Effect of achiral and mixed chiral ligands on the asymmetric synthesis of γ-nitrophosphonates via Michael addition

Article abstract of DOI:10.1016/j.tetasy.2008.03.006

Changes in the diastereo- and/or enantioselectivity were observed when the Li-cinchonine catalyzed conjugate addition of phosphonates to nitroalkenes was carried out in the presence of achiral/chiral additives. Although the conjugate addition in the absence of such additives proceeded in better yields and selectivities as reported previously, the dramatic change in selectivity in the presence of additives provides an opportunity to synthesize different stereoisomers of the product, γ-nitrophosphonate, using primarily the same chiral source.

Full text of DOI:10.1016/j.tetasy.2008.03.006

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 767–772
Effect of achiral and mixed chiral ligands on the asymmetric
synthesis of c-nitrophosphonates via Michael addition
Vishal Rai and Irishi N. N. Namboothiri*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
Received 7 February 2008; accepted 10 March 2008
Available online 15 April 2008
Abstract—Changes in the diastereo- and/or enantioselectivity were observed when the Li–cinchonine catalyzed conjugate addition of
phosphonates to nitroalkenes was carried out in the presence of achiral/chiral additives. Although the conjugate addition in the absence
of such additives proceeded in better yields and selectivities as reported previously, the dramatic change in selectivity in the presence of
additives provides an opportunity to synthesize different stereoisomers of the product, c-nitrophosphonate, using primarily the same chi-
ral source.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ligands has been reported in the asymmetric alkylation of
aldehydes,5 hydrogenation of imines6 and olefins,7 hydro-
formylation8 and the addition of organozinc reagents to
a-keto esters.9 However, reports on the reversal of enantio-
selectivity by achiral ligands are limited to metal–ligand
catalyzed boronic acid addition to activated olefins,10 olefin
hydrogenation,11 dialkylzinc addition to aldehydes12 and
Diels–Alder reactions.13
The stereoselective synthesis of a molecule in both the
enantiomeric forms is a challenging task if only one of
the enantiomers of the chiral source is easily available.1
Convenient and economical means of overcoming this dif-
ficulty involve controlling the reactivity of the existing chi-
ral source, for example, a ligand–metal complex, via
structural modification2 or via changing the local chiral
atmosphere by employing additional chiral/achiral ligands
that can bind to the metal centre.3 If ligands L1 and L2 are
employed as a mixture, three catalyst combinations, that is,
two homochiral ML1L1, ML2L2 and one heterochiral
ML1L2, that interconvert rapidly are generated and if
the heterochiral combination is more active than the homo-
chiral ones, a new catalyst profile emerges.4 This approach
is particularly attractive because the active catalyst species
is generated in situ by mixing ligands, thus obviating the
need to pre-synthesize and screen numerous ligands for
asymmetric catalysis. Application of such dynamic combi-
natorial libraries of ligand-metal complexes in asymmetric
catalysis is currently attracting considerable interest.3
Non-linear effects due to mixtures of chiral ligands com-
plexed with a metal have been observed in Sharpless asym-
metric dihydroxylation,14 the addition of dialkylzinc to
aldehydes,15 hydrogenation2,4,16,17 and alkylation and
arylation of aldehydes.18 To the best of our knowledge,
inversion of enantioselectivity induced by an auxiliary
chiral ligand remains unreported. Furthermore, besides
one recent example,10 there are no reports on the effect of
achiral and mixed chiral ligands on ligand-metal catalyzed
Michael addition to activated alkenes.
2. Results and discussion
The role of achiral ligands in enhancing the reactivity and
selectivity in asymmetric reactions has been investigated by
several groups in recent years.3,5–13 Thus, catalysis by
metal-ligand complexes containing both achiral and chiral
Recently, we reported the lithiated cinchonine catalyzed
diastereo- and enantioselective synthesis of c-nitrophosph-
onates by the Michael addition of phosphonates to nitro-
alkenes (Scheme 1).19 Herein, we report on the dramatic
catalytic role of achiral ligands and the mixture of chiral
ligands which enabled us to synthesize various stereoiso-
mers of c-nitrophosphonates in a selective fashion. Whilst
*
Corresponding author. Tel.: +91 22 2576 7196; fax: +91 22 2576 7152;
e-mail: irishi@iitb.ac.in
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.006

768
V. Rai, I. N. N. Namboothiri / Tetrahedron: Asymmetry 19 (2008) 767–772
EtO
EtO
O
LDA (3 equiv), THF
P
O OEt
P OEt
L1 (50 mol %)
Ar
Ar
+
Ar'
NO2
-78ºC (8 h) to rt (10 h)
Ar'
1
2
3
NO2
Scheme 1. Michael addition of phosphonates 2 to nitroalkenes 1.
