Asymmetric Catalytic Approach to Multilayer 3D Chirality

Article abstract of DOI:10.1002/chem.202100700

The first asymmetric catalytic approach to multilayer 3D chirality has been achieved by using Suzuki-Miyaura cross-couplings. New chiral catalysts were designed and screened under various catalytic systems that proved chiral amide-phosphines to be more efficient ligands than other candidates. The multilayer 3D framework was unambiguously determined by X-ray structural analysis showing a parallel pattern of three layers consisting of top, middle and bottom aromatic rings. The X-ray structure of a catalyst complex, dichloride complex of Pd-phosphine amide, was obtained revealing an interesting asymmetric environment nearby the Pd metal center. Three rings of multilayer 3D products can be readily changed by varying aromatic ring-anchored starting materials. The resulting multilayer products displayed strong luminescence under UV irradiation and strong aggregation-induced emission (AIE). In the future, this work would benefit not only the field of asymmetric synthesis but also materials science, in particular polarized organic electronics, optoelectronics and photovoltaics.

Full text of DOI:10.1002/chem.202100700

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Asymmetric Catalytic Approach to Multilayer 3D Chirality
Guanzhao Wu+,[a, b] Yangxue Liu+,[a] Hossein Rouh+,[a] Liulei Ma,[a] Yao Tang,[a] Sai Zhang,[a]
Peng Zhou,[b] Jia-Ying Wang,[b] Shengzhou Jin,[b] Daniel Unruh,[a] Kazimierz Surowiec,[a]
Yanzhang Ma,[c] and Guigen Li*[a, b]
Dedicated to Prof. Dr. Lutz F. Tietze on the occasion of his 80th birthday
Abstract: The first asymmetric catalytic approach to multi-
layer 3D chirality has been achieved by using Suzuki-Miyaura
cross-couplings. New chiral catalysts were designed and
screened under various catalytic systems that proved chiral
amide-phosphines to be more efficient ligands than other
candidates. The multilayer 3D framework was unambiguously
determined by X-ray structural analysis showing a parallel
pattern of three layers consisting of top, middle and bottom
aromatic rings. The X-ray structure of a catalyst complex,
dichloride complex of Pd-phosphine amide, was obtained
revealing an interesting asymmetric environment nearby the
Pd metal center. Three rings of multilayer 3D products can be
readily changed by varying aromatic ring-anchored starting
materials. The resulting multilayer products displayed strong
luminescence under UV irradiation and strong aggregation-
induced emission (AIE). In the future, this work would benefit
not only the field of asymmetric synthesis but also materials
science, in particular polarized organic electronics, optoelec-
tronics and photovoltaics.
Introduction
during drug action process.[6a] Therefore, asymmetric synthesis
and catalysis have arisen as active topics in chemical
synthesis[8–14] for several decades so as to meet requirements by
pharmaceutical and medical research and industry,[15] as well as
by nano and optoelectronic materials.[16,17] However, it has been
proven to be extremely challenging to develop and discover
new molecular chirality to serve for the above purposes.[18,19]
Although an enormous progress has been made on helical
chirality and its attractive properties in material sciences,[20,21]
the work on organo planar chirality showing multiply stacked/
spaced and nearly paralleled patterned has been very rare in
both organic and materials sciences. Our literature search
revealed there has been no asymmetric catalytic methods
available to generate this type of chirality so far.
