Naplephos: a modular library of chiral phosphines based on d-glucose for highly enantioselective asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2010.01.005

Simple functionalisation of N-acetylglucosamine produces the modular ligand library naplephos, which combines the performance of 'privileged' ligands based on 1,2-trans-cyclohexanediamine with flexibility and accessibility. With the proper choice of substituents, the basic structure was suitably adapted to the Pd-catalysed asymmetric allylic alkylation of rac-(E)-1,3-diphenyl-2-propenyl acetate with dimethyl malonate, producing the (S)-product in ee's of up to 96% ee.

Full text of DOI:10.1016/j.tetasy.2010.01.005

Tetrahedron: Asymmetry 21 (2010) 171–176
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Naplephos: a modular library of chiral phosphines based on D-glucose
for highly enantioselective asymmetric catalysis
*
Vincenzo Benessere, Francesco Ruffo
Dipartimento di Chimica ‘Paolo Corradini’, Università di Napoli ‘Federico II’, Complesso Universitario di Monte S. Angelo, Via Cintia, I-80126 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 November 2009
Accepted 18 January 2010
Simple functionalisation of N-acetylglucosamine produces the modular ligand library naplephos, which
combines the performance of ‘privileged’ ligands based on 1,2-trans-cyclohexanediamine with flexibility
and accessibility. With the proper choice of substituents, the basic structure was suitably adapted to the
Pd-catalysed asymmetric allylic alkylation of rac-(E)-1,3-diphenyl-2-propenyl acetate with dimethyl
malonate, producing the (S)-product in ee’s of up to 96% ee.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
6
MeO
O
5
3
4
1
2
Homogeneous enantioselective catalysis is a fundamental tech-
nology for the production of fine chemicals.1 In addition to the
choice of the active metal, crucial for its effective application is
the accurate design of the chiral ligand, which must exhibit a sui-
ted and well-defined structure for orienting the stereochemistry of
the reaction.
O
O
OBz
O
O
HN
R
Ph2P
naplephos
Figure 1. General formula of naplephos ligands.
Accordingly, in 2002 Jacobsen2 a few selected ligands of wide
and proven applicability indicated as privileged. Over the years,
this original class of privileged ligands has been gradually ex-
tended to include other effective structures, and in 2008, the Al-
drich Chemical Company has reviewed3 an entire class
comprising more than 30 structures.
O
O
O
O
[Pd/L]
O
O
(a)
(b)
(c)
N
NHTs TsNH
A strategy from our group was focussed on the attainment of
effective chiral ligands by simple and immediate derivatisation of
Ts
common carbohydrates,4 for example,
D-glucose. This successful
R
O
O
[Cu/L]
ZnR2
approach5 has produced the modular ligands’ library naplephos
as shown in Figure 1, which combines the essential structural mo-
tifs of the ‘privileged’ ligands based on 1,2-trans-cyclohexanedi-
amine3 with increased flexibility and accessibility. In fact, by
proper choice of the R residue, the basic structure naplephos has
been already effectively adapted5b,c to two different enantioselec-
tive processes, affording in all cases the chiral product in high
ee’s (reactions a and b in Scheme 1). Herein we report its successful
application in another relevant reaction, that is, the asymmetric
allylic alkylation6 (AAA) as depicted by reaction c in Scheme 1,
which demonstrates the versatility of the structure and its aptitude
to afford chiral ligands of broad and established applicability.
C5H11
Me
C5H11
Me
CH(CO2Me)2
Ph
AcO
Ph
[Pd/L]
NaCH(CO2Me)2
Ph
Ph
1
2
Scheme 1. Pd-catalysed desymmetrisation of meso-diols (a), Cu-catalysed addition
of dialkylzinc to enones (b), allylic alkylation of (E)-1,3-diphenyl-2-propenyl acetate
with dimethyl malonate.
2. Results and discussion
The distinctive structure of the naplephos ligands is clearly
defined, and is optimised for both synthetic convenience and
catalytic performance (Scheme 2). Starting from inexpensive
* Corresponding author. Tel.: +39 0816 74460; fax: +39 0816 74090.
E-mail address: ruffo@unina.it (F. Ruffo).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.005

172
V. Benessere, F. Ruffo / Tetrahedron: Asymmetry 21 (2010) 171–176
HO
HO
HO
HO
O
O
6
6
6
O
O
(i)
5
3
MeO
O
5
3
(ii)
5
3
4
1
2
4
1
2
OH
O
OCH2Ph
O
4
1
2
OCH2Ph
O
HN
HO
HN
HO
HN
HO
Me
Me
Me
3
5
4
(iii)
O
O
6
MeO
O
5
3
O
6
4
1
O
OBz
O
MeO
2
5
3
(iv)
4
1
2
O
OCH2Ph
HN
HO
NH2
HO
Ph2P
7
6
(iii)
O
6
a, R= o-C6H4-PPh2
b, R= Me
MeO
O
5
3
4
1
2
O
O
OBz
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
Scheme 2. Synthesis of naplephos ligands. Reagents and conditions: (i) BzOH, H+; (ii) 4-MeO–C6H4–CHO, ZnCl2; (iii) KOH, EtOH; (iv) o-C6H4–PPh2–CO2H, DCC, DMAP; (v)
RCO2H, DCC, DMAP.
N-acetylglucosamine, C1 is selectively benzylated at the
a
-position
to a cone angle within 120–126° (entries 5–7). Further enlarge-
ment decreases both the activity and the selectivity (entries 8–9).
The presence of an additional stereocenter in the ester group R
has little effect on the catalyst performance. In fact, similar enanti-
oselectivity and conversion rate were observed when using naple-
phos-f and naplephos-g (entry 5 vs entry 6), which only differ in
the configuration of this substituent [R = (R)-CH(Et)Ph and (S)-
CH(Et)Ph, respectively]. In other words, the significant steric role
of the substituent is independent of its configuration.
