Organocatalytic domino Michael-Knoevenagel condensation reaction for the synthesis of optically active 3-diethoxyphosphoryl-2-oxocyclohex-3- enecarboxylates

Article abstract of DOI:10.1002/chem.200802285

A novel, organocatalytic, highly enantio- and diastereoselective synthetic approach towards optically active 6-substituted-3-diethoxyphosphoryl-2- oxocyclohex-3-enecarboxylates is presented. Our methodology utilizes a Michael-Knoevenagel domino reaction s

Full text of DOI:10.1002/chem.200802285

FULL PAPER
DOI: 10.1002/chem.200802285
Organocatalytic Domino Michael–Knoevenagel Condensation Reaction
for the Synthesis of Optically Active
3-Diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates
Łukasz Albrecht,[a, b] Bo Richter,[a] Carlos Vila,[a] Henryk Krawczyk,[b] and
Karl Anker Jørgensen*[a]
Abstract: A novel, organocatalytic, highly enantio- and diastereoselective synthetic
approach towards optically active 6-substituted-3-diethoxyphosphoryl-2-oxocyclo-
hex-3-enecarboxylates is presented. Our methodology utilizes a Michael–Knoeve-
nagel domino reaction sequence of ethyl 4-diethoxyphosphoryl-3-oxobutanoate
and a,b-unsaturated aldehydes catalyzed by a chiral diarylprolinol ether. The
cyclohexenecarboxylates obtained are particularly well suited for the preparation
of highly functionalized cyclohexene and cyclohexane derivatives, with up to four
chiral centers and high levels of stereocontrol.
Keywords: asymmetric synthesis ·
domino reactions · Michael–Knoe-
venagel reactions · organocatalysis ·
phosphonates
Introduction
access to molecules of complex architecture without isola-
tion and purification of the intermediates, are of great im-
portance in organic chemistry. As it has been demonstrated,
organocatalysis provides a possibility to perform such reac-
tions in an asymmetric fashion with high levels of stereocon-
trol. The immense progress in this field of organocatalysis
has been recently reviewed.[4] In our efforts to contribute to
this extensively developing research area, we have recently
established several multicomponent domino processes, dem-
onstrating that even up to five stereocenters[5h] can be
formed in an organocatalytic domino reaction with excellent
enantio- and diastereoselectivity.[5] Synthetic utility of orga-
nocatalytic domino processes in which the first step consists
of an iminium-catalyzed Michael reaction for the synthesis
of optically active carbo- and heterocyclic products is well
recognized.[5,6] However, to the best of our knowledge, the
cascade reaction proceeding as a Michael–Knoevenagel con-
densation sequence is essentially unknown.
Continuously growing interest in the chemistry of natural
products and other molecules of general importance such as
pharmaceuticals, chiral building blocks, and agromaterials
has resulted in development of a great number of synthetic
approaches towards these types of compounds, based on
stereodifferentiating reactions by using inductors of chirality
in sub-stochiometric amounts. In recent years, asymmetric
organocatalysis has emerged as a very attractive method for
the construction of enantiomerically pure and enriched com-
pounds, being complementary to metal and enzyme cataly-
sis.[1] In particular, a number of highly enantioselective
transformations of carbonyl substrates catalyzed by chiral
secondary amines involving the corresponding enamine[2] or
iminium[3] intermediates have been successfully performed.
Domino reactions, in which more than one bond is being
formed in a multistep one-pot reaction sequence, giving
Chiral, differently substituted, 2-oxocyclohex-3-enecar-
boxylates constitute an important group of organic mole-
cules that has found many applications as useful building
blocks in organic synthesis.[7] As a consequence, a number of
preparative routes to these compounds has been devel-
oped.[7,8] One of the most effective and operationally simple
is that based on the [3+3] annulation reaction.[7e,8b–d] The
synthesis of optically active 3-diethoxyphosphoryl-2-oxocy-
clohex-3-enecarboxylates has not been previously described
in the literature. However, this class of phosphonates is par-
[a] Ł. Albrecht, B. Richter, C. Vila, 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
[b] Ł. Albrecht, Prof. Dr. H. Krawczyk
Department of Chemistry, Institute of Organic Chemistry
˙
Technical University of Lodz, Zeromskiego 116
90-924 Lodz (Poland)
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Table 1. Screening of the reaction conditions of cinnamaldehyde 2a with
ethyl 4-diethoxyphosphoryl-3-oxobutanoate 1 catalyzed by 4.[a]
ticularly interesting due to the their potential synthetic
utility.
Therefore, we report an organocatalytic, diastereo- and
enantioselective Michael–Knoevenagel domino one-pot ap-
proach towards highly functionalized 6-substituted-3-dieth-
oxyphosphoryl-2-oxocyclohex-3-enecarboxylates (3). We en-
visioned the reaction sequence involving Michael addition
of ethyl 4-diethoxyphosphoryl-3-oxobutanoate (1) to a,b-un-
saturated aldehydes (2) by using iminium activation, fol-
lowed by subsequent Knoevenagel condensation of the re-
sulting adducts as a facile and efficient approach to the
target compounds (Scheme 1). Our methodology benefits
Solvent
Conc. [m]
T [8C]
Yield [%]
ee [%][b]
dr[c]
1
2
3
4
5
6
7
CH2Cl2
CHCl3
EtOH
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.1
0.1
0.1
0.1
0.2
0.5
0.2
0.2
0.2
RT
RT
RT
RT
RT
RT
0
66
67
55
42
68
51
65
72
76
94
94
96
94
97
98
98
98
98
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
8[d]
9[e]
À30
À30
[a] All reactions were performed at 0.125 mmol scale with two equiva-
Scheme 1. Enantioselective organocatalytic approach towards 6-substitut-
lents of the aldehyde in the presence of 4 (10 mol%) for 24 h. [b] Deter-
ed-3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates 3.
mined by HPLC on
a chiral stationary phase. [c] Determined by
31P NMR spectroscopy. [d] Reaction conducted for 48 h. [e] Reaction per-
formed with PhCO2H (10 mol%) as co-catalyst.
from operational simplicity and benign reaction conditions.
Moreover, we present that these optically active products
are useful starting materials for further diastereoselective
transformations leading to the formation of various enantio-
merically enriched cyclohexene and cyclohexane derivatives
with up to four stereocenters. Therefore, the optically active
products obtained, can be considered as versatile building
blocks for the synthesis of molecules of higher complexity.
affording 3a with high levels of stereocontrol (entries 1–4).
However, chlorinated solvents were the most useful in terms
of yields (Table 1, entries 1 and 2). CH2Cl2 turned out to be
the solvent of choice and was used for concentration screen-
ing. Those studies revealed that enantioselectivity of the re-
action was improved with increasing concentration of phos-
phonate 1 (Table 1, entries 5, 6). Finally, the temperature
effect was evaluated (Table 1, entries 7–9) and the key pa-
rameters of the reaction were found (Table 1, entry 9). Per-
forming the reaction at À308C in the presence of PhCO2H
(10 mol%) as co-catalyst allowed us to obtain 3a in 76%
yield, and with excellent enantio- and diastereoselectivity
within 24 h.
With the optimized conditions in hand, we investigated
the scope of the reaction. The results are summarized in
Table 2. Various substituted cinnamaldehydes 2b–f were
treated with ethyl 4-diethoxyphosphoryl-3-oxobutanoate (1).
The reaction proved to be general, since good yields (76–
95%), high diastereoselectivities (ranging from 87:13 to
>95:5), and excellent enantioselectivities (97–98% ee) were
observed in all the cases. The position of the substituent on
the aromatic ring had no significant influence on the stereo-
chemical outcome of the reaction. Moreover, the Michael–
Knoevenagel domino reaction with cinnamaldehydes bear-
ing either electron-withdrawing or electron-donating sub-
stituents proceeded without noticeable changes in yield or
stereoselectivity. The use of heteroaromatic 2-furyl substitut-
ed aldehyde 2g is also worth mentioning, leading to the for-
mation of 3g with 71% yield, 9:1 dr and 97% ee (Table 2,
entry 7). As expected, the opposite enantiomer of the cata-
lyst (R)-4 gave access to the enantiomeric product ent-3a as
a single diastereoisomer with 98% ee (Table 2, entry 8).
