New tagged naplephos ligands for asymmetric allylic substitutions under traditional and unconventional conditions

Article abstract of DOI:10.1016/j.tet.2011.05.013

This paper demonstrates the versatility of the class of chiral ligands naplephos, which has been further refined by preparing new 'tagged' versions for selective use in polar media (e.g., ionic liquids). These modified types, along with the best performin

Full text of DOI:10.1016/j.tet.2011.05.013

Tetrahedron 67 (2011) 4826e4831
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New tagged naplephos ligands for asymmetric allylic substitutions under
traditional and unconventional conditions
,
,
,b,
*
Vincenzo Benessere a b, Matteo Lega a b, Alba Silipo c, Francesco Ruffo a
a
ꢀ
Dipartimento di Chimica ‘Paolo Corradini’, Universita di Napoli ‘Federico II’, Complesso Universitario di Monte S. Angelo, via Cintia, 80126 Napoli, Italy
Consorzio Interuniversitario di Reattivita Chimica e Catalisi, Italy
Dipartimento di Chimica Organica e Biochimica, Universita di Napoli “Federico II, Complesso Universitario di Monte S. Angelo, via Cintia, 80126 Napoli, Italy
b
c
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper demonstrates the versatility of the class of chiral ligands naplephos, which has been further
refined by preparing new ‘tagged’ versions for selective use in polar media (e.g., ionic liquids). These
modified types, along with the best performing original varieties, have been examined in two
Pd-catalysed asymmetric processes involving CeC and CeN bond formation. High ees have been ach-
ieved in traditional solvents, while the experiments performed in ionic liquids confirm the difficulty of
predicting the outcome of a reaction in these media and the general decrease in the catalytic
performance.
Received 4 March 2011
Received in revised form 14 April 2011
Accepted 5 May 2011
Available online 12 May 2011
Keywords:
Palladium
Asymmetric catalysis
Carbohydrates
Chiral ligands
Ionic liquids
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
More precisely, in position 2 there is a rigid diphenylphos-
phinoamide arm, essential coordination motif of Trost’s privileged
Homogeneous enantioselective catalysis is a fundamental tech-
nology for the production of fine chemicals.1 Within this field, in-
novative metal catalysts can be rationally prepared by selecting
building blocks for the ligands from the chiral pool. A first benefit of
this approach is the wide choice of natural molecules, which allows
selecting multi-functional building blocks with the same accurate
three-dimensional motifs of the outstanding ‘privileged’ chiral li-
gands.2 A further advantage is the possibility of creating rich libraries
of modular ligands, which present precise differences in the stereo-
chemistry of coordination, in the backbone of the ligand or in both.
In addition, the multi-functional natural scaffold provides ad-
ditional sites for tagging3 the ligand and defining the physical
properties of the catalyst according to the conditions to be used.
Finally, the same multi-functional structure offers hemilabile
coordination sites, which can recognise or attract a substrate, thus
making the catalyst more active and/or selective.4 Within this
framework, we recently prepared the class of ligands naplephos
(Fig. 1).5,6
ligands based on trans-cyclohexanediamine.7 Position 1 shows
a
a
-benzyl (R0¼CH2Ph), of immediate and selective introduction.
Positions 4 and 6, so far protected with a benzylidene ring, are
potentially useful for phase-tagging the ligands and, hence, for
defining the physical properties of the catalyst. Position 3 is
instead useful for introducing tailored steric hindrance next to the
metal centre.
Within previous studies, the naplephos structure has already
been successfully adapted to three different enantioselective
hemilabile coordination sites
O
6
phase tag
O
5
3
4
1
2
O
O
OR'
O
O
HN
R
steric control
The structure of this library, which shows glucose as the natural
building block, has been optimised for combining synthetic via-
bility and high performance in catalysis.
P
Ph Ph
coordinating function
naplephos
* Corresponding author. E-mail address: ruffo@unina.it (F. Ruffo).
Fig. 1. General formula of naplephos ligands.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.013

V. Benessere et al. / Tetrahedron 67 (2011) 4826e4831
4827
processes (Scheme 1), carried out in traditional conditions, thus
giving proof of its versatility.
O
O
O
O
-
O
O
O
6
6
n-Bu4N+
P
O
P
O
5
3
5
3
4
1
2
Cl
OBn
O
4
1
2
OBn
O
O
O
CH(CO2Me)2
AcO
Ph
[Pd/L]
HN
O
HN
O
NaCH(CO2Me)2
R
R
(S)
Ph
Ph
Ph
1)
2)
Ph2P
Ph2P
1
2
R= o-C6H4-PPh2: naplephos-a'
R= CHPh2: naplephos-h'
R= o-C6H4-PPh2: naplephos-a"
R= CHPh2: naplephos-h"
O
O
O
(R)
O
[Pd/L]
O
O
N
Fig. 3. Structures of naplephos-a0, naplephos-a00, naplephos-h0 and naplephos-h00.
