C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.


Introduction
Chirality and its asymmetric control have been among the most important and active topics in science and technology for over half a century because chirality phenomena widely exist in nature in varuous forms ranging from functional molecules to microscopic living organisms (e.g., helical bacteria) to macroscopic objects (e.g., sea shells) [1][2][3][4][5][6].It is well known that chiral functional biomolecules, including peptides/proteins, DNA/RNA, and carbohydrates, play crucial roles in biological processes in human beings, animals, and plants [7][8][9][10].This field has become even more important and active since an increasingly larger number of modern drugs, agrochemicals, clinical candidates, and their precursors involve chirality in their structures and subunits [11,12].By changing the chirality of molecular medicine, potency and selectivity can be substantially enhanced to reduce dosages and unwanted side effects [11,12].In modern materials science, controlling chirality has also been proven to be effective for achieving challenging photo-and optoelectronic properties [13][14][15][16][17][18].It is worth noting that asymmetric synthesis and catalysis have been playing key roles in the discovery and development of new chiral drugs and materials for the past several decades [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33].
Molecules 2024, 29, x FOR PEER REVIEW 2 of 13 auxiliaries and catalysts (Figure 1a) in which one single carbon-carbon bond forming led to multilayer chirality [49].A category of these chiral targets is stabilized by aromatic/aromatic interaction (w in Figure 1a) as proven by X-ray structures.In this chiral multilayer framework, a pro-chiral center (x in Figure 1a) and an orientational axis (y in Figure 1a) exist.The pro-phosphorus chiral center is directly connected to a naphthyl ring, and two phenyl groups are differentiated by parallel packing.The atropisomerism along the C-P axis is made possible jointly by Ar-Ar interaction and the parallel arrangement of phenyl ring on the bottom of the structural framework.Concurrently, the Sparr and Jørgensen labs independently reported an asymmetric catalytic approach to obtaining stable atropisomers containing C(sp 2 )−cyclized C(sp 3 ) bonds as axes (Figure 1b,c) [50,51].The atropisomeric chirality of their reports follows the well-known Felkin-Ahn-type model [52,53].In this molecular framework, one of the three groups on C(sp 3 ) is arranged perpendicularly to the C(sp 2 ) plane.Very recently, we proposed the concept of orientational chirality and assembled its molecular architectures, in which chiral tetrahedron centers and blocking groups are anchored remotely through space [6,54,55] (Figure 2).In orientational chirality, two different rotamers were observed in their crystals, as revealed by X-ray diffraction analysis (Figure 2IA,IB).This work made it possible to achieve individual atropisomers centered on sp 3 carbon with four independent open-chain and flexible motifs, which are differentiated from previous systems containing cyclized rigid substituents centered on sp 3 carbon [54,55].Among three open-chain orientational isomers, we selectively controlled one of them in which the amino branch is directed away from the remote anchor (Figure 2IA).As a result, the orientatiomers with the alkyl branches being forced away from the remote anchor were challenging in regard to the combinational design of two levers/arms on the planar naphthyl pier of the through-space structural framework.Herein, we would like to report our preliminary results of this asymmetric control.A category of these chiral targets is stabilized by aromatic/aromatic interaction (w in Figure 1a) as proven by X-ray structures.In this chiral multilayer framework, a prochiral center (x in Figure 1a) and an orientational axis (y in Figure 1a) exist.The prophosphorus chiral center is directly connected to a naphthyl ring, and two phenyl groups are differentiated by parallel packing.The atropisomerism along the C-P axis is made possible jointly by Ar-Ar interaction and the parallel arrangement of phenyl ring on the bottom of the structural framework.Concurrently, the Sparr and Jørgensen labs independently reported an asymmetric catalytic approach to obtaining stable atropisomers containing C(sp 2 )−cyclized C(sp 3 ) bonds as axes (Figure 1b,c) [50,51].The atropisomeric chirality of their reports follows the well-known Felkin-Ahn-type model [52,53].In this molecular framework, one of the three groups on C(sp 3 ) is arranged perpendicularly to the C(sp 2 ) plane.Very recently, we proposed the concept of orientational chirality and assembled its molecular architectures, in which chiral tetrahedron centers and blocking groups are anchored remotely through space [6,54,55] (Figure 2).In orientational chirality, two different rotamers were observed in their crystals, as revealed by X-ray diffraction analysis (Figure 2IA,IB).This work made it possible to achieve individual atropisomers centered on sp 3 carbon with four independent open-chain and flexible motifs, which are differentiated from previous systems containing cyclized rigid substituents centered on sp 3 carbon [54,55].Among three open-chain orientational isomers, we selectively controlled one of them in which the amino branch is directed away from the remote anchor (Figure 2IA).As a result, the orientatiomers with the alkyl branches being forced away from the remote anchor were challenging in regard to the combinational design of two levers/arms on the planar naphthyl pier of the through-space structural framework.Herein, we would like to report our preliminary results of this asymmetric control.
auxiliaries and catalysts (Figure 1a) in which one single carbon-carbon bond forming led to multilayer chirality [49].A category of these chiral targets is stabilized by aromatic/aromatic interaction (w in Figure 1a) as proven by X-ray structures.In this chiral multilayer framework, a pro-chiral center (x in Figure 1a) and an orientational axis (y in Figure 1a) exist.The pro-phosphorus chiral center is directly connected to a naphthyl ring, and two phenyl groups are differentiated by parallel packing.The atropisomerism along the C-P axis is made possible jointly by Ar-Ar interaction and the parallel arrangement of phenyl ring on the bottom of the structural framework.Concurrently, the Sparr and Jørgensen labs independently reported an asymmetric catalytic approach to obtaining stable atropisomers containing C(sp 2 )−cyclized C(sp 3 ) bonds as axes (Figure 1b,c) [50,51].The atropisomeric chirality of their reports follows the well-known Felkin-Ahn-type model [52,53].In this molecular framework, one of the three groups on C(sp 3 ) is arranged perpendicularly to the C(sp 2 ) plane.Very recently, we proposed the concept of orientational chirality and assembled its molecular architectures, in which chiral tetrahedron centers and blocking groups are anchored remotely through space [6,54,55] (Figure 2).In orientational chirality, two different rotamers were observed in their crystals, as revealed by X-ray diffraction analysis (Figure 2IA,IB).This work made it possible to achieve individual atropisomers centered on sp 3 carbon with four independent open-chain and flexible motifs, which are differentiated from previous systems containing cyclized rigid substituents centered on sp 3 carbon [54,55].Among three open-chain orientational isomers, we selectively controlled one of them in which the amino branch is directed away from the remote anchor (Figure 2IA).As a result, the orientatiomers with the alkyl branches being forced away from the remote anchor were challenging in regard to the combinational design of two levers/arms on the planar naphthyl pier of the through-space structural framework.Herein, we would like to report our preliminary results of this asymmetric control.

