Asymmetric Enamide–Imine Tautomerism in the Kinetic Resolution of Tertiary Alcohols

Article abstract of DOI:10.1002/anie.202106151

An efficient protocol for kinetic resolution of tertiary alcohols has been developed through an unprecedented asymmetric enamide-imine tautomerism process enabled by chiral phosphoric acid catalysis. A broad range of racemic 2-arylsulfonamido tertiary allyl alcohols could be kinetically resolved with excellent kinetic resolution performances (with s-factor up to >200). This method is particularly effective for a series of 1,1-dialkyl substituted allyl alcohols, which produced chiral tertiary alcohols that would be difficult to access via other asymmetric methods. Facile and versatile transformations of the chiral α-hydroxy imine and enamide products, especially the efficient stereodivergent synthesis of all four stereoisomers of β-amino tertiary alcohols using one enantiomer of the catalyst, demonstrated the value of this kinetic resolution method.

Full text of DOI:10.1002/anie.202106151

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Accepted Article
Title: Asymmetric Enamide-Imine Tautomerism in the Kinetic
Resolution of Tertiary Alcohols
Authors: Mengyao Tang, Huanchao Gu, Shunlong He, Subramani
Rajkumar, and Xiaoyu Yang
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Asymmetric Enamide-Imine Tautomerism in the Kinetic
Resolution of Tertiary Alcohols
Mengyao Tang,[a],[b],[c] Huanchao Gu,[a] Shunlong He,[a] Subramani Rajkumar,[a] and Xiaoyu Yang*,[a]
Dedicated to Prof. F. Dean Toste on the occasion of his 50th birthday
[a]
M. Tang, H. Gu, S. He, Dr. S. Rajkumar and Prof. Dr. X. Yang
School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
E-mail: yangxy1@shanghaitech.edu.cn
[b]
[c]
M. Tang
University of Chinese Academy of Sciences, Beijing 100049, China
M. Tang
Shanghai Institute of Organic Chemistry, Shanghai 200032, China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An efficient protocol for kinetic resolution of tertiary
alcohols has been developed through an unprecedented asymmetric
enamide-imine tautomerism process enabled by chiral phosphoric
acid catalysis. A broad range of racemic 2-arylsulfonamido tertiary
allyl alcohols could be kinetically resolved with excellent kinetic
resolution performances (with s-factor up to >200). This method is
particularly effective for a series of 1,1-dialkyl substituted allyl
alcohols, which produced chiral tertiary alcohols that would be
difficult to access via other asymmetric methods. Facile and versatile
transformations of the chiral α-hydroxy imine and enamide products,
especially the efficient stereodivergent synthesis of all four
stereoisomers of β-amino tertiary alcohols using one enantiomer of
asymmetric O-silylations[12] and Maruoaka group disclosed the
KR of tertiary diols via asymmetric O-benzylations[13] (Figure 1,
a). Moreover, another efficient strategy has been developed for
KR of tertiary alcohols recently, which utilized the asymmetric
cyclizations of the hydroxy group. List and co-workers developed
KR of tertiary alcohols via asymmetric transacetalizations.[14] Our
group reported the KR of tertiary alcohols via asymmetric
intramolecular
transesterifications[15]
and
dehydrative
condensations[16] enabled by chiral phosphoric acid catalysis.
Recently, Zhou and co-workers disclosed the KR of tertiary
benzyl alcohols via Pd/chiral norbornene cooperatively catalyzed
cyclizations with aryl iodides[17] (Figure 1, b). However, all these
the catalyst, demonstrated the value of this kinetic resolution method. strategies[18] utilized asymmetric conversions of the hydroxy
group and could only produce one enantiomeric alcohol product,
if not undergoing the corresponding deprotection step. Recently,
during the preparation of this manuscript, Zhou and coworkers
reported the first kinetic resolution of tertiary propargyl alcohols
Introduction
through
the
asymmetric
Cu(I)-catalyzed
azide–alkyne
Chiral β-amino alcohols are important and valuable structural
motifs in a wide array of biologically active molecules.[1] In
addition, they have also been extensively used as privileged
chiral auxiliaries and ligands in asymmetric synthesis.[2]
Consequently, the asymmetric synthesis of enantioenriched β-
amino alcohols, particularly via asymmetric catalytic reactions,
has drawn considerable attentions.[3] Despite the fact that a
series of elegant methods have been developed for asymmetric
synthesis of β-amino alcohols,[4] methods that can generate
chiral β-amino tertiary alcohols are still limited.[5]
cycloaddition (CuAAC) reactions, which didn’t involve the
transformations of the OH group. Both enantiomeric alcohols
were produced in these reactions with high enantioselectivities,
albeit the substrate scope was limited to α-acetal and α-
fluoroalkyl substituted tertiary propargyl alcohols[19] (Figure 1, c).
