Catalytic asymmetric transformations with fine-tunable biphenol-based monodentate ligands

Article abstract of DOI:10.1016/j.tetasy.2005.12.035

A library of new fine-tunable monodentate phosphite and phosphoramidite ligands based on chiral biphenol have been designed and developed. These monodentate phosphorus ligands have exhibited excellent enantioselectivity in the Pd-catalyzed asymmetric allylic alkylation and Rh-catalyzed asymmetric hydrogenation.

Full text of DOI:10.1016/j.tetasy.2005.12.035

Tetrahedron: Asymmetry 17 (2006) 642–657
Catalytic asymmetric transformations with fine-tunable
biphenol-based monodentate ligands
Bruno D. Chapsal, Zihao Hua and Iwao Ojima*
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
Received 29 November 2005; accepted 17 December 2005
Available online 20 March 2006
Abstract—A library of new fine-tunable monodentate phosphite and phosphoramidite ligands based on chiral biphenol have been
designed and developed. These monodentate phosphorus ligands have exhibited excellent enantioselectivity in the Pd-catalyzed
asymmetric allylic alkylation and Rh-catalyzed asymmetric hydrogenation.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
etherification.27,28 It is worth mentioning that the large
majority of these ligands are based on BINOL, TAD-
DOL, spiroindanediol, or achiral biphenol bearing a
chiral alcohol moiety or amine. We have been develop-
ing a new class of chiral monodentate phosphite and
phosphoramidite ligands derived from readily accessible
enantiopure axially chiral biphenol units (Fig. 1).13,17,22
One of the salient features of these novel monodentate
phosphorus ligands is their fine-tuning capability
through modifications of the R1, R2, and R3 groups.
This feature is of critical importance because it allows
a combinatorial approach to finding the most efficient
ligand for a specific reaction or process.
Recently, chiral monodentate phosphorus ligands have
been attracting increasing interest because of their struc-
tural simplicity as well as excellent efficiency in a variety
of catalytic asymmetric transformations. The emergence
of chiral monodentate ligands comes after three decades
of predominance by chiral bidentate ligands with C2-
symmetry, which was often considered as a prerequisite
for efficient asymmetric induction. Currently, the sim-
plicity and ease of the synthesis and structural modifica-
tion of chiral monodentate ligands can be considered as
highly advantageous because these characteristics fit very
well to a combinatorial approach to finding the most
suitable ligand for a particular catalytic asymmetric
transformation. Thus, this approach is now considered
most practical as opposed to developing one universal
and almighty ligand for different types of catalytic asym-
metric reactions. Moreover, it has recently been demon-
strated that using a mixture of chiral monodentate
ligands, through a combinatorial approach, can offer
superior results than the use of single ligand.1–6
R1
R2
R1
R2
3
5
3
5
2 O
2
R3
O
O
6
6
P
OR3
P N
6'
6'
O
R3'
2'
2'
R1 5'
R2
R1 5'
R2
3'
3'
Phosphites
Phosphoramidites
Chiral monodentate phosphorus ligands have been suc-
cessfully applied to a variety of catalytic asymmetric
reactions such as hydrogenation,2,4,7–13 1,4-addition of
dialkylzinc,14–18 and boronic acids5,19 to a,b-conjugated
systems, hydrovinylation,20 hydrosilylation,21 hydro-
formylation,22 allylation of aldehydes,23 intramolecular
Heck reaction,24 allylic alkylation,25,26 amination, and
Figure 1. Biphenol based phosphites and phosphoramidites.
We describe here the applications of these novel mono-
dentate phosphorus ligands with transition metal
catalyst precursors to catalytic asymmetric transforma-
tions, which demonstrate the remarkable advantages
that their fine-tuning capability can offer for achieving
high catalyst efficiency and enantioselectivity. The cata-
lytic asymmetric transformations that are discussed here
are Pd-catalyzed asymmetric allylic alkylation and its
*
Corresponding author. Tel.: +1 631 632 7890; fax: +1 631 632
7942; e-mail: iojima@notes.cc.sunysb.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.035

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
643
application to the total synthesis of enantiopure (+)-c-
lycorane and Rh-catalyzed asymmetric hydrogenation
of dimethyl itaconate.
2.2. Total synthesis of enantiopure (+)-c-lycorane using
Pd-catalyzed asymmetric allylic alkylation in the key step
Catalytic asymmetric allylic substitution provides one of
the most powerful methods for the stereo-controlled for-
mation of carbon–carbon or carbon–heteroatom bonds.
This reaction serves as a reliable method for the synthe-
sis of enantiopure natural and unnatural products.32–35
Extensive studies have been performed to address mech-
anistic issues relevant to the regio- and stereoselectivity
of this reaction.32,36–40 Trost et al. pioneered asymmetric
allylic alkylation reactions using modular ligands based
on C2-symmetrical chiral diamines bearing bis(diaryl-
phosphino)benzoic acid units.41 These ligands have
achieved high efficiency in various systems through
rational modification of the C2-symmetrical diphos-
phine ligand module.33,36 Catalytic asymmetric allylic
substitution reactions have found a wide range of appli-
cations in organic syntheses, to date, along with the de-
sign and development of a variety of chiral ligands for
these reactions.
2. Results and discussion
2.1. Synthesis of monodentate phosphorus ligands
We designed and synthesized a library of chiral mono-
phosphite and monophosphoramidite ligands having
various substituents at the 3,30-positions of the enantio-
pure 6,60-dimethylbiphenol skeleton as well as different
alkoxy, aryloxy, and dialkylamine moieties (Fig. 2).
The enantiopure 6,60-dimethylbiphenols were synthe-
sized following the literature procedure.29 Substituents
at the 3,30-positions were introduced according to the
methods described previously.13 Up to five different
substituents, that is, H, Me, Br, t-Bu, and Ph, have been
introduced onto the biphenol skeleton (Scheme 1). In
general, a biphenol is reacted with an alkoxyphosphor-
ous dichloride or a dialkylaminophosphorous dichloride
in the presence of Et3N in THF at room temperature for
12 h. The amines and alcohols used are commercially
available with the exception of chiral bis[(1-aryl)ethyl]-
amines, which were prepared by a literature method.30,31
The use of chiral monodentate phosphorus ligands in
catalytic asymmetric allylic alkylation has been reported
with an Ir-complex precursor, which generally leads to
the formation of branched products with excellent
R2
R2
R2
R2
R2
Pr-i
Pr-i
Bn
Bn
O
O
O
O
O
O
O
O
O
O
P
N
P
O
P O
P
N
P N
R2
R2
R2
R2
R2
(S)-L2 : R2 = H
(S)-L3 : R2 = H
(R)-L1 : R2 = H
(S)-L16a : R2 = t-Bu
(S)-L16b : R2 = H
(S)-L15a : R2 = t-Bu
(S)-L15b : R2 = H
R2
R2
Ph
N
Ph
R2
R2
O
O
O
O
P
P
N
O
O
P O
O
P O
O
Ph
Ph
R2
R2
R
R
(S,R,R)-L4a: R2 = H
(S,R,R)-L4b : R2 = Me
(S,R,R)-L4c: R2 = Br
(S,R,R)-L4d : R2 = Ph
(S,R,R)-L4e : R2 = t-Bu
2
R2
R2
(R,R,R)-L5a
(R,R,R)-L5b
: R = H
2
: R = Me
(S)-L17a : R2 = t-Bu; R = H
(S)-L17b : R2 = H; R = H
(S)-L17c : R2 = t-Bu; R = Ph
(R )-L18a : R2 = t-Bu; R = H
(R )-L18b : R2 = H; R = H
(R )-L18c : R2 = t-Bu; R = Ph
R2
R2
R2
R3
O
O
O
O
P O
O
P O
O
P N
R3'
(R2=H)
R2
R2
R2
(S)-L19a : R2 = t-Bu
(S)-L20a : R2 = t-Bu
(S)-L20b : R2 = H
(S)-L20c : R2 = Me
(S)-L20d : R2 = Br
(S)-L20e : R2 = Ph
(S,S,S)-L10 : R3 = 2-MeO-Ph; R3' = Ph
(S,S,S)-L11 : R3 = 2-MeO-Ph; R3' = 1-Np
(S,S,S)-L12 : R3 = 2-MeO-Ph; R3' = 2-Np
(S,S,S)-L13 : R3 = o-Tol; R3' = o-Tol
(S)-L19b : R2 = H
(S,S,S)-L6 : R3 = R3' = Ph
(S,S,S)-L7 : R3 = R3' = 1-Np
(S,S,S)-L8 : R3 = R3' = 2-Np
(S,S,S)-L9 : R3 = o-Tol; R3' = Ph
(S,S,S)-L14 : R3 = 2-MeO-Ph; R3' = 2-MeO-Ph
Figure 2. Library of chiral monodentate phosphoramidite and phosphite ligands.

644
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
R2
R2
R3OPCl2 or
(R3)2NPCl2
OH
OH
O
O
P
X
Et3N, THF,
rt, overnight
X = OR3, N(R3)2
R2
R2
Scheme 1. Synthesis of chiral monodentate phosphorus ligands.
regioselectivity.42 However, the corresponding Pd-cata-
lyzed reactions with chiral monodentate phosphorous
ligands have only been poorly explored in spite of the
fact that palladium is the metal of choice for asymmetric
allylic substitution reactions in general.26,43,44 Accord-
ingly, we set out to explore the use of our novel mono-
dentate phosphoramidite ligands in Pd-catalyzed
asymmetric allylic alkylation reactions, especially for
the asymmetric synthesis of a pentacyclic alkaloid, (+)-
c-lycorane.
This short total synthesis appears to have a lot of room
for improvement. Thus, we decided to revisit this pro-
cess by applying a library of our new chiral monoden-
tate phosphoramidite ligands for optimization of the
enantioselectivity and chemical yield and then accom-
plish a highly efficient total synthesis of (+)-c-lycorane.
Prior to investigation into the key step in the (+)-c-
lycorane synthesis, we performed a preliminary study
on the desymmetrization of a meso-dibenzoate, cis-1,4-
dibenzoyloxycyclohex-2-ene, using dibenzyl malonate
as simple nucleophile. Trost et al. previously investi-
gated the desymmetrization of this meso-dibenzoate,50
which provided useful insights into the mechanism of
this reaction as well as the critical enantio-discrimina-
tion that a chiral ligand could exert during the ioniza-
tion step of the catalytic cycle.41,50
(+)-c-Lycorane isolated from the plants of Amaryllida-
cae family belongs to a class of alkaloids that exhibit a
variety of biological activities.44 Due to its unique
pentacyclic structure, (+)-c-lycorane has inspired many
synthetic chemists to develop a number of innovative
approaches toward its total synthesis.44–49 However,
very few approaches to the asymmetric synthesis of this
compound have been reported so far.45,49 In 1995, Mori
et al. reported the first asymmetric synthesis of (+)-c-
lycorane, featuring a Pd-catalyzed allylic alkylation in
the key step, wherein a sequential allylic alkylation,
allylic amination, and Heck reaction led to the target
pentacyclic system (Scheme 2).49 However, the best
enantioselectivity achieved in this key step (step i in
Scheme 2) using (S)-BINAPO was 54% ee, giving 3 in
30% yield (using 2.6 equiv of 2 and LDA). The yield
and enantiopurity of 3 were dependent on the amounts
of 2 and LDA used. Thus, 3 was obtained in 66% yield
and 40% ee on using 1.1 equiv of 2 and LDA. This prod-
uct (40% ee) was used to complete the total synthesis in
17% overall yield. The expedited five-step total synthe-
sis, incorporating one-pot protocol, gave (+)-c-lycorane
with 46% ee in 23% overall yield.
First, a molecular modeling study (Spartan Program,
MM2/PM3) was performed in order to see, which ligand
moiety would play a crucial role in the enantio-discrim-
ination step. It has been shown that the stereo-differen-
tiation of a leaving group occurs before the ionization
step in the catalytic cycle.41,50 Accordingly, we examined
the molecular arrangements of a Pd(0) complex bearing
two molecules of monodentate phosphorous ligand L1
and the meso-dibenzoate. Figure 3 shows the energy
minimized structure of Pd(L*)2(olefin) [L* = (R)-L1; ole-
fin = cis-1,4-dibenzoyloxycyclohex-2-ene].
As Figure 3 illustrates, the Pd(L*)2(olefin) complex
adopts two L1 ligands with C2-symmetrical arrangement
around the Pd metal, and the two dimethylamine moie-
ties are pointing toward the coordination site of the ole-
O
CO2Me
OBz
MeO2C
Br
N
CONH
H
i
+
O
O
Br
OBz
O
O
OBz
3
2
1
O
H
H
H
MeO2C
O
O
N
ii
iii, iv, v
N
O
(+)-(γ)-lycorane
O
4
Scheme 2. Reagents and conditions:49 (i) Pd(OAc)2, (S)-BINAPO, 2 (2.6 equiv), LDA (2.6 equiv), THF/CH3CN, 0 ꢁC, 1 h; (ii) Pd(OAc)2–dppb,
NaH, DMF, 50 ꢁC, 3 h then Et(i-Pr)2N, 100 ꢁC, 5 h; (iii) NaCl (1 equiv), DMSO/H2O; (iv) Pd/C, H2, MeOH; (v) LiAlH4, reflux, 1 h.