Molecular chirality has been existing in nature from the
beginning of earth lives. Among natural chiralities, the layered
chirality widely exists in natural products and plays a crucial
role in controlling functions of biomolecules, such as DNA, RNA
and proteins.[1–4] This chirality phenomenon also exists in
microscopic living organisms (e.g., helical bacteria) and in
macroscopic objects (e.g., sea shells).[5] Consequently, an
increasing number of drugs have been found to show chiral
subunits in their structures for over the past century, and their
biomedical actions heavily depend on chirality types in regard
to potency and selectivity toward receptors and other targets
on the surface and inside of cells.[6,7] Chiral modifications of
drugs can substantially reduce or avoid unwanted side effects
Recently, our lab reported a new form of chirality which is
different from traditional planar and helical counterparts. It is
an unique multilayer 3D chirality showing highly compacted
and spaced folding held together primarily by aromatic-
aromatic interactions (π-stacking).[22] This chirality displays key
elements of both planar and axial chirality in regard to
rotational stereoisomerism, i.e., it shows its top and bottom
layers restrict each other from free rotation. Essentially, this
chirality would disappear if either top or bottom layer is
removed. The first multilayer 3D chirality work was based on
the template of phosphoramide which was originated from the
GAP (Group-Assisted-Purification) chemistry by taking advant-
age of phosphornyl/phosphinyl functional groups to control
solubility allowing the greener synthesis of achiral/chiral
products.[23,24] In GAP synthesis, products are purified simply by
filtrating and washing with common solvents so as to avoid
traditional purification (mainly chromatography and recrystalli-
zation). The CÀ N bond-based multilayer 3D chirality was made
[a] Dr. G. Wu,+ Y. Liu,+ H. Rouh,+ L. Ma, Y. Tang, S. Zhang, Dr. D. Unruh,
Dr. K. Surowiec, Prof. Dr. G. Li
Department of Chemistry and Biochemistry
Texas Tech University
Lubbock, TX 79409 (USA)
E-mail: guigen.li@ttu.edu
[b] Dr. G. Wu,+ P. Zhou, J.-Y. Wang, S. Jin, Prof. Dr. G. Li
Institute of Chemistry and BioMedical Sciences
School of Chemistry and Chemical Engineering
Nanjing University
Nanjing, 210093 (P. R. China)
[c] Prof. Dr. Y. Ma
Mechanical Engineering
Texas Tech University
Lubbock, TX 79409 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100700
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possible via double Buchwald-Hartwig cross-couplings.[25,26] It is
noteworthy that the former chirality exhibits a new type of
pseudo C2-symmetry, that is, multilayer pseudo C2-chirality
(Scheme 1a, i).
We also established the CÀ C bond-based multilayer 3D
chirality by conducting double Suzuki-Miyaura cross-
couplings[27] with its asymmetric induction controlled by chiral
auxiliaries (Scheme 1a, ii).[22b] This work would be the first
enantioselective synthesis of sandwich-shaped organic mole-
cules controlled by asymmetric aromatic interactions. In this
multilayer 3D chirality, the thiadiazole ring was employed as a
bridge, and its ring can be opened leading to free aromatic
diamines. Interestingly, when these aromatic diamines are
for efficient catalysts, ligands and catalytic systems. In this
communication, we would like to disclose our preliminary
results on this endeavor as represented by the reaction of 4-(8-
phnylnaphthalen-1-yl)-7-pin-benzo[c][1,2,5]thiadiazole with (1-
bromonaphthalen-2-yl)diphenylphosphine oxides catalyzed by
the complexes of chiral phosphines and transition metal Pd
(Scheme 1b). The resulting multilayer 3D structures has been
unambiguously confirmed by X-ray structural analysis clearly
showing a parallel pattern of three layers consisting top, middle
and bottom aromatic rings. This work represents the first
asymmetric catalytic synthesis of multilayer 3D chirality.
protected with various carbonyl groups, luminescence colors Results and Discussion
can be changed from gold to deep blue under UV irradiation.
These multilayer 3D chiral molecules presented strong aggrega-
tion-induced emission (AIE).[22b] Furthermore, some of the above
products displayed macro chirality that can be directly
visualized by the naked eyes without an aid of any microscopic
devices. Nearly all 3D chiral products showed strong
fluorescence in both solid states and in solutions, on TLC plates
and inside silica gel columns which makes purifications much
more convenient.