The imine-enamine tautomerism, a particular case of
isomerism, plays an important role in modern organic chemistry,
biochemistry, and medicinal chemistry.[20] Since the relatively
low energy barrier than the analogic keto-enol tautomerism, the
imine-enamine tautomerism has been involved in a number of
reaction mechanisms of organic reactions, typically in the
asymmetric chiral amine catalytic cycles.[21] However, due to the
equilibrium nature of this process, the development of
asymmetric catalytic version of this reaction is extremely
challenging and unprecedented. Herein, we disclose a novel
kinetic resolution of 2-arylsulfonamido tertiary allylic alcohols via
an unprecedented asymmetric enamide-imine tautomerism
enabled by chiral phosphoric acid (CPA) catalysis,[22] in which
the stereodivergent synthesis of all the stereoisomers of β-amino
tertiary alcohols could be readily realized by using only one
enantiomer of the CPA catalyst (Figure 1, d).
Kinetic resolution (KR) is one of the most reliable and
practical methods to produce enantioenriched alcohols in both
academia and industry, and
a large number of elegant
biocatalytic and nonenzymatic methods have been developed to
date.[6] However, in contrast to the well-developed methods of
kinetic resolution of secondary alcohols,[7] the highly efficient
kinetic resolution of tertiary alcohols has been less explored,
probably due to the requirement to distinguish three non-
hydrogen groups. Despite of these challenges, a number of
ingenious methods for KR of tertiary alcohols have been
disclosed by researchers, among which the mostly studied
strategy is the asymmetric protections of the OH group. Miller,[8]
Zhao,[9] Smith[10] and Suga[11] groups developed efficient KR
protocols for tertiary alcohols via asymmetric O-acylations, while
Oestreich group developed KR of tertiary propargyl alcohols via
1
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10.1002/anie.202106151
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loading from 10 mol% to 2 mol% provided almost the same KR
performance, albeit requiring longer reaction time (16 h, entry
15).
Table 1. Optimization of reaction conditions.[a]
[b]
Entry
1
Cat
A1
A2
A3
A4
A5
A6
A7
A8
A7
A7
A7
A7
A7
A7
A7
Solvents
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
ers[b]
70.5:29.5
94:6
erp
C (%)[c]
35
S[d]
11
8.4
1.6
4.1
5.4
3.9
79
33
36
30
79
80
70
57
76
88:12
2
75.5:24.5
54.5:45.5
64.5:35.5
68.5:31.5
75:25
63
3
67.5:32.5
91:9
80
4
74
5
93:7
70
6
64.5:35.5
96:4
37
7
96:4
50
8
85:15
94:6
44
9
76:24
95.5:4.5
95:5
36
10
11
12[e]
13[f]
14[g]
15[h]
CHCl3
73.5:26.5
96:4
34
benzene
toluene
toluene
toluene
toluene
96:4
50
94.5:5.5
95.5:4.5
89:11
96.5:3.5
95:5
46
50
96:4
46
95.5:4.5
96:4
50
[a] Reactions were performed with 1a (0.05 mmol), CPA catalyst (0.005 mmol,
10 mol%), 3 Å MS (20 mg) in solvents (1 mL) at 25 oC for 4 h. [b] Er values
were determined by HPLC analysis using a chiral stationary phase. [c]
Conversion (C) = ees/(ees+eep). [d] s = ln[(1-C)(1-ees)]/ln[(1-C)(1+ees)] [e] At
10 oC. [f] At 35 oC. [g] Without 3 Å MS. [h] With CPA A7 (2 mol%), 16 h.
Figure 1. Kinetic resolution of tertiary alcohols.