Results and Discussion
Screening and scope: At the outset of our studies, investiga-
tions were carried out in order to find the optimal reaction
conditions for the formation of enantiomerically enriched 6-
substituted-3-diethoxyphosphoryl-2-oxocyclohex-3-enecar-
boxylates 3 (Table 1). We anticipated that 2-[bis(3,5-bistri-
fluoromethylphenyl)trimethyl-silylanyloxymethyl]pyrroli-
dine 4 should be particularly well suited as a catalyst of our
envisioned domino reaction, since its general catalytic activi-
ty has been confirmed in numerous aminocatalytic transfor-
mations.[9]
Cinnamaldehyde 2a was chosen as a model substrate. To
our delight its reaction with ethyl 4-diethoxyphosphoryl-3-
oxobutanoate 1 in CH2Cl2 in the presence of 4 (10 mol%)
was found to take place efficiently at room temperature and
was completed within 24 h (Table 1, entry 1). We also ob-
served that the originally formed Michael adduct under-
went, under these conditions, spontaneous intramolecular
Knoevenagel reaction to give cyclohex-2-enecarboxylate 3a
with high enantioselectivity (94% enantiomeric excess (ee))
and excellent diasteroselectivity (>95:5). In the next stage
of the studies, different solvents, concentrations, and temper-
atures were screened. The Michael–Knoevenagel domino re-
action could be efficiently performed in all solvents tested
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Organocatalysis
FULL PAPER
Table 2. 2-[Bis(3,5-bistrifluoromethylphenyl)trimethylsilylanyloxy-
ACHTUNGTRENNUNG
sponding enol, is crucial for the reaction to proceed in a de-
sired manner (Table 3, entries 3–6). 1,4-Diazabicyclo-
AHCTUNGTREG[NNUN 2.2.2]octane (DABCO) was found to be the best achiral
basic additive, affording the Michael–Knoevenagel domino
product 3h efficiently with 90% ee and 4:1 diastereomeric
ratio (Table 3, entry 5). In the next stage of screening, we
decided to evaluate the influence of a chiral, basic co-cata-
lyst on the reaction outcome. The use of hydroquinine
(DHQ) as a chiral Brønsted base slightly increased enantio-
selectivity of the reaction (94% ee, Table 3, entry 6). Further
screening revealed that loading of both catalyst and co-cata-
lyst could easily be lowered to 10 and 5 mol%, respectively,
without diminishing neither yield, nor stereoselectivity
(Table 3, entry 7). Moreover, the presence of the chiral co-
catalyst had no major impact on the stereochemical out-
come of the reaction, indicating that no matching–mismatch-
ing interactions between catalyst and co-catalyst occur. The
absolute configuration of the product is determined only by
the chirality of the catalyst 4 (compare entries 7 and 8). It is
also worth noting that the relative ratio of catalyst and co-
catalyst had appreciable influence on the results obtained.
Increase of DHQ loading to 20 mol%, while maintaining
catalyst loading at 10 mol%, significantly suppressed the re-
action rate (8 days were required for full conversion of the
starting phosphonate) leading to the formation of the prod-
uct with lower yield and enantioselectivity (Table 3, entry 9).
Further experiments revealed that the enantioselectivity of
the reaction is slightly temperature dependent and it in-
creased with decrease of the reaction temperature to À308C
(Table 3, entries 11, 12). Once again addition of PhCO2H
(2.5 mol%) turned out to be necessary to complete the reac-
tion within 24 h (Table 3, entry 12).
Ar
Yield [%]
ee [%][b]
dr[c]
1
2
3
4
5
6
C6H5- (2a)
79
95
81
94
76
78
71
76
98
98
98
97
97
98
97
À98
>95:5
87:13
>95:5
92:8
>95:5
>95:5
90:10
>95:5
4-NO2-C6H4- (2b)
4-CF3-C6H4- (2c)
2-CH3O-C6H4- (2d)
3-CH3O-C6H4- (2e)
biphenyl (2 f)
7
2-furyl (2g)
C6H5- (2a)
8[d]
[a] All reactions were performed at 0.25 mmol scale with two equivalents
of the aldehyde in CH2Cl2 (1.25 mL) for 24 h. [b] Determined by HPLC
on a chiral stationary phase. [c] Determined by 31P NMR spectroscopy.
[d] Reaction performed with enantiomeric catalyst (R)-4.
To our surprise, aliphatic enals turned out to be unreac-
tive under the applied conditions. Therefore, a screening of
a model reaction between 2-pentenal (2h) and compound 1
had to be performed and different additives were evaluated
(Table 3). It became evident that the use of an additional
basic co-catalyst, to facilitate the formation of the corre-
Table 3. Screening of the reaction conditions of 2-pentenal (2h) with
ethyl 4-diethoxyphosphoryl-3-oxobutanoate (1) catalyzed by 4.[a]
The optimal reaction conditions (Table 3, entry 12) were
applied to the 2-[bis(3,5-bistrifluoromethylphenyl)trimethyl-
silylanyloxymethyl]pyrrolidine-catalyzed reaction of differ-
ent aliphatic aldehydes 2h–l with compound 1 (Table 4). In
all the cases, the reaction sequence involving Michael addi-
Catalyst Additive
[mol%] [mol%]
Conv.
T
Yield ee
dr[d]
Table 4. 2-[Bis(3,5-bistrifluoromethylphenyl)trimethylsilylanyloxy-
AHCTUNGTRENNUNG
G
G
[%][b] [8C] [%]
[%][c]
1
2
3
4
5
6
7
8
S (20)
S (20)
S (20)
S (20)
S (20)
S (20)
S (10)
R (10)
S (10)
S (10)
–
0
7
55
55
89
100
93
86
94
100
67
RT nd
RT nd
RT nd
RT nd
RT 61
RT 56
RT 63
RT 65
RT 41
nd
nd
nd
nd
90
nd
nd
nd
nd
4:1
4.5:1
4.8:1
4:1
5.2:1
4.4:1
6.5:1
4:1
PhCO2H (10)
KF (10)
K2CO3 (10)
DABCO (10)
DHQ (10)
DHQ (5)
DHQ (5)
DHQ (20)
DHQ (5)
DHQ (5)
DHQ (5)
94
94
À94
R
Yield [%]
ee [%][b]
dr[c]
9[e]
10[f]
85
0
56
93
97
96
1
2
3
4
5
Et (2h)
76
83
80
86
72
96
96
96
96
94
4:1
3:1
3:1
4:1
4:1
11[f,g] S (10)
12[f,h] S (10)
À30 60
iPr (2i)[d]
100
À30 74
n-C7H15 (2j)
(Z)-n-hex-3-enyl (2k)
CH2OBn (2l)
[a] All reactions were performed at 0.125 mmol scale with two equiva-
lents of the aldehyde in CH2Cl2 (1.25 mL) for 24 h. [b] Estimated after
24 h by 31P NMR spectroscopy of the crude reaction mixture. [c] Deter-
[a] All reactions were performed at 0.25 mmol scale with two equivalents
of the aldehyde in CH2Cl2 (1.25 mL) for 24 h. [b] Determined by HPLC
on a chiral stationary phase. [c] Determined by 31P NMR spectroscopy.
[d] Performed using two equivalents of aldehyde 2i, 10 mol% (S)-4,
5 mol% DHQ, RT, 24 h.
mined by HPLC on
a chiral stationary phase. [d] Determined by
31P NMR spectroscopy. [e] Reaction conducted for 8 d. [f] Concentration
0.2m. [g] Reaction conducted for 48 h. [h] Reaction performed in the
presence of PhCO2H (2.5 mol%) as co-catalyst.
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K. A. Jørgensen et al.
tion and subsequent Knoevenagel condensation proceeded
smoothly affording the products 3h–l in good yields (72–
86%) and with excellent enantioselectivities (94–96% ee).
However, the diastereoselectivities were lower than those
observed in the reactions with cinnamaldehyde (2a) and its
derivatives 2b–g. The reaction conditions developed for the
reaction of the aliphatic a,b-unsaturated aldehydes in
Table 3 are indicative of an interesting combination of cova-
lent and non-covalent organocatalysis.
chemistry of the C-6 stereogenic center in 3, controlled by
the chirality of the catalyst, was unambiguously confirmed
by single-crystal X-ray analysis of the compound 12a
(Figure 1)[10] and is in accordance with the results obtained
Mechanistic considerations: The proposed mechanism for
the highly enantioselective, organocatalytic Michael–Knoe-
venagel domino reaction is outlined in Scheme 2. The Mi-
chael addition proceeds through the standard catalytic cycle
reported in the literature for various similar iminium-cata-
lyzed transformations. In the first step a,b-unsaturated alde-
hyde 2 is activated by the formation of iminium ion 5 in the
reversible reaction with amine catalyst 4. Chemo- and regio-
selective nucleophilic attack by the C-2 methylene atom of 1
at the b-carbon of iminium ion 5 takes place preferentially
from the less hindered Re-face of 5, to avoid unfavorable
steric interactions with the bulky substituent at C-2 in the
catalyst. Subsequent hydrolysis of the intermediate 6 releas-
es the catalyst and leads to the formation of 7. Finally, com-
pound 7 undergoes intramolecular Knoevenagel condensa-
tion, probably catalyzed by an amine in the case of aliphatic
a,b-unsaturated aldehydes, to afford 3. The absolute stereo-
Figure 1. X-Ray structure of compound 12a. C gray, H white, O red, P
purple.
in other Michael additions catalyzed by 4. The relative con-
figuration of C-1 and C-6 stereogenic centers was based on
NMR spectroscopic studies. The observed values of the cou-
pling constants (3J
ACTHUNTGRENNG(U H1,H6)=10.7–13.2 Hz) clearly proved
trans-diaxial arrangement of the protons at C-1 and C-6 in
the major diastereoisomers and, by analogy, allowed us to
assign 1S,6R absolute configuration to the products 3a–h
and 3j–l and 1S,6S to 3i. Taking into account the mechanis-
tic pathway, it is reasonable to assume that the absolute con-
figuration at the C-6 stereogenic center in the minor diaster-
oisomers is the same as in the major ones. Both isomers
differ in absolute configuration at C-1. Values of the cou-
pling constant (3J
ACTHUNRTGNE(GNU H1,H6)=4.5–4.9 Hz) for the minor diaste-
reoisomer indicates a cis-arrangement of the carboxylate
moiety and R group. Formation of the minor diastereoiso-
mer can be rationalized by the high acidity of the hydrogen
at C-1 making it prone to rapid epimerization.
