Silicon-based Bulky Group?Tuned Parallel Kinetic Resolution in Copper-Catalyzed 1,3-Dipolar Additions

Article abstract of DOI:10.1002/adsc.201800220

The development of new strategies or reaction processes that tease new reactivity of functional groups continues to spur synthetic chemists toward innovative solutions that access new compounds. Herein, we find that the silicon-based bulky group enables a 1,3-dipolar addition?initiated parallel kinetic resolution (PKR) to occur unexpectedly, leading to the highly enantioselective synthesis of two structurally different types of amino acid derivatives via chemodivergent [3+2] cycloaddition reactions and tandem conjugate addition-elimination reaction respectively. The resulting and structurally divergent enantioenriched amino acid derivatives that contain four contiguous stereogenic centers and an all-carbon quaternary center were obtained with up to 99% ee with >95:1 dr and good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800220

Title: Silicon-based Bulky Group –Tuned Parallel Kinetic Resolution in
Copper-Catalyzed 1,3-Dipolar Additions
Authors: Yang Yuan, Zhan-Jiang Zheng, Li Li, Xing-Feng Bai, Zheng
Xu, yuming cui, jian cao, Ke-Fang Yang, and Li-Wen Xu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800220
Link to VoR: http://dx.doi.org/10.1002/adsc.201800220

10.1002/adsc.201800220
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Silicon-based Bulky Group–Tuned Parallel Kinetic Resolution
in Copper-Catalyzed 1,3-Dipolar Additions
Yang Yuan a, Zhan-Jiang Zheng a, Li Li a, Xing-Feng Bai a,b, Zheng Xu a, Yu-Ming Cuia,
Jian Cao a, Ke-Fang Yang a, and Li-Wen Xu a,b*
a
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University, Hangzhou 311121, P. R. China.
[Fax: 86 2886 5135; Tel: 86 2886 8720; E-mail: liwenxu@hznu.edu.cn]
Suzhou Research Insititue and State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
b
Chemical Physics, Chinese Academy of Sciences, Lanzhou, P. R. China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
rearrangement[7c] or [4+2] annulation of 4-alkynals
Abstract. The development of new strategies or reaction
processes that tease new reactivity of functional groups
continues to spur synthetic chemists toward innovative
with isocyanates[7d]
.
Notably, except rhodium
catalysis, there are few methods focused on metal-
solutions that access new compounds. Herein, we find that catalyzed transformations in the field of PKR.
the silicon-based bulky group enables a 1,3-dipolar
addition–initiated parallel kinetic resolution (PKR) to occur
unexpectedly, leading to the highly enantioselective
synthesis of two structurally different types of amino acid
derivatives via chemodivergent [3+2] cycloaddition
reactions and tandem conjugate addition-elimination
reaction respectively. The resulting and structurally
divergent enantioenriched amino acid derivatives that
contain four contiguous stereogenic centers and an all-
carbon quaternary center were obtained with up to 99% ee
with >95:1 dr and good yields.
Therefore, it is rewarding to exploit a powerful PKR
via rational design of functional group-based
transformation in order to improve enantioselection
by kinetic resolution.
(a) Asymmetric tandem conjugate addition-elimination
OAc
CO2Me
CO2Me
R2
CO2Me
Ag/DTBM-Segphos
R2

1
+
ee up to 99%
N
R1
ref. 8
3
R1
N
CO2Me
2
Keywords: Kinetic resolution; organosilicon; 1,3-dipolar
(b) Asymmetric 1,3-dipolar [3+2] cycloaddition
cycloaddition; chiral ligand; copper.
