,
which has been published concurrently with the preparation
of the present manuscript, deals with the synthesis of gemi-
nal bisphosphonate-based molecules, in an asymmetric fash-
ion.[15]
In this paper we wish to report a highly enantioselective
Michael-type addition of b-ketoesters to vinylidene bi-
sphosphonate 1 promoted by cinchona alkaloids as chiral-
base catalysts. The efficient and operationally simple proto-
col developed affords the corresponding bisphosphonate de-
rivatives bearing an all-carbon substituted quaternary ste-
reocenter with high enantioselectivities (up to >99% ee)
[Eq. (1)]. Importantly, the addition products belong to the
class of carbonyl-containing bisphosphonate esters which
are potent anti-inflammatory and antiarthritic agents.[10b,c]
Nowadays, the use of prochiral b-ketoesters in organoca-
talyzed asymmetric Michael additions[16] is a valuable strat-
Geminal bisphosphonates are structural and stable ana-
logues of naturally occurring pyrophosphates and constitute
an important class of pharmacologically active molecules. A
significant number of these compounds are currently being
used for the treatment of several bone disorders such as
Pagetꢀs disease, myeloma, bone metastases and osteoporo-
sis,[1] as well as in some childhood diseases.[2] Recently, bi-
sphosphonate drugs have also been found to have activity
against the in vitro proliferation of several protozoan para-
sites, including Trypanosoma brucei which causes African
trypanosomiasis or sleeping sickness in human and ani-
mals.[3] Consequently, the well-proven clinical utility of bi-
sphosphonates has fostered the development of several
methodologies for the preparation of novel derivatives;
structure–activity studies have actually indicated that bioac-
tivity is highly dependent on the nature of substituents
linked to the bisphosphonic skeleton.[4] Different synthetic
strategies have been proposed based on the alkylation of
tetraalkyl methylene bisphosphonate,[5] reaction of phospho-
rus electrophiles with enolates,[6] Diels–Alder reaction,[7] pal-
ladium catalysis[8] and radical chemistry.[9] Among these, the
[a] M. Capuzzi, Dr. D. Perdicchia, Prof. Dr. K. A. Jørgensen
Department of Chemistry
Danish National Research Foundation: Centre for Catalysis
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
128
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Chem. Eur. J. 2008, 14, 128 – 135

FULL PAPER
egy for the enantioselective construction of quaternary ste-
reogenic centers which still remains a great challenge to the
synthetic chemist. Moreover, the replacement of metal-
based catalysts with readily available and inexpensive orga-
nocatalysts[17] offers an environmentally-friendly approach
for the stereocontrolled synthesis of chiral molecules.
with full conversion at the same reaction times. Quinine I
catalyzed the conjugate addition with higher enantioselectiv-
ity compared with cinchonidine II (entries 2, 3). However,
further explorations of other catalysts based on quinine skel-
eton clearly demonstrated the importance of the not pro-
tected C9-OH and the presence of methoxyl group on C6I
to induce high levels of stereoselectivity, since catalysts IV
and V gave 3aa with poor enantiomeric excess (entries 5, 6).
The commercially available dihydroquinine III proved to be
the most promising catalyst affording the addition product
with moderate enantioselectivity (entry 4). Further screen-
ing of temperatures, solvents and concentrations (entries 7–
12) indicated that toluene is the solvent of choice; more-
over, the decrease of both the temperature to À608C and
the concentration reaction to 0.1m improved significantly
the enantioselectivity to 87% ee, still maintaining short reac-
tion times.
With the optimized reaction conditions in hand, we then
studied the effect of modifying the ester group of the 2-car-
boxylate 1-indanone moiety on the enantioselectivity
(Table 2, entries 1–4). As expected, the bulkiness of the
ester substituent had a pronounced influence on the enan-
tiocontrol,[18] since with the bulkier tert-butyl ester 2d the
enantioselectivity was remarkably enhanced to 97% ee
(entry 4) compared with analogous methyl, benzyl and iso-
propyl esters 2a–c (entries 1–3). Importantly, the use of
“pseudoenantiomer” dihydroquinidine allowed access to the
Results and Discussion
The feasibility of our organocatalytic asymmetric approach
to the bisphosphonate Michael adducts was first explored
employing 1-oxoindan-2-carboxylate 2a (see Figure 2) as
model nucleophile for the addition to tetraethyl ethylidene-
bisphosphonate 1a (Table 1) in presence of a catalytic
amount of cinchona alkaloid derivatives (Figure 1).
The reaction was initially carried out in CH2Cl2 (0.5m) at
À208C and the representative results of the catalyst screen-
ing are summarized in Table 1, entries 2–6. Although the ad-
dition of 2a to 1a occurred quantitatively in less than
10 min at room temperature without any catalyst (entry 1),
we were pleased to find that cinchona alkaloids were able to
promote chiral induction affording the addition product 3aa
Table 1. Organocatalytic asymmetric addition of model substrate 2a to
1a: Screening of catalysts and reaction conditions.[a]
Table 2. Enantioselective Michael-type addition of b-ketoesters 2a–m to
1a,b.[a]
Entry Catalyst[b] Solvent (c [m])[c] T [8C] Yield[d] [%] ee[e] [%]
[f]
1
2
3
4
5
6
7
8
–
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
toluene (0.5)
CH3CN (0.5)
THF (0.5)
RT
À2
86
0
72
0
0
0
82
0
0
–
I
II
80
48
À20
À2
24
III
IV
V
III
III
III
III
III
III
84
76
78
56
2
38
À2
Entry VBP[b] Nu[c] t [h] T [8C] Product Yield[d] [%] ee[e] [%]
À2
À20
À2
60
1
2
3
4
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1a
2a
2b
2c
2d
2d
2e
2 f
2i
2 f
2g
2h
2j
0.8
0.8
0.6
0.6
À60
À60
À60
À60
3aa
3ab
3ac
3ad
ent-3ad
3ae
3af
76
80
70
75
94
90
97
60
84
83
75
98
93
95
72
À87
À84
79
80
40
54
9
À2
À87
10
11
12
toluene (0.5)
toluene (0.5)
toluene (0.1)
RT
À60
À60
84
8278
76
40
87
À97
5[f]
6
0.25 À60
+96
À97
0.2
0.6
24
6
À60
À60
À40
À60
À60
À40
À30
À60
À60
7[g]
8
À98
[a] The reactions were performed using 1a (0.2mmol), 2a (0.22 mmol)
and the catalyst (0.04 mmol). [b] Structures of catalysts are reported in
Figure 1. [c] In brackets is reported the concentration of the reaction
mixture calculated on the basis of mmoles of 1a. [d] Isolated yields after
FC on silica gel. [e] The ee was determined by CSP-HPLC analysis.
[f] Reaction performed without catalyst.
3ai
3bf
+84
À92
9
10
11[f]
12
13
14
15
6
60
8
1
2
3ag
3ah
3aj
3ak
3al
À98[h]
À84
>À99
À99
2k
2l
2m
>À99
0.25 À60
3am
À54
[a] The reactions were performed using 1 (0.2mmol), 2 (0.22 mmol) and
the catalyst (0.04 mmol), unless otherwise specified. [b] Vinyl bisphosph-
onate (VBP) structures are indicated in the Scheme above. [c] Structures
of nucleophiles 2 are reported in Figure 2. [d] Isolated yields after FC on
silica gel. [e] The ee was determined by CSP-HPLC analysis. [f] Reaction
performed with dihydroquinidine. [g] The reaction was scaled-up using
1 mmol of 1a. [h] The ee was not directly determined for 3ag, see deriva-
tization into 5 (Scheme 1).
Figure 1. Screened cinchona alkaloid catalysts.
