Two aspects of the desymmetrization of selected prochiral aromatic or vinylic dihalides: enantioselective halogen-lithium exchange and prochiral recognition in chiral liquid crystals

Article abstract of DOI:10.1016/j.tetasy.2008.12.003

Several classes of prochiral dihalides have been identified as potential candidates for asymmetric halogen-lithium exchange. Bis-aryl compounds 1 and 2, 2,3-dibromonorbornadiene 3, and 1,2-diiodoferrocene 4 were prepared and used as substrates in the asym

Full text of DOI:10.1016/j.tetasy.2008.12.003

Tetrahedron: Asymmetry 19 (2008) 2666–2677
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Two aspects of the desymmetrization of selected prochiral aromatic or vinylic
dihalides: enantioselective halogen–lithium exchange and prochiral
recognition in chiral liquid crystals
Chun-An Fan a, , Benoît Ferber a, Henri B. Kagan a, , Olivier Lafon b,à, Philippe Lesot b,§
*
a Laboratoire de Catalyse Moléculaire, Université de Paris-Sud (XI), UMR-CNRS 8182, ICMMO, Bât. 420, 91405 Orsay, France
b Laboratoire de Chimie Structurale Organique, RMN en Milieu Orienté, Université de Paris-Sud (XI), UMR-CNRS 8182, ICMMO, Bât. 410, 91405 Orsay, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Several classes of prochiral dihalides have been identified as potential candidates for asymmetric halo-
gen–lithium exchange. Bis-aryl compounds 1 and 2, 2,3-dibromonorbornadiene 3, and 1,2-diiodoferro-
cene 4 were prepared and used as substrates in the asymmetric halogen–lithium exchange reaction.
The enantioselective mono-lithiation was achieved in good yields by various combinations of n-BuLi
and chiral ligands. Enantioselectivities in the range of 20–35% ee have been detected for this new type
of asymmetric synthesis. The prochiral compounds 3 and 4 were also dissolved in a chiral liquid crystal
Received 16 September 2008
Revised 24 November 2008
Accepted 3 December 2008
Available online 12 January 2009
Dedicated to Professor Miguel Yus
based on organic solutions of poly-c-benzyl-L-glutamate and analyzed using natural abundance deute-
rium 2D NMR spectroscopy. The spectroscopic discrimination of enantiotopic sites in these solutes has
been observed and discussed from the point of view of orientational order.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
flates were described for an enantioselective mono cross-coupling
in the presence of a chiral Pd catalyst leading to an atropoisomer
The halogen–lithium exchange reaction was independently
developed by Wittig and Gilman in 1938,1,2 and has become one
of the most fundamental synthetic methods for preparing various
organolithium compounds,3a–g which have been extensively used
in both organic and inorganic chemistry.4 Over the past six dec-
ades, most of research efforts were substantially focused on vari-
ous original synthetic applications3,4 as well as some mechanistic
insights.3a,3d,5 To the best of our knowledge, however, there is no
report on the asymmetric version of the above process.6 Recently,
we have explored the possibility of an enantioselective mono-hal-
ogen–lithium exchange on some achiral dibromo-aromatic com-
pounds. Dibromides 1 and meso-2 with an average Cs symmetry
were devised as models as shown in Figure 1.
with up to 93% ee.7 The enantioselective monolithiation of meso-
dibromide 2 could provide another approach where the molecular
mirror symmetry breaking creates a chiral structure with two dif-
ferentiated stereocenters.8 Dibromide 3 can also be considered as a
meso compound, the monolithiation should give access to a prod-
uct with two asymmetric centers. Similarly, the ferrocene diiodide
4 is a potential substrate for the enantioselective monosubstitution
with planar chirality. Concomitantly with the desymmetrization
approach proposed here, we will examine the possibility of dis-
criminating between the enantiotopic directions of prochiral diha-
lides, 3 and 4, interacting with a polypeptide chiral liquid crystal.
The enantiotopic discriminations will be revealed by natural abun-
dance deuterium NMR spectroscopy.
In the prochiral diaryl derivative 1, the stereoselective replace-
ment of one of two enantiotopic bromines should allow us to gen-
erate various chiral atropoisomeric structures. A similar principle
was pioneered by Hayashi et al., wherein diaryl ortho,ortho0-bis-tri-
2. Results
2.1. Synthesis of the prochiral dihalides
One of the most straightforward potential routes for the synthe-
sis of the dibromide 1 is the Suzuki–Miyaura cross-coupling reac-
tion between an aryl halide and an organoboronic reagent.9
However, an aryl–aryl coupling between ortho-dibromoaromatic
iodide and pyrene pinacol boronic ester has been unsuccessful
due to steric hindrance.10 Several tunable influencing factors
(e.g., catalyst, ligand, base, and solvent) in the Suzuki–Miyaura
cross-coupling reaction prompted us to search for an appropriate
* Corresponding author. Tel.: +33 (0)16 915 7895; fax: +33 (0)16 915 4680.
E-mail addresses: kagan@icmo.u-psud.fr (H.B. Kagan), philesot@icmo.u-psud.fr
(P. Lesot).
Current address: State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China.
à
Current address: ENSC de Lille, Unité de Catalyse et de Chimie du Solide, UMR-
CNRS 8181, Cité Scientifique, Bât. C7, 59652 Villeneuve d’Ascq cedex, France.
§
For questions or information about NAD 2D NMR analysis in oriented chiral
solvents, contact P. Lesot: Tel.: +33 (0)16 915 4759.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.003

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2667
O
O
I
Br
Br
Br
Br
Br
I
Fe
Br
1
meso-2
4
3
Figure 1. Four different types of prochiral dihalides.
Table 1
reaction conditions for access to the dibromide 1 on the basis of
this concise coupling strategy. After optimization of experimental
conditions, the expected prochiral compound 1 could be smoothly
obtained via a chemoselective cross-coupling of sterically hindered
1,3-dibromo-2-iodo-5-methylbenzene 5 and 1-naphthylboronic
acid 6 with 82% yield on the gram scale (Scheme 1 and Table 1).
The meso-dibromide 2 was synthesized in three steps from 2-
bromobenzaldehyde 7 (Scheme 2). The cyanide-catalyzed benzoin
condensation of 7 under classical conditions11 gave about 30%
yield of 8. Among the reducing agents examined in the diastereo-
selective reduction of benzoin 8,12 commercially available L-Select-
ride provided the best results, while meso-diol 9 was obtained in
78% yield with >95% de after careful purification by column chro-
matography. The desired meso-dibromoketal 2 could be finally ob-
tained in 95% yield by standard ketalization.13
Optimization for the synthesis of prochiral dibromide 1
Entry
Pd(PPh3)4 (equiv)
Base
Solvent
T (°C)
t (h)
Yielda (%)
b
b
b
b
c
1
2
3
4
5
6
0.5
0.5
0.5
0.5
0.5
0.1
CsF
CsF
NaOH
Cs2CO3
Cs2CO3
LiOH
110
90
85
85
70
70
27
48
18
95
12
12
43
37
45
25
70
82
d
a
Isolated yields.
b
CH3CN/H2O (10:1) as solvent was used without degassing. During this coupling,
the aryl iodide 5 could not be completely consumed, and the desired product was
always contaminated by some uncharacterized by-products.
c
The solvent CH3CN/H2O (10:1) was strictly degassed.
The solvent CH3CN/H2O (10:1) was strictly degassed three times according to
d
the standard cooling-vacuum process under argon.
2,3-Dibromonorbornadiene 3 has been prepared according to
the literature by deprotonation of norbornadiene by a Schlosser
base (t-BuOK/n-BuLi) and treatment with 1,2-dibromoethane.14a
The 1,2-diiodoferrocene 4 was synthesized in good yields from
p-tolylsulfoxide 10 by the reactions depicted in Scheme 3. The
preparation from 1114b of 1,2-bis-Sn(n-Bu)3-ferrocene (precursor
of 4) is described in Section 5. This new synthesis of 4 avoids the
use of mercury salts as previously reported.14c
cule. In particular, the C–H directions denoted b and b0 (see
Fig. 2b) in the substituted Cp ring are enantiotopic.
Whatever the flexibility of the prochiral molecule is, the
enantiotopic C–H directions should be oriented differently (and
so spectrally discriminated) using chiral oriented systems made
of poly-c-benzyl-L-glutamate dissolved in the usual organic
solvents (e.g., CHCl3, DMF or THF).16,19 In 2H–{1H} NMR, this enan-
tiodiscrimination is revealed when two 2H quadrupolar doublets
(generally) centered on the same 2H chemical shift are observed
on the spectra. The origin of this inequivalence lies with the sym-
metry breaking of the molecular orientational distribution function
2.2. Analysis of prochiral compounds 3 and 4 using NAD NMR in
chiral oriented solvents
Concurrent to the synthetic developments, we have studied the
orientational behavior of compounds 3 and 4 (precursors of 23 and
25) interacting with chiral oriented media by using natural abun-
dance deuterium (NAD) NMR spectroscopy in a polypeptide liquid
crystal.15,16 From a stereochemical point of view, molecule 3 is a ri-
gid prochiral molecule of Cs symmetry, and thus possesses both
enantiotopic (a,a0 and b,b0) and diastereotopic (c,d) C–H directions
(see Fig. 2a). For ferrocene derivative 4, the cyclopentadienyl ring is
fast rotating (1012 sꢀ1 at 300 K).17 Therefore, the exchange between
the protons of the cyclopentadienyl ring is fast on the NMR time-
scale, and these nuclei are homotopic. In the fast exchange regime,
the enantiodiscriminations can be predicted from the average sym-
metry.18 Compound 4 belongs to the average symmetry point
group Cs, and can thus be considered as a flexible prochiral mole-
when prochiral solute interacts with a D symmetry environment
1
(chiral medium).20
To reveal this phenomenon, we recorded the NAD NMR spec-
trum of 3 and 4 in a PBLG/CHCl3 mesophase using 14.1 T spectrom-
eter (600 MHz) equipped with selective 5-mm 2H cryoprobe. This
technological combination allows us to either record NAD spectra
in a very short time or analyze small amounts of solute with large
molecular weights.21 Figures 2a and b show the NAD 1D spectrum
of 3 recorded in 1 h (100 mg of solute/Mw = 254 g molꢀ1) and the
tilted NAD Q-COSY Fz 2D spectrum22 of 4 recorded in 5 h (40 mg
of solute/Mw = 439 g molꢀ1), respectively. Proton decoupling is ap-
plied all along the 1D and 2D NMR experiments. Details on the ori-
ented sample preparation and the NMR method can be found in
Refs. 16 and 19. It should be noted that in NAD NMR in a chiral ori-
Pd(PPh3)4 (cat.)
Base (4.0 equiv)
B(OH)2
+
Br
Br
CH3CN/H2O (10:1)
Ar, 85-110 oC
Br
Br
I
5
6
1
Scheme 1. Synthesis of prochiral dibromide 1.

