Enantio- And Diastereodivergent Construction of 1,3-Nonadjacent Stereocenters Bearing Axial and Central Chirality through Synergistic Pd/Cu Catalysis

Article abstract of DOI:10.1021/jacs.1c05087

In contrast to the widely explored methods for the asymmetric synthesis of molecules bearing a single stereocenter or adjacent stereocenters, the concurrent construction of 1,3-stereogenic centers in an enantio- and diastereoselective manner remains a challenge, especially in acyclic systems. Herein, we report an enantio- and diastereodivergent construction of 1,3-nonadjacent stereocenters bearing allenyl axial and central chirality through synergistic Pd/Cu-catalyzed dynamic kinetic asymmetric allenylation with racemic allenylic esters. The protocol is suitable for a wide range of substrates including the challenging allenylic esters with less sterically bulky substituents and provided chiral allenylic products bearing 1,3-nonadjacent stereocenters with high levels of enantio- and diastereoselectivities (up to >20:1 dr and >99% ee). Furthermore, several representative transformations involving axial-to-central chirality transfer were conducted, affording useful structural motifs containing nonadjacent stereocenters in a diastereodivergent manner.

Full text of DOI:10.1021/jacs.1c05087

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Enantio- and Diastereodivergent Construction of 1,3-Nonadjacent
Stereocenters Bearing Axial and Central Chirality through
Synergistic Pd/Cu Catalysis
Jiacheng Zhang,∥ Xiaohong Huo,∥ Junzhe Xiao,∥ Ling Zhao, Shengming Ma,* and Wanbin Zhang*
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ABSTRACT: In contrast to the widely explored methods for the
asymmetric synthesis of molecules bearing a single stereocenter or
adjacent stereocenters, the concurrent construction of 1,3-
stereogenic centers in an enantio- and diastereoselective manner
remains a challenge, especially in acyclic systems. Herein, we
report an enantio- and diastereodivergent construction of 1,3-
nonadjacent stereocenters bearing allenyl axial and central chirality
through synergistic Pd/Cu-catalyzed dynamic kinetic asymmetric
allenylation with racemic allenylic esters. The protocol is suitable
for a wide range of substrates including the challenging allenylic
esters with less sterically bulky substituents and provided chiral
allenylic products bearing 1,3-nonadjacent stereocenters with high
levels of enantio- and diastereoselectivities (up to >20:1 dr and
>99% ee). Furthermore, several representative transformations involving axial-to-central chirality transfer were conducted, affording
useful structural motifs containing nonadjacent stereocenters in a diastereodivergent manner.
molecules containing nonadjacent stereocenters is highly
desired, which might change the manner in which scientists
think about designing and building molecules.4
INTRODUCTION
■
The synthesis of chiral molecules in enantiomerically pure
form is a prominent theme in organic synthesis. A large
number of methods have been developed for the preparation
of chiral molecules containing a single stereocenter.1 In
addition, the asymmetric synthesis of molecules bearing
adjacent stereocenters, including the challenging unfavored
diastereomers, has also been realized with efficient enantio-
and diastereocontrol by adjusting the structural properties of
chiral catalysts.2 However, the concurrent construction of 1,3-
stereogenic centers in an enantio- and diastereoselective
manner is still challenging, especially for the acyclic systems
and cyclic systems in which two 1,3-stereogenic centers are not
in the same ring (Scheme 1A). In classic single catalyst modes,
the chiral catalyst is responsible for the co-constructions of the
two nonadjacent stereogenic centers, thus is of limitation for
the divergent syntheses of all the four stereoisomers. In
principle, much more complex chiral catalysts possessing
elaborate chiral skeletons, electronic, steric, or directing effects
are required in order to achieve satisfactory stereocontrol of
nonadjacent stereocenters. Thus, only a limited number of
catalytic systems for the asymmetric construction of 1,3-
nonadjacent stereocenters have been disclosed.3 In view of the
structural motifs containing nonadjacent stereocenters widely
present in numerous natural products and bioactive com-
pounds, the development of a simple catalytic system or
strategy for the enantio- and diastereoselective construction of
Allene chemistry has become an important branch in organic
chemistry due to the unique structural feature of the allene
moiety, that is, two cumulated double bonds allowing for axial
chirality.5 Consequently, synthetic organic chemists have long
pursued general and efficient methods for the catalytic
asymmetric synthesis of chiral allenes.6−9 Indeed, significant
progress has been achieved in the asymmetric construction of
single allenyl axial chirality.6−8 Furthermore, adjacent stereo-
centers bearing allenyl axial chirality and central chirality could
also be efficiently constructed through metal- or organo-
catalyzed approaches.9 However, the concurrent construction
of nonadjacent stereocenters in this area remains a long-
standing challenge, and no stereodivergent example has been
reported yet (Scheme 1B).3g Importantly, nonadjacent stereo-
centers bearing allenyl axial and central chirality are frequently
embedded in diverse bioactive molecules5 and also provide an
important method for preparing two nonadjacent central
Received: May 17, 2021
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A

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knowledge, stereodivergent dual catalysis for the construction
of nonadjacent stereocenters has not been reported yet.16
Therefore, in continuation of our interest in stereodivergent
bimetallic catalysis13a,b,e,i,l and allene chemistry,6d,e,g,h,8d,g−i we
envisioned bimetallic catalysis would provide a general
platform for the enantio- and diastereodivergent construction
of nonadjacent stereocenters (allenyl axial chirality and central
chirality). It is expected that all four stereoisomers of a desired
product bearing allenyl axial chirality and nonadjacent central
chirality could be unprecedentedly obtained if each catalyst
allows for full control over the configuration of the respective
stereocenter (Scheme 1C).