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129

K. A. Jørgensen et al.
opposite enantiomer of 3d with comparable enantioselectiv-
ity and in shorter reaction time (entry 5).
We subsequently investigated the scope of the reaction
performing a systematic study with variously functionalized
toxycarbonyl group, in complete diastereoselectivity. Subse-
quent benzoylation of both hydroxyl functions allowed us to
determine the value of 98% ee for the derivative 5
(Scheme 1).
Figure 2. b-Ketoesters used in the Michael-type addition to 1a,b.
indanone structures as well as with different ester groups on
the electrophile. Experiments carried out with 1a and 5-sub-
stituted indanones 2e and f revealed that the enantioselec-
tivity is not influenced by electronic effects, since either with
electron-withdrawing or electron-donating substituents in
the aromatic ring, such as chlorine and methoxyl groups, re-
spectively, excellent enantioselectivities were achieved as
well (entries 6, 7). The addition of 2-indanone 2i bearing a
tert-butyloxy carbonyl group at C-1 to 1a was slower com-
pared with analogous 1-indanones 2a–f, affording the
adduct 3ai after 24 h at À408C[19] in acceptable yield and
good enantioselectivity (entry 8).
Scheme 1. Reduction of bisphosphonate b-ketoester 3ag to diol 4 and
subsequent benzoylation to 5.
The absolute configuration of the optically active diol 4
was established to be (1R), (2R) by X-ray analysis
(Figure 3).[22]
The prospect of more complex conjugates, which would
arise from the linkage between a free hydroxyl group of the
phosphonate moiety and an organic unit, prompted us to
extend our protocol also to tetrabenzyl ethylidenebi-
sphosphonate 1b, in view of the possibility to remove selec-
tively only one benzyl group from the diphosphonate
ester.[20] The study of Michael addition performed with the
indanone derivative 2 f as nucleophile demonstrated that the
tetrabenzylated addition product 3bf can be obtained with-
out considerable loss of enantioselectivity (entry 9), com-
pared with tetraethyl ester 3af (entry 7), while at the same
time taking advantage of a more versatile protecting group.
It seemed also interesting to test the reactivity of heteroa-
tom-substituted indanone nucleophiles in the organocata-
lyzed addition to 1a, using the benzofuranone 2g and the
novel benzothiophenone 2h. In these cases, the correspond-
ing addition products 3ag and 3ah could be isolated after
prolonged reaction times with good levels of enantioselectiv-
ities (entries 10, 11). However, for the benzofuranone deriv-
ative 3ag we were not able to determine directly the enan-
tiomeric excess by chiral stationary phase-HPLC analysis.
Therefore, considering also the importance of polyhydroxyl-
ated dihydrobenzofuran skeleton in certain natural com-
pounds,[21] we envisaged the possibility to transform 3ag into
corresponding diol. The reduction of both carbonyl and tert-
butoxycarbonyl groups, performed with an excess of borane/
methylsulfide complex, afforded diol 4, derived from the
attack of the borane from the opposite side of the tert-bu-
Figure 3. X-ray crystal structure of compound 4 (C gray, H white, O red,
P orange).
Based on the absolute configuration of the product
formed and taking into account the role of the various
groups in the catalyst, we proposed the intermediate in-
volved and its approach to the bisphosphonate, as outlined
to the left in Figure 4, to account for the enantioselectivity
observed in the reaction. In the less-favored intermediate, to
the right in Figure 4, steric repulsion between the aromatic
part of the catalyst and the enolate of the b-ketoester is pro-
posed to disfavour this reaction path.
Moreover, we found that addition products 3 could be
useful precursors of synthetically valuable vinyl phospho-
nate derivatives.[23] Indeed, by Horner–Wadsworth–Emmons
olefination of 3ag, it was possible to isolate in good yields
the vinyl phosphonate 6, even if with a slight erosion of
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Organocatalyzed Michael-Type Additions
FULL PAPER
selectivity, as confirmed by the same value of ee measured
for the tetramethyl bisphosphonate 8, obtained in turn by
esterification of 7 with trimethylsilyldiazomethane in quanti-
tative yield (Scheme 3).
Figure 4. Proposed approach of the intermediates to the bisphosphonate.
On the left, the reaction path leading to the observed configuration and
on the right, the less-favored reaction path having steric repulsion.
enantiopurity, due to a inevitable partial retro-Michael reac-
tion under basic conditions (Scheme 2).
Scheme 3. Hydrolysis of the tetraethyl ester 3af to bisphosphonic acid 7
and subsequent esterification to 8.
Conclusion
In summary, we have developed the first example of asym-
metric addition of b-ketoesters to vinyl bisphosphonate
esters, catalyzed by cheap and commercially available dihy-
droquinine. High yields and enantioselectivities were ach-
ieved under simple conditions for a wide range of indanone-
based b-ketoesters, as well as various unprecedented 5-tert-
butyloxycarbonyl cyclopentenones. Furthermore we have
demonstrated that the bisphosphonate adducts can be con-
veniently elaborated to other interesting derivatives and can
also be easily hydrolyzed to the corresponding acids. There-
fore, our protocol allows access to a class of new optically
pure geminal bisphosphonates, opening attractive prospects
in the field of asymmetric synthesis targeted to bisphospho-
nate derivatives.
Scheme 2. HWE reaction for the synthesis of vinyl phosphonate 6.
Next, in light of the considerable importance of cyclopen-
tenone-bearing compounds in anticancer drug design,[24] we
desired to study the reactivity and the enantioselective be-
havior of cyclic five-membered ring b-ketoesters in the orga-
nocatalyzed addition to 1a. We focused on three novel dif-
ferently functionalized tert-butyl esters of cyclopentenone
2j, k and l, bearing a cyclic protected 1,3-diketone, a b-sus-
bstituted cyclopentenone and a cyclic protected 1,2-diketone
derivatives respectively.[25] With our satisfaction, the addi-
tion products 3aj, ak and al were isolated in very high yields
and excellent enantioselectivities (entries 12–14), providing
a valuable class of molecules that might contribute to the
development of novel therapeutic bisphosphonate deriva-
tives.
Also the acyclic a-fluorinated b-ketoester 2m was tested
in the organocatalyzed addition to 1a, but unfortunately, al-
though dihydroquinine catalyzed the reaction quantitatively
in only 15 min, only moderate enantioselectivity was ach-
ieved (entry 15). Change of catalyst and/or replacement
with a bulkier tert-butyl ester produced lower enantiomeric
excess.
After having demonstrated the feasibility of our asymmet-
ric approach leading to optically active bisphosphonate ester
derivatives, we have finally deemed it important to optimize
a procedure aimed to convert the bisphosphonic ester prod-
ucts into the corresponding bisphosphonic acids, due to the
large applications of the latter in the therapy of most bone
diseases.[1] To this purpose, the tetraethyl ester 3af, chosen
as model substrate, was treated with bromotrimethylsilane
in presence of N,O-bis(trimethylsilyl)acetamide (BSA).[26]
Successive methanolysis of the silyl esters afforded bisphos-
phonic acid 7 quantitatively. We were able to demonstrate
that this transformation occurs without any loss of enantio-
Experimental Section
General methods: NMR spectra were acquired running at 400, 100 and
160 MHz for 1H, 13C and 31P NMR, respectively. Chemical shifts (d) are
1
reported in ppm relative to CHCl3 (d=7.26) for H NMR, relative to the
central resonance of CDCl3 (d=77.0) for 13C NMR and relative to exter-
nal H3PO4 85% (d=0.00) for 31P NMR, unless otherwise noted.
13C NMR spectra were acquired on a broad band decoupled mode. Mass
spectra were recorded using electrospray (ES+) ionization techniques.