Results and Discussion
With the optimal reaction conditions in hand, we started to
investigate the scope of 1,1-dialkyl-substituted allyl alcohols in
this KR reaction under the catalysis of CPA (S)-A7 (2 mol%)
(Table 2). A series of alkyl groups other than the iPr group were
examined in this reaction, which were all well tolerated with the
standard conditions (1b-1f). It is worth mentioning that the
primary alkyl group/Me-disubstituted tertiary alcohols (1d-1f)
afforded high KR performances as well, highlighting the
excellent enantiodifferential ability of this asymmetric catalytic
system. Switching the other group from Me group to Et and vinyl
groups was also amenable to the optimal conditions, which
generated both imine products and recovered enamides with
>95:5 er (1g and 1h). Finally, the substitution at the 3-position of
tertiary allyl alcohols was studied, which indicated that a series
of substituted phenyl groups and heteroaryl groups were well
compatible in this reaction (1i to 1l). Furthermore, the 3-alkyl-
substituted allyl alcohols were also feasible in this reaction,
providing moderate to high KR performances, which expanded
the scope of this method (1m and 1n). The absolute
configurations of the chiral imine and enamide products were
assigned by analogy to recovered (S)-1j, whose structure was
unambiguously determined by X-ray crystallography.[24]
We started our study by using racemic 2-NHTs-substituted
1,1-dialkyl tertiary allylic alcohol 1a as model substrate (Table 1).
Interestingly, under the catalysis of CPA A1 (TRIP, 10 mol%),
substrate 1a was smoothly converted into imine 2a with the
presence of 3 Å molecular sieves (MS) in toluene at 25 oC,
which produced 2a with 88:12 enantiomeric ratio (er) and the
recovered 1a with 70.5:29.5 er after 4 h, corresponding to a
selectivity factor[23] (s) of 11 (entry 1). With this promising result
in hand, we set out to screen a series of BINOL-derived CPA
catalysts (entries 2-7), and found that the CPA A7 (TCYP) could
dramatically improve the s-factor to 79, with both 2a and
recovered 1a with over 95:5 er (entry 7). Switching the chiral
scaffold of CPA A7 from BINOL to H8-BINOL led to the
decrease of KR performance (entry 8). Next, the solvents were
also investigated (entries 9-11), which suggested that both DCM
and CHCl3 provided diminished selectivity factors and benzene
afforded identical KR performance. Subsequently, the reaction
temperature was studied. Decrease of the reaction temperature
to 10 oC provided identical s-factor with slower reaction rate
(entry 12), while increasing the reaction temperature to 35 oC led
to a bit erosion of KR performance (entry 13). Additionally, the
role of 3 Å MS was also examined, which was suggested to be
important for both the stereoselectivity and reaction rate of this
reaction (entry 14). Encouragingly, decrease of the catalyst
Table 2. Scope for KR of 1,1-dialkyl-substituted allylic alcohols through
asymmetric enamide-imine tautomerism.[a]
2
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10.1002/anie.202106151
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enamide products with high enantioselectivities (1p-1s, Table 3,
b). Substitution at the 3-phenyl group was also amenable in this
reaction (1t). Other alkyl groups than the Me group were also
examined, which also generated the chiral imines and enamides
with excellent KR performances (1u and 1v). It is worth
mentioning that only one round of KR process was required for
the Bn-substituted allyl alcohol 1v to achieve satisfactory
conversion, which suggested that the equilibrium between
enamide and imine under these conditions was also highly
substrate-dependent.
Table 3. Scope for KR of 1-aryl-1-alkyl-disubstituted allylic alcohols through
asymmetric enamide-imine tautomerism.[a]
[a] Reactions were performed with 1 (0.2 mmol), CPA (S)-A7 (0.004 mmol, 2
mol%), 3 Å MS (80 mg) in toluene (4 mL) at 25 oC. Yields are isolated yields.
Er values were determined by HPLC analysis using a chiral stationary phase.
Conversion (C) = ees/(ees+eep). s = ln[(1-C)(1-ees)]/ln[(1-C)(1+ees)]. b10 mol%
CPA (S)-A7 was used.
[a] Reactions were performed with 1 (0.2 mmol), CPA (S)-A7 (0.02 mmol, 10
mol%), 3 Å MS (80 mg) in benzene (4 mL) at 25 oC. After achieving the
equilibrium, separation of these products by column chromatography gave (R)-
2 and (S)-1 (with moderate er). A second round of KR of (S)-1 with (S)-A7 (5
mol%) produced the (S)-1 with high ers, and the yields and er values of imines
(R)-2 were determined by combination of the imine products in two rounds of
KR processes. [b] One round of KR process was performed.