Scheme 1. Enantio- and Diastereodivergent Construction of
1,3-Nonadjacent Stereocenters Bearing Axial and Central
Chirality
RESULTS AND DISCUSSION
■
Initially, racemic allenylic acetate 1a was selected as the model
substrate for the dynamic kinetic asymmetric transformation
(DyKAT)17 with imino esters18 in the presence of Cs2CO3
using a [Pd/L + Cu/L] catalyst combination (Table 1). At
first, several classic biphosphine ligands were screened to
explore the effect of the chiral ligands on the Pd catalyst in this
reaction, and the product (R,R)-3aa′ was obtained in >99%
enantioselectivity with seemingly irregular yields and diaster-
eoselectivities (entries 1−3). Careful analysis suggested that as
a
Table 1. Optimization of the Reaction Conditions
stereocenters via efficient axial-to-central chirality transfer
(Scheme 2).
c
L for L for
T
yield
ee (%)
b
c
entry
1
2
R
Pd
Cu
(°C) (%)
dr
(config.)
Scheme 2. Representative Bioactive Molecules Bearing
Chiral Allene Motifs and the Chiral Allene Chemistry
2a′
Me
L1
L5
0
0
0
88
92
39
1:1 >99
(R,R)
1:1 >99
(R,R)
15:1 >99
(R,R)
2
3
2a′
2a′
Me
Me
L2
L3
L5
L5
4
5
2a′
2a′
Me
Me
L4
L3
L5
L6
0
0
48
55
1:6 >99 (R,S)
11:1 >99
(R,R)
6
7
8
9
2a′
2a
Me
Et
L3
L3
L3
L3
L6
L6
L6
L6
−10
−10
−10
−10
50
80
62
86
>20:1 >99
(R,R)
>20:1 >99
(R,R)
2a″
2a‴
Bn
tBu
12:1 >99
(R,R)
13:1 >99
(R,R)
d
10
11
12
2a
2a
2a
Et
Et
Et
L3
−
L3
−
L6
L6
−10
−10
−10
14
nr
nr
1:2 >99 (R,S)
e
−
−
−
−
f
Stereodivergent syntheses are gaining increasing attention as
the stereochemistry of the chiral molecules has an important
influence on their bioactivity.10−14 Dual catalysis has become
one of the most powerful methods for stereodivergent
synthesis, and many types of motifs bearing adjacent
stereocenters have been efficiently synthesized in an enantio-
and diastereodivergent manner.12−15 To the best of our
a
Reaction conditions: 1a (0.30 mmol, 1.5 equiv), 2 (0.20 mmol, 1.0
equiv), [Pd(η3-allyl)Cl]2 (2.5 mol %), L1−L4 (5.5 mol %),
[Cu(CH3CN)4]PF6 (5.0 mol %), L5−L6 (5.5 mol %), Cs2CO3
b
(0.24 mmol, 1.2 equiv), 24 h. Isolated yield of all diastereoisomers;
nr = no reaction. Determined by HPLC analysis. Without Cu
catalyst. Without Pd catalyst. Without base Cs2CO3.
c
d
e
f
B
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the dihedral angle in the chiral backbone decreases [(R)-
BINAP (73.49°), (R)-MeO-BIPHEP (68.56°), and (R)-
SegPhos (64.99°)],19 the diastereoselectivity increases but
the yield drops by more than half. Although it is difficult to rule
out the electronic effects of the ligands, the dihedral angle of
the axially chiral ligands seems to play a crucial role in
reactivity and diastereoselectivity. Higher diastereoselectivity
was obtained with the chiral ligand possessing the smaller
dihedral angle, which could exert much better asymmetric
induction. Although it is difficult to understand the low
reactivity of this reaction with (R)-SegPhos L3, the underlying
reason might be the three-dimensional space incompatibility
between the chiral Pd complex and the chiral Cu complex.