2668
C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
1) LiBH(s-Bu)3
CHO
Br
O
THF, -78 oC to rt
NaCN (0.2 equiv)
EtOH, reflux, 4 h
Br
2) NaOH/H2O
H2O2, 0 oC
OH Br
7
rac-8
O
O
Br
OH
Me2C(OMe)2
PTSA (cat.)
Br
Br
n-hexane, 40 oC
OH Br
meso-9
meso-2
Scheme 2. Preparation of meso-dibromide 2.
Br
Br
ref. 14a
3
p-Tol
p-Tol
SnBu3
Fe
O
:
O
:
S
I
S
I
i)
v)
iii)
Fe
Fe
Fe
then vi)
then ii)
then iv)
4
10
11
Scheme 3. Synthesis of prochiral dibromide 3 and diiodide 4. Reagents: (i) t-BuLi/t-BuOK; (ii) (S)-(ꢀ)-menthyl p-tolylsulfinate; (iii) LDA; (iv) ClSn(n-Bu)3; (v) 2 equiv t-BuLi
then 2 equiv ClSn(n-Bu)3; (vi) 2 equiv I2.
ented medium, the discrimination between enantiotopic C–D
directionsin prochiral molecules is notpossiblebecausethe probabil-
ity to observe dideuterated isotopomers is too low (2.42 ꢁ 10ꢀ6 %).
Actually in NAD NMR, only monodeuterated isotopomers are de-
tected and can be enantiodiscriminated if they are chiral by virtue
of the isotopic substitution.23 In both cases, the molecular recogni-
tion mechanisms are the same, and so with the exception of the
signal intensity, the NAD spectrum of an isotopically unmodified
compound is identical to the 2H spectrum of the related uniformly
deuterated molecule.24 Hence, in the following, NAD results are
discussed indifferently in terms of stereo-isotopomers or stereo-
chemical topicity.
of the unsubstituted pentadienyl ring, thus showing the homotopo-
city of these sites as expected due to the fast rotation of cyclopenta-
dienyl ring. The most deshielded doublet pair corresponds to the
enantiotopic directions (denoted b and b0) of the disubstituted
cyclopentadienyl ring. The presence of the two iodide atoms from
each side of the symmetry plane plays the same role as the bromide
atoms in 3. Finally, the doublet located intermediately (denoted a)
was assigned to the single deuteron contained in the symmetry
plan. Here again, we show that 4 interacts selectively with the poly-
peptide fibers, thus producing a discrimination of enantiotopic
directions in this particular prochiral metallic complex.
The 1D spectrum of 3 shows six distinct quadrupolar doublets
(see Fig. 2a, bottom) centered on four distinct chemical shifts: (i)
two pairs of doublets (located around 7 and 3.8 ppm, respectively)
corresponding to the ethylenic and bridgehead deuterium sites
(denoted a and b); (ii) two doublets associated with the diastereo-
topic sites of the bridge (denoted c and d). The assignment of dou-
blets has been made using 2D Q-COSY Fz experiment (not shown).
The presence of two doublets for sites a/a0 and b/b0 demonstrates
that the enantiotopic directions (that can be also seen as enantio-
2.3. Enantioselective halogen–lithium exchange reaction
n-BuLi, s-BuLi, and t-BuLi are well-known for their ability to
give the halogen–lithium exchange reactions with aryl halides in
an appropriate reaction medium.3a In the model system shown in
Scheme 4, the lithiated intermediate 12, which should result from
the asymmetric bromide–lithium exchange reaction of the prochi-
ral dibromide 1 in the presence of a series of chiral ligands (Fig. 3),
was quenched by electrophilic di-tert-butyl azodicarboxylate
(BocN@NBoc)25,26 to generate the dissymmetric molecule 13a.
The halogen–lithium mono-exchange was first investigated
with a combination of n-BuLi/(ꢀ)-sparteine 1427 prepared in situ
from premixing n-BuLi and 14 in toluene at ꢀ78 °C for 30 min.
An enantiomeric excess of 24% was measured by HPLC analysis
of 13a (Table 2, entry 1). However, the isolated yield was only
36% yield in this case. Sometimes, this halogen–lithium exchange
process only proceeded partially at ꢀ78 °C, presumably because
meric isotopomers) are spectrally discriminated since they are
pro-R
CD
characterized by distinct local order parameters, S
– SpCrDo-S. This
result reveals the existence of solute-polypeptide enantioselective
interactions that are able to discriminate between the two faces of
molecular symmetry plane of compound 3.
The analysis of NAD tilted Q-COSY Fz map of 4 shows four quad-
rupolar doublets centered on three distinct chemical shifts. The
most intense doublet is assigned to the five equivalent deuterons

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2669
To investigate the influence of reaction medium on the enantio-
selectivity, diethyl ether as a coordinative polar solvent (Table 2,
entry 3) and hexane as a non-chelating apolar medium (Table 2,
entry 4) were used. However, lower ee values of around 15% were
obtained in comparison with that in toluene. Based on the above
screening, Procedure A in the Experimental was developed for the
halogen–lithium exchange on dibromide 1 with n-BuLi as the stan-
dard lithiating reagent in combination with the use of toluene as a
solvent in the presence of CaH2.
According to the above optimization, a number of chiral ligands
with different structural frameworks (15–19 in Fig. 3) were
screened in the lithiation process, and some results are shown in en-
tries 7–12 of Table 2. We can see that the enantioselectivity and iso-
lated yields vary with ligand structure. For example, the
bisoxazoline 15 (Table 2, entry 7) led to a reversal of enantioselec-
tivity with 30% ee as evidenced by the specific rotation and chiral
HPLC analysis. It should be noted that this halogen–lithium ex-
change in the presence of 15 proceeded readily as seen by thin layer
chromatography (TLC). However, the desired quenching product
13a was obtained in only 19% yield, while the predominant isolated
product was monobromide 13b (Scheme 4). Two explanations can
be tentatively proposed: (i) an intrasystem protonation of the lithi-
ated intermediate 12 in the presence of the oxazoline-type ligand 15
occurred before quenching with BocN@NBoc; (ii) the generation of
hetero-aggregates incorporating the organolithium 1229 and pre-
venting the quenching by BocN@NBoc. Analogously, only 20% yield
of 13a was obtained with 8% ee when another bisoxazoline 16 was
subjected to this protocol in diethyl ether (Table 2, entry 9), but no
quenching product 13a could be isolated if carried out in toluene
(Table 2, entry 8). The aminoether ligand 18 (Table 2, entry 11),30
which was derived from the commercially available (ꢀ)-N-methyl-
ephedrine, furnished a 15% ee with an opposite enantioselectivity in
comparison with that of (ꢀ)-sparteine 14.
We have established that the expected halogen–lithium ex-
change of 1 with n-BuLi essentially did not proceed in toluene at
ꢀ78 °C in the absence of a ligand (Table 2, entry 13). This observa-
tion indicates that the formation of a ligand-solvated organolith-
ium crucially activates the halogen–lithium exchange process in
toluene at low temperature. Consequently, the Procedure B de-
scribed in the Experimental Section was then developed, in which
the chiral ligand and the starting material were premixed in a sus-
pension of toluene and CaH2 at ꢀ78 °C followed by the addition of
n-BuLi. Under stoichiometric conditions, product 13a was obtained
in 63% yield with 25% ee (Table 2, entry 5). Remarkably, further
investigation revealed that substoichiometric amounts of (ꢀ)-spar-
teine 14 also could promote this lithiation process in 66% yield
with 26% ee (Table 2, entry 6), displaying a potential in the devel-
opment of catalytic asymmetric fashion on the halogen–lithium ex-
change protocol.
Figure 2. (a) 92.1 MHz NAD 1D spectrum of 3 recorded at 300 K and obtained by
adding 2500 scans. (b) NAD Tilted Q-COSY Fz 2D map of 4 after a double FT. The 2D
spectrum was recorded at 305 K using 96 scans per t1 increment and a 2D matrix of
2500(t2) ꢁ 256(t1) data points. The assignment x/x0 reported on the spectra is
arbitrary relative to the enantiotopic direction labeling shown in the corresponding
structures.
of moisture. We found that the addition of calcium hydride pow-
der28 to the current reaction system could realize the complete
consumption of starting material with a satisfying reproducibility
of results on our experiment scale (4.0 ꢁ 10ꢀ2 mmol). Following
this modified experimental condition, a yield of over 71% and an
ee value of 26% were readily afforded (Table 2, entry 2), in which
the absolute configuration of 13a is yet to be established.
E+
RLi / L*
Br
E
Br
Br
Br
Li, L*
-78 oC
-78 oC
1
12
13
13a E = N(Boc)NHBoc
13b E = H
13c E = D
Scheme 4. Asymmetric halogen–lithium exchange protocol of 1.