OH
OH
CO2tBu
CuBF4/P-Ligand
Ph
Ph
ButO2C
Efficient kinetic resolution (KR) is widely used
method to obtain enantioenriched products from
racemic materials, and continue to play a critical or
practical role in chiral synthesis.[1] Traditional kinetic
resolution that based on an unequal reaction rate of
each enantiomer gives a maximum of 50% product,
in which the enantioenriched stating material is
94% yield
1:1 dr
+
CO2Me
N
H
Ph
p-Cl
95% and 85% ee
p-Cl Ph
N
CO2Me
ref. 10
CO2Me
CO2Me
(c) This work: Parallel kinetic resolution (PKR)
R2
O[Si]
 N
CO2Me
R2
3
R1
Cu catalysis
recovered
or
another
enantiomer
remains
+
unchanged.[2] As an alternative to kinetic resolution,
parallel kinetic resolution (PKR)[3,4] provided an
attracting and useful process to stereoselective and
structurally divergent synthesis of chiral compounds,
in which both enantiomers of the starting material
react with a reagent to give distinct products with
high enantiomeric excess.[5] Recently, much interest
has been devoted to PKR[6], where a really impressive
example is Bode’s PKR based on flow chemistry and
polymer-supported pseudoenantiomeric acylating
agents. Interestingly, rhodium catalysts were proved
to be worked well to create parallel kinetic resolution
of different compounds via cycloisomerization[7a],
High dr
High ee
1
O[Si]
R2
+
MeO2C
R1
N
CO2Me
CO2Me
R1
N
H
2
4
Figure 1. Silicon-based bulky group (SBG) -tuned parallel
kinetic resolution: 1,3-Dipolar addition-initiated [3+2]
cycloaddition reaction and tandem conjugate addition-
elimination reaction.
hydroarylations[7b]
,
cyclopropanation/cope
1
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
Very recently, our group described a silver-catalyzed
[3+2] cycloaddition of various glycine aldimino
esters with activated alkenes[8a-d] and asymmetric
tandem conjugate addition-elimination reaction of
glycine aldimino esters with racemic Morita-Baylis-
Hillman (MBH) adducts (MBH acetates) that though
Scheme 1. Kinetic resolution of racemic MBH-derived
silyl ether 1a-1e by screening of various catalyst systems
and chiral ligands: Effect of silicon-based bulky group on
the copper-catalyzed reaction of 1 and 2.
1,3-dipolar activation (Figure 1, equation a)[8e]
,
Herein, we reported an unprecedented and highly
allowing for facile preparation of a variety of
glutamic acid derivatives in high ee values (up to
99% ee). Although the racemic MBH acetates are
ideal model compounds in PKR chemistry, we did
not detect another 1,3-dipolar [3+2] cycloaddition
reaction except tandem conjugate addition-
elimination reaction in this work. Very surprisingly,
racemic MBH adducts have seldom been employed
as activated alkenes in catalytic asymmetric [3+2]
cycloaddition reactions. Although numerous reports
on highly chemo-, diastereo-, and enantio-selective
[3+2] cycloaddition of azomethine ylides with
activated olefins have been achieved in the past
decade[9], to date, only one example has been
documented by Wang and co-workers[10], in which
they found the racemic Morita–Baylis–Hillman
adduct could be applie in 1,3-dipolar [3+2]
cycloaddition reaction with the azomethine ylide to
give two diastereomers in 94% yield and excellent
enantioselectivities (95% ee and 85% ee) but with 1:1
diastereoselectivity (Figure 1, equation b). Distinct
from these findings, we envisioned that the
introduction of silicon-based bulky group[11] into the
racemic MBH adducts could tune the reactivity and
stereoselectivity of MBH adducts in the
intermolecular cycloaddition and PKR of more stable
MBH-derived silyl ethers with glycine aldimino
esters is also possibly to be established for the
enantioselective
copper-catalyzed
[3+2]
cycloaddition of racemic Morita-Baylis-Hillman
(MBH) adducts with glycine aldimino esters that
tuned by silicon-based bulky group –initiated steric
repulsion and catalyst-substrate interaction. In
addition, it is a novel parallel kinetic resolution
approach to highly substituted pyrrolidine derivatives
and glutamic acid derivatives via chemodivergent
[3+2] cycloaddition and tandem conjugate addition-
elimination reaction (Figure 1, equation c).
Table 1. Control experiments for intermolecular reaction
of MBH adducts 1 with glycine aldimino ester 2a.
