Kinetic Resolution of Tertiary Benzyl Alcohols via Palladium/Chiral Norbornene Cooperative Catalysis

Article abstract of DOI:10.1002/anie.202103428

Herein we report a highly enantioselective kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis. With simple aryl iodides as the resolution reagent, a wide range of readily available racemic tertiary benzyl alcohols are applicable to this method. Both chiral tertiary benzyl alcohols and benzo[c]chromene products are obtained in good to excellent enantioselectivities (selectivity factor up to 544). The appealing synthetic utility of the obtained enantioenriched tertiary alcohols is demonstrated by the facile preparation of several valuable chiral heterocycles. Preliminary mechanism studies include DFT calculations to explain the origin of enantiodiscrimination and control experiments to uncover the formation of a transient axial chirality during the kinetic resolution step.

Full text of DOI:10.1002/anie.202103428

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How to cite:
International Edition: doi.org/10.1002/anie.202103428
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Cooperative Catalysis Very Important Paper
Kinetic Resolution of Tertiary Benzyl Alcohols via Palladium/Chiral
Norbornene Cooperative Catalysis
Yu Hua+, Ze-Shui Liu+, Pei-Pei Xie, Bo Ding, Hong-Gang Cheng, Xin Hong,* and
Qianghui Zhou*
Abstract: Herein we report a highly enantioselective kinetic
resolution of tertiary benzyl alcohols via palladium/chiral
norbornene cooperative catalysis. With simple aryl iodides as
the resolution reagent, a wide range of readily available
racemic tertiary benzyl alcohols are applicable to this method.
Both chiral tertiary benzyl alcohols and benzo[c]chromene
products are obtained in good to excellent enantioselectivities
(selectivity factor up to 544). The appealing synthetic utility of
the obtained enantioenriched tertiary alcohols is demonstrated
by the facile preparation of several valuable chiral heterocycles.
Preliminary mechanism studies include DFT calculations to
explain the origin of enantiodiscrimination and control experi-
ments to uncover the formation of a transient axial chirality
during the kinetic resolution step.
C
atalytic kinetic resolution (KR) is a practical strategy to
access enantioenriched chiral alcohols because the corre-
sponding racemates are usually readily available.[1] Although
KR of secondary alcohols has been well-developed, KR of
tertiary alcohols remains a challenging task and has been
rarely explored, which is mainly attributed to the innate low
reactivity of sterically congested tertiary alcohols and diffi-
culties in precise differentiation of three non-hydrogen
substituents.[2–4] Since chiral tertiary benzyl alcohols are
important structural motifs prevalent in pharmaceuticals
(Figure 1A), considerable efforts have been devoted to the
challenging KR of these tertiary alcohols so far, culminating
in the development of a few elegant strategies (Fig-
ure 1B).[2–13] Pioneered by Miller[2] and later on by Zhao,[3]
Smith[4] and Suga,[5] the nonenzymatic[6] acylative KRs using
pentapeptide or chiral Lewis base catalyst were developed.
List and Yang successively developed efficient KR strategies
[*] Y. Hua,[+] Dr. Z.-S. Liu,[+] B. Ding, Prof. Dr. H.-G. Cheng,
Prof. Dr. Q. Zhou
Figure 1. Approaches to access chiral tertiary alcohols via KRs.
Sauvage Center for Molecular Sciences, Engineering Research Center
of Organosilicon Compounds & Materials (Ministry of Education),
College of Chemistry and Molecular Sciences, and The Institute for
Advanced Studies, Wuhan University
Wuhan, 430072 (China)
E-mail: qhzhou@whu.edu.cn
based on chiral phosphoric acid-catalyzed (trans)acetaliza-
tion,[7] transesterification[8] or condensation.[9] Additionally,
efficient KR strategies based on transition metal catalysis
were also developed by Hayashi,[10] Ma,[11] Oestreich[12] and
Zhou.[13] Despite these stunning progresses, there is still room
for improvement with regard to KR efficiency, substrate
generality and so on. Therefore, the development of more
versatile KR methods using readily available reagents are
highly desirable.
P.-P. Xie, Prof. Dr. X. Hong
Department of Chemistry, State Key Laboratory of Clean Energy
Utilization, Zhejiang University
Hangzhou, 310058 (China)
E-mail: hxchem@zju.edu.cn
[+] These authors contributed equally to this work.
The palladium/norbornene (Pd/NBE) cooperative catal-
ysis, firstly reported by Catellani and co-workers,[14] has
become a powerful tool for expeditious synthesis of polysub-
stituted arenes.[15] Pd/chiral NBE* cooperative catalysis is
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202103428.