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
645
Table 1. Pd-catalyzed asymmetric allylic alkylation–desymmetrization
of 1 with dibenzyl malonate
O
O
[Pd(allyl)Cl]2 (1 mol%)
Ligand (4 mol%)
OBz
BnO
OBn
NaCH(CO2Bn)2 (1.1 eq.)
THF, 0 oC to rt
OBz
OBz
5
1
Entry
Ligand
Conv.a (%)
5 (% ee)b
1
2
3
4
5
(R)-L1
(S)-L2
(S,R,R)-L4a
(R,R,R)-L5a
(R,R,R)-L5b
80
82
70
82
50
28.7 (ꢀ)
48.1 (+)
68.4 (+)
81.3 (ꢀ)
10.8 (ꢀ)
a Determined by 1H NMR.
b Determined by HPLC using a Daicel Chiralpak AD column.
Figure 3. Energy minimized structure of Pd(L*)2(olefin) complex.
fin. It is clearly indicated that the dimethylamine moiety
would play a key role in differentiating the two benzoate
groups. Accordingly, we hypothesized that the stereo-
electronic nature of the amine moiety of our phospho-
ramidite ligands would exert a critical effect on the
enantioselectivity of the desymmetrization reaction.
benzoate leaving groups, and (ii) introduction of methyl
groups at the 3,30-positions of the biphenyl moiety of
L5a (i.e., L5b, R2 = Me) causes a detrimental effect on
the enantioselectivity as well as the conversion of the
reaction. These observations are consistent with indica-
tions based on the molecular modeling of the complex
shown in Figure 3. These preliminary results served as
the starting point of our total synthesis of enantiopure
(+)-c-lycorane.
With this hypothesis in mind, the Pd-catalyzed asym-
metric allylic alkylation–desymmetrization of 1 with
dibenzyl malonate, as a model study, was carried out
for preliminary screening of effective phosphoramidite
ligands. The results are summarized in Table 1. Since
[Pd(allyl)Cl]2 gave better results than Pd(OAc)2 as the
Pd-catalyst precursor, only the results with the use of
[Pd(allyl)Cl]2 are presented.
According to our planned route to (+)-c-lycorane
through revisiting Mori’s first asymmetric synthesis,
it was necessary to prepare nucleophile 2, which is a
malonate half amide. Since the synthesis of 2 was not
reported in Mori’s paper, or anywhere else by literature
search, we synthesized 2 from commercially available
piperonal 6 through the steps shown in Scheme 3. All
attempted reductive amination of 7 to 9 failed because
of a very facile coupling of aldehyde 7 with amine 9
formed in the reaction. Thus, we had to convert 7 to
oxime 8 first, followed by reduction with zinc/HCl, to
obtain 9 in excellent yield. Amine 9 was reacted with
methyl malonyl chloride to give 2 in 86% yield.
As Table 1 shows, a substantial increase in enantioselec-
tivity for the formation of 5 is observed as the size of the
amine moiety of the phosphoramidite ligand increases,
that is, from L1 with the smallest Me2N moiety
(28.7% ee) to L5a with the bulkiest (PhMeCH)2N moi-
ety (81.3% ee) (R2 = H in all cases). It is noteworthy that
(i) the ligands with a (S)-biphenol moiety give the (+)-
enantiomer of 5 as the major product, while that with
a (R)-biphenol moiety affords (ꢀ)-5 as the major prod-
uct, that is, the axial chirality of the ligand controls
the direction of enantio-discrimination of the two
Next, the efficacy of phosphoramidite ligands L4a and
L5a, which gave promising results in the model study
(Table 1), as well as L3 was evaluated in the asymmetric
Br
NOH
H
CHO
Br
O
HCl.H2NOH (1.1 eq.)
NaHCO3 (1 eq.)
Br2 (excess)
H
AcOH/CS2, I2(cat.)
H2O/EtOH
O
O
O
rt, 2 days
70%
rt, 5 h
93%
O
O
O
8
6
7
CO2Me
Br
NH2
ClC(O)CH2CO2Me
(1.2 eq.)
CO
NH
Zn (10 eq.)
O
O
2N HCl, THF
reflux, 2.5 h
91%
Et3N, CH2Cl2
rt, 12 h
O
Br
O
86%
2
9
Scheme 3. Synthesis of nucleophile 2.

646
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
allylic alkylation–desymmetrization reaction of 1 with
‘real’ nucleophile 2. The reactions of 1 were run using
2.6 equiv of 2 and LDA in the presence of Pd-catalyst,
prepared by mixing [Pd(allyl)Cl]2 (2 mol %) with a
ligand (8 mol %), in THF/CH3CN (1:1) at 0 ꢁC. The reac-
tions gave a 54/46 diastereomer mixture of 3 due to
epimerization of the acidic methine of the malonate half
amide moiety. Thus, the additional two steps, leading to
10, were necessary to determine the enantioselectivity of
the reaction. The enantiopurity of 10 was unambigu-
ously determined by chiral HPLC analysis using a Dai-
cel Chiralpak AD-RH column. As Table 2 shows, L5a
gave the best results (68% ee) among the three ligands
examined (entries 1–3) under these conditions. The use
of ligand L5b (R2 = Me) led to almost no conversion,
indicating a detrimental effect of the methyl groups at
the 3,30-positions of the biphenol moiety on the reaction
(entry 4). Accordingly, we carried out the optimization
of reaction conditions using L5a as the ligand. The reac-
tion in THF at ꢀ78 to 0 ꢁC for 12 h (started at ꢀ78 ꢁC
using 1.2 equiv of 2 and LDA, followed by warming up
to 0 ꢁC) gave 3 with 84.4% ee in 95% isolated yield (entry
5). Thus, the solvent and the reaction temperature
appear to have dramatic effects on the reaction. When
the reaction temperature was kept constant at ꢀ60 ꢁC,
the reaction completed in 15 h to give 3 in 93% yield
and 86.2% ee (entry 6). We also examined the effects
of the amounts of 2 and LDA on the reaction in THF
at ꢀ60 ꢁC. The reactions with 2.0 and 2.6 equiv of 2
and LDA gave 3 with 89.5% ee and 92.6% ee, respec-
tively (entries 7 and 8). [Note: L6 (S,S,S) is the enantio-
mer of L5a.] The results indicate that the use of excess
amounts of 2 and LDA increases the enantioselectivity
of the reaction. However, the observed increase
in enantioselectivity is accompanied by a significant
decrease in the yield of 3.
from the second allylic alkylation reaction of 3 with 2.
Naturally, the amount of 11 increases on using excess
2 and LDA. However, how is the increase in the enan-
tiopurity of 3 related to the formation of 11? We believe
that enantiomer-selective kinetic resolution by the chiral
Pd catalyst is taking place in the second allylic alkyl-
ation of 3 with 2. A proposed mechanism is illustrated
in Figure 4.
It is reasonable to hypothesize that the minor enantio-
mer of 3 yielded in the first asymmetric allylic alkylation,
ent-3, reacts with chiral Pd complex much faster than 3
to form the corresponding p-allylic Pd-complex, which
reacts with 2 to afford the dialkylated product 11. This
is because the remaining benzoate group in ent-3 is the
preferred leaving group for the chiral Pd-catalyst.
Accordingly, enrichment of 3 may occur through selec-
tive conversion of ent-3 to 11, but decrease in the yield
of 3 would be inevitably accompanied.
Although it was already a remarkable improvement that
3 was obtained in 93% isolated yield and 86.2% ee as
compared with Mori’s original work (40% ee in 66%
yield or 54% ee in 30% yield),49 we strongly felt that
more improvement would be possible through syste-
matic optimization of L6 (S,S,S), which gives 3 with
the correct absolute configuration for the total synthesis
of (+)-c-lycorane. Accordingly, we designed and synthe-
sized a new optimization library of phosphoramidite
ligand L6 by introducing various C2-symmetric, pseu-
do-C2-symmetric and non-symmetrical N,N-bis(1-aryl-
ethyl)amine moieties bearing different aryl groups,
including those with an ortho substituent (ligands L7–
14, Fig. 2).
For the introduction of ortho substituents to the C2- and
pseudo-C2-symmetric N,N-bis(1-arylethyl)amine moiety
of BINOL-based phosphoramidite ligands, Alexakis
et al. recently reported the markedly favorable effects
of such substituents on the enantioselectivity as well as
We found that the observed decrease in the yield of 3
was associated with the formation of dialkylated prod-
uct 11. This side product 11 was obviously obtained
Table 2. Pd-catalyzed asymmetric allylic alkylation–desymmetrization of 1 with nucleophile 2 using ligands L3, L4a, L5a, L5b, and L6
O
Br
O
O
OBz
MeO2C
[Pd(allyl)Cl]2
Ligand
N
N
Br
i, ii
H
O
2, LDA
OBz
O
O
OBz
1
3
10
Entry
Ligand
2 (equiv)
Conditions
Yielda (%)
10 (% ee)b
1
2
3
4
5
6
7
8
L4a
L3
2.6
2.6
2.6
2.6
1.2
1.2
2.0
2.6
THF/CH3CN, 0 ꢁC to rt, 1.5 h
THF/CH3CN, 0 ꢁC to rt, 1.5 h
THF/CH3CN, 0 ꢁC to rt, 1.5 h
THF/CH3CN, 0 ꢁC to rt, 1.5 h
THF, ꢀ78 to 0 ꢁC, 12 h
THF, ꢀ60 ꢁC, 15 h
46
58
62
31.3 (+)
42.1 (+)
68.0 (ꢀ)
NA
84.4 (ꢀ)
86.0 (ꢀ)
89.5 (+)
92.6 (ꢀ)
L5a
L5b
L5a
L5a
L6
Low conv.
95
93
63
27
THF, ꢀ60 ꢁC, 15 h
L5a
THF, ꢀ60 ꢁC, 20 min
(i) [Pd(allyl)Cl]2, dppb, LDA, CH3CN–THF, ꢀ50 ꢁC to rt, 2.5 h; (ii) NaCl, DMSO–H2O, 175 ꢁC, 2.5 h.
a Isolated yield of 3.
b Determined by chiral HPLC analysis using a Daicel Chiralpak AD-RH column.