Analytical thin layer chromatography (TLC) was performed using pre-
coated aluminium-backed plates and visualized by ultraviolet irradiation
or KMnO4 dip. Optical rotations were measured on a Perkin–Elmer 241
polarimeter and reported in degcm3 gÀ1; concentrations are reported in
gcmÀ3. The enantiomeric excess (ee) of the products was determined by
chiral stationary phase HPLC (Daicel Chiralpak AD or Chiralcel OD
columns). Absolute configuration of the bisphosphonate derivative 4 was
established by single-crystal X-ray analysis. The same approach of the nu-
cleophile to ethylidene bisphosphonates 1a and b was assumed for as-
signing the absolute configuration for the rest of the compounds.
Materials: Analytical grade solvents and commercially available reagents
were used without further purification, unless otherwise noted. Tetrahy-
drofuran and trimethylsilylbromide were freshly distilled before use.
Chromatography was carried out by flash chromatography (FC) using
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131

K. A. Jørgensen et al.
Merck silica gel 60, 230–400 mesh. The reactions were carried out in not
inert conditions, unless otherwise specified. Tetraethyl ethylidenebis-
phosphonate (1a) and tetrabenzyl ethylidenebisphosphonate (1b) were
prepared according to literature procedure.[10g,20] tert-Butyl b-ketoesters
1a and 2d according to the general procedure after 40 min as a colorless
oil (80 mg, 75%). [a]D20
=
À61.2( c=1.0, CHCl3, 97% ee); 1H NMR
(400 MHz, CDCl3, 2 58C): d=7.72(d, J=7.7 Hz, 1H), 7.59 (t, J=7.6 Hz,
1H), 7.46 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 4.21–4.06 (m, 8H),
3.65 (A of AB system, J=17.6 Hz, 1H), 3.55 (B of AB system, J=
17.6 Hz, 1H), 2.92–2.77 (m, 1H), 2.69–2.54 (m, 1H), 2.43–2.30 (m, 1H),
1.34–1.26 ppm (m, 21H); 13C NMR (100 MHz, CDCl3, 2 58C): d=200.0,
169.0, 154.0, 135.2, 127.5, 126.2, 124.6, 82.0, 62.9–62.5 (m), 60.8–60.7 (m),
37.1, 33.0 (t, J=131.6 Hz), 29.5 (t, J=4.1 Hz), 27.7, 16.4–16.2 ppm (m);
31P NMR (160 MHz, CDCl3, 2 58C): d=23.7, 23.2 ppm; HRMS: m/z:
calcd for C24H38NaO9P2: 555.1889, found: 555.1899 [M+Na]+. The ee was
determined by HPLC using two Chiralpak AD columns combined in
series (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; tminor =35.1 min,
tmajor =43.3 min (97% ee).
2 f and
i were prepared from the corresponding methyl esters by
Bu2SnO-catalyzed transesterification with tBuOH in refluxing toluene;
tert-butyl b-ketoesters 2j–l were prepared from the corresponding cyclo-
pent-2-enones by acylation with 1-(tert-butoxycarbonyl)-imidazole.[27]
Racemic samples were prepared using Et3N as catalyst.
General procedure of addition of b-ketoesters 2a–m to ethylidenebis-
phosphonate esters 1a,b: A cooled (À608C) solution of ethylidene bis-
phosphonate 1 (0.2mmol) in toluene (0.5 mL) was added dropwise to a
stirred cooled (À608C, unless otherwise specified) solution of b-ketoester
2 (0.22 mmol) and DH-quinine (13 mg, 0.04 mmol) in toluene (1.5 mL).
The resulting clear solution was stirred until 1 was completely consumed
as indicated by TLC analysis. The reaction mixture was directly subjected
to FC (pentane/EtOAc 2:8) to give the desired addition product 3.
(R)-tert-Butyl
2-(2,2-bis(diethoxyphosphoryl)ethyl)-1-oxo-2,3-dihydro-
1H-indene-2-carboxylate (ent-3ad): The title compound ent-3ad (enantio-
mer of 3ad) was obtained from 1a and 2d according to the general pro-
cedure after 15 min, using dihydroquinidine, as a colorless oil (100 mg,
94%). Spectral data were identical to compound 3ad. [a]2D0 = +61.0 (c=
1.0, CHCl3, 96% ee). The ee was determined by HPLC using two Chiral-
pak AD columns combined in series (hexane/iPrOH 98:2); flow rate
1.0 mLminÀ1; tminor =35.5 min, tmajor =43.3 min (96% ee).
(R)-Methyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-1-oxo-2,3-dihydro-1H-
indene-2-carboxylate (3aa): The title compound was obtained from 1a
and 2a according to the general procedure after 50 min as a colorless oil
(77 mg, 76%). [a]D20
=
À45.1 (c=1.0, CHCl3, 87% ee); 1H NMR
(400 MHz, CDCl3, 2 58C): d=7.71 (d, J=7.3 Hz, 1H), 7.59 (t, J=7.3 Hz,
1H), 7.45 (d, J=7.3 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 4.20–4.01 (m, 8H),
3.74 (A of AB, J=17.6 Hz, 1H), 3.65 (s, 3H), 3.51 (B of AB, J=
17.6 Hz), 2.94–2.80 (m, 1H), 2.68 (tt, J=24.1 Hz, J=5.1 Hz), 2.49–2.32
(m, 1H), 1.37–1.20 ppm (m, 12H); 13C NMR (100 MHz, CDCl3, 2 58C):
d=200.7, 170.0, 152.9, 135.1, 134.3, 127.3, 125.9, 124.3, 62.5–62.2 (m), 59.5
(t, J=4.6 Hz), 52.3, 36.4, 32.4 (t, J=132.7 Hz), 29.6 (t, J=4.6 Hz), 15.9–
15.8 ppm (m); 31P NMR (160 MHz, CDCl3, 2 58C): d=23.4, 23.2 ppm;
HRMS: m/z: calcd for C21H32NaO9P2: 513.1419, found: 513.1437
[M+Na]+. The ee was determined by HPLC using a Chiralpak AD
column hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; tminor =43.6 min,
tmajor =50.0 min (87% ee).
(R)-tert-Butyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-5-chloro-1-oxo-2,3-di-
hydro-1H-indene-2-carboxylate (3ae): The title compound was obtained
from 1a and 2e according to the general procedure after 10 min as a col-
orless oil (102mg, 90%). [ a]D20
=
À59.6 (c=1.0, CHCl3, 97% ee);
1H NMR (400 MHz, CDCl3, 2 58C): d=7.63 (d, J=8.1 Hz, 1H), 7.45 (s,
1H), 7.32(d, J=8.1 Hz), 4.20–4.06 (m, 8H), 3.62 (A of AB system, J=
17.9 Hz, 1H), 3.52(B of AB system, J=17.9 Hz, 1H), 2.90–2.76 (m, 1H),
2.70–2.54 (m, 1H), 2.39–2.67 (m, 1H), 1.33–1.26 ppm (m, 21H);
13C NMR (100 MHz, CDCl3, 2 58C): d=200.5, 168.6, 155.4, 141.8, 133.3,
128.3, 126.4, 125.6, 82.3, 62.9–62.5 (m), 61.1–61.0 (m), 36.9, 33.0 (dd, J=
131.2Hz, 133.8 Hz), 27.7, 16.3–16.2ppm (m);
31P NMR (160 MHz,
(R)-Benzyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-1-oxo-2,3-dihydro-1H-
indene-2-carboxylate (3ab): The title compound was obtained from 1a
and 2b according to the general procedure after 50 min as a colorless oil
CDCl3, 2 8C5): d=23.5, 23.1 ppm; HRMS: m/z: calcd for
C24H37ClNaO9P2: 589.1499, found: 589.1511 [M+Na]+. The ee was deter-
mined by HPLC using a Chiralpak AD column (hexane/iPrOH 90:10);
flow rate 1.0 mLminÀ1; tminor =21.6 min, tmajor =26.6 min (97% ee).