Product elaborations: Optically active 6-substituted-3-dieth-
oxyphosphoryl-2-oxocyclohex-3-enecarboxylates (3) were
used for the preparation of various enantiomerically en-
riched cyclohexene and cyclohexane derivatives. Initially we
attempted a hydrolysis-decarboxylation reaction as an entry
to
5-substituted-2-(diethoxyphosphoryl)cyclohex-2-enones
(11; Scheme 3). Since acid-catalyzed hydrolysis-decarboxyla-
tion of tert-butyl 2-oxocyclohex-3-enecarboxylates constitute
a well-established strategy to access 2-cyclohexenones, we
decided to perform the Michael–Knoevenagel domino reac-
tion of tert-butyl 4-diethoxyphosphoryl-3-oxobutanoate (9)
and cinnamaldehyde (2a) catalyzed by 4 to afford tert-butyl
2-oxocyclohex-3-enecarboxylate (10; Scheme 3). Methane-
sulfonic acid catalyzed hydrolysis-decarboxylation of 10 con-
ducted in toluene at elevated temperature (908C) for 3 h
yielded the target compound 2-diethoxyphosphoryl-5-phe-
nylcyclohex-2-enone (11) in 96% ee. More interestingly,
compound 11 could easily be obtained in a one-pot reaction,
by using toluene as a solvent for both addition–cyclization
Scheme 2. Proposed mechanism for highly enantio- and diastereoselec-
tive organocatalytic Michael–Knoevenagel domino reaction leading to
the formation of optically active 6-substituted-3-diethoxyphosphoryl-2-
oxocyclohex-3-enecarboxylates 3.
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Organocatalysis
FULL PAPER
Scheme 5. Horner–Wadsworth–Emmons reaction of 13 and 14. Reagents
and conditions: a) K2CO3 (3 equiv), HCHO (12 equiv), THF/H2O, 0 8C,
overnight.
Scheme 3. Stepwise and one-pot approach for the synthesis of optically
active 2-diethoxyphosphoryl-5-phenylcyclohex-2-enone 11.
This reaction led to the formation of particularly interest-
ing a-methyleneketones 15a and b, existing as fully enolized
forms 16a and b, in a highly enantio- and diastereoselective
manner and good overall yield. Assignment of relative and
absolute configuration to the products 10–16 was based on
single-crystal X-ray analysis of 12a and NMR spectroscopic
studies.
and hydrolysis–decarboxylation steps, in good yield, and
proceeded without lowering the optical purity achieved in
the Michael addition step.
The synthetic potential of carboxylates 3 was further dem-
onstrated
in
other
stereoselective
transformations
(Scheme 4). To begin with, application of various reduction
Conclusion
In summary, we have developed a novel, stereoselective, or-
ganocatalytic Michael–Knoevenagel domino reaction of
ethyl 4-diethoxyphosphoryl-3-oxobutanoate with a,b-unsatu-
rated aldehydes, catalyzed by diarylprolinol ether leading to
enantiomerically enriched 6-substituted-3-diethoxyphosphor-
yl-2-oxocyclohex-3-enecarboxylates.
Our
methodology
proved to be general, since a wide range of a,b-unsaturated
aldehydes with both aromatic and aliphatic substituents
easily could be reacted, affording the corresponding prod-
ucts with high levels of stereocontrol. Furthermore, the ap-
plication of optically active 6-substituted-3-diethoxyphos-
phoryl-2-oxocyclohex-3-enecarboxylates in various stereose-
lective transformations has been demonstrated providing
access to a range of cyclohexene and cyclohexane deriva-
tives with up to four stereocenters, thus indicating the high
synthetic utility of the compounds obtained.
Scheme 4. Stereoselective transformations of 3a. Reagents and condi-
tions: a) NaBH4 (2 equiv), CaCl2 (1 equiv), MeOH, 08C, 2 h; b) H2, 10%
Pd/C, MeOH, RT, overnight; c) PhMgBr (1.2 equiv), CuI (1.2 equiv),
THF, 08C, 2 h.
conditions allowed us to obtain different phosphonates 12
and 13 in a highly chemo- and diastereoselective manner.
For instance, reduction of 3a with NaBH4 in MeOH in the
presence of CaCl2 afforded fully reduced b-hydroxyphosph-
onate 12 with four stereocenters in high yield and with good
diastereoselectivity (4:1 dr). On the other hand, Pd/C-cata-
lyzed hydrogenation of the double bond in 3a yielded b-ke-
tophosphonate 13 as the only product. Moreover, compound
3a turned out to be an effective Michael acceptor. Conju-
gate addition of phenylmagnesium bromide to 3a in the
presence of CuI afforded phosphonate 14. b-Ketophospho-
nates 13 and 14 were obtained as mixtures of two diastereo-
isomers differing in configuration at the C-3 stereogenic
center and were not purified, but used as a crude for further
elaborations. The results show that, due to the presence of
the activated diethoxyphosphoryl moiety, compounds 13 and
14 could be efficiently utilized in Horner–Wadsworth–
Emmons olefination of formaldehyde (Scheme 5).
Experimental Section
General methods: NMR spectra were run at 400, 162, and 100 MHz for
1H, 31P, and 13C, respectively. Chemical shifts (d) are reported in ppm rel-
ative to residual solvent signals (CHCl3, d=7.26 ppm for 1H NMR,
CDCl3, d=77.0 ppm for 13C NMR). The following abbreviations are used
to indicate the multiplicity in 1H NMR spectra: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad signal. 13C NMR spectra were acquired on
a broad-band decoupled mode. Chemical shifts for phosphorus are re-
ported in ppm relative to phosphoric acid (H3PO4, 0 ppm) used as an ex-
ternal standard. All phosphorus nuclear magnetic resonance spectra are
proton-decoupled. Mass spectra were recorded using electrospray (ES+)
ionization techniques. Analytical TLC was performed by using precoated
aluminum-backed plates and visualized by ultraviolet irradiation or
KMnO4 dip. Melting points are uncorrected. Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter. The enantiomeric excess (ee)
of the products was determined by chiral stationary phase HPLC (Daicel
Chiralpak AS/AD or Daicel Chiralcel OD/OJ columns).
Materials: Analytical grade solvents and commercially available reagents
were used without further purification. Catalysts (S)-4 and (R)-4 were
Chem. Eur. J. 2009, 15, 3093 – 3102
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3097

K. A. Jørgensen et al.
purchased from Sigma-Aldrich. Ethyl[11a] and tert-butyl[11b] 4-diethoxy-
phosphoryl-3-oxobutanoates 1 and 9 were prepared according to litera-
ture procedures. Flash chromatography (FC) was carried out by using Ia-
trobeads 6RS-8060 (spherical silica gel) or silica gel purchased from
Fluka (silica gel 60, 230–400 mesh). Racemic samples were prepared by
using a racemic mixture of the catalyst 4.
3.98 (m, 2H), 3.79–3.74 (m, 2H), 2.91–2.82 (m, 1H), 2.73–2.63 (m, 1H),
1.35–1.30 (m, 6H), 1.04 ppm (t, J=6.8 Hz, 3H); 13C NMR (CDCl3): d=
190.5 (d, JCP =7.4 Hz), 168.2, 161.4 (d, JCP =5.9 Hz), 144.4, 131.4 (d, JCP=
183.4 Hz), 130.2 (q, JCF=32.4 Hz), 127.8 (2ꢁ), 126.1 (q, JCF=3.6 Hz, 2ꢁ),
124.1 (d, JCF=270.7 Hz), 63.0 (dd, JCP =2.2, 5.9 Hz, 2ꢁ), 61.5, 60.1 (d, JCP=
7.7 Hz), 43.1, 34.4 (d, JCP=15.2 Hz), 16.5 (d. JCP=5.9 Hz, 2ꢁ), 14.0 ppm;
31P NMR
(CDCl3):
d=12.63 ppm;
HRMS:
m/z
calcd
for
General procedure for the preparation of alkyl 3-diethoxyphosphoryl-2-
oxocyclohex-3-enecarboxylates 3a–g and 10: An ordinary vial equipped
with a magnetic stirring bar was charged with catalyst 4 (0.025 mmol,
14.9 mg), PhCO2H (0.025 mmol, 3 mg), and CH2Cl2 (1.25 mL). Then, the
solution was cooled to À308C and the a,b-unsaturated aldehyde 2a–g
[C20H24F3O6PNa]+: 471.1160; found: 471.1164; the ee was determined by
HPLC analysis using a Chiralcel OJ column (hexane/iPrOH 90:10): flow
rate 1.0 mLminÀ1
À11.4 (c=1.09 in CHCl3).