OTBDPS
CO Me
2
Ph
Si
1
+
O
Ph
CO Me
2
Standard Conditions:
Cu(CH CN) BF (3 mol%)
DTBM-Segphos (5 mol%)
CO Me
2
CO Me
2
3
4
4
1e
racemic
(0.2 mmol)
Ph

N
o
3a
+
K CO , THF, - 20
C
2
3
Ph
+
O
OTBDPS
O
O
N
CO Me
PAr
PAr
2
2
MeO C
2
2
CO Me
2
2a
N
H
(0.11 mmol)
O
(R)-DTBM-Segphos
4a-e
Ar = 3,5-(t-Bu) -4-MeO-C H
2
6
2
Entry
Variations from the
standard conditions
Yield
4a-e
enantioselective
construction
of
biologically
(%)[a]
attractive and multi-substituted heterocycles bearing
four contiguous stereogenic centers and an all-carbon
quaternary center.
dr[a]
ee(%)[b]
1
2
3
4
5
6
no
34
51
35
34
26
95/5
99/99
O[Si]
1a instead of 1e
1b instead of 1e
1c instead of 1e
1d instead of 1e
84/16 98/99
74/26 99/99
75/25 99/99
88/12 99/99
CO2Me
1
+
O[Si]
CO2Me
CO2Me
CO2Me
Cu (?)
P-Ligand (?)
Ph

1
N
1 equiv of 2a instead of 42
0.55 equiv[c]
95/5
99/99
base(?), solvent (?), - 20 o
C
racemic
3a
Ph
+
+
(see Table S1-S3)
CO2Me
(Supporting Information)
O[Si]
N
7
0 oC instead of -20 oC[d] 36
96/4
99/99
2a
MeO2C
CO2Me
Note: [a] The yield and dr value of 4 was determined by
N
H
[b]
NMR analysis.
The ee value of two enantiomers was
4a-e
determined by chiral HPLC. [c] The 40% of product 3a was
detected in this case. [d] Based on the condition of entry 6.
Et
Et
Me
Si
Me
Si
Si
Si
O
O
O
O
Et
CO2Me
Me
CO2Me
CO2Me
CO2Me
Ph
Our initial investigations started by the kinetic
resolution of racemic MBH-derived silyl ether 1a by
screening of various catalyst systems and chiral
ligands (Scheme 1 and see Supporting Information).
When the reaction of racemic MBH-derived silyl
ether (1a) with glycine aldimino ester (2a) was
carried out using 3 mol % Cu(CH3CN)4BF4 and 5
Ph
Ph
Ph
1a
1b
1c
1d
2
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
o
o
mol% P-ligand in THF at -20 C, enantioselective
[3+2] cycloaddition reaction proceeded smoothly to
give product 4a in good yields (Table S1, see
Supporting Information). Among different phosphine
ligands, the DTBM-Segphos (see Table 1) was the
most efficient ligand and afforded the desired adduct
4a with good diastereoselectivity (84/16 dr) and
excellent enantioselectivity (98% ee for major isomer
and 99% ee for minor isomer) and enantioenriched
MBH-derived silyl ether 1a by kinetic resolution. The
use of Cu(CH3CN)4PF6 as a catalyst was similarly
effective (see Table S2 of Supporting Information,
50% conversion, 84/16 dr, and 98% ee and 99% ee
for two enantiomers), and interestingly, the reaction
performed with AgOAc also provided 4a in 53%
yield (see Table S2, 77/23 dr, and 98% ee for both
enantiomers). However, these catalysts still exhibit
inferior activity in this reaction in comparison to that
of Cu(CH3CN)4BF4 in term of diastereoselectivity
and enantioselectivity of all the products. And the
screening of various bases for the copper-catalyzed
[3+2] cycloaddition reaction, K2CO3 should be the
room temperature or 0 C in THF and other solvents
gave negative effect on the diastereoselectivity or
conversion (Table S5). Finally, it deserves
mentioning
that
this
catalytic
asymmetric
transformation provides a facile approach to the
enantioselective construction of pyrrolidines bearing
four contiguous stereogenic centers and featuring a
quaternary stereocenter.
To further expand the synthetic utility of this silicon-
based bulky group (TBDPS) –tuned parallel kinetic
resolution,
the
1,3-dipolar
[3+2]
cycloaddition/tandem conjugate addition-elimination
reaction was examined with diverse glycine aldimino
esters and MBH-derived silyl ethers generated from a
series of aldehydes and glycine (Scheme 2). As
expected, various MBH-derived silyl ethers with
different substituents underwent the parallel kinetic
resolution in moderate to good yield (60–98%).