NHTs TsNH
(S)
Ts
3
4
2. Results and discussion
R
O
O
[Cu/L]
ZnR2
3)
2.1. Synthesis of naplephos-a0, naplephos-a00, naplephos-h0 and
naplephos-h00
(R)
C5H11
Me
C5H11
Me
5
6
Ionic liquids are among the most promising green solvents.9
Although their use does not require specific tagging of the
catalysts, on several occasions10 their affinity for the ionic
liquid has been shown to improve with the polarity of the li-
gands. This also inhibits leaching of the catalyst in the organic
product phase and increases the possibility of further catalyst
re-cycles.
This approach has been pursued during this work, by providing
selected naplephos ligands of appropriate tags (Fig. 3), whose choice
has been dictated by at least three important considerations. First,
the tag must be polar or ionic, for securing solubility in the ionic
solvent. Then, its structure must preserve the conformational
rigidity of the glucose chair, as the benzylidene ring is able to do.
Furthermore, the synthesis must be straightforward and easy to
carry out.
Scheme 1. Pd-catalysed desymmetrization of meso-diols (a), Cu-catalysed addition of
dialkylzinc to enones (b), allylic alkylation of (rac)-(E)-1,3-diphenyl-2-propenyl acetate
with dimethylmalonate.
When R is an alkyl group of suitable steric hindrance (i.e., naple-
phos-h, Fig. 2), the ligands can be used in the asymmetric allylic
alkylation of (rac)-(E)-1,3-diphenylpropenyl acetate (1) with so-
dium malonate catalysed by Pd (ee 96%).5 Instead, if R is a diphe-
nylphosphinoester function (i.e., naplephos-a, Fig. 2), the ligands are
active in the desymmetrization of cyclic diols (3) catalysed by Pd
(ee 98%)8 and in the addition of diethylzinc to enones (5) promoted
by Cu (ee 95%).4
Aiming to demonstrate the versatility of the naplephos structure,
we have further refined the ligands by preparing new ‘tagged’
versions (Fig. 3) for selective use in ionic liquids. These modified
types, along with the best performing original varieties, have been
examined in reactions 1 and 2 of Scheme 1 under traditional and
unconventional conditions.
We devised an approach, which combines these benefits
by introducing a 4,6-phosphate moiety within the sugar ring, as
depicted in Scheme 2.
By reacting the 4,6-deprotected precursors 7 and 8 with POCl3 in
dry dichloromethane, the corresponding 4,6-oxychlorophosphate
compounds naplephos-a0 and naplephos-h0 were isolated in high
yield. Subsequent controlled hydrolysis of the PeCl bond in
a water/dioxane mixture afforded the ionic products naplephos-
a00 and naplephos-h00 as their tetra-n-butylammonium salts. The
choice of this hydrophobic cation was dictated by the aim of
facilitating the synthetic work-up, which involves separation of the
ligand from a water phase.
The ligands were characterised through elemental analysis and
NMR spectroscopy. As anticipated, the 4,6-phosphate ring assumes
a chair conformation,11 which is clearly revealed by the coupling
constants within the sugar protons.
O
6
a, R= o-C6H4-PPh2
MeO
O
5
3
b, R= Me
4
1
2
O
O
OBn
O
c, R= CH2Ph
d, R= CH2Cy
e, R= t-Bu
HN
O
f, R= (R)-CHMe(Ph)
g, R= (S)-CHMe(Ph)
h, R= CHPh2
i, R= CMePh2
j, R= CHCy2
k, R= Ph
R
Ph2P
naplephos
l, R= CH2C6F5
Fig. 2. The library of ligands naplephos.
HO
O
O
O
O
-
O
O
O
6
6
6
n-Bu4N+
O
P
O
5
P
O
5
3
5
3
4
1
4
1
2
HO
O
OBn
O
Cl
OBn
O
4
1
2
OBn
O
3
2
(i)
(ii)
O
O
HN
Ph2P
O
HN
O
HN
O
R
R
R
Ph2P
Ph2P
R= o-C6H4-PPh2: 7
R= CHPh2: 8
R= o-C6H4-PPh2: naplephos-a'
R= CHPh2: naplephos-h'
R= o-C6H4-PPh2: naplephos-a"
R= CHPh2: naplephos-h"
(i) POCl3, Et3N, dichloromethane, 298 K; (ii) n-Bu4NOH, water/dioxane, 298 K
Scheme 2. Synthesis of naplephos-a0, naplephos-a00, naplephos-h0 and naplephos-h00.

4828
V. Benessere et al. / Tetrahedron 67 (2011) 4826e4831
In naplephos-a0 and naplephos-h0 the phosphorous atom of the
save precious chemicals, (iv) confirm the versatility of the ligands,
(v) recycle the metal catalyst. The first conditions can be in prin-
ciple satisfied by using dichloromethane as solvent, since the
reactions can be performed in milder conditions by generating the
nucleophile with BSA.
phosphate ring is stereogenic, and two diastereomers can be in
principle observed in solution. Notably, even though not com-
pletely unexpectedly,12 the NMR spectra reveal that both ligands
exist as a unique diastereomer.