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-(2-methoxyphenyl)-2-oxocyclo-
; =
tmajor =36.6 min, tminor =16.3 min (97% ee); [a]DRT
(0.50 mmol) and 4-diethoxyphosphoryl-3-oxobutanoate
1
or
9
(0.25 mmol) were added. The stirring was maintained at À308C for about
24 h until completion of the reaction (monitored by 31P NMR spectrosco-
py) and then directly subjected to FC on Iatrobeads to afford the prod-
ucts 3a–g or 10.
hex-3-enecarboxylate (3d): Following the general procedure with catalyst
(S)-4, compound 3d was isolated by FC using Iatrobeads (CH2Cl2/Et2O
4:1), as a yellow oil in 94% yield as a mixture of diastereoisomers (92:8).
Major diastereoisomer: 1H NMR (CDCl3): d=7.90 (ddd, J=2.6, 5.5,
20.2 Hz, 1H), 7.17 (dt, J=1.6, 7.9 Hz, 1H), 7.04 (dt, J=1.5, 7.9 Hz, 1H),
6.84–6.80 (m, 2H), 4.18–4.06 (m, 4H), 4.06 (d, J=13.2 Hz, 1H), 3.95 (dq,
J=0.6, 7.1 Hz, 2H), 3.90–3.80 (m, 1H), 3.78 (s, 3H), 2.85 (dddd, J=2.6,
4.5, 10.1, 20.1 Hz, 1H), 2.75 (ddt, J=2.1, 5.4, 20.2 Hz, 1H), 1.30–1.25 (m,
ACHTUNGTRENNUNG(1S,6R)-Ethyl 3-(diethoxyphosphoryl)-2-oxo-6-phenylcyclohex-3-enecar-
boxylate (3a): Following the general procedure with catalyst (S)-4, com-
pound 3a was isolated by FC over Iatrobeads (CH2Cl2/Et2O 4:1), as a
yellow oil in 76% yield as single diastereoisomer (dr >95:5). 1H NMR
(CDCl3): d=7.93 (ddd, J=2.0, 5.6, 20.0 Hz, 1H), 7.33–7.20 (m, 5H),
4.25–4.08 (m, 4H), 4.00 (dq, J=1.6, 7.2 Hz, 2H), 3.71 (d, J=12.9 Hz,
1H), 3.65–3.55 (m, 1H), 2.92–2.82 (m, 1H), 2.75–2.64 (m, 1H), 1.37–1.29
(m, 6H), 1.01 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3): d=191.2 (d,
6H), 0.96 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=192.0 (d, JCP
6.8 Hz), 168.9 (d, JCP =1.3 Hz), 163.4 (d, JCP =5.8 Hz), 157.8, 130.7 (d,
CP =182.8 Hz), 129.0, 128.9, 128.0, 120.9, 111.3, 62.9 (d, JCP =4.7 Hz, 2ꢁ),
61.1, 58.6 (d, JCP =7.7 Hz), 55.6, 39.8, 32.6 (d, JCP =14.9 Hz), 16.6 (d, JCP
=
J
=
6.2 Hz, 2ꢁ), 14.1 ppm; minor diastereoisomer (representative signals):
1H NMR (CDCl3): d=8.11 (ddd, J=2.0, 6.3, 20.5 Hz, 1H), 7.09 (dd, J=
1.3, 7.7 Hz, 1H), 0.87 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=
J
CP =7.0 Hz), 168.5 (d, JCP =1.3 Hz), 162.2 (d, JCP =5.8 Hz), 140.3, 131.2
(d, JCP =183.2 Hz), 129.1 (2ꢁ), 127.9, 127.4 (2ꢁ), 62.9 (d, JCP =5.9 Hz,
2ꢁ), 61.2, 60.5 (d, JCP =7.6 Hz), 43.3, 34.7 (d, JCP =15.1 Hz), 16.6 (d, JCP
=
6.3 Hz, 2ꢁ), 14.1 ppm; 31P NMR (CDCl3): d=13.01 ppm; HRMS: m/z
calcd for [C19H25O6Na]+: 403.1286; found: 403.1292; the ee was deter-
mined by HPLC analysis using a Chiralpak AD column (hexane/iPrOH
70:30): flow rate 1.0 mLminÀ1; tmajor =9.5 min, tminor =16.9 min (98% ee);
[a]RDT =À7.24 (c=0.72 in CHCl3).
165.5 (d, JCP =6.1 Hz), 128.7, 127.1, 120.6, 110.5, 60.7, 57.0 (d, JCP
=
7.6 Hz), 55.5, 35.7, 28.3 ppm (d, JCP =14.4 Hz); 31P NMR (CDCl3): d=
14.26 (8%), 13.52 ppm (92%); HRMS: m/z calcd for [C20H27O7PNa]+:
433.1392; found: 433.1396; the ee was determined by HPLC analysis
using
a Chiralpak AD column (hexane/iPrOH 70:30): flow rate
1.0 mLminÀ1; tmajor =10.6 min, tminor =20.6 min (97% ee); [a]RDT =À12.89
(c=1.03 in CHCl3).
ACHTUNGTRENNUNG(1R,6S)-Ethyl 3-(diethoxyphosphoryl)-2-oxo-6-phenylcyclohex-3-enecar-
boxylate (ent-3): Following the general procedure with catalyst (R)-4,
compound ent-3a was isolated by FC using Iatrobeads (CH2Cl2/Et2O
4:1), as a yellow oil in 76% yield as single diastereoisomer (dr>95:5).
The ee was determined by HPLC analysis using a Chiralpak AD column
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-(3-methoxyphenyl)-2-oxocyclo-
hex-3-enecarboxylate (3e): Following the general procedure with catalyst
(S)-4, compound 3e was isolated by FC using Iatrobeads (CH2Cl2/Et2O
4:1), as a yellow oil in 76% yield as single diastereoisomer (dr >95:5).
1H NMR (CDCl3): d=7.94 (ddd, J=2.3, 5.7, 20.1 Hz, 1H), 7.23 (d, J=
7.9 Hz, 1H), 6.82–6.75 (m, 3H), 4.24–4.12 (m, 4H), 4.04 (dq, J=1.8,
7.1 Hz, 2H), 3.78 (s, 3H), 3.76 (d, J=12.8 Hz, 1H), 3.71–3.64 (m, 1H),
2.91–2.84 (m, 1H), 2.74–2.65 (m, 1H), 1.39 (dt, J=0.5, 7.1 Hz, 3H), 1.33
(dt, J=0.5, 7.1 Hz, 3H), 1.06 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3):
d=190.9 (d, JCP =6.5 Hz), 168.2 (d, JCP =1.1 Hz), 161.9 (d, JCP =5.8 Hz),
159.7, 141.7, 130.9 (d, JCP =182.2 Hz), 129.8, 119.2, 113.1, 112.6, 62.7 (d,
(hexane/iPrOH 70:30): flow rate 1.0 mLminÀ1; tmajor =16.7 min, tminor
=
9.8 min (98% ee); [a]RDT =+7.63 (c=1.42 in CHCl3). Spectral data were
identical to compound 3a.
ACHTUNGTRENNUNG(1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-(4-nitrophenyl)-2-oxocyclohex-
3-enecarboxylate (3b): Following the general procedure with catalyst (S)-
4, 3b was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1), as a yellow
oil in 95% yield as a mixture of diastereoisomers (87:13). Major diaste-
reoisomer: 1H NMR (CDCl3): d=8.14 (d, J=8.7 Hz, 2H), 7.87 (ddd, J=
2.2, 5.7, 20.0 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 4.16–4.08 (m, 4H), 4.03–
3.91 (m, 2H), 3.83–3.76 (m, 1H), 3.74 (d, J=12.8 Hz, 1H), 2.86–2.80 (m,
1H), 2.70–2.62 (m, 1H), 1.30–1.26 (m, 6H), 1.02 ppm (t, J=7.1 Hz, 3H);
13C NMR (CDCl3): d=189.9 (d, JCP =7.0 Hz), 167.7 (d, JCP =1.3 Hz),
160.7 (d, JCP =5.8 Hz), 150.7, 147.4, 131.3 (d, JCP =183.5 Hz), 128.2 (2ꢁ),
124.1 (2ꢁ), 62.8 (d, JCP =5.5 Hz, 2ꢁ), 61.4, 59.6 (d, JCP =5.7 Hz), 42.8,
33.9 (d, JCP =15.2 Hz), 16.3 (d, JCP =6.1 Hz, 2ꢁ), 13.9 ppm; minor diaste-
reoisomer (representative signals): 1H NMR (CDCl3): d=8.05 (d, J=
8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.09 (ddd, J=2.3, 6.1, 19.3 Hz, 1H).