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Table 1: Optimization of reaction conditions.[a]
treated as a potential strategy for asymmetric synthesis.
However, owing to multiple formidable challenges,[16] it has
rarely been realized so far.[17] Recently, we developed an
efficient method to access axially chiral biaryls via Pd0/chiral
NBE* cooperative catalysis.[17c] Inspired by this chemistry, we
envisioned a strategy for KR of tertiary benzyl alcohols. As
shown in Figure 1C, aryl iodide 2 undergoes sequential
Entry
Ligand
[NBE]
ee [%][b]
C [%][c]
S [%][d]
À
oxidative addition, chiral NBE* insertion and ortho-C H
1a
3a
activation to generate the chiral aryl-NBE palladacycle
(ANP) species I, which is then selectively oxidized by one
enantiomer of the racemic tertiary benzyl alcohol bearing an
aryl bromide motif (eg. (S)-1) to produce the PdIV intermedi-
ate II, leaving the other enantiomer (eg. (R)-1) unreacted.
Intermediate II subsequently undergoes reductive elimina-
tion and b-carbon elimination to form axially chiral complex
III and replenish the chiral NBE*. Finally, an intramolecular
etherification occurs via complex III to give the central chiral
benzo[c]chromene product (S)-3,[18] alongside disappearance
of the transient axial chirality. Potential features of this KR
method included the unprecedented resolution mode, the use
of simple aryl iodides as the resolution reagent and providing
two valuable chiral molecules in one operation. Nevertheless,
multiple challanges are foreseeable. For example, the iden-
tification of a suitable chiral NBE* co-catalyst to ensure both
good reactivity and enantiodiscrimination,[16] the innate low
reactivity of 2,6-disubstituted arylbromide motif of the
tertiary alcohols,[17c] and the dichotomy between required
high reaction temperature and expected good KR effciency.
To probe this challenging process, we initiated our studies
with a model reaction between racemic tertiary benzyl
alcohol 1a (1.0 equiv) and 1-iodonaphthalene 2a (0.5 equiv)
in the presence of Pd(OAc)2 (2.5 mol%), tri(2-furyl)phos-
phine (TFP) (7.5 mol%), and (1S,4R)-2-methyl ester-substi-
tuted NBE (N1*, 99% ee, 50 mol%)[17a] (Table 1). Gratify-
ingly, KR of racemic tertiary benzyl alcohol (Æ)-1a was
indeed achieved with good efficiency (the selectivity factor
(S) is 104), providing the desired benzo[c]chromene product
3a with 96% ee and recovered 1a with 71% ee (entry 1).
Subsequently, the KR effect of other chiral NBEs* was
investigated. The C2-ethyl ester substituted chiral NBE*
(N2*)[17b–c] behaved similarly to N1* (entry 2), and the C2-
amide substituted chiral NBE* (N3*)[16] led to erosion of the S
factor (entry 3). In sharp contrast, the C5-methyl ester
substituted chiral NBE* (N4*) resulted in almost a complete
loss of KR selectivity (entry 4). Then we investigated the
effect of phosphine ligand on KR efficiency (entries 5–8). The
use of PPh3 as the ligand led to a lower conversion (entry 5),
while other ligands such as JohnPhos, XPhos or PCy3, resulted
in low efficiency or even no reaction (entries 6–8). Notably,
the loading of N1* could be reduced to 30 mol% with a slightly
lower conversion (entry 9). Lastly, increasing the amount of
2a (to 0.8 equiv) and TFP (to 10 mol%) gave the best results
(51% conversion, S = 127), which was determined as the
optimal reaction conditions (entry 10).
1
2
3
TFP
TFP
TFP
N1*
N2*
N3*
N4*
N1*
N1*
N1*
N1*
N1*
N1*
71
68
89
21
44
10
0
0
53
96
96
96
92
18
95
94
–
–
96
94
43
41
49
54
31
10
0
0
36
51
104
100
72
2
60
36
–
–
83
127
4
TFP
5[e]
6[e]
7[e]
8[e]
9[f]
10[f,g]
PPh3
JohnPhos
XPhos
PCy3
TFP
TFP
[a] All reactions were performed on a 0.2 mmol scale. [b] Determined by
chiral HPLC analysis. [c] Conversion (C)=ees/(ees +eep). [d] S=ln-
[(1ÀC) (1Àeep)]/ln[(1ÀC) (1+eep)]. [e] N1* (97% ee) was applied.
