Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Reduction of Capsorubin and Cryptocapsin

(6′S)‐ and (6′R)‐‘Capsorubol‐6‐one' (=(3S,3′S,5R,5′R,6′S)‐ and (3S,3′S,5R,5′R,6′R)‐3,3′,6′‐trihydroxy‐κ,κ‐caroten‐6‐one; 8 and 9 , resp.), (6S,6′R)‐ and (6R,6′R)‐capsorubol (=3S,3′S,5R,5′R,6S,6′R)‐ and (3S,3′S,5R,5′R,6R,6′R)‐κ,κ‐carotene‐3,3′,6,6′‐tetrol; 11 and 12 , resp.) and (6′S)‐ and (6′R)‐cryptocapsol (=(3′S,5′R,6′S)‐ and (3′S,5′R,6′R)‐β,κ‐carotene‐3′,6′‐diol; 5 and 6 , resp.) were prepared in crystalline from by the reduction of capsorubin (=(3S,3′S,5R,5′R)‐3,3′‐dihydroxy‐κ,κ‐carotene‐6,6′‐dione; 7 ) and cryptocapsin (=(3′S,5′R)‐3′‐hydroxy‐β,κ‐caroten‐6′‐one; 4 ) and characterized by their UV/VIS, CD, ¹H‐NMR, and mass spectra.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines: Synthesis of Synthons for Tyr(2Me) and Dopa(2Me), and Their Incorporation into Dipeptides

The synthesis of novel unsymmetrically 2,2‐disubstituted 2H‐azirin‐3‐amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)‐ 2a , b and (1′R,2R)‐ 2a , b (c.f. Scheme 1 and Table 1), which are synthons for (S)‐ and (R)‐2‐methyltyrosine and 2‐methyl‐3′,4′‐dihydroxyphenylalanine. Another new synthon 2c , i.e., a synthon for 2‐(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc‐Val‐OH yielded the monothiodiamides 11 , the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13 , each protecting group was removed selectively under standard conditions (cf. Schemes 5–7 and Tables 5–6). The configuration at C(2) of the amino acid derivatives (1R,1′R)‐ 11a , (1R,1′R)‐ 11b , (1S,1′R)‐ 12b , and (1R,1′R)‐ 12b was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group.     

1,3‐Oxathiolanes from the Reaction of Aromatic and Enolized Thioketones with Monosubstituted Oxiranes

The reactions of 4,4′‐dimethoxythiobenzophenone ( 1 ) with (S)‐2‐methyloxirane ((S)‐ 2 ) and (R)‐2‐phenyloxirane ((R)‐ 6 ) in the presence of a Lewis acid such as BF₃?Et₂O, ZnCl₂, or SiO₂ in dry CH₂Cl₂ led to the corresponding 1 : 1 adducts, i.e., 1,3‐oxathiolanes (S)‐ 3 with Me at C(5), and (S)‐ 7 and (R)‐ 8 with Ph at C(4) and C(5), respectively. A 1 : 2 adduct, 1,3,6‐dioxathiocane (4S,8S)‐ 4 and 1,3‐dioxolane (S)‐ 9 , respectively, were formed as minor products (Schemes 3 and 5, Tables 1 and 2). Treatment of the 1 : 1 adduct (S)‐ 3 with (S)‐ 2 and BF₃?Et₂O gave the 1 : 2 adduct (4S,8S)‐ 4 (Scheme 4). In the case of the enolized thioketone 1,3‐diphenylprop‐1‐ene‐2‐thiol ( 10 ) with (S)‐ 2 and (R)‐ 6 in the presence of SiO₂, the enesulfanyl alcohols (1′Z,2S)‐ 11 and (1′E,2S)‐ 11 , and (1′Z,2S)‐ 13 , (1′E,2S)‐ 13 , (1′Z,1R)‐ 15 , and (1′E,1R)‐ 15 , respectively, as well as a 1,3‐oxathiolane (S)‐ 14 were formed (Schemes 6 and 8). In the presence of HCl, the enesulfanyl alcohols (1′Z,2S)‐ 11 , (1′Z,2S)‐ 13 , (1′E,2S)‐ 13 , (1′Z,1R)‐ 15 , and (1′E,1R)‐ 15 cyclize to give the corresponding 1,3‐oxathiolanes (S)‐ 12 , (S)‐ 14 , and (R)‐ 16 , respectively (Schemes 7, 9, and 10). The structures of (1′E,2S)‐ 11 , (S)‐ 12 , and (S)‐ 14 were confirmed by X‐ray crystallography (Figs. 1–3). These results show that 1,3‐oxathiolanes can be prepared directly via the Lewis acid‐catalyzed reactions of oxiranes with non‐enolizable thioketones, and also in two steps with enolized thioketones. The nucleophilic attack of the thiocarbonyl or enesulfanyl S‐atom at the Lewis acid‐complexed oxirane ring proceeds with high regio‐ and stereoselectivity via an S_n 2‐type mechanism.     