Structural Design and Models
In our previous work, both phenyl and alkyl levers (blue units in Figure 3) were utilized as anchors for bringing remote blockers and sp 3 chiral carbon centers closer, as represented by the orientational isomers in Figure 3 [6,54,55].If two aromatic rings and amino branches are attached to sp 3 chiral carbon centers with an alkynyl lever (C(sp)-C(sp 3 )) axis, the amino branch on the chiral carbon and one of the two individual aromatic branches are directed out of the plane, while another aromatic group remains on the plane and is selectively directed away from the remote chiral amide blocker on the phenyl lever [54,55].In these cases, two chiral auxiliaries, carbonyl and sulfonyl amides, are necessary to jointly control the orientation of aromatic moieties (Figure 3a,b).A DFT computational study was performed on orientational individual orientatiomers in regard to their relative energy (Figure 3).Meanwhile, a rotational profile was also obtained by scanning the rotational dihedral angle θ, supporting the experimental observations in which the resulting orientatiomers are proven to be stable enough at constant temperatures and to be synthesized asymmetrically.

Structural Design and Models
In our previous work, both phenyl and alkyl levers (blue units in Figure 3) were utilized as anchors for bringing remote blockers and sp 3 chiral carbon centers closer, as represented by the orientational isomers in Figure 3 [6,54,55].If two aromatic rings and amino branches are attached to sp 3 chiral carbon centers with an alkynyl lever (C(sp)-C(sp 3 )) axis, the amino branch on the chiral carbon and one of the two individual aromatic branches are directed out of the plane, while another aromatic group remains on the plane and is selectively directed away from the remote chiral amide blocker on the phenyl lever [54,55].In these cases, two chiral auxiliaries, carbonyl and sulfonyl amides, are necessary to jointly control the orientation of aromatic moieties (Figure 3a,b).A DFT computational study was performed on orientational individual orientatiomers in regard to their relative energy (Figure 3).Meanwhile, a rotational profile was also obtained by scanning the rotational dihedral angle θ, supporting the experimental observations in which the resulting orientatiomers are proven to be stable enough at constant temperatures and to be synthesized asymmetrically.Interestingly, when one of two aromatic rings on the sp 3 chiral carbon center was replaced by alkyl groups, and concurrently, the alkynyl and aryl levers were switched as [(C(sp 2 )-C(sp 2 )-right)/[(C(sp)-C(sp)-left) axes, the orientatiomers with amino branches directed away from the remote anchor were controlled selectively [6].This situation exists due to the combinaion of aryl/aryl levers, the [(C(sp 2 )-C(sp 2 )-right)/[(C(sp 2 )-C(sp 2 )-left) axis, for remote blockers and the chiral carbon center [54,55].For the latter oreintation chirality, DFT computation was also conducted, presenting relative stability with the rotation of individual orientatiomers.In order to selectively control the orientatiomers in which the alkyl branches are directed away from the remote anchor, we then focused on the use of two alkynyl levers, [(C(sp)-C(sp)-right/(C(sp)-C(sp)-left axis), for both the C(sp 3 ) center and remote blockers.As shown by the asymmetric synthesis below, this design led to the results sought and is presented in forty examples.