the same chiral source in the presence of different achiral
ligands has been employed in the first approach, the second
approach utilized heterochiral species generated from a
mixture of pseudoenantiomers.20
crown-4 A5 provided improved yields without affecting
the stereoselectivity (Table 1, entries 4–6). Surprisingly,
the addition of NMM A6 to the precatalyst, that is, L1–
Li complex, provided low yields (25%), and caused a rever-
sal of enantioselectivity (10:90 er, (S,S)-major isomer)
whilst maintaining good diastereoselectivity (92:08 dr,
Table 1, entry 7). Encouraged by such a reversal of enantio-
selectivity, we employed other achiral additives such as
DMAP A7 and diethyl ether A8 (Table 1, entries 8–10).
Although the yields improved with DMAP A7 and diethyl
ether A8 as additives, both the diastereo- and enantioselec-
tivities dropped considerably (Table 1, entries 8–9). At this
point, we decided to employ diethyl ether A8 as a solvent in
the place of THF and were pleased to note the enhance-
ment of selectivity (Table 1, entry 10). More importantly,
Herein, cinchonine–Li was used as the precatalyst under
typical reaction conditions (Scheme 1). In our mixed ligand
approach using achiral additives, A1–A8 (Fig. 1) were used
in conjunction with cinchonine L1 (Table 1). First of all, in
the absence of any additives, high yield, diastereo- and
enantioselectivities were obtained as reported earlier (Table
1, entry 1).19 Similar stereoselectivities, but low yields were
obtained when TMEDA A1 and HMPA A2 were used as
achiral additives (Table 1, entries 2 and 3). Other additives,
such as ethylenediamine A3, ethylene glycol A4 and 12-
O
P
Me2N
NMe2
H2N
NMe2 Me2N
NH2
Ethylenediamine, A3
NMe2
A1
TMEDA,
HMPA, A2
N
OH
O
NMe2
O
O
O
O
HO
OH
OH
Ethylene
glycol, A4
N
O
N
N
N
N
Diethyl
L1
L2
A8
12-Crown-4, A5 NMM, A6 DMAP, A7 ether,
(+)-Cinchonine,
(-)-Cinchonidine,
Figure 1. Catalysts and additives.
Table 1. Achiral ligand effect in the cinchonine–Li complex catalyzed Michael addition of benzyl phosphonate 2a to p-chloronitrostyrene 1a
Cl
EtO
EtO
O
O OEt
P
LDA (3 equiv), THF
L1
Cl
P
OEt
(50 mol %)
+
Achiral ligand (10 mol%)
-78 °C (8 h) to rt (10 h)
NO2
3a
2a
1a
NO2
Entry
Additive, A1–A8
% Yielda
drb
erb,c
1
2
3
4
5
6
7
8
9
None
TMEDA A1
HMPA A2
Ethylenediamine A3
Ethylene glycol A4
12-Crown-4 A5
NMM A6
DMAP A7
Diethyl ether A8
Diethyl ether A8e
81
15
17
56
55
44
25
51
60
55
96:04
92:08
97:03
97:03
97:03
97:03
92:08
85:15
82:18
94:06
100:0 (R,R)d
100:0 (R,R)
100:0 (R,R)
100:0 (R,R)
100:0 (R,R)
99:01 (R,R)
10:90 (S,S)
21:79 (S,S)
20:80 (S,S)
0:100 (S,S)
10
a Isolated yield.
b Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane).
c For the major diastereomer.
d The absolute configuration of 3a was determined by X-ray crystallography, see Ref. 19.
e Used as solvent without any THF.