[f] 30 mol% of N1* was applied. [g] 10 mol% of TFP and 0.8 equiv of 2a
were applied.
providing the desired chiral benzo[c]chromene products as
well as the recovered 1a with good to excellent enantiopurity
(78–99% ees). In general, electron-withdrawing aryl iodides
were inferior to the reaction (2e and 2m) and provided
smaller S factors. Besides the alkyl substituents (2b–d),
various functional groups of aryl iodides, including fluoro (2 f,
2h and 2k), chloro (2g), bromo (2l and 2n), trifluoromethyl
(2e) and nitro (2m) groups were tolerated. In addition,
bicyclic aryl iodides (2n and 2o) and heteroaryl iodide (2p)
were competent to afford excellent KR results.
Subsequently, the reaction scope of racemic tertiary
benzyl alcohols (1) were evaluated, with 1-iodonaphthalene
2a as the resolution reagent (Table 3). Firstly, we investigated
the aryl/Me-type tertiary benzyl alcohols, and found that good
KR results could be obtained with various groups (eg. methyl,
fluoro and methoxy) at different positions of the phenyl motif
(1b–g). The S factor reached 544 for the alcohol with an
ortho-methyl phenyl group (1d), although longer reaction
time was required (probably due to the increased steric
hindrance). Notably, tertiary alcohols with a heteroaryl motif
(1h and 1i) were also smoothly resolved with good efficiency.
Next, the more challenging alkyl/Me-type tertiary alcohols
were investigated. After screening, we found only the ones
with a proper steric differentiation of the two alkyl groups (1j
and 1k) gave good S factors. We also explored the reaction
scope of Ph/alkyl-type tertiary alcohols. Both the Ph/Et- and
Ph/CF3-substituted ones (1l and 1m) afforded good S factors.
Finally, we probed the scope of ortho substituent of the aryl
bromide moiety of tertiary alcohols, and found ethyl (1n),
cyanomethyl (1o), TBS-protected hydroxymethyl (1p), N,N-
dimethylaminomethyl (1q), pyrrolidin-1-ylmethyl (1r), mor-
With the optimal reaction conditions established, we first
set out to explore the reaction scope of aryl iodide 2, with (Æ)-
1a as the reaction partner (Table 2). To our delight, a wide
range of aryl iodides containing electron-donating or elec-
tron-withdrawing groups all proved to be suitable substrates,
2
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Table 2: Reaction scope of aryl iodide.[a]
Table 3: Reaction scope of tertiary alcohol.[a]
[a] All reactions were performed on a 0.2 mmol scale. The reactions were
monitored by chiral HPLC analysis. Reported yields are for the isolated
products. The ee values were determined by chiral HPLC analysis.
[b] 5 mol% of Pd(OAc)2 and 20 mol% of TFP were applied. [c] 1108C.
[a] All reactions were performed on a 0.2 mmol scale. The reactions were
monitored by chiral HPLC analysis. Reported yields are for the isolated
products. The ee values were determined by chiral HPLC analysis.
pholino-methyl (1s) and naphthyl (1t) were well tolerated.
The absolute configuration of 3T was unambiguously deter-
mined to be (S) by X-ray crystallographic analysis[19] and
those of other products and recovered enantioenriched
tertiary alcohols were assigned by analogy. Notably, the
ortho-bromo substitution in the recovered enatioenriched
tertiary benzyl alcohols (R)-1b–t could act as a good synthetic
handle for further manipulations (see Scheme 1).
Since the obtained enantioenriched tertiary benzyl alco-
hols are valuable intermediates, eg. assembling biorelevant
heterocycles, a series of follow-up transformations were
demonstrated (Scheme 1). For instance, isobenzofuranone 4
was synthesized from (R)-1a in just one step by palladium-
catalyzed carbonylation (63% yield, 94% ee).[20] In addition,
a versatile chiral amino alcohol 5 was readily obtained from
(R)-1a and ammonia by Ullmann-type amination in 75%
yield and 92% ee.[21] To our delight, 5 could be further
transformed into a variety of chiral heterocycles. For example,
condensation of 5 with benzaldehyde under acidic conditions
afforded the benzoxazine 6 in good yield and diastereoselec-
tivity (81%, 8:1 dr, 94% ee).[9a] The reaction of 5 with 4-
nitrophenyl chloroformate and a following base treatment
afforded benzoxazinone 7 in 90% yield and 93% ee.[22]
Moreover, subjecting 5 to ethyl isothiocyanate then iodine
provided benzofused heterocycle 8,[23] an analogue of the
Scheme 1. Application of enantioenriched tertiary benzyl alcohol in
heterocycles synthesis.
anticonvulsant drug etifoxine. It is worth mentioning that all
these transformations proceeded without any erosion of the
enantiopurity.