2670
C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
Table 2
One-pot enantioselective monolithiation/amination sequence of 1
Boc
N
1) RLi, L*, Solvent
Additive, −78oC, Ar
Br
N
H
Br
Br
Boc
2) BocN=NBoc
−78oC, Ar
1
13a
Entry
Procedurea
L
n-BuLi/L (equiv)
Solvent
Additive
Productb
Yieldc (%)
eed (%)
*
*
1
2
3
4
5
6
7
8
9
10
11
12
13
A
A
A
A
B
B
A
A
A
A
A
A
A
14
14
14
14
14
14
15
16
16
17
18
19
1.3:1.3
1.3:1.3
1.3:1.3
1.3:1.3
1.3:1.3
1.3:0.3
1.3:1.3
1.3:1.3
1.3:1.3
1.3:1.3
1.3:3.0
1.3:1.3
1.3:0.0
Toluene
Toluene
OEt2
n-Hexane
Toluene
Toluene
Toluene
Toluene
OEt2
Toluene
Toluene
Toluene
Toluene
None
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
CaH2
(ꢀ)-13a
(ꢀ)-13a
(ꢀ)-13a
(ꢀ)-13a
(ꢀ)-13a
(ꢀ)-13a
(+)-13a
—
(ꢀ)-13a
(+)-13a
(+)-13a
(+)-13a
—
36e
71
60
53
63
66
24
26
16
15
25
26
30
—
8
4
15
4
—
19
f
20
76
62
69
g
None
a
Procedure A: L*, Additive and solvent were added into a Schlenk flask. The mixture was cooled to ꢀ78 °C, and n-BuLi was then introduced. Sequentially, the dibromide 1 in
toluene was added. After 15 min, the reaction mixture was quenched with BocN@NBoc at ꢀ78 °C; Procedure B: L*, dibromide 1, additive (CaH2) and solvent were added into a
Schlenk flask. The mixture was cooled to ꢀ78 °C, and n-BuLi was then introduced. After 15 min, the reaction mixture was quenched with BocN@NBoc at ꢀ78 °C.
b
The specific rotation was measured in CHCl3.
Isolated yields.
Undetermined absolute configuration.
About 60% reaction conversion.
No expected quenching product 13a could be isolated although the halogen–lithium exchange process proceeded readily.
No halogen-lithium reaction could be observed.
c
d
e
f
g
H
H
O
O
O
O
N
H
N
N
N
N
N
Ph
Ph
t-Bu
t-Bu
H
15
16
14
N
N
N
Ph
O
O
N
Ph
OMe
17
18
19
Figure 3. Several kinds of chiral ligands.
The behavior of meso-dibromide 2 was subsequently explored
in the presence of (ꢀ)-sparteine 14 following Procedure B (Scheme
5). The quenching of lithiated intermediate 20 with D2O gave the
desired monobromide product 21, its absolute configuration un-
known. The enantiomeric excess of 13% was rather modest, but
the level of deuterium incorporation was excellent.
The monolithiation of dibromonorbornadiene 3 (Scheme 6) into
22 was realized by 1 equiv of the combination n-BuLi/sparteine at
ꢀ78 °C. The quenching by benzophenone gave the tertiary alcohol
23a in 82% yield. The enantiomeric excess was measured by HPLC
and found to be 20%. When the monolithonorbornadiene was left
at ꢀ120 °C for 1 h before the addition of benzophenone, the prod-
uct 23a was obtained in 30% yield and 35% ee. We are currently
trying to determine the absolute configuration of this compound.
The monolithiation of 1,2-diiodoferrocene 4 treated under the
standard conditions followed by an electrophilic quenching of 24
by benzophenone gave compound 25 in 86% yield with 27% ee
(Scheme 6). The exchange reaction at ꢀ78 °C and then at room
temperature (all others conditions unchanged) followed by
quenching at ꢀ78 °C gave 25 in 86% yield with 34% ee.

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2671
O
O
O
O
O
O
n-BuLi
Br
Br
(1.3 equiv)
Br
D
D2O
Br
Li,L*
+
14
-78 oC, Ar
toluene, CaH2
-78 oC, Ar
20
meso-2
21
65 % yield
13 % ee
Scheme 5. Enantioselective halogen–lithium exchange of meso-2.
Ph
Ph
Li,L*
Br
ii)
i)
OH
Br
Br
Br
23a
22
3
iii)
iv)
OH
OH
Br
Br
23c
23b
Ph
Ph
I
Li,L*
OH
I
I
I
ii)
i)
Fe
Fe
Fe
4
24
25
Scheme 6. Enantioselective halogen–lithium exchange on 3 and 4. Reagents: (i) n-BuLi/sparteine; (ii) benzophenone; (iii) cyclohexanone; (iv) fluorenone.
ture. In contrast to entry 3 in Table 2, the product 13a was obtained
only in a racemic form. This is a good support for the kinetic enan-
tioselective discrimination occurring at the halogen–lithium ex-
3. Discussion
3.1. Aryl dibromide 1
change step, thus eliminating
a
dynamic thermodynamic
resolution process.27d
The aforementioned experimental results show that some chiral
recognition may occur between the chiral alkyllithium generated
in situ and the aryl dibromide 1, wherein the formation of the aryl-
lithium intermediate 12 was confirmed by the isolation of 13b and
13c after its protonolysis and deuterolysis, respectively (Scheme
4).31,32 Aryllithium 12 should be enantiomerically stable at
ꢀ78 °C. Indeed, the quenching with BocN@NBoc led to the stable
enantioenriched atropoisomeric 13a, where the ee value was mea-
sured by chiral HPLC. The possibility of thermodynamic control by
racemization of 12 (see Scheme 4) via the rotation around the aryl-
aryl bond at ꢀ78 °C followed by an equilibration between the dia-
3.2. 1,2-Dibromonorbornadiene 3
The quenching of 22 (Scheme 6) with ketones less reactive than
benzophenone suggests that the selectivity is dependent on the
nature of the electrophile. For example, cyclohexanone and fluore-
none gave the expected alcohol in excellent yield (87% and 85%,
respectively), but the enantioselectivity is decreased (8% ee with
cyclohexanone and 2% ee with fluorenone). Thus, in the norborna-
diene series a dynamic racemization may be present during the
quenching, resulting in decreased ee of 23. Despite our various tri-
als with different concentrations and ligands, no significant
improvement was observed. The absolute configuration of prod-
ucts 23 has not been established.
stereomeric pairs of rac-12 and the chiral ligand (L ) was ruled out
*
in the following way. (ꢀ)-Sparteine 14 as a ligand was added to the
solution of dl-12 firstly prepared from 1 and n-BuLi in diethyl ether
at ꢀ78 °C followed by subsequent stirring at the same tempera-

