Dynamic parallel kinetic resolution of α-ferrocenyl cation initiated by chiral Br?nsted acid catalyst

Article abstract of DOI:10.1039/d1sc02122b

The dynamic parallel kinetic resolution (DPKR) of an α-ferrocenyl cation intermediate under the influence of a chiral conjugate base of a chiral phosphoric acid catalyst has been demonstrated in an S_N1 type substitution reaction of a racemic ferrocenyl derivative with a nitrogen nucleophile. The present method provides efficient access to a ferrocenylethylamine derivative in a highly enantioselective manner, which is potentially useful as a key precursor of chiral ligands for metal catalysis. The mechanism of the present intriguing resolution system was elucidated by control experiments using the enantio-pure precursor of relevant α-ferrocenyl cation intermediates and the hydroamination of vinylferrocene. Further theoretical studies enabled the elucidation of the origin of the stereochemical outcome as well as the efficient DPKR. The present DPKR, which opens a new frontier for kinetic resolution, involves the racemization process through the formation of vinylferrocene and the chemo-divergent parallel kinetic resolution of the enantiomeric α-ferrocenyl cations generated by the protonation/deprotonation sequence of vinylferrocene.

Full text of DOI:10.1039/d1sc02122b

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Dynamic parallel kinetic resolution of a-ferrocenyl
cation initiated by chiral Brønsted acid catalyst†
Cite this: Chem. Sci., 2021, 12, 10306
b
a
Yasunori Toda, ‡a Toshinobu Korenaga,
Ren Obayashi,a Jun Kikuchi
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
*
and Masahiro Terada
The dynamic parallel kinetic resolution (DPKR) of an a-ferrocenyl cation intermediate under the influence of
a chiral conjugate base of a chiral phosphoric acid catalyst has been demonstrated in an SN1 type
substitution reaction of a racemic ferrocenyl derivative with a nitrogen nucleophile. The present method
provides efficient access to a ferrocenylethylamine derivative in a highly enantioselective manner, which
is potentially useful as a key precursor of chiral ligands for metal catalysis. The mechanism of the present
intriguing resolution system was elucidated by control experiments using the enantio-pure precursor of
relevant a-ferrocenyl cation intermediates and the hydroamination of vinylferrocene. Further theoretical
studies enabled the elucidation of the origin of the stereochemical outcome as well as the efficient
DPKR. The present DPKR, which opens a new frontier for kinetic resolution, involves the racemization
process through the formation of vinylferrocene and the chemo-divergent parallel kinetic resolution of
the enantiomeric a-ferrocenyl cations generated by the protonation/deprotonation sequence of
vinylferrocene.
Received 15th April 2021
Accepted 28th June 2021
DOI: 10.1039/d1sc02122b
rsc.li/chemical-science
a powerful stereocontrolling element.7 Hence, it is naturally
expected that the catalytic KR of a racemic cationic species
Introduction
using the chiral conjugate base of CPA would expand the scope
of KR.8 The method would not only establish a novel class of
fundamental strategies for asymmetric synthesis, but also
empower chiral Brønsted acid catalysis as the master of cation
control.
The kinetic resolution (KR) of racemic mixtures is one of the
most fundamental and powerful methods for the preparation of
enantiomerically enriched compounds.1 In general, KR occurs
because the two enantiomers of a racemic substrate react at
different rates. To date, electronically neutral substrates,
namely, non-charged organic molecules, have been employed in
KR reactions.1d,2 On the other hand, cationic molecules, despite
being attractive chemical species, have rarely been used as KR
reactants3,4 and thus the development of an efficient method for
the resolution of racemic cations under catalytic conditions is
expected to open a new frontier for KR. Cationic molecules are
attractive because they are common reactive species and oen
invoked as key intermediates in typical Brønsted acid catalysis.