Compared to the previous Felkin-Ahn-type model, the atropisomeric chirality is mainly based on the dialog relationship between two adjacent blocking C(sp 2 ) and chiral C(sp 3 ) scaffolds (I, II, III in Figure 4A).However, in orientational chirality cases in which [(C(sp)-C(sp)-right lever)/[C(sp 3 ) stereogenic center] or [(C(sp 2 )-C(sp 2 )-right lever)/[C(sp 3 ) stereogenic centre] structural combinations are shown, the remotely anchored groups block rotation along the C(sp 2 )−C(sp 3 ) or C(sp 2 )−C(sp 3 ) axis (Figure 4B), i.e., the new orientational chirality is focused on the dialog relationship between C(sp 3 ) centers and remotely anchored chiral amide and aryl functional groups.Since there is a single interaction (the heavy black line in the model, Figure 4B) existing in each of the three orientatiomers, there are only three energy barriers instead of six existing in the previous atropisomerism.While the nomenclature of previous molecular frameworks follows the Cahn−Ingold−Prelog (CIP) rules, it seems difficult to find a nomenclature rule for the present chirality systems at this stage.The relationship among three orientatiomers ((1), Interestingly, when one of two aromatic rings on the sp 3 chiral carbon center was replaced by alkyl groups, and concurrently, the alkynyl and aryl levers were switched as [(C(sp 2 )-C(sp 2 )-right)/[(C(sp)-C(sp)-left) axes, the orientatiomers with amino branches directed away from the remote anchor were controlled selectively [6].This situation exists due to the combinaion of aryl/aryl levers, the [(C(sp 2 )-C(sp 2 )-right)/[(C(sp 2 )-C(sp 2 )-left) axis, for remote blockers and the chiral carbon center [54,55].For the latter oreintation chirality, DFT computation was also conducted, presenting relative stability with the rotation of individual orientatiomers.In order to selectively control the orientatiomers in which the alkyl branches are directed away from the remote anchor, we then focused on the use of two alkynyl levers, [(C(sp)-C(sp)-right/(C(sp)-C(sp)-left axis), for both the C(sp 3 ) center and remote blockers.As shown by the asymmetric synthesis below, this design led to the results sought and is presented in forty examples.
Compared to the previous Felkin-Ahn-type model, the atropisomeric chirality is mainly based on the dialog relationship between two adjacent blocking C(sp 2 ) and chiral C(sp 3 ) scaffolds (I, II, III in Figure 4A).However, in orientational chirality cases in which [(C(sp)-C(sp)-right lever)/[C(sp 3 ) stereogenic center] or [(C(sp 2 )-C(sp 2 )-right lever)/[C(sp 3 ) stereogenic centre] structural combinations are shown, the remotely anchored groups block rotation along the C(sp 2 )−C(sp 3 ) or C(sp 2 )−C(sp 3 ) axis (Figure 4B), i.e., the new orientational chirality is focused on the dialog relationship between C(sp 3 ) centers and remotely anchored chiral amide and aryl functional groups.Since there is a single interaction (the heavy black line in the model, Figure 4B) existing in each of the three orientatiomers, there are only three energy barriers instead of six existing in the previous atropisomerism.While the nomenclature of previous molecular frameworks follows the Cahn−Ingold−Prelog (CIP) rules, it seems difficult to find a nomenclature rule for the present chirality systems at this stage.The relationship among three orientatiomers ((1), (2) and (3) in Figure 4B) does not belong to the classical enantiomeric or diastereomeric isomerism.In both previous and present cases, there exist three pairs of enantiomers and six pairs of diastereomers, which is not often encountered in stereochemistry.
Molecules 2024, 29, x FOR PEER REVIEW 4 of 13 (2) and (3) in Figure 4B) does not belong to the classical enantiomeric or diastereomeric isomerism.In both previous and present cases, there exist three pairs of enantiomers and six pairs of diastereomers, which is not often encountered in stereochemistry.