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C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
3.3. 1,2-Diiodoferrocene 4
amount. A systematic screening of chiral ligands and prochiral sub-
strates is now being actively pursued. From the NMR results ob-
tained in chiral oriented solvents arise pertinent and exciting
questions on a possible correlation between the magnitude of
spectral enantiotopic discriminations in prochiral compounds dis-
solved in those media and the ee measured after the chemical
desymmetrization of the molecule.
The absolute configuration of the products generated by the
enantioselective lithiation with sparteine was established in the
following way. The quenching of lithiated ferrocene 24 with DMF
gave (Sp)-2-iodoferrocenecarboxaldehyde 26,
a known com-
pound,14b in 20% ee (Scheme 7). To confirm this result, alcohol
25 was synthesized starting from sulfoxide (SS)-10 (Scheme 8). It
was deprotonated by LDA, and the lithiated derivative was
quenched with benzophenone. Two equivalents of t-BuLi were
added to deprotonate the alcohol and to remove the sulfinyl group,
a subsequent addition of 1,2-diiodoethane led to the expected
product (Sp)-25 (Scheme 8).
5. Experimental
5.1. General
All reactions involving air-sensitive compounds were carried
out under an argon atmosphere in an oven or flame-dried Schlenk
flasks, which were cooled by the vacuum-argon cycle. The solvents
used were purified by distillation over the drying agents (indicated
in brackets), and were transferred under argon: hexane (CaH2),
OEt2 (Na), THF (Na), CH2Cl2 (CaH2), and toluene (CaH2). n-BuLi
(1.6 M and 2.5 M in hexanes), t-BuLi (1.5 M in pentane), and
CaH2 (93%, 0–2 mm) were purchased from Acros Organics and used
as received. Other commercially available compounds were also
used as received (unless otherwise noted). (R)-Tetrahydrofuran-
2-carboxylic acid (Acros) is 99% purity and 98% ee. All reactions
were monitored by thin-layer chromatography (TLC) on Merck Sil-
ica Gel 60 F254 plates using UV light as a visualizing agent, and a 5%
solution of phosphomolybdic acid in EtOH and heat as developing
agents. Merck silica gel (230–400 mesh) was used for the flash col-
umn chromatography. Preparative thin-layer chromatography
(PLTC) separations were carried out on self-made 0.3 mm Merck
Silica Gel 60 F254 plates. 1H NMR and 13C NMR spectra were re-
corded in CDCl3 solution (unless otherwise noted) on an AC–200
Bruker spectrometer (m1 = 200 MHz and (m13 = 50 MHz). Chemical
shifts (d) are denoted in ppm and calibrated by using residual
undeuterated solvent as an internal reference. Coupling constants
are reported in Hertz. The GC–MS and MS data were obtained with
EI (70 eV) or ESI technique, and the relative intensity (%) is given in
brackets. High-resolution mass spectral analysis (HRMS) data were
measured on a MS Finnigan-MAT-95-S by means of EI or ESI tech-
nique. Optical rotations were measured using a 1 mL cell with a
1 dm path length on Perkin Elmer 341 polarimeter, and concentra-
tions (c) were reported in g/100 mL. Analytical HPLC was recorded
on a HPLC machine equipped with a Spectra Series P100 pump and
a Spectra Series UV100 detector. The chiral stationary phases were
either Daicel Chiralcel OD-H, (S,S)-Whelk 01, Chiralpak AD or (S,S)-
ULMO.
The stereochemical course of the formation of 1,2-disubstituted
ferrocenes from (SS)-10 (similar to those depicted in Scheme 8) has
been firmly established.33,34 We have thus clearly proved that the
pro-R iodide in 4 had been exchanged preferentially when (ꢀ)-
sparteine is the chiral auxiliary (Scheme 7).35 It is interesting to no-
tice that the use of two or more equivalent of n-BuLi does not yield
to the double iodide–lithium exchange reaction in ferrocene and
norbornadiene series. Only the mono-exchanged compounds were
obtained. This result originates from the unfavorable charge repul-
sion of vicinal dianionic species.
3.4. Possible correlation between anisotropic NMR and
chemical desymmetrization
From a comparison of the results obtained in chemistry and in
NMR in chiral mesophases arises an intriguing conceptual ques-
tion. Is it possible to draw a parallel between the magnitude of
spectroscopic enantiodiscriminations occurring in a series of ana-
loguous prochiral compounds interacting with PBLG systems and
the efficiency of desymmetrization of those same molecules when
using a chiral reagent? Here, the role of the chiral auxiliary and the
polypeptide is rather similar with regards to the site recognition
phenomenon. In this context, it could be useful to find empirical
correlations or rules between both phenomena (ee vs magnitude
of spectral enantiotiopic discriminations) in order to predict, from
NMR measurements, the ee that could be obtained by desymmet-
rizing a given prochiral substrate, or vice versa. Such challenging
investigations are currently underway.
H
C
4. Conclusion
We have, for the first time, shown an enantioselective halogen–
lithium mono-exchange reaction of some prochiral and meso aro-
matic or vinylic dihalides. This exploratory study paves the way
to the design and use of structurally diverse achiral substrates in
asymmetric halogen–metal exchange reaction. Presently, (ꢀ)-spar-
teine is the best ligand for the protocol of enantioselective halo-
gen–lithium exchange. The preliminary screening of various
chiral ligands showed some positive results giving hope of the dis-
covery of more effective ligands, even efficient in a catalytic
5.2. Preparation of 1,3-dibromo-5-methyl-2-(10-
naphthyl)benzene 1
To a Schlenk flask cooled by the vacuum-argon cycle were sepa-
rately added 1,3-dibromo-2-iodo-5-methylbenzene 5 (600.0 mg,
1.6 mmol), 1-naphthaleneboronic acid 6 (274.5 mg, 1.6 mmol), LiOH
(153.6 mg, 6.4 mmol), and Pd(PPh3)4 (184.4 mg, 1.6 ꢁ 10ꢀ1 mmol).
Ph
Ph
CHO
I
I
OH
I
I
OEt2
OEt2
Fe
Fe
Fe
i) n-BuLi, sparteine
i) n-BuLi, sparteine
ii) PhCOPh
ii) DMF
(Sp)-26
(Sp)-25
4
Scheme 7. Synthesis of (Sp)-25 and (Sp)-26 from 4.

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2673
Ph
Ph
Ph
I
Ph
OH
O
O
OH
S
S
°
°
iii) t-BuLi
°
i) LDA
°
Fe
Fe
Fe
p-tolyl
p-tolyl
iv) C2H4I2