In particular, during the past decades, chiral phosphoric acids
(CPAs) have emerged as effective Brønsted acid catalysts for
enantioselective electrophilic activation. In fact, CPAs have
enabled a wide variety of enantioselective transformations5,6 in
which the chiral conjugate base of a CPA catalyst functions as
The challenge of governing the reactivity of racemic cationic
molecules as active intermediates using a chiral conjugate base
has inspired the design of a fascinating resolution system. A
CPA-catalysed SN1 type substitution reaction of a-ferrocenyl
alcohol derivatives is a viable and attractive approach to
accomplish the KR of a racemic cationic molecule. In principle,
the substitution at the a-position of ferrocenyl alcohol deriva-
tives should proceed through a stepwise pathway (Fig. 1).9
Elimination occurs as the initial step, generating an a-ferro-
cenyl cation,10 and subsequent addition of a nucleophile to the
cation affords a substitution product. More importantly, the
chirality at the a-position is completely preserved in a retentive
manner during the course of the reaction because the central
chirality at the a-position of ferrocenyl derivatives is cleanly
transformed into the “planar” chirality of the cation via neigh-
bouring group participation of the iron centre. It should be
pointed out that the chiral cation does not undergo racemiza-
tion in this particular type of substitution reaction. Taking into
consideration the unique features of this cationic intermediate,
we envisioned that cation A generated from racemic ferrocenyl
derivative 1 using CPA catalyst 2 would be resolved in the
reaction with nitrogen nucleophile 3 (Fig. 2).11,12 In the present
aDepartment of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku,
Sendai 980-8578, Japan. E-mail: mterada@tohoku.ac.jp; ytoda@shinshu-u.ac.jp;
Web: http://www.orgreact.sakura.ne.jp/en-index.html
bDepartment of Chemistry and Biological Sciences, Faculty of Science and Engineering,
Iwate University, Morioka 020-8551, Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. See DOI: 10.1039/d1sc02122b
‡ Present address: Department of Materials Chemistry, Faculty of Engineering,
Shinshu University, Nagano 380-8553, Japan.
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Herein we disclose the formation of highly enantio-enriched
ferrocenylethylamine derivative 4, which has been potentially
useful as a key precursor of chiral ligands for metal catalysis,9,15
by virtue of the distinctive KR of racemic a-ferrocenyl cation A.
In the present resolution system, it was conrmed that DKR,
namely, the involvement of a racemization process between
enantiomeric cations A, also occurs simultaneously during PKR
of these cations. Mechanistic studies revealed that the forma-
tion of vinylferrocene (5) and its protonation/deprotonation
sequence are the key to accomplishing the present intriguing
resolution system, termed “dynamic PKR (DPKR)”.
Results and discussion
The initial experiment was performed using racemic 1, 5 mol%
of CPA (R)-2 (G ¼ 9-anthryl), 0.5 equivalent of 4-toluenesulfo-
namide (3a), and molecular sieve (MS) 5A in toluene at room
temperature for 6 h (Table 1, entry 1). The reaction cleanly
afforded substitution product 4 with moderate enantiose-
lectivity and elimination product 5. Then, screening for cata-
lysts, solvents, and temperatures was conducted; however, none
of the conditions led to an improvement in the initial result (see
ESI† for details). Importantly, investigation of amine nucleo-
philes 3 revealed that the N-protecting group strongly affected
both reactivity and enantioselectivity (Table 1, entries 1–7).11a
Whereas relatively nucleophilic 4-anisidine (3b) and other
nitrogen nucleophiles, such as phosphinamide 3c and carba-
mate 3d, exhibited poor reactivity (Table 1, entries 2–4), less
nucleophilic 3f and 3g bearing electron-withdrawing 4- and 2-
nitrobenzenesulfonyl groups, respectively, were crucial for
achieving high enantioselectivity (Table 1, entries 6 and 7). In
particular, the reaction of 2-nitrobenzenesulfonamide (nosyla-
mide: 3g) afforded substitution product (S)-4g in 95% ee (Table
1, entry 7), and the best chemo- and stereocontrol was achieved
when 2.0 equivalents of nosylamide (3g) was employed (Table 1,
entry 8).