Asymmetric Synthesis
The asymmetric synthesis of orientatiomeric products

Asymmetric Synthesis
The asymmetric synthesis of orientatiomeric products

Asymmetric Synthesis
The asymmetric synthesis of orientatiomeric products  Surprisingly, when we conducted the final assembly of the final orientatiomeric product under Sonogashira and the previous modified catalytic coupling systems (Scheme 4), we found that all known conditions did not work well.We thus investigated various catalysts which have been commonly used in previous coupling reactions.Among them, NiCl 2 (PPh 3 ) 2, PdCl 2 and Pd(OAc) 2 did not provide the target product at all; rather, the raw materials were recovered almost quantitatively (Table 1, entries 1, 3, and 5).PdCl 2 (PPh 3 ) 2 produced the product ((R,S)-7a) in a 45% yield (Table 1, entry 2), which highlights the advantages of palladium catalysis.A dramatically lower yield of 28% was obtained when Pd(PPh 3 ) 4 (Table 1, entry 4) was employed, and PdCl 2 (PPh 3 ) 2 is proven to be more appropriative than PdCl 2 (dppf) 2 (Table 1, entry 6) for this step.Several solvents, including THF and DMF, were subsequently screened (Table 1, entries 7-9), while Cs 2 CO 3 or Et 3 N was used as the base, with inferior results obtained in each case.In addition, we found that changing temperatures showed a significant impact on chemical yield (Table 1, entries [10][11].The optimal conditions for this reaction are PdCl 2 (PPh 3 ) 2 (2 mol %) and CuI (5 mol %) in Et 3 N as both a base and a solvent under argon at 50 • C for 24 h (Table 1, entries 10), leading to a yield of 68%.Control experiments were used to demonstrate that PdCl 2 (PPh 3 ) 2 and CuI were found to be crucial to this modified Sonogashira cross-coupling (Table 1, entry 12).Surprisingly, when we conducted the final assembly of the final orientatiomeric product under Sonogashira and the previous modified catalytic coupling systems (Scheme 4), we found that all known conditions did not work well.We thus investigated various catalysts which have been commonly used in previous coupling reactions.Among them, NiCl2(PPh3)2, PdCl2 and Pd(OAc)2 did not provide the target product at all; rather, the raw materials were recovered almost quantitatively (Table 1, entries 1, 3, and 5).PdCl2(PPh3)2 produced the product ((R,S)-7a) in a 45% yield (Table 1, entry 2), which highlights the advantages of palladium catalysis.A dramatically lower yield of 28% was obtained when Pd(PPh3)4 (Table 1, entry 4) was employed, and PdCl2(PPh3)2 is proven to be more appropriative than PdCl2(dppf)2 (Table 1, entry 6) for this step.Several solvents, including THF and DMF, were subsequently screened (Table 1, entries 7-9), while Cs2CO3 or Et3N was used as the base, with inferior results obtained in each case.In addition, we found that changing temperatures showed a significant impact on chemical yield (Table 1, entries 10-11).The optimal conditions for this reaction are PdCl2(PPh3)2 (2 mol %) and CuI (5 mol %) in Et3N as both a base and a solvent under argon at 50 °C for 24 h (Table 1, entries 10), leading to a yield of 68%.Control experiments were used to demonstrate that PdCl2(PPh3)2 and CuI were found to be crucial to this modified Sonogashira crosscoupling (Table 1, entry 12).Surprisingly, when we conducted the final assembly of the final orientatiomeric product under Sonogashira and the previous modified catalytic coupling systems (Scheme 4), we found that all known conditions did not work well.We thus investigated various catalysts which have been commonly used in previous coupling reactions.Among them, NiCl2(PPh3)2, PdCl2 and Pd(OAc)2 did not provide the target product at all; rather, the raw materials were recovered almost quantitatively (Table 1, entries 1, 3, and 5).PdCl2(PPh3)2 produced the product ((R,S)-7a) in a 45% yield (Table 1, entry 2), which highlights the advantages of