The structural unit of benzo[c][1,2,5]thiadiazole is among the
most important synthons in material sciences, especially in
conductive polymers, optoelectronic materials and aggrega-
tion-induced emission (AIE).[16] Our previous work has proven
that benzo[c][1,2,5]thiadiazole-derived boronic acids or esters
are efficient scaffolds for double Suzuki-Miyaura cross-cou-
plings. Therefore, we utilized this core structural unit serving as
the bridge function for the present asymmetric catalysis.
After we achieved the auxiliary-controlled synthesis of
multilayer 3D chirality, we now turned our attention to
asymmetric catalytic approach to this framework by searching
The synthesis of double-layer reactants (6a–i) (Scheme 2)
was started from the treatment of 4,7-dibromo-2,1,3-benzothia-
diazole (4) with bis(pinacolato)diboron under in situ catalytic
Scheme 1. The strategy and progress of multilayer 3D chirality.
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Scheme 2. Synthesis of double-layer reactants 6a–i.
systems involving KOAc as a base additive and (1,1-bis
(diphenylphosphino)ferrocene) dichloropalladium (II) as the
catalyst in 1,4-dioxane to give 4,7-bis(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole (5).[27] 1-Bromo-8-ar-
ylnaphthalenes (3a–i) were synthesized by conducting the
(Figure 1a). In the meanwhile, we utilized recyclable and re-
usable GAP-catalysts for asymmetric Diels-Alder and Friedel-
Crafts reactions and stereoselective alkene isomerization.[23,24]
The above work inspired us to take the advantage of GAP-
catalysts for the initial model reaction between 4-(8-phnylnaph-
thalen-1-yl)-7-pin-benzo[c][1,2,5]thiadiazole and (1-bromonaph-
thalen-2-yl)diphenylphosphine oxides under Suzuki-Miyaura
cross-coupling condition. In this system, toluene and EtOH were
employed as co-solvents, K2CO3 as a base additive, GAP amides
and Pd(OAc)2 (L1&L2, Scheme 3) as the catalysts. The GAP-
catalyst (L1&L2) was made by treating aromatic amines with
NaH followed by reacting with GAP-Cl.[28] Both catalysts L1 and
L2 resulted in modest enantiomeric selectivity of er values of
63:37 and 60:40, respectively. Similarly, two peptide-phos-
phines, L3&L4, led to er values of 44:66 and 51:49, respectively.
A newly reported chiral sulfonimine-based mono phosphine
by Zhang and coworkers, (R)-N-((S)-(2-(diphenylphosphaneyl)
phenyl)(4-methoxyphenyl)methyl)-2-methylpropane-2-sulfina-
mide (L5) was also synthesized and examined for this reaction
to only give er of 29:71, although this ligand was proven to be
highly efficient for axially directing chiral biaryl formations.[12c,f]
It should be noted our labs had previously proven sulfonamides
are recyclable and re-usable due to the similar polarity of S=O
to P=O bonds.[23,24] We next tested a simple phosphine amide
L6 which is anticipated to have recyclable and re-usable
potentials upon their being deprotonated by bases, such as
NaH, LiH, BuLi, etc. Unfortunately, this ligand led to a decreased
er of 53:47. Interestingly, its crystalline complex with Pd is
readily formed for X-ray structural analysis as shown in Fig-
ure 1b. It displays an obvious asymmetric environment gen-
erated by the two phenyl rings on P of two ligands. These two
rings are arranged nearly parallel to each other without planarly
overlapping. Based on this detailed analysis, we envisioned the
chiral conformation nearby Pd(0) center would be enhanced if
the amide moiety is further modified. We then came up with an
idea of replacing (R)-1-phenylethan-1-amino group of the ligand
6 with (R)-bis((R)-1-phenylethyl)amino counterpart. Gratifyingly,
this modification resulted in a much higher er of 87:13 and a
yield of 55%.