ii) PhCOPh
(Sp)-25
27
(SS)-10
Scheme 8. Synthesis of (Sp)-25 from (SS)-10 via 27.
This Schlenk flask was kept in vacuo and then backfilled with argon
3 times. A freshly prepared solution of CH3CN/H2O (10:1, 200 mL)
was strictly degassed 3 times following the standard freezing-vac-
uum/warming-vacuum process under argon to give the oxygen-
free solution of CH3CN/H2O (10:1, 120 mL). This solution was
transferred into the above Schlenk flask through a double-tipped
needle under argon. The mixture was stirred and heated at about
70 °C under argon, in which the yellowish reaction solution faded
slowly and a white suspension was generated gradually. After
12 h, the heating was stopped, and the distilled n-pentane
(300 mL) was added to the above reaction mixture which was
cooled to rt. n-Pentane phase was separated, and the aqueous
CH3CN layer was extracted with n-pentane (5 ꢁ 300 mL), and the
combined n-pentane phases were dried over MgSO4. After removal
of the solvent in vacuo, the residue was purified by flash column
chromatography on silica gel eluting with distilled n-pentane to af-
5.4. Preparation of 2,3-dibromonorbornadiene 3
This compound was prepared according to the literature
procedure.14a
5.5. Preparation of 1,2-diiodoferrocene 4
(S)-Ferrocenylsulfoxide (SS)-10 was prepared according to the
literature.14b It was treated by LDA and then by ClSnBu3 giving
sulfoxide (SS,Rp)-11 in 87% isolated yield, in agreement with Ref.
14a. The preparation of 1,2-bis(tri-n-butyltin)ferrocene from 11
has been achieved as follows. Under argon, 11 (2.9 g, 4.7 mmol)
was dissolved in Et2O (30 mL). At ꢀ78 °C, t-BuLi (3.77 mL,
5.65 mmol) was added dropwise to the mixture, and the stirring
was maintained for 30 min. Then tri-n-butyltin chloride (1.66 mL,
6.11 mmol) was added dropwise. The mixture was stirred for a fur-
ther 30 min at this low temperature and then 2 h at rt. The mixture
was quenched by adding water (20 mL) and diluted with Et2O
(30 mL). The organic layer was washed twice with water, dried
over Na2SO4, filtered, and the solvent was then removed under re-
duced pressure. By-products were evaporated by heating the crude
oil at 60 °C under vacuum. Most of t-Bu p-Tol sulfoxide was re-
moved by crystallization with pentane in the freezer (ꢀ30 °C).
The bis(tri-n-butyltin)ferrocene isolated was not analyzed but used
as such to undergo the iodide–tin exchange reaction. The transfor-
mation of the bis–tin compound into 4 was carried out by the addi-
tion of 2 equiv of I2 in CH2Cl2 (stirring overnight at rt). Isolated
yield: 83% (from 11), as a red oily solid. 1H NMR: d = 4.51 (d, 2H,
J = 2.5 Hz, H ortho), 4.24 (t, 1H, J = 2.5 Hz, H meta), 4.18 (s, 5H,
Cp); 13C NMR: d = 74.5 (2 ꢁ CH), 74.1 (5 ꢁ CH), 70.5, 51.9 (2 ꢁ C);
Anal. Calcd for C10H8FeI2: C, 27.43; H, 1.84. Found: C, 27.63; H,
1.89. Spectroscopic data in agreement with the literature.14b
ford aryl dibromide
1
(492.0 mg, 1.3 mmol, 82%). 1H NMR:
d = 7.99–7.95 (m, 2H), 7.64–7.34 (m, 7H), 2.44 (s, 3H); 13C NMR:
d = 140.7, 138.8, 138.4, 133.5, 132.4 (2 ꢁ CH), 131.1, 128.5, 128.4,
127.2, 126.4, 126.0, 125.3, 125.0 (2 ꢁ C), 124.9, 20.5; GC–MS
(70 eV): m/z (%): 378 (7.9) [M(81Br2)]+, 376 (15.2) [M(81Br,79Br)]+,
374 (7.5) [M(79Br2)]+, 217 (16.8) [Mꢀ2Br+H]+, 216 (100) [M-
2Br]+, 215 (64.6) [Mꢀ2BrꢀH]+, 213 (18.6), 189 (8.4), 108 (29.0),
94 (31.3); HRMS (EI): m/z calcd for C17H1279Br2: 373.9300; found:
373.9330 [M]+
.
5.3. Preparation of meso-2,2-dimethyl-4,5-bis(20-
bromophenyl)-1,3-dioxolane 2
Meso-9 (227.0 mg, 6.1 ꢁ 10ꢀ1 mmol), 1,2-dimethoxypropane
(2.0 mL, 16.2 mmol), and p-toluene-sulfonic acid (8.0 mg,
4.6 ꢁ 10ꢀ2 mmol) were stirred in anhydrous hexane (10 mL) under
argon. After stirring for 30 min at 50 °C, the reaction mixture was
kept at 40 °C for 6 h. A saturated aqueous solution of NaHCO3
was added and stirring continued for 30 min. The mixture was ex-
tracted with OEt2 (3 ꢁ 150 mL), and the extract dried over MgSO4
and evaporated under reduced pressure. The crude product was
purified by flash column chromatography on silica gel, eluting with
n-pentane/ethyl acetate 100/0?100/1, to give meso-2 (238.8 mg,
5.8 ꢁ 10ꢀ1 mmol, 95%). 1H NMR: d = 7.31 (dd, J = 1.2, 7.8 Hz,
2 ꢁ 1H; 3-ArH), 7.29 (dd, J = 1.7, 7.8 Hz, 2 ꢁ 1H; 6-ArH), 7.08 (td,
J = 1.2, 7.8 Hz, 2 ꢁ 1H; 5-ArH), 6.95 (td, J = 1.7, 7.8 Hz, 2 ꢁ 1H; 4-
ArH), 6.02 (s, 2 ꢁ 1H), 1.84 (s, 3H), 1.66 (s, 3H); 13C NMR:
d = 136.4 (2 ꢁ C), 132.1 (2 ꢁ CH), 129.8 (2 ꢁ CH), 128.9 (2 ꢁ CH),
126.4 (2 ꢁ CH), 123.5 (2 ꢁ C), 108.7, 79.4 (2 ꢁ CH), 26.7, 24.4;
GC–MS (70 eV): m/z (%): 414 (0.1) [M(81Br2)]+, 412 (0.2)
[M(81Br,79Br)]+, 410 (0.1) [M(79Br2)]+, 399 (0.2) [M(81Br2)ꢀCH3]+,
397 (0.4) [M(81Br,79Br)ꢀCH3]+, 395 (0.2) [M(79Br2)–CH3]+, 228
(79.0) [M(81Br,Br)ꢀBrC6H4CHO]+, 226 (84.3) [M(79Br,Br)ꢀBrC6
H4CHO]+, 171 (29.8), 169 (32.4), 165 (30.8), 147 (100), 129
(33.0), 90 (10.6), 89 (86.7), 77 (14.3), 63 (9.8), 43 (26.6); HRMS
(EI): m/z calcd for C16H13O279Br2: 394.9277; found: 394.9262
[MꢀCH3]+.
5.6. Preparation of 1,3-dibromo-2-iodo-5-methylbenzene 5
4-Methyl-2,6-dibromoaniline (10.0 g, 38.0 mmol) was dissolved
in concentrated AcOH (200 mL) and added to concentrated H2SO4
(40 mL) at 0 °C. This solution was added slowly at 0 °C to a mixture
of NaNO2 (6.9 g, 100.0 mmol), concentrated H2SO4 (50 mL), and
concentrated AcOH (100 mL) under argon for 1 h at 0 °C, and the
reaction temperature was maintained in the range ꢀ5 °C to +5 °C.
After stirring for 1 h at 0 °C, the mixture was warmed to rt. The
resulting mixture was added to a freshly prepared solution of KI
(34.7 g, 209.0 mmol), I2 (48.0 g, 189.0 mmol), urea (4.6 g,
76.0 mmol), H2O (400 mL), and CHCl3 (100 mL). The above solution
was strongly stirred at rt overnight, and then Na2SO3 (46.0 g,
365.0 mmol) was added. The aqueous layer was separated and ex-
tracted with CHCl3 (2 ꢁ 300 mL). The combined organic phases
were washed with
a saturated aqueous solution of Na2CO3
(300 mL), and then dried over MgSO4. Evaporation of the solvent
under reduced pressure gave the crude product, which was puri-
fied by flash column chromatography on silica gel eluting with
n-pentane to yield dibromo iodide 5 (12.2 g, 32.4 mmol, 86%). 1H