In the 31P NMR spectra the signal typical of a monophosphate
diester group appeared in the range [ꢀ2.5, ꢀ3.5] ppm. In the case of
naplephos-a00 its location was achieved by analysis of 31Pe1H HSQC
spectrum (Fig. S1 of Supplementary data). The 31Pe1H HSQC
showed three groups of cross peaks, two at 31P NMR values of ꢀ7.07
and ꢀ5.15 ppm correlated with proton signals in the aromatic
region and were attributed to the phenylphosphine groups. The
third phosphate group at ꢀ2.49 ppm was linked at O-4 and O-6 of
As for the catalyst recycle, a proven alternative is the use of an
unconventional solvent, such as an inexpensive ionic liquid, capa-
ble of selectively dissolving the metal catalyst.
On this basis, the allylic alkylation of (rac)-(E)-1,3-diphenyl-
propenyl acetate with dimethylmalonate was first performed in dry
dichloromethane by setting the naplephos/Pd ratio to 1:1, and by
generating the nucleophile in the presence of BSA and catalytic
lithium acetate.
A comparison of the results (Table 1) with those obtained in THF
discloses two important trends. First, analogous steric effects hold
true in the two solvents, in that the higher ee is achieved with the
newly described naplephos-h0 ligand (97% ee), while more or less
crowded ligands produce a less enantioriched product.
Furthermore, the effect of the ligand/Pd ratio is reversed. When
ligand/Pd ratios higher than 1:1 were used in dichloromethane,
both conversion and enantioselectivity decreased. This effect is
reproducible, although its origin is not yet clearly explained.13
The steric effect can be reasonably elucidated on the grounds of
both literature results14 and molecular models. It is likely5,13,15 that
the ligands coordinate Pd through the phosphorous atom and the
amido carbonyl oxygen in position 2, and, hence, the expected
oxidative addition of the acetate affords the two diastereomeric
the substituted
a
-GlcN, as testified by the cross peak between this
31P signal at ꢀ2.49 ppm and H-4 and H6eq/ax resonating,
respectively, at 4.51 ppm and 3.92/4.28 ppm. Furthermore, corre-
lations of the phosphodiester group with H5 and H3 were also
visible. The low-field shifts of H4 and H6 were a further confir-
mation of the location of the cyclic phosphate.
As predicted, both neutral and cationic phosphate ligands dis-
play high solubility in the ionic liquid [BMIM]BF4, as well as in
common organic solvents (THF, dichloromethane, chloroform or
toluene).
2.2. Asymmetric allylic alkylation of (rac)-(E)-1,3-
diphenylpropenyl acetate
p
-allyl intermediates Pi1 and Pi2 (as shown for naplephos-h in
Scheme 3).
On the grounds of the acknowledged mechanism,14 nucleophilic
As mentioned in the Introduction section, naplephos ligands
have already been investigated in the asymmetric allylic alkylation
of (rac)-(E)-1,3-diphenylpropenyl acetate with dimethylmalonate.5
In a recent paper,5 we described how both the steric hindrance in 3
and the ligand/Pd ratio were decisive for the enantioselectivity of
the reaction. In fact, naplephos-h produced the (S)-product in ees up
to 96% by increasing the ligand/Pd ratio up to 4:1 with dry THF as
solvent, and by using Na(CHCO2Me)2 as the nucleophile (Table 1).
Although in these conditions the reaction is fast and selective,
we were strongly motivated to assess the performance of the
ligands in other conditions, aiming to (i) use lower and more con-
venient ligand/Pd ratios, (ii) reduce the impact of the process, (iii)
attack of malonate takes place preferentially at the allyl carbon
termini located trans to P, with formation of the corresponding
alkene products Ak1 and Ak2. Enantioselectivity ensues from the
diverse rates of nucleophilic attack. By assuming that the geometry
of the transition state of the attack is close to that of Ak1 and Ak2, it
is reasonable that k1>k2, because Ak2 is selectively hindered by the
ester substituent in position 3. Thus, a bulky R group (i.e., R¼CHPh2)
helps the enantioselectivity, although undue hindrance (e.g.,
R¼CHCy2 of naplephos-j) reduces the catalyst’s performance,
Table 1
Asymmetric allylic alkylation of (rac)-(E)-1,3-diphenyl-2-propenyl acetate with naplephos ligands
no.
Ligand
Cone anglea (ꢁ) (Charton parameter)a
Solvent and conditions
THFc
CH2Cl2
Conversionc (%)
Time (h)
ee(S)b
%
Refs.
1
2
3
4
5
6
7
8
Naplephos-c
Naplephos-c
Naplephos-f
Naplephos-f
Naplephos-g
Naplephos-g
Naplephos-h
Naplephos-h
Naplephos-h0
Naplephos-h00
naplephos-h0
Naplephos-h00
naplephos-h00
Naplephos-i
Naplephos-i
Naplephos-j
Naplephos-j
106 (0.70)
106 (0.70)
121 (1.18)
121 (1.18)
121 (1.18)
121 (1.18)
126 (1.25)
126 (1.25)
126 (1.25)
126 (1.25)
126 (1.25)
126 (1.25)
126 (1.25)
136
99
99
99
50
99
40
99
99
99
d
5
18
2
18
2
85
88
91
95
86
90
91
96
97
d
5
d
This work
5
This work
5
This work
5
This work
This work
This work
This work
This work
This work
5
This work
5
This work
THFc
d
CH2Cl2
THFc
d
CH2Cl2
18
2
THFc
d
CH2Cl2
CH2Cl2
CH2Cl2
18
18
18
18
18
18
18
18
18
18
d
9
d
10
11
12
13
14
15
16
17
e
BMIMBF4
99
30
30
99
99
50
99
0
e
BMIMBF4
67
55
80
96
80
76
1ꢁ recycle
THFc
d
136
144
144
CH2Cl2
THFc
d
CH2Cl2
a
Relative to the R substituent in the carbonyl
Evaluated by NMR spectroscopy of the crude reaction mixture.