Suzuki-Miyaura
cross-coupling
between
1,8-dibromo-
naphthalene (1) and arylboronic acids (2a–i) which are either
directly purchased or readily synthesized by following literature
procedures.[22b,27] The Suzuki-Miyaura coupling of 1-bromo-8-
arylnaphthalenes (3a–i) with 4,7-bis(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole (5) led to the for-
mation of double-layered reactants (6a–i) in an overall chemical
yields arranging from 47% to 68% (see Supporting Informa-
tion).
The synthesis of other reactants of (1-bromonaphthalen-2-
yl)diarylphosphine oxides was performed via the protection 1-
bromo-2-naphthol with triflic anhydride to give 1-bromonaph-
thalen-2-yl trifluoromethanesulfonate in the presence of pyir-
idine, followed by the CÀ P coupling with diaryl phosphine
oxide by using Pd2(dba)3 as the catalyst.[12c] Among these
substrates,
phosphine oxide, was synthesized starting from nucleophilic
substitution of diethyl phosphate with 4-meth-
(1-bromonaphthalen-2-yl)bis(4-methoxyphenyl)
oxyphenylmagnesium bromide to generate bis(4-meth-
oxyphenyl)phosphine oxide followed by subjecting to the
catalytic coupling with 1-bromo-2-naphthyl triflate.[12c]
It should be noted that the two aromatic rings, benzothia-
diazole (red) and aryls (blue), in double-layer reactants
(Scheme 2, 6a–i) would be able to rotate freely. This is due to
the fact that there are not enough steric groups on their rings
and on naphthalene anchor to block their rotating. This
situation leads to kinetic dynamic resolution during asymmetric
catalytic induction processes. Upon the CÀ C bond is formed
asymmetrically, this free rotation is limited due to the steric
effect between the naphthalene anchor and the five-membered
ring of benzothiadiazole. There is no racemization observed for
enantiomerically enriched products when they are stored in
room temperature for several months.
The key intermediate involving a mono phosphine ligand
and benzothiadiazole moiety has been isolated and confirmed
by X-ray structural analysis in our previous racemic process
Other commercial phosphine ligands readily available in our
labs, such as (S)-(+)-N,N-dimethyl-1-[(R)-2-(diphenylphosphino)
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Figure 1. (a) A crystal structure of a mono phosphine ligand and benzothiadiazole moiety. (b) A crystalline complex of L6-Pd. (c) X-ray structure of 8a. (d)
Arrangement of layered columns (blue part). Deposition numbers 2078680 (8a), and 2078803 (L6-Pd) contain the supplementary crystallographic data for this
paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures
service.
Scheme 3. Screened ligands. Conditions A: all reactions were carried out with 7a (0.05 mmol), 6a (0.10 mmol), Pd(OAc)2 (5 mol%), ligand (6 mol%), K2CO3
(3.0 equiv) in 2 mL solvent (PhMe/EtOH=1:1) for 36 h under Ar.
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ferrocenyl]ethylamine, (R)-SIPHOS-PE, 1-dicyclohexylphosphino-
1’-{(R)-{(RP)-2-[(S)-1-(dimethylamino)ethyl]ferrocenyl}phenyl-
phosphino}ferrocene, were also tested leading to low er values
arranging from 54:46 to 40:60.
In the meantime, we also examined various chiral bis-
phosphine ligands already stored in our labs. Surprisingly, as
shown below that nearly all of these bis-phosphine ligands did
not come up with any enantioselective improvement for this
multilayer 3D control under the standard in situ catalytic
systems, except for one case of 1,1’-bis[(R)-[(1S)-2-[(1S)-1-(
dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene af-
fording an acceptable er of 67:33. Other ligands including (S)-
BINAP (er, 53:47), bis(di-p-tolylphosphaneyl)-1,1’-binaphthalene,
(+)-1,2-bis((2R,5R)-2,5-diphenylphospholano)ethane (er, 57:43),
(S,S)-F-BINAPHANE (er, 59:41), (1R,1’R)-1,1’-bis[bis[3,5-bis
(trifluoromethyl)phenyl]phosphino]-2,2’-bis[(R) (dimethylamino)
phenylmethyl]ferrocene (er, 61:39), and 1-dicyclohexylphosphi-
no-1-{(R)-{(RP)-2-[(S)-1-(dimethylamino)ethyl]ferrocenyl}phenyl-
phosphino}ferrocene (er, 54:46), all resulted in lower er values
in general. However, the chiral bis-phosphine ligand of Pd(S-
BINAP)Cl2 did give a similar er ratio of 82:18 and the same
major enantiormer as ligand L7 generated.