13C NMR (CDCl3): d=160.7 (d, JCP =5.0 Hz), 147.3, 127.8 (2ꢁ), 123.6
J
CP =6.0 Hz, 2ꢁ), 61.0, 60.2 (d, JCP =7.7 Hz), 55.1, 43.1, 34.5 (d, JCP =
15.1 Hz), 16.3 (d, JCP =6.2 Hz, 2ꢁ), 13.8 ppm; 31P NMR (CDCl3): d=
13.0 ppm; HRMS: m/z calcd for [C20H27O7PNa]+: 433.1392; found:
433.1392.; the ee was determined by HPLC analysis using a Chiralpak
AD column (hexane/iPrOH 70:30): flow rate 1.0 mLminÀ1
; tmajor =
11.7 min, tminor =17.4 min (97% ee); [a]RDT =À8.9 (c=1.47 in CHCl3).
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 6-(biphenyl-4-yl)-3-(diethoxyphosphoryl)-2-oxocyclohex-3-
enecarboxylate (3 f): Following the general procedure with catalyst (S)-4,
compound 3 f was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1), as
a yellow oil in 78% yield as single diastereoisomer (dr>95:5). 1H NMR
(CDCl3): d=7.89 (ddd, J=2.0, 5.6, 20.0 Hz, 1H), 7.48 (dd, J=1.6, 7.6 Hz,
4H), 7.35 (t, J=7.6 Hz, 2H), 7.28–7.17 (m, 3H), 4.20–4.04 (m, 4H), 3.97
(dq, J=1.2, 7.2 Hz, 2H), 3.74 (d, J=12.8 Hz, 1H) 3.72–3.63 (m, 1H),
2.87–2.79 (m, 1H), 2.71–2.62 (m, 1H), 1.27 (dt, J=5.6, 7.2 Hz, 6H),
(2ꢁ), 62.5 (d, JCP =5.0 Hz, 2ꢁ), 60.8 (d, JCP =8.9 Hz), 32.5 (d, JCP
=
15.7 Hz), 16.2 (d, JCP =10.6 Hz, 2ꢁ), 13.7 ppm; 31P NMR (CDCl3): d=
13.65 (13%), 12.40 ppm (87%); HRMS: m/z calcd for [C19H24NO8PNa]+:
448.1137; found: 448.1139; the ee was determined by HPLC analysis
0.98 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3): d=191.1 (d, JCP
6.9 Hz), 168.5, 162.1 (d, JCP =5.9 Hz), 140.7, 140.6, 139.3, 131.2 (d, JCP
=
=
using
a Chiralpak AD column (hexane/iPrOH 70:30): flow rate
0.8 mLminÀ1; tmajor =23.4 min, tminor =42.9 min (98% ee); [a]RDT =À15.57
(c=1.32 in CHCl3).
183.3 Hz), 129.0 (2ꢁ), 127.7 (2ꢁ), 127.7 (2ꢁ), 127.6, 127.1 (2ꢁ), 63.0 (d,
CP =5.4 Hz, 2ꢁ), 61.3, 60.6 (d, JCP =7.7 Hz), 43.0, 34.7 (d, JCP =15.1 Hz),
16.5 (d, JCP =6.0 Hz, 2ꢁ), 14.1 ppm; 31P NMR
(CDCl3): d=13.04 ppm;
HRMS: m/z calcd for [C25H29O6PNa]+: 479.1599; found: 479.1595; the ee
J
ACHTUNGTRENNUNG(1S,6R)-Ethyl 3-(diethoxyphosphoryl)-2-oxo-6-(4-(trifluoromethyl)phe-
AHCTUNGTRENNUNG
nyl)cyclohex-3-enecarboxylate (3c): Following the general procedure
with catalyst (S)-4, compound 3c was isolated by FC using Iatrobeads
(CH2Cl2/Et2O 4:1), as a yellow oil in 81% yield as single diastereoisomer
(dr>95:5). 1H NMR (CDCl3): d=7.92 (ddd, J=2.0, 5.6, 20.0 Hz, 1H),
7.58 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.25–4.09 (m, 4H), 4.09–
was determined by HPLC analysis using
a Chiralcel OD column
(hexane/iPrOH 70:30): flow rate 0.8 mLminÀ1; tmajor =30.9 min, tminor
24.5 min (97% ee); [a]RDT =À18.80 (c=1.65 in CHCl3).
=
3098
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3093 – 3102

Organocatalysis
FULL PAPER
A
3-(diethoxyphosphoryl)-6-(furan-2-yl)-2-oxocyclohex-3-
the absence of PhCO2H at RT, compound 3i was isolated by FC using Ia-
trobeads (CH2Cl2/Et2O 4:1), as a yellow oil in 83% yield as a mixture of
diastereoisomers (3:1). Major diastereoisomer: 1H NMR (CDCl3): d=
7.87 (ddd, J=2.8, 5.4, 20.1 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.13–4.01
(m, 4H), 3.32 (d, J=11.4 Hz, 1H), 2.58–2.49 (m, 1H), 2.46–2.39 (m, 1H),
2.32–2.23 (m, 1H), 1.72–1.60 (m, 1H), 1.27–1.20 (m, 9H), 0.91 (d, J=
6.9 Hz, 3H), 0.82 ppm (d, J=6.9 Hz, 3H); 13C NMR (CDCl3): d=191.8
(d, JCP =6.8 Hz), 169.3, 163.1 (d, JCP =5.5 Hz), 130.6 (d, JCP =183.9 Hz),
62.6 (d, JCP =5.8 Hz), 62.5 (d, JCP =5.8 Hz), 61.2, 58.5 (d, JCP =7.6 Hz),
42.1, 28.9, 26.0 (d, JCP =15.0 Hz), 20.3, 16.5, 16.3 (d, JCP =6.2 Hz), 16.2 (d,
enecarboxylate (3g): Following the general procedure with catalyst (S)-4,
compound 3g was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1), as
a yellow oil in 71% yield as a mixture of diastereoisomers (9:1). Major
diastereoisomer: 1H NMR (CDCl3): d=7.90 (ddd, J=3.2, 5.2, 20.4 Hz,
1H), 7.30 (dd, J=0.8, 2.0 Hz, 1H), 6.25 (dd, J=2.0, 3.2 Hz, 1H), 6.07 (d,
J=3.2 Hz, 1H), 4.23–4.05 (m, 6H), 3.89–3.83 (m, 1H), 3.71 (d, J=
10.8 Hz, 1H), 2.97–2.76 (m, 2H), 1.34–1.25 (m, 6H), 1.17 ppm (t, J=
7.2 Hz, 3H; 13C NMR (CDCl3): d=190.3 (d, JCP =7.2 Hz), 168.5. 161.8 (d,
J
J
J
CP =6.4 Hz), 14.1 ppm; minor diastereoisomer (representative signals):
1H NMR (CDCl3): d=7.95 (ddd, J=2.1, 5.8, 20.4 Hz, 1H), 3.60 (dd, J=
2.3, 4.5 Hz, 1H), 2.65–2.58 (m, 1H), 1.85–1.73 (m, 1H), 1.17 (t, J=
7.1 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.91 ppm (d, J=6.6 Hz, 3H);
13C NMR (CDCl3): d=191.5 (d, JCP =6.6 Hz), 165.2 (d, JCP =6.0 Hz), 62.3
16.5 (d, JCP =6.3 Hz, 2ꢁ), 14.2 ppm; minor diastereoisomer (representa-
tive signals): 1H NMR (CDCl3): d=8.07 (ddd, J=1.6, 5.2, 20.4 Hz, 1H),
7.33 (d, J=1.6 Hz, 1H), 6.30 (dd, J=1.6, 3.2 Hz, 1H), 6.12 (d, J=3.2 Hz,
1H), 3.24–3.10 (m, 2H), 1.07 ppm (t, J=7.2 Hz, 3H); 31P NMR (CDCl3):
d=13.54 (10.0%), 13.96 ppm (90.0%); HRMS: m/z calcd for
[C17H23O7PNa]+: 393.1079; found: 393.1050; the ee was determined by
HPLC analysis using a Chiralpak AD column (hexane/iPrOH 60:40):
(d,
JCP =5.0 Hz, 2ꢁ), 43.9, 30.1, 29.2 (d, JCP =14.7 Hz), 20.4, 20.4,
14.0 ppm; 31P NMR (CDCl3): d=14.12 (25%), 13.33 ppm (75%);
HRMS: m/z calcd for [C16H27O6PNa]+: 369.1443; found: 369.1448; the ee
flow rate 0.7 mLminÀ1; tmajor =9.0 min, tminor =11.0 min (97% ee); [a]RDT
À10.83 (c=1.21 in CHCl3).
