Computational Insight into 1,2-Diamine, -Diether, and -Amino Ether Chiral Ligand-Mediated Carbolithiation: A Case of Enantioinduction Reversal

Article abstract of DOI:10.1021/acs.joc.0c00832

trans-1,2-Cyclohexanediamine, -diether, and -amino ether were compared as chiral inducers in the asymmetric intramolecular carbolithiation of olefinic aryllithiums. Switching from diamine to ethereal ligands inverts the sense of asymmetric induction. This reversal of stereoselectivity was investigated through density functional theory calculations. High enantioselectivities observed with diether and amino ether ligands arise from favorable weak interactions between the ligand and the substrate. The relative efficiency of the three ligands and sense of stereoinduction for the most efficient diether and amino ether ligands prove to be foreseeable by modeling the reaction with the parent achiral 1,2-bidentate additives and comparing the diastereomeric transition states stemming from the two half-chair conformations of their lithium chelate.

Full text of DOI:10.1021/acs.joc.0c00832

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Article
Computational insight into 1,2-diamine, -diether, and -amino ether chiral
ligands-mediated carbolithiation: a case of enantioinduction reversal
Hélène Guyon, Anne-Sophie Castanet, and Anne Boussonnière
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00832 • Publication Date (Web): 29 Jun 2020
Downloaded from pubs.acs.org on June 29, 2020
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Computational insight into 1,2-diamine, -diether, and -amino ether chiral ligands-
mediated carbolithiation: A case of enantioinduction reversal
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Hélène Guyon, Anne-Sophie Castanet,* and Anne Boussonnière*
Institut des Molécules et Matériaux du Mans (IMMM) - UMR 6283 CNRS - Le Mans Université,
Avenue Olivier Messiaen, 72085 Le Mans, France
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anne.boussonniere@univ-lemans.fr, anne-sophie.castanet@univ-lemans.fr
Table of contents
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Li
or
MeO
OMe MeO
NMe2
up to 9:91 (exp.)
up to 1:99 (calc.)
Key
Li
non-covalent interactions
Li
71:29 (exp.)
80:20 (calc.)
Me2N
NMe2
ABSTRACT. trans-1,2-cyclohexanediamine, -diether and -amino ether were compared as chiral inducers in the
asymmetric intramolecular carbolithiation of olefinic aryllithiums. Switching from diamine to ethereal ligands
inverts the sense of asymmetric induction. This reversal of stereoselectivity was investigated through DFT
calculations. High enantioselectivities observed with diether and amino ether ligands arise from favorable weak
interactions between the ligand and the substrate. The relative efficiency of the three ligands and sense of
stereoinduction for the most efficient diether and amino ether ligands prove to be foreseeable by modeling the
reaction with the parent achiral 1,2-bidentate additives and comparing the diastereomeric transition states
stemming from the two half-chair conformations of their lithium chelate.
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Introduction
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Bidentate Lewis donor bases, such as 1,2-diamines and diethers, are known to alter organolithiums
reactivity, notably by reshaping their aggregation state in solution.1 This ability has long been exploited to achieve
asymmetric reactions by using (−)-sparteine in association with organolithiums.2 Major progress in this field has
also been achieved by the design of C2-symmetric diamine or diether ligands, e.g. L1 and L2, as efficient chiral
inducers (Figure 1).3,4
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Figure 1. Examples of bidentate Lewis donor bases
We recently described an alternative novel class of ligands, natural amino acid-derived 1,2-amino ethers L3a, which
at least equals and often outperforms the above-mentioned ligands in asymmetric intramolecular carbolithiation.
5,6
To date, identification of an effective chiral ligand still relies on a trial-and-error approach, mostly by modifying its
chiral carbon backbone. As a consequence, the key structural features of the ligands, responsible for achieving high
stereoselectivity, are not clearly identified and understood. In particular, there remains the intriguing question of
the impact of the Lewis basic chelating functional groups of the ligand (diamine, diether, amino ether) on the
stereoselectivity of the reaction. Indeed, little information on this particular point can be found in the literature
(Scheme 1).
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Bailey [6d]
Br
:
1. t-BuLi / L* (2.2 equiv)
L*
(R:S) er
R
pentane/Et2O or Et2O, -78 °C
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(R,R)-L4a 81:19
(S,S)-L2 88:12
(S,S)-L3b 90:10
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N
N
2. -78 °C to -40 °C
3. MeOH
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Alexakis [3b]
:
OMe
OMe
PhLi (2 equiv)
L* (2 equiv)
L*
(R:S) er
Ph
(R,R)-L4a 77:23
(R,R)-L2
S
t-Bu
N
t-Bu
N
Toluene, -25 °C
7:93
H
Our previous work [7]
:
1. NaphtLi (2.2 equiv)
L* (2.4 equiv)
L*
(Ra:Sa) er
F
CO2H
(R,R)-L4a 32:68
(R,R)-L4b 94: 6
Ra
toluene, -65 °C
CO2H
2. H3O+
Scheme 1. Comparison of chiral diamines, diethers and amino ethers as chiral ligands in literature
During an extensive screening of chiral ligands in enantioselective intramolecular carbolithiation - one of the scarce
study including amino ether ligands - Bailey observed that diamine (R,R)-L4a leads to the same major enantiomer
as both the diether (S,S)-L2 and amino ether (S,S)-L3b. 6d In their report on asymmetric 1,2-addition of aryllithium
to imines, Alexakis and al. described an enantioreversal between a 1,2-diamine and a 1,2-diether despite of the
same chirality of the ligand scaffolds. 3b However, from a rigorous point of view, the differences in the carbon
backbone of the ligands compared in these two studies prevents any formal conclusion on the impact of the
chelating groups. More conclusive results can be found from our study on atroposelective SNAr reaction, since a
reversal in product chirality was observed by switching from cyclohexanediamine (R,R)-L4a to parent diether (R,R)-
L4b. 7
Taken together, all the above results strongly suggest that the observed enantioreversal is not an accidental
phenomenon limited to SNAr but might be rather general when organolithium reagents are used as nucleophiles.
To further probe this assumption, we decided to formally compare diamine, diether and aminoether ligands (S,S)-
L4a-c (Figure 1) in the same enantioselective reaction. Our objective was not restricted to experimental results but
more importantly we aimed at a better understanding of the underlying factors responsible for the stereoinduction
through DFT studies, as this information could help further rational design of chiral ligands. Toward that goal, we
selected the intramolecular carbolithiation reaction as our model reaction, guided by our interest for this
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transformation5 and inspired by recent mechanistic studies on “racemic” carbolithiation8a-b. In this article, we report
the first computational study elucidating the origin of the enantioinduction reversal observed when switching from
1,2-diamine to 1,2-ethereal ligands in intramolecular carbolithiation.
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Computational methods
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PM6 semi-empirical conformational analyses were conducted with Spartan 14. Geometry optimizations
and IRC analysis were performed with the help of Gaussian 16 package in gas-phase at 298 K, employing DFT
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functional B3LYP-D3/6-31+G(d), including dispersion corrections by means of Grimme's D3 model. All the
optimized geometries were submitted to single point energy calculation and vibrational analysis at the B3LYP-D3/6-
311+G(d,p) level using polarizable continuum model (PCM) for implicit solvation with toluene. QTAIM analyses were
carried out by using AIMAll package (Version 15.09.27).10 The NCI analyses were conducted with the help of
Multiwfn11 and visualized using VMD. 12
Results and Discussion
Experimental results
To understand the influence of the amino versus the ether function of the chiral ligand on a carbolithiation
stereochemical course, we investigated a series of three 1,2-bidentate ligands: C2-symmetric diamine and diether
L4a and L4b and pseudo-C2-symmetric amino ether L4c.