The absolute stereochemistry was determined by X-ray
structural analysis on the model reaction product of diphenyl(1-
(7-(8-phenylnaphthalen-1-yl)benzo[c][1,2,5]thiadiazol-4-yl)
naphthalen-2-yl)phosphine oxide (Figure 1c), and concurrently,
compared with a similar stereoselective control as reported by
Zhang and coworkers by using (S)-N,N-Dimethyl-1-[(R)-2-
(diphenylphosphino)ferrocenyl] ethylamine as the catalyst,
resulting in the same major enantiormer as Pd(S-BINAP)Cl2
generated for an axial induction in literature.[12]
As shown in X-ray structure that phosphine oxide function-
ality played the key role for the present multilayer 3D chirality
by offering its naphthyl group and the bridge anchor. It also
provides one of its two phenyl rings to serve as a planar layer.
Another phenyl ring on P is directed toward up direction away
from the three-layered core structure. Interestingly, this phenyl
ring is forced to be nearly perpendicularly to the two naphthyl
rings, which is unusual in structures of aryl phosphine oxides.
The present three layers, top/center/bottom, are assembled
more parallelly than those of our previous multilayer 3D
molecules.[22] The five-membered thiadiazole ring is directed
opposite to P=O (anti stereochemistry). Two naphthyl bridge
columns are arranged along the same direction (syn stereo-
chemistry), essentially on the same plans. This is opposite to
that of our previous multilayer 3D products in which naphthyl
bridge columns are arranged in anti direction, which has been
proven by our newly developed polymerization of layered
monomeric units (Figure 1d).[29]
Figure 2. Asymmetric induction hypothesis of multilayer 3D synthesis.
thiadiazoles and (1-bromonaphthalen-2-yl)diarylphosphine ox-
ides were proven to be amenable to the present catalytic
conditions to give up to acceptable enantioselectivity and
chemical yields. For the former, the bottom aromatic rings can
be anchored with electron-donating groups (8b–8e) including
a strong one (OMe, 8b) and electron-withdrawing (8f--8h)
including relatively strong ones (3,5-di-F and para-CN, 8g and
8h, respectively). Three of these cases even showed comparable
enantioselectivity to that of non-substituted substrate (8a)
arranging from er of 83:17 to 87:13. It is important for para-
substituted substrates are effective for this reaction because
this offers the flexibility to modify para moieties for structural
extension. For example, para-Ph case (8e) provides an extra
parallelly planar pattern for overlapping with the bridge column
of naphthylrene ring. This will benefit the search for challenging
properties of polarized organic electronics, optoelectronics, and
photovoltaics in material sciences. The para-OMe and À CN can
be further converted into many other groups, especially, to a
series of aromatics via cross-couplings for the above purposes.
For the latter, similar substrate scope was displayed in
regard to functional groups on phosphorous oxides in which
both Me and OMe worked well to give up to 85:15 er and
chemical yield 60%, respectively. It is noteworthy that the
phosphorous oxide functionality proved to show strong
fluorescence and AIE properties, strong fluorescence sensitivity
even in their solid forms under UV light at various wavelengths
and displayed aggregation-induced emission (AIE) properties,
This also indicates the great potentials for material science by
modifying this functionality. In fact, as revealed below, the
randomly selected products did show above properties well.