Almost all substrates furnished the enantioenriched
glutamic acid derivatives 3 (up to 95% ee) and highly
substituted
diastereomeric mixtures (from 87:13 to 99:1).
best choice (See Table S3 of Supporting Information). Pleasingly, all the aromatic MBH-derived silyl ether
pyrrolidines4,
albeit
yielding
Based on the observation that Cu(CH3CN)4BF4
combined with DTBM-Segphos undergo highly
enantioselective [3+2] cycloaddition of MBH-derived
silyl ether 1a with glycine aldimino ester 2a at mild
reaction conditions, whereas the recovered MBH-
derived silyl ether are normally obtained with
moderate ee values, we hypothesized that the
introduction of silicon-based bulky group to MBH-
derived silyl ethers may allow highly efficient kinetic
resolution or [3+2] cycloaddition reaction from
racemic MBH-derived silyl ethers. Therefore, we
began by exploring the effect of silicon-based bulky
group on the copper-catalyzed [3+2] cycloaddition by
kinetic resolution under the optimized reaction
conditions (Table 1).
As shown in Table 1, the TBDPS-containing racemic
MBH-derived silyl ether (1e) did lead to product 4e
with excellent diastereoselectivity (95:5 dr) and
excellent enantioselectivity (99% ee), but when other
silicon-based bulky groups were used, product 4a
was obtained with almost the same level of
diastereoselectivity, albeit the enantioselectivity is
also excellent in each case. Notably, the recovered
starting material 1 was obtained with varying degrees
of enantioselectivity, which prompted us to examine
the [3+2] cycloaddition of TBDPS-containing MBH-
derived silyl ether (1e) with an equal amount of
glycine aldimino ester 2a. Gratifying, a parallel
kinetic resolution was confirmed in this case, in
which two different enantiomers with high ee values
(93% ee of 3a and 99% ee of 4e respectively) were
obtained synchronously by asymmetric 1,3-dipolar
[3+2] cycloaddition reaction and tandem conjugate
addition-elimination reaction of glycine aldimino
ester 2a with MBH-derived silyl ether 1e (Table 1,
entry 7). This outcome represents the first Cu-
promoted parallel kinetic resolution based on 1,3-
dipolar [3+2] cycloaddition reaction of glycine
aldimino ester with MBH-derived silyl ether under
mild conditions. We also discovered that the parallel
kinetic resolution process completed within 12 h at
substrates undergoes the 1,3-dipolar [3+2]
cycloaddition process with glycine aldimino esters in
good enantioselectivities to generate the substituted
pyrrolidines 4 with four contiguous stereogenic
centers. Except the aliphatic MBH-derived silyl ether,
the enantioselectivities of pyrrolidines 4 were slightly
independent of the electronic properties of
substituents in the 1,3-dipolar [3+2] cycloaddition
process, with a narrow range from 91% ee to 99% ee.
Substrates with electron-rich aromatic substrates on
para-position of arenes were more reactive than that
on ortho-position. meta-Substituted MBH-derived
silyl ethers also reacted selectively with glycine
aldimino ester in this 1,3-dipolar [3+2] cycloaddition
process. The tandem conjugate addition-elimination
reaction is sensitive to substituents in the ortho-
position and no enantioselectivity was obtained when
o-chloro -substituted glycine aldimino ester was used
in this reaction. This fact was in agreement with the
parallel kinetic resolution that had similar kA(R) ≈ kA(S)
rates (preferably identical) and occurred without
mutual interferences. Due to the certain enantiomer -
directed [3+2] cycloaddition, the enantioselectivity of
product would be varied from low to high
enantioselectivity via tandem conjugate addition-
elimination reaction, that different from previous
silver-catalyzed asymmetric tandem conjugate
addition-elimination reaction of glycine aldimino
esters with racemic MBH adducts.[8] Notably,
aliphatic substituents was also found to have a
significant influence on the stereoselectivity and
reactivity, for example, when methyl 3-(tert-
butyldiphenylsilyloxy)-2-methylenepentanoate (Et-
substituted MBH-derived silyl ether) or methyl 2-
((tert-butyldiphenylsilyloxy)(cyclohexyl)methyl)-
acrylate (Cy-substituted MBH-derived silyl ether)
was utilized, the reaction occurred smoothly in good
yield and diastereoselectivity but with decreased
enantioselectivity (Scheme 2). Even though, we were
pleased to observe that various aromatic MBH-
derived silyl ethers and glycine aldimino esters
3
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
bearing different substituents (F, Cl, Br, OMe, Me,
naphthyl, thiophenyl) gave similar results and did not
cause limitations in the parallel kinetic resolution.