(91 mg, 80%). [a]D20
=
À48.3 (c=1.0, CHCl3, 84% ee); 1H NMR
(400 MHz, CDCl3, 2 58C): d=7.68 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.4 Hz,
1H), 7.40 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.25–7.15 (m, 5H),
5.07 (A of AB system, J=12.6 Hz, 1H), 5.02 (B of AB system, J=
12.6 Hz, 1H), 4.10–3.98 (m, 8H), 3.70 (A of AB system, J=17.7 Hz, 1H),
3.50 (B of AB system, J=17.7 Hz, 1H), 2.93–2.79 (m, 1H), 2.73–2.58 (m,
1H), 2.46–2.30 (m, 1H), 1.25–1.18 ppm (m, 12H); 13C NMR (100 MHz,
CDCl3, 2 58C): d=200.0, 169.0, 154.0, 135.2, 127.5, 126.2, 124.6, 82.0,
62.9–62.6 (m), 60.8 (t, J=4.6 Hz), 37.1, 33.0 (t, J=132.7 Hz), 29.5 (t, J=
4.6 Hz), 27.7, 16.3–16.2 ppm (m); 31P NMR (160 MHz, CDCl3, 2 58C): d=
23.3, 23.1 ppm; HRMS: m/z: calcd for C27H36NaO9P2: 589.1732, found:
589.1750 [M+Na]+. The ee was determined by HPLC using a Chiralpak
(R)-tert-Butyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-5-methoxy-1-oxo-2,3-
dihydro-1H-indene-2-carboxylate (3af): The title compound was obtained
from 1a and 2 f according to the general procedure after 40 min as a col-
orless oil (103 mg, 92%). [a]D20
=
À71.6 (c=1.0, CHCl3, 97% ee);
1H NMR (400 MHz, CDCl3, 2 58C): d=7.63–7.60 (m, 1H), 6.89–6.83 (m,
2H), 4.20–4.04 (m, 8H), 3.84 (s, 3H), 3.59 (A of AB system, J=18.1 Hz,
1H), 3.50 (B of AB system, J=18.1 Hz, 1H), 2.92–2.74 (m, 1H), 2.70–
2.53 (m, 1H), 2.37–2.22 (m, 1H), 1.38–1.21 ppm (m, 21H); 13C NMR
(100 MHz, CDCl3, 2 85C): d=199.8, 169.2, 165.7, 157.1, 128.0, 126.2,
115.8, 109.0, 81.8, 62.8–62.4 (m), 61.1–61.0 (m), 55.5, 37.0, 33.1 (t, J=
131.7 Hz), 29.6, 27.7, 16.3–16.2 ppm (m); 31P NMR (160 MHz, CDCl3,
258C): d=23.5, 23.3 ppm; HRMS: m/z: calcd for C25H40NaO10P2:
585.1994, found: 585.1994 [M+Na]+. The ee was determined by HPLC
AD column (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; t
55.0 min, tminor =64.2min (84% ee).
=
major
(R)-Isopropyl
2-(2,2-bis(diethoxyphosphoryl)ethyl)-1-oxo-2,3-dihydro-
using
a Chiralpak AD column (hexane/iPrOH 90:10); flow rate
1H-indene-2-carboxylate (3ac): The title compound was obtained from
1a and 2c according to the general procedure after 40 min as a colorless
1.0 mLminÀ1; tminor =30.1 min, tmajor =39.5 min (97% ee).
oil (72mg, 70%). [ a]D20
=
À47.2( c=1.0, CHCl3, 87% ee); 1H NMR
(S)-tert-Butyl
1-(2,2-bis(diethoxyphosphoryl)ethyl)-2-oxo-2,3-dihydro-
1H-indene-1-carboxylate (3ai): The title compound was obtained from
1a and 2i according to the general procedure, at À408C after 24 h as a
(400 MHz, CDCl3, 2 58C): d=7.69 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.5 Hz,
1H), 7.44 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 4.98–4.88 (m, 1H),
4.18–4.03 (m, 8H), 3.65 (A of AB system, J=17.8 Hz, 1H), 3.53 (B of
AB system, J=17.8 Hz, 1H), 2.91–2.76 (m, 1H), 2.68–2.53 (m, 1H), 2.46–
2.31 (m, 1H), 1.31–1.23 (m, 12H), 1.10 ppm (t, J=6.5 Hz, 6H); 13C NMR
(100 MHz, CDCl3, 2 85C): d=201.5, 169.5, 153.6, 135.3, 134.8, 127.5,
126.2, 124.6, 69.2, 62.8–62.5 (m), 60.0–59.9 (m), 36.8, 32.7 (t, J=
132.7 Hz), 29.6 (t, J=4.4 Hz), 21.4, 21.3, 16.2–16.1 ppm (m); 31P NMR
(160 MHz, CDCl3, 2 58C): d=23.6, 23.1 ppm; HRMS: m/z: calcd for
C23H36NaO9P2: 541.1732, found: 541.1732 [M+Na]+. The ee was deter-
mined by HPLC using a Chiralpak AD column (hexane/iPrOH 90:10);
flow rate 1.0 mLminÀ1; tminor =26.2 min, tmajor =31.4 min (87% ee).
colorless oil (64 mg, 60%). [a]D20
= +20.0 (c=1.0, CHCl3, 84% ee);
1H NMR (400 MHz, CDCl3, 2 58C): d = 7.33–7.16 (m, 4H), 4.12–3.86 (m,
8H), 3.67 (A of AB system, J=21.9 Hz, 1H), 3.59 (B of AB system, J=
21.9 Hz, 1H), 3.17–3.02 (m, 1H), 2.85–2.74 (m, 1H), 2.28–2.09 (m, 1H),
1.32–1.16 ppm (m, 21H); 13C NMR (100 MHz, CDCl3, 2 58C): d=211.1,
169.0, 139.4, 139.2, 128.4, 127.2, 125.1, 124.3, 82.5, 65.6–65.5 (m), 62.7–
62.4 (m), 43.5, 32.3 (t, J=135.7 Hz), 27.4, 26.5, 16.3–16.1 ppm (m);
31P NMR (160 MHz, CDCl3, 2 58C): d=23.7, 22.8 pppm; HRMS: m/z:
calcd for C24H38NaO9P2: 555.1889, found: 555.1893 [M+Na]+. The ee was
determined by HPLC using a Chiralpak AD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tminor =33.2min, tmajor =26.9 min (84%
ee).