To ensure that the trends in stereoselectivities are not substrate-dependent, two different substrates, 1a and 1b,
were evaluated in the L4-mediated enantioselective intramolecular carbolithiation (Scheme 2).
1. t-BuLi / (S,S)-L4 (2.2 equiv.)
toluene, -78 °C
4b
(S:R) er
4a
(R:S) er
Br
2. warm
3. MeOH
79:21
12:88
8:92
Z
Z
(S)-4a
(R)-4b
L4a
L4b
L4c
71:29
9:91
1a Z = CH2
1b Z = N-allyl
15:85
Scheme 2. Evaluation of ligands L4a-c in the intramolecular carbolithiation of substrates 1a and 1b.
Aryl bromides 1a and 1b were submitted to lithium-bromide exchange at -78 °C in toluene with 2.2 equiv. of the
preformed t-BuLi/chiral ligand complex. The resulting aryllithiums were warmed respectively to room temperature
and -40 °C to achieve the cyclization, then methanolized.13 The enantiomeric ratios were determined by chiral
stationary phase GC analysis. The highest stereoselectivities were obtained with either diether L4b (9:91 e.r. from
1a) or amino ether L4c (8:92 e.r. from 1b). In the field of chiral ligand-mediated synthesis, C2-symmetric chiral
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inducers have long been favored. As their element of symmetry reduces the number of diastereomeric pathways
of a reaction, they were believed to consistently lead to the best level of stereoinduction.14 This assumption has
restrained the design of C1-symmetric ligands, but numerous studies support now the relevance of such non-
symmetric chiral additives.15 The good levels of enantioinduction obtained with amino ether L4c further
demonstrate the potential of C1-symmetric ligands. Furthermore, as anticipated, a distinct reversal of
stereoselectivity was observed on both substrates between the ethereal ligands and diamine L4a, confirming that
the nature of the chelating functions affects not only the level of enantioselectivity but also its sense. In an effort
to rationalize these intriguing experimental results, we engaged in a computational study of the stereochemical
course of the bidentate ligand-mediated intramolecular carbolithiation of 1a.
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Earlier theoretical studies support a carbolithiation mechanism involving a lithium-alkene coordination, prior to the
intramolecular addition of the organolithium across the double bond.8 This coordination would take place upon
disaggregation of an oligomeric form of the aryllithium toward a monomeric complex. Thus, we assumed the
formation of complex 2a, preceding the carbolithiation, with a tetracoordination around the lithium atom, bound
to the double bond, the anionic carbon on the aromatic ring, and the bidentate Lewis donor base (Scheme 3).
1a
Li-Br exchange
4a
MeOH
Aggregated state
of aryllithium
Aggregated state
of 3a
Disaggregation
Aggregation
L
*
‡
*
L
'
*
L
L'
L
L'
Li
Li
Li
2a
intramolecular carbolithiation
transition state (TS)
3a
Stereodetermining step of the reaction
Scheme 3. Global carbolithiation process from bromoarene 1a to indane 4a
Once the cyclization is achieved via a four-center transition state, the resulting organolithium 3a likely evolves
towards a more stable aggregated state with tetracoordinated lithium atoms. Our focus being on the
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stereochemical course of the carbolithiation, the following study aims at modeling the stereodetermining step of
the reaction (2a  TS  3a).
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To validate the model, the computation was first carried out on the carbolithiation reaction mediated by achiral
bidentate additives L5a-c (Figure 1).16
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Achiral 1,2-bidentate ligands
For each ligand a similar approach was carried out to investigate the reaction pathway17: a semi-empirical
conformational analysis of the precomplexes 2a was conducted followed by elucidation of the corresponding
transition states (TS2a-3a) at the B3LYP-D3/6-31+G(d) DFT level in gas-phase at 298 K. For each resolved TS, an
Intrinsic Reaction Coordinate (IRC) analysis was conducted and the corresponding precomplex 2a and final product-
ligand complex 3a geometries were optimized at the same DFT level. Eventually the energies of 2a, TS, and 3a were
refined at the PCM(toluene)/B3LYP-D3/6-311+G(d,p) level.18
With achiral ligands L5a-c, pathways leading to carbolithiation products (R)-3a and (S)-3a are isoenergetic. As a
consequence, our calculations were restricted to a sole configuration of the newly formed indan ring, arbitrarily
chosen as the S configuration. Our investigation primarily focused on the two symmetric additives TMEDA (L5a)
and DME (L5b). As the five-membered chelate ring formed between the lithium atom and the ligand adopts either
a λ or δ half-chair conformation,19 two favored diastereomeric TSs, both leading to the SC2-indan, were identified
for each ligand (Figure 2).
Figure 2. Representations of diastereomeric carbolithiation TSs stemming from λ and δ half-chairs of the lithium-ligand
chelate ring.
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Figure 3 shows, for L5a (top) and L5b (bottom), the Gibbs free energy profiles of the cyclization 2a  TS  3a (left
part), the geometries of the diastereomeric TS (central part) and their electronic (ΔΔE), enthalpic (ΔΔH298) and Gibbs
free (ΔΔG298) energy differences (right part).20
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ΔG298
+ 14.2 TS-L5a-λ-SC2
+ 14.1 TS-L5a-δ-SC2
Me2N
NMe2
Li
L5a
Li
N
N
N
N
0
ΔΔE ΔΔH298 ΔΔG298
TS-L5a-λ-SC2 0.00 0.00 0.10
TS-L5a-δ-SC2 0.20 0.22 0.00
TS-L5a-λ-SC2
TS-L5a-δ-SC2
- 11.2
+14.9 TS-L5b-λ-SC2
+13.8 TS-L5b-δ-SC2
MeO
OMe
Li
O
Li
L5b
O
O
O
2.6 Å
ΔΔE ΔΔH298 ΔΔG298
0
7
TS-L5b-λ-SC2 2.06 1.90 1.07
TS-L5b-δ-SC2 0.00 0.00 0.00
TS-L5b-λ-SC2
TS-L5b-δ-SC2
- 11.3
Figure 3. Computation of achiral ligands L5a- and L5b-mediated cyclization of 2a (most H atoms are omitted).
ΔG ‡
The Gibbs free energies of activation 298 (2a  TS) are around 14 kcal/mol for both ligands and final complexes
3a are more stable than the starting complexes 2a by 11 kcal/mol. These values are consistent with an irreversible
cyclization at room temperature. Noteworthy, the two most favored L5b-mediated TSs exhibit both methyl groups
on the ether functions in pseudo-equatorial (e’) positions. Their analogs with one methyl group in a pseudo-axial
(a’) position were found to be at least 2 kcal/mol (ΔΔG298) above TS-L5b-δ-SC2 and are thus neglected to focus the
following discussion on a reasonable number of favored TSs.