Reaction conditions: rt, THF, 0.50 mmol of substrate, 1.5 mmol of dimethylmalonate, 1.5 mmol of NaH, 0.010 mmol of [Pd(
a
position. Respectively taken from Refs. 19 and 20.
b
c
m
-Cl)(m
3-C3H5)]2, 0.040 mmol of naplephos.
-Cl)(
3-C3H5)]2, LiOAc, 0.020 mmol
d
Reaction conditions: rt, dichloromethane, 0.50 mmol of substrate, 1.5 mmol of dimethylmalonate, 1.5 mmol of BSA, 0.010 mmol of [Pd(
m
m
of naplephos.
e
Reaction conditions: rt, [BMIM]BF4, 0.50 mmol of substrate, 2.5 mmol of dimethylmalonate, 2.5 mmol of BSA, 0.010 mmol of [Pd(
naplephos.
m-Cl)(m
3-C3H5)]2, LiOAc, 0.020 mmol of

V. Benessere et al. / Tetrahedron 67 (2011) 4826e4831
4829
H
H
O
O
N
O
N
O
P
O
P
O
O
O
O
Ar
O
Ar
Pd
Pd
Ph
O
O
Ph
Ph
Ph
Pi1
Nu-
Pi2
Nu-
k1
k2
H
H
O
O
N
N
P
O
P
O
O
O
O
O
O
Ar
O
Ar
Pd
Ph
Nu
Pd
O
O
Ph
(R)
(
S
)
Ph
Ph
Ak2
Nu
Ak1
Scheme 3. Possible intermediates in the allylic alkylation of (rac)-(E)-1,3-diphenyl-2-propenyl acetate with dimethylmalonate by using 1 equiv of naplephos ligands.
plausibly because it hampers the carbonyl coordination and the
steric control moves away from the catalytic centre.
2.3. Asymmetric desymmetrization of meso-cyclopenten-2-
ene-1,4-diol
It is interesting to note that the 4,6-oxychlorophosphate naple-
phos-h0 induced the highest enantioselectivity (97% ee, entry 9 of
Table 1), close to the untagged version naplephos-h (96% ee, entry 8).
This demonstrates that the presence of the phase-tag has no effect
on the stereochemistry of the reaction.
Moreover, in dichloromethane naplephos-h gave a better per-
formance compared to THF (96 vs 91% ee, entry 8 vs entry 7), thus
achieving the target of its use in the more convenient 1:1 Pd/ligand
ratio.
Ligand naplephos-a00 was instead investigated in the asymmetric
cyclization reaction that leads to the formation of 4 (Scheme 1).
As mentioned in the Introduction section the untagged version
naplephos-a was already successfully tested under traditional
conditions,8 which allowed to isolate the product in ee up to 98%.
On that occasion we described also the only example so far known
in RTIL for this reaction, which involved the use of 8 as polar ligand,
namely the 4,6-deprotected precursor of naplephos-a. Disappoint-
ingly, in the ionic solvent [BMIM]BF4 the ee dropped to 55%.8
Even on the basis of literature reports, we attributed8 this sig-
nificant reduction to two main factors: (i) the ionic nature of the
solvent, which can play a detrimental effect on the enantiose-
lectivity (on the basis of the acknowledged mechanism for this
reaction) and (ii) the lack of sufficient rigidity in the sugar chair of 8,
due to the absence of the 4,6-benzylidene fragment.
For this second reason, we were very interested to assess the
effect of the cyclic phosphate tag, which combines the due polarity
to the desired rigidity. Quite surprisingly, by using naplephos-a00 the
ee of the reaction was nearly the same, and the product (S,S)-4 was
again isolated in ee of 57%. This result, although not fully appreci-
ated, has the merit of providing clear evidence on the relative im-
portance of the two effects mentioned above. In particular, it can be
interpreted by assuming that the ionic nature of the solvent plays
the dominant role in determining the enantioselectivity of the
reaction.
Instead, lack of activity was evidenced by using naplephos-h00,
which only shows a negative charge in its backbone with respect to
its parent naplephos-h00. This failure is plausibly due to the bulky
counterion n-Bu4Nþ, which in dichloromethane is expected to form
a steady ionic couple with the charged complex.
On the other hand, this ligand, as well its parent naplephos-h0,
could be both used in RTIL due to their high solubility in the ionic
medium. It should be noted that very few examples of asymmetric
allylic alkylation in ionic liquids have been reported so far,16ꢀ18 and
in all cases a marked or even dramatic reduction of both conversion
and enantioselectivity was observed.