(R)-tert-Butyl
2-(2,2-bis(diethoxyphosphoryl)ethyl)-1-oxo-2,3-dihydro-
1H-indene-2-carboxylate (3ad): The title compound was obtained from
132
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 128 – 135

Organocatalyzed Michael-Type Additions
FULL PAPER
(R)-tert-Butyl
2-(2,2-bis-(bisbenzyloxyphosphoryl)ethyl)-5-methoxy-1-
90:10); flow rate 1.0 mLminÀ1; tminor =26.2 min, tmajor =27.7 min (99%
ee).
oxo-2,3-dihydro-1H-indene-2-carboxylate (3bf): The title compound was
obtained from 1b and 2 f according to the general procedure after 6 h as
a colorless oil (136 mg, 84%). [a]2D0 = À29.6 (c=1.0, CHCl3, 92 %ee);
1H NMR (400 MHz, CDCl3, 2 58C): d=7.55 (d, J=8 Hz, 1H), 7.32–7.26
(m, 20H), 6.84–6.82 (d, J=8 Hz, 1H), 6.74 (s, 1H), 5.07–4.92(m, 8H),
3.85 (s, 3H), 3.48 (A of AB system, J=18 Hz, 1H), 3.37 (B of AB
system, J=18 Hz, 1H), 3.07–2.79 (m, 2H), 2.54–2.41 (m, 1H), 1.30 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3, 2 58C): d=200.1, 169.6, 165.9, 157.2,
136.3, 128.7–128.2, 126.6, 116.0, 109.4, 82.2, 68.7–68.5 (m), 68.4–68.3 (m),
61.2–61.1 (m), 55.9, 37.3, 34.0 (t, J=131.0 Hz), 29.7, 27.9 ppm; 31P NMR
(160 MHz, CDCl3, 2 58C): d=23.5, 23.2 ppm; HRMS: m/z: calcd for
C45H48NaO10P2: 833.2620, found: 833.2635 [M+Na]+. The ee was deter-
mined by HPLC using a Chiralpak AD column (hexane/iPrOH 70:30);
flow rate 1.0 mLminÀ1; tminor =21.4 min, tmajor =49.3 min (92% ee).
(S)-tert-Butyl 1-(2,2-bis(diethoxyphosphoryl)ethyl)-3-methoxy-4-methyl-
2-oxocyclopent-3-enecarboxylate (3al): The title compound was obtained
from 1a and 2l according to the general procedure after 2h as a colorless
oil (100 mg, 95%). [a]2D0 = À52.6 (c=1.0, CHCl3, >99% ee); 1H NMR
(400 MHz, CDCl3, 2 58C): d=4.14–4.01 (m, 8H), 3.74 (s, 3H), 2.78 (AB
system, J=19.1 Hz, 2H), 2.68–2.53 (m, 2H), 2.13–2.01 (m, 1H), 1.91 (s,
3H), 1.31–1.22 ppm (m, 21H); 13C NMR (100 MHz, CDCl3, 2 58C): d=
198.3, 168.8, 155.1, 150.6, 82.0, 63.0–62.7 (m), 58.6–58.4 (m), 57.0–56.0
(m), 38.5, 33.1 (t, J=132.1 Hz), 29.6, 27.9, 16.6–16.4 (m), 14.9 ppm;
31P NMR (160 MHz, CDCl3, 2 58C): d=23.6, 23.4 ppm; HRMS: m/z:
calcd for C22H40NaO10P2: 549.1994, found: 549.2007 [M+Na]+. The ee
was determined by HPLC using two Chiralpak AD columns combined in
series (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; tminor =23.9 min,
tmajor =29.5 min (>99% ee).
(S)-tert-Butyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-3-oxo-2,3-dihydroben-
zofuran-2-carboxylate (3ag): The title compound was obtained from 1a
and 2g according to the general procedure after 6 h as a colorless oil
tert-Butyl 2-acetyl-4,4-bis(diethoxyphosphoryl)-2-fluorobutanoate (3am):
The title compound was obtained from 1a and 2m according to the gen-
(89 mg, 83%). [a]D20
=
À33.1 (c=1.0, CHCl3); 1H NMR (400 MHz,
eral procedure after 15 min as a colorless oil (64 mg, 72%). [a]D20
=
À16.0 (c=1.0, CHCl3, 54% ee); 1H NMR (400 MHz, CDCl3, 2 58C): d=
4.28–4.08 (m, 10H), 2.82–2.55 (m, 3H), 2.28 (d, J=4.5, 3H), 1.31–
1.29 ppm (m, 15H); 13C NMR (100 MHz, CDCl3, 2 58C): d=200.6 (d, J=
28.3 Hz), 165.7 (d, J=25.9 Hz), 99.2 (d, J=202.5 Hz), 62.9–62.8 (m), 30.6
(t, J=133.9 Hz), 28.6 (d, J=21.1 Hz), 25.6 (d, J=3.7 Hz), 16.2, 13.8 ppm;
31P NMR (160 MHz, CDCl3, 2 58C): d=22.5, 22.2 ppm; 19F NMR (CDCl3,
258C): d = À166.2ppm (dt, J=19.1 Hz, J=2.8 Hz); HRMS: m/z: calcd
for C16H31FNaO9P2: 471.1325, found: 471.1312 [M+Na]+. The ee was de-
CDCl3, 2 58C): d=7.65–7.61 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 7.10 (t, J=
8.8 Hz, 1H), 4.23–4.00 (m, 8H), 3.05–2.90 (m, 1H), 2.77–2.51 (m, 2H),
1.40 (s, 9H), 1.35–1.17 ppm (m, 12H); 13C NMR (100 MHz, CDCl3,
258C): d=195.6, 172.2, 164.0, 138.2, 124.7, 122.5, 119.6, 113.3, 89.4–89.3
(m), 83.8, 63.0–62.6 (m), 31.7 (t, J=133.7 Hz), 28.4, 27.6, 16.3–16.0 ppm
(m); 31P NMR (160 MHz, CDCl3, 2 58C): d=22.5, 22.3 ppm; HRMS: m/
z:calcd for C23H36NaO10P2: 557.1681, found: 557.1672[ M+Na]+.
(S)-tert-Butyl 2-(2,2-bis(diethoxyphosphoryl)ethyl)-3-oxo-2,3-dihydroben-
zo-[b]thiophene-2-carboxylate (3ah): The title compound was obtained
from 1a and 2h (2equiv) according to the general procedure after 60 h
at À408C, using dihydroquinidine, as a colorless oil (89 mg, 75%). [a]D20
= À83.7 (c=1.0, CHCl3, 84% ee); 1H NMR (400 MHz, CDCl3, 2 58C):
d=7.73 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.38 (d, J=7.7 Hz,
1H), 7.21 (t, J=7.7 Hz), 4.23–3.93 (m, 8H), 3.14–3.00 (m, 1H), 2.98–2.83
(m, 1H), 2.65 (tt, J=24.4 Hz, J=4.8 Hz, 1H), 1.35–1.29 ppm (m, 21H);
13C NMR (100 MHz, CDCl3, 2 58C): d=197.4, 167.2, 151.0, 135.6, 130.2,
126.9, 125.2, 123.9, 83.2, 67.3–67.0 (m), 63.0–62.3 (m), 33.4 (t, J=
134.0 Hz), 28.0, 27.4, 16.4–16.0 ppm (m); 31P NMR (160 MHz, CDCl3,
258C): d=23.4, 22.4 ppm; HRMS: m/z: calcd for C23H36NaO9P2S:
573.1453, found: 573.1458 [M+Na]+. The ee was determined by HPLC
using two Chiralpak AD columns combined in series (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; t major =42.4 min, tminor =48.5 min (84%
ee).
termined by HPLC using
a Chiralpak AD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tminor =16.6 min, tmajor =18.3 min (54%
ee).
Reduction of 3ag into the corresponding diol 4: A large excess of
borane/methylsulfide complex (1.5 mL, 15.8 mmol) was added dropwise
under an argon atmosphere to a stirred solution of bisphosphonate deriv-
ative 3ag (310.5 mg, 0.58 mmol) in anhydrous toluene (1 mL). After stir-
ring for 20 h at RT, the mixture was cooled to 08C and quenched with
EtOH (4 mL). The solvent was removed under reduced pressure and the
crude product (single diasteroisomer in the 1H NMR spectrum) was sub-
jected to FC (MeOH/EtOAc 2:98) to give the desired diol 4 as a white
solid (97 mg, 73%).