While the TMEDA diastereoisomeric transition states, TS-L5a-λ-SC2 and TS-L5a-δ-SC2, are energetically similar, in the
case of DME TS-L5b-δ-SC2 is favored over TS-L5b-λ-SC2 by more than 1 kcal/mol. This difference could originate from
the pseudo-axial position of one oxygen’s lone pair in TS-L5b-δ-SC2 which points toward an aromatic hydrogen (H-
C7) with a distance of 2.6 Å, consistent with a weak hydrogen bond length.21 To further support this hypothesis, a
topological analysis of the electron density, based on Bader’s theory of atoms in molecules (QTAIM) was
conducted.10, 22 A bond critical point (BCP) is indeed found between one oxygen atom and H-C7 with an electron
density (ρ = 0,0084 au) and its Laplacian value (∇2ρ = 0,029 au) consistent with a weak hydrogen bond.23, 21c
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Switching to amino ether L5c introduces additional complexity since this hybrid ligand forms unsymmetrical half-
chair chelates. As a result the lithium atom becomes stereogenic and accordingly four TSs were computed: two
half-chair conformations with an S configuration of the lithium atom (SLi) and two with the opposite R configuration
(RLi) (Figure 4).24
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ΔG298
+15.5 λ-SLi-SC2
TS-L5c
MeO
NMe2
+14.6 δ-SLi-SC2
+14.2 λ-RLi-SC2
+13.7 δ-RLi-SC2
L5c
Li
Li
N
O
N
O
2.6 Å
TS-L5c ΔΔE ΔΔH298 ΔΔG298
7
λ-RLi-SC2 0.47 0.43
δ-RLi-SC2 0.00 0.00
λ-SLi-SC2 2.50 2.29
δ-SLi-SC2 1.29 1.18
0.54
0.00
1.80
0.94
TS-L5c-λ-RLi-SC2
TS-L5c-δ-RLi-SC2
0
Li
Li
O
N
O
N
- 11.0
TS-L5c-λ-SLi-SC2
TS-L5c-δ-SLi-SC2
Figure 4. Computation of achiral ligand L5c-mediated cyclization of 2a (most H atoms are omitted).
These four TSs show a pseudo-equatorial methyl group on the ether function and L5c-mediated TSs presenting a
pseudo-axial methyl group were found to be significantly unfavored.25 Furthermore, as observed with DME, the
most favored TS, TS-L5c-δ-RLi-SC2, presents an oxygen lone pair likely bonding with the aromatic H-C7 (2,6 Å),
confirmed by the QTAIM analysis results (ρ = 0,0088 au; ∇2ρ = 0,030 au). This supports the hypothesis that the
energy difference between the diastereomeric TSs might be driven by favorable weak interactions (vide infra).
Chiral (pseudo) C2-symmetric 1,2-bidentate ligands
We then modeled the transition structures for the cyclohexyl-based ligands L4a-c (Figure 1). The six-
membered ring of the carbon skeleton is locked in the chair conformation in which both dimethylamino and/or
methoxy groups are equatorial. As a result, the fused five-membered chelate formed between (S,S)-L4 ligands and
the lithium atom is frozen in the δ half-chair conformation. Figure 5 shows the two diastereomeric transition states
leading to either R-indan (RC2) or S-indan (SC2) for diamino and diether ligands L4a and L4b as well as the related
energy profiles.
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ΔG298
+ 15.0 TS-L4a-SC2
+ 14.4 TS-L4a-RC2
5
6
Li
Li
N
N
N
N
Me2N
NMe2
L4a
7
8
9
0
ΔΔE ΔΔH298 ΔΔG298 er
TS-L4a-RC2 0.00 0.00
TS-L4a-SC2 0.83 0.77
0.00 74
- 12.4 3a-L4a-SC2
- 12.8 3a-L4a-RC2
0.62 26
TS-L4a-RC2
TS-L4a-SC2
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+16.2 TS-L4b-RC2
+14.3 TS-L4b-SC2
Li
Li
O
O
O
O
MeO
OMe
L4b
2.6 Å
ΔΔE ΔΔH298 ΔΔG298 er
0
7
TS-L4b-RC2 2.64 2.46
TS-L4b-SC2 0.00 0.00
1.92
4
0.00 96
TS-L4b-RC2
TS-L4b-SC2
- 9.4 3a-L4b-SC2
- 10.6 3a-L4b-RC2
Figure 5. Computation of chiral ligand L4a-b-mediated cyclization of 2a (most H atoms are omitted).
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As with achiral ligands L5, these free energy profiles are consistent with irreversible carbolithiation reactions.
Moreover, the energy profile with diether L4b shows 3a-L4b-RC2 and 3a-L4b-SC2 to be respectively the
thermodynamic and the kinetic products of this process. As the experimental major enantiomer of the indan is SC2,
this is an additional proof of the kinetic control of this process.
According to the Curtin-Hammett principle,26 the enantioselectivity of the carbolithiation should be in correlation
with the difference between the Gibbs free energies of the two competing diastereoisomeric TSs (ΔΔG298). In the
case of diamine (S,S)-L4a, the difference between TS-L4a-RC2 and TS-L4a-SC2 is 0.62 kcal/mol in favor of the
formation of the (R)-indan. According to Boltzmann distribution law, at 298K, this gap should lead to a R:S ratio of
74:26. This theoretical result is, indeed, in good agreement with the experimental 71:29 e.r. observed when the
carbolithiation is conducted with (S,S)-L4a at room temperature. The slightly lower experimental stereoselectivity
could arise from minor background (unliganded) reaction or secondary reaction pathways involving for example
oligomeric organolithium structures, which have not been accounted for in the present study. In the case of diether
(S,S)-L4b, the difference between the two diastereomeric TSs is completely reversed in favor of the (S)-indan in a
predicted 4:96 (R:S) ratio. As discussed previously with achiral L5b (Figure 3), the stabilization of TS-L4b-SC2 is likely
based on a weak stabilizing hydrogen bond between an oxygen atom and the aromatic hydrogen H-C7 (2,6 Å; ρ =
0,0091 au; ∇2ρ = 0,031 au). Again, the experimental stereoselectivity obtained with L4b (9:91 R:S) is rather
consistent with the predicted enantiomeric ratio, which confirms the relevance of our model.
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Eventually, a similar analysis was conducted to compute (S,S)-L4c transition states. Like achiral L5c (vide supra), this
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unsymmetrical ligand generates two configurations of the lithium atom (RLi and SLi). Accordingly, four
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diastereomeric TSs have been modeled (Figure 6).
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ΔG298
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+15.8 RLi-RC2
TS-L4c
+14.6 SLi-RC2
Li
N
O
Li
N
O
MeO
NMe2
+14.9 SLi-SC2
+14.1 RLi-SC2
L4c
2.6 Å
TS-L4c ΔΔE ΔΔH298 ΔΔG298 er
7
RLi-RC2 3.44 3.19
RLi-SC2 0.00 0.00
SLi-RC2 1.60 1.55
SLi-SC2 1.36 1.24
2.30 4.5
0.00 75.6
1.67 1.6
0.84 18.3
TS-L4c-RLi-RC2
TS-L4c-RLi-SC2
0
Li
O
N
Li
O
N
Global calc. er : 6 : 94 (RC2/SC2
)
-8.8 RLi-SC2
- 9.5 RLi-RC2
-9.8 SLi-SC2
-10.6 SLi-RC2
TS-L4c-SLi-RC2
TS-L4c-SLi-SC2
Figure 6. Computation of chiral ligand L4c-mediated cyclization of 2a (most H atoms are omitted).