V. Rai, I. N. N. Namboothiri / Tetrahedron: Asymmetry 19 (2008) 767–772
769
Table 2. Mixed chiral ligand effect in the alkaloid–Li complex catalyzed Michael addition of benzyl phosphonate 2a to p-chloronitrostyrene 1a
Cl
EtO
EtO
O
LDA (3 equiv), THF
L1+L2
O OEt
P
Cl
(50 mol %)
P
OEt
+
-78 °C (8 h) to rt (10 h)
70-80% yield
NO2
3a
2a
1a
NO2
Entry
L1:L2
dra
er (R,R):(S,S)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
100:0
95:05
90:10
80:20
75:25
70:30
60:40
50:50
40:60
30:70
20:80
10:90
05:95
0:100
96:04
94:06
98:02
>99:<1
100:0
100:0
99:01
86:14
97:03
96:04
96:04
97:03
98:02
98:02
100:0
07:93
02:98
<1:>99
0:100
0:100b
<1:>99
05:95
<1:>99
04:96
02:98
06:94
08:92
100:0c
a Ratio was determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane) whilst the absolute configuration of 3a was determined by X-ray
crystallography, see Ref. 19.
b When this reaction was carried out in ether, the selectivities were, respectively, 97:3 dr and 95:5 er (no reversal, but more (S,S)-isomer was formed with
respect to entry 1).
c When this reaction was carried out in ether, the selectivities were, respectively, 100:0 dr and 0:100 er (reversal).
entries 1 and 10 (Table 1) reveal that the two enatiomers
(R,R) and (S,S) could be synthesized with absolute enantio-
selectivity by performing the reaction in two different sol-
vents, THF and ether, respectively.14
Subsequently, we proceeded to screen a mixture of chiral
ligands, namely cinchonine L1 and cinchonidine L2. Inter-
estingly, in the presence of 50 mol % of either of these
pseudoenantiomeric catalysts L1 or L2, the same (R,R)-
enantiomer of the product 3a was formed (Table 2, entries
1 and 14). This unusual result suggested that the stereo-
chemistry at C-8 and C-9 in L1 and L2 has no influence
on the selectivity. In other words, the stereoinducing region
of the chiral ligand is away from the site of reaction in this
case.21 A possible involvement of dimeric or oligomeric
Figure 2. Non-linear effect as a result of mixture of chiral ligands.
assemblies of the catalyst, which are in dynamic equilib-
rium with the monomer, being the active catalyst species,
appears quite likely in this case (vide infra).20
compositions of L1 and L2 having any bearing on the
selectivity can be ruled out. Therefore, the main reason
for this non-linear effect appears to be the greater activity
of the heterochiral catalyst assembly over the homochiral
assembly which forms the inactive reservoir. Of course, this
phenomenon arises from the structure of the catalyst com-
plex and its kinetic behaviour.17
We further investigated the influence of the L1/L2 ratio on
the selectivity (Table 2 and Fig. 2). A notable reversal in
the selectivities was observed when mixtures of L1 and
L2 in different ratios were employed. For instance, entries
2–13 (Table 2) show the formation of the opposite (S,S)-
enantiomer of 3a as the major or exclusive isomer over a
wide range of L1:L2 ratios. The presence of even small
amounts of the pseudoenantiomeric catalyst was sufficient
to reverse the selectivity (Table 2, entries 2 and 13), that
is, L2 controlled the selectivity in the entire range of L1/
L2 ratio (95:5 to 5:95).22 Since both the pseudoenantiomer-
ic ligands L1 and L2 independently provide the same (R,R)
enantiomer, and the mixture of L1 and L2, over a wide
range of ratios (95:5 to 5:95), provides the opposite isomer,
the difference in kinetic behaviour of L1 and L2 or different
The diastereo- and enantioselectivities are relatively low at
a L1:L2 ratio of 50:50 which gradually increase whilst
going towards either end, though the overall effect is mar-
ginal (Fig. 2).