AHCTRE(GNU 2R,3R)-Tetraethyl 2-(3-hydroxy-2-(hydroxymethyl)-2,3-dihydrobenzofur-
an-2-yl)ethane-1,1-diyldiphosphonate (4): [a]2D0 = À8.5 (c=1.0, CHCl3);
1H NMR (400 MHz, CDCl3, 2 58C): d=7.39 (d, J=8.0 Hz, 1H), 7.20 (t,
J=8.0 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.09
(brs, 1H), 5.04 (s, 1H), 4.44–3.70 (m, 10H), 3.57 (brs), 2.90–2.60 (m,
1H), 2.48–2.24 (m, 1H), 2.23–1.94 (m, 1H), 1.60–0.95 ppm (m, 12H);
13C NMR (100 MHz, CDCl3, 2 58C): d=158.4, 130.3, 127.5, 126.5, 121.1,
110.5, 90.3–90.2(m), 77.6, 63.6–62.4 (m), 59.6, 30.7 (t, J=133.3 Hz), 28.1,
16.2ppm; 31P NMR (160 MHz, CDCl3, 2 58C): d=25.5 (d, J=4.9 Hz),
22.5 ppm (d, J=4.9 Hz); HRMS: m/z: calcd for C19H32NaO9P2: 489.1419,
found: 489.1429 [M+Na]+.
(S)-tert-Butyl 1-(2,2-bis(diethoxyphosphoryl)ethyl)-4-methoxy-2-oxocy-
clopent-3-enecarboxylate (3aj): The title compound was obtained from
1a and 2j according to the general procedure, at À308C after 8 h as a
colorless oil (100 mg, 98%). [a]2D0 = À58.8 (c=1.0, CHCl3, > 99% ee);
1H NMR (400 MHz, CDCl3, 2 58C): d=5.18 (s, 1H), 4.19–4.08 (m, 8H),
3.82(s, 3H), 3.12(A of AB system, J=18.1 Hz, 1H), 3.03 (B of AB
system, J=18.1 Hz), 2.86–2.68 (m, 2H), 2.15–1.98 (m, 1H), 1.38–
1.26 ppm (m, 21H); 13C NMR (100 MHz, CDCl3, 2 58C): d=200.3, 191.3,
168.5, 101.0, 81.9, 62.8–62.4 (m), 59.7, 58.8, 38.9, 33.5 (t, J=133.4 Hz),
29.9, 27.7, 16.4–16.2 ppm (m); 31P NMR (160 MHz, CDCl3, 2 58C): d=
23.4, 23.3 ppm; HRMS: m/z: calcd for C21H38NaO10P2: 535.1838, found:
535.1832[ M+Na]+. The ee was determined by HPLC using two Chiral-
pak AD columns combined in series hexane/iPrOH 90:10); flow rate
1.0 mLminÀ1; tminor =67.1 min, tmajor =60.1 min (> 99% ee).
Benzoylation of diol 4 to the corresponding diester 5: 3,5-Dinitrobenzoyl
chloride (92.2 mg, 0.4 mmol) was added to a stirred solution of diol 4
(46.6 mg, 0.1 mmol) in anhydrous CH2Cl2 (2mL), and then Et 3N
(0.2mL) and a catalytic amount of DMAP (2mg). After stirring for 1 h
at RT, the solvent was removed under reduced pressure and the crude
product was purified by FC (pentane/EtOAc 3:7) affording the corre-
sponding diester 5 as a yellow oil (70 mg, 82%).
(S)-tert-Butyl 1-(2,2-bis(diethoxyphosphoryl)ethyl)-3-methyl-2-oxocyclo-
pent-3-enecarboxylate (3ak): The title compound was obtained from 1a
and 2k according to the general procedure after 1 h as a colorless oil
AHCTRE(UGN 2R,3R)-2-(2,2-bis(diethoxyphosphoryl)ethyl)-2-((3,5-dinitrobenzoyloxy)-
methyl)-2,3-dihydro-benzofuran-3-yl 3,5-dinitrobenzoate (5): [a]D20
=
(92mg, 93%). [ a]D20
=
À37.8 (c=1.0, CHCl3, 99% ee); 1H NMR
À41.0 (c=1.0, CHCl3, 98% ee); 1H NMR (400 MHz, CDCl3, 2 58C): d=
9.25–9.10 (m, 2H), 9.05–8.98 (m, 2H), 8.95–8.88 (m, 2H), 7.55–7.30 (m,
2H), 7.10–6.85 (m, 3H), 4.89 (A of AB system, J=12.0 Hz, 1H), 4.84 (B
of AB system, J=12.0 Hz, 1H), 4.45–3.95 (m, 8H), 3.00–2.55 (m, 3H),
(400 MHz, CDCl3, 2 58C): d=7.34 (s, 1H), 4.20–4.07 (m, 8H), 3.99 (AB
system, J=19.4 Hz, 2H), 2.75–2.55 (m, 2H), 2.19–2.07 (m, 1H), 1.75 (s,
3H), 1.40–1.27 ppm (m, 21H); 13C NMR (100 MHz, CDCl3, 2 58C): d=
204.9, 168.8, 158.2, 139.3, 81.7, 62.8–62.4 (m), 58.2–58.1 (m), 37.8, 32.9 (t,
J=133.8 Hz), 29.6, 27.7, 16.3–16.2 (m), 10.4 ppm; 31P NMR (160 MHz,
CDCl3, 2 58C): d=23.7, 23.4 ppm; HRMS: m/z: calcd for C21H38NaO9P2:
519.1889, found: 519.1890 [M+Na]+. The ee was determined by HPLC
using two Chiralpak AD columns combined in series (hexane/iPrOH
1.60–1.15 ppm (m, 12H); 13C NMR (CDCl3): d
= 162.3, 161.9, 159.3,
148.7, 148.6, 133.1, 132.7, 132.3, 129.3, 126.6, 123.0, 122.9, 122.8, 122.6,
122.5, 122.2, 110.7, 88.8–88.6 (m), 80.5, 64.9, 63.4–62.6 (m), 31.3 (t, J=
134.1 Hz), 29.8, 16.3 ppm; 31P NMR (160 MHz, CDCl3, 2 58C): d=22.3 (d,
J=3.0 Hz), 22.2 ppm (d, J=3.0 Hz); HRMS: m/z: calcd for
Chem. Eur. J. 2008, 14, 128 – 135
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
133

K. A. Jørgensen et al.
C33H36N4NaO19P2: 877.1347, found: 877.1343 [M+Na]+. The ee was deter-
mined by HPLC using a Chiralcel OD column (hexane/iPrOH 50:50);
flow rate 0.5 mLminÀ1; tmajor =62.9 min, tminor =84.3 min (98% ee).
columns combined in series (hexane/iPrOH 80:20); flow rate
0.7 mLminÀ1; tminor =89.3 min, tmajor =95.7 min (98% ee).
Derivatization of 3ag into the corresponding vinyl phosphonate 6 by
Horner-Wadsworth-Emmons reaction: In a 2-necked flask a solution of
bisphosphonate derivative 3ag (88 mg, 0.16 mmol) in anhydrous THF
(5 mL) was cooled at À408C under an argon atmosphere. In a separate
two-necked flask paraformaldehyde (2g) was placed under argon and
subsequently heated to 2008C to promote paraformaldehyde depolymeri-
zation. Formaldehyde gas was collected by cannula to the flask contain-
ing the cooled solution of 3ag until complete saturation, then a solution
of LHMDS (0.18 mmol, 1.06m in THF) was added dropwise over 15 min.
After stirring at À408C for 10 min, the mixture was quenched with water
and extracted with diethyl ether (3”20 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered and evaporated under
reduced pressure. Purification of the crude mixture by FC (pentane/
EtOAc 1:1) afforded the vinyl phosphonate 4 as colorless oil (50 mg,
76%).