As discussed above, TS-L4c-RLi-SC2 is presumably stabilized by the existence an C7-HO weak bond (2.6 Å; electron
density ρ = 0,008 au; Laplacian value Δ2ρ = 0,028 au). This TS is indeed enthalpically favored by more than 1 kcal/mol
over the three others diastereomeric TS. Although ΔΔG298 values follow the same trend as ΔΔH298 (enthalpic control
of stereoselectivity), the influence of the entropy factor is not negligible in the case of amino ether L4c. TS-L4c-RLi-
RC2 and TS-L4c-SLi-SC2, which are respectively 3.19 and 1.24 kcal/mol over the most favored TS-L4c-RLi-SC2 in terms
of enthalpy energy (ΔΔH298), see their Gibbs free energy difference (ΔΔG298) with the latter reduced to 2.30 and
0.84 kcal/mol. In other words, the entropic terms (-TΔΔS) relative to TS-L4c-RLi-SC2, are -0.89 kcal/mol for TS-L4c-
RLi-RC2 and -0.40 kcal/mol for TS-L4c-SLi-SC2. It can be inferred that the entropy factor is probably more detrimental
to the TSs featuring the alkenyl chain of the substrate close to the dimethylamino side of the ligand. This results in
noticeable contributions of these two TSs to the predicted stereoselectivity of (S,S)-L4c-mediated reaction, which
reaches an enantiomeric ratio of 6:94 (R:S). This theoretical value is slightly lower than the one calculated for the
diether ligand (S,S)-L4b and this trend is reflected in the experimental stereoselectivity levels of 15:85 e.r. with (S,S)-
L4c against 9:91 e.r. with (S,S)-L4b.
ΔG ‡
It should be noted that although the activating energies of the carbolithiation
are similar for the diamine,
298
diether and amino ethers ligands, it does not necessarily reflect the rate of the global process. In fact, these values
are not in accordance with our experimental observation that indan 4a and indoline 4b are formed more rapidly
27
when ligands featuring amine functions are used.
This suggests that the rate-determining step of this
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transformation would not be the stereo-determining cyclization step but more likely the formation of the
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monomeric lithium-olefin complex 2a from aggregated form(s) of the aryllithium and ligand complex (Scheme 2).8b
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Distortion / Interaction analysis
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To complete our understanding of the stereo-determining factors of this reaction, a distortion/interaction
(D/I) analysis was conducted. This consists in investigating the activation barrier (ΔE‡) of a reaction as a combination
of a distortion energy and an interaction energy (Equation 1).28 The distortion energy (or activation strain), ΔEdist, is
the energy required by the reactants to reach their transition-state geometries as individual components whereas
the interaction energy, ΔEint, represents the balancing favorable bonding between these components in the TS. In
the present case, we fragmented precomplex 2a and the TS into the ligand on one hand and the aryllithium on the
other (Figure 7). For each TS and corresponding precomplex 2a, the distortion energy could be then decomposed
into 1) the ligand-aryllithium dissociation energy in precomplex 2a, ΔEdist-2a, 2) the distortion energy of the
substrate, ΔEdist-sub, 3) the distortion energy of the ligand, ΔEdist-lig (Equation 2).
ΔE‡ = ΔEdist + ΔEint
(1)
ΔEdist = ΔEdist-2a + ΔEdist-sub + ΔEdist-lig
(2)
Figure 7. Distortion/Interaction analysis: decomposition of activation barrier into a distortion energy
(ΔEdist-2a+ΔEdist-sub+ΔEdist-lig) and an interaction energy ΔEint.
The results of the D/I analysis are presented using the most stable precomplex 2a as the energy reference point for
each ligand (Figure 8).
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Me2N
NMe2
MeO
OMe
MeO
NMe2
L4a
L4b
L4c
0.2
0.5
0.4
0.7
13.3
30.4
13.6
12.9
13.1
28.9
13.5
12.4
13.0
13.0
-29.9
-29.5
14.6
-24.0
15.9
-25.7
13.3
-26.6
16.4
-28.6
14.5
-27.7
14.3
-29.4
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30.2
0.1
29.0
0.7
28.1
1.0
28.5
1.4
26.2
25.3
0.7
13.8
12.9
RC2
ΔΔE = 0.0 kcal/mol
SC2
0.8 kcal/mol
RC2
2.6 kcal/mol
SC2
0.0 kcal/mol
RLi-RC2
3.4 kcal/mol
RLi-SC2
0.0 kcal/mol
SLi-RC2
1.6 kcal/mol
SLi-SC2
1.4 kcal/mol
Figure 8. D/I analysis results for all TSs of L4a-c-mediated carbolithiation (ΔEdist-2a+ΔEdist-sub+ΔEdist-lig and ΔEint in kcal/mol)
The relative energy of the less stable precomplexes 2a is indicated by the value in grey. Regardless of the ligand,
the energy profiles show substrate distortion energies ΔEdist-sub about 13 kcal/mol while ligand distortion energies
ΔEdist-lig are systematically lower than 1 kcal/mol. Furthermore, the strength of the ligand-organolithium bonding,
in both the precomplex 2a (ΔEdist-2a) and the TS (ΔEint), decreases in the following order diamine L4a > amino ether
L4c > diether L4b. This agrees with the relative Lewis base strength of the amine and ether functions. More
importantly, the distortion / interaction study allows to understand which energy factor drives the stereoselectivity
of the reaction in terms of difference of activation barriers (ΔΔE‡) between the diastereoisomeric TSs of each ligand.
For diamine L4a, the small energy difference ΔΔE‡ between the RC2 and SC2 pathways (0.8 kcal/mol) results from
small contributions of unfavorable ΔEdist-sub and ΔEdist-lig in the SC2 pathway as well as a slightly more favorable ΔEint
in the RC2 pathway. By contrast, for diether L4b, the more important ΔΔE‡ (2.6 kcal/mol), in favor of the SC2 pathway,
mainly arises from significant favorable ligand-aryllithium interactions in the TS ( ΔEint = 25.7 kcal/mol for SC2 and
ΔEint = 24.0 kcal/mol for RC2). To a lesser extent the same statement can be made in the case of amino ether L4c,
for the RLi-SC2 pathway presents the greater favorable ΔEint. Actually, both the SC2 pathway with L4b and the RLi-SC2
pathway with L4c, for which the AIM analysis reveal favorable weak hydrogen bond in the corresponding TSs, are
the only energy profiles to present stronger stabilizing interactions between the ligand and the organolithium in
the TS (ΔEint) than in the precomplex 2a (ΔEdist-2a). However, the RLi-SC2 pathway with L4c appears to be also favored
by lowest distortion energies: 12.4 kcal/mol for ΔEdist-sub and virtually non-existent ΔEdist-lig
.
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To further identify the presence of non-covalent interactions in these TSs, a non-covalent interactions (NCI)
analysis was conducted.29 This analysis allows the visualization of the reduced density gradient isosurfaces, for
which the color code is green for weakly attractive, blue for strongly attractive and red for strongly repulsive
interactions. Figure 9 shows the interactions taking place in diastereomeric TSs with L4a and L4b.