Then, the ligand with higher steric hindrance (R)-DTBM-
SegPhos L4 was applied in this reaction. Interestingly, the
complementary diastereomer (R,S)-3aa′ was obtained in 48%
yield and 1:6 dr and >99% ee (entry 4). This result suggested
that the bulky steric environment of the (R)-DTBM-SegPhos
L4 could overwrite the stereocontrol ability of the chiral Cu
catalyst and directly control both stereocenters of the allenyl
esters and the nucleophiles. Subsequently, isopropyl-substi-
tuted Phosferrox (R,Rp)-L6 instead of tert-butyl-substituted
Phosferrox (R,Rp)-L5 was subjected to this reaction (entry 5 vs
entry 3). The yield was obviously improved with comparable
enantioselectivity and diastereoselectivity. Furthermore, the
diastereoselectivity increased rapidly when the reaction
temperature was decreased to −10 °C (entry 6). To our
generality of enantio- and diastereodivergency was demon-
strated by the synthesis of all four stereoisomers of 3aa using
all four combinations of SegPhos L3 and Phosferrox L6.
Gratifyingly, almost perfect stereoselectivities (>20:1 dr and
>99% ee) with high reactivity were achieved using the same set
of starting materials and under identical reaction conditions,
which verified the efficiency of the stereodivergent bimetallic
catalysis for the stereocontrol of the 1,3-nonadjacent stereo-
centers.
Having established the optimized reaction conditions, we
explored the specific performance of our bimetallic catalytic
system in the DyKAT of racemic allenylic acetates in a
diastereodivergent manner (Table 2). For most of the
substrates, there is no obvious difference in catalytic activity
and stereoinduction of the two catalyst combinations. First, for
the substrates bearing the synthetically attractive tertiary amine
and alcohol groups (1b−1h), the substitution reaction
proceeded smoothly to afford the desired products (3ba-
3ha) with 1,3-nonadjacent axial and central chirality in high
yields, and with excellent diastereoselectivities (10:1 to >20:1
dr) and enantioselectivities (96% to >99% ee). In general,
sterically bulky substituent of 1,3-disubstituted allenes together
with the elaborate sterically hindered ligand DTBM-SegPhos
are indispensable for achieving high enantioselectivity due to
the loosening nature of the allene axial chirality spreading over
three carbon atoms.6d,e,g Accordingly, we were very curious
whether our bimetallic catalytic system is suitable for substrates
substituted with much less sterically bulky group. To our
delight, the allenylic esters bearing a linear 1°-alkyl group (1i−
1n) reacted with imine ester to afford products (3ia−3na)
with high diastereoselectivities (up to 9:1 dr) and excellent
enantioselectivities (up to >99% ee). Furthermore, the
substrates with a secondary alkyl group (1o) afforded the
desired products (R,S)-3oa and (S,S)-3oa with moderate
diastereoselectivities (12:1 dr and 4:1 dr, respectively) and
complete enantiocontrol. To achieve satisfactory diastereose-
lectivity of the products (R,S)-3ia−3oa, Pd/(R)-DTBM-
SegPhos and Cu/(S,Sp)-L6 were employed. However, the
three-dimensional space incompatibility between the Pd/(R)-
DTBM-SegPhos and the Cu/(S,Sp)-L6 led to relatively low
yields. Additionally, 1p bearing a planar phenyl group is also
compatible with this Pd/Cu dual catalytic system, giving the
corresponding products (R,S)-3pa and (S,S)-3pa with
satisfactory results (82% yield, >20:1 dr, >99% ee and 50%
yield, 9:1 dr, >99% ee).