The UV-Vis absorbance of 8a, 8f, 8g, 8h, 8i and 8n in DCM
solution is displayed in Figure 3a. The overall shape and the
location of the band maxima of different substrates are quite
consistent, which are 240 nm, 300 nm and 370 nm, respectively.
Changing substituents on both substrates has made little
difference for absorption wavelength. Notably, the photolumi-
nescence (PL) spectra of selected compounds upon excitation
at 532 nm exhibit bands at different wavelengths (Figure 3b).
As a basis substrate, 8a shows extremely strong bands at
~595 nm. Further decorations with electron donating/with-
drawing groups only on the phenyl ring (8h, 8g, 8i and 8f)
could adjust the peaks slightly within 25 nm, located at 580–
620 nm wavelength. However, modifications on 8i and 8n have
expanded the range of emission maximum from 550 nm to
650 nm, illustrates that functionalizing the phosphine oxide
counterpart should have more significant effects on the
The resulting stereochemistry assignment indicates a tran-
sition metal catalytic transition state is similar to that of
previous axial chirality control by Zhang and coworkers (Fig-
ure 2), although the chiral ligands are different in these two
systems.[12]
With the above optimal conditions in hand, we decided to
examine the substrate scope of this asymmetric reaction. As
shown in Scheme 4, both doubly layered benzo[c][1,2,5]
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Scheme 4. Results of asymmetric catalytic multilayer 3D synthesis. All reactions were carried out with 7 (0.05 mmol), 6 (0.10 mmol), Pd(OAc)2 (5 mol%), L7
(6 mol%), K2CO3 (3.0 equiv) in 2 mL solvent (PhMe/EtOH=1:1) for 36 h under Ar. Product enantiomer excesses were determined by chiral HPLC. Isolated yield
are reported, based on substrate 7.
emission. This preliminary result has offered a reliable direction
for further applied research on various optical properties.
Furthermore, the aggregation-induced emission (AIE)/aggrega-
tion-enhanced emission (AEE) study of 8a (Figure 3b), in which
the luminescence becomes much more intense with higher
fraction of bad solvent (water in this case), supports the
previous findings on multilayer 3D chiral molecules we
reported.[22,30–32] Finally, It is interesting that most doubly-layered
reactants also displayed strong luminescence under UV irradi-
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3D framework was unambiguously determined by X-ray struc-
tural analysis showing a parallel pattern of three layers
consisting of top, middle, and bottom aromatic rings. The
synthesis showed an excellent substrate scope in which three
rings of products can be readily varied. The resulting multilayer
3D products showed strong luminescence under UV irradiation,
and displayed strong aggregation-induced emission (AIE).
Applications of this work in asymmetric catalysis by attaching
ligand motifs onto the bottom aromatic ring will be explored in
the near future.
Acknowledgements
We would like to acknowledge the financial support from
Robert A. Welch Foundation (D-1361, USA) and the National
Natural Science Foundation of China (No. 22071102 and
91956110).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: aggregation-induced emission · chirality · multilayer
organic frameworks · Suzuki-Miyaura cross-coupling
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Conclusion
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multilayer 3D chirality by using Suzuki-Miyaura cross-couplings
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Manuscript received: February 25, 2021
Accepted manuscript online: April 8, 2021
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These are not the final page numbers!

FULL PAPER
Dr. G. Wu, Y. Liu, H. Rouh, L. Ma, Y.
Tang, S. Zhang, P. Zhou, J.-Y. Wang, S.
Jin, Dr. D. Unruh, Dr. K. Surowiec,
Prof. Dr. Y. Ma, Prof. Dr. G. Li*
1 – 9
Asymmetric Catalytic Approach to
Multilayer 3D Chirality
The first asymmetric catalytic
multilayer products showed strong lu-
minescence under UV irradiation, and
displayed strong aggregation-induced
emission (AIE).
approach to multilayer 3D chirality by
using Suzuki-Miyaura cross-couplings
in the presence of new chiral amide-
phosphines is reported. The resulting