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C7-H
H-C(OMe)
H-CH2-O
O
π
H-CH2N
π
π
H-CH2N
π
TS-L4a-RC2
ΔΔE = 0.0 kcal/mol
TS-L4a-SC2
ΔΔE = 0.8 kcal/mol
TS-L4b-RC2
ΔΔE = 2.6 kcal/mol
TS-L4b-SC2
ΔΔE = 0.0 kcal/mol
Figure 9. Non-covalent interactions analysis: Visualization of the reduced density gradient isosurfaces for L4a-b TSs
(density cutoff of 0.4 au).
Diastereomeric transition states with diamine L4a, TS-L4a-RC2 and TS-L4a-SC2, exhibit comparable weak favorable
interactions, including weak hydrogen bonds between the electron-rich π system and hydrogens from one of the
NMe group (πH-CH2N).30 This is consistent with their limited electronic energy difference (ΔΔE = 0.8 kcal/mol).
By contrast, TS-L4b-SC2 clearly presents a more prominent number of stabilizing interactions than TS-L4b-RC2. At
least three weak hydrogen bond types, C7-HO, πH-CH2O and πH-C(OMe) appear in TS-L4b-SC2. This
suggests that the significant electronic energy gap between these two diastereomeric TSs (ΔΔE = 2.6 kcal/mol)
arises from a sum of multiple weakly attractive interactions between the ligand and the substrate. For amino ether
L4c TSs, the NCI analysis also supports the presence of numerous noncovalent interactions operating in concert in
the most stable TS-L4c-RLi-SC2 (Figure 10).
C7-H
O
π
H-CH2O
π
H-C(NMe2)
π
H-CH2N
π
H-CH2-N
TS-L4c-RLi-RC2
ΔΔE = 3.4 kcal/mol
TS-L4c-RLi-SC2
ΔΔE = 0.0 kcal/mol
TS-L4c-SLi-RC2
ΔΔE = 1.6 kcal/mol
TS-L4c-SLi-SC2
ΔΔE = 1.4 kcal/mol
Figure 10. Non-covalent interactions analysis: Visualization of the reduced density gradient isosurfaces for L4c TSs
(density cutoff of 0.4 au).
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Favorable interactions between the π system and the ligand, πH-CH2N and πH-CH2O, can also be noticed in
TS-L4c-SLi-RC2 and TS-L4c-SLi-SC2 respectively whereas in TS-L4c-RLi-RC2 no NMe or OMe group is facing the aromatic
ring and therefore no significant πH bond is observed. This is in good agreement with the relative electronic
energies of these three less favorable TSs (Figure 6).
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Achiral versus chiral 1,2-bidentate ligands modeling
When considered as isolated entities, the λ and δ half-chair chelates formed from lithium and achiral ligand
L5 are enantiomers. Accordingly, the λ half-chair TS leading to the (SC2)-indan (TS-L5-λ-SC2) is enantiomeric and so
energetically equal to the δ half-chair TS leading to the (RC2)-indan (TS-L5-δ-RC2).31 As a consequence, it can be
foreseen from the energy difference values depicted in figures 3 and 4, how a given half-chair would favor the
formation of one indan enantiomer. Table 1 presents the ratios of RC2 / SC2 indan formation 1) for the δ half chair of
achiral ligands L5 (calculated value) 2) for chiral ligands L4 of (S,S) absolute configuration (experimental and
calculated values).
Table 1. Comparison of (virtual) enantioselectivities for a given half-chair with achiral ligands L5 and for a given configuration
of chiral ligands L4.
δ(RC2) / δ(SC2) TSs ratio
for achiral ligands L5
RC2 /SC2 TSs ratio
for (S,S)-L4 ligands
L5a
L5b
-
L5c
L4a
L4b
9:91
4:96
L4c
Experimental
-
-
71:29
74:26
15:85
6:94
Calc. from ΔΔG298
46:54
14:86
27:73
These ratios were calculated using Boltzmann distribution law, at 298K, from the Gibbs free energy difference
ΔΔG298 between the diastereomeric TSs. For the ethereal achiral ligands L5b-c, the δ half-chair TSs give
predominantly the (SC2)-indan. In contrast, for the diamino ligand L5a, the δ half-chair TSs lead to almost equimolar
amount of (SC2)- and (RC2)-indans. The experimental and theoretical results with (S,S)-L4a-c, which locks the lithium
chelate as a δ half-chair, follow similar trends : the relative efficiency is also diether > amino ether > diamine and,
for the ethereal ligands, the sense of stereoinduction is effectively in favor of the formation of SC2-indan. It appears
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that to reach high enantioselectivity with a chiral 1,2-bidentate ligand, its achiral parent must present a noticeable
discrimination between the diastereomeric pathways stemming from the formation of the two half-chairs of its
lithium chelate. Therefore, the preliminary computational study on 1,2-bidentate achiral ligands already allows 1)
to identify the most promising chelating patterns between different classes of ligands, 2) to predict the sense of
stereoinduction for the related chiral ligand, by considering the preferred half-chair conformation of its lithium
chelate - this preferential conformation is governed by the absolute configuration of the ligand.
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From a more general point of view, what could this mean for the modeling of asymmetric reactions mediated by
1,2-bidentate ligands? This implies that computing only one stereoselective course of a reaction with different
achiral 1,2-bidentate ligands for both their λ or δ half-chair conformations, should allow to relatively predict how
parent chiral 1,2-bidentate ligands will perform as chiral inducers, provided that their absolute configurations
clearly favor one of these chelate conformations. Therefore, the screening of chelating patterns for the design of
new 1,2-bidentate chiral ligands could be expedited thanks to reasonable calculation times reduced by neglecting
the carbon backbone of such chiral ligands.
Conclusions
In summary we have conducted the first experimental and theoretical formal comparison of three 1,2-
bidentate ligand classes with the intramolecular carbolithiation as a model reaction. For (pseudo) C2-symmetric
cyclohexanediamine, -diether and -amino ether ligands, modeling of the diastereomeric transition states led to
conclusive theoretical levels of stereoselectivity matching the experimental results. The distortion/interaction
analysis suggest that the high levels of stereoinduction with the ethereal ligands originate from stabilizing
interactions in their most favorable transition states. AIM and NCI indeed allowed for the identification of several
weak hydrogen bonds between the substrate and the ligands in the TS. These interactions appear as largely
responsible for the discrimination between the diastereomeric reaction pathways in the case of the diether and
amino ether ligands. Interestingly, modeling the reaction with related achiral 1,2-bidentate ligands already leads to
the identification of diastereomeric TSs due to the formation of λ and δ half-chair conformations of the lithium
chelate. Comparing the relative energy differences of these TSs allows for the qualitative prediction of the sense of
stereoinduction and the relative efficiency of the (pseudo) C2-symmetric chiral ligands. This paves the way for
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simplified theoretical studies of chiral 1,2-bidentate ligands-mediated asymmetric additions. Ongoing experimental
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Experimental section
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General information
All air- and moisture-sensitive manipulations were performed under argon atmosphere with anhydrous solvents in
flame-dried glassware. The solvents (THF, CH2Cl2, Et2O, Toluene) were dried by activated alumina column (glass
technology GTS 100). t-BuLi was purchased as 1.7 M solution in pentane and was titrated periodically against N-
benzylbenzamide.32 Other commercially available reagents were used without further purification, unless
otherwise indicated. Flash column chromatography was carried out using Merk Kieselgel 60 silica gel (particle size :
32-63 Å). Analytical TLC was performed using Merk precoated silica gel 60 F-254 sheets with spot detection under
UV light or using potassium permanganate stain or cerium ammonium molybdate stain. 1H and 13C {1H} NMR spectra
were recorded on a BRUKER DPX 200 or on a BRUKER Advance 400 spectrometer. Coupling constants J are reported
in Hertz (Hz). Multiplicity is indicated as follow, s (singlet), d (doublet), t (triplet), q (quartet), sext (sextuplet), sept
(septuplet), oct (octuplet), dd (doublet of doublet), bs (broad singlet), m (multiplet) and “app.” stands for apparent.