According to our assumptions, the presence of the polar phase
tags resulted in prompt dissolution of both naplephos-h0 and
naplephos-h00 (and of the corresponding Pd complexes) in [BMIM]
BF4 where the reactions were performed by adding the substrate
and the nucleophile to a solution of the catalyst at 298 K. After 18 h
the organic product was extracted with diethyl ether and analysed.
The catalyst phase was possibly re-cycled for further runs (Table 1).
Naplephos-h00 produced an acceptable ee, 67% of (S)-product, in
moderate yield (30%), that is, with a certain drop of performance
with respect to the traditional condition (entry 12 vs 9). The first
recycle gave a reproducible behaviour, although accompanied by
a reduction of ee (55%, entry 13).
3. Conclusion
This paper demonstrates the versatility of the naplephos struc-
ture, which has been adapted to asymmetric catalytic processes
involving CeC and CeN bond formation, via Pd promoted allylic
substitution. The multi-functional site offered by the sugar scaffold
has been used to provide the ligands of a polar and ionic tag, thus
making the corresponding catalysts readily soluble in RTIL. In the
Remarkably, naplephos-h0, which was the most effective ligand
in traditional conditions, only afforded a racemic product, even
though in complete conversion (entry 11).

4830
V. Benessere et al. / Tetrahedron 67 (2011) 4826e4831
ionic solvent the results corroborate the pioneering studies
obtained so far for this type of reaction, confirming that the diffi-
culty of predicting the outcome of a reaction is accompanied by
a general lowering of the catalytic activity.
C
46H40ClNO8P2 requires C, 66.39; H, 4.84; N, 1.68]; [
a
] ꢀ38.7 (c 1.0,
CHCl3);
nmax (Nujol): 3462 (NH amide), 1740 (C]O ester), 1663
(C]O amide) cmꢀ1
;
dH 7.4e6.9 (29H), 6.27 (d, 1H, 3JNHeH2¼9.6 Hz,
NH), 5.53 (t, 1H, 3JH3ꢀH2¼3JH3eH4¼10.0 Hz, H3), 5.10 (s, 1H, CHPh2),
4.95 (d, 1H, 3JH1eH2¼3.6 Hz, H1), 4.65(d, 1H, 2Jgem¼3.6 Hz, CHHPh),
4. Experimental
4.58 (d, 1H, CHHPh), 4.47 (dt, 1H, H2), 4.3e4.1 (m, 4H, H4, H5, H6eq,
H6ax); dC 172.89, 168.62, 140e125 (aromatics), 98.25, 79.26, 71.85,
69.94, 69.74, 62.66, 57.17, 52.24; dP ꢀ2.56 (d), ꢀ8.90.
4.1. General considerations
NMR spectra were recorded in CDCl3 (CHCl3
77, as internal standards) with a 200 and 300 MHz (Varian Model
Gemini), a 400 MHz (Bruker DRX-400) and a 600 MHz (Bruker 600
DRX equipped with a cryo probe) spectrometers. 31P NMR experi-
ments were carried out using aqueous 85% phosphoric acid as ex-
d
7.26 and 13CDCl3
4.4. General procedure for the preparation of the tetra-n-
butylammonium salts of the phosphate ligands (naplephos-
a00,-h00)
d
The appropriate 4,6-oxychlorophosphate ligand (naplephos-
a0 or naplephos-h0) (0.40 mmol) was dissolved in dioxane (3 mL)
under stirring at rt. A 40% (w/w) solution in water of tetra-n-
butylammonium hydroxide was added (0.52 g, 0.80 mmol), and
after 1 h the solution was diluted with 10 mL of water and 10 mL of
dichloromethane. The organic phase was extracted with water
(5ꢂ10 mL) and then dried with anhydrous sodium sulfate. The
solvent was evaporated under vacuum affording the pure product
as a white powder (naplephos-a00: 0.40 g, 88%; naplephos-h00: 0.36 g,
86%). Detailed presentation of physical data for naplephos-a00:
[Found: C, 69.82; H, 6.74; N, 2.35. C67H79N2O9P3 requires C, 70.02;
ternal reference (d 0). The following abbreviations were used for
describing NMR multiplicities: s, singlet; d, doublet; dd, double
doublet; t, triplet; dt, double triplet; m, multiplet; app, apparent.
Specific optical rotatory powers [a] were measured with a Per-
kineElmer Polarimeter (model 141) at 298 K and 589 nm in chlo-
roform (c¼1.0 g/100 mL). Naplephos-a,-c,-f,-g,-h,-i,-j5 and 78 were
prepared according to literature methods. THF was distilled from
LiAlH4, dichloromethane from CaH2.
4.2. Preparation of 8
H, 6.93; N, 2.44]; [
a
] þ1.54 (c 1.0, CHCl3); nmax (Nujol): 3462 (NH
A mixture (10 mL) of TFA/water (1:1 v/v) was added to a solution
of naplephos-h (0.74 g, 0.85 mmol) in dichloromethane (10 mL). The
resulting biphasic system was stirred vigorously for 30 min at rt.