The enantiomeric excess of most of pyrrolidine
products can be reached up to 99% ee under mild
reaction conditions.
Scheme 2. Substrate scope for the parallel kinetic
resolution: Asymmetric 1,3-dipolar [3+2] cycloaddition
reaction and tandem conjugate addition-elimination
reaction.
Notably, the importance of silicon-based bulky group
on racemic MBH-derived silyl ethers on the PKR
process is also supported by the investigation of
substrate scope. For example, the use of racemic
MBH-derived silyl ether 1f (MePh2Si-) led to the
corresponding product 4z with only 58:42 dr, while
racemic MBH-derived silyl ether 1g (Ph3Si-) yielded
the adduct 4aa with only 87:13 dr (Scheme S1 of
Supporting Information). In addition, the absolute
configuration of the pyrrolidine product 4 was
confirmed by X-ray analysis of 4s (Figure 2)[12] and
NMR analysis (See Supporting Information, nosy
spectra of corresponding product 4e) based on chiral
MBH-derived silyl ether (R-configuration), and it was
also supported indirectly by the absolute
configuration of known product 3 because it has the
same configuration at -position of amino acid
backbone. Notably, we also performed the present
PKR procedure on the gram scale, and it was found
that much better enantioselectivity of major isomer of
4h was achieved under the optimized reaction
conditions (97% ee versus 90% ee, see Scheme S1 of
Supporting Information, eq. 3).
Me
O
Si
MeO C
2
CO Me
2
N
H
Figure 2. X-ray structure of 4s (CCDC 1584134).
To detect the ee value of 3a or 4e
CO Me
2
OTBDPS
CO Me
CO Me
2
Ph
2

N
Cu(CH CN) BF (3 mol%)
3
4
4
3a
Ph
DTBM-Segphos (5 mol%)
1e
racemic
+
o
K CO , THF, 0
C
2
3
OTBDPS
+
1 ~ 5 hours
N
CO Me
2
MeO C
2
CO Me
2
2a
N
H
4e
100
98
96
94
92
90
88
86
MeO2C
CO2Me
OTBDPS
CO2Me
N
R2
R2
R1
Cu(CH3CN)4BF4 (3 mol%)
(R)-DTBM-SegPhos (5 mol%)
3
+
1
K2CO3 (10 mol%)
R2
MeO2C
R1
OTBDPS
+
THF, 0 o
C
R1
N
CO2Me
CO2Me
Product 3a
Product 4e
2
N
H
4
OTBDPS
MeO2C
OTBDPS
0
1
2
3
4
5
6
OTBDPS
CO2Me
MeO2C
N
Reaction time (h)
MeO2C
H
R
CO2Me
R
N
CO2Me
R = F
H
N
H
4k: 32% yield, 93/7 dr, 97% ee
3g: 34% yield, 76% ee
R = Cl
4l: 31% yield, 95/5 dr, 93% ee
3h: 39% yield, 2% ee
R = Br
4m: 40% yield, 90/10 dr, 91% ee
3i: 52% yield, 89% ee
R = OMe
4n: 39% yield, 96/4 dr, 96% ee
3j: 48% yield, 85% ee
R = Br
R
4o: 41% yield, 85/15 dr, 98% ee
3k: 40% yield, 96% ee
Figure 3. Relationship between the optical purity of the
product 3a/4e and reaction time (h).