Fig. 1 Stereoretentive substitution at a-position of ferrocenyl deriv-
atives and application of cationic intermediate to KR.
characteristic KR, the competition between the substitution and
elimination reactions would take place in parallel during the
resolution. We thus assumed that both the substitution
product, ferrocenylethylamine derivative 4, and the elimination
product, vinylferrocene (5), would be ideally formed in
a comparable fashion and hence the chemo-divergent parallel
kinetic resolution (PKR)13 of a-ferrocenyl cation A would be
feasible. Because only a limited number of PKRs have been re-
ported, it is of particular interest whether the use of racemic
cation A enables the present unique PKR under the inuence of
the chiral conjugate base of CPA 2. In addition, vinylferrocene
(5) can be readily converted into racemic methyl ether 1 through
the addition of methanol to the vinyl moiety of 5 in the presence
of a strong Brønsted acid,§ and regenerated 1 is subjected to the
same reaction sequence. Therefore, a formal dynamic kinetic
resolution (DKR)14 would be established by the present method.
Keeping the above postulate in mind, we performed the SN1
type substitution reaction of racemic ferrocenyl derivative 1
with nitrogen nucleophile 3 catalysed by CPA 2 (G ¼ 9-anthryl).
The present reaction proceeds in a stepwise manner. First,
the C–O bond cleavage by CPA (R)-2 generates a-ferrocenyl
Fig. 2 Proposal: parallel kinetic resolution of a-ferrocenyl cation catalysed by CPA.
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Table 1 Screening for amine nucleophiles in the parallel kinetic
resolution of a-ferrocenyl cationa
equivalents, and it seems that the second step would be the key
to achieving efficient KR. To conrm the proposed mechanism,
a control experiment was performed in the reaction without
using nucleophile 3g and the reaction was quenched prior to
complete conversion (Fig. 3a). As expected, the reaction in the
absence of 3g resulted in the recovery of nearly racemic 1,
clearly suggesting that there is only a slight difference in the
reaction rate between enantiomers 1 in the C–O bond cleavage
step. Again, it is worth noting that the inuence of the nucle-
ophile on the enantioselectivity is a further indication that the
resolution occurs in the second step, in which competitive
amination and deprotonation reactions take place.
Next, the mechanism was further investigated using enantio-
pure starting material 1. Based on the efficiency of the observed
KR, it was assumed that (Sp)-cation A generated from (S)-1 and
chiral conjugate base (R)-2ꢀ would undergo C–N bond forma-
tion (amination) with 3g to afford (S)-4g smoothly (C–N
matched), whereas (R)-1 would selectively lead to the formation
of vinylferrocene (5) via (Rp)-cation A (C–N mismatched). As
expected, (S)-1 (99% ee) gave (S)-4g (98% ee) with nearly
complete retention of chirality. However, it is worth mentioning
that the formation of a considerable amount of vinylferrocene
(5) was also observed (Fig. 3b). In contrast, in the reaction of the
mismatched combination, namely, enantio-pure (R)-1 and CPA
(R)-2, elimination product 5 was formed as the major product
(Fig. 3c). More interestingly, a small amount of (S)-4g was ob-
tained with inversion at the stereogenic center (89% ee), despite
the fact that the nucleophilic substitution of ferrocenyl alcohol
derivatives generally proceeds in a retentive manner.
Entry 3: R
Time (h) Yieldb (%) 4/5 eec (%)
1
2
3
4
5
6
7
8d
3a: Ts
3b: 4-MeOC6H4
3c: Ph2(O)P
6
50/50
<5
<5
34/26
50/50
44/52
40/60
47(47)/51(43)
40
—
—
<1
28
82
95
95
24
24
24
6
2
2
3d: Cbz
3e: 4-MeOC6H4SO2
3f: 4-NO2C6H4SO2
3g: 2-NO2C6H4SO2 (Ns)
3g
2
a
Unless otherwise noted, all reactions were performed using 0.20 mmol
of 1, 5 mol% of catalyst 2, and 0.5 equivalent of 3 in toluene (0.2 M) at
b
room temperature. Determined by crude 1H NMR analysis (in C6D6)
using 1,3-benzodioxole as the internal standard. Isolated yields are
c
shown in parentheses. Determined by chiral stationary phase HPLC
d
analysis. 2.0 equivalents of 3g was used. The absolute conguration
of 4g was determined by derivatization into a known compound. See
ESI for details.