Preparation and (E/Z)‐Isomerization of the Diastereoisomers of Violaxanthin

Violaxanthin A (=(all‐E,3S,5S,6R,3′S,5′S,6′R)‐5,6 : 5′,6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐3,3′‐diol =syn,syn‐violaxanthin; 5 ) and violaxanthin B (=(all‐E,3S,5S,6R,3′S,5′R,6′S)‐5,6 : 5′,6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐3,3′‐diol=syn,anti‐violaxanthin; 6 ) were prepared by epoxidation of zeaxanthin diacetate ( 1 ) with monoperphthalic acid. Violaxanthins 5 and 6 were submitted to thermal isomerization and I₂‐catalyzed photoisomerization. The structure of the main products, i.e., (9Z)‐ 5 , (13Z)‐ 5 , (9Z)‐ 6 , (9′Z)‐ 6 , (13Z)‐ 6 , and (13′Z)‐ 6 , was determined by their UV/VIS, CD, ¹H‐NMR, ¹³C‐NMR, and mass spectra.     

Preparation of Partially Acetylated Carotenoids

Partially acetylated carotenoids were prepared from fully acetylated carotenoids by reaction with NaBH₄, and were characterized by UV/VIS, CD, ¹H‐NMR and mass spectra. The 3,6′‐diacetate, 3′,6′‐diacetate, and 6′‐acetate 10 – 12 , respectively, of (6′R)‐capsanthol (=(3R,3′S,5′R,6′R)‐β,κ‐carotene‐3,3′,6′‐triol; 4 ) were obtained from (6′R)‐capsanthol‐3,3′,6′‐triacetate ( 9 ), and the 3‐ and 3′‐acetates 13 and 14 , respectively, of 4 from (6′R)‐capsanthol 3,3′‐diacetate ( 8 ). The utility of this method was also demonstrated by the preparation of zeaxanthin and lutein monoacetates 16, 19 , and 20 .     

Stereoselective Reduction of `Capsanthol‐3′‐ones' (=3,6′‐Dihydroxy‐β,κ‐caroten‐3′‐ones) by Complex Hydrides

The (3R,5′R,6′R)‐ and (3R,5′R,6′S)‐capsanthol‐3′‐one (=3,6′‐dihydroxy‐β,κ‐caroten‐3′‐one; 4 and 5 , resp.) were reduced by different complex metal hydrides containing organic ligands. The ratio of the thus obtained diastereoisomeric (3′S)‐capsanthols 2 and 3 or (3′R)‐capsanthols 6 and 7 , respectively, was investigated. Four complex hydrides showed remarkable stereoselectivity and produced the (3′R,6′S)‐capsanthol ( 6 ) in 80 – 100% (see Table 1). The starting materials and the products were characterized by UV/VIS, CD, ¹H‐ and ¹³C‐NMR, and mass spectra.     

Atropselective Dibrominations of a 1,1′‐Disubstituted 2,2′‐Biindolyl with Diverging Point‐to‐Axial Asymmetric Inductions. Deriving 2,2′‐Biindolyl‐3,3′‐diphosphane Ligands for Asymmetric Catalysis

On the ¹H NMR timescale, 2,2′‐biindolyls with (R)‐configured (1‐alkoxyprop)‐2‐yl, (1‐hydroxyprop)‐2‐yl, or (1‐siloxyprop)‐2‐yl substituents at C‐1 and C‐1′ are atropisomerically stable at <0 °C and interconvert at >30 °C. A 2,2′‐biindolyl (R,R)‐ 17 a of that kind and achiral (!) brominating reagents gave the atropisomerically stable 3,3′‐dibromobiindolyls (M)‐ and/or (P)‐ 18 a at best atropselectively—because of point‐to‐axial asymmetric inductions—and atropdivergently, exhibiting up to 95 % (M)‐ and as much (P)‐atropselectivity. This route to atropisomerically pure biaryls is novel and should extend to other substrates and/or different functionalizations. The dibromobiindolyls (M)‐ and (P)‐ 18 a furnished the biindolyldiphosphanes (M)‐ and (P)‐ 14 without atropisomerization. These syntheses did not require the resolution of a racemic mixture, which distinguishes them from virtually all biaryldiphosphane syntheses known to date. (M)‐ and (P)‐ 14 acted as ligands in catalytic asymmetric allylations and hydrogenations. Remarkably, the β‐ketoester rac‐ 25 c was hydrogenated trans‐selectively with 98 % ee; this included a dynamic kinetic resolution.     

(E/Z