Having developed achiral and mixed chiral ligand methods
for the synthesis of c-nitrophosphonate 3a in both the
enantiomeric forms using our model substrates 1a and 2a
(Tables 1 and 2), we proceeded to investigate whether

770
V. Rai, I. N. N. Namboothiri / Tetrahedron: Asymmetry 19 (2008) 767–772
our methods would be suitable for the selective synthesis of
stereoisomers of other c-nitrophosphonates 3b–e, by
screening representative substrates, nitroalkenes 1a–c and
phosphonates 2a–c (Table 3). First of all, the results of Ta-
bles 1 and 2 are summarized in entries 1–3, Table 3. Whilst
the original experiment (L1/50 mol %, THF, method 1)19
provides the (R,R)-isomer of 3a in excellent yield and selec-
tivity (entry 1, Table 3), the (S,S)-isomer could be obtained
under two different conditions (methods 2 and 3). When
ether is used as achiral ligand + solvent with L1
(50 mol %) as the chiral catalyst (method 2), the yield
drops, whilst the selectivities remain high (Table 3, entry
2). On the other hand, the mixed chiral ligand method
(L1:L2 = 70:30/50 mol %, THF, method 3) provided the
(S,S)-isomer in high yield and absolute selectivity (entry
3, Table 3). The results obtained for 3b (entries 4–6) and
3c (entries 7–9) are as follows. The best yields and dr’s were
obtained by method 1 (Table 3, entries 4 and 7). Interest-
ingly, a reversal of dr was observed (from (R,R) + (S,S)
to (R,S) + (S,R)) in the case of 3b and 3c by both the
methods (methods 2 and 3, Table 3, entries 5–6 and 8–9).
However, analysis of the minor diastereomer (entries 5–6
and 8–9 in parentheses) showed no appreciable change in
enantioselectivity under the conditions of methods 2 and
3, as compared to method 1 in the case of 3b, but a dra-
matic reversal in the case of 3c.
10–15, Table 3). As in the case of 3a and 3c, a reversal of
enantioselectivity was observed for 3d by method 2. In
stark contrast, there was no change in selectivity when
method 3 was employed. Although there was no reversal
in the case of 3e, an enhancement in selectivity for the
minor enantiomer under the conditions of methods 2 and
3 was observed (Table 3, entries 13–15).
Preliminary analysis of the phosphonate 2a–Li complex
and the phosphonate 2a–Li–alkaloid complex using 31P
NMR suggests the involvement of higher order catalyst
species. For instance, benzyl phosphonate 2a appears as a
sharp peak at d 25.89 in the 31P NMR spectrum. Upon
treatment with LDA, three peaks resonating at d 28.04,
32.46 and 45.83 are observed in an integration ratio of
9.4:53.9:36.5. Whilst the peak at d 28.04 is sharp, the other
two are broad, indicating that the peaks at d 32.46 and
45.83 represent the two tautomeric forms of lithiated benz-
yl phosphonate. The sharp peak at d 28.04 in all probabil-
ity is a relatively stable and symmetrical complex. This
lithiated phosphonate on treatment with cinchonidine L2
presumably leads to the formation of the 2a–Li–L2 com-
plex. Examination of the spectrum reveals that one of the
tautomers of lithiated 2a remains as such (d 32.43), whilst
the other formed a complex with L2. More importantly,
two new peaks appeared at d 27.71 and 28.30, and the peak
for free 2a reappeared at d 25.77. These two new peaks in a
ꢀ1:3 ratio can be attributed to 2a–Li–L2 complexes.
Although the structure and geometry of the complexes
Subsequently, c-nitrophosphonates 3d and 3e were pre-
pared under the conditions of methods 2 and 3 (entries
Table 3. Michael addition of phosphonates 2a–c to various nitroalkenes 1a–c23
EtO
O
P
O OEt
P OEt
EtO
Method 1: L1 (50 mol %), THF
LDA (3 equiv)
-78 ºC (8 h) to rt (10 h)
Ar
Ar
Ar'
Method 2: L1 (50 mol %), Diethyl ether
Method 3: L1:L2(70:30, 50 mol %), THF
NO2
Ar'
+
1
2
3
NO2
1a: Ar = p-ClPh
2a: Ar' = Ph
3a: Ar = p-ClPh, Ar' = Ph
3d: Ar = Ph, Ar' = Ph
1b: Ar = p-OMePh
1c: Ar = Ph
2b: Ar' = p-ClPh
2c: Ar' = Naph
3b: Ar = p-OMePh, Ar' = Ph 3e: Ar = p-ClPh, Ar' = Naph
3c: Ar = p-ClPh, Ar' = p-ClPh
Entry
3
Ma
% Yieldb
drc (d1:d2)d
erc,e
Major diastereomer
Ligand effect
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
M1
M2
M3
M1
M2
M3
M1
M2
M3
M1
M2
M3
M1
M2
M3
81
55
78
99
51
81
69
42
44
95
52
64
74
42
46
96:04
94:06
100:0
88:12
11:89
41:59
100:0
22:78
37:63
68:32
94:06
62:38
0:100
39:61
18:82
100:0
0:100
0:100
91:09
62:38 [88:12]e
100:0 [98:02]e
100:0
83:17 [25:75]e
96:04 [25:75]e
99:01
(R,R):(S,S)f
(R,R):(S,S)
(R,R):(S,S)
(R,R):(S,S)
(R,S):(S,R) or (S,R):(R,S) [(R,R):(S,S)]d,e
(R,S):(S,R) or (S,R):(R,S) [(R,R):(S,S)]d,e
(R,R):(S,S)
(R,S):(S,R) or (S,R):(R,S) [(R,R):(S,S)]d,e
(R,S):(S,R) or (S,R):(R,S) [(R,R):(S,S)]d,e
(R,R):(S,S)
(R,R):(S,S)
(R,R):(S,S)
(R,S):(S,R) or (S,R):(R,S)
(R,S):(S,R) or (S,R):(R,S)
(R,S):(S,R) or (S,R):(R,S)
3a
er reversal
er reversal
3b
3c
3d
3e
dr reversal [er no major change]
dr reversal [er no major change]
dr reversal [er reversal]
dr reversal [er reversal]
34:66
100:0
100:0
86:14
er reversal
No major change
dr and er enhancement for minor
dr and er enhancement for minor
74:26
a Method.