After dilution with 10 mL of water and 10 mL of dichloromethane,
sodium carbonate (about 4.6 g) was added slowly up to the end of
the effervescence. The organic phase was extracted with water
(3ꢂ10 mL), dried with anhydrous sodium sulfate and concentrated
(1 mL) under vacuum. The white solid product was precipitated by
adding petroleum ether, washed with petroleum ether and dried
under vacuum (0.54 g, 85%). Detailed presentation of physical data
for 8: [Found: C, 73.64; H, 5.55; N, 1.88. C46H42NO7P requires
amide),1712 (C]O ester),1662 (C]O amide) cmꢀ1
;
dH 8.25 (m,1H),
7.51 (m, 1H), 7.49 (m, 2H), 7.4e7.1 (m, 27H), 6.98 (m, 2H), 6.42 (d,
1H, 3JNHeH2¼9.2 Hz, NH), 5.45 (t, 1H, 3JH3eH2¼3JH3eH4¼10.0 Hz, H3),
3
2
4.88 (d, 1H, JH1eH2¼3.60 Hz, H1), 4.58 (d, 1H, Jgem¼11.6 Hz,
CHHPh), 4.50 (t, 1H, 3JH4eH5¼9.6 Hz, H4), 4.42 (dt, 1H, H2), 4.40 (d,
1H, CHHPh), 4.26 (t, 1H, JH6axeH5¼3JH6axeH6eq¼10.0 Hz, H6ax
)
3
4.00e3.77 (m, 2H, H5, H6eq); dC 171.0, 168.9, 141e129 (aromatics),
77.9, 72.8, 68.7, 67.8, 61.3, 55.5, 32.1, 26.5, 22.1, 16.1; dP ꢀ3.11, ꢀ5.81,
ꢀ8.41. Detailed presentation of physical data for naplephos-h00:
[Found: C, 70.01; H, 7.39; N, 2.72. C62H76N2O9P2 requires C, 70.57; H,
7.26; N, 2.65]; [
a
] þ0.33 (c 1.0, CHCl3); nmax (Nujol): 3432 (NH
C, 73.49; H, 5.63; N, 1.86]; [
a
] ꢀ4.23 (c 1.0, CHCl3); dH 7.4e6.9
amide),1732 (C]O ester),1656 (C]O amide) cmꢀ1
;
dH 7.82 (m, 1H),
3
(m, 29H), 6.26 (d, 1H, JNHeH2¼9.6 Hz, NH), 5.29 (t, 1H,
7.66 (m, 2H), 7.6e7.0 (m, 26H), 6.72 (m, 1H), 6.21 (d, 1H,
3JH3eH2¼3JH3eH4¼8.8 Hz, H3), 5.11 (s, 1H, CHPh2), 4.84 (d, 1H,
3JNHeH2¼9.2 Hz, NH), 5.42 (t,1H, 3JH3eH2¼3JH3eH4¼10.0 Hz, H3), 5.10
3JH1eH2¼3.2 Hz, H1), 4.63 (d, 1H, Jgem¼3.2 Hz, CHHPh), 4.42
2
2
(s, 1H, CHPh2), 4.60 (d, 1H, Jgem¼11.6 Hz, CHHPh), 4.52 (d, 1H,
(d, 1H, CHHPh), 4.38 (dt, 1H, H2), 3.9e3.5 (m, 4H, H4, H5, H6eq
,
3JH1eH2¼3.2 Hz, H1), 4.44 (d, 1H, CHHPh), 4.31 (t, 1H,
H6ax); dC 183.1, 177.6, 150e135 (aromatics), 106.4, 83.9, 80.8, 79.2,
78.2, 71.0, 66.1, 61.1; dP ꢀ8.81.
3JH4eH5¼9.6 Hz, H4), 4.21 (t, 1H, JH6axeH5¼3JH6axeH6eq¼9.2 Hz,
3
H6ax), 4.07 (dt, 1H, H2), 3.98e3.89 (m, 2H, H5, H6eq); dC 173.4, 167.5,
97.6, 75.4, 72.3, 70.3, 66.5, 65.5, 59.0, 56.8, 52.6, 31.6, 24.2, 10.0; dP
ꢀ3.52, ꢀ8.55.
4.3. General procedure for the preparation of the 4,6-
oxychlorophosphate ligands (naplephos-a0,-h0)
The appropriate precursor (7 or 8) (0.72 mmol) was dissolved in
dry dichloromethane (2.5 mL) under stirring at rt. Triethylamine
4.5. NMR spectroscopy for structural assignments of
naplephos-a00
(240
(80
m
L, 1.73 mmol) was added, and then phosphorus oxychloride
m
L, 0.86 mmol). After 1 h, the solution was diluted with 10 mL of
ROESY and NOESY experiments were recorded using data sets
(t1ꢂt2) of 4096ꢂ256 points. Double quantum-filtered phase-sen-
sitive COSY experiments were performed using data sets of
4096ꢂ256 points. TOCSY experiments were performed with spin-
lock times of 100 ms, using data sets (t1ꢂt2) of 4096ꢂ256 points. In
all homonuclear experiments the data matrix was zero-filled in
both dimensions to give a matrix of 4Kꢂ2K points and was reso-
lution enhanced in both dimensions by a cosine-bell function
before Fourier transformation. Coupling constants were de-
termined by 2D phase-sensitive DQF-COSY. HSQC and HMBC ex-
periments were measured in the 1H-detected mode via single
quantum coherence with proton decoupling in the 13C domain,
using data sets of 2048ꢂ256 points. Experiments were carried out
in the phase-sensitive mode. In all heteronuclear experiments the
data matrix was extended to 2048ꢂ1024 points using forward
linear prediction extrapolation.