Thus, best results were obtained with naplephos-h, which
afforded the product in 91% ee under the given experimental con-
ditions. Naplephos-h was therefore selected for further refinement
of the results, as reported in Table 2.
The performance of the catalyst could be greatly improved upon
by increasing the ligand/Pd ratio (entries 1–3), and the conversion
was complete in only 10 min with an ee of 96% when 4 equiv of li-
gand was added (entry 3). The addition of a tetrabutylammonium
salt (entry 6) increases the enantioselectivity although the reaction
rate did decrease.
(i in Scheme 2), thus avoiding a tedious separation of anomers.
Positions 4 and 6 are protected with a 4-MeO-benzylidene ring
(ii in Scheme 2), which stabilises the chair conformation of the su-
gar ring, with possible consequent benefit for the outcome of the
catalysis.5c At the same time, this protection can also be easily re-
moved if a different functionalisation is desired.
At the 2-position, a rigid coordinating diphenylphosphinoamido
arm (iii and iv in Scheme 2) is introduced, which reproduces the
essential coordinating feature of the privileged Trost ligand.3 The
ester R group is the only variable (v in Scheme 2), and is chosen
according to the type of catalytic reaction. When R is again a
diphenylphosphino function, the corresponding naplephos-a can
be productively applied in both the Pd-catalysed desymmetrisa-
tion of meso-diols5c (ee up to 98%) and the Cu-catalysed addition
of dialkylzinc to enones5b (ee up to 95%).
Within this study, by selecting an R among the simple alkyl and
aryl groups (b–l, see Scheme 2), we demonstrate that the fine tun-
ing of their steric hindrance produces high enantioselectivity in the
prototypical Pd asymmetric allylic alkylation (AAA) of rac-(E)-1,3-
diphenyl-2-propenyl acetate 1 with dimethylmalonate (reaction c
in Scheme 1).7
All the ligands, naplephos(b–l), were characterised via NMR
spectroscopy. The sugar protons were assigned according to both
their expected chemical shifts and the consistence of the coupling
constants within the glucose ring.
The catalytic results are collected in Table 1. After some preli-
minary runs, the ligand/Pd ratio was conveniently set to 2:1 in
most of the experiments (see below). All the reactions were com-
plete within a few hours, affording 2 as the only product. A neat
trend was observed, in that both the conversion and the enantiose-
lectivity showed a clear dependence upon the steric hindrance of
the ester substituent in 3 (Table 1 also reports both the cone an-
gles8 and the Charton parameters9,10 of the R group). The gradual
increase in the dimension of the R group along the series naple-
phos-b through naplephos-h (entries 1–9) enhances the perfor-
mance of the catalyst, reaching a maximum which corresponds
The performance of the catalyst was nearly identical when
the chloride ion was preliminarily precipitated as a silver salt
(entry 4), while the generation of the nucleophile by using BSA
resulted in lower reaction rates and ee’s (entries 7 and 8).
A key argument for the interpretation of the results collected in
Tables 1 and 2 is the strong dependence of the catalyst’s perfor-
mance on (i) the ligand/palladium ratio (entries 1–3 of Table 2)
and (ii) the steric hindrance of the R group at the 3-position.
Therefore, some experiments were addressed to study the coor-
dination modes of naplephos-h as a function of the ligand/Pd ratio.
In the first test, 1 equiv of naplephos-h was added to a THF-d8
solution of the cationic precursor [Pd(THF-d8)n(g
3-C3H5)]+(TfOÀ).11
The following pieces of diagnostic evidence were observed in the
NMR spectra of the resulting complex:
– A shift at high frequency (d 8.82) of the NH signal in the proton
spectrum with respect to the free ligand (d 7.70).
– The presence of a single resonance at d 23.3 in the P spectrum.

V. Benessere, F. Ruffo / Tetrahedron: Asymmetry 21 (2010) 171–176
173
Table 1
Asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethylmalonatea
No.
Ligand
Cone angleb (°)
Charton parameterb
Conversionc (%)
Time (h)
eed (S) (%)
1
2
3
4
5
6
7
8
9
Naplephos-b
Naplephos-c
Naplephos-d
Naplephos-e
Naplephos-f
Naplephos-g
Naplephos-h
Naplephos-i
Naplephos-j
Naplephos-k
Naplephos-l
87
106
115
118
121
121
126
136
144
0.52
0.70
99
99
99
99
99
99
99
99
50
99
50
8
5
2
2
2
2
2
18
18
18
18
39
85
87
89
91
86
91
80
80
45
60
1.24
1.18
1.18
1.25
10
11
a
b
c
Reaction conditions: rt, 0.25 mmol of substrate, 0.75 mmol of dimethylmalonate, 0.75 mmol of NaH, 0.0050 mmol of [Pd(
Relative to the R substituent at the carbonyl -position. Taken, respectively, from Refs. 8 and 9.
Evaluated by NMR spectroscopy of the crude reaction mixture.
l-Cl)(g
3-C3H5)]2, 0.022 mmol of naplephos.
a
d
Determined by HPLC on Chiracel OD-H, using 2-propanol/hexane 2:98, 1.0 mL/min, UV, 254 nm.
Table 2
Asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethylmalonate and naplephos-h as liganda
No.
Nucleophile
L/Pd
Additive
Conversionb (%)
Time (h)
eec (S) (%)
1
2
3
NaCH(CO2Me)2
NaCH(CO2Me)2
NaCH(CO2Me)2
NaCH(CO2Me)2
NaCH(CO2Me)2
NaCH(CO2Me)2
BSA/CH2(CO2Me)2
BSA/CH2(CO2Me)2
1.1:1
2:1
4:1
2:1
2:1
2:1
2:1
2:1
—
—
—
—
99
99
99
99
99
70
99
99
18
2
0.2
2
2
4
80
91
96
90
93
95
70
86
4d
5e
6
—
f
Bu4NBF4
KOAcg
LiOAcg
7
8
5
5
a
b
c
d
e
f
Reaction conditions: rt, 0.25 mmol of substrate, 0.75 mmol of nucleophile, 0.0050 mmol of [Pd(
Evaluated by NMR spectroscopy of the crude reaction mixture.