IR spectra were recorded neat or as thin films using a Nicolet Avatar 370 DTGS FT-IR spectrometer. Melting points
were measured on a Melting Point B-540 apparatus and are uncorrected. Optical rotations were measured on Jasco
P-2000 polarimeter using a quartz cell (l=10 cm), with a high-pressure sodium lamp ( = 589 cm). []D values are
given in 10-1deg.cm2.g-1. High Resolution Mass Spectrometry (HRMS) was performed on a Waters Micromass GTC
Premier spectrometer or Bruker MicroTOF QIII spectrometer. 2-bromo-1-(3-butenyl)benzene33 (1a) was
synthesized by the reaction of 2-bromobenzyl bromide34 and allylmagnesium bromide and N,N-diallyl-2-
bromoaniline6d (1b) by N,N-diallylation of 2-bromoaniline.
Ligands synthesis
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(1S,2S)-N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine (L4a). Ligand L4a was synthesized via resolution of
racemic trans-1,2-cyclohexanediamine using D-(-)-tartaric acid followed by Eschweiler-Clarke reaction on the
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tartrate salt. 3c, 35
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(1S,2S)-1,2-dimethoxycyclohexane (L4b). (1S, 2S)-cyclohexane-1,2-diol36 (2.64 g, 22.7 mmol) was added portionwise
to a suspension of sodium hydride (3.27 g, 136.2 mmol, 6 equiv) in anhydrous Et2O (100 mL). The mixture was
stirred at room temperature for 4h. After cooling at 0oC, methyl iodide (14 mL, 227 mmol, 10 equiv) was added
dropwise. After 24h stirring at reflux (heating mantle), water (5 mL) was added dropwise and the mixture was
vigorously stirred for 1h at room temperature. The reaction mixture was extracted with Et2O (3 50 mL) and the
combined organic layers were dried over MgSO4. Distillation on CaH2 at reduced pressure afforded (S,S)-1,2-
[훼]24
o
dimethoxycyclohexane (L4b) (2.78 g, 85 %) as a colorless oil. Bp = 29 C at 0.2 mbar.
: + 53.6 (c = 1.05, CHCl3).
퐷
1H NMR (400 MHz, CDCl3) : 3.42 (s, 6H, 2OCH3), 3.09 - 3.07 (m, 2H, 2CH), 2.05- 2.01 (m, 2H, CH2), 1.68 - 1.64 (m,
2H, CH2), 1.25 - 1.18 (m, 4H, 2CH2). 13C {1H} NMR (100 MHz, CDCl3) : 82.5 (2CH), 57.2 (2CH3), 29.3 (2CH2), 23.6
(2CH2). HRMS (CI+) m/z: [M+H]+ : Calcd for C8H17O2 145.1229; Found 145.1222.
(1S,2S)-2-methoxy-N,N-dimethylcyclohexanamine (L4c). Step A : di-tert-butyl dicarbonate (8.12 g, 37.2 mmol, 1.2
equiv) was added slowly to a solution of (1S,2S)-2-(methylamino)cyclohexanol37 (4.0 g, 31 mmol, 1 equiv) in 2M
NaOH(aq) (81 mL). The mixture was stirred overnight at 30 °C (heating mantle) prior to the addition of CH2Cl2 (40
mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×40 mL). The combined organic
phases were dried over Na2SO4, filtered and concentrated under vacuum providing crude tert-butyl (1S,2S)-2-
hydroxycyclohexyl(methyl)carbamate (5.75 g, 81 %). Step B : Methyl iodide (2.6 mL, 42,2 mmol, 1.7 equiv) and NaH
(60% in mineral oil, 1.7 g, 42.2 mmol, 1.7 equiv) were successively added to a solution of crude tert-butyl (1S,2S)-2-
hydroxycyclohexyl(methyl)carbamate (5,7g, 24.8 mmol, 1 equiv) in THF (70 mL) at 0 °C. The reaction mixture was
stirred overnight at room temperature prior to the careful addition of saturated NH4Cl(aq) (50 mL) at 0 °C. The
aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered
and concentrated under vacuum. Chromatography on silica gel (cyclohexane / EtOAc: 80/20 → 70/30) gave tert-
[훼]20
butyl (1S,2S)-2-methoxycyclohexyl(methyl)carbamate (4.63 g, 77 %) as a colorless oil.
: +11.9 (c = 1.15, CHCl3).
퐷
1H NMR (400 MHz, DMSO) : 3.61 (bs, 1H, CH), 3.22-3.12 (m, 4H, OCH3+CH), 2.68 (s, 3H, NCH3), 2.11 (m, 1H, CH2),
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1.68-1.63 (m, 2H, CH2), 1.58-1.43 (m, 2H, 2CH2), 1.39 (s, 9H, C(CH3)3), 1.22-1.01 (m, 3H, 2CH2). C {1H} NMR (100
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MHz, DMSO) : 155.0 (C=O), 78.1 (CH), 77.8 (C), 59.0 (CH), 55.0 (OCH3), 30.2 (NMe), 29.0 (2CH2), 28.1 (3CH3), 24.8
(CH2), 23.8 (CH2). IR (neat) ν : 2931, 1687, 1365, 1149, 1100, 944 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for
C13H25NO3Na266.1727; Found 266.1726. TLC : Rf 0.43 (cyclohexane / EtOAc : 6 /2, KMnO4). Step C : To a suspension
of LiAlH4 (2.2 g, 57 mmol, 3 equiv) in dry Et2O (35 mL) at 0 °C was added a solution of crude tert-butyl (1S,2S)-2-
methoxycyclohexyl(methyl)carbamate (4,43g, 19,0 mmol, 1 equiv) in dry Et2O (70 mL). The reaction mixture was
refluxed overnight (heating mantle), cooled to 0 °C and diluted with Et2O (25 mL). After the careful portionwise
addition of Na2SO4.10H2O (3 equiv), the resulting mixture was stirred at room temperature for 1 h. The solids were
removed by filtration through a pad of celite and were washed with Et2O (25 mL). The filtrate was dried over Na2SO4
and diethyl ether was removed by simple distillation. Bulb-to-bulb distillation (150 °C, 300 mbar) gave (1S,2S)-2-
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[훼]20
methoxy-N,N-dimethylcyclohexanamine (L4c) (2.43 g, 81 %) as a colorless oil.