dichloromethane, and was extracted with water (3ꢂ10 mL). The
organic phase was dried with anhydrous sodium sulfate, and the
solvent was evaporated under vacuum affording the analytically
pure product as a white powder (naplephos-a0: 0.60 g, 90%;
naplephos-h0: 0.51 g, 85%). Detailed presentation of physical data
for naplephos-a0: [Found: C, 66.49; H, 4.71; N, 1.48.
C51H43ClNO8P3 requires C, 66.13; H, 4.68; N, 1.51]; [
CHCl3);
max (Nujol): 3428 (NH amide), 1744 (CꢃO ester), 1663 (C]
O amide) cmꢀ1
a] þ14.9 (c 1.0,
n
;
dH 8.10 (m, 1H), 7.5e6.9 (m, 32H), 6.43 (d, 1H,
3JNHeH2¼9.60 Hz, NH), 5.62 (t, 1H, JH3eH2¼3JH3eH4¼9.96 Hz, H3),
3
4.95 (d, 1H, 3JH1eH2¼3.44 Hz, H1), 4.51 (s, 2H, CH2Ph), 4.80 (dt, 1H,
3
H2), 4.34 (t, 1H, JH4eH5¼9.6 Hz, H4), 4.23e4.00 (m, 3H, H5, H6eq
,
H6ax); dC 168.7, 166.2, 145e125 (aromatics), 98.2, 79.0, 71.9, 69.6,
62.5, 52.7; dP ꢀ2.35 (d), ꢀ5.15, ꢀ8.64. Detailed presentation of
physical data for naplephos-h0: [Found: C, 66.78; H, 4.70; N, 1.75.

V. Benessere et al. / Tetrahedron 67 (2011) 4826e4831
4831
4.6. Allylic alkylation of (rac)-(E)-1,3-diphenylpropenyl
acetate in dichloromethane
solution of [Pd(dba)2] (0.014 g, 0.025 mmol) and ligand
(0.045 mmol) in dry THF (0.9 mL) held at the same temperature.
The orange reaction mixture was stirred for 30 min. The solvent
was removed under vacuum, and column chromatography on silica
gel (1:10 ethyl acetate/hexane) gave the desired product as a white
solid in 80e85% yield. The enantiomeric excesses were determined
by chiral HPLC, Chiracel OD-H, 1:10 isopropanol/hexane, UV
254 nm, retention times: (3R,6S)-4: 22e24 min; (3S,6R)-4:
30e32 min. The absolute configuration was obtained by compari-
son with a sample of known chirality.
A solution of [Pd(m-Cl)(h
3-C3H5)]2 (0.0035 g, 0.010 mmol) and
the appropriate naplephos (0.022 mmol) in 1.0 mL of dry
dichloromethane was stirred under nitrogen for 0.5 h. A solution of
(rac)-(E)-1,3-diphenyl-2-propenyl acetate (0.120 g, 0.50 mmol) in
1.0 mL of the same solvent was then added. After stirring the
resulting light yellow solution for additional 0.5 h, a solution of
dimethylmalonate (165 mL, 1.50 mmol), BSA (355 mL, 1.50 mmol)
and lithium acetate (0.001 g, 0.015 mmol) in 2 mL of dry
dichloromethane was added. After the required reaction time, the
system was quenched by addition of aqueous ammonium chloride.
The organic phase was dried over sodium sulfate, and the product
was isolated by column chromatography on silica gel (dichloro-
methane). The enantiomeric excesses were determined by HPLC on
Chiracel OD-H, using 2-propanol/hexane 2:98, 1.0 mL/min, UV,
254 nm: (R)-2 9.6 min, (S)-2 10.3 min.
In [BMIM]BF4: naplephos-a00 (0.015 mmol) and [Pd(dba)2]
(0.0057 g, 0.010 mmol) were dissolved in [BMIM]BF4 (1 mL) under
vigorous stirring. meso-2-Cyclopenten-1,4-diol-isocyanate (0.043 g,
0.10 mmol) and triethylamine (0.010 g, 0.10 mmol) were added to
the solution, and after 30 min the product was extracted from the
catalytic phase with diethyl ether (3ꢂ15 mL) in 70e80% yield and
analysed.
Acknowledgements
4.7. Allylic alkylation of (rac)-(E)-1,3-diphenylpropenyl
acetate in [BMIM]BF4
ꢀ
The authors thank the CIMCF (Universita di Napoli ‘Federico II’)
for NMR facilities. M.L. thanks the Consorzio Interuniversitario di
A solution of [Pd(m-Cl)(h
3-C3H5)]2 (0.0035 g, 0.010 mmol) and
ꢀ
Reattivita Chimica e Catalisi for a scholarship. Thanks are also given
the appropriate naplephos (0.022 mmol) in 1.0 mL of [BMIM]BF4
was vigorously stirred under nitrogen for 0.5 h. (rac)-(E)-1,3-
Diphenylpropenyl acetate (0.120 g, 0.50 mmol) was then added and
the resulting light yellow solution was stirred for additional 0.5 h.
to Mr. Vincenzo Calcagno (Calcageno) for technical assistance.