Determined by HPLC on Chiracel OD-H, using 2-propanol/hexane 2:98, 1.0 mL/min, UV, 254 nm.
The catalyst was treated with a stoichiometric amount of AgBF4 prior the addition of the reagents.
Reaction conditions: rt, 0.10 mmol of substrate, 0.30 mmol of nucleophile, 0.0050 mmol of [Pd(l-Cl)(
0.75 mmol.
l
-Cl)(
g
3-C3H5)]2.
g
3-C3H5)]2.
g
0.010 mmol.
– A shift at high frequency from d 169.4 to d 173.2 of the amido
carbonyl group in the carbon spectrum.
from d 8.82 to the original region at around d 7.7 was also
observed.
This finding strongly indicates12a competitive coordination of
two phosphines in a C2-symmetrical fashion affording a more
active catalytic species when the ligand/Pd ratio is equal to two
or higher.
According to previous literature,7a,12a,13,14 all these features do
clearly indicate P,O-chelation through the amide carbonyl function
at the 2-position (Fig. 2), and, hence, in the presence of only 1 equiv
of ligand, the active species are plausibly cationic chelated com-
By combining these pieces of evidence with the aforementioned
dependence of the enantioselectivity on the hindrance of R, the
results can be interpreted by assuming that two phosphines coor-
plexes [Pd(
g
3-allyl)(P,O-naplephos)]+.
dinate as illustrated in I, which represents the most active p-allyl
intermediate of the catalytic cycle (Scheme 3).6d
According to the mechanism proposed by Pfaltz for C2-symmet-
rical ligands,6d the enantioselectivity originates from the different
rates of nucleophilic attacks (i and ii) at the allyl carbon termini.
These are governed by the rotation6d of the allyl fragment to give
H
O
N
P
O
g
2-fashion in P1
O
O
(S)-2 and (R)-2, respectively, coordinated in an
O
Ar
Pd
O
and P2. In this case, it is clear how the attainment of P2 is hampered
by steric repulsion between the substituents on (R)-2 and R, and, as
a consequence, a gradual increase of the cone angle of R regularly
favours the formation of (S)-2.
OBz
Figure 2. Structure of complex [Pd(
g
3-C3H5)(P,O-naplephos-h)]+.
More interesting within this context is what happened upon the
addition of the second equivalent of ligand to [Pd(
3-C3H5)(P,O-
Furthermore, in the P,P-coordination mode, the N–H units are
available for hydrogen-bond interactions with the carbonyl nucle-
ophile, an additional feature which can be beneficial for both rate
and selectivity.15
This is also in agreement with the fact that the R group is steri-
cally effective, but stereochemically inactive (see above, entry 5 vs
entry 6), and with the observation that the enantioselectivity of the
reaction is mainly governed by the pocket created by the chiral
ligands.
g
naplephos-h)]+, because these are the conditions which largely
favour both conversion and ee (e.g., entry 1 vs entry 2 of Table 2).
The immediate phosphorous spectrum displayed the signal of
the free ligand at d À9.5, along with the aforementioned signal at
d 23.3. On standing, the former signal gradually decreased, while
a new singlet at d 28.5 grew. After a few hours this was by far
the prevailing species. The contemporaneous shift of the NH signal

174
V. Benessere, F. Ruffo / Tetrahedron: Asymmetry 21 (2010) 171–176
Ar Ar
Ar
O
O
O
O
O
O
H
H
H
O
O
O
O
O
O
BzO
BzO
BzO
O
O
O
HN
HN
HN
O
O
O
(i), k1
(ii), k2
Ph2P
Ph
Ph2P
Ph
Ph2P
PPh2
NH
PPh2
NH
PPh2
NH
Pd
Ph
Pd
Ph
Pd
Ph
(R)
(i)
Nu- Nu-
(S)
(ii)
Ph
O
O
O
O
O
O
Nu
Nu
OBz
OBz
OBz
O
O
O
O
O
O
H
H
H
O
O
O
O
Ar
O
Ar
O
Ar
P1
I
P2
Scheme 3. Possible intermediates in the allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate by using 2 equiv of naplephos ligands.
The fact that very large substituents (cone angle of R >126°)
lower the performance of the catalysts can be ascribed to the poor
enantioselective processes, affording in all cases the chiral product
in high ee’s. This demonstrates the convenience and the flexibility
of the ligand structure, and its prospective ability for a wider and
established applicability.
coordination ability of the crowded ligands. In fact, when the cat-
ionic precursor [Pd(THF-d8)n(g
3-C3H5)]+(TfOÀ) was treated with
2 equiv of naplephos-j, very slow coordination was seen by the
recording spectra. This means that under catalytic conditions the
active species are present at very low concentration, which is in
agreement with the observed reduction of the rate of reaction
(e.g., entry 7 vs entry 8 in Table 1).
4. Experimental
4.1. General considerations
Notably, the importance of the sugar backbone for the catalyst’s
performance was confirmed by preparing ligand 8 based on trans-
(1S,2S)-aminocyclohexanol (Fig. 3),16 which reproduces the essen-
tial coordinating features of naplephos-h. By using 8, product (S)-2
was again obtained in 91% ee, but the conversion was only 25%
after 18 h (compare with entry 2 of Table 2). This demonstrates
the prominent role played by the sugar scaffold (and its substitu-
ents) in enhancing the activity of the catalysts.