With the excellent KR results for 1,1-dialkyl-substituted
allylic alcohols, we turned our attention to 1-aryl-1-alkyl-
disubstituted allylic alcohols, whose disubstitutions should be
easier to be differentiated in general sense (Table 3). Treatment
of racemic 1o with CPA (S)-A7 (10 mol%) in benzene[25] at 25 oC
provided the imine product 2o with 98:2 er and recovered 1o
with 82.5:17.5 er after 3 h, corresponding to an excellent s-factor
(s = 100). However, prolonging the reaction time could not
improve the conversion, and the enantioselectivity of imine 2o
gradually decreased over time (see Table S1 in Supporting
Information for details), which suggested the presence of an
equilibrium in the enamide-imine tautomerism process for this
substrate. Attempt to improve the conversion by modulating the
reaction temperature led to no success. Finally, a second round
of KR of the recovered 1o (with 82.5:17.5 er) with the standard
conditions produced (S)-1o in 44% yield with 95.5:4.5 er, and
combination of the imine products in two rounds of KR reactions
gave 2o in 46% overall yield with 95.5:4.5 er (Table 3, a). With
this two-steps KR protocol in hand, we investigated a range of
substituted phenyl groups at the 1-position of the allyl alcohols
and found that substitutions at the para-, meta- and ortho-
position were all well tolerated, which produced both imine and
To shed light on the mechanisms of this unprecedented KR
reaction, some control experiments were performed (Scheme 1).
Two achiral enamides 3a and 3b were prepared and subjected
into the standard KR conditions (Scheme 1, a). Interestingly,
enamide 3a bearing an adjacent hydroxy group readily
underwent the tautomerism in the presence of CPA catalyst to
give the imine 4a in 80% yield, while no imine product 4b was
generated from 3b under the same conditions. Moreover, an O-
TMS protected allyl alcohols 5a was prepared and examined
under the KR conditions as well, which only provided trace
amount of the imine product 6a and almost in its racemic form
(Scheme 1, b). All these results clearly implied that the adjacent
hydroxy group is vital to both the reactivities and
stereoselectivities of these asymmetric tautomerism reactions,
which should play an important role in the asymmetric transition
state. Interestingly, an intramolecular hydrogen bonding
3
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10.1002/anie.202106151
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between the hydroxy group with one of the S=O moiety in Ts
group was observed in the X-Ray structures of the recovered
(S)-1j and the β-amino alcohol (2R,3R)-10a as well (see
Scheme 2, d). The intermolecular competitive kinetic isotope
effect (KIE) experiment between the model substrate bearing N-
H or N-D moiety (1aD) was also performed, which provided the
imine product 2aD with much lower deuterium ratio than the
recovered SM, corresponding to a KIE value of 6.5 (Scheme 1,
c). This result suggested that the N-H bond cleavage was
probably involved in the rate-determining step. In addition, the
proton(deuterium) transfer step was highly stereoselective and
only one of the two methylene protons (Hβ) in 2aD was
deuterated in this reaction, which was determined by NOE
analysis on a cyclic conformation of 2aD, derived from the X-Ray
structure of (S)-1j and (2R,3R)-10a.
1.0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80
100
ee of cat A7 (%)
Figure 2. Non-linear effect experiment.