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C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
NMR (200 MHz): d = 7.38 (s, 2H), 2.25 (s, 3H); 13C NMR: d = 141.0,
131.9 (2 ꢁ CH), 130.7 (2 ꢁ C), 104.8, 20.4; GC–MS (70 eV): m/z (%):
378 (51.8) [M(81Br2)]+, 376 (100) [M(81Br,79Br)]+, 374 (62.4)
[M(79Br2)]+, 297 (27.5) [M(81Br,Br)ꢀBr]+, 295 (24.9) [M(79Br,Br)ꢀBr]+,
251 (4.0) [M(81Br2)ꢀI]+, 249 (8.6) [M(81Br,79Br)ꢀI]+, 247 (4.2)
[M(79Br2)ꢀI]+, 170 (40.7) [M(81Br,Br)ꢀBrꢀI], 168 (36.4) [M(79Br,Br)ꢀ
BrꢀI], 127 (8.4) [I]+, 90 (10.0), 89 (93.5) [Mꢀ2BrꢀI]+, 86 (21.5), 63
(31.0), 44 (24.6).
via microsyringe, and the resulting mixture was stirred for
30 min at ꢀ78 °C. Dibromide 1 (15.0 mg, 4.0 ꢁ 10ꢀ2 mmol) in
anhydrous toluene (2 mL) was then slowly added dropwise. After
15 min, the substrate was completely consumed as monitored by
TLC, and then a powder of freshly recrystallized di-tert-butyl azo-
dicarboxylate, BocN@NBoc (18.4 mg, 8.0 ꢁ 10ꢀ2 mmol), was di-
rectly added at ꢀ78 °C. This reaction medium was vigorously
stirred for 2 h at ꢀ78 °C, and quenched by saturated brine
(10 mL) at the same temperature. The aqueous layer was extracted
with EtOAc (3 ꢁ 100 mL), and the combined organic phases dried
over MgSO4. Evaporation of the solvent followed by purification
by flash column chromatography on silica gel, eluting with n-pen-
tane/ethyl acetate 10:1, gave the product 13a (15.0 mg,
5.7. Preparation of 1,2-bis(20-bromophenyl)-2-hydroxyetha-
none 8
To a 100 mL flask fitted with a reflux condenser were added
2-bromobenzaldehyde
7
(12.6 g, 68.1 mmol) and EtOH (99%,
2.85 ꢁ 10ꢀ2 mmol, 71%; ½a 2D0
¼ ꢀ2:8 (c 1.4, CHCl3)). An enantio-
ꢂ
15 mL). A solution of NaCN (667.0 mg, 13.6 mmol) in 95% EtOH
(15 mL) was added. It was stirred and refluxed for 4 h under argon,
and then cooled to rt. The reaction solvent was directly evaporated
in vacuo followed by the addition of saturated brine (75 mL) and
EtOAc (100 mL). The aqueous layer was extracted with EtOAc
(3 ꢁ 100 mL) (Caution: this aqueous cyanide solution is highly toxic),
and the combined organic phases were dried over MgSO4. Evapora-
tion of the solvent under reduced pressure gave the crude product,
which was purified by flash column chromatography on silica gel
(n-pentane/ethyl acetate 50/1?20/1) to give oily rac-benzoin 8
(3.8 g, 10.3 mmol, 30%). 1H NMR: d = 7.58–7.10 (m, 8H), 6.37 (s,
1H), 4.55 (br s, 1H; OH); 13C NMR: d = 201.4, 137.4, 136.1, 133.5,
133.1, 132.2, 130.2, 129.2, 128.8, 127.9, 126.9, 124.1, 119.6, 77.2;
GC–MS (70 eV): m/z (%): 291 (2.1) [M(81Br,Br)ꢀBr]+, 289 (2.3)
meric excess of 26% was determined by HPLC using Chiralpak AD
column (hexane/i-PrOH 95:5; flow rate 0.5 mL/min;
smajor = 11.5 -
min, minor = 14.8 min). The enantiomer with the shorter retention
s
time is levorotatory in CHCl3. 1H NMR: d = 7.91 (m, 1H), 7.87 (m,
1H), 7.56–7.35 (m, 7H), 6.33–5.26 (m, 1H), 2.44 (s, 3H, Me),
1.47–1.22 (m, 18H, t-Bu). The complexity of the spectra is coming
from rotamers introduced by the N(Boc)–NHBoc system; MS (ESI):
m/z (%): 552 (29.4) [M(81Br)+H+Na]+, 551 (100) [M(81Br)+Na]+, 550
(30.8) [M(79Br)+H+Na]+, 549 (96.3) [M(79Br)+Na]+, 451 (46.3)
[M(81Br)ꢀCO2ꢀH2C@C(CH3)2+Na]+, 449 (45.7) [M(79Br)–CO2–H2C@
C(CH3)2+Na]+, 395 (29.5) [m/z 451–H2C@C(CH3)2]+, 393 (29.8) [m/z
449–H2C@C(CH3)2]+, 351 (9.6) [m/z 395–CO2]+, 349 (9.6) [m/z 393–
CO2]+, 311 (8.1), 275 (12.6), 231 (37.7); HRMS (EI): m/z calcd for
C27H31O4N279Br: 526.1462; found: 526.1446 [M]+.
[M(79Br,Br)ꢀBr]+, 187 (18.7)
[
81BrC6H4CH(OH)]+, 185 (100)
79BrC6H4C@O]+,
[
81BrC6H4C@O+79BrC6H4CH(OH)]+, 183 (87.5)
[
5.10. Procedure B for the synthesis of N,N0-bis(tert-
butoxycarbonyl)-3-bromo-5-methyl-2-(1-naphthyl)-phenyl-
hydrazine (13a, entry 5 of Table 2)
157 (17.9), 155 (13.0), 78 (12.3), 77 (39.4), 76 (11.8).
5.8. Preparation of meso-1,2-bis(20-bromophenyl)ethane-1,
2-diol 9
To a 25 mL Schlenk flask were added (ꢀ)-sparteine (12.2 mg,
12.0
l
L, 5.2 ꢁ 10ꢀ2 mmol), dibromide
1
(15.0 mg, 4.0 ꢁ 10ꢀ2
mmol), CaH2 (10.0 mg, 2.4 ꢁ 10ꢀ1 mmol), and dry toluene (3 mL)
under argon at rt. This solution was efficiently stirred for 30 min,
and then cooled to ꢀ78 °C with an acetone/dry ice bath. A solution
To a 100 mL Schlenk flask were added rac-benzoin 8 (518.0 mg,
1.4 mmol) and dry THF (15 mL) under argon. This stirred solution
was cooled to ꢀ78 °C with an acetone/dry ice bath. A solution of
LiBH(s-Bu)3 (L-Selectride) (1.0 M in THF, 5.6 mL, 5.6 mmol) was
added dropwise to the above reaction mixture via microsyringe,
and then stirred at ꢀ78 °C for 5 h. The reaction mixture was
quenched with aqueous NaOH (3 M, 8 mL) followed by a slow
addition of H2O2 (35%, 4 mL) at 0 °C. The resulting mixture was
strongly stirred for additional 2 h at rt. After the extraction of
EtOAc (3 ꢁ 100 mL), the combined organic phases were washed
with saturated brine, dried over MgSO4, and concentrated under
reduced pressure on a rotatory evaporator. The crude product
was carefully purified by flash column chromatography on silica
gel (n-pentane/ethyl acetate 15/1?10/1) to furnish meso-9
(393.0 mg, 1.1 mmol, 78% yield, >95% de). 1H NMR (CDCl3):
d = 7.43–7.38 (m, 2 ꢁ 1H), 7.29–7.06 (m, 2 ꢁ 3H), 5.56 (s, 2 ꢁ 1H),
3.12 (br s, 2H; 2 ꢁ OH); 13C NMR: d = 137.8 (2 ꢁ C), 132.0
(2 ꢁ CH), 129.2 (2 ꢁ CH), 129.1 (2 ꢁ CH), 127.0 (2 ꢁ CH), 123.9
(2 ꢁ C), 74.2 (2 ꢁ CH).
of n-BuLi (1.6 M in hexane, 32.0
l
L, 5.2 ꢁ 10ꢀ2 mmol) was added
via microsyringe to the above cold solution, and the resulting mix-
ture was stirred vigorously at ꢀ78 °C. After 15 min, the substrate
disappeared completely as seen by TLC. A powder of freshly recrys-
tallized BocN@NBoc (18.4 mg, 8.0 ꢁ 10ꢀ2 mmol) was added di-
rectly to the above reaction mixture. It was stirred for 2 h at
ꢀ78 °C, and then quenched by saturated brine (10 mL) at the same
temperature. The aqueous phase was extracted with EtOAc
(3 ꢁ 100 mL), and the combined extracts dried over MgSO4. Evap-
oration of the solvent followed by purification by flash column
chromatography on silica gel, eluting with n-pentane/ethyl acetate
10:1, gave the product 13a (13.0 mg, 2.5 ꢁ 10ꢀ2 mmol, 62%;
½
a 2D0
ꢂ
¼ ꢀ5:3 (c 0.3, CHCl3)). An enantiomeric excess of 25% was
determined by HPLC as above. All other analytical data are the
same to those in the General Procedure A mentioned above.
5.11. Preparation of 2-bromo-4-methyl-1-(10-
naphthyl)benzene 13b
5.9. Procedure A for the synthesis of N,N-bis(tert-
butoxycarbonyl)-3-bromo-5-methyl-2-(10-naphthyl)-
phenylhydrazine (13a, entry 2 of Table 2)
To a 25 mL Schlenk flask were added (ꢀ)-sparteine 14 (40.5 mg,
40.0
l
L, 17.3 ꢁ 10ꢀ2 mmol), CaH2 (20.0 mg, 4.8 ꢁ 10ꢀ1 mmol), and
dry toluene (3 mL) under argon at rt. This solution was vigorously
To a 25 mL Schlenk flask cooled by the vacuum-argon cycle
stirred for 30 min, and then cooled to ꢀ78 °C with an acetone/dry
were added (ꢀ)-sparteine (12.2 mg, 12.0
l
L, 5.2 ꢁ 10ꢀ2 mmol),
ice bath.
A solution of n-BuLi (2.5 M in hexane, 69.0 lL,
CaH2 (10.0 mg, 2.4 ꢁ 10ꢀ1 mmol), and dry toluene (3 mL) under ar-
gon at rt. This solution was efficiently stirred for 30 min, and then
was cooled to ꢀ78 °C with an acetone/dry ice bath. A solution of
17.3 ꢁ 10ꢀ2 mmol) was added via microsyringe to the above cold
solution, and the resulting mixture was stirred for 30 min at
ꢀ78 °C. Dibromide 1 (50.0 mg, 13.3 ꢁ 10ꢀ2 mmol) in anhydrous
toluene (2 mL) was slowly added dropwise to the above cold
n-BuLi (2.5 M in hexane, 21.0
l
L, 5.2 ꢁ 10ꢀ2 mmol) was added