palladium catalysis.A dramatically lower yield of 28% was obtained when Pd(PPh3)4 (Table 1, entry 4) was employed, and PdCl2(PPh3)2 is proven to be more appropriative than PdCl2(dppf)2 (Table 1, entry 6) for this step.Several solvents, including THF and DMF, were subsequently screened (Table 1, entries 7-9), while Cs2CO3 or Et3N was used as the base, with inferior results obtained in each case.In addition, we found that changing temperatures showed a significant impact on chemical yield (Table 1, entries 10-11).The optimal conditions for this reaction are PdCl2(PPh3)2 (2 mol %) and CuI (5 mol %) in Et3N as both a base and a solvent under argon at 50 °C for 24 h (Table 1, entries 10), leading to a yield of 68%.Control experiments were used to demonstrate that PdCl2(PPh3)2 and CuI were found to be crucial to this modified Sonogashira crosscoupling (Table 1, entry 12).Having established the optimized conditions, we synthesized a series of orientational isomeric products by varying aryl alkyne substrates 6 with the results listed in Scheme 5.With the use of PdCl 2 (PPh 3 ) 2 (2 mol %) and CuI (5 mol %), substrates 6 bearing various aliphatic substituents underwent coupling reactions with chiral alkynyl precursors (R,R-5a), with moderate yields from 34% to 68%, showing that the electronic and steric nature of the aryl group on the benzyl acrylate appear to influence the reaction.Heteroaromatic rings, such as thiophene and pyridine ((R,S)-7ac, 7ad, and 7af), are especially compatible with this synthesis, and the yields range from 47% to 56%.For the cases of (R,S)-7ba and (R,S)-7bb, in which the n-butyl group in (R,R)-5a was replaced with isopropyl and isobutyl groups, respectively, stable rotamers were shown as expected.The opposite configuration of building block (S,S)-5a can also be smoothly converted into the corresponding orientational isomer (S,R)-7bc ′ with a chemical yield of 55%.
It is worth noting that several of the resulting orientational amino targets are attached with scaffolds of natural and medicinal products, including D-menthol, L-menthol, vitamin C, pregnenolone, and estrone (R,S)-7ag-(R,S)-7ak, with moderate yields and a single orientational configuration under these conditions.This shows their potential for pharmaceutical and medicinal applications in the future, especially for amino acid-and peptide-derivatized targets when the aliphatic or aromatic branch is replaced by a carboxylic acid group.a Reaction conditions: Reactions were carried out with 6a (64 mg, 0.20 mmol), (R,R)-5a (59.2, 0.20 mmol), cat.(5 mol %), CuI (10 mol %), and a base (0.6 mmol, 3.0 eq) in solvent (2.0 mL) under argon for 24 h.b Isolated yields of (R,S)-7a after purification by column chromatography.c Reaction was carried out with PdCl2(PPh3)2 (2 mol%) and CuI (5 mol%) under argon for 24 h.n. r. represents no reaction.
Having established the optimized conditions, we synthesized a series of orientational isomeric products by varying aryl alkyne substrates 6 with the results listed in Scheme 5.With the use of PdCl2(PPh3)2 (2 mol%) and CuI (5 mol%), substrates 6 bearing various aliphatic substituents underwent coupling reactions with chiral alkynyl precursors (R,R-5a), with moderate yields from 34% to 68%, showing that the electronic and steric nature of the aryl group on the benzyl acrylate appear to influence the reaction.Heteroaromatic rings, such as thiophene and pyridine ((R,S)-7ac, 7ad, and 7af), are especially compatible with this synthesis, and the yields range from 47% to 56%.For the cases of (R,S)-7ba and (R,S)-7bb, in which the n-butyl group in (R,R)-5a was replaced with isopropyl and isobutyl groups, respectively, stable rotamers were shown as expected.The opposite configuration of building block (S,S)-5a can also be smoothly converted into the corresponding orientational isomer (S,R)-7bc′ with a chemical yield of 55%.