NMR spectra were recorded in CDCl3 (CHCl3, d 7.26, and 13CDCl3
d 77, as internal standards) with a 200 and 300 MHz spectrometers
(Varian Model Gemini). 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-
kin–Elmer Polarimeter (model 141) at 298 K and 589 nm in chloro-
form (c 1.0 g/100 mL). Benzyl-4,6-O-[(4-MeO)-benzylidene]-2-
deoxy-2-amino-a-D-glucoside 6 was prepared according to litera-
ture methods.5c THF was distilled from LiAlH4, dichloromethane
from CaH2.
4
2
5
1
6
3
O
O
HN
O
4.2. Preparation of 7
Ph2CH
Ph2P
A solution of 6 (1.22 g, 2.0 mmol), 2-diphenylphosphinobenzoic
acid (2.0 mmol), 4-dimethylaminopyridine (0.024 g, 0.2 mmol) and
1,3-dicyclohexylcarbodiimide (0.82 g, 4.0 mmol) in dry dichloro-
methane (20 mL) was stirred for 12 h at room temperature under
an inert atmosphere to afford a suspension. The residue was re-
moved by filtration. The resulting solution was evaporated under
vacuum, and the residue was chromatographed on silica gel (2:1
ethyl acetate/hexane) affording the pure product as a white solid
(yield: 85%).
8
Figure 3. Formula of (1S,2S)-2-[(diphenylphosphino)benzoyl]amino cyclohexyl
diphenylacetate 8.
3. Conclusion
The simple functionalisation of commercially available N-ace-
tylglucosamine provides an efficient library of chiral ligands naple-
phos. Along with an anomeric
a-benzyl group and the rigid
Detailed presentation of physical data for 7: [a] = +6.7 (c 1,
3
CHCl3); selected 1H NMR data: 6.41 (d, 1H, JNH–H2 = 9.2 Hz, NH),
benzylidene ring in C4 and C6, the distinctive feature of the ligands
is a coordinating diphenylphoshino arm in the equatorial 2-posi-
tion. Esterification at the 3-position with readily accessible carbox-
ylic acid RCO2H allows us to functionalise the ligands with fine
control of the steric hindrance.
3
5.70 (s, 1H, OCHO), 5.05 (d, 1H, JH1–H2 = 4.2 Hz, H1), 4.80 (d, 1H,
2Jgem = 11.7 Hz, CHHPh), 4.58 (d, 1H, CHHPh), 4.52 (dt, 1H, 3JH2–H3
=
3
2
10.2 Hz, H2), 4.35 (dd, 1H, JH6eq–H5 = 4.2 Hz, JH6eq–H6ax = 9.0 Hz,
3
H6eq), 4.07 (t, 1H, JH3–H4 = 10.2 Hz, H3), 4.02 (dt overlapped, 1H,
3JH5–H4 = 3JH5–H6ax = 9.9 Hz, H5), 3.97 (s, 3H, OMe), 3.91 (t, 1H,
H4), 3.80 (t, 1H, H6ax); selected 13C NMR data: d = 170.0, 102.2,
By the appropriate choice of the R residue, the basic structure
naplephos has already been effectively adapted to three different

V. Benessere, F. Ruffo / Tetrahedron: Asymmetry 21 (2010) 171–176
175
3
97.4, 82.0, 70.9, 70.0, 69.2, 63.3, 55.5, 55.2. Anal. Calcd for
C40H38NO7P: C, 71.10; H, 5.67; N, 2.07. Found: C, 70.89; H, 5.45;
N, 2.11.
(dt, 1H, JH5–H4 = 3JH5–H6ax = 10.0 Hz, H5), 3.80 (s, 3H, OMe), 3.72
3
(t, 1H, H4), 3.66 (t, 1H, H6ax), 3.51 (t, 1H, JH–H = 7.4 Hz, CHEtPh),
3
2.10 (m, 1H, CHHMe), 1.71 (m, 1H, CHHMe), 0.75 (t, 3H, JH–
H = 8.0 Hz, Me); selected 13C NMR data: d = 174.6, 168.5, 101.2,
98.1, 79.4, 70.4, 69.8, 68.9, 63.3, 55.5, 53.5, 52.7, 26.5, 12.2. Anal.
Calcd for C50H48NO8P: C, 73.07; H, 5.89; N, 1.70. Found: C, 73.22;
H, 5.83; N, 1.61.
4.3. General procedure for the preparation of naplephos(b-l)
ligands
A solution of 7 (1.15 g, 2.0 mmol), the appropriate RCO2H acid
(2.5 mmol), 4-dimethylaminopyridine (0.24 g, 2.0 mmol) and 1,3-
dicyclohexylcarbodiimide (0.82 g, 4.0 mmol) in dry dichlorometh-
ane (10 mL) was stirred for 12 h at room temperature under an in-
ert atmosphere affording a suspension. The residue was removed
by filtration. The resulting solution was evaporated under vacuum,
and the residue was chromatographed on silica gel (1:2 ethyl ace-
tate/hexane) affording the pure product as a white solid (yield: 80–
85%).