: + 55.8 (c = 1.0, CHCl3). 1H NMR
퐷
(400 MHz, CDCl3) : 3.31 (s, 3H, OCH3), 3.05 (m, 1H, CH), 2.32 (m, 1H, CH), 2.26 (s, 6H, N(CH3)2), 2.11 (m, 1H, CH2),
1.74 (m, 1H, CH2), 1.66-1.64 (m, 2H, CH2), 1.14-1.07 (m, 4H, 2CH2). 13C {1H} NMR (100 MHz, CDCl3) : 79.9 (CH), 66.9
(CH), 55.9 (OCH3), 41.0 (N(CH3)2), 30.3 (CH2), 25.0 (CH2), 24.4 (CH2), 23.8 (CH2). IR (neat) ν : 2928, 2859, 2820, 2775,
1452, 1102 cm-1 HRMS (ESI+) m/z: [M+H]+ Calcd for C9H20NO 158.1539; Found 158.1548.
Carbolithiation reactions – General procedure for the preparation of indane 4a and indoline 4b
A solution of ligand (2.2 equiv) in anhydrous toluene (4 mL) was cooled to –78 °C in a flame-dried Schlenk tube
under argon. t-BuLi in pentane (2.2 equiv) was added dropwise and an intense yellow solution formed. A solution
of bromoarene 1 (0.5 mmol, 1 equiv) in anhydrous toluene (1 mL) was then added dropwise and the mixture was
stirred for an additional 10 min at –78 °C. The reaction vessel was then transferred to a constant-temperature bath
maintained at the specified temperature (20 °C for 1a, –40 °C for 1b) and stirred for 1–3 h. The reaction mixture
was then recooled to –78 °C, quenched by the addition of 1 mL of deoxygenated dry MeOH, and allowed to reach
room temperature. An aqueous saturated NH4Cl solution (5 mL) was added, the phases were separated, and the
organic layer was dried over MgSO4. The enantiomeric ratios were determined by CSP-GC analysis of an aliquot of
the organic layer.
(S)-1-methylindan (4a). Following the carbolithiation general procedure, the ligand (1.1 mmol), t-BuLi (0.72 mL, 1.53
M in pentane, 1.1 mmol) and 2-bromo-1-(3-butenyl)benzene (1a) (106 mg, 0.5 mmol) were reacted at rt for 1 h.
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After standard work-up, the enantiomeric ratio of 4a was determined by chiral stationary-phase gas
chromatography (CSP-GC) (30 m  250 m  0.25 m Rt-βDEXcst column; Carrier gas : helium ; 1.5 mL/min ;
Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 90 °C (hold 5 min.) to 140 °C at 5 °C/min): (R)-4a
tr = 11.4 min, (S)-4a tr = 11.6 min. An analytically pure sample of 4a was obtained by flash chromatography on silica
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[훼]24
gel (pentane). Colorless oil. For an enantiomeric ratio of 9:91 (R/S),
[훼]2퐷4
–2.7 (c = 1.1, CHCl3) (lit. 38 er = 94:6 (R/S) :
퐷
+2.35 (c = 1.0, CHCl3)). 1H NMR (400 MHz, CDCl3) : 7.30–7.10 (m, 4H), 3.18 (m, 1H), 2.95–2.68 (m, 2H), 2.30
(m, 1H), 1.60 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) : 148.8, 143.9, 128.5, 126.1, 124.3,
123.2, 39.4, 34.8, 31.5, 19.9 (consistent with lit.6a).
(R)-1-allyl-3-methylindoline (4b). Following the carbolithiation general procedure, the ligand (1.1 mmol), t-BuLi
(0.72 mL, 1.52 M in pentane, 1.1 mmol) and N,N-diallyl-2-bromoaniline (1b) (126 mg, 0.5 mmol) were reacted at –
40 °C for 3 h. After standard work-up, the enantiomeric ratio of 4b was determined by chiral stationary-phase gas
chromatography (CSP-GC) (30 m  250 m  0.25 m CP-Chirasil-Dex CB column; carrier gas : helium ; 1.5 mL/min ;
Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 115 °C (hold 14 min.) to 180 °C at 20 °C/min):
(S)-4b tR = 12.8 min, (R)-4b tR = 13.1 min. An analytically pure sample of 4b had been previously obtained by flash
chromatography on silica gel (cyclohexane / CH2Cl2: 100/0 → 85/15).5 Colorless oil. For an enantiomeric ratio of
[훼]28
[훼]28
–50.6 (c = 0.97, CH2Cl2)).1H NMR (400 MHz, CDCl3)
퐷
95:5 (R/S),
–59.4 (c = 0.98, CH2Cl2) (lit. 6a er = 93:7 :
퐷
: 7.08–7.04 (m, 2H), 6.68 (td, J = 7.4, 0.9 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 5.90 (ddt, J = 17.2, 10.2, 6.0 Hz, 1H), 5.28
(app. dq, J = 17.2, 1.7 Hz, 1H), 5.18 (app. dq, J = 10.2, 1.7 Hz, 1H), 3.78 (app. ddt, J = 15.1, 6.0, 1.7 Hz, 1H), 3.61 (app.
ddt, J = 15.1, 6.0, 1.7 Hz, 1H), 3.55 (app. t, J = 8.6 Hz, 1H), 3.28 (m, 1H), 2.85 (app. t, J = 8.6 Hz, 1H) 1.30 (d, J = 6.8
Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) : 151.8, 135.2, 134.2, 127.4, 123.1, 117.7, 117.2, 107.3, 61.3, 52.0, 35.2,
18.6 (consistent with lit. 6a).
Associated contents
The supporting information, including spectra of all new compounds, chiral stationary phase chromatograms and
computed geometries and energies, is available free of charge on the ACS Publications website at :
Author information
Corresponding Authors
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*E-mail : anne.boussonniere@univ-lemans.fr
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*E-mail : anne-sophie.castanet@univ-lemans.fr
ORCID
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Anne Boussonnière : 0000-0002-1113-099X
Anne-Sophie Castanet : 0000-0003-4704-4724
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Notes
The authors declare no competing financial interest.
Acknowledgments
We gratefully acknowledge the French Ministry of Higher Education, Research and Innovation for H.G. PhD
fellowship and the CNRS and Le Mans Université for financial support. We also thank Arnaud Martel for his help on
the computational study and Rémi Busselez, Frédéric Legros, the NMR, mass spectroscopy and computation
platforms for the technical support.
References and notes
1
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3
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For L2 ligand, see: a) Hasegawa, M.; Taniyama, D.; Tomioka, K., Facile Asymmetric Synthesis of α-Amino Acids
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(13), 2833-2839; d) Nishimura, K.; Fukuyama, N.; Yamashita, M.; Sumiyoshi, T.; Yamamoto, Y.; Yamada, K.-i.;
Tomioka, K., Cyclic Model for the Asymmetric Conjugate Addition of Organolithiums with Enoates. Synthesis
2015, 47 (15), 2256-2264 and references cited therein.
5
Guyon, H.; Boussonnière, A.; Castanet, A.-S., Readily Accessible 1,2-Amino Ether Ligands for Enantioselective
Intramolecular Carbolithiation. J. Org. Chem. 2017, 82 (9), 4949-4957.