Computational and VT NMR Studies
All DFT calculations were performed with the Gaussian 16 package [62].T geometry optimizations of minima were carried out for the B3LYP-D3(BJ) function [63,64] and the 6-31G(d,p) [65,66] basis sets.The vibrational frequencies were comput at the same level to check whether each optimized structure was an energy minimu (zero imaginary frequency) and to evaluate its zero-point vibration energy (ZPE) a thermal corrections at 323.15 K in kcal‧mol −1 .The single-point energies and solvent effe in triethylamine (ε = 2.3832) were computed with the B3LYP-D3(BJ) function and the 311++G(d,p) basis set using the SMD solvation model [67,68].The DFT-optimiz structures were illustrated using CYLView (Figure 6) [69,70].Scheme 6.Further transformations of orientational products.
The absolute orientational configuration was unambiguously confirmed by the X-ray diffraction analysis of (R)-2-methyl-N-((R)-1-phenyl-1-(4-(8-(p-tolylethynyl)naphthalen-1yl)phenyl)pentyl)propane-2-sulfinamide (R,S)-7bc and its enantiomer (Figure 5).In these two structures, i-propyl is clearly shown to be pushed away by the remote controller on its backside.This structural arrangement of two alkynyl/alkynyl levers is different from that of alkynyl/aryl levers in which the amino branch on the chiral carbon is directed away from the remote blocker.The latter case is similar to that of aryl/aryl lever-based orientational configuration with an alkyl group on the chiral carbon center.However, the present case shows a similar orientation in which the amino branch is pointed away from the plane (Figure 5).