Next, the scope of the nucleophile was investigated in a
diastereodivergent manner to explore the generality and
limitations of our dual catalytic system. As described in
Table 3, the influence of the substituents on the aromatic ring
was initially investigated, and it was apparent that the position
and electronics of the substituted groups exerted a limited
effect, affording the desired products in high yields with
excellent stereoselectivities (up to >20:1 dr and >99% ee). For
example, both electron-donating and electron-withdrawing
groups at the para position of the phenyl ring were well
tolerated and delivered the corresponding products 3ab−3ae
in high yields, with 12:1 to >20:1 dr and >99% ee. As shown
by examples 3af−3aj, substituents at the meta and ortho
positions were also compatible as well. Furthermore, reactions
involving naphthyl-, piperonyl, and furyl-substituted substrates
also proceeded well to deliver their desired products (3ak−
3am) in high yields and with excellent stereoselectivities. The
t
delight, the imino esters substituted with Et, Bn, and Bu are
also compatible with this dual catalysis system, providing the
corresponding products in high yields and with high to
excellent diastereoselectivities and enantioselectivities (entries
7−9, for 2a, 80% yield, >20:1 dr, >99% ee). Subsequently,
control experiments were conducted to gain insight into the
cooperative interplay of the bimetallic catalytic system (entries
10−12). The substituted product was obtained in only 14%
yield in the absence of the Cu catalyst and the dr decreased
rapidly from >20:1 to 1:2. No reaction occurred in the absence
of the Pd catalyst. These results suggested that the combined
use of two chiral metal catalysts appears to be important for
the reactivity and stereochemical control of this reaction.
After establishing the feasibility of an enantio- and
diastereoselective synthesis of 1,3-nonadjacent axial and central
stereocenters, we then speculated if the present Pd/Cu
catalytic system could furnish products with full control over
the absolute and relative configuration of both axial and central
chirality (Scheme 3). Indeed, by simply changing (R,Rp)-L6,
the ligand for Cu, to (S,Sp)-L6 while keeping the same
enantiomer of (R)-SegPhos L3, (R,S)-3aa was formed
successfully in high yield with excellent diastereoselectivity
(>20:1 dr) and enantioselectivity (>99% ee). Next, the
Scheme 3. Synthesis of All Four Stereoisomers of 3aa
C
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a
Table 2. Enantio- and Diastereodivergent Allenylation with Allenylic Acetates
a
b
c
Reaction conditions: See Table 1, entry 7. Using DTBM-SegPhos instead of SegPhos. Using DM-SegPhos instead of SegPhos.
absolute configurations of (R,S)-3ak and (S,S)-3ak were
determined by X-ray crystallography.
(Scheme 4). Initially, when the allenylic substrate bearing a
chiral secondary alcoholic group 1q was conducted with 2a,
four of the possible stereoisomers of 3qa were successfully
obtained with this protocol by the random combinations of
SegPhos L3 and Phosferrox L6. The key to success might be
due to the loosening feature of the axial allene chirality
spreading over three carbon atoms, which leads to negligible
asymmetric induction of the existing chiral alcohol motif on
the axial and central chirality. Expectedly, the four remaining
stereoisomers of 3qa were expediently prepared using 1q′ and
a similar protocol. Finally, all eight isomers of 3qa were
obtained in high yields with excellent stereocontrol (up to
>20:1 dr).
Glycine-based ketimine ester (2n) was also employed in our
Pd/Cu bimetallic catalytic system. The desired products (R,S)-
3an and (S,S)-3an were smoothly obtained in high yields and
with high stereoselectivities (Table 4). Additionally, five
aldimine esters (2o−2s) derived from both natural and non-
n
natural amino acids (R = Me, Et, Pr, allyl, and CH2OtBu)
were utilized in our Pd/Cu bimetallic catalytic system. The
allenylated amino acid products (3ao−3as) were smoothly
obtained in high yields and high to excellent stereoselectivities
(up to >20:1 dr and >99% ee).
Subsequently, we wondered whether these reaction
conditions could be extended to the stereodivergent synthesis
of all eight stereoisomers of 3qa bearing three stereocenters
A preliminary mechanism has been proposed in Scheme 5.
For the Pd catalytic cycle, the reaction is initiated with Pd0/L3,
D
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a
a
Table 3. Substrate Scope of Imino Esters
Table 4. Substrate Scope of Aldimine Esters
a
b
Reaction conditions: See Table 1, entry 7. The yield of product was
determined after hydrolysis. The dr and ee values were measured after
N-protecting with TsCl.