Detailed presentation of physical data for naplephos-g:
3
[
a
] = +41.1 (c 1, CHCl3); selected 1H NMR data: 6.38 (d, 1H, JNH–
3
H2 = 9.5 Hz, NH), 5.66 (s, 1H, OCHO), 5.64 (t, 1H, JH3–H2 = 3JH3–
3
H4 = 10.4 Hz, H3), 5.07 (d, 1H, JH1–H2 = 3.6 Hz, H1), 4.82 (d, 1H,
2Jgem = 12.0 Hz, CHHPh), 4.70 (dt, 1H, H2), 4.61 (d, 1H, CHHPh),
3
2
4.35 (dd, 1H, JH6eq–H5 = 4.8 Hz, JH6eq–H6ax = 10.4 Hz, H6eq), 4.07
(dt, 1H, JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5), 3.97 (s, 3H, OMe), 3.94 (t,
1H, H4), 3.92 (t, 1H, H6ax), 3.68 (t, 1H, JH–H = 7.2 Hz, CHEtPh),
3
3
3
2.52 (m, 1H, CHHMe), 1.93 (m, 1H, CHHMe), 0.98 (t, 3H, JH–
Detailed presentation of physical data for naplephos-b:
H = 7.2 Hz, Me); selected 13C NMR data: d = 170.6, 164.4, 97.4,
95.2, 75.5, 66.3, 64.8, 59.3, 51.3, 49.7, 48.8, 22.9, 8.1. Anal. Calcd
for C50H48NO8P: C, 73.07; H, 5.89; N, 1.70. Found: C, 71.93; H,
5.68; N, 1.81.
3
[
a
] = À7.9 (c 1, CHCl3); selected 1H NMR data: 6.30 (d, 1H, JNH–
H2 = 9.4 Hz, NH), 5.49 (s, 1H, OCHO), 5.42 (t, 1H, JH3–H2 = 3JH3–
3
3
H4 = 9.8 Hz, H3), 4.86 (d, 1H, JH1–H2 = 3.4 Hz, H1), 4.70 (d, 1H,
2Jgem = 11.8 Hz, CHHPh), 4.50 (m, 2H, CHHPh and H2), 4.21 (dd,
Detailed presentation of physical data for naplephos-h:
3
2
1H, JH6eq–H5 = 4.0 Hz, JH6eq–H6ax = 10.0 Hz, H6eq), 3.92 (dt, 1H,
3JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5), 3.80 (s, 3H, OMe), 3.76 (t, 1H,
H4), 3.75 (t, 1H, H6ax), 2.36 (s, 3H, Me); selected 13C NMR data:
d = 169.0, 166.3, 99.3, 95.1, 76.6, 67.7, 66.3, 60.6, 52.8, 50.2, 18.7.
Anal. Calcd for C42H40NO8P: C, 70.28; H, 5.62; N, 1.95. Found: C,
70.48; H, 5.59; N, 1.88.
[a
] = À23.0 (c 1, CHCl3); selected 1H NMR data: d = 6.34 (d, 1H,
3
3JNH–H2 = 9.8 Hz, NH), 5.64 (t, 1H, JH3–H2 = 3JH3–H4 = 10.2 Hz, H3),
3
5.46 (s, 1H, OCHO), 5.16 (s, 1H, CHPh2), 4.95 (d, 1H, JH1–
2
H2 = 3.6 Hz, H1), 4.71 (d, 1H, Jgem = 11.6 Hz, CHHPh), 4.61 (dt, 1H,
3
2
H2), 4.48 (d, 1H, CHHPh), 4.30 (dd, 1H, JH6eq–H5 = 4.6 Hz, JH6eq–
H6ax = 10.2 Hz, H6eq), 3.96 (dt, 1H, JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5),
3
Detailed presentation of physical data for naplephos-c:
3.85 (s, 3H, OMe), 3.75 (t, 1H, H4), 3.75 (t, 1H, H6ax); selected
13C NMR data: d = 173.3, 168.1, 101.3, 97.9, 79.2, 70.7, 70.3, 68.8,
63.3, 56.9, 55.5, 52.5. Anal. Calcd for C54H48NO8P: C, 74.55; H,
5.56; N, 1.61. Found: C, 74.10; H, 5.49; N, 1.62.
[
a
] = +7.8 (c 1, CHCl3); selected 1H NMR data: d = 6.27 (d, 1H,
3
3JNH–H2 = 9.8 Hz, NH), 5.41 (t, 1H, JH3–H2 = 3JH3–H4 = 9.9 Hz, H3),
3
5.40 (s, 1H, OCHO), 4.87 (d, 1H, JH1–H2 = 3.4 Hz, H1), 4.68 (d, 1H,
2Jgem = 11.6 Hz, CHHPh), 4.60 (dt, 1H, H2), 4.47 (d, 1H, CHHPh),
Detailed presentation of physical data for naplephos-i: [a] = -
3
2
3
4.19 (dd, 1H, JH6eq–H5 = 4.4 Hz, JH6eq–H6ax = 9.8 Hz, H6eq), 3.92
28.6 (c 1, CHCl3); selected 1H NMR data: d = 6.25 (d, 1H, JNH–
(dt, 1H, JH5–H4 = 3JH5–H6ax = 10.0 Hz, H5), 3.81, (s, 3H, OMe), 3.76
H2 = 9.6 Hz, NH), 5.55 (t, 1H, JH3–H2 = 3JH3–H4 = 9.4 Hz, H3), 5.39
3
3
3
(t, 1H, H4), 3.72 (t, 1H, H6ax), 3.65 (app d, 2H, CH2Ph); selected
13C NMR data: d = 172.3, 168.7, 101.6, 97.9, 79.8, 70.8, 70.4, 69.0,
63.4, 55.5, 52.9, 41.5. Anal. Calcd for C48H44NO8P: C, 72.62; H,
5.59; N, 1.76. Found: C, 72.87; H, 5.50; N, 1.65.
(s, 1H, OCHO), 4.82 (d, 1H, JH1–H2 = 3.3 Hz, H1), 4.62 (d, 1H,
2Jgem = 11.7 Hz, CHHPh), 4.48 (dt, 1H, H2), 4.42 (d, 1H, CHHPh),
3
2
4.13 (dd, 1H, JH6eq–H5 = 5.1 Hz, JH6eq–H6ax = 10.2 Hz, H6eq), 3.89
(dt, 1H, JH5–H4 = 3JH5–H6ax = 10.2 Hz, H5), 3.85 (s, 3H, OMe), 3.67
3
Detailed presentation of physical data for naplephos-d:
(t, 1H, H4), 3.65 (t, 1H, H6ax), 1.85 (s, 3H, Me); selected 13C NMR
data: d = 175.9, 168.3, 101.7, 98.2, 79.4, 71.0, 70.5, 69.0, 63.4,
57.0, 57.6, 52.7, 27.1. Anal. Calcd for C55H50NO8P: C, 74.73; H,
5.70; N, 1.58. Found: C, 72.28; H, 5.81; N, 1.54.