=
was determined by HPLC analysis using
a Chiralpak AD column
(hexane/iPrOH 80:20): flow rate 1.0 mLminÀ1; tmajor =8.9 min, tminor
10.1 min (96% ee); [a]RDT =À16.12 (c=1.67 in CHCl3).
=
A
3-(diethoxyphosphoryl)-2-oxo-6-phenylcyclohex-3-
enecarboxylate (10): Following the general procedure with catalyst (S)-4
in the absence of PhCO2H at RT, compound 10 was isolated by FC using
Iatrobeads (CH2Cl2/Et2O 4:1), as a yellow oil in 87% yield as single dia-
stereoisomer (dr>95:5). 1H NMR (CDCl3): d=7.89 (ddd, J=2.4, 5.6,
20.4 Hz, 1H), 7.31–7.10 (m, 5H), 4.23–4.04 (m, 4H), 3.64–3.55 (m, 2H),
2.87–2.77 (m, 1H), 2.71–2.59 (m, 1H), 1.30 (dq, J=1.6, 6.8 Hz, 6H),
1.18 ppm (s, 9H); 13C NMR (CDCl3): d=191.4 (d, JCP =6.7 Hz), 167.4,
161.9 (dd, JCP=1.6, 5.8 Hz), 140.4, 131.1 (d, JCP=182.8 Hz), 128.8 (2ꢁ),
127.6, 127.4 (2ꢁ), 81.8, 62.8 (t, JCP =6.0 Hz, 2ꢁ), 61.3 (d, JCP=7.5 Hz),
43.6, 34.9 (d, JCP=15.2 Hz), 27.7 (s, 3ꢁ), 16.5 ppm (d, JCP=6.3 Hz, 2ꢁ);
31P NMR (CDCl3): d=13.40 ppm; HRMS: m/z calcd for [C21H29O6PNa]+:
431.1599; found: 431.1604; the ee was determined by HPLC analysis
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-heptyl-2-oxocyclohex-3-enecar-
boxylate (3j): Following the general procedure with catalyst (S)-4, com-
pound 3j was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1), as a
yellow oil in 80% yield as a mixture of diastereoisomers (3:1). Major dia-
stereoisomer: 1H NMR (CDCl3): d=7.88 (ddd, J=2.9, 5.1, 20.2 Hz, 1H),
4.25–4.07 (m, 6H), 3.23 (d, J=10.7 Hz, 1H), 2.76 (ddt, J=2.5, 5.0,
20.0 Hz, 1H), 2.56–2.48 (m, 1H), 2.30–2.21 (m, 1H), 1.35–1.21 (m, 21H),
0.87 ppm (t, J=6.7 Hz, 3H); 13C NMR (CDCl3): d=191.7 (d, JCP
6.9 Hz), 169.5, 162.7 (d, JCP =5.7 Hz), 130.8 (d, JCP =183.2 Hz), 62.9 (t,
=
J
J
CP =6.6 Hz, 2ꢁ), 61.5, 60.4 (d, JCP =7.5 Hz), 36.7, 33.8, 31.9, 31.4 (d,
CP =15.0 Hz), 29.6, 29.3, 26.2, 22.8, 16.6 (d, JCP =6.2 Hz), 16.6 (d, JCP
=
6.4 Hz), 14.4, 14.2 ppm; minor diastereoisomer (representative signals):
1H NMR (CDCl3): d=7.99 (dt, J=3.8, 20.0 Hz, 1H), 3.49 ppm (dd, J=
2.2, 4.8 Hz, 1H); 13C NMR (CDCl3): d=167.9, 164.9 (d, JCP =5.7 Hz),
63.8 (d, JCP =5.8 Hz), 62.6 (d, JCP =5.1 Hz), 61.3, 57.3 (d, JCP =7.4 Hz),
37.2, 32.9, 31.9, 31.1 (d, JCP =14.6 Hz), 26.7 ppm; 31P NMR (CDCl3): d=
14.16 (25%), 13.41 ppm (75%); HRMS: m/z calcd for [C20H35O6PNa]+:
425.2069; found: 425.2071; the ee was determined by HPLC analysis
using
a Chiralpak AD column (hexane/iPrOH 80:20): flow rate
1.0 mLminÀ1
;
tmajor =20.8 min, tminor =30.8 min (94% ee); [a]RDT =À4.7
(c=0.92 in CHCl3).
General procedure for the preparation of ethyl 3-diethoxyphosphoryl-2-
oxocyclohex-3-enecarboxylates 3h–l: An ordinary vial equipped with a
magnetic stirring bar was charged with catalyst 4 (0.025 mmol, 14.9 mg),
dihydroquinine (DHQ; 0.0125 mmol, 4.1 mg), PhCO2H (0.00625 mmol,
0.8 mg), and CH2Cl2 (1.25 mL). The resulting solution was cooled to
À308C and the a,b-unsaturated aldehyde 2 (0.50 mmol) and compound 1
(0.25 mmol, 66.6 mg) were added. The stirring was maintained at À308C
for about 24 h until completion of the reaction (monitored by 31P NMR
spectroscopy) and then directly subjected to FC on Iatrobeads to afford
the products 3h–l.
using
a Chiralpak AD column (hexane/iPrOH 80:20): flow rate
1.0 mLminÀ1
;
tmajor =8.4 min, tminor =9.5 min (96% ee); [a]RDT =À15.18
(c=1.59 in CHCl3).
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-((Z)-hex-3-enyl)-2-oxocyclohex-
3-enecarboxylate (3k): Following the general procedure with catalyst (S)-
4, compound 3k was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1),
as a yellow oil in 86% yield as a mixture of diastereoisomers (4:1).
Major diastereoisomer: 1H NMR (CDCl3): d=7.82 (ddd, J=3.0, 5.1,
20.2 Hz, 1H), 5.37–5.30 (m, 1H), 5.23–5.16 (m, 1H), 4.20–4.02 (m, 6H),
3.20 (d, J=10.7 Hz, 1H), 2.72 (dtd, J=2.5, 5.1, 19.9 Hz, 1H), 2.54–2.43
(m, 1H), 2.27–2.17 (m, 1H), 2.10–1.92 (m, 4H), 1.47–1.41 (m, 1H), 1.36–
1.30 (m, 1H), 1.27–1.16 (m, 9H), 0.89 ppm (t, J=7.5 Hz, 3H); 13C NMR
(CDCl3): d=191.5 (d, JCP =6.8 Hz), 169.4, 162.7 (d, JCP =5.7 Hz), 133.0,
ACHTUNGTRENNUNG(1S,6R)-Ethyl 3-(diethoxyphosphoryl)-6-ethyl-2-oxocyclohex-3-enecar-
boxylate (3h): Following the general procedure with catalyst (S)-4, com-
pound 3h was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1), as a
yellow oil in 76% yield as a mixture of diastereoisomers (4:1). Major dia-
stereoisomer: 1H NMR (CDCl3): d=7.84 (ddd, J=2.9, 5.2, 20.1 Hz, 1H),
4.19–4.02 (m, 9H), 3.19 (d, J=10.8 Hz, 1H), 2.69 (ddt, J=2.6, 5.1,
20.0 Hz, 1H), 2.53–2.37 (m, 1H), 2.25–2.16 (m, 1H), 1.49–1.40 (m, 2H),
1.27–1.20 (m, 9H), 0.88 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3): d=
130.9 (d, JCP =183.5 Hz), 127.5, 62.9 (d, JCP =6.4 Hz), 62.8 (d, JCP
=
6.1 Hz), 61.5, 60.3 (d, JCP =7.5 Hz), 36.3, 33.7, 31.2 (d, JCP =15.0 Hz), 29.9,
23.8, 20.7, 16.6 (d, JCP =6.1 Hz), 16.5 (d, JCP =6.3 Hz), 14.3 ppm; minor
diastereoisomer (representative signals): 1H NMR (CDCl3): d=7.92 (dt,
J=4.0, 20.3 Hz, 1H), 3.43 ppm (dd, J=2.2, 4.9 Hz, 1H); 13C NMR
191.4 (d, JCP =6.6 Hz), 169.21, 162.5 (d, JCP =5.9 Hz), 130.5 (d, JCP
183.2 Hz), 62.6 (d, JCP =6.4 Hz), 62.5 (d, JCP =7.0 Hz), 61.2, 59.8 (d, JCP
=
=
7.6 Hz), 37.8, 30.5 (d, JCP =15.0 Hz), 26.2, 16.3 (d, JCP =6.4 Hz), 16.2 (d,
CP =6.3 Hz), 14.0, 10.4 ppm; minor diastereoisomer (representative sig-
(CDCl3): d=164.7 (d, JCP =5.8 Hz), 133.1, 127.5, 61.4, 57.9 (d, JCP
=
J
7.6 Hz), 36.5, 32.7, 31.0 (d, JCP =14.7 Hz), 25.5, 24.4, 14.4 ppm; 31P NMR
(CDCl3): d=14.07 (20%), 13.33 ppm (80%); HRMS: m/z calcd for
[C19H31O6PNa]+: 409.1756; found: 409.1754; the ee was determined by
HPLC analysis using a Chiralpak AD column (hexane/iPrOH 80:20):
nals): 1H NMR (CDCl3): d=7.93 (ddd, J=2.9, 4.8, 20.2 Hz, 1H), 3.46
(dd, J=2.2, 4.9 Hz, 1H), 0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3):
d=167.6, 164.7 (d, JCP =5.6 Hz), 61.1, 36.7, 25.6, 13.9, 10.3 ppm; 31P NMR
(CDCl3): d=14.14 (20%), 13.38 ppm (80%); HRMS: m/z calcd for
[C15H25O6PNa]+: 355.1286; found: 355.1291; the ee was determined by
HPLC analysis using a Chiralpak AD column (hexane/iPrOH 80:20):
flow rate 1.0 mLminÀ1
; tmajor =10.6 min, tminor =12.0 min (96% ee);
[a]RDT =À7.66 (c=1.59 in CHCl3).