R = H
4e: 32% yield, 96/4 dr, 99% ee
3a: 28% yield, 96% ee
R = F
4f: 32% yield, 96/4 dr, 97% ee
3b: 44% yield, 93% ee
R = Cl
4g: 34% yield, 90/10 dr, 94% ee
3c: 42% yield, 95% ee
R = Br
4h: 35% yield, 90/10 dr, 90% ee
3d: 38% yield, 93% ee
R = Me
4i: 33% yield, 95/5 dr, 99% ee
3e: 44% yield, 95% ee
R = OMe
4j: 35% yield, 99/1 dr, 98% ee
3f: 58% yield, 94% ee
OTBDPS
MeO2C
Based on the reaction results of parallel kinetic
resolution as well as the relationship between the
optical purity of the product 3a/4e and reaction time
(Figure 3), we proposed the following reaction
mechanism for the present parallel kinetic resolution
(Figure 4). Although a full mechanistic process on the
highly competitive and stepwise reaction that copper-
catalyzed tandem conjugate addition-elimination
reaction and cycloaddition occurred synchronously
should await further studies, the initial coordination
of the phosphine ligand with copper(I) to the
formation of Cu-complex A (Figure S3 of ESI)
resulted into the formation of a key copper-bound
azomethine ylide by interaction with glycine
aldimino esters.[9,12] A subsequent conjugate addition
by attacking the carbon-carbon double bond of
activated MBH-derived silyl ether 1 gave divergent
CO2Me
N
H
4p: 40% yield, 96/4 dr, 97% ee
3l: 58% yield, 81% ee
OTBDPS
R
MeO2C
CO2Me
N
H
OTBDPS
MeO2C
R = Br
4t: 32% yield, 97/3 dr, 94% ee
3p: 52% yield, 83% ee
R = Me
4u: 37% yield, 98/2 dr, 95% ee
3q: 40% yield, 81% ee
R = Me
CO2Me
N
R
H
OTBDPS
MeO2C
4v: 43% yield, 93/7 dr, 97% ee
3r: 46% yield, 83% ee
CO2Me
N
OTBDPS
R
OTBDPS
S
H
MeO2C
MeO2C
R = F
CO2Me
CO2Me
N
4q: 32% yield, 96/4 dr, 97% ee
3m: 48% yield, 76% ee
R = Br
4r: 31% yield, 99/1 dr, 95% ee
3n: 47% yield, 81% ee
R = Me
N
H
H
R
R = Et (4y) or Cy (4z)
R = H (4w) or Br (4x)
4w: 38% yield, 99/1 dr, 97% ee
3s: 44% yield, 84% ee
4x: 40% yield, 87/13 dr, 99% ee
3t: 37% yield, 85% ee
4y: 26% yield, 87/13 dr, 74% ee
3u: 37% yield, 75% ee
4z: 31% yield, 97/3 dr, 51% ee
3v: 35% yield, 42% ee
4s: 34% yield, 96/4 dr, 96% ee
3o: 36% yield, 89% ee
4
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
process with the almost the same level of reaction
rate, in which the transformation of catalyst-substrate
complex B containing (S)-1 would be possibly
beneficial to undergo elimination of TBDPS -silyl
ether group to give the desired enantioenriched
glutamic acid derivatives 3 simultaneously. Because
of high activity of 1,3-dipolarophile intermediate
derived from (R)-1, the 1,3-dipolar [3+2]
cycloaddition of racemic 1 and 2 to form the
pyrrolidine product 4 would be sterically favorable
process (Figure 4). Therefore, the observed formation
of pyrrolidines 4 bearing four contiguous stereogenic
centers can be explained by steric repulsion between
the intermediate A and MBH-derived silyl ether from
C through this stepwise mechanism, in which the
substituent R/Ar of two substrates as well as
TBDPSO group on the sp3 carbon atom of MBH-
derived silyl ether 1 would be an important factor to
discriminate enantiomers (R)-1 and (S)-1 in this
parallel kinetic resolution.
the efficient conversion of a racemic MBH adducts to
two structurally different types of amino acid
derivatives with high optical purity (up to 99% ee).
This is an unprecedented and highly enantioselective
1,3-dipoalr addition-initiated chemodivergent PKR
process that can be accomplished smoothly by using
copper/DTBM-Segphos catalyst system. We believe
that this PKR strategy reported in this work will be
proved to be particularly useful for synthetic
transformation of racemic materials.