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
647
Nu
Nu
– OBz
L*2Pd0
L*2PdII
Nu–
Nu–
L*2PdII
–OBz
OBz
Fast
OBz
Slow
OBz
Nu
ent-3
L*2Pd0
dialkylated
product
Fast
OBz
Nu
11
Nu–
OBz
Slow
L*2PdII
OBz
–OBz
Nu–
L*2Pd0
– OBz
L*2PdII
Nu
Nu
3
Figure 4. Proposed mechanism for the formation of the dialkylated product.
reaction rate in their Ir-catalyzed asymmetric allylic sub-
stitution reactions.25,51 Thus, we set out to examine the
ortho substitution effect in our biphenol-based ligand–
Pd-catalyst system. In addition, we also designed non-
symmetrical N,N-bis(1-arylethyl)amine moieties based
on a combination of different aryl groups, that is, phe-
nyl, o-tolyl, o-methoxyphenyl, 1-naphthyl, and 2-naph-
thyl groups.
As Table 3 shows, a very interesting and rather unantic-
ipated substituent effect of the aryl groups of the amine
moiety on the enantioselectivity as well as catalytic
activity is observed. First of all, the markedly contrast-
0
ing results for the use of L7 ðR3 ¼ R3 ¼ 1-NpÞ and
0
L8 ðR3 ¼ R3 ¼ 2-NpÞ are worth mentioning (entries 2
and 3). The result for L8 is similar to that for L6 with
85.5% ee (entries 3 and 1), while the reaction with L7
almost did not proceed under the same conditions and
no change was observed even when forcing the reaction
at room temperature. The result for L7 appears to indi-
cate that the reaction is very sensitive to the bulkiness
and arrangement of the aryl moiety at the coordination
site. Even one 1-naphthyl group seems sufficient to kill
the Pd-catalyst 0 activity. Thus, the reaction using L11
ðR3 ¼ 1-Np, R3 ¼ 2-MeO–PhÞ virtually did not pro-
ceed (entry 6). To our surprise, ligands L13 and L14,
bearing C2-symmetric N,N-bis(1-arylethyl)amine moie-
ties, behaved very poorly, resulting in no conversion
(entry 8) and <5% conversion (entry 9), respectively.
Even when the reaction with L14 was carried out at
ꢀ30 ꢁC for 24 h, the reaction did not complete (72%
conversion) and formed a large quantity of the dialkyl-
ated side product 11 (entry 10). These results are unanti-
cipated, since the same amine moieties were reported
to give excellent results in the Ir-catalyzed reactions with
BINOL-based ligands.25,31
The efficacy of L6 congeners was examined in the Pd-
catalyzed reaction of 1 with 2 using [Pd(allyl)Cl]2 and
1.2 equiv of 2 and LDA in THF at ꢀ60 ꢁC for 15 h.
In each case, the amount of the dialkylated product
was also determined. The separation of 3 and the dialkyl-
ated product 11 was performed. The enantioselectivity
of the reaction was determined by converting 3 to 10
in the same manner as that described above (see Table
2). The results are summarized in Table 3.
Table 3. Pd-catalyzed asymmetric allylic alkylation–desymmetrization
of 1 with 2 using a focused library of L6 congenersa
Entry
Ligand
3 (%)b
11 (%)b
3 (% ee)c
1
2
3
4
5d
6
7d
8
L5a
L7
93
6
—
7
13
19
—
16
—
—
29
86.2 (ꢀ)
—
85.5 (+)
83.0 (+)
99.7 (+)
—
99.4 (+)
—
—
n.d.f
<5% conv.
92
85
76
L8
L9
L10
L11
L12
L13
L14
L14
A breakthrough in the enantioselectivity was achieved
0
by ligands L10 ðR3 ¼ 2-MeO–Ph, R3 ¼ PhÞ and L12
<5% conv.
83
0
ðR3 ¼ 2-MeO–Ph, R3 ¼ 2-NpÞ, bearing non-symmetri-
cal N,N-bis(1-arylethyl)amine moieties wherein one of
the aryl groups is 2-MeO-phenyl. The reactions with
L10 and L12 gave 3 with 99.7% ee (76% yield) and
99.4% ee (83% yield), respectively (entries 5 and 7). Both
reactions reached 100% conversion in 8 h. Formation of
11 was 19% for the reaction with L10 and 16% for that
with L12. Accordingly, a certain level of enantiomer
enrichment, mentioned above, may have taken place in
these cases, which has contributed to the achievement
of extremely high enantioselectivity observed. It appears
that 2-methoxyphenyl group in the non-symmetrical
0% conv.
<5% conv.
43 (72% conv.)
9
10e
a Reactions were run with 100 mg (0.31 mmol) of 1, [Pd(allyl)Cl]2
(2 mol %), a ligand (8 mol %), 2 (1.2 equiv), LDA (1.2 equiv) in THF
at ꢀ60 ꢁC for 15 h unless otherwise noted.
b Isolated yield.
c Estimated based on the enantiopurity of 10 determined by chiral
HPLC analysis using a Daicel Chiralpak AD-RH column.
d Reaction time was 8 h.
e Reaction was run at ꢀ30 ꢁC for 24 h.
f n.d. = not determined.

648
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
1) Pd(OAc)2 (5 mol%)
Br
O
O
dppb (10 mol%)
NaH (1.1 eq.)
MeO2C
N
H
MeO2C
DMF, 50 oC, 3h
N
O
O
2) Et(i-Pr)2NH (2 eq.)
O
110 oC, 8h
O
OBz
61% for 2 steps (one-pot)
4
(+)-3 (99.4% ee)
1) NaCl (3 equiv)
DMSO:H2O (3:1)
175 oC, 12h
H
H
H
N
O
O
4
2) 5% Pd/C,H2, MeOH,
rt,1.5 h
3) LiAlH4, THF, reflux,1.5 h
(+)-γ−lycorane (> 99% ee)
41% overall yield
[α]D22 = +18.1 (c 1.1, EtOH)
81% for 3 steps
lit. [α]D25 = +17.1 (c 0.25, EtOH)
Scheme 4. Completion of the total synthesis of enantiopure (+)-c-lycorane from (+)-3.
N,N-bis(1-arylethyl)amine moiety has a profound effect
on the enantioselectivity and reaction rate. It is possible
to hypothesize that the oxygen of 2-methoxyphenyl
group interacts with the Pd metal to fix the orientation
of the phenyl ring, which has a crucial effect on the enan-
tio-differentiation (desymmetrization) of the two benzo-
ate groups in meso-1. Since the isolation of 3 from the
reaction mixture is very easy, the reaction with L12 pro-
vides a highly practical process for the total synthesis of
enantiopure (+)-c-lycorane.
biphenol-based monophosphite ligands13 to the Rh(I)-
catalyzed asymmetric hydrogenation of dimethyl itaco-
nate and discussions about the possible active catalyst
species.
As shown in Figure 2, we have designed and synthesized
a library of novel biphenol-based monophosphite
ligands bearing different alkoxy and aryloxy moieties
along with different substituents at the 3,30-positions
(L15–L20).13
The total synthesis of (+)-c-lycorane was completed, fol-
lowing Mori’s procedure with some modifications as
shown in Scheme 4. As Scheme 4 illustrates, 3 (99.4%
ee) was converted to pentacyclic oxo-lycorane 4 in
61% yield through one-pot tandem allylic amination–
intramolecular Heck reaction. Then, 4 was subjected
to the sequential demethoxycarbonylation, hydrogena-
tion, and LiAlH4-reduction to give the desired (+)-c-
lycorane (>99% ee) in 41% overall yield (six steps)
from 1.
First, the reactions were carried out using ligands L15–
L19, L20a and [Rh(COD)2]BF4 in CH2Cl2 at room
temperature and 0.689 MPa of H2 for 20 h. The results
are summarized in Table 4.
Table 4. Asymmetric hydrogenation of dimethyl itaconate catalyzed
a
by monodentate phosphite–[Rh(COD)2]BF4
[Rh(COD)2]BF4
Ligand*
CO2Me
CO2Me
MeO2C
MeO2C
*
H2 (0.689 MPa)
CH2Cl2, rt, 20 h
14
13
This successful total synthesis of enantiopure (+)-c-lyco-
rane demonstrates the advantage of the fine-tuning
capability of our novel phosphoramidite ligands in
developing extremely efficient ligand for a specific asym-
metric transformation through optimization of a lead
ligand by rational design.
Entry
Ligand
Conv. (%)b
% eeb,c
1
2
3
4
5
6
7
8
L15a
L15b
L16a
L16b
L17a
L17b
L18a
L18b
L17c
L18c
L19a
L19b
L20a
90
100
97
100
100
100
100
100
3.5
4.3
<1
<1
<1
14.0 (R)
96.5 (S)
19.0 (R)
96.4 (S)
25.0 (R)
92.0 (S)
44.0 (S)
93.0 (R)
24.3 (R)
32.0 (S)
—
2.3. Asymmetric hydrogenation of dimethyl itaconate
Recently, chiral monodentate phosphorus ligands have
shown high efficiency in the asymmetric hydrogenation
of prochiral olefins.7–9,13 Since the early work of Reetz
and Mehler,51 Feringa and co-workers,7,52 and Claver
et al.,53 a number of new monodentate phosphorus
ligands have been developed.4,7–13,54 However, newer
and more efficient chiral ligands along this line are clearly
needed to achieve excellent enantiopurity and high cata-
lyst efficiency for particular substrates and reactions. We
describe here the application of a new class of chiral
9
10
11
12
13
—
—
a Reactions were run in CH2Cl2 at 23 ꢁC and 0.689 MPa of H2 for 20 h
[substrate (0.5 mmol, 0.1 M)/[Rh(COD)2]BF4/ligand = 200:1:2].
b Conversion and enantiopurity were determined by GC analysis.
c The absolute configuration was determined by comparing the chiral
GC spectra with those of authentic samples.