Acknowledgement
This work was made possible by grant from The Danish National Re-
search Foundation.
[1] For a recent review on the clinical use of bisphosphonates, see: S.
Zhang, G. Gangal, H. Uludag¯, Chem. Soc. Rev. 2007, 36, 507–531.
[2] T. Srivastava, U. S. Alon, Eur. J. Pediatr. 2003, 162, 735–751.
[3] E. Kotsikorou, Y. Song, J. M. W. Chan, S. Faelens, Z. Tovian, E. Bro-
derick, N. Bakalara, R. Docampo, E. Olfield, J. Med. Chem. 2005,
48, 6128–6139, and references therein.
[4] a) G. H. Ebetino, A. V. Bayless, L. Amburgey, K. J. Ibbotson, S.
Dansereau, A. Ebrahimpour, Phosphorus Sulfur Silicon 1996, 109/
110, 217–220; b) E. van Beek, C. Lowik, I. Que, S. Papapoulos, J.
Bone Miner. Res. 1996, 11, 1492–1497.
[5] a) V. Chaleix, M. Lecouvey, Tetrahedron Lett. 2007, 48, 703–706;
b) X. Liu, X. R. Zhang, G. M. Blackburn, Chem. Commun. 1997,
87–88; c) H. J. Cristau, C. Brahic, J. L. Pirat, Tetrahedron 2001, 57,
9149–9156; d) F. H. Ebetino, C. R. Gegenhardt, L. A. Jamison, D. C.
Burdsall, Heterocycles 1990, 30, 855–862.
(S)-tert-Butyl 2-(2-diethoxyphosphoryl)allyl)-3-oxo-2,3-dihydrobenzofu-
ran-2-carboxylate (6): [a]2D0 = À33.0 (c=1.0, CHCl3, 88% ee); 1H NMR
(400 MHz, CDCl3, 2 58C): d=7.64–7.60 (m, 2H), 7.17 (d, J=8.7 Hz, 1H),
7.09 (t, J=7.6 Hz, 1H), 6.19–6.00 (m, 2H), 4.11–3.94 (m, 4H), 3.36–3.25
(m, 1H), 2.79–2.73 (m, 1H), 1.39 (s, 9H), 1.31 (t, J=7.1 Hz, 3H),
1.24 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3, 2 58C): d=
195.3, 172.3, 163.8, 138.5, 133.9, 132.4–132.2 (m), 124.8, 122.5, 119.0,
113.4, 90.6, 83.8, 61.9–61.7 (m), 34.4 (d, J=12.9 Hz), 27.5, 16.3–16.1 ppm
(m); 31P NMR (160 MHz, CDCl3, 2 85C): d=18.0 ppm; HRMS: m/z:
calcd for C20H27NaO7P: 433.1392, found: 433.1392 [M+Na]+. The ee was
determined by HPLC using a Chiralpak AD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tminor =14.4 min, tmajor =16.4 min (88%
ee).
[6] Y. Du, K. Y. Jung, D. Wiemer, Tetrahedron Lett. 2002, 43, 8665–
8668.
[7] R. Ruzziconi, G. Ricci, A. Gioiello, H. Couthon-Gourves, J. P.
Gourves, J. Org. Chem. 2003, 68, 736–742.
[8] P. Moreau, M. Maffei, Tetrahedron Lett. 2004, 45, 743–746.
[9] a) F. Gagosz, S. Z. Zard, Synlett 2003, 387–389; b) J. H. Byers, J. G.
Thissel, M. A. Thomas, Tetrahedron Lett. 1995, 36, 6403–6406.
[10] a) D. G. Piotrwska, Tetrahedron 2006, 62, 12306–12317; b) H. Cou-
thon-Gourv›s, G. Simon, J.-P. Haelters, B. Corbel, Synthesis 2006,
81–88; c) L. Lazzarato, B. Rolando, M. L. Lolli, G. C. Tron, R. Frut-
tero, A. Gasco, G. Deleide, H. L. Guenther, J. Med. Chem. 2005, 48,
1322–1329; d) S. H. Szajnman, A. Montalvetti, Y. Wang, R. Docam-
po, J. B. Rodriguez, Bioorg. Med. Chem. Lett. 2003, 13, 3231–3235;
e) S. Inoue, T. Okauchi, T. Minami, Synthesis 2003, 1971–1976;
f) M. L. Lolli, L. Lazzarato, A. Di Stilo, R. Fruttero, A. Gasco, J. Or-
ganomet. Chem. 2002, 650, 77–83; g) P. C. Bulman Page, J. P. G.
Moore, I. Mansfield, M. J. McKenzie, W. B. Bowler, J. A. Gallagher,
Tetrahedron 2001, 57, 1837–1847; h) S. T. Schlachter, L. A. Galinet,
S. K. Shields, D. A. Aspar, C. J. Dunn, N. D. Staite, R. A. Nugent,
Bioorg. Med. Chem. Lett. 1998, 8, 1093–1096; i) R. A. Nugent, S. T.
Schlachter, M. Murphy, C. J. Dunn, N. D. Staite, L. A. Galinet, S. K.
Shields, H. Wu, D. G. Aspar, K. Richard, J. Med. Chem. 1994, 37,
4449–4454; j) G. Sturtz, J. Guervenou, Synthesis 1991, 661–662.
[11] D. W. Hutchinson, D. M. Thornton, J. Organomet. Chem. 1998, 346,
341–348.
[12] S. H. Szajnman, G. G. LiÇares, P. Moro, J. B. Rodriguez, Eur. J. Org.
Chem. 2005, 3687–3696.
[13] G. Bansal, J. E. I. Wright, S. Zhang, R. F. Zernicke, H. Uludag, J.
Biomed. Mater. Res. Part A 2005, 74, 618–628.
[14] L. Delain-Bioton, A. Turner, N. Lejeune, D. Villemin, G. B. Hix, P.-
A. Jaffr›s, Tetrahedron 2005, 61, 6602–6609.
[15] S. Sulzer-Mosse’, M. Tissot, A. Alexakis, Org. Lett. 2007, 9, 3749–
3752.
[16] a) H. Wynberg, R. Helder, Tetrahedron Lett. 1975, 16, 4057–4060;
b) K. Hermann, H. Wynberg, J. Org. Chem. 1979, 44, 2238–2244;
c) H. Brunner, B. Kimel, Monatsh. Chem. 1996, 127, 1063–1072;
d) N. Kobayashi, K. Iwai, J. Am. Chem. Soc. 1978, 100, 7071–7072;
e) A. Sera, K. Takagi, H. Katayama, H. Yamada, J. Org. Chem.
1988, 53, 1157–1161; f) R. Alvarez, M.-A- Hourdin, C. Cave, J.
D’Angelo, P. Chaminade, Tetrahedron Lett. 1999, 40, 7091–7094;
g) G. Szollosi, M. Bartok, Chirality, 2001, 13, 614–618; h) T. Ooi, T.
Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi, K. Maruoka, Angew.
Chem. 2003, 115, 3926–3928; Angew. Chem. Int. Ed. 2003, 42, 3796–
Hydrolysis of 3af into the corresponding bisphosphonic acid 7: Under
argon, freshly distilled TMSBr (0.6 mL) was added dropwise to a stirred
solution of tetraethyl bisphosphonate 3af (0.3 mmol), previously dried-up
under vacuum over P2O5 for 12h, in BSA (1.5 mL). The mixture was
stirred at RT for 24 h. The residue was first evaporated at reduced pres-
sure, then co-evaporated with o-xylene (5 mL) three times. The crude
mixture was treated with MeOH (5 mL) and the resulting mixture stirred
overnight. Evaporation of the solvent at reduced pressure afforded pure
bisphosphonic acid 7 as a white solid (133 mg, 99%).