Experimental Section
General procedure for the copper-catalyzed PKR
process: catalytic asymmetric cycloaddition and
Michael addition of iminoesters with Morita-Baylis-
Hillman -derived silyl ethers. Under N2 atmosphere, (R)-
DTBM-SegPhos
(11.8
mg,
0.01
mmol)
and
Cu(CH3CN)4BF4 ( 1.9 mg, 0.006 mmol) were dissolved in
2 mL dry THF, and stirred at room temperature for about
0.5 h. Then iminoesters 2 (0.20 mmol) and K2CO3 (0.02
mmol) were added sequentially, the mixture was dropped
to 0oC and then the TBDPS-protected Morita-Baylis-
Hillman adducts 1 (0.20 mmol) was added. Once starting
material was consumed (monitored by TLC), the mixture
was filtered through celite and the filtrate was concentrated
[CuI]+
CO2Me
N
Ar
Ar
O
OTBDPS
CO2Me
OTBDPS
CO2Me
PAr2
N
O
O
1
Cu
R
to dryness. A portion of the residue was analyzed with H
R
PAr
2O
NMR to determine the diastereomeric ratio. The crude was
purified by column chromatography to give the
corresponding known product 3 and new product 4, which
was then directly analyzed by HPLC to determine the
enantiomeric excess. All the products 3 have been analysed
by NMR, HRMS and chiral HPLC (see Supporting
Information).
O
OMe
A
Parallel Kinetic Resolution (PKR)
Ar
O
Ar
O
R
OTBDPS
CO2Me
R
OTBDPS
O
PAr2
Cu
N
N
PAr2
Cu
O
O
O
PAr
2 O
CO2Me
PAr2
O
OMe
O
OMe
O
C
B
fast
fast
R
OTBDPS
[CuI]+
Acknowledgements
[CuI]+
[CuI]+
MeO2C
Ar
This Project was supported by the National Natural Science
Foundation of China (No. 21472031, 21503060, 21702211, and
21773051), and Zhejiang Provincial Natural Science Foundation
of China (LZ18B020001, LY16E030009, LY17E030003, and
LY17B030005). The authors also thank Dr. Xu-Qiong Xiao, Dr.
C. Q. Sheng, Dr. Q. H. Pan, Dr. K. Z. Jiang, and Z. R. Qu (all at
HZNU) for their technical and analytical support. This
manuscript is dedicated to the 110th Anniversary of Hangzhou
Normal University and the 90th Anniversary of Anhui Normal
University.
N
CO2Me
CO2Me
R
Ar
HN
D
CO2Me
N
MeO2C
path-b
elimination
path-a
OTBDPS
Ar
Mannich addition
R
MeO2C
3
4
X
Ar
Ar
Ar
CO2Me
R
R
O
Ar
O
Si
path a
HN
P
N
O
O
References
OTBDPS
Cu
CO2Me
MeO2C
P
O
C
OMe
O
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201800220
Advanced Synthesis & Catalysis
COMMUNICATION
Silicon-based Bulky Group–Tuned Parallel Kinetic
Resolution in Copper-Catalyzed 1,3-Dipolar
Additions
MeO2C
R2
CO2Me
Parallel Kinetic
Resolution (PKR)
TBDPS is the best!
N
R1
Cu(CH3CN)4BF4
(R)-DTBM-SegPhos
up to 95% ee
O[Si]
+
CO2Me
R2
O
Adv. Synth. Catal. Year, Volume, Page – Page
R2
MeO2C
R1
OTBDPS
O
+
PAr2
PAr2
O
O
CO2Me
R1
N
CO2Me
N
Yang Yuan, Zhan-Jiang Zheng, Li Li, Xing-Feng
Bai, Zheng Xu, Yu-Ming Cui, Jian Cao, Ke-Fang
Yang, and Li-Wen Xu*
H
up to 99% ee
up to 99:1 dr
PKR
t-BuPh2Si > Ph3Si > MePh2Si > i-Pr3Si > t-BuMe2Si > Et3Si > Me3Si
8
This article is protected by copyright. All rights reserved.