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
649
Table 5. Asymmetric hydrogenation of dimethyl itaconate using
As Table 4 shows, the Rh catalysts with ligands L15b–
L18b (R2 = H) exhibited excellent enantioselectivity
(92–96.5% ee) along with complete conversion (entries
2, 4, 6, and 8). However, the Rh-catalyst with ligands
bearing a tert-butyl group at the 3,30-positions of the
biphenol moiety (L15–L19, L20a, L17c, and L18c)
exhibited poor to excellent catalyst activity and low to
moderate enantioselectivity (entries 1, 3, 5, 7, 9–11,
and 13). The introduction of (ꢀ)-menthol as a chiral
alkoxy moiety (L17b and L18b) did not improve the
enantioselectivity as compared to that achieved by the
use of L15b and L16b, which contain an achiral aryloxy
moiety (entries 6 and 8 vs entries 2 and 4). Furthermore,
the diastereomeric ligands L17b (S-biphenyl) and L18b
(R-biphenyl) bearing the same (ꢀ)-menthol moiety gave
virtually the same level of enantioselectivity (entries 6
and 8). Accordingly, it appears that the chiral alkoxy
moiety has little effect on the enantioselectivity. In sharp
contrast, substitution at the 3,30-positions of the biphe-
nol moiety exerts a critical influence on the direction and
the extent of the asymmetric induction. Thus, the
ligands bearing a hydrogen at the 3,30-positions (L15b,
L16b, L17b, and L18b) show excellent enantioselectivity
(92.0–96.5% ee), giving (S)-methylsuccinate [(R) for
L18b] (entries 2, 4, 6, and 8). However, the ligands with
a tert-butyl group at the 3,30-positions (L15a, L16a,
L17a, and L18a) show a reversal in the direction of
asymmetric induction to afford (R)-dimethylsuccinate
with low to moderate enantiopurity (14–44% ee) [(S)
for L18a] (entries 1, 3, 5, and 7). The ligands, L17c
and L18c, bearing a phenylmenthyloxy group exhibited
very low conversion and enantioselectivity, but the
ligands bearing a bulky 2-phenylcyclohexyloxy group
(L19a, L19b, and L20a) did not show any appreciable
activity under the same conditions (entries 9–13).
[Rh(COD)2]SbF6 with monodentate phosphite ligandsa
[Rh(COD)2]SbF6
Ligand*
H2 (0.689 MPa)
CO2Me
CO2Me
MeO2C
MeO2C
*
ClCH2CH2Cl
or CH2Cl2, 50 oC
13
14
Entry
Ligand
Solvent
Conv. (%)b
% eeb,c
1
2
3
4
5
6
7
8
L15a
L16a
L17a
L18a
L17c
L18c
L19a
L20a
L17c
L18c
L19a
L20a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
100
100
100
100
100
100
100
100
100
100
100
100
16.4 (R)
22.5 (R)
14.5 (R)
9.3 (S)
94.4 (R)
97.6 (S)
97.8 (R)
99.0 (R)
98.9 (R)
98.7 (S)
99.6 (R)
99.1 (R)
9
10
11
12
a The reaction was performed at 50 ꢁC and 0.689 MPa of H2 for 20 h
[substrate (0.5 mmol, 0.1 M)/[Rh(COD)2]SbF6/ligand = 200:1:2].
b Conversion and enantiopurity were determined by GC analysis.
c The absolute configuration was determined by comparing chiral GC
spectra with those of authentic samples.
ingly, we examined the effect of other counterions, using
[Rh(NBD)2]ClO4 and [Rh(COD)2]OTf as catalyst pre-
cursors and L20a as the chiral ligand in CH2Cl2 under
the same conditions (see footnote a of Table 5). To
our surprise, no enantioselectivity was observed
although the reaction proceeded in 100% conversion in
each case. Moreover, the reactions using [Rh(COD)2]-
BF4 with L19a and L20a under the same conditions
gave racemic methylsuccinate in 100% and 3.8% yields,
respectively. These results confirmed the remarkable
and unanticipated effect of counterions in this asymmet-
ric catalysis.
Next, we examined the effects of Rh-catalyst precursor
species and solvents on the catalytic activity and enantio-
selectivity. The reaction temperature was increased to
50 ꢁC by taking into account the poor catalyst activity
on using bulky ligands. As Rh-catalyst precursors,
[Rh(COD)2]SbF6, [Rh(NBD)2]ClO4, and [Rh(COD)2]-
OTf were examined in place of [Rh(COD)2]BF4.
We also examined the effect of solvents on the reaction
using [Rh(COD)2]SbF6 and L20a and L19a (only for
CHCl3). To our surprise, the reactions under the same
conditions mentioned above in MeOH (82.3% conv.),
THF (100% conv.), toluene (30.7% conv.), EtOAc
(91.2% conv.), and CHCl3 (1.2% conv. using L19a) did
not exhibit any enantioselectivity, yielding racemic
product. Thus, it appears that this process using
[Rh(COD)2]SbF6 as the catalyst precursor with chiral
monodentate phosphite ligands is effective only in
chlorine-containing solvents, that is, CH2Cl2 and
ClCH2CH2Cl. Similar solvent effects were recently
reported for BINOL-based phosphoramidite ligands.7
These results would provide us with very important
information about the nature of active catalyst species.
It is worth mentioning that the reactions using
[Rh(COD)2]SbF6 gave markedly different results from
those using [Rh(COD)2]BF4 as shown in Table 4, espe-
cially when bulky ligands bearing a tert-butyl group at
the 3,30-positions (L17c, L18c, L19a, and L20a) were
used. The results are listed in Table 5. As Table 5 shows,
these bulky ligands achieved excellent enantioselectivity
(94.4–99.6% ee) and complete conversion when the reac-
tions were carried out in CH2Cl2 or ClCH2CH2Cl at
50 ꢁC (entries 5–12). On the contrary, the ligands bear-
ing an aryloxy moiety (L15a and L16a) or (ꢀ)-menthyl-
oxy moiety (L17a and L18a) did not show any
improvement (entries 1–4). Nevertheless, in all cases,
the catalytic activity was greatly improved, affording
the product in quantitative yield.
Next, we investigated the effect of the substituent at the
3,30-positions of the biphenol moiety on the enantio-
selectivity and catalytic activity, using L20 series. Thus,
in addition to a t-Bu group (L20a), H (L20b), Me
(L20c), Br (L20d), and Ph (L20e) were introduced as
R2 (Fig. 2). The reactions were carried out in CH2Cl2
under the same conditions mentioned above. The results
These results clearly indicate a remarkable effect of the
counteranion of the cationic Rh catalyst species on the
catalytic activity as well as enantioselectivity. Accord-

650
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
Table 7. Effect of ligand/Rh ratio on the enantioselectivity and
conversion of the asymmetric hydrogenation of dimethyl itaconate
are listed in Table 6. As Table 6 shows, the bulkiness of
R2 exerts a critical effect on the enantioselectivity as well
as the direction of asymmetric induction. Thus, the
enantioselectivity decreases in accordance with the
change in the size of the substituent from large to small,
that is, in the order t-Bu, Ph, Br, Me, and H. In the case
of L20b (R2 = H), the reaction did not complete and the
other enantiomer, that is, (S)-methylsuccinate, was ob-
tained with only 2.7% ee. These results reconfirm the
salient feature of our chiral monodentate phosphorus
ligands that have a fine-tuning capability.
Entry
Ligand
L/Rh
Conv. (%)c
% eec,d
1
2
3
L18ba
L18ba
L18ba
1
2
3
100
100
7.0
93.0 (R)
93.0 (R)
57.8 (R)
4
5
6
L18cb
L18cb
L18cb
1
2
3
100
100
100
98.7 (S)
98.8 (S)
98.6 (S)
a See footnote a of Table 4.
b See footnote a of Table 5.
c Conversion and enantiopurity were determined by GC analysis.
d The absolute configuration was determined by comparing chiral GC
spectra with those of authentic samples.
Table 6. Asymmetric hydrogenation of dimethyl itaconate using
[Rh(COD)2]SbF6 with ligands L20a–ea
[Rh(COD)2]SbF6
Ligand*
H2 (0.689 MPa)
BINOL-based monodentate phosphoramidite ligand.7
In sharp contrast to the L18b case, the ligand/Rh ratio
did not have any appreciable influence on the enantio-
selectivity and conversion when the bulky ligand L18c
was used. Thus, the reactions gave (S)-methylsuccinate
with 98.6–98.8% ee in quantitative yield.
CO2Me
CO2Me
MeO2C
MeO2C
CH2Cl2, 50oC
*
13
14
R2
O
O
R2 = t-Bu, H, Me, Br, Ph
(L20a-e)
P O
Ligand* =
These results are intriguing in that two ligand–Rh com-
plex systems show very different behaviors that may be
arising from the bulkiness of the chiral ligands as well
as the nature of the counterions. Accordingly, we set
out to investigate the Rh-ligand species in solution by
means of 31P NMR analysis. Figures 5 and 6 show the
31P NMR spectra of L18b–[Rh(COD)2]BF4 complexes
and L19a–[Rh(COD)2]SbF6 complexes, respectively,
with different Rh/ligand ratios in CD2Cl2 at room
temperature.
R2
Entry
Ligand
R2
Conv.b (%)
% eeb,c
1
2
3
4
5
L20a
L20b
L20c
L20d
L20e
t-Bu
H
CH3
Br
100
81
100
100
100
99.0 (R)
2.7 (S)
76.9 (R)
97.1 (R)
97.8 (R)
C6H5
a,b,c See the footnotes of Table 5.
Since the emergence of chiral monodentate phosphorus
ligands in asymmetric catalytic transformations, several
studies have been performed by means of X-ray crystal-
lography,7,12,53,54 NMR,53,55 and mass spectrometric ana-
lyses.7 It is believed that two chiral monodentate
phosphorus ligands would bind to the Rh metal to form
an active catalyst species.53,54 In order to shed light on
the possible structure of active catalyst species, we exam-
ined the ligand to Rh ratio on the enantioselectivity
of this reaction and also analyzed their structures by
31P NMR. For these experiments, two ligands, L18b
(R2 = R = H) and L18c (R2 = t-Bu, R = Ph), possessing
very different bulkiness to each other, were used. The
reaction with Rh-L18b catalyst was run using
[Rh(COD)2]BF4 as the catalyst precursor in CH2Cl2 at
room temperature for 20 h, while that with Rh-L18c
was carried out using [Rh(COD)2]SbF6 as the catalyst
precursor in CH2Cl2 at 50 ꢁC for 20 h. The results of
the asymmetric hydrogenation of dimethyl itaconate
with different ligand/Rh ratios are listed in Table 7.
Figure 5. 31P NMR of rhodium complexes with L18b. The samples
were prepared by mixing [Rh(COD)2]BF4 with L18b at different ratios
in CD2Cl2. 31P NMR spectra were measured at rt.
As Table 7 shows, the reactions using 1 or 2 equiv of
L18b to Rh gave (R)-methylsuccinate with the same
enantiopurity (93% ee) in quantitative yield (entries 1
and 2). However, both catalyst activity and enantio-
selectivity decreased considerably when 3 equiv of L18b
to Rh was used (7.0% conversion, 57.8% ee) (entry 3).
A similar phenomenon has recently been reported in
the hydrogenation of a dehydroamino acid using a
As shown in Figure 5, only one doublet (d 120 ppm,
J = 259 Hz) for a L18b–[Rh(COD)2]BF4 complex ap-
peared with the ligand/Rh ratio of 1 (Spectrum A) and
3 (Spectrum B). A tiny peak of the free ligand was ob-
served at d 151 ppm at the ratio of 4 and became clearly
visible when the ratio was increased to 6 (Spectrum C).