3
[
a
] = +20.8 (c 1, CHCl3); selected 1H NMR data: 6.35 (d, 1H, JNH–
3
H2 = 10.0 Hz, NH), 5.48 (s, 1H, OCHO), 5.43 (t, 1H, JH3–H2 = 3JH3–
3
H4 = 9.4 Hz, H3), 4.88 (d, 1H, JH1–H2 = 4.2 Hz, H1), 4.68 (d, 1H,
2Jgem = 11.6 Hz, CHHPh), 4.47 (m, 2H, CHHPh and H2), 4.18 (dd,
Detailed presentation of physical data for naplephos-j:
3
2
3
1H, JH6eq–H5 = 4.2 Hz, JH6eq–H6ax = 9.2 Hz, H6eq), 3.89 (dt, 1H,
3JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5), 3.79 (s, 3H, OMe), 3.74 (t, 1H,
H4), 3.70 (t, 1H, H6ax), 2.21 (m, 2H, CH2Cy); selected 13C NMR
data: d = 173.0, 164.4, 99.6, 97.5, 94.0, 75.4, 65.9, 64.9, 59.4, 51.4,
49.9, 38.3, 30.9, 28.9, 21.9. Anal. Calcd for C48H50NO8P: C, 72.07;
H, 6.30; N, 1.75. Found: C, 71.69; H, 6.36; N, 1.82.
[a
] = +14.5 (c 1, CHCl3); selected 1H NMR data: 6.54 (d, 1H, JNH–
H2 = 9.0 Hz, NH), 5.46 (t, 1H, JH3–H2 = 3JH3–H4 = 10.2 Hz, H3), 5.44
3
3
(s, 1H, OCHO), 4.92 (d, 1H, JH1–H2 = 3.3 Hz, H1), 4.66 (d, 1H,
2Jgem = 11.7 Hz, CHHPh), 4.48 (m, 2H, CHHPh and H2), 4.14 (dd,
3
2
1H, JH6eq–H5 = 4.8 Hz, JH6eq–H6ax = 10.2 Hz, H6eq), 3.92 (dt, 1H,
3JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5), 3.74 (s, 3H, OMe), 3.70 (t, 1H,
H4), 3.65 (t, 1H, H6ax), 2.02 (t, 1H, 3JH–H = 6.6 Hz, CHCy2); selected
13C NMR data: d = 175.7, 167.5, 101.7, 97.9, 79.5, 70.3, 69.3, 68.9,
63.2, 57.4, 55.3, 52.9, 36.5. Anal. Calcd for C54H60NO8P: C, 73.53;
H, 6.86; N, 1.59. Found: C, 73.77; H, 6.76; N, 1.55.
Detailed presentation of physical data for naplephos-e: [a] =
3
À2.2 (c 1, CHCl3); selected 1H NMR data: d = 6.47 (d, 1H, JNH–H2
=
=
9.6 Hz, NH), 5.67 (s, 1H, OCHO), 5.59 (t, 1H, JH3–H2 = 3JH3–H4
3
3
10.0 Hz, H3), 4.98 (d, 1H, JH1–H2 = 3.6 Hz, H1), 4.84 (d, 1H,
2Jgem = 11.7 Hz, CHHPh), 4.68 (dt, 1H, H2), 4.63 (d, 1H, CHHPh),
4.22 (dd, 1H, 3JH6eq–H5 = 4.5 Hz, 2JH6eq–H6ax = 9.9 Hz, H6eq), 4.08 (dt,
1H, 3JH5–H4 = 3JH5–H6ax = 10.2 Hz, H5), 3.96 (s, 3H, OMe), 3.91 (t, 1H,
H4), 3.89 (t, 1H, H6ax), 1.29 (s, 9H, t-Bu); selected 13C NMR data:
d = 180.7, 168.4, 101.3, 98.2, 79.6, 70.5, 70.0, 69.0, 63.4, 55.5, 52.8,
39.2, 27.3. Anal. Calcd for C45H46NO8P: C, 71.13; H, 6.10; N, 1.84.
Found: C, 71.46; H, 6.29; N, 1.89.
Detailed presentation of physical data for naplephos-k: [a] = -
3
2.0 (c 1, CHCl3); selected 1H NMR data: 6.38 (d, 1H, JNH–
3
H2 = 9.6 Hz, NH), 5.68 (t, 1H, JH3–H2 = 3JH3–H4 = 10.0 Hz, H3), 5.55
3
(s, 1H, OCHO), 4.91 (d, 1H, JH1–H2 = 3.6 Hz, H1), 4.71 (d, 1H,
2Jgem = 11.8 Hz, CHHPh), 4.66 (dt, 1H, H2), 4.48 (d, 1H, CHHPh),
3
2
4.22 (dd, 1H, JH6eq–H5 = 4.2 Hz, JH6eq–H6ax = 9.6 Hz, H6eq), 4.10
(dt, 1H, JH5–H4 = 3JH5–H6ax = 9.6 Hz, H5), 3.85 (t, 1H, H4), 3.83 (t,
3
Detailed presentation of physical data for naplephos-f:
1H, H6ax), 3.75 (s, 3H, OMe); selected 13C NMR data: d = 168.7,
160.1, 101.4, 97.9, 79.5, 70.7, 70.3, 68.8, 63.3, 55.3, 52.7. Anal. Calcd
for C47H42NO8P: C, 72.39; H, 5.43; N, 1.80. Found: C, 72.73; H, 5.48;
N, 1.84.