b Isolated yield.
c Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane).
d d1:d2 = [(R,R) + (S,S)]:[(R,S) + (S,R)].
e er of minor diastereomer in parenthesis.
f The absolute configuration of 3a was determined by X-ray crystallography whilst for 3b–e, it was based on comparison of the 1H NMR chemical shifts
for the CH2NO2 group, see Ref. 19.

V. Rai, I. N. N. Namboothiri / Tetrahedron: Asymmetry 19 (2008) 767–772
771
9. Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2005, 127, 15453.
10. Duursma, A.; Pena, D.; Minnaard, A. J.; Feringa, B. L.
Tetrahedron: Asymmetry 2005, 16, 1901.
11. Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593.
12. Lutz, F.; Igarashi, T.; Kawasaki, T.; Soai, K. J. Am. Chem.
Soc. 2005, 127, 12206.
are a matter of speculation, the ratio of (Li–2a–L2):
(2a+Li–2a) = 11.07:88.93 = 1:8 suggests that the catalyst
complex could be oligomeric in nature. Investigations are
currently underway to better understand the exact nature
of the catalyst species.
13. (a) Desimoni, G.; Faita, G.; Invernizzi, A. G.; Righetti, P.
Tetrahedron 1997, 53, 7671; (b) Kobayashi, S.; Ishitani, H. J.
Am. Chem. Soc. 1994, 116, 4083; (c) Naraku, G.; Hori, K.;
Ito, Y. N.; Katsuki, T. Tetrahedron Lett. 1997, 38, 8231.
14. Zhang, S. Y.; Girard, C.; Kagan, H. B. Tetrahedron:
Asymmetry 1995, 6, 2637, to the best of our knowledge, this
paper is also the only example, which describes a dramatic
solvent effect on enantioselectivity.
15. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6327.
16. (a) Huck, W.-R.; Mallat, T.; Baiker, A. Catal. Lett. 2003, 87,
241; (b) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed.
2000, 39, 3889.
17. Blackmond, D. G.; Rosner, T.; Neugebauer, T.; Reetz, M. T.
Angew. Chem., Int. Ed. 1999, 38, 2196.
18. Bolm, C.; Muniz, K.; Hildebrand, J. P. Org. Lett. 1999, 1,
491.
19. Rai, V.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2007, 18, 2719.
3. Conclusions
In conclusion, the effect of achiral and a mixture of chiral
ligands on the stereoselectivity in the conjugate addition
of phosphonates to nitroalkenes has been investigated.
Amongst the various achiral additives screened, in conjunc-
tion with a cinchonine–Li complex as the catalyst, diethyl
ether turned out to be superior to others when used as an
additive as well as a solvent, providing stereoisomers differ-
ent from the ones obtained in THF, often with a reversal of
enantioselectivity. When a pseudoenantiomeric mixture of
catalysts (cinchonine/cinchonidine 70:30) was used, similar
change in selectivity was observed indicating the kinetic
advantage of heterochiral complexes in controlling the ste-
reochemical outcome. The major advantage of these
approaches over traditional approaches in asymmetric
catalysis is that the catalyst can be optimized by utilizing
achiral ligands and the mixture of chiral ligands offering
flexibility and ready access to a diverse array of potential
catalysts. Detailed investigations to determine the exact
origin of the selectivity change/reversal,24 and the applica-
tion of this strategy to other reactions are currently under-
way in our laboratory.