Scheme 4. Synthesis of All Eight Stereoisomers of 3qa
a
Reaction conditions: See Table 1, entry 7.
which is generated from [Pd(allyl)Cl]2 via the attack of
nucleophile. Subsequently the chiral Pd0/L3 catalyst would
undergo oxidative addition reaction with racemic allenyl
substrate 1a, producing the four possible α-alkynylidene π-
allylpalladium species 4A, 4B, 4C, and 4D. These four
diastereomeric intermediates could interconvert via σ-(1,3-
dien-2-yl)palladium 5.20 For the Cu catalytic cycle, the imino
ester 2a can be easily transformed into the nucleophilic N-
metalated azomethine ylide 6 in the presence of a chiral Cu/L6
catalyst and Cs2CO3. The nucleophile 6 then attacks the
electrophilic α-alkynylidene π-allylpalladium intermediate 4 to
give the corresponding product 3aa.
In order to explore the specific performance of this
bimetallic catalytic system in the DyKAT of racemic allenyl
substrates, the reaction of rac-1a with 2a was monitored at 0.5
h, 1.0 h, 3.0 h, 6.0 h, 8.0 h, and 10.0 h, and the recovered
allenyl substrate 1a was analyzed by HPLC with a chiral
CHIRALPAK IC-3 column (Figure 1A). These results
indicated that (R)-1a and (S)-1a21 were consumed together
at almost the same speed. Additionally, the conversion of 2a
was determined by GC-MS using mesitylene as the internal
standard, and the ee and dr values of the crude products at
different times were determined by HPLC with a chiral
CHIRALPAK IC-3 column (Figure 1B). It was found that the
enantioselectivities and diastereoselectivities of the corre-
sponding products (R,S)-3aa were almost unchanged.
E
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Scheme 5. Proposed Mechanism of Stereodivergent Pd/Cu-Catalyzed Dynamic Kinetic Asymmetric Allenylation with Racemic
Allenylic Esters
Scheme 6. Reactions with Enantiomerically Pure (R)-1a and
(S)-1a
Figure 1. (A) Yields and ee values of recovered 1a at 0.5 h, 1.0 h, 3.0
h, 6.0 h, 8.0 h, and 10.0 h. (B) The conversion of 2a and ee and dr
values of the crude products 3aa at 0.5 h, 1.0 h, 3.0 h, 6.0 h, 8.0 h, and
10.0 h.
According to the Curtin−Hammett principle,22 the ratio of
products is mainly controlled by the difference (ΔΔG⧧) in the
To gain an in-depth insight of this DyKAT process,
reactions with enantiomerically pure (R)-1a and (S)-1a were
conducted under the standard reaction conditions (Scheme 6).
The same products (R,S)-3aa were obtained in high yields
(82% vs 92% yield) and with almost the same stereo-
selectivities (>20:1 dr and >99% ee). Furthermore, reactions
of enantiomerically pure (R)-1a and (S)-1a in the presence of
10 mol % of 2a were also conducted under the standard
reaction conditions, and no obvious racemization was found
(10 mol % of 2a is responsible for the generation of the
catalytically active Pd0 species from [Pd(η3-C3H5)Cl]2). Based
on the above-mentioned results and the previous work,6d−g we
propose that the rapid interconversion among the four α-
alkynylidene π-allylpalladium intermediates (4A, 4B, 4C, and
4D) via σ-(1,3-dien-2-yl)palladium 5 occurs before attack by
the nucleophile 6 (Scheme 5).20
standard free energies of the transition states of the
nucleophilic substitution step. Subsequently, theoretical
calculations were conducted to investigate this process using
the combinations of Pd/(R)-L3 and Cu/(S,Sp)-L6. In the
previous work, the stereocontrol of Cu/(S,Sp)-L6 on the imino
ester nucleophile has been well studied by DFT calcula-
tions.13l,23 Thus, four possible nucleophilic substitution
pathways were established (Scheme 7).24 The calculations
indicated that the relative energies of these four transition
states [4A−7A]⧧, [4B−7B]⧧, [4C−7C]⧧, and [4D−7D]⧧ are
0.0, 10.27, 9.84, and 13.64 kcal, respectively. The experiments
and calculations suggested that rac-1a first reacts with the Pd0/
L3 generated in situ, affording the four α-alkynylidene π-
allylpalladium intermediates 4A, 4B, 4C, and 4D, which could
interconvert rapidly. Next, the nucleophile 6 attacks the
electrophilic π-allylpalladium intermediates, affording the
F
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To demonstrate the practical applications of this method-
ology, we devoted our efforts to examining the transformations
of the products (Scheme 8). The chiral allene product (R,S)-
Scheme 7. Study of Four Reaction Pathways of rac-1a with
2a Using the Combinations of Pd/(R)-L3 and Cu/(S,Sp)-L6
by Theoretical Calculations
Scheme 8. Representative Transformations of the Chiral
Allenylic Products Involving Axial-to-Central Chirality
a
Transfer
major product (R,S)-3aa from the intermediate 4A via the
transition state [4A−7A]⧧ with the lowest Gibbs free energy.