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
651
(ligand)3Rh+ species is slow or the formation of the
(ligand)3Rh+ species is unfavorable in the absence of
molecular hydrogen that would eliminate COD from
the Rh coordination site. (iv) An appreciable bump ap-
pears around d 133 ppm, which might be attributed to
the (ligand)4Rh+ or (ligand)3Rh+ species in equilibrium
with free ligand. Although these interpretations are still
speculative in nature, these findings and interpretations
warrant further mechanistic studies in these catalyst
systems.
3. Conclusion
A series of novel monodentate phosphite and phospho-
ramidite ligands based on axially chiral biphenol have
been developed and applied to asymmetric allylic alkyl-
ation and hydrogenation reactions. The salient features
of these ligands include easy preparation and modifica-
tion, enabling de facto fine-tuning capability of these
ligand systems. The advantage of the fine-tuning capa-
bility has been demonstrated in the two asymmetric
transformations presented here, that is, the best-fit
ligands for particular reaction-types and their substrates
have been successfully developed through rational opti-
mization of lead ligands. It is worth mentioning that the
substituents at the 3,30-positions of the biphenol moiety
exert a critical influence on the enantioselectivity and
catalyst activity. The alcohol and amine moieties for
phosphites and phosphoramidites, respectively, are also
of critical importance for the efficacy of the chiral
ligands. A short total synthesis of enantiopure (+)-c-
lycorane was successfully completed using highly effi-
cient asymmetric allylic alkylation–desymmetrization
reaction in the key step. Some insight into the active cat-
alyst species in the asymmetric hydrogenation was
obtained though more studies are necessary. Further
investigations into the expansion of the ligand library
as well as its applications to a variety of catalytic asym-
metric transformations are actively underway in our
laboratory.
Figure 6. 31P NMR of rhodium complexes with ligand L19a. The
samples were prepared by mixing [Rh(COD)2]SbF6 with ligand L19a
at different ratios in CD2Cl2. 31P NMR spectra were measured at rt.
As shown in Figure 6, in the case of L19a–[Rh(COD)2]-
SbF6 combinations, only one doublet appeared at
almost the same position as that shown in Figure 5 (d
118.5 ppm, J = 255 Hz) when the ligand/Rh ratio was
1 (Spectrum A) or 2 (Spectrum B). However, the peak
of the free ligand was clearly observed at d 144.5 ppm
when the ratio was increased to 3.
The results for the L19a–[Rh(COD)2]SbF6 system seem
straightforward in that a (ligand)2Rh+ species is
formed selectively even when 1 equiv of the ligand to
Rh is used, and a (ligand)3Rh+ species is not formed
when 3 equiv of the ligand to Rh is present in the system
because of the bulkiness of the ligand. Thus, it is reason-
able to assume that ½ðL19aÞ2Rh(S)ꢁþSbF6ꢀ (S = solvent
or COD) is formed. This complex should have a
C2-symmetry with two magnetically equivalent phos-
phorus nuclei, since no P–Rh–P coupling is observed.
The results for the L18b–[Rh(COD)2]BF4 system are,
however, more complicated. From the result presented
in Table 7, it is clear that a (ligand)3Rh+ species is gen-
erated in this system in the presence of molecular hydro-
gen, which has much less catalytic activity than the
corresponding (ligand)2Rh+ species because of excessive
congestion in the coordination site for this reaction. The
enantioselectivity is also markedly decreased. Neverthe-
less, Spectrum B in Figure 5 does not show the forma-
tion of such (ligand)3Rh+ species. The existence of free
ligand becomes clear only after adding 6 equiv of the
ligand to Rh (Spectrum C, Fig. 5). The possible interpre-
tations of the phenomena are as follows: (i) The
½ðligandÞ2Rh(S)ꢁþBF4ꢀ species is formed as a stable com-
plex in the same way as that in the L19a–
[Rh(COD)2]SbF6 system. (ii) The (ligand)3Rh+ species
is partially formed at the ligand/Rh ratio of 3, but this
species is in equilibrium with the (ligand)2Rh+ species
and free ligand at room temperature, which may be near
the coalescence temperature of this equilibrium. This is
why the (ligand)3Rh+ species is not visible. (iii) The
equilibrium between the (ligand)2Rh+ species and the
4. Experimental
4.1. General method and material
1H, 13C, and 31P NMR spectra were measured on a Var-
1
ian Inova-400 NMR (400 MHz H, 100 MHz 13C, and
162 MHz 31P), a Varian Inova-500 NMR (500 MHz
1H), or a Varian Gemini-2300 (300 MHz H, 75 MHz
1
13C, and 121 MHz 31P) spectrometer in a deuterated
solvent using residual protons (CHCl3: 7.26 ppm 1H,
1
77.0 ppm 13C; C6H6: 7.15 ppm H) as the internal stan-
dard or phosphoric acid as the external reference
(0.0 ppm). Analytical gas chromatography was per-
formed with a Hewlett–Packard 5890 Series II gas chro-
matograph (FID) system using a Supelco Beta Dex-225
chiral column. Analytical HPLC was carried out with a
Shimadzu LC-2010A HPLC system using a Chiralpak
ADRH column. Melting points were measured on a
Thomas Hoover Capillary melting point apparatus
and are uncorrected. Optical rotations were measured

652
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
on a Perkin–Elmer Model 241 polarimeter. TLC was
performed on Merck DC-alufolien with Kieselgel 60F-
254 and flash chromatography was carried out on silica
gel 60 (Silicyle; 40–63 lm particle size). High-resolution
mass spectrometric analyses were carried out at the
Mass Spectrometry Laboratory, University of Illinois
Urbana-Champaign, Urbana, IL. All reactions were
carried out under argon or nitrogen atmosphere in
oven-dried glassware using standard Schlenck tech-
niques unless otherwise noted. The solvents were of re-
agent grade and were freshly distilled before use.
Tetrahydrofuran was distilled from sodium/benzophe-
none under nitrogen. Acetonitrile and dichloromethane
were distilled from calcium hydride. Anhydrous N,N-di-
methyl formamide was purchased from DrySolvꢂ and
used without further purification. Enantiopure N,N-
bis(1-arylethyl)amines were synthesized, following the
reported procedure and were in full agreement with
the reported data.30,31 N,N-[(S)-1-(Naphthalen-2-yl)-
ethyl][(S)-1-(2-methoxyphenyl)ethyl]-amine had not been
previously reported and was synthesized using the same
method.31 1,4-cis-Dibenzoyloxycyclohex-2-ene 156 and
6-bromopiperonal 757 were prepared by the literature
methods.57 Cationic rhodium complexes, [Rh(COD)2]-
BF4 and [Rh(COD)2]SbF6, were prepared following
the literature method.58
was quickly filtered off on a short pad of silica gel and
washed with ether. The combined solution was concen-
trated in vacuo to give a crude product. Purification of
the crude product by flash chromatography on a short
silica gel column using hexane/EtOAc as the eluent
afforded the desired phosphoramidite ligand.
4.2.1. O,O0-(S)-(5,50,6,60-Tetramethyl-biphenyl-2,20-diyl)-
N,N-bis[(S)-1-(naphthalen-1-yl)ethyl]phosphoramidite L7.
Purified by flash chromatography on silica gel (eluent:
hexanes/EtOAc = 50:1 then 40:1); white solid; yield
60%; Rf = 0.35 (SiO2, hexanes/EtOAc = 10:1); mp
22
222.5–224 ꢁC; ½aꢁD ¼ þ168:2 (c 1.32, CHCl3); 1H
NMR (300 MHz, CDCl3) d 1.65 (d, J = 6 Hz, 6H),
1.98 (s, 6H), 2.07 (s, 3H), 2.31 (s, 3H), 5.42 (m, 2H),
6.58 (q, J = 8.1 Hz, 2H), 7.00 (t, J = 7.8 Hz, 2H),
7.14–7.41 (m, 8H), 7.64–7.73 (m, 6H); 13C NMR
(75 MHz, CDCl3) d 17.29, 17.46, 19.99, 20.29, 23.04,
23.21, 52.91, 53.07, 118.36, 118.91, 118.95, 123.23,
123.26, 124.44, 124.51, 124.83, 124.92, 125.30, 126.87,
128.46, 129.26, 129.29, 129.88, 130.65, 131.69, 133.24,
133.46, 136.33, 135.36, 139.63, 139.67, 149.41, 149.60,
149.71; 31P NMR (121.5 MHz, CDCl3) d 151.03. HRMS
(ESI) calcd for C40H39NO2P [M+H]+ 596.2718; found
596.2706 (D = ꢀ2.1 ppm).
4.2.2. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-bis[(S)-1-(naphthalen-2-yl)ethyl]phosphoramidite L8.
Purified by flash chromatography on silica gel (eluent:
hexanes/EtOAc = 40:1); white solid; yield 78%;
4.1.1. N,N-[(S)-1-(Naphthalen-2-yl)ethyl][(S)-1-(2-meth-
oxy-phenyl)ethyl]amine. The crude amine was synthe-
sized according to the literature procedure for this
class of compounds,31 starting from (S)-1-(naphthalen-
2-yl)ethyl amine (99.0%) and 2-methoxyacetophenone.
The crude amine, thus obtained, was purified by flash
chromatography on silica gel (eluent: hexanes/EtOAc =
Rf = 0.36 (SiO2, hexanes/EtOAc = 10:1); mp 167–
22
169.5 ꢁC; ½aꢁD ¼ ꢀ415:3 (c 0.98, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.78 (d, J = 7 Hz, 6H), 1.97 (s,
3H), 2.02 (s, 3H), 2.19 (s, 3H), 2.30 (s, 3H), 4.56 (m,
2H), 6.84 (m, 2H), 7.11 (d, J = 8 Hz, 1H), 7.20 (d,
J = 8.5 Hz, 1H), 7.33–7.42 (m, 5H), 7.46 (s, 2H), 7.54
(t, J = 9 Hz, 3H), 7.71 (d, J = 8 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 17.36, 17.62, 20.14, 20.26, 22.92,
23.08, 54.53, 54.67, 118.687, 118.93, 118.97, 125.49,
125.64, 126.42, 126.46, 126.94, 126.98, 127.08, 127.34,
127.87, 128.29, 129.28, 129.87, 129.89, 130.54, 131.73,
132.33, 132.97, 133.37, 133.39, 136.39, 137.27, 140.84,
149.31, 149.43, 149.67; 31P NMR (121.5 MHz, CDCl3)
10:1 then 8:1) to give diastereoisomerically pure amine
22
as a light yellow oil (69% yield): ½aꢁD ¼ ꢀ187 (c 1.66,
CHCl3). 1H NMR (300 MHz, CDCl3) d 1.32 (d,
J = 6.6 Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1.92 (br s,
1H), 3.70 (q, J = 6.6 Hz, 1H), 3.74 (s, 3H), 3.79 ( q,
J = 6.6 Hz, 1H), 6.88–6.98 (m, 2H), 7.15 (dd, J = 1.5,
7.2 Hz, 1H), 7.14–7.27 (m, 1H), 7.43–7.49 (m, 3H),
7.62 (s, 1H), 7.78–7.85 (m, 3H). 13C NMR (75 MHz,
CDCl3) d 22.8, 25.07, 51.59, 55.10, 55.45, 110.69,
120.58, 125.22, 125.24, 125.50, 125.70, 127.52, 12761,
127.70, 127.92, 127.95, 132.79, 133.29, 133.47, 143.41,
157.53. HRMS (EI) calcd for C21H23NO [M]+
305.1772; found 305.1779 (D = 2.2 ppm).
d
145.75; HRMS (ESI) calcd for C40H39NO2P
[M+H]+ 596.2718; found 596.2739 (D = 3.4 ppm).
4.2.3. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-[(S)-1-phenylethyl][(S)-1-o-tolylethyl]phosphorami-
dite L9. Purified by flash chromatography on short sil-
ica gel column (hexanes/EtOAc = 40:1); white solid;
4.2. General procedure for the preparation of phos-
phoramidite ligands
yield 76%; Rf = 0.45 (SiO2, hexanes/EtOAc = 20:1);
22
Phosphorous trichloride (87 lL, 1.0 mmol) was added
dropwise to Et3N (70 lL, 5 mmol) at 0 ꢁC under N2.
To this mixture, a solution of amine (1.0 mmol) was
added in THF (2 mL). The mixture was stirred at room
temperature and monitored by 31P NMR until the peak
of the aminophosphorous dichloride was solely
observed together with the disappearance of the peak
of PCl3. The mixture was then cooled to 0 ꢁC and
mp 73–75 ꢁC; ½aꢁD ¼ ꢀ126 (c 1.1, CHCl3); 1H NMR
(500 Hz, CDCl3) d 1.54 (d, J = 6.5 Hz, 3H), 1.61 (d,
J = 6.5 Hz, 3H), 1.67 (s, 3H), 2.01 (d, J = 10.5 Hz,
6H), 2.04 (s, 3H), 2.31 (s, 3H), 4.33 (m, 1H), 4.52 (m,
1H), 6.81–6.87 (m, 3H), 7.00–7.25 (m, 9H), 7.91 (d,
J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
17.36, 17.58, 18.53, 20.13, 20.20, 20.25, 25.31, 25.65,
52.11, 52.39, 54.66, 118.54, 118.92, 118.96, 126.01,
126.12, 126.30, 126.58, 126.76, 127.19, 128.20, 129.28,
129.60, 129.82, 130.57, 130.63, 131.64, 133.31, 133.34,
134.19, 136.31, 137.23, 137.25, 141.71, 144.07, 149.49,
149.61; 31P NMR (121.5 MHz, CDCl3) d 146.46. HRMS
a
solution of 5,50,6,60-tetramethylbiphenyl-2,20-diol
(1.0 mmol, 242 mg) in THF (3 mL) was added. The
resulting mixture was stirred for 12 h at room tempera-
ture. After addition of ether (2 mL), the resulting solid