Computational and VT NMR Studies
All DFT calculations were performed with the Gaussian 16 package [62].The geometry optimizations of minima were carried out for the B3LYP-D3(BJ) functional [63,64] and the 6-31G(d,p) [65,66] basis sets.The vibrational frequencies were computed at the same level to check whether each optimized structure was an energy minimum (zero imaginary frequency) and to evaluate its zero-point vibration energy (ZPE) and

Computational and VT NMR Studies
All DFT calculations were performed with the Gaussian 16 package [62].The geometry optimizations of minima were carried out for the B3LYP-D3(BJ) functional [63,64] and the 6-31G(d,p) [65,66] basis sets.The vibrational frequencies were computed at the same level to check whether each optimized structure was an energy minimum (zero imaginary frequency) and to evaluate its zero-point vibration energy (ZPE) and thermal corrections at 323.15 K in kcal•mol −1 .The single-point energies and solvent effects in triethylamine (ε = 2.3832) were computed with the B3LYP-D3(BJ) function and the 6-311++G(d,p) basis set using the SMD solvation model [67,68].The DFT-optimized structures were illustrated using CYLView (Figure 6) [69,70].We also conducted variable temperature NMR (VT NMR) experiments to explore the stability of orientational isomer 7bc (Figure 7).The variable temperature spectra were acquired in 10-degree increments in the range of 25 °C to 55 °C.As shown in Figure 7 and the Supplementary Materials (pp SI 76), after undergoing VT-NMR, we can clearly see that the chemical shifts in protons and carbons in all corresponding functionality remain consistent.This indicates that the structure shown in the 7bc is a stable isomer within this temperature range.We also conducted variable temperature NMR (VT NMR) experiments to explore the stability of orientational isomer 7bc (Figure 7).The variable temperature spectra were acquired in 10-degree increments in the range of 25 • C to 55 • C. As shown in Figure 7 and the Supplementary Materials (pp SI 76), after undergoing VT-NMR, we can clearly see that the chemical shifts in protons and carbons in all corresponding functionality remain consistent.This indicates that the structure shown in the 7bc is a stable isomer within this temperature range.
stability of orientational isomer 7bc (Figure 7).The variable temperature spectra were acquired in 10-degree increments in the range of 25 °C to 55 °C.As shown in Figure 7 and the Supplementary Materials (pp SI 76), after undergoing VT-NMR, we can clearly see that the chemical shifts in protons and carbons in all corresponding functionality remain consistent.This indicates that the structure shown in the 7bc is a stable isomer within this temperature range.

Conclusions
We conducted the design and asymmetric synthesis of a series of chiral targets of orientational chirality by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira coupling catalysis.Orientational isomers were readily controlled through alkynyl/alkynyl levers [C(sp)-C(sp) axis], and unambiguously determined by X-ray structural analysis.The key structural element of the resulting orientational chirality is characterized by remote through-space blocking.Forty examples of multi-step synthesis were performed, exhibiting modest to good yields and excellent orientational selectivity.It is worth noting that several of the resulting orientational amino targets are attached with scaffolds of natural and medicinal products, including D-menthol, L-menthol, vitamin C, pregnenolone, and estrone, showing their potential for pharmaceutical and medicinal applications in the future, especially for amino acid-and peptide-derivatized targets when the aliphatic or aromatic branches are replaced by carboxylic acid groups.Further physical organic chemistry studies of new orientational compounds will be conducted in due course [50][51][52][53]71].

Figure 7 .
Figure 7. 1 H VT-NMR spectra of 7bc in CDCl3 (more spectra are provided in SI).Figure 7. 1 H VT-NMR spectra of 7bc in CDCl 3 (more spectra are provided in SI).

Figure 7 .
Figure 7. 1 H VT-NMR spectra of 7bc in CDCl3 (more spectra are provided in SI).Figure 7. 1 H VT-NMR spectra of 7bc in CDCl 3 (more spectra are provided in SI).

Table 1 .
Optimization of the reaction conditions.

Table 1 .
Optimization of the reaction conditions.