cation A, and then the C–N bond formation (amination) by
nosylamide (3g) yields substitution product (S)-4g or the
deprotonation affords 5. As shown in Table 1, the amine
nucleophile had the greatest impact on the enantioselectivity
with respect to both the substituent and the number of
Fig. 3 Mechanistic studies using (R)-2 (G ¼ 9-anthryl): (a) the kinetic
resolution of racemic 1 in the absence of 3g. (b) The substitution Fig. 4 Proposed mechanism for the formation of anomalous inversion
reaction of enantio-pure (S)-1 with 3g. (c) The substitution reaction of product (S)-4g from (R)-1 and the racemization process between (Sp)-
enantio-pure (R)-1 with 3g. (d) The hydroamination of 5 with 3g.
and (Rp)-cations A through vinylferrocene (5).
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The formation of anomalous inversion product (S)-4g from
(R)-1 is presumably rationalized by the enantioselective hydro-
amination of 5 catalysed by CPA 2 aer elimination of methanol
from (R)-1, as shown in Fig. 4: (i) (Rp)-cation A generated from
(R)-1 is resolved by chiral conjugate base (R)-2ꢀ, affording 5 as
the major product along with a small amount of retentive
substitution product (R)-4g; (ii) elimination product 5 is further
protonated at the double bond by CPA 2 to generate enantio-
meric (Sp)- and (Rp)-cations A; (iii) because of the matched
combination of (Sp)-cation A and (R)-2ꢀ, the nucleophilic attack
of 3g on (Sp)-cation A gives rise to (S)-4g with inversion at the
stereogenic centre from initial (R)-1, although the deprotona-
tion also takes place, affording 5 to some extent, as shown in
Fig. 3b; and (iv) (Rp)-cation A repeats the same resolution
process as proposed above.
To conrm whether the enantioselective hydroamination of
5 by CPA 2 is involved in the present reaction, 5 was treated with
nosylamide (3g) under the optimized reaction conditions
(Fig. 3d). As expected, hydroamination product (S)-4g was ob-
tained with high enantioselectivity (95% ee) even though the
reaction was considerably sluggish and thus resulted in
a diminished yield of (S)-4g. The enantiomeric excess (ee) of 4g
[89% ee (S), Fig. 3c] obtained from (R)-1 was lower than that
[95% ee (S), Fig. 3d] in the hydroamination of 5 because a small
amount of product (R)-4g was furnished via the retentive
substitution reaction of (R)-1. The ee observed in Fig. 3c is the
sum of the stereochemical outcomes obtained for this retentive
substitution and the hydroamination of 5. Hence, these results
are consistent with the proposed mechanism.
As depicted in Fig. 4, the overall scheme for the enantiose-
lective hydroamination of vinylferrocene (5) with 3g under the
inuence of CPA catalyst (R)-2 is also well described. It is
pointed out that during the protonation/deprotonation
sequence of 5, the free rotation around the C1–C6 single bond
of 5 enables one enantiomer of A to isomerize into the other.
Thus, the racemization between (Sp)- and (Rp)-cations A is
allowed through the formation of vinylferrocene (5), although
the direct racemization of enantiomeric cations A is absolutely
prevented by the ferrocenyl neighboring effect. More impor-
tantly, the substitution of racemic 1 and the hydroamination of
5 exhibited the same enantioselectivity (95% ee) and hence it is
considered that both the hydroamination and the substitution
reaction proceed through common cation A.