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
653
(ESI) calculated for C33H36NO2P [M+H]+ 510.2559;
found 510.2558 (D = ꢀ0.2 ppm).
4.2.4. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-[(S)-1-phenylethyl][(S)-1-(2-methoxyphenyl)ethyl]-
phosphoramidite L10. Purified by flash chromatogra-
phy on silica gel (eluent: hexanes/EtOAc = 50:1); white
48.47, 48.64, 54.40, 109.29, 118.74, 118.96, 118.99,
120.13, 125.23, 125.78, 126.40, 127.15, 127.21, 127.51,
127.90, 127.98, 129.25, 129.82, 131.58, 132.13, 132.82,
133.25, 134.08, 136.33, 137.23, 139.63, 149.59, 149.72,
155.24; 31P NMR (121.5 MHz, CDCl3) d 146.32. HRMS
(ESI) calcd for C37H39NO3P [M+H]+ 576.2668; found
576.2659 (D = ꢀ1.4 ppm).
4.2.7. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-bis[(S)-1-o-tolylethyl]phosphoramidite L13. Puri-
fied by flash chromatography on short silica gel column
(eluent: hexanes/EtOAc = 40:1); white solid; yield 60%;
solid; yield 65%; Rf = 0.33 (hexanes/EtOAc = 40:1);
22
mp 77–78.5 ꢁC; ½aꢁD ¼ ꢀ102:4 (c 1.25, CHCl3); 1H
NMR (400 MHz, C6D6) d 1.58 (d, J = 6.8 Hz, 6H),
1.82 (s, 3H), 1.85 (dd, J = 2, 7.6 Hz, 3H), 1.87 (s, 3H),
1.91 (s, 3H), 2.02 (s, 3H), 3.06 (s, 3H), 5.04 (m, 2H),
6.31 (dd, J = 1.2, 7.6 Hz, 1H), 6.76 (d, J = 8.4 Hz,
1H), 6.90–7.04 (m, J = 6.8 Hz, 6H), 7.26 (t,
J = 6.8 Hz, 2H), 7.32 (d, J = 8 Hz, 2H), 8.06 (dt,
J = 1.6, 7.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) d
17.36, 17.60, 20.15, 20.25, 20.46, 20.53, 24.63, 24.96,
48.80, 49.07, 54.52, 54.80, 109.55, 118.71, 189.94,
118.98, 120.13, 125.99, 126.84, 127.19, 127.74, 127.87,
128.30, 129.21, 129.77, 130.57, 130.68, 131.54, 133.20,
133.23, 134.11, 136.27, 137.20, 141.97, 149.55, 149.66,
149.72, 155.48; 31P NMR (121.5 MHz, CDCl3) d
147.32. HRMS (ESI) calcd for C33H37NO3P [M+H]+
526.2511; found 526.2506 (D = 1.0 ppm).
Rf = 0.35 (SiO2, hexanes/EtOAc = 30:1); mp 75–77 ꢁC;
22
½aꢁD ¼ þ72 (c 1.05, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.33 (dd, J = 1.5, 6.9 Hz, 6H), 1.95 (s, 6H),
2.00 (s, 6H), 2.25 (s, 3H), 2.31 (s, 3H), 4.52 (m, 2H),
6.76 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.8 Hz, 3H), 7.05
(dt, J = 1.5, 7.5 Hz, 2H), 7.15–7.22 (m, 4H), 7.75 (d,
J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 17.28,
17.43, 18.85, 20.09, 20.27, 22.55, 22.78, 55.05, 55.21,
118.24, 118.92, 118.96, 126.03, 126.23, 126.28, 126.35,
129.41, 129.87, 129.98, 131,50, 134.94, 143.26, 143.28,
149.64, 150.01, 150.12; 31P NMR (121.5 MHz, CDCl3)
d 150.71. HRMS (ESI) calculated for C34H39NO2P
[M+H]+ 524.2718; found 524.2727 (D = 1.6 ppm).
4.2.5. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-[(S)-(naphthalen-1-yl)ethyl][(S)-1-(2-methoxy-phenyl)-
ethyl]phosphoramidite L11. Purified by flash chromato-
graphy on silica gel (eluent: hexanes/EtOAc = 40:1);
4.2.8. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-bis[(S)-1-(2-methoxyphenyl)ethyl]phosphoramidite
L14. Purified by flash chromatography on a short
silica gel column (eluent: hexanes/EtOAc = 30:1);
white solid; yield 53%; Rf = 0.32 (SiO2, hexanes/
22
EtOAc = 30:1); mp 92–94 ꢁC; ½aꢁD ¼ þ96:7 (c 1.23,
white solid; yield 68%; Rf = 0.30 (SiO2, hexanes/
22
CHCl3); 1H NMR (400 MHz, CD2Cl2) d 1.4 (d,
J = 7.2 Hz, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.98 (s, 6H),
2.12 (s, 3H), 2.32 (s, 3H), 3.58 (s, 3H), 3.75 (m, 1H),
5.37 (m, 1H), 6.49–6.67 (m, 4H), 6.89 (td, J = 0.8,
7.2 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 7.22 (d, J = 8 Hz,
1H), 7.29 (t, J = 8 Hz, 1H), 7.37 (m, 2H), 7.58 (d,
J = 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.71 (m,
1H), 7.81 (m, 1H); 13C NMR (100 MHz, CD2Cl2) d
17.62, 17.79, 20.32, 20.57, 22.89, 22.99, 23.17, 23.32,
51.67, 50.70, 55.29, 109.90, 119.01, 119.40, 120.37,
124.09, 124.12, 124.72, 124.76, 125.40, 125.45, 125.83,
127.61, 127.70, 128.36, 128.42, 128.93, 129.80, 130.31,
131.66, 132.35, 133.08, 134.02, 134.20, 136.95, 137.98,
140.72, 140.76, 150.14, 150.32, 150.39, 156.41; 31P
NMR (121.5 MHz, CDCl3) d 151.12; HRMS (ESI)
calcd for C37H39NO3P [M+H]+ 576.2668; found
576.2668 (D = 0.2 ppm).
EtOAc = 30:1); mp 149–150.5 ꢁC; ½aꢁD ¼ þ34:4 (c
1
0.64, CHCl3); H NMR (500 MHz, CDCl3) d 1.46 (d,
J = 7.5 Hz, 6H), 2.01 (d, J = 8 Hz, 6H), 2.24 (s, 3H),
2.31 (s, 3H), 3.63 (s, 6H), 4.89 (m, 2H), 6.51 (d,
J = 8 Hz, 2H), 6.72 (d, J = 10 Hz, 1H), 6.81 (m, 3H),
7.05 (m, 3H), 7.18 (d, J = 8 Hz, 1H), 7.53 (d,
J = 8 Hz, 2H);. 13C NMR (125 MHz, CDCl3) d 17.31,
17.49, 20.14, 20.23, 22.16, 22.26, 50.43, 50.53, 54.63,
110.14, 118.70, 119.00, 119.55, 127.17, 127.72, 127.76,
129.13, 129.69, 131.13, 132.84, 133.07, 136.03, 137.13,
149.67, 156.09; 31P NMR (121.5 MHz, CDCl3) d
151.20. HRMS (ESI) calcd for C34H39NO4P [M+H]+
556.2617; found 556.2707 (D = ꢀ1.7 ppm).
4.3. Synthesis of nucleophile 2
4.3.1. 2-Bromo-4,5-(methylenedioxy)benzaldehyde oxime
8. Hydroxylamine hydrochloride (1.55 g, 22.3 mmol)
was added in portions to a solution of NaHCO3
(1.83 g, 21.8 mmol) in 50 mL of water at room tempera-
ture. The solution was added to a vigorously stirred sus-
pension of 7 (5.0 g, 21.8 mmol) in ethanol (45 mL). The
resulting mixture was stirred for 5 h and then left at
ꢀ20 ꢁC overnight. The suspension was filtered, washed
with a few milliliters of cold ethanol, and dried under
a vacuum to give 8 as a pure white solid (4.9 g, 93%):
Rf: = 0.39 (eluent: hexanes/EtOAc = 2:1); mp 153–
155 ꢁC; IR (KBr) 3463, 3325, 3101, 1500, 1473, 1249,
4.2.6. O,O0-(S)-(5,50,6,60-Tetramethylbiphenyl-2,20-diyl)-
N,N-[(S)-1-(naphthalen-2-yl)ethyl][(S)-1-(2-methoxy-phenyl)-
ethyl]phosphoramidite L12. Purified by flash chromato-
graphy on silica gel (hexanes/EtOAc = 40:1); white
solid; yield 77%; Rf = 0.29 (SiO2, hexanes/EtOAC =
22
1
30:1); mp 103–105 ꢁC; ½aꢁD ¼ ꢀ246 (c 0.8, CHCl3); H
NMR (500 MHz, CDCl3) d 1.63 (dd, J = 7.5, 16 Hz,
6H), 2.01 (d, J = 13.5 Hz, 6H), 2.20 (s, 3H), 2.31 (s,
3H), 2.99 (s, 3H), 4.66 (m, 1H), 4.71 (m, 1H), 6.26 (d,
J = 8 Hz, 1H), 6.85–6.91 (m, 3H), 7.00 (t, J = 8.5 Hz,
1H), 7.10 (d, J = 8 Hz 1H), 7.20 (d, J = 7.5 Hz, 1H),
7.27 (m, 1H), 7.38 (m, 3H), 7.58 (s, 1H), 7.61–7.68 (m,
2H), 7.81 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 17.37, 17.61, 20.12, 20.24, 25.09, 25.29,
1
1041 cmꢀ1; H NMR (400 MHz, DMSO-d6) d 6.11 (s,
2H) 7.24 (s, 1H), 7.27 (s, 1H), 8.22 (s, 1H), 11.48 (s,
1H); 13C NMR (100 MHz, DMSO-d6) d 102.38,
105.39, 112.45, 114.27, 125.12, 146.64, 147.60, 149.45.