These results are in good agreement with the experimental
observations (Figure 2).
a
Reaction conditions: (a) KOH, EtOH, reflux. (b) I2, hexane, rt. (c)
TBAF, THF, rt. (d) Ph3PAuCl, AgOTf, CH2Cl2, rt. (e) PdCl2, allylic
bromide, DMA, rt. (f) 10% citric acid, THF, rt. (g) TsCl, pyridine, rt.
3aa was simply hydrolyzed to the corresponding allenyl acid,
which was further converted into the chiral spirocycle product
(S,S)-8 without any loss of enantioselectivity and diaster-
eoselectivity via electrophilic iodocyclization in the presence of
I2.25 The structure of the cyclization product was confirmed by
X-ray crystallography. Moreover, rearrangement of the
deprotected products 9 of chiral allenes 3ba into trisubstituted
dihydrofuran (R,S)-11 and (S,S)-11 was performed with
gold(I) catalysis, providing the products in a diastereodiver-
gent manner with retention of the enantioselectivity.6d
Analogously, dihydrofuran derivatives (R,S)-12 and (S,S)-12
can be obtained by rearrangement of the deprotected products
10 from the chiral allenes 3ga, respectively. To our delight, the
Pd-catalyzed cyclization of allenyl alcohol 9 provided the
tertsubstituted dihydrofuran (R,S)-13 and (S,S)-13 in high
yields and with high stereoselectivities (13:1 dr and 5:1 dr,
Figure 2. Relative energies of four transition states [4A−7A]⧧, [4B−
7B]⧧, [4C−7C]⧧, and [4D−7D]⧧ of α-alkynylidene π-allylpalladium
intermediates (4A, 4B, 4C, and 4D) with the nucleophile 6.
G
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respectively).26 Furthermore, amino acids bearing a chiral
allene unit, (R,S)-3eo and (S,S)-3eo, could also be converted
into dihydrofuran (R,S)-14 and (S,S)-14 through efficient
axial-to-center chirality transfer.
Xiaohong Huo − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
Junzhe Xiao − State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China
Ling Zhao − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
CONCLUSIONS
■
In summary, we have successfully realized the enantio- and
diastereoselective construction of nonadjacent stereocenters in
one step through synergistic Pd/Cu catalysis. A series of
nonadjacent stereocenters bearing allenyl axial and central
chirality could be easily obtained in an enantio- and
diastereodivergent manner. Importantly, a broad range of
allene substrates, including many examples with less sterically
bulky substituents, were also tolerated and delivered the
corresponding products in high yields and with high to
excellent enantio- and diastereoselectivities. This method
represents a rare example of the stereodivergent synthesis of
1,3-nonadjacent stereocenters from the same set of starting
materials. Furthermore, the products bearing nonadjacent
allenyl axial and central chirality could be applied to the
asymmetric synthesis of spirocycle and dihydrofuran structural
motifs containing nonadjacent stereogenic centers, which are
widely present in numerous important bioactive compounds.
Complete contact information is available at:
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Author Contributions
∥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Shanghai Sailing Program
(19YF1421900), Shanghai Municipal Education Commission
(no. 201701070002E00030), the Science and Technology
Commission of Shanghai Municipality (19JC1430100), and
National Natural Science Foundation of China (nos.
21690063, 21831005, 21901158, and 21991112).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05087.
■
sı
Experimental procedures, computational details, and
characterization data for all reactions and products,
1
including H and 13C NMR spectra, 19F NMR spectra,
REFERENCES
■
HPLC spectra, and HRMS (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Wanbin Zhang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China; orcid.org/0000-0002-4788-4195;
Email: wanbin@sjtu.edu.cn
Shengming Ma − State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China; Research Centre for Molecular Recognition and
Synthesis, Department of Chemistry, Fudan University,
Shanghai 200433, China; orcid.org/0000-0002-2866-
2431; Email: masm@sioc.ac.cn
Authors
Jiacheng Zhang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
H
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published on August 5, 2021, with an incorrect
structure in Scheme 1. The corrected version was reposted on
August 9, 2021.
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