In order to acquire insights into the origin of the stereo-
chemical outcome and elucidate the present resolution system,
we theoretically pursued the transition states in the C–N bond
formation (amination) step, namely, the resolution step, of
enantiomeric cations A with sulfonamide nucleophile 3g under
the inuence of chiral conjugate base (R)-2ꢀ. Geometrical
optimization of transition states TSs and TSr leading to a pair of
enantiomers (S)- and (R)-4g, respectively, was thoroughly con-
ducted by DFT calculations.16–19{ As shown in Fig. 5, in opti-
mized transition structures TSs and TSr, chiral conjugate base
(R)-2ꢀ interacts not only with the N–H proton of sulfonamide
nucleophile 3g but also with a couple of protons of the vinyl-
ferrocene unit through hydrogen bonds. Thus, TSs and TSr
feature multi-coordinating hydrogen bonds, which are an
Fig. 5 3D structures and schematic representation models of the
most energetically favorable transition states for the C–N bond
formation step, TSs and TSr, are shown. The 3D structures of each
fragment are represented as follows: ferrocene and nosylamide frag-
ments and phosphoric acid subunit: “tube” model; iron and atoms
involved in the hydrogen bonding interaction: “ball & bond type”
model; and binaphthyl backbone and substituent (G): “wire” model.
Relative free energies (kcal molꢀ1) obtained by single-point energy
calculations are shown for the optimized transition states at the M06-
2X/6-311+G** level18 in the solution phase according to the SCꢀR1F
of the optimized structures at the B3LYP/6-31G* level17 in the gas
phase are shown in parentheses. Hydrogen bond lengths are indicated
in blue (angstroms): (a) (Sp)-cation A/3g/(R)-2ꢀ (G ¼ 9-anthryl) for TSs.
(b) (Rp)-cation A/3g/(R)-2ꢀ (G ¼ 9-anthryl) for TSr.
method based on CPCM19 (toluene). Relative free energies (kcal mol
)
essential interaction mode observed widely in CPA-catalysed
reactions5–7 and are benecial for controlling the stereochem-
ical outcome.20,21 Among the interactions observed, it is note-
worthy that the hydrogen bond is formed between the vinyl
proton of cation A and the oxygen atom of chiral conjugate base
(R)-2ꢀ in both transition states TSs and TSr.
The relative energy difference between TSs and TSr is suffi-
cient for good stereochemical outcome in favor of TSs (DDGs
¼
2.3 kcal molꢀ1) and consistent with the experimental observa-
tion, namely, the formation of (S)-4g as the major product.
However, in the present characteristic KR, the C–N bond
formation (amination) and the deprotonation compete with
each other in both reactions using enantiomeric substrates 1, as
shown in the control experiments (Fig. 3b and c). In the
matched combination of (Sp)-cation A/(R)-2ꢀ, these reactions
are comparable and thus the transition state of the
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deprotonation step and TSs are energetically similar. In of 5, affording (S)-4g in high yield without any detrimental
contrast, the mismatched combination of (Rp)-cation A/(R)-2ꢀ effect on the enantioselectivity.
markedly facilitates the deprotonation and thus TSr is ener-
The amended method is also applicable to the substitution
getically unfavourable relative to the transition state of the reaction of racemic 1 with 3g, affording (S)-4g in comparable
deprotonation step. From the above considerations, it was yield to the hydroamination while maintaining the high enan-
assumed that in the deprotonation of enantiomeric cations A by tioselectivity (Fig. 6b vs. 6a). The established DPKR realized the
chiral conjugate base (R)-2ꢀ, the energy difference between (Sp)- enantio-convergent process in which both enantiomers of
and (Rp)-cations A would not be signicant. In fact, DFT racemic 1 were transformed into single enantiomer (S)-4g in
calculations of the transition states revealed that the deproto- a nearly quantitative manner.22†† In addition, the nosyl (Ns)
nation of (Sp)-cation A by chiral conjugate base (R)-2ꢀ is ener- group attached to the nitrogen atom of substitution product 4g
getically comparable to that of (Rp)-cation
A
(DDGs
¼
can be readily removed to afford the primary amine derivative
0.3 kcal molꢀ1).k More importantly, the backward reaction, (see ESI† for details), which has been widely used as an
namely, the protonation of vinylferrocene (5) by CPA (R)-2, also important precursor of chiral ligands for metal catalysis.9,15 It
proceeds through the same transition states because of the should be emphasized again that the formation of vinyl-
equilibrium between cation A and 5. Hence, the protonation of ferrocene (5) is the key to allowing the racemization of enan-
5 by CPA (R)-2 affords a nearly racemic mixture of cation A.