654
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
HRMS (ESI) calcd for C8H7BrNO3 [M+H]+ 243.9609;
found 243.9612 (D = 1.2 ppm).
0.186 mL, 0.37 mmol) was added at ꢀ78 ꢁC under N2.
Separately, solution of [Pd(allyl)Cl]2 (2.24 mg,
a
0.006 mmol) and a ligand (0.024 mmol) in THF (3 mL)
was stirred at room temperature for 10 min. Dibenzoate
1 (100 mg, 0.31 mmol) was added at once to this catalyst
solution and the resulting mixture was cooled to ꢀ78 ꢁC.
The nucleophile (i.e, 2 + LDA) solution was then slowly
cannulated into the substrate–catalyst solution. The
mixture was stirred at the given temperature until TLC
showed completion of the reaction or no more progress
in the reaction. A saturated NH4Cl solution was added
(2 mL) to quench the reaction and the reaction mixture
was extracted with CH2Cl2. The two layers were sepa-
rated and the water layer was further extracted with
CH2Cl2 (3 · 2 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The resulting crude oil was purified by
flash chromatography on silica gel (eluent: hexanes/
EtOAc = 3:1 then 2:1) to give 3 as a white foamy solid.
Product 3 was obtained as a mixture of two diastereo-
isomers (dr = 54:46 by NMR). Rf = 0.4 (SiO2, hexanes/
EtOAc = 1:1): mp = 57–61 ꢁC for a diastereoisomer
mixture; IR (KBr): 3294, 3070, 1743, 1708, 1654, 1481,
4.3.2. 1-Bromo-6-aminomethyl-3,4-(methylenedioxy)-benz-
ene 9. To a solution of 8 (4.0 g, 16.3 mmol) in THF
(200 mL) a 2 M HCl solution (80 mL) was added, fol-
lowed by zinc (10.4 g, 160 mmol). The mixture was vig-
orously stirred under reflux for 2.5 h until the reaction
was complete. The reaction mixture was cooled to room
temperature, filtered on a Celite pad to remove the
excess zinc, and condensed under reduced pressure to
about 90 mL. The aqueous layer was extracted with
EtOAc (50 mL) and then its pH adjusted to >10 by
the addition of saturated ammonia solution. The result-
ing precipitate was filtered off through a Celite pad and
washed with EtOAc (50 mL). The two layers were sepa-
rated and the water layer was washed with EtOAc
(4 · 75 mL). The combined organic layers were dried
over anhydrous K2CO3, filtered, and evaporated in
vacuo to give crude 9 as an oil. The oil was purified
by passing through a short silica gel column (eluent:
EtOAc/2% Et3N). The combined fractions were concen-
trated in vacuo to afford amine 9 as a clear oil (3.4 g,
91% yield): Rf = 0.4 (SiO2, EtOAc/10% Et3N); 1H
NMR (300 MHz, CDCl3) d 1.62 (br s, 2H), 3.79 (s,
2H), 5.95 (s, 2H), 6.87 (s, 1H), 6.98 (s, 1H). 13C NMR
(75 MHz, CDCl3) d 46.76, 101.62, 109.08, 112.78,
113.54, 135.46, 147.18, 147.46. HRMS (ESI) calcd for
C8H9BrNO2 [M+H]+ 229.9817; found 229.9822
(D = 2.2 ppm).
1
1272, 1238 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.55–
2.06 (m, 4H), 2.87 (m, 1H), 3.20 (d, J = 10 Hz, 0.54H),
3.26 (d, J = 9.2 Hz, 0.46H), 3.73 (s, 1.6H), 3.75 (s,
1.7H), 4.42 (m, 2H), 5.41 (m, 1H), 5.81–5.89 (m, 1H),
5.90–6.00 (m, 1H), 5.94 (s, 2H), 6.86 (s, 1H), 6.94 (m,
NH, 0.51H), 6.99 (d, J = 2.8 Hz, 1H), 7.12 (m, NH,
0.47H), 7.42 (m, 2H), 7.54 (m, 1H), 8.00 (m, 2H); 13C
NMR (100 MHz, CDCl3, a mixture of two diastereoiso-
mers) d [22.23, 22.41], 27.01, [37.41, 37.55], 43.96, 44.07,
[52.47, 52.55], [57.44, 57.76], [66.59, 66.84], [101.83,
101.86], [110.29, 110.45], 112.75, 114.22, [127.07, 127.26],
128.28, [129.57, 129.99], [130.03, 130.50], 132.86,
[133.17, 133.36], 147.47, 148.01, 165.99, [166.67, 166.71],
[171.81, 171.48]. HRMS (ESI) calcd for C18H19-
BrNO5 [MꢀPhCO2H]+ 408.0447; found 408.0438 (D =
ꢀ2.0 ppm).
4.3.3. Methyl N-[6-bromo-3,4-(methylenedioxy)-benz-
yl]carbamoylacetate 2. To a solution of amine 9
(615 mg, 2.67 mmol) in CH2Cl2 (25 mL) was added
Et3N (0.93 mL, 680 mg, 6.7 mmol) at 0 ꢁC under N2.
Then, methyl malonyl chloride (0.35 mL, 440 mg,
3.2 mmol) in CH2Cl2 (5 mL) was slowly added. The mix-
ture was stirred at room temperature for 12 h. Saturated
NaHCO3 solution (10 mL) was added to quench the reac-
tion. The resulting two layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 · 15 mL).
The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated
in vacuo to give the crude product as yellow oil. The
crude product was purified by flash chromatography on
silica gel (eluent: hexanes/EtOAc = 2:1 then 1:1) to afford
pure 2 as a white solid (756 mg, 86% yield): mp 118–
119 ꢁC; IR (KBr) 3273, 3071, 1738, 1630, 1550, 1503,
4.4.2. 1,4-Bis[{2-bromo-4,5-(methylenedioxy)benzyl}carb-
amoyl(methoxylcarbonyl)methyl]cyclohex-2-ene 11. Rf =
0.29 (SiO2, EtOAc = 1:2); 1H NMR (400 MHz, CDCl3) d
1.46 (m, 2H), 1.64 (m, 2H), 2.80 (m, 2H), 3.08–3.18 (m,
2H), 3.71 (s, 3H), 3.18 (s, 3H), 4.39 (m, 4H), 5.61 (m,
2H), 5.96 (s, 4h), 6.85 (m, 2H), 6.91 (m, NH, 0.5H),
6.97 (m, 3H), 7.07 (m, NH, 0.5H); 13C NMR
(100 MHz, CDCl3) d 23.24, 24.41, 23.46, 23.55, 36.21,
36.44, 36.58, 43.89, 43.98, 52.39, 52.44, 52.46, 57.41,
57.48, 57.58, 57.84, 101.82, 101.84, 110.23, 110.26,
110.31, 110.35, 112.71, 112.74, 114.14, 129.64, 129.72,
129.78, 130.05, 130.09, 147.44, 147.90, 147.96, 166.85,
166.91, 166.99, 171.25, 171.27, 171.37, 171.41. HRMS
(ESI) calcd for C30H31Br2N2O10 [M+H]+ 737.0345;
found 737.0359 (D = 1.8 ppm).
1
1479, 1205, 1034 cmꢀ1; H NMR (400 MHz, CDCl3) d
3.35 (s, 2H), 3.75 (s, 3H), 4.44 (d, 2H, J = 6 Hz), 5.96
(s, 2H), 6.85 (s, 1H), 7.00 (s, 1H), 7.54 (br s, 1H); 13C
NMR (100 MHz, CDCl3) d 40.76, 43.70, 52.44, 101.78,
110.25, 112.72, 114.20, 130.19, 147.45, 147.89, 164.68,
169.84. HRMS (ESI) calcd for C12H13BrNO5 [M+H]+
329.9977; found 329.9977 (D = ꢀ0.2 ppm).
4.4. General procedure for the Pd-catalyzed asymmetric
allylic alkylation–desymmetrization reaction
4.4.3. (3aR*,7aS*)-1-[60-Bromo-3,4-(methylenedioxy)-benz-
yl]-3-(methoxycarbonyl)-3a,4,5,7a-tetrahydro-indolin-
2-one 3a.
A solution of [Pd(allyl)Cl]2 (2.65 mg,
4.4.1. Methyl (10S*,40R*)-2-(40-benzoyloxy-20-cyclohex-
en-10-yl)-2-N-[600-bromo-300,400-(methylene-dioxy)benzyl]-
carbamoylacetate 3. To a solution of 2 (122 mg,
0.37 mmol) in THF (3 mL) LDA (2 N in THF,
7.24 lmol) and dppb (6.2 mg, 15 lmol) was stirred in
CH3CN (2 mL) under N2 for 1 h. Separately, a solution
of 3 (156 mg, 0.294 mmol) in THF (2 mL) was cooled to
ꢀ50 ꢁC under N2. LDA (0.154 mL, 2 M soln) was added