3
[
a
] = À16.6 (c 1, CHCl3); selected 1H NMR data: 6.30 (d, 1H, JNH–
3
H2 = 9.6 Hz, NH), 5.43 (t, 1H, JH3–H2 = 3JH3–H4 = 10.0 Hz, H3), 5.33
3
(s, 1H, OCHO), 4.86 (d, 1H, JH1–H2 = 3.6 Hz, H1), 4.65 (d, 1H,
2Jgem = 11.4 Hz, CHHPh), 4.49 (dt, 1H, H2), 4.45 (d, 1H, CHHPh),
Detailed presentation of physical data for naplephos-l:
3
2
4.15 (dd, 1H, JH6eq–H5 = 4.4 Hz, JH6eq–H6ax = 9.8 Hz, H6eq), 3.81
[a =
] = +12.7 (c 1, CHCl3); selected 1H NMR data: 6.26 (d, 1H, 3JNH–H2

176
V. Benessere, F. Ruffo / Tetrahedron: Asymmetry 21 (2010) 171–176
3
9.2 Hz, NH), 5.47 (s, 1H, OCHO), 5.41 (t, 1H, JH3–H2 = 3JH3–H4
=
Acknowledgements
3
9.8 Hz, H3), 4.84 (d, 1H, JH1–H2 = 4.2 Hz, H1), 4.66 (d, 1H,
2Jgem = 11.6 Hz, CHHPh), 4.60 (dt, 1H, H2), 4.47 (d, 1H, CHHPh),
The authors thank MIUR (2007X2RLL2) for financial support
and the CIMCF (Università di Napoli ‘Federico II’) for NMR facilities.
Thanks are also given to Dr. Maria Elena Cucciolito (Dr. Gioia) for
helpful discussion, and Mr. Matteo Lega (Mettiulig) for technical
assistance.
3
2
4.18 (dd, 1H, JH6eq–H5 = 4.4 Hz, JH6eq–H6ax = 9.6 Hz, H6eq), 3.91
(dt, 1H, JH5–H4 = 3JH5–H6ax = 10.0 Hz, H5), 3.80 (s, 3H, OMe), 3.70
3
(t, 1H, H4), 3.65 (t, 1H, H6ax); selected 13C NMR data: d = 168.8,
160.2, 101.4, 97.6, 79.1, 71.9, 70.2, 68.7, 63.2, 55.3, 52.3, 28.0. Anal.
Calcd for C48H39F5NO8P: C, 65.23; H, 4.45; N, 1.58. Found: C, 65.15;
H, 4.44; N, 1.50.
References
1. Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale, 1st ed.; Wiley-
VCH: Weinheim, Germany, 2004.
4.4. Preparation of 8
2. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
3. ChemFiles, Asymmetric Catalysis, Privileged Ligands and Complexes, Vol. 8, Aldrich
Chemical, 2008.
A
solution of 2-(diphenylphosphino)-N-[(1S,2S)-2-hydroxy-
cyclohexyl]benzamide16 (0.46 g, 1.0 mmol), diphenylacetic acid
(0.42 g, 2.0 mmol), 4-dimethylaminopyridine (0.24 g, 2.0 mmol)
and 1,3-dicyclohexylcarbodiimide (0.41 g, 2.0 mmol) in dry dichlo-
romethane (10 mL) was stirred for 12 h at room temperature under
inert atmosphere to afford a suspension. The residue was removed
by filtration. The resulting solution was evaporated under vacuum,
and the residue was chromatographed on silica gel (1:2 ethyl ace-
tate/hexane) affording the pure product as a white solid (yield: 85%).
4. Also other groups are active within this field of research. For reviews, see: (a)
Steinborn, D.; Junicke, H. Chem. Rev. 2000, 100, 4283; (b) Diéguez, M.; Pàmies,
O.; Ruiz, A.; Diàz, Y.; Castillón, S.; Claver, C. Coord. Chem. Rev. 2004, 248, 2165;
(c) Diéguez, M.; Pàmies, O.; Claver, C. Chem. Rev. 2004, 104, 3189; (d) Diàz, Y.;
Castillón, S.; Claver, C. Chem. Soc. Rev. 2005, 34, 702; (e) Diéguez, M.; Claver, C.;
Pàmies, O. Eur. J. Org. Chem. 2007, 4621; (f) Diéguez, M.; Pàmies, O. Chem. Eur. J.
2008, 944; (g) Boysen, M. M. K. Chem. Eur. J. 2007, 13, 8648; Benessere, V.; De
Roma, A.; Del Litto, R.; Ruffo, F. Coord. Chem. Rev. 2009. doi:10.1016/
j.ccr.2009.05.001.
5. (a) Benessere, V.; Del Litto, R.; Ruffo, F.; Moberg, C. Eur. J. Org. Chem. 2009,
1352; (b) De Roma, A.; Ruffo, F.; Woodward, S. Chem. Commun. 2008, 5384; (c)
Benessere, V.; De Roma, A.; Ruffo, F. ChemSusChem 2008, 1, 425.
6. For reviews, see: (a) Tsuji, J. Palladium Reagents in Catalysis. In Innovation in
Organic Synthesis; Wiley: New York, 1995; (b) Trost, B. M.; Van Vranken, D. L.
Chem. Rev. 1996, 96, 395; (c) Johannsen, M.; Jorgensen, A. Chem. Rev. 1998, 98,
1689; (d) Pfaltz, A.; Lautens, M.. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2,
Chapter 24; (e) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (f)
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336; (g) Lu, Z.; Ma, S. Angew.
Chem., Int. Ed. 2008, 120, 258.