tiomeric cations A generated from racemic 1 or the protonation
As shown in Fig. 3d, the control experiment revealed that of 5. Otherwise, it is impossible to achieve the present enantio-
the protonation of vinylferrocene (5) by CPA (R)-2 occurred convergent process.
albeit in low efficiency. Furthermore, in the protonation of 5
by CPA (R)-2, the formation of a nearly racemic mixture of
cation A is predicted by DFT studies. However, the efficient
Conclusions
PKR of racemic cation A has been established in the substi- We have demonstrated the dynamic parallel kinetic resolution
tution reaction of racemic 1 with 3g as well as the hydro- (DPKR) of an a-ferrocenyl cation under the inuence of a chiral
amination of 5 with 3g, both of which proceed through the conjugate base of a phosphoric acid catalyst. The mechanism of
same cation A. More importantly, the racemization between the present intriguing resolution system was elucidated by
(Sp)- and (Rp)-cations A is allowed through the formation of control experiments using the enantio-pure precursor of the
vinylferrocene (5). Integrating these features enabled us to relevant a-ferrocenyl cation intermediates and the hydro-
establish the innovative system termed DPKR because the amination of vinylferrocene. Further theoretical studies
racemization process takes place prior to the resolution step. enabled us to understand the origin of the stereochemical
In order to achieve the intended DPKR of enantiomeric cations outcome as well as to establish an efficient DPKR. The present
A, we further explored the reaction conditions to accelerate the resolution system was accomplished by virtue of the dynamic
protonation of 5 by CPA (R)-2 and also the formation of racemization process of enantiomeric a-ferrocenyl cations
product 4g efficiently. As shown in Fig. 6a, the use of chloro- through vinylferrocene and the chemo-divergent PKR of these
benzene, instead of toluene, as the solvent facilitated the cations. The present method enables the formation of a ferro-
hydroamination of 5 with 3g under the inuence of CPA (R)-2 cenylethylamine derivative, which is a key precursor of chiral
presumably because of the stabilization of cations A generated ligands for metal catalysis, in a nearly quantitative manner with
in the slightly polar solvent, chlorobenzene.** The modica- high enantioselectivity. The established DPKR features the
tion of the conditions resulted in the complete consumption integrated aspects of conventional KR and related variants.
Further development of an efficient and distinctive kinetic
resolution system using chiral phosphoric acid and its deriva-
tives is in progress.
Data availability
The exploratory investigation, experimental procedures,
computational data, and characterization data are available.
Author contributions
Y. T.: conceptualization, data curation, formal analysis, inves-
tigation (experimental studies), and writing – original dra. T.
K.: data curation, formal analysis, and investigation (theoretical
studies). R. O.: data curation, formal analysis, and investigation
(experimental studies). J. K.: data curation, formal analysis, and
investigation (experimental studies). M. T.: conceptualization,
project administration, writing – review & editing, supervision,
and funding acquisition.
Fig. 6 DPKR of enantiomeric cations A using (R)-2 (G ¼ 9-anthryl): (a)
the hydroamination of 5 with 3g. (b) The substitution reaction of
racemic 1 with 3g achieving enantio-convergent process.
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Synthetic Methods, ed. M. H. Todd, Wiley & Sons, New York,
2014, pp. 75–89.