B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
655
to this solution and the mixture was stirred for 5 min
and warmed to room temperature. The Pd–dppb cat-
alyst solution was then quickly added to the substrate
solution and the mixture was stirred at rt for 2.5 h.
TLC analysis showed that the reaction was complete.
To the reaction mixture, saturated NH4Cl solution
was added (3 mL) to quench the reaction and the reac-
tion mixture was extracted with CH2Cl2. The organic
layer was separated and the aqueous layer was further
extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The resulting oil was purified by
flash chromatography using hexanes/EtOAc (3:1) as
the eluent to give 3a as a colorless oil (85 mg, 71% yield):
Rf = 0.36 (SiO2, hexanes/EtOAc = 1:1); 1H NMR
(400 MHz, CDCl3) d 1.62 (m, 1H), 1.76 (m, 1H), 2.06
(m, 3H), 2.80 (m, 1H), 3.32 (d, 1H, J = 6.8 Hz), 3.79
(s, 3H), 3.99 (m, 1H), 4.27 (d, 1H, J = 16 Hz), 4.80 (d,
1H, J = 16 Hz), 5.70 (m, 1H), 5.93–5.97 (m, 1H), 5.95
(s, 2H), 6.82 (s, 1H), 6.97 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 21.81, 23.24, 35.83, 44.14, 52.35,
52.55, 53.40, 101.80, 109.21, 112.50, 113.54, 122.86,
128.49, 131.64, 147.85, 169.38, 170.12. HRMS (ESI)
calcd for C18H19BrNO5 [M+H]+ 408.0447; found
408.0460 (D = 3.3 ppm).
of Pd(OAc)2 (1.7 mg, 7.5 lmol) and dppb (6.5 mg,
15 lmol) in DMF (0.5 mL) was prepared separately
and cannulated to the reaction mixture of 3 and NaH
in DMF at 0 ꢁC. The temperature was raised to 50 ꢁC
and the reaction monitored until the disappearance of
3 and the clean formation of the allylic amination prod-
uct 3a was confirmed (3 h). Then, diisopropylethylamine
(55 lL, 0.3 mmol) was added to the reaction mixture
and the temperature was raised to 110 ꢁC. The reaction
mixture was stirred for 7 h and cooled to room temper-
ature. Water (3 mL) was added to quench the reaction
and the reaction mixture was extracted with ethyl ace-
tate (5 · 5 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduce pressure to give crude Heck
reaction product 4 as a brown oil. The crude oily prod-
uct was purified by flash chromatography on silica gel
(eluant: hexanes/EtOAc = 2:1) to yield pure 4 as a col-
orless oil (26 mg, 61% yield): Rf = 0.27 (SiO2, hexanes/
EtOAc = 2:3); ½aꢁD ¼ ꢀ19:6 (c 0.51, CHCl3); H NMR
(500 MHz, CDCl3) d 2.26 (m, 2H), 3.20 (d, J = 5 Hz,
1H) 3.28 (m, 2H), 3.80 (s, 3H), 4.16 (d, J = 17.5 Hz,
1H), 4.22 (dd, J = 4.5, 8 Hz, 1H), 4.85 (d, J = 17.5 Hz,
1H), 5.71 (d, J = 9.5 Hz, 1H), 5.92–5.95 (m, 1H), 5.96
(s, 2H), 6.58 (s, 1H), 6.66 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 26.71, 34.34, 38.29, 42.41, 52.74,
55.52, 55.71, 101.11, 105.96, 108.80, 124.02, 126.75,
129.25, 133.77, 146.93, 147.00, 168.61, 170.67. HRMS
(ESI) calcd for C18H18NO5 [M+H]+ 328.1185; found
328.1185.(D = 0.1 ppm).
22
1
4.4.4. (3aR*,7aS*)-1-[60-Bromo-3,4-(methylenedioxy)-benz-
yl]-3a,4,5,7a-tetrahydroindolin-2-one 10. To a solution
of 3a (37 mg, 0.09 mmol) in DMSO (1 mL), water
(0.3 mL) and NaCl (15 mg) were added. The resulting
solution was stirred at 175 ꢁC for 2.5 h. TLC analysis
showed the completion of the reaction. Water (2 mL)
was added and the reaction mixture was extracted with
Et2O/CH2Cl2 (1:1) (4 · 5 mL). The combined organic
layers were dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The resulting oil was
chromatographed on a silica gel column (eluent: hex-
anes/EtOAc = 5:3) to give 10 as a white crystalline solid
(29 mg, 91% yield): Rf = 0.25 (SiO2, hexanes/
EtOAc = 1:1); mp 85–86 ꢁC; 1H NMR (400 MHz,
CDCl3) d 1.50–1.80 (m, 3H), 1.92–2.20 (m, 2H), 2.28
(m, 1H), 2.40–2.60 (m, 2H), 3.86 (m, 1H), 4.27 (d, 1H,
J = 20.8 Hz), 4.74 (d, 1H, J = 15.6 Hz), 5.75 (m, 1H),
5.93–5.99 (m, 1H), 5.96 (s, 2H), 6.76 (s, 1H), 6.98 (s,
1H); 13C NMR (100 MHz, CDCl3) d 22.2, 24.11,
31.02, 35.72, 43.98, 54.76, 101.78, 109.26, 112.58,
113.50, 123.22, 129.30, 131.82, 147.74, 174.44. HRMS
(ESI) calcd for C16H17NO3Br [M+H]+ 350.0392; found
350.0383 (D = ꢀ2.4 ppm).
4.5.2.
(3aR,12bS,12cS)-1,2-Dehydro-5-oxo-c-lycorane
12a. To a solution of 4 (23 mg, 0.07 mmol) in DMSO
(1.5 mL), water (0.5 mL) and NaCl (13 mg) was added.
The mixture was stirred at 175 ꢁC for 15 h. The reaction
mixture was cooled to room temperature and 2 mL of
water was added. The reaction mixture was extracted
with ethyl acetate (5 · 5 mL) and the combined organic
layers were dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure to give the crude
product. Purification of the crude product by flash chro-
matography on silica gel (eluant: hexanes/EtOAc =
1:1.5) afforded pure 12 as a white solid (18 mg, 93%
yield): mp 174–177 ꢁC (decomp.); Rf = 0.21 (SiO2, hex-
anes/EtOAc = 1:5); 1H NMR (500 MHz, CDCl3) d
2.10–2.21 (m, 3H), 2.66 (dd, J = 9.5, 17 Hz, 1H), 2.88
(m, 1H), 3.28 (m, 1H), 4.05 (m, 1H), 4.11 (d,
J = 17 Hz, 1H), 4.79 (d, J = 17 Hz, 1H), 5.65 (d,
J = 9.5 Hz, 1H), 5.88 (m, 1H), 5.94 (d, J = 2.5 Hz,
2H), 6.58 (s, 1H), 6.70 (s, 1H). HRMS (ESI) calcd for
C16H16NO3P [M+H]+ 270.1130; found 270.1118
(D = ꢀ1.3 ppm).
The determination of the enantiopurity of 10 was per-
formed on a Shimadzu LC-2010A HPLC system using
a Chiralpak ADRH column (eluent CH3CN/H2O
60:40, flow 0.5 mL/min).
4.5.3. (3aR,12bS,12cS)-5-Oxo-c-lycorane 12b. 5-Oxo-
dihydrolycorane 12a (11 mg, 0.04 mmol) was dissolved
in methanol (1.5 mL) and 5% Pd/C (10 mg) was added
at once. The solution was stirred under ambient pressure
of H2 at room temperature for 1.5 h (TLC analysis
showed that the reaction was completed). The catalyst
was filtered off on a short Celite pad and the filtrate
was concentrated under reduced pressure to give the
crude product. The crude product was purified by flash
chromatography on silica gel (eluent: hexane/
4.5. Synthesis of (+)-c-lycorane
4.5.1. (3aR,12bS,12cS)-1,2-Dehydro-4-(methoxycarbon-
A solution of 3 (70 mg,
yl)-5-oxo-c-lycorane 4.
0.132 mmol) in degassed dry DMF (0.5 mL) was slowly
added to a suspension of NaH (60% oil, 5.8 mg,
0.145 mmol) in DMF (1 mL) under N2 at ꢀ78 ꢁC. The
solution was slowly warmed to 0 ꢁC. A stirred solution

656
B. D. Chapsal et al. / Tetrahedron: Asymmetry 17 (2006) 642–657
EtOAc = 1:1.5) to afford 5-oxo-lycorane 12b (10.7 mg,
through a short pad of silica gel and the filtrate was sub-
jected to gas chromatographic analysis using a Supelco
Beta Dex-225 column for the determination of the con-
version and enantiomeric purity of dimethyl methylsuc-
cinate: the analysis showed that the conversion was
100% with 100% product selectivity and (R)-dimethyl
methylsuccinate with 99.6% ee was formed.
95% yield) as colorless crystals: mp 169–170 ꢁC;
22
Rf = 0.31 (SiO2, hexanes/EtOAc = 1:5); ½aꢁD ¼ þ83:8
1
(c 0.74, CHCl3); H NMR (500 MHz, CDCl3) d 1.13–
1.38 (m, 3H), 1.67–1.76 (m, 3H), 2.09 (d, 1H,
J = 26.5 Hz), 2.41 (m, 1H), 2.57 (dd, 1H, J = 11.5,
27 Hz), 2.75 (td, 1H, J = 7.5, 14 Hz), 3.77 (t, 1H,
J = 7.5 Hz), 4.32 (d, AB, J = 29 Hz), 4.54 (d, 1H,
J = 29 Hz), 5.93 (dd, AB, 2H, J = 2, 7.5 Hz), 6.60 (d,
2H, J = 9.5 Hz); 13C NMR (125 MHz, CDCl3) d
23.64, 27.89, 30.27, 32.98, 39.85, 40.32, 42.71, 55.73,
101.03, 106.69, 108.49, 123.33, 131.61, 146.64, 146.72,
175.67. HRMS (ESI) calcd for C16H16NO3P [M+H]+
272.1287; found 272.1281 (D = ꢀ1.9 ppm).
Other reactions were performed practically in the same
manner with variations in the reaction temperature,
the Rh-catalyst precursor, and the solvent used.
Acknowledgments
4.5.4. (+)-c-Lycorane. To a suspension of LiAlH4
(10 mg, 0.28 mmol) in THF (1 mL), a solution of
5-oxo-lycorane 12b (15 mg, 0.055 mmol) was added in
THF (2 mL) at 0 ꢁC under N2. The solution was refluxed
for 1.5 h (TLC showed that the reaction was completed).
A saturated Na2SO4 solution (1 mL) was carefully
added at 0 ꢁC and the reaction mixture was stirred for
2 h. After the addition of 1 N NaOH (2 mL), the two
layers were separated and the aqueous layer was washed
with EtOAc (4 · 5 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated to give the crude product as a
yellow oil. Purification of the crude product through sil-
ica gel chromatography (eluent: hexanes/EtOAc = 1:2
then 1:4) afforded pure (+)-c-lycorane as a colorless
oil (13 mg, 92% yield): Rf = 0.37 (SiO2, hexanes/
EtOAc = 1:6); ½aꢁD ¼ þ18:1 (c 1.1, EtOH); H NMR
(500 MHz, CDCl3) d 1.27–1.35 (m, 3H), 1.43–1.52 (m,
3H), 1.62–1.64 (m, 1H), 1.69–1.71 (m, 1H), 1.74–1.77
(m, 1H), 2.00–2.03 (m, 1H), 2.13–2.20 (m, 1H), 2.38
(m, 1H), 2.74 (m, 1H), 3.21 (d, J = 14.5 Hz, 1H), 3.38
(m, 1H), 4.02 (d, J = 14.5 Hz, 1H), 5.89 (dd, J = 3.5,
5 Hz, 2H), 6.49 (s, 1H), 6.61 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 25.19, 29.28, 30.38, 31.69, 37.36,
39.46, 53.73, 57.11, 62.90, 100.65, 106.24, 108.33,
(127.1), 133.16, 145.64, 146.04. HRMS (ESI) calcd for
C16H20NO2 [M+H+] 258.1494; found 258.1487
(D = ꢀ2.7 ppm).
This work was supported by grants from the National
Institutes of Health (NIGMS) and National Science
Foundation. Generous support from Mitsubishi Chemi-
cal Corporation is also gratefully acknowledged.
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