flow rate 1.0 mLminÀ1; tmajor =9.8 min, tminor =10.8 min (96% ee); [a]RDT
À14.2 (c=1.19 in CHCl3).
=
AHCTUNGTERG(NNUN 1S,6R)-Ethyl 6-(benzyloxymethyl)-3-(diethoxyphosphoryl)-2-oxocyclo-
hex-3-enecarboxylate (3l): Following the general procedure with catalyst
(S)-4, compound 3l was isolated by FC using Iatrobeads (CH2Cl2/Et2O
4:1), as a yellow oil in 72% yield as a mixture of diastereoisomers (4:1).
ACHTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 3093 – 3102
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3099

K. A. Jørgensen et al.
Major diastereoisomer: 1H NMR (CDCl3): d=7.88 (ddd, J=3.2, 4.8,
20.0 Hz, 1H), 7.36–7.24 (m, 5H), 4.49–4.41 (m, 2H), 4.23–4.02 (m, 6H),
3.52 (d, J=11.2 Hz, 1H), 3.42 (d, J=4.0 Hz, 2H), 2.83–2.71 (m, 1H),
2.70–2.57 (m, 2H), 1.33–1.22 ppm (m, 9H); 13C NMR (CDCl3): d=191.5
(d, J=6.8 Hz), 169.2, 162.9 (dd, J=2.2, 5.9 Hz), 137.9, 130.7 (d, J=
182.2 Hz), 128.6 (2ꢁ), 128.0, 127.8 (2ꢁ), 73.6, 71.0, 62.9 (d, J=5.7 Hz,
2ꢁ), 61.5, 56.8 (d, J=7.5 Hz), 37.5, 29.3 (d, JCP =15.1 Hz), 16.5 (d, J=
6.2 Hz), 16.5 (d, JCP =6.3 Hz), 14.3 ppm; minor diastereoisomer (repre-
sentative signals): 1H NMR (CDCl3): d=8.01–7.93 (m, 1H), 3.64–
3.59 ppm (m, 1H); 13C NMR (CDCl3): d=164.2 ppm (dd, J=2.5, 6.4 Hz);
31P NMR (CDCl3): d=13.82 (20%), 13.31 ppm (80%); HRMS: m/z calcd
for [C21H29O7PNa]+: 447.1549; found: 447.1543; the ee was determined
by HPLC analysis using a Chiralpak AD column (hexane/iPrOH 75:25):
57.8 (d, JCP =16.5 Hz), 46.1, 42.1 (d, JCP =138.6 Hz), 32.9 (d, JCP =
15.8 Hz), 24.7 (d, JCP =5.8 Hz), 16.75 (dd, J=5.8 Hz), 16.69 (dd, J=
5.9 Hz), 14.0 ppm; 31P NMR (CDCl3): d=31.49 ppm; HRMS: m/z calcd
for [C19H29O6PNa]+: 407.1599; found: 407.1585; the ee was determined
by HPLC analysis using a Chiralpak AD column (hexane/iPrOH 90:10):
flow rate 1.0 mLminÀ1; tmajor =10.7 min, tminor =9.4 min (96% ee, recrys-
tallized to 99% ee); [a]RDT =À15.35 (c=0.71 in CHCl3).
(1S,2S,3R,6R)-Ethyl 3-(diethoxyphosphoryl)-2-hydroxy-6-phenylcyclo-
hexanecarboxylate (12b; major diastereomer): Compound 12b was iso-
lated by FC using Iatrobeads (EtOAc/Pen 70:30), as a colorless oil in
75% yield. 1H NMR (CDCl3): d=7.26 (t, J=7.5 Hz, 2H), 7.19–7.16 (m,
3H), 4.63 (d, J=6.5 Hz, 1H), 4.26–4.11 (m, 4H), 3.93–3.84 (m, 2H), 3.78
(s, 1H), 3.23 (dt, J=3.7, 12.3 Hz, 1H), 2.66 (dd, J=2.1, 12.1 Hz, 1H),
2.17–2.05 (m, 1H), 2.04–1.93 (m, 2H), 1.89–1.84 (m, 1H), 1.50 (ddd, J=
4.0, 13.3, 26.2 Hz, 1H), 1.35 (dt, J=1.7, 7.0 Hz, 6H), 0.89 ppm (t, J=
7.1 Hz, 3H); 13C NMR (CDCl3): d=173.4 (d, JCP =4.0 Hz), 143.6, 128.3
(2ꢁ), 127.4 (2ꢁ), 126.5, 66.1 (d, JCP =4.5 Hz), 62.4 (d, JCP =6.5 Hz), 61.7
(d, JCP =6.8 Hz), 60.5, 53.3 (d, JCP =15.8 Hz), 40.2 (d, JCP =142.0 Hz),
39.4, 33.9 (d, JCP =16.9 Hz), 20.1 (d, JCP =2.9 Hz), 16.5 (d, JCP =6.0 Hz,
2ꢁ), 13.7 ppm; 31P NMR (CDCl3): d=31.41 ppm; HRMS: m/z calcd for
[C19H29O6PNa]+: 407.1599; found: 407.1585; the ee was determined by
HPLC analysis using a Chiralpak AD column (hexane/iPrOH 90:10):
flow rate 1.0 mLminÀ1; tmajor =9.7 min, tminor =12.0 min (94% ee); [a]RDT
À32.30 (c=1.71 in CHCl3).
=
Preparation of diethyl 6-oxo-4-phenylcyclohex-1-enylphosphonate (11)
Method A—decarboxylation of tert-butyl 3-diethoxyphosphoryl-2-oxocy-
clohex-3-enecarboxylate (10): Methanesulfonic acid (50.0 mol%) was
added to a heated (908C) solution (0.2m) of phosphonate 10 in toluene
(1.25 mL) and the resulting mixture was stirred at elevated temperature
for 3 h, cooled to RT, concentrated in vacuo, and directly subjected to
FC on Iatrobeads to afford the product 11.
flow rate 1.0 mLminÀ1; tmajor =10.7 min, tminor =9.4 min (96% ee); [a]RDT
À2.18 (c=0.79 in CHCl3).
=
Method B—one-pot synthesis: An ordinary vial equipped with a magnetic
stirring bar was charged with catalyst (S)-4 (0.025 mmol, 14.9 mg) and
toluene (1.25 mL). The a,b-unsaturated aldehyde 2a (1.00 mmol) and
Preparation of ethyl 2-hydroxy-3-methylene-6-phenylcyclohex-1-enecar-
boxylate (16a): Pd/C (10 mol%,52.0 mg, 0.048 mmol) was added to a so-
lution of 3a (76 mg, 0.2 mmol) in EtOAc (5 mL), and the resulting mix-
ture was stirred under H2 atmosphere for 90 min. Then the mixture was
filtered through Celite and concentrated in vacuo. The residue was dis-
solved in THF (1 mL), and formaldehyde (aq 37%, 0.180 mL, 2.4 mmol)
and a solution of K2CO3 (83 mg, 0.6 mmol) in H2O (1 mL) were added to
this solution. The resulting mixture was stirred at RT overnight and then
quenched with brine (10 mL) and extracted with CH2Cl2 (3ꢁ15 mL). The
combined organic layers were dried over MgSO4 and evaporated. Com-
pound 16a was isolated by FC using Iatrobeads (DCM/Et2O 4:1), as a
tert-butyl 4-diethoxyphosphoryl-3-oxobutanoate
9 (0.25 mmol) were
added. The stirring was maintained at RT for about 20 h until completion
of the domino Michael–Knoevenagel reaction (monitored by 31P NMR
spectroscopy); then the mixture was heated to 908C and methanesulfonic
acid was added (0.125 mmol, 50 mol%). The reaction was stirred at ele-
vated temperature for 3 h, cooled to RT, concentrated in vacuo, and di-
rectly subjected to FC on Iatrobeads to afford the product 11.