Conflicts of interest
2 Dynamic thermodynamic resolution has been reported by
Beak et al., see: (a) P. Beak, D. R. Anderson, M. D. Curtis,
J. M. Laumer, D. J. Pippel and G. A. Weisenburger, Acc.
Chem. Res., 2000, 33, 715–727; (b) W. K. Lee, Y. S. Park and
P. Beak, Acc. Chem. Res., 2009, 42, 224–234.
There are no conicts to declare.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
3 Some catalytic asymmetric reactions may proceed via the KR
pathway for cationic intermediates under equilibrium
conditions between the cations and the achiral reactants.
In most of those cases, it is considered that enantio-
enriched cationic intermediates are formed from the
achiral reactants under the inuence of chiral catalysts.
See: (a) S. E. Denmark, W. E. Kuester and M. T. Burk,
Angew. Chem., Int. Ed., 2012, 51, 10938–10953; (b) K. Murai
and H. Fujioka, Heterocycles, 2013, 87, 763–805.
tic Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” (No. 23105002
&
26105704) and “Hybrid Catalysis for Enabling Molecular
Synthesis on Demand” (No. JP17H06447) from MEXT, Japan.
We also thank the Japan Society for the Promotion of Sciences
for the JSPS Research Fellowship for Young Scientists (Y. T.).
Notes and references
4 Jacobsen et al. reported the dynamic kinetic resolution of
seleniranium ions, see: H. Zhang, S. Lin and
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§ The acid-catalysed methanol addition to vinylferrocene (5) successfully regen-
erated methyl ether 1 in over 90% yield. See ESI† for details.
{ All calculations were performed with the Gaussian 09 package.16 Geometrical
optimization of transition states TSs and TSr was conducted at the B3LYP/6-31G*
level17 and characterized using frequency calculations, and the free energies were
computed for the gas phase. Single-point energy calculations for the optimized
transition states (at the B3LYP/6-31G* level) were also evaluated at the M06-2X/6-
311+G** level18 in the solution phase according to the SCRF method based on
CPCM (3 ¼ 2.3741 for toluene).19 The free energies in toluene were calculated from
the sum of the single-point energies in toluene and the value of thermal correction
to Gibbs free energy in the gas phase.
k All calculations were performed with the Gaussian 09 package.16 The transition
states of the deprotonation step of enantiomeric cations A by chiral conjugate
base (R)-2ꢀ were optimized at the B3LYP/6-31G* level17 in the gas phase and
characterized using frequency calculations. Single-point energy calculations for
the optimized transition states were conducted at the M06-2X/6-311+G** level18 in
the solution phase according to the SCRF method based on CPCM (3 ¼ 2.3741 for
toluene).19 The free energies in toluene were calculated from the sum of the single-
point energies in toluene and the value of thermal correction to Gibbs free energy
in the gas phase.
** The reaction in toluene under the same reaction conditions (at room
temperature for 24 h) afforded (S)-4g in 24% yield with 94% ee.
†† In order to enhance the utility of the developed DPKR, we attempted the
reaction of ferrocenyl derivative methyl ether having ethyl substituent, instead of
methyl substituent of 1. Initially, the optimized reaction conditions were applied
to this derivative. However, demethoxylation product, namely, 1-propenylferro-
cene, was formed as the sole product and no desired substitution product was
obtained at all, despite the complete consumption of the starting methyl ether.
Similarly, the use of more nucleophilic TsNH2 (3a) rather than NsNH2 (3g) was
also unsuccessful, affording 1-propenylferrocene quantitatively. These results
indicate that protonation to 1-propenylferrocene became markedly sluggish using
parent CPA (R)-2. Therefore CPAs having strong acidity, such as a triylamide
derivative and a bisphosphoric acid, were further investigated. As expected, these
strong acids gave rise to the corresponding substitution product in moderate
yield, albeit low enantioselectivity. The present intriguing DPKR is established by
the well-balanced system between the deprotonation of cation A and the selective
introduction of a nucleophile to enantiomeric cations A. Hence, to achieve the
efficient DPKR with high enantioselectivity, optimization of CPAs and reaction
conditions would be strictly required for each substrate. See ESI† for details.
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