To demonstrate the practicability of this method, a 1 mmol-
scale KR of racemic alcohol 1a was studied using CPA (S)-A7
(2 mol%), which generated the imine product (R)-2a in 50% yield
with 96:4 er and the recovered (S)-1a in 49% yield with 96:4 er
as well (Scheme 2, a). Derivatizations of the chiral imine and
enamide products were also studied to showcase the utilities of
this method. The chiral imine (R)-2a could be readily converted
into enamide (R)-1a upon treatment with LiHMDS at -78 oC with
high efficiency (Scheme 2, b), while the recovered enamide (S)-
1a could be transformed into imine (S)-2a as well in the
presence of Et3N (Scheme 2, c). Thus, both two enantiomers of
the enantioenriched enamides and imines could be efficiently
generated through one KR reaction. In addition, hydrolysis of
imine (R)-2a in the presence of basic Al2O3 afforded the α-
tertiary-hydroxy ketone 7a in 92% yield with 96:4 er. Treatment
of enamide (S)-1a with NBS facilely produced the α-brominated
imine 8a with high diastereoselectivity (12:1 dr). Additionally, the
oxidative cleavage of the enamide moiety of (S)-1a using
RuCl3/NaIO4 provided the α-hydroxyl amide 9a in decent yield
(Scheme 2, c). Notably, the enantiopurities of the chiral tertiary
alcohols were retained through these transformations. With both
enantiomers of α-hydroxy imine 2a in hand, the stereodivergent
asymmetric synthesis[28] of β-amino tertiary alcohols was studied
(Scheme 2, d). First, the respective stereoselective reduction of
(S)/(R)-2a with L-Selectride at -78 oC produced β-amino alcohols
(2S,3S)-
and
(2R,3R)-10a
with
excellent
syn-
Scheme 1. Control experiments and plausible reaction mechanism.
diastereoselectivities (>25:1 dr). Furthermore, treatment of imine
2a with BH3·THF at -78 C could generate the amino alcohols
o
In order to gain a clearer picture of the enantiodetermining
transition state, the relationship between differential kinetic
enantiomeric enhancement (DKEE)[26] and the ee of catalyst A7
in the KR reaction of racemic 1a was studied, and an
approximately linear relationship was observed, which
suggested the absence of multiple chiral components in the
asymmetric transition state (Figure 2). Based on these
experimental results, a plausible reaction mechanism was
10a with high anti-selectivities (9:1 dr), resulting in the formation
of the other two stereoisomers of β-amino alcohols 10a, namely
(2R,3S)- and (2S,3R)-10a.[29] The absolute configurations of
these β-amino alcohols were assigned by X-ray crystallography
of product (2R,3R)-10a.[30] It is worth noting that only one
enantiomer of the CPA catalyst was used in this protocol to
provide access to all four stereoisomers of the β-amino tertiary
alcohol products, which highlighted the power of this protocol.
proposed, which involved
a
concerted CPA-mediated
asymmetric proton transfer[27] of the exocyclic enamide-like
substrate, due to the formation of intramolecular H-bonding
between the OH group and sulfonyl group (Scheme 1, d). Under
the guidance of (S)-CPA A7, the proton approaches the
enamide from the Si-face with high stereoselectivity.
4
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We gratefully acknowledge NSFC (Grant No. 21702138) and
ShanghaiTech University start-up funding for financial support.
The authors thank the support from Analytical Instrumentation
Center (# SPST-AIC10112914), SPST, ShanghaiTech
University and Dr. Na Yu for the X-ray crystallographic analysis.
Keywords: asymmetric catalysis • chiral Brønsted acids •
enamide-imine tautomerism • kinetic resolution • tertiary alcohols
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Scheme 2. Derivatizations of chiral products.
Conclusion
In conclusion, we disclose an unprecedented kinetic
resolution of tertiary allylic alcohols through asymmetric enamide
to imine tautomerisms enabled by chiral phosphoric acid
catalysis.
A wide array of 1,1-dialkyl- and 1-aryl-1-alkyl-
disubstituted 2-arylsulfonamido allyl alcohols were compatible
with these methods, producing both chiral α-hydroxy imines and
enamides with high enantioselectivities (with s factor up to >200).
Control experiments and preliminary experimental mechanistic
studies were performed to highlight the critical role of the
hydroxy group in these asymmetric tautomerism reactions.
Facile and versatile derivatizations of the chiral products,
especially the stereodivergent synthesis of all the four
stereoisomers of β-amino tertiary alcohol by using only one
enantiomer of the CPA catalyst, demonstrated the power of
these methods in asymmetric synthesis of value-added chiral
products. Further applications of this novel CPA-catalyzed
enamide-imine tautomerism process in kinetic resolution are
under investigation in our group.
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6
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Entry for the Table of Contents
An unprecedented kinetic resolution of 2-amido tertiary allyl alcohols through chiral phosphoric acid-catalyzed enamide-imine
tautomerism is reported. Both dialkyl- and aryl-alkyl-disubstituted allyl alcohols were compatible with this protocol, generating α-
hydroxy imines and enamides with high enantioselectivities. Stereodivergent synthesis of all stereoisomers of β-amino tertiary alcohol
from the products demonstrated the power of this method.
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