ACHTUNGTRENNUNG(6R)-Diethyl 6-oxo-4-phenylcyclohex-1-enylphosphonate (11) Following
one of the procedures above, compound 11 was isolated by FC using Ia-
trobeads (CH2Cl2/Et2O 4:1), as a colorless oil in 50% or 52% yield re-
spectively. 1H NMR (CDCl3): d=7.95 (ddd, J=2.2, 5.6, 20.4 Hz, 1H),
7.34 (d, J=7.6 Hz, 2H), 7.26 (t, J=7.3 Hz, 1H), 7.21 (d, J=7.5 Hz, 2H),
4.25–4.10 (m, 4H), 3.4–3.32 (m, 1H), 2.86–2.61 (m, 4H), 1.34 (t, J=
7.1 Hz, 3H), 1.33 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=195.6
(d, JCP =6.1 Hz), 162.2 (d, JCP =6.0 Hz), 142.2, 131.6 (d, JCP =183.5 Hz),
128.9 (2ꢁ), 127.2, 126.5 (2ꢁ), 62.6 (d, JCP =4.9 Hz), 62.5 (d, JCP =5.6 Hz),
45.3 (d, JCP =7.7 Hz), 40.2, 34.6 (d, JCP =15.2 Hz), 16.4 (d, JCP =6.3 Hz),
16.4 ppm (d, JCP =6.3 Hz); 31P NMR (CDCl3): d=14.30 ppm; HRMS: m/z
calcd for [C16H21O4Na]+: 331.1075; found: 331.1076; the ee was deter-
mined by HPLC analysis using a Chiralpak AS column (hexane/iPrOH
95:5): flow rate 1.0 mLminÀ1; tmajor =30.0 min, tminor =35.2 min (96% ee).
[a]RDT =À8.75 (c=1.00 in CHCl3).
Procedure for the preparation of ethyl 3-(diethoxyphosphoryl)-2-hy-
droxy-6-phenylcyclohexanecarboxylate (12): A solution of 3a (76 mg,
0.2 mmol) in CH2Cl2 (1 mL) was added to a solution of CaCl2 in MeOH
(0.4m, 1.5 mL). The mixture was left stirring for approximately 30 min at
RT, after which it was cooled to À308C and NaBH4 was added
(0.30 mmol, 11.4 mg). The reaction was left stirring for 45 min (followed
by TLC), diluted with Et2O (2 mL), and quenched with aqueous 1m
0.6 mL NaHSO3. The phases were separated and the aqueous phase ex-
tracted two times with CH2Cl2 (20 mL), the organic phases were collect-
ed, dried over MgSO4 and concentrated in vacuo. The residue was puri-
fied by FC on Iatrobeads to afford the compound 12.
white solid (m.p. 63–668C) in 39% yield (over
2
steps). 1H NMR
(CDCl3): d=12.43 (s, 1H), 7.27 (d, J=7.3 Hz, 2H), 7.19–7.15 (m, 3H),
5.96 (s, 1H), 5.26 (s, 1H), 4.10–4.00 (m, 3H), 2.42–2.36 (m, 1H), 1.98 (dt,
J=3.6, 15.0 Hz, 1H), 2.08–2.00 (m, 1H), 1.80–1.76 (m, 1H), 1.00 ppm (t,
J=7.2 Hz, 3H); 13C NMR (CDCl3): d=172.7, 165.2, 144.8, 138.2, 128.0
(2ꢁ), 127.6 (2ꢁ), 125.9, 116.6, 110.9, 60.5, 39.4, 31.0, 26.1, 13.8 ppm;
HRMS: m/z calcd for [C16H18O3Na]+: 281.1154; found: 281.1158; the ee
was determined by HPLC analysis using a Chiralcel OJ column (hexane/
iPrOH 93:7): flow rate 1.0 mLminÀ1
; tmajor =4.3 min, tminor =4.9 min
(97% ee); [a]RDT =+ 58.21 (c=0.52 in CHCl3).
Preparation of ethyl 2-hydroxy-3-methylene-4,6-diphenylcyclohex-1-ene-
carboxylate (16b): A solution of 3a (75 mg, 0.197 mmol) in THF (2 mL)
was added dropwise to a solution of CuI (46.0 mg, 0.24 mmol) and
PhMgBr (1m in THF, 0.24 mL, 0.24 mmol) in THF (2 mL) at 08C. The
reaction was stirred at this temperature for 1 h. The mixture was acidified
with 1m HCl (8 mL) and extracted with CH2Cl2 (4x10 mL). The com-
bined organic layers were washed with brine, dried (MgSO4), and concen-
trated in vacuo. The residue was dissolved in THF (1 mL), and formalde-
hyde (aq 37%, 0.180 mL, 2.4 mmol) and a solution of K2CO3 (83 mg,
0.6 mmol) in H2O (1 mL) were added to this solution. The resulting mix-
ture was stirred at RT overnight and then quenched with aqueous sat.
NaCl solution (10 mL) and extracted with CH2Cl2 (3ꢁ15 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in vacuo.
Compound 16b was isolated by FC using Iatrobeads (CH2Cl2/Et2O 4:1),
as a colorless oil in 44% yield (over 2 steps) as a mixture of diastereoiso-
mers (>95:5). Major diastereoisomer: 1H NMR (CDCl3): d=12.59 (s,
1H), 7.31–7.26 (m, 4H), 7.23–7.19 (m, 4H), 7.11 (dd, J=1.5, 8.0 Hz, 2H),
6.15 (s, 1H), 4.89–4.88 (m, 1H), 4.12–4.05 (m, 3H), 3.55 (ddd, J=2.4, 5.7,
12.5 Hz, 1H), 2.40 (dt, J=5.4, 12.9 Hz, 1H), 1.98 (dt, J=3.4, 12.9 Hz,
1H), 1.02 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=172.7, 165.3,
144.4, 143.1, 142.3, 128.5 (2ꢁ), 128.4 (2ꢁ), 128.1 (2ꢁ), 127.6 (2ꢁ), 126.6,
126, 119.1, 101.4, 60.6, 41.1, 38.6, 38.5, 13.9 ppm; minor diastereoisomer:
1H NMR (400 MHz, CDCl3): d=12.39 (s, 1H), 5.91–5.90 (s, 1H), 4.51–
(1S,2R,3R,6R)-Ethyl 3-(diethoxyphosphoryl)-2-hydroxy-6-phenylcyclo-
hexanecarboxylate (12a; minor diastereomer): Compound 12a was iso-
lated by FC using Iatrobeads (EtOAc/Pen 70:30), as a colorless solid
(m.p. 85–888C) in 20% yield. 1H NMR (CDCl3): d=7.28–7.22 (m, 2H),
7.21–7.13 (m, 3H), 4.42 (brs, 1H), 4.25–4.05 (m, 4H), 3.86 (ddq, J=7.2,
10.8, 24.4 Hz, 2H), 2.80 (dt, J=3.6, 12.0 Hz), 2.58 (t, J=10.4 Hz), 2.11–
2.02 (m, 1H), 2.00–1.86 (m, 2H), 1.70–1.46 (m, 3H), 1.36 (t, J=7.2 Hz,
3H), 1.34 (t, J=7.2 Hz, 3H), 0.81 ppm (t, J=7.2 Hz, 3H); 13C NMR
(CDCl3): d=173.6 (d, JCP =3.9 Hz), 142.2, 128.6 (2ꢁ), 127.6 (2ꢁ), 127.1,
70.6 (d, JCP =4.4 Hz), 62.7 (d, JCP =6.6 Hz), 62.4 (d, JCP =6.4 Hz), 60.5,
3100
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3093 – 3102

Organocatalysis
FULL PAPER
4.49 (m, 1H), 1.05 ppm (t, J=7.1 Hz, 3H); HRMS: m/z calcd for
[C22H22O3Na]+: 357.1467; found: 357.1461; the ee was determined by
HPLC analysis using a Chiralcel OJ column (hexane/iPrOH 90:10): flow
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rate 1.0 mLminÀ1
; =
tmajor =4.6 min, tminor =5.2 min (96% ee); [a]DRT
+38.21 (c=0.78 in CHCl3).
Acknowledgements
This work was made possible by a grant from Danish National Research
Foundation and OChemSchool.
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Received: November 4, 2008
Published online: January 28, 2009
3102
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Chem. Eur. J. 2009, 15, 3093 – 3102