20. Reviews on NLE: (a) Girard, C.; Kagan, H. B. Angew.
Chem., Int. Ed. 1998, 37, 2922; (b) Kagan, H. B. Synlett 2001,
888; (c) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402.
21. For a computational mapping study to determine regions of
stereoinduction around chiral catalysts: Lipkowitz, K. B.;
D’Hue, C. A.; Sakamoto, T.; Stack, J. N. J. Am. Chem. Soc.
2002, 124, 14255.
22. For a similar observation in a hydrogenation reaction
involving (a) cinchonidine (CD) and quinidine (QD), see:
Huck, W.-R.; Mallat, T.; Baiker, A. Adv. Synth. Catal. 2003,
345, 255; (b) cinchonidine (CD) and PhOCD, see Ref. 2.
23. General procedure for methods 1–3: A solution of LDA
(1.5 mmol) in solvent (1.5 ml) was prepared by dropwise
addition of n-BuLi (0.95 ml, 1.5 mmol, 1.6 M solution in
hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in
solvent (1.5 ml) at 0 °C followed by stirring for 30 min at the
same temperature. To this freshly prepared LDA, cooled to
À78 °C, phosphonate 2 (0.5 mmol) was added dropwise.
After stirring the reaction mixture for 1 h, cinchonine L1
(74 mg, 0.25 mmol, for methods 1 and 2) or cinchonine
L1 + cinchonidine L2 (52 + 22 mg, 70:30, 0.25 mmol, for
method 3) in solvent (1 ml) was added and the reaction
mixture was stirred for an additional 30 min. Subsequently,
nitroalkene 1 (0.75 mmol) in solvent (1 ml) was added to the
reaction mixture and the temperature was maintained at
À78 °C for an additional 8 h. The reaction mixture was
warmed to ambient temperature and stirring continued for
10 h. The reaction mixture was quenched with saturated
aqueous NH4Cl (2 ml), further saturated with NaCl and
extracted with ethyl acetate (3 Â 5 ml). The combined organic
layers were washed with brine (5 ml), dried over anhyd
Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (ethyl acetate/pet ether,
0–50%, gradient elution). The solvent was THF for methods 1
and 3, and diethylether for method 2.
Acknowledgements
The authors thank DST, India, for financial assistance.
V.R. thanks CSIR, India, for a senior research fellowship.
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Mehler, G. Angew. Chem., Int. Ed. 2003, 42, 790.
5. Lurain, A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005,
70, 1262.
6. Reetz, M. T.; Bondarev, O. Angew. Chem., Int. Ed. 2007, 46,
4523.
24. In order to test the possible reversibility of the reaction and
its influence on the stereoselectivity, we treated diastereo- and
enantiomerically pure (S,S)-3a with LDA/cinchonine L1
under standard conditions (see Ref. 23). Analysis of the
reaction mixture by 1H NMR showed the presence of two
diastereomers of 3a, 4-chloronitrostyrene 1a and benzyl
phosphonate 2a in a 56:02:21:21 ratio. This means that 26%
7. (a) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard,
A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A.
H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed.
2005, 44, 4209; (b) Reetz, M. T.; Li, X. G. Angew. Chem., Int.
Ed. 2005, 44, 2959.
8. Reetz, M. T.; Li, X. G. Angew. Chem., Int. Ed. 2005, 44, 2962.

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of the product 3a underwent reverse reaction to the starting
product (in the presence of excess of one of the starting
materials, for example, nitroalkene, as in our original
experiment, the equilibrium is further shifted towards the
product). In other words, under our experimental conditions,
the diastereo- or enantioselectivity reversal does not seem to
take place to any significant extent via a reverse reaction and
readdition.
materials whereas 2% of 3a epimerized. Further HPLC
analysis showed that the major diastereomer of 3a (56%)
consisted of (S,S)- and (R,R)-isomers in 99:1 ratio and the
minor diastereomer (2%), (R,S) + (S,R) or (S,R) + (R,S), in
86:14 ratio. We conclude from these results that although the
reaction is reversible, the equilibrium is in favour of the