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2675
solution of the n-BuLi/14 complex. After 15 min, the substrate was
completely consumed as monitored by TLC, after which H2O
(2.0 mL) was directly added at ꢀ78 °C. The mixture was separated,
and the aqueous phase was extracted with Et2O (3 ꢁ 100 mL), and
the combined organic layers were dried over MgSO4. Evaporation
of the solvent at rt followed by purification by preparative TLC with
n-pentane as eluent gave monobromide 13b (31.5 mg,
10.6 ꢁ 10ꢀ2 mmol, 80%). The enantiomeric excess of 13b could
not be measured by chiral HPLC at rt. 1H NMR: d = 7.93–7.88 (m,
2H), 7.58–7.34 (m, 6H), 7.25–7.24 (m, 2H), 2.44 (s, 3H); 13C
NMR: d = 139.2, 139.1, 138.3, 133.4, 133.1, 131.7, 131.6, 128.2,
128.0, 127.9, 127.1, 126.0 (2 ꢁ CH), 125.8, 125.1, 124.0, 20.8; GC–
MS (70 eV): m/z (%): 298 (33.0) [M(81Br)]+, 296 (35.0) [M(79Br)]+,
217 (73.1) [MꢀBr]+, 202 (100) [MꢀBrꢀCH3]+, 108 (16.9), 107
(44.6), 94 (24.9); HRMS (EI): m/z calcd for C17H1379Br: 296.0195;
by purification by column chromatography on silica gel (n-pen-
tane/acetone 10:1) gave (R)-N,N-dibenzyl-tetrahydrofuran-2-car-
boxamide (546.8 mg, 1.8 mmol, 86%). 1H NMR: d = 7.41–7.18 (m,
10H), 4.74–4.47 (m, 5H), 4.11–4.00 (m, 1H), 3.95–3.82 (m, 1H),
2.40–2.28 (m, 1H), 2.17–1.85 (m, 3H); 13C NMR: d = 172.2, 137.0,
136.5, 128.8 (2 ꢁ CH), 128.5 (2 ꢁ CH), 128.1 (2 ꢁ CH), 127.5,
127.3, 126.7 (2 ꢁ CH), 75.8, 69.2, 49.4, 48.0, 28.9, 25.8; GC–MS
(70 eV): m/z (%): 295 (2.1) [M]+, 226 (2.4), 205 (5.5), 204 (41.2)
[MꢀC6H5CH2]+, 106 (35.0), 91 (100) [C6H5CH2]+, 71 (53.8), 43
(11.8). With this amide intermediate in hand, the preparation of
amine 19 was conducted as follows: to a 100 mL Schlenk flask
were added LiAlH4 (0.3 g, 7.9 mmol) and dry THF (5 mL) at
ꢀ78 °C under argon atmosphere. A solution of (R)-N,N-dibenzyl-
tetrahydrofuran-2-carboxamide (367.0 mg, 12.4 ꢁ 10ꢀ1 mmol) in
dry THF (15 mL) was added to the above suspension of LiAlH4 in
THF. After removing the cooling bath, the reaction mixture was
stirred at reflux overnight. The mixture was cooled to rt, and care-
fully quenched with aqueous NaOH (3M, 4 mL), followed by the
addition of EtOAc (40 mL). The organic layer was separated, and
the aqueous phase was extracted with EtOAc (3 ꢁ 100 mL). The
combined extracts were dried over MgSO4, and concentrated in va-
cuo. The residue was purified by column chromatography on silica
gel eluting with n-pentane/EtOAc (20:1) to give the oily amine 19
found: 296.0189 [M]+
.
The preparation of deuterated analog 13c and the relative ana-
lytical data are given in Ref. 32b.
5.12. Preparation of (1R,2R)-N,N0-dimethyl-N,N0-bis((10-
naphthyl)methyl)cyclohexane-1,2-diamine 17
To a solution of (1R,2R)-N,N0-dimethylcyclohexane-1,2-diamine
(0.1 g, 0.7 mmol) and AcOH (0.13 mL, 2.2 mmol) in MeOH (4 mL)
was added 1-naphthaldehyde (0.3 mL, 2.2 mmol) at rt. After stir-
ring for 0.5 h, NaBH3CN (138.0 mg, 2.2 mmol) was added. After
36 h, the solvent was removed in vacuo. Concentrated HCl was
added at 0 °C until pH < 2, followed by the addition of Et2O
(10 mL). The residue was taken up in 5 mL of H2O and extracted
with three 10-mL portions of Et2O. The aqueous solution was
brought to pH > 10 with solid KOH, saturated with NaCl, and ex-
tracted with five 10-mL portions of Et2O. The combined organic
phases were dried over MgSO4. After removal of the solvent under
reduced pressure, the crude product was purified by flash column
chromatography on silica gel eluting with EtOAc to afford the oily
(283.2 mg, 1.0 mmol, 81%; ½a D20
ꢂ
¼ þ30:0 (c 3.0, CHCl3)). 1H NMR:
d = 7.46ꢀ7.23 (m, 10H), 4.18ꢀ4.05 (m, 1H), 3.89–3.69 (m, 2H),
3.80 (ABq, J = 13.7 Hz, 2 ꢁ 1H), 3.60 (ABq, J = 13.7 Hz, 2 ꢁ 1H),
2.62 (d-ABq, J = 5.8, 17.1 Hz, 1H), 2.58 (d-ABq, J = 5.9, 17.1 Hz,
1H), 2.04–1.74 (m, 3H), 1.63–1.50 (m, 1H); 13C NMR: d = 139.8
(2 ꢁ C), 128.8 (2 ꢁ 2CH), 128.1 (2 ꢁ 2CH), 126.7 (2 ꢁ CH), 77.8,
67.8, 59.0 (2 ꢁ CH2), 57.5, 30.0, 25.3; GC–MS (70 eV): m/z (%):
281 (0.8) [M]+, 211 (12.2) [(C6H5CH2)2NCH3]+, 210 (72.4)
[(C6H5CH2)2NCH2]+, 181 (7.4), 92 (7.8) [C6H5CH3]+, 91 (100)
[C6H5CH2]+, 65 (5.6); HRMS (ESI): m/z calcd for C19H24ON:
282.1852; found: 282.1861 [M+H]+.
diamine 17 (0.1 g, 2.4 ꢁ 10ꢀ1 mmol, 34%; ½a D20
ꢂ
¼ þ15:2 (c 2.1,
5.14. Preparation of 4-(20-bromophenyl)-5-(20-deuterophenyl)-
2,2-dimethyl-1,3-dioxolane 21
CHCl3)). 1H NMR: d = 8.29 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.0 Hz,
2H), 7.76 (d, J = 7.6 Hz, 2H), 7.48–7.24 (m, 8H), 4.12 (ABq,
J = 13.4 Hz, 2 ꢁ 1H), 4.06 (ABq, J = 13.4 Hz, 2 ꢁ 1H), 2.83–2.79 (m,
2H), 2.19 (s, 6H), 2.18–2.08 (m, 2H), 1.85–1.81 (m, 2H), 1.38–
1.22 (m, 4H); 13C NMR: d = 136.0 (2 ꢁ C), 133.7 (2 ꢁ C), 132.6
(2 ꢁ C), 128.1 (2 ꢁ CH), 127.3 (2 ꢁ CH), 126.8 (2 ꢁ CH), 125.3
(2 ꢁ 2CH), 125.1 (2 ꢁ 2CH), 62.9 (2 ꢁ CH2), 56.4 (2 ꢁ CH), 36.2
(2 ꢁ CH3), 25.9 (2 ꢁ CH2), 25.4 (2 ꢁ CH2); GC–MS (70 eV): m/z
(%): 422 (3.0) [M]+, 282 (3.9), 281 (20.7) [MꢀC10H7CH2]+, 171
(12.4), 142 (14.1), 141 (100.0) [C10H7CH2]+, 115 (12.3), 112 (3.6),
44 (2.9); HRMS (ESI): m/z calcd for C30H35N2: 423.2795; found:
423.2790 [M+H]+.
To a 25 mL Schlenk flask were added (ꢀ)-sparteine 14 (11.1 mg,
11.0
l
L, 4.7 ꢁ 10ꢀ2 mmol), meso-2 (15.0 mg, 3.6 ꢁ 10ꢀ2 mmol),
CaH2 (10.0 mg, 2.4 ꢁ 10ꢀ1 mmol), and dry toluene (3 mL) under ar-
gon at rt. This solution was efficiently stirred for 30 min, and then
cooled to ꢀ78 °C with an acetone/dry ice bath. A solution of n-BuLi
(2.5 M in hexane, 19.0
l
L, 4.7 ꢁ 10ꢀ2 mmol) was added via micro-
syringe, and the resulting mixture was stirred for 15 min at ꢀ78 °C.
After the complete conversion as seen by TLC, it was quenched
with D2O (0.1 mL, 5.5 mmol) at ꢀ78 °C. After being stirred effi-
ciently for 1 h at rt, it was extracted with Et2O (3 ꢁ 100 mL). The
combined organic phases were dried over MgSO4, concentrated un-
der reduced pressure, and purified by PTLC, elution with n-pen-
tane/ethyl acetate 10:1, to give the deuterated product 21
(7.9 mg, 2.3 ꢁ 10ꢀ2 mmol, 72%). An ee of 13% was determined by
HPLC using Chiralpak AD column (hexane; flow rate 0.4 mL/min;
5.13. Preparation of (R)-N,N-dibenzyl-(tetrahydrofuran-2-
yl)methanamine 19
To a 100 mL Schlenk flask were added (R)-tetrahydrofuran-2-
carboxylic acid (250.0 mg, 21.6 ꢁ 10ꢀ1 mmol) and dry CH2Cl2
(6 mL) under argon atmosphere. The reaction solution was cooled
to about ꢀ15 °C, and treated with freshly distilled oxalyl chloride
(0.28 mL, 32.6 ꢁ 10ꢀ1 mmol) followed by a few drops of DMF.
The mixture was then warmed to rt, and stirred overnight. The sol-
vent was removed from the colorless reaction solution under re-
duced pressure and subsequently in vacuo, and then dry CH2Cl2
(3 mL) was added again under argon. The resulting solution of acyl
chloride was added dropwise to a solution of dibenzylamine
(1.3 mL, 6.5 mmol) in dry CH2Cl2 (15 mL) at rt under argon. After
stirring overnight, brine (20 mL) was added. The aqueous layer
was extracted with CH2Cl2 (3 ꢁ 100 mL), and the combined organic
phases were dried over MgSO4. Evaporation of the solvent followed
s
minor = 20.6 min, s
major = 24.5 min). 1H NMR: d = 7.28 (dd,
J = 1.7 Hz, 1H), 7.23 (dd, J = 1.2 Hz, 1H), 7.13–6.97 (m, 5H), 6.87
(td, J = 1.7, 7.6 Hz, 1H), 5.84 (ABq, J = 7.5 Hz, 1H), 5.63 (ABq,
J = 7.5 Hz, 1H), 1.82 (s, 3H), 1.61 (s, 3H); 13C NMR: d = 137.8,
137.1, 131.7, 128.6, 128.5, 127.3 (2 ꢁ CH), 127.2, 127.1, 126.7,
122.0, 108.7, 80.2, 80.1, 26.6, 24.3, and one carbon (C2H) was not
observed because of its weak 13C NMR signal; GC–MS (70 eV): m/
z
(%): 335 (0.2) [M(81Br)]+, 333 (0.2) [M(79Br)]+, 320 (0.7)
[M(81Br)ꢀCH3]+, 318 (0.7) [M(79Br)ꢀCH3]+, 278 (3.0) [M(81Br)–
CH3COCH3+H], 276 (3.1) [M(79Br)–CH3COCH3+H], 228 (67.5)
½Mð81BrÞ ꢀ C6H42HCHOꢂþ, 226 (71.7) ½Mð79BrÞ ꢀ C6H42HCHOꢂþ, 171
(26.2), 169 (26.9), 149 (90.7) [MꢀBrC6H4CHO]+, 148 (58.6), 147
(100), 129 (28.5), 106 (23.3), 92 (29.3), 91 (45.1), 89 (82.6), 77