6
For articles on asymmetric intramolecular carbolithiation, see: a) Bailey, W. F.; Mealy, M. J., Asymmetric
Cyclization of Achiral Olefinic Organolithiums Controlled by a Stereogenic Lithium: Intramolecular
Carbolithiation in the Presence of (-)-Sparteine. J. Am. Chem. Soc. 2000, 122 (28), 6787-6788; b) Sanz Gil, G.;
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Groth, U. M., Enantioselective Synthesis of 3-Substituted Indolines by Asymmetric Intramolecular
Carbolithiation in the Presence of (-)-Sparteine. J. Am. Chem. Soc. 2000, 122 (28), 6789-6790; c) Barluenga, J.;
Fañanás, F. J.; Sanz, R.; Marcos, C., Intramolecular carbolithiation of allyl o-lithioaryl ethers: A new
enantioselective synthesis of functionalized 2,3-dihydrobenzofurans. Chem. Eur. J. 2005, 11 (18), 5397-5407;
d) Mealy, M. J.; Luderer, M. R.; Bailey, W. F.; Sommer, M. B., Effect of Ligand Structure on the Asymmetric
Cyclization of Achiral Olefinic Organolithiums. J. Org. Chem. 2004, 69 (18), 6042-6049; e) Groth, U.; Koettgen,
P.; Langenbach, P.; Lindenmaier, A.; Schuetz, T.; Wiegand, M., Enantioselective synthesis of 3,3-disubstituted
indolines via asymmetric intramolecular carbolithiation in the presence of (-)-sparteine. Synlett 2008, (9),
1301-1304; f) Gómez-SanJuan, A.; Sotomayor, N.; Lete, E., Inter- and intramolecular enantioselective
carbolithiation reactions. Beilstein J. Org. Chem. 2013, 9, 313-322.
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Nguyen, T. T. T.; Guyon, H., Nguyen, K.P.P., Boussonnière, A.; Mortier, J.; Castanet, A.-S. Chiral Ligand-
Mediated Nucleophilic Aromatic Substitution of Naphthoic Acids: A Fast and Efficient Access to Axially Chiral
Biaryls. Eur. J. Org. Chem. 2020, 10.1002/ejoc.202000317.
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a) Mattalia, J.-M.; Nava, P., A Computational Study of the Intramolecular Carbolithiation of Aryllithiums:
Solvent and Substituent Effects. Eur. J. Org. Chem. 2016, (2), 394-401; b) Liu, S.; Gray, D.; Zhu, L.; Girolami, G.
S., Lithium–Olefin π-Complexes and the Mechanism of Carbolithiation: Synthesis, Solution Behavior, and
Crystal Structure of (2,2-Dimethylpent-4-en-1-yl)lithium. Organometallics 2019, 38 (9), 2199-2210; c) Bailey,
W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B., Stereoselectivity of
cyclization of substituted 5-hexen-1-yllithiums: regiospecific and highly stereoselective insertion of an
unactivated alkene into a carbon-lithium bond. J. Am. Chem. Soc. 1991, 113 (15), 5720-5727; d) Liu, H.; Deng,
K.; Cohen, T.; Jordan, K. D., Computational Study of the Stereochemistry of Intramolecular Carbolithiation of
an Alkene by a Secondary Alkyllithium:ꢀ Stereochemistry Change Caused by a Single THF Molecule of Solvation.
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10 AIMAll (Version 15.09.27), Todd A. Keith, TK Gristmill Software, Overland Park KS, USA, 2017
(aim.tkgristmill.com).
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11 The NCI analyses were conducted with the help of Multiwfn : Lu, T.; Chen, F., Multiwfn: A multifunctional
wavefunction analyzer. J. Comput. Chem. 2012, 33 (5), 580-592.
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12 VMD was used for visualization of the NCI analyses: Humphrey, W.; Dalke, A.; Schulten, K., VMD: Visual
molecular
dynamics.
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16 For a similar approach, see: Gessner, V. H.; Koller, S. G.; Strohmann, C.; Hogan, A.-M.; O'Shea, D. F., Mechanistic
insight into stereoselective carbolithiation. Chem. Eur. J. 2011, 17 (10), 2996-3004.
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18 The SI includes cartesian coordinates of all the geometries of 2a, TS and 3a for ligands L4a-c and L5a-c.
19 a) Saito, Y., Absolute Configuration of Transition Metal Complexes. In Stereochemistry of Optically Active
Transition Metal Compounds, American Chemical Society: 1980; Vol. 119, pp 13-42; b) Harris, S. E.; Pascual, I.;
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Aggregation State. J. Am. Chem. Soc. 1996, 118 (44), 10707-10718; d) Ehnbom, A.; Ghosh, S. K.; Lewis, K. G.;
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20 For greater clarity TS are represented without most of their hydrogens.
21 a) Desiraju, G. R.; Steiner, T., The Weak Hydrogen Bond: In Structural Chemistry and Biology. Oxford University
Press: 2001. For reviews on non-classical C-HX bonding and their involvement in asymmetric processes, see:
b) Johnston, R. C.; Cheong, P. H.-Y., C–H…O non-classical hydrogen bonding in the stereomechanics of organic
transformations: theory and recognition. Org. Biomol. Chem. 2013, 11 (31), 5057-5064; c) Ajitha, M. J.; Huang,
K.-W., Non-Classical C-H···X Hydrogen Bonding and Its Role in Asymmetric Organocatalysis. Synthesis 2016, 48
(20), 3449-3458.
22 a) Bader, R. F. W., Atoms in Molecules: A Quantum Theory. Clarendon Press: 1994; b) Matta, C. F.; Boyd, R. J.;
Becke, A., The Quantum Theory of Atoms in Molecules: From Solid State to DNA and Drug Design. Wiley: 2007.
23 Koch, U.; Popelier, P. L. A., Characterization of C-H-O Hydrogen Bonds on the Basis of the Charge Density. J.
Phys. Chem. 1995, 99 (24), 9747-9754.
24 Heinl, T.; Retzow, S.; Hoppe, D.; Fraenkel, G.; Chow, A., Experimental and Theoretical Investigations of Lithio-
Indenyl Carbamate/(−)-Sparteine and (−)-α-Isosparteine Complexes. Chem. Eur. J. 1999, 5 (12), 3464-3470.
25 Only the parent transition state of TS-L5c-λ-RLi-SC2 with its OMe group in pseudo-axial position could be
resolved and was 2 kcal/mol above TS-L5c-δ-RLi-SC2.
26 a) Seeman, J. I., Effect of conformational change on reactivity in organic chemistry. Evaluations, applications,
and extensions of Curtin-Hammett Winstein-Holness kinetics. Chem. Rev. 1983, 83 (2), 83-134; b) the
assumption is made that diastereomeric complexes 2a are interconverting rapidly in comparison to the
carbolithiation kinetic.
27 For example, conversions determined by the ratio of indan 4a and dehalogenated product arising from
aryllithium 2a, after the same reaction time (1h) were 89, 79 and 72 % for the diamine L4a, the amino ether
L4c and the diether L4b respectively.
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29 For the theory behind non-covalent interactions analysis, see: Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.;
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31 Reciprocally, a δ half-chair TS leading to the (SC2)-indan is enantiomeric and so energetically equal to the 
half-chair TS leading to the (RC2)-indan.
32 Burchat, A. F.; Chong, J. M.; Nielsen, N., Titration of alkyllithiums with a simple reagent to a blue endpoint. J.
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37 (1S,2S)-2-(methylamino)cyclohexanol is commercial or can be prepared by resolution of (±)-2-
(methylamino)cyclohexanol with (R)-mandelic acid. Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani,
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38 Wang, Y.-M.; Bruno, N. C.; Placeres, Á. L.; Zhu, S.; Buchwald, S. L. Enantioselective Synthesis of Carbo- and
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