Lastly, a possible catalytic cycle of the reaction was
proposed in Figure 2A, based on the obtained data and
previous mechanistic studies on Catellani-type reactions.[24]
To shed light on this catalytic cycle, some mechanistic studies
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conditions. Besides the recovered enantioenriched (R)-1a
and normal product (S)-3a, the intermolecular Heck-type
terminating product 9 containing both axial and central
chirality was also isolated in a comparable 20% yield with
excellent enantioselectivity and diastereoselectivity (98% ee,
> 20:1 dr). The formation of 9 is a solid evidence of the
transient axial chirality generated during the KR step, which
provides a strong experimental support for the mechanism
proposed in Figure 2A.
In summary, we have developed a highly efficient method
for the KR of tertiary benzyl alcohols, based on palladium/
chiral norbornene cooperative catalysis. With simple aryl
iodides as the resolution reagent, a wide range of readily
available racemic tertiary benzyl alcohols are applicable to
this method, providing both chiral tertiary benzyl alcohols
and benzo[c]chromene products with excellent enantioselec-
tivities. The synthetic utility is demonstrated by the facile
synthesis of diversified biorelevant heterocycles. Preliminary
mechanism studies are performed to elucidate the origin of
enantiodiscrimination and the formation of a transient axial
chirality during the KR step.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (grant nos. 21871213, 22071189 for Q.Z., and
21873081 for X.H.), Fundamental Research Funds for the
Central Universities (2020XZZX002-02 for X.H.), and the
State Key Laboratory of Clean Energy Utilization
(ZJUCEU2020007 for X.H.) for financial support. We
thank Dr. Liming Cao and Mr Tao Yang for technical
assistance.
Figure 2. Proposed catalytic cycle and related reaction mechanism
studies.
were performed. First, density functional theory (DFT)
calculations were carried out to rationalize the enantiodiscri-
mination process, the sequential oxidative addition and
reductive elimination from B to D. The detailed free energy
Conflict of interest
Q.Z., Y.H. and Z.-S.L. have filed a provisional patent
application (2021103260547). All other authors declare no
conflict of interest.
À
profiles of the generation of both (S)- and (R)-C C axial
chirality intermediates are included in the Supporting Infor-
mation (Figure S1). We found that the oxidative addition of
aryl bromide (Æ)-1a to chiral ANP B is the enantiodiscrimi-
nation step that differentiates the two diastereomer inter-
Keywords: chiral norbornene · cooperative catalysis ·
kinetic resolution · tertiary benzyl alcohol ·
transient axial chirality
À
mediates C with (S)-C C axial chirality. The optimized
structures and relative free energies of the enantioselective
oxidative addition transition states TS1 and TS1’ are shown in
Figure 2B. Transition state TS1’ ((R)-1a with B) is disfavored
because of steric repulsions arising from the proximal place-
ment of the bulky phenyl substituent and the chiral NBE*
fragment. Such steric repulsions are not present in the favored
transition state TS1 ((S)-1a with B), which leads to the
2.1 kcalmolÀ1 free energy difference between the two com-
peting oxidative addition processes and eventually results in
an excellent KR efficiency (S = 110). The DFT results well
explained the origin of enantiodiscrimination which was
consistent with the experimental results. Additionally, a con-
trol experiment introducing styrene as a competitive termi-
nating reagent was conducted under the standard reaction
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Manuscript received: March 9, 2021
Accepted manuscript online: March 30, 2021
Version of record online: && &&, &&&&
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Communications
Cooperative Catalysis
A highly enantioselective kinetic reso-
lution of tertiary benzyl alcohols via pal-
ladium/chiral norbornene cooperative
catalysis is developed. Simple aryl iodides
is used as the resolution reagent. Both
enantioenriched tertiary benzyl alcohols
and benzo[c]chromene products are
obtained in good to excellent enantiose-
lectivities. The synthetic applications are
demonstrated by the facile synthesis of
diversified biorelevant heterocycles.
Y. Hua, Z.-S. Liu, P.-P. Xie, B. Ding,
H.-G. Cheng, X. Hong,*
Q. Zhou*
&&&& — &&&&
Kinetic Resolution of Tertiary Benzyl
Alcohols via Palladium/Chiral
Norbornene Cooperative Catalysis
6
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