2676
C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
(17.4), 43 (34.0); HRMS (EI): m/z calcd for C16H132HO279Br:
318.0234; found: 318.0234 [MꢀCH3]+.
in Et2O (1 mL) was added to the mixture. The mixture was stirred
at ꢀ78 °C for 1 h and then cyclohexanone (50 L, 0.48 mmol) in
l
Et2O (1 mL) was added dropwise. The temperature was maintained
at this low temperature for 1 h and then the cooling bath was re-
moved. The mixture was stirred at room temperature for another
2 h and then quenched with saturated NH4Cl aqueous solution.
The organic layer was washed twice with water, and dried over
MgSO4. After filtration, the solvent was removed under reduced
pressure. The crude product was purified on TLC plate eluting pen-
tane/Et2O (8/2) yielding 93 mg (87%) of a pale yellow oil. 1H NMR:
d = 6.88 (dd, 1H, J = 3.2 Hz, J = 5.0 Hz), 6.78 (dd, 1H, J = 3.0 Hz,
J = 4.8 Hz), 3.71 (br s, 1H), 3.47 (br s, 1H), 2.17 (d, 1H, J = 6.0 Hz),
1.94 (d, 1H, J = 6.0 Hz), 1.67 (m, 10H), CH2. 13C NMR: d = 154.12,
142.39, 141.79, 126.90, 72.82, 70.77, 60.55, 52.84, 35.48, 35.11,
5.15. Preparation of (3-bromobicyclo[2.2.1]hepta-2,5-dien-2-
yl)-diphenyl-methanol 23a
(ꢀ)-Sparteine (101
l
L, 0.56 mmol) was dissolved in Et2O (4 mL).
Under argon at ꢀ78 °C, n-BuLi (192
l
L, 0.44 mmol) was added
dropwise, and the mixture was stirred at this temperature for
30 min. 2,3-Dibromonorbornadiene (100 mg, 0.4 mmol) dissolved
in Et2O (1 mL) was added to the mixture. The mixture was stirred
at ꢀ78 °C for 1.5 h, and then benzophenone (96 mg, 0.48 mmol)
in diethyl ether (1 mL) was added dropwise. The temperature was
maintained at this low temperature for 1 h and then the cooling
bath was removed. The mixture was stirred at room temperature
for another 2 h and then quenched with saturated NH4Cl aqueous
solution. The organic layer was washed twice with water, and dried
over MgSO4.. After filtration, the solvent was removed under re-
duced pressure. The crude product was purified on TLC plate eluting
with pentane/Et2O (9/1) yielding 115 mg (85%) of an uncolored oil.
1H NMR: d = 7.35 (m, 10H), 6.83 (dd, 1H, J = 3.0 Hz, J = 4.4 Hz), 6.53
(dd, 1H, J = 3.0 Hz, J = 4.4 Hz), 3.62 (br s, 1H), 3.47 (br s, 1H), 3.05 (s,
1H), 2.41 (d, 1H, J = 6.0 Hz), 1.99 (d, 1H, J = 6.2 Hz). 13C NMR:
d = 152.98, 143.79, 142.45, 140.12, 129.7, 128.04, 127.93, 127.54,
80.70, 70.26, 60.65, 54.46. HRMS (ES): m/z calcd for C20H17BrONa:
375.04 (100.0%), 376.04 (21.9%), 377.03 (97.3%), 378.04 (21.3%),
found 375.1 (100%), 376.1 (21.5%), 377.1 (97%), 378.1 (21.7%). 25%
ee (measured by HPLC on (S,S)-ULMO column with hexane/i-PrOH
25.45, 21.39 (2 C); HRMS (ES): m/z calcd for C13H17BrONa:
*
291.04 (100.0%), 292.04 (14.3%), 293.03 (98.4%), 294.04 (13.9%),
295.04 (1.1%), found: 291.04 (99.0%), 293.03 (100.0%). 8% ee (mea-
sured by HPLC on ODH column with hexane/i-PrOH 99/1; flow rate
0.8 mL/min; sminor = 8.0 min, smajor = 8.38 min).
5.18. Preparation of 1-iodo, 2-diphenylmethanol-ferrocene
(Sp)-25
(ꢀ)-Sparteine (60
l
L, 0.25 mmol) was dissolved in Et2O (2 mL).
Under argon at ꢀ78 °C, n-BuLi (100
lL, 0.25 mmol) was added
dropwise, and the mixture was stirred at this temperature for
30 min. 1,2-Diiodoferrocene 4 (100 mg, 0.23 mmol) dissolved in
Et2O (1 mL) was added to the mixture. The mixture was stirred
at ꢀ78 °C for 1.5 h and then benzophenone (54 mg, 0.29 mmol)
in Et2O (1 mL) was added dropwise. The low temperature was
maintained for 1 h and then the cooling bath was removed. The
mixture was stirred at rt for another 2 h and hydrolyzed with sat-
urated NH4Cl aqueous solution. The organic layer was washed
twice with water, and dried over MgSO4. After filtration, the sol-
vent was removed under reduced pressure. The crude product
was purified on a TLC plate eluting with pentane/Et2O (9/1) yield-
ing 97 mg (86%) of a yellow solid. 34% ee (measured by OD-H with
hexane/i-PrOH 99/1; flow rate 0.8 mL/min; sminor (Rp) = 7.6 min,
smajor (Sp) = 8.2 min). 1H NMR: d = 7.45 (m, 2H), 7.30 (m, 6H),
7.15 (m, 2H), 4.57 (br s, 1H), 4.30 (s, 5H), 4.18 (t, 1H, J = 2.5 Hz),
3.74 (s, 1H), 3.56 (dd, 1H, J = 1.5 Hz, J = 2.3 Hz). 13C NMR:
d = 173.92, 146.46, 145.48, 127.75, 127.66, 127.26, 127.01,
126.90, 97.52, 78.20, 71.77, 71.63, 68.22, 40.85. HRMS (ES): m/z
calcd for C23H19FeIO: 491.99 (6.4%), 493.98 (100.0%), 494.99
(25.1%), found: 491.2 (6.5%), 493.98 (100.0%), 494.99 (21.2%).
99/1; flow rate 0.8 mL/min; sminor = 6.9 min, smajor = 7.5 min).
5.16. Preparation of 9-(3-bromobicyclo[2.2.1]hepta-2,5-dien-2-
yl)-9H-fluoren-9-ol 23b
(ꢀ)-Sparteine (101
l
L, 0.56 mmol) was dissolved in Et2O (4 mL).
Under argon at ꢀ78 °C, n-BuLi (192
l
L, 0.44 mmol) was added
dropwise, and the mixture was stirred at this temperature for
30 min. 2,3-Dibromonorbornadiene (100 mg, 0.4 mmol) dissolved
in diethyl ether (1 mL) was added to the mixture. The mixture
was stirred at ꢀ78 °C for 1.5 h after which fluorenone (87 mg,
0.48 mmol) in Et2O (1 mL) was added dropwise. The low tempera-
ture was maintained for 1 h and then the cooling bath was re-
moved. The mixture was stirred at rt for another 2 h and then
quenched with saturated NH4Cl aqueous solution. The organic
layer was washed twice with water, and dried over MgSO4. After
filtration, the solvent was removed under reduced pressure. The
crude product was purified on TLC plate eluting with pentane/
Et2O (8/2) yielding 119 mg (85%) of a very pale yellow oil. 1H
NMR: d = 7.84 (d, 2H, J = 6.8 Hz), 7.61 (d, 2H, J = 7.2 Hz, 7.53 (m,
4H, 6.82 (dd, 1H, J = 2.7 Hz, J = 4.7 Hz, 6.51 (dd, 1H, J = 3.0 Hz,
J = 5.0 Hz, 3.60 (br s, 1H, 3.45 (br s, 1H), 3.05 (s, 1H), 2.39 (d, 1H,
J = 6.2 Hz), 1.97 (d, 1H, J = 6.3 Hz). 13C NMR: d = 196.77, 143.88,
142.52, 140.21, 137.64, 132.44, 130.09, 129.76, 128.31, 128.12,
128.01, 127.62, 80.8, 70.35, 60.74, 54.56. HRMS (ES): m/z calcd
for C20H15BrONa: 373.02 (99.0%), 374.02 (21.7%), 375.03 (100.0%),
376.02 (21.2%), 377.03 (2.2%), found: 373.1 (99.0%), 374.02
(21.4%), 375.1 (100.0%), 376.1 (21.2%), 377.1 (2.1%). 2% ee (mea-
sured by HPLC on (S,S)-ULMO column with hexane/i-PrOH 99/1;
5.19. Preparation of 1-iodo, ferrocenecarboxaldehyde (Sp)-26
See Ref. 14b.
5.20. NMR in PBLG solvent
The compositions of the oriented NMR samples for compounds
3 (and 4) are: 100 mg/(100 mg) of PBLG with DP = 782, 100 mg/
(40 mg) of solute, and 450 mg/(570 mg) of dry chloroform. Further
details on the method and NMR 2D experiments in PBLG can be
found in Refs. 16 and 19.
flow rate 0.8 mL/min; sminor = 8.15 min, smajor = 8.53 min).
Acknowledgments
5.17. Preparation of 1-(3-bromobicyclo[2.2.1]hepta-2,5-dien-2-
yl)-cyclohexanol 23c
We thank Université de Paris-Sud (XI) and CNRS for funding this
work. Two of us (C.-A. F. and B. F.) acknowledge Institut de Chimie
des Substances Naturelles of Gif-sur-Yvette for a financial support.
O.L. acknowledges CNRS MNESER for a Ph.D. grant. We are also
grateful to Dr. François Guibé for a generous gift of Pd(PPh3)4.
(ꢀ)-Sparteine (101
l
L, 0.56 mmol) was dissolved in Et2O (4 mL).
Under argon at ꢀ78 °C, n-BuLi (192
l
L, 0.44 mmol) was added
dropwise, and the mixture was stirred at this temperature for
30 min. 2,3-Dibromonorbornadiene (100 mg, 0.4 mmol) dissolved

C.-A. Fan et al. / Tetrahedron: Asymmetry 19 (2008) 2666–2677
2677
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