Supplementary data
Dimethylmalonate (285 mL, 2.5 mmol), BSA (625 mL, 2.5 mmol) and
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.013.
lithium acetate (0.001 g, 0.015 mmol) were added. After the
required reaction time, the product was extracted with dry diethyl
ether (2ꢂ2 mL), the residual ether was removed by vacuum, and
the recycle was performed in the same condition mentioned above.
The reunified organic phases were evaporated, and the product was
isolated by column chromatography on silica gel (dichloro-
methane). The enantiomeric excesses were determined by HPLC on
Chiracel OD-H, using 2-propanol/hexane 2:98, 1.0 mL/min, UV,
254 nm: (R)-2 9.6 min, (S)-2 10.3 min.
References and notes
1. Asymmetric Catalysis on Industrial Scale, 1st ed.; Blaser, H. U., Schmidt, E., Eds.;
Wiley-VCH: Weinheim, Germany, 2004.
2. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
3. Multiphase Homogeneous Catalysis, 1st ed.; Cornils, B., Herrmann, W. A., Hor-
varth, I. T., Leitner, W., Mecking, S., Olivier-Borbigou, H., Vogt, D., Eds.; Wiley-
VCH: Weinheim, Germany, 2005.
4. De Roma, A.; Ruffo, F.; Woodward, S. Chem. Commun. 2010, 5384.
5. Benessere, V.; Ruffo, F. Tetrahedron: Asymmetry 2010, 21, 171.
6. Also other groups are active within this field of research. For reviews, see: (a)
4.8. Desymmetrization of meso-2-cyclopenten-1,4-diol-
isocyanate in THF
ꢁ
ꢀ
Steinborn, D.; Junicke, H. Chem. Rev. 2000, 100, 4283; (b) Dieguez, M.; Pamies,
ꢀ
ꢁ
O.; Ruiz, A.; Diaz, Y.; Castillon, S.; Claver, C. Coord. Chem. Rev. 2004, 248, 2165;
Without NEt3: Tosyl isocyanate (0.202 g, 1.02 mmol) was added
to a solution of cis-2,4-cyclopentenediol (0.056 g, 0.5 mmol) in dry
THF (0.9 mL). The colourless solution was stirred at rt for 15 min
and at 333 K for 30 min. The reaction mixture was allowed to reach
the desired catalysis temperature (Table 1) and then added drop-
wise to an orange solution of [Pd(dba)2] (0.014 g, 0.025 mmol) and
ligand (0.045 mmol) in dry THF (0.9 mL) held at the same tem-
perature. The orange reaction mixture was stirred for 30 min. The
solvent was removed under vacuum, and column chromatography
on silica gel (1:10 ethyl acetate/hexane) gave the desired product as
a white solid in 80e85% yield. The enantiomeric excesses were
determined by chiral HPLC, Chiracel OD-H, 1:10 isopropanol/hex-
ane, UV 254 nm, retention times: (3R,6S)-4: 22e24 min;
(þ)-(3S,6R)-4: 30e32 min. The absolute configuration was obtained
by comparison with a sample of known chirality.
ꢁ
ꢀ
ꢀ
(c) Dieguez, M.; Pamies, O.; Claver, C. Chem. Rev. 2004, 104, 3189; (d) Diaz, Y.;
Castillon, S.; Claver, C. Chem. Soc. Rev. 2005, 34, 702; (e) Dieguez, M.; Claver, C.;
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Dieguez, M.; Pamies, O.; Woodward, S. Coord. Chem. Rev. 2010, 254, 2007.
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Weinheim, Germany, 2003.
10. See Ref. 3, Chapter 5.
11. Coulter, C. L. J. Am. Chem. Soc. 1976, 98, 4997.
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13. Addition of 1 equiv of naplephos-h to a CD2Cl2 solution of
results in immediate formation of the expected diastereomeric couple of
species [Pd(P, O-naplephos-h)(
3-C3H5)]Cl (31P NMR,
m
-[PdCl(
h
3-C3H5)]2
-allyl
p
h
d
¼27.9 and 27.1). Further
addition of ligand simply causes the growth of the signal pertaining to the free
ligand.
14. Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, Chapter 24.
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2003, 14, 3329.
With NEt3: Tosyl isocyanate (0.202 g, 1.02 mmol) was added to
a solution of cis-2,4-cyclopentenediol (0.056 g, 0.5 mmol) in dry
THF (0.9 mL). The colourless solution was stirred at rt for 15 min
and at 333 K for 30 min. The reaction mixture was allowed to cool
to rt, and triethylamine (0.101 g, 1.00 mmol) was added. The
resulting white slurry was allowed to reach the desired catalysis
temperature (Table 1) and then added dropwise to an orange
ꢁ
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ꢂ
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