Detailed presentation of physical data for 8: [
a] = À59.4 (c 1,
CHCl3); selected 1H NMR data: 5.92 (d, 1H, JNH–H1 = 8.4 Hz, NH),
3
5.04 (s, 1H, CHPh2), 4.66 (dt, 1H, JH2–H1 = 3JH2–H3ax = 12 Hz,
3
3JH2–H3eq = 4.4 Hz, H2), 4.01 (m, 1H, H1); selected 13C NMR data:
d = 173.6, 168.3, 75.3, 57.1, 53.0, 31.6, 30.9, 24.0. Anal. Calcd for
C39H36NO3P: C, 78.37; H, 6.07; N, 2.34. Found: C, 78.89; H, 6.21; N,
2.19.
7. For recent examples of AAA performed with sugar-based ligands, see: (a)
Głegola, K.; Framery, E.; Goux-Henry, C.; Pietrusiewicz, K. M.; Sinou, D.
Tetrahedron 2007, 63, 7133; (b) Johannesen, S. A.; Głegola, K.; Sinou, D.;
Framery, E.; Skrydstrup, T. Tetrahedron Lett. 2007, 48, 3569; (c) Bauer, T.;
Bartoszewicz, A. Polish J. Chem. 2007, 81, 2115; (d) Castillo, A. B.; Favier, I.;
Teuma, E.; Castillón, S.; Godard, C.; Aghmiz, A.; Claver, C.; Gómez, M. Chem.
Commun. 2008, 6197; (e) Głegola, K.; Johannesen, S. A.; Thim, L.; Goux-Henry,
C.; Skrydskrup, T.; Framery, E. Tetrahedron Lett. 2008, 49, 6635; (f) Khiar, N.;
Navas, R.; Álvarez, E.; Fernàndez, I. ARKIVOC 2008, 8, 211; (g) Raluy, E.; Pàmies,
O.; Diéguez, M. Adv. Synth. Catal. 2009, 351, 1648.
4.5. General procedure for the catalytic reaction
With the sodium salt of dimethylmalonate: a solution of [Pd(
l-Cl)-
(g
3-allyl)]2 (0.0020 g, 0.0050 mmol) and the appropriate naplephos
(0.022 mmol) in 0.5 mL of dry THF was stirred under nitrogen for
0.5 h. A solution of (E)-1,3-diphenyl-2-propenyl acetate (0.063 g,
0.25 mmol) in 0.5 mL of the same solvent was then added. After
stirring the resulting light yellow solution for additional 0.5 h, a
solution of the sodium salt of dimethylmalonate (0.116 g,
0.750 mmol) (and the additive when present, see Table 2) in 4 mL
of dry THF was added. After the required reaction time, the system
was quenched by the addition of aqueous ammonium chloride.
The product was extracted with dichloromethane and, after drying
over sodium sulphate, the product was isolated by column chroma-
tography on silica gel (dichloromethane).
8. Taken from: http://www.bu.edu/qale/.
9. (a) Charton, M. J. Am. Chem. Soc. 1969, 91, 615; (b) Charton, M. J. Am. Chem. Soc.
1975, 97, 3691.
10. Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7663.
11. Prepared by mixing [Pd(l-Cl)(g
3-C3H5)]2 with a stoichiometric amount of
AgOTf in 0.6 mL of THF-d8. After filtering AgCl, naplephos-h was added to the
solution affording the complex. The decision to generate a cationic species by
removing the chloride ion from the solution aimed at simulating the catalytic
conditions. In fact, it is likely that in the presence of a large excess of sodium
ions coming from the malonate salt, precipitation of NaCl occurs, affording
cationic Pd compounds, as also proposed by other authors.12
With BSA/dimehylmalonate: a solution of [Pd(l-Cl)(g
3-allyl)]2
12. (a) Tollabi, M.; Framery, E.; Goux-Henry, C.; Sinou, D. Tetrahedron: Asymmetry
2003, 14, 3329; (b) Konovets, A.; Głegola, K.; Penciu, A.; Framery, E.; Jubault, P.;
Goux-Henry, C.; Pietrusiewicz, K. M.; Quirion, J. C.; Sinou, D. Tetrahedron:
Asymmetry 2005, 16, 3183; (c) Amatore, C.; Jutand, A.; Mensah, L.; Ricard, L. J.
Organomet. Chem. 2007, 692, 1457; (d) Marinho, V. R.; Rodriguez, A. I.; Burke, A.
J. Tetrahedron: Asymmetry 2008, 19, 454.
13. Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C. Chem. Commun. 1999,
1707.
14. Mahadik, G. S.; Knott, S. A.; Sezezepura, L. F.; Peters, S. J.; Standard, J. M.;
Hitchcock, S. R. J. Org. Chem. 2009, 74, 8164.
(0.0020 g, 0.0050 mmol) and the appropriate naplephos (0.022
mmol) in 0.5 mL of dry dichloromethane was stirred under nitro-
gen for 0.5 h. A solution of (E)-1,3-diphenyl-2-propenyl acetate
(0.063 g, 0.25 mmol) in 0.5 mL of the same solvent was then added.
After stirring the resulting light yellow solution for additional
0.5 h, a solution of dimethylmalonate (0.0997 g, 0.750 mmol),
BSA (0.152 g, 0.750 mmol) and a pinch of the acetate salt in 2 mL
of dry dichloromethane was added. After the required reaction
time, the system was quenched by the addition of aqueous ammo-
nium chloride. The organic phase was dried over sodium sulphate,
and the product was isolated by column chromatography on silica
gel (dichloromethane).
15. Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P.-O.; Sale, D. A.; Schramm, Y. J.
Am. Chem. Soc. 2009, 131, 9945.
16. For a ligand related to 8, see: Głegola, K.; Midrier, C.; Framery, E.; Pietrusiewicz,
K. M. Phosphorus, Sulfur Silicon 2009, 184, 1065.