(R)-2-(2-(tert-Butoxycarbonyl)-5-methoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)ethane-1,1-diyldiphosphonic acid (7):[28] [a]D20
=
À71.1 (c=1.0,
MeOH); 1H NMR (400 MHz, CD3OD, 258C): d=7.63 (d, J=8.5 Hz,
1H), 7.05 (d, J=2Hz, 1H), 6.96 (dd, J=8.5 Hz, J=2Hz, 1H), 3.90 (s,
3H), 3.67 (A of AB system, J=17.9 Hz, 1H), 3.58 (B of AB system, J=
17.9 Hz, 1H), 2.98–2.76 (m, 1H), 2.58–2.38 (m, 1H), 2.35 (m, 1H), 1.36
(s, 9H); 13C NMR (100 MHz, CD3OD, 258C): d=202.6, 171.0, 167.8,
159.3, 128.9, 127.2, 117.2, 110.4, 83.1, 62.9–62.7 (m), 56.5, 38.4, 35.6 (t, J=
125.7 Hz), 30.9, 28.1; 31P NMR (160 MHz, CD3OD, 258C): d=21.2,
20.7 ppm; HRMS: m/z: calcd for C17H24NaO10P2: 473.0742, found:
473.0740 [M+Na]+.
Esterification of bisphosphonic acid 7 to the corresponding tetramethyl
ester 8: A solution of TMSCHN2 2m in hexane (1.1 mL) was added drop-
wise to a stirred solution of bisphosphonic acid 7 (0.1 mmol) in MeOH
(2mL). After stirring for 15 min at RT the solvent was evaporated at re-
duced pressure affording pure tetramethyl bisphosphonate 8 as a color-
less oil (49 mg, 98%).
(R)-tert-Butyl 2-(2,2-bis(dimethoxyphosphoryl)ethyl)-5-methoxy-1-oxo-
2,3-dihydro-1H-indene-2-carboxylate (8): [a]2D0 = À69.9 (c=1.0, CHCl3,
98% ee); 1H NMR (400 MHz, CDCl3, 2 58C): d=7.64 (d, J=7.5, 1H),
6.94–6.85 (m, 2H), 3.87 (s, 3H), 3.84–3.69 (m, 12H), 3.60 (A of AB
system, J=17.6 Hz, 1H), 3.40 (B of AB system, J=17.6 Hz, 1H), 2.90–
2.68 (m, 2H), 2.39–2.21 (m, 1H), 1.35 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3, 2 58C): d=199.7, 169.1, 165.8, 156.9, 127.9, 126.3, 115.9, 109.1,
82.0, 60.9–60.8 (m), 55.6, 53.6–52.8 (m), 37.3, 32.2 (t, J=131.4 Hz), 29.7,
27.7 ppm; 31P NMR (160 MHz, CDCl3, 2 85C): d=24.9, 24.5 ppm;
HRMS: m/z: calcd for C21H32NaO10P2: 529.1368, found: 529.1364
[M+Na]+. The ee was determined by HPLC using two Chiralpak AD
134
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Chem. Eur. J. 2008, 14, 128 – 135

Organocatalyzed Michael-Type Additions
FULL PAPER
3798; i) E. J. Park, M. H. Kim, D. A. Kim, J. Org. Chem. 2004, 69,
6897–6899; j) Y. Hoashi, T. Yabuta, Y. Takemoto, Tetrahedron Lett.
2004, 45, 9185–9188; k) T. B. Poulsen, L. Bernardi, M. Bell, K. A.
Jørgensen, Angew. Chem. 2006, 118, 6071–6074; Angew. Chem. Int.
Ed. 2006, 45, 6551–6554; l) F. Wu, H. Li, R. Hong, L. Deng, Angew.
Chem. 2006, 118, 961–964; Angew. Chem. Int. Ed. 2006, 45, 947–
950; m) G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli,
A. Mazzanti, P. Ricci, L. Sambri, P. Melchiorre, Angew. Chem. 2006,
118, 5088–5092; Angew. Chem. Int. Ed. 2006, 45, 4966–4970;
n) T. B. Poulsen, L. Bernardi, J. Alemµn, J. Overgaard, K. A. Jørgen-
sen, J. Am. Chem. Soc. 2007, 129, 441–449.
[19] Attempts to improve enantioselectivity decreasing the reaction tem-
perature to À608C failed, due to the very low reactivity of 2i at this
temperature.
[20] P. C. B. Page, M. J. McKenzie, J. A. Gallagher, Synth. Commun.
2002, 32, 211–218, and references therein.
[21] a) B. B. Snider, X. Wu, Heterocycles 2006, 70, 279–294; b) Y. Zou,
M. Lobera, B. B. Snider, J. Org. Chem. 2005, 70, 1761–1770.
[22] CCDC-656632 (4) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[17] For books on organocatalysis, see: a) P. I. Dalko, Enantioselective
Organocatalysis, Wiley-VCH, Weinheim (Germany), 2007; b) A.
Berkessel, H. Grçger, Asymmetric Organocatalysis, Wiley-VCH,
Weinheim (Germany), 2005. For reviews on organocatalysis, see:
c) J. Seayed, B. List, Org. Biomol. Chem. 2005, 3, 719–724; d) P. I.
Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–5286, Angew.
Chem. Int. Ed. 2004, 43, 5138–5175; e) Special Issue: “Asymmetric
Organocatalysis”, Acc. Chem. Res. 2004, 37.
[23] For a review on synthetic application of vinyl phosphonates, see: T.
Minami, J. Motoyoshiya, Synthesis 1992, 333–349.
[24] M. Conti, Anti-Cancer Drugs 2006, 17, 1017–1022.
[25] For the preparation of 2j–l, we developed a convenient and efficient
procedure starting from the corresponding cyclic enones and em-
ploying the commercially available N-tert-butoxycarbonyl imidazole
as acylating agent. This protocol provided a valid alternative to the
use of more common tert-butyl cyanoformate.
[18] Similar significant effects of changing the ester group of the ketoes-
ter have already been observed, see for example refs. [16l,m], and
following: a) J. Alemµn, B. Richter, K. A. Jørgensen, Angew. Chem.
2007, 119, 5611–5615; Angew. Chem. Int. Ed. 2007, 46, 5515–5519;
b) Y. Hamashima, D. Hotta, N. Umebayashi, Y. Tsuchiya, T. Suzuki,
M. Sodeoka, Adv. Synth. Catal. 2005, 347, 1576–1586; c) G. Kumar-
aswamy, N. Jena, M. N. V. Sastry, M. Padmaja, B. Markondaiah,
Adv. Synth. Catal. 2005, 347, 867–871; d) N. Makoto, S. Yamamoto,
Y. Yamaguchi, S. Nakamura, S. Hashimoto, Tetrahedron 2003, 59,
7307–7313; e) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem.
Soc. 2002, 124, 11240–11241.
[26] The use of BSA led to a clean profile of the hydrolysis reaction,
while in experiments carried out in absence of this reagent only sev-
eral by-products were obtained.
[27] For detailed experimental procedures, see Supporting Information.
[28] Chemical shifts (d) are reported in ppm relative to CD3OH (d=
1
4.84) for H NMR, relative to the central resonance of CD3OD (d=
49.05) for 13C NMR and relative to external H3PO4 85% (d=0.00)
for 31P NMR.
Received: August 24, 2007
Published online: October 11, 2007
Chem. Eur. J. 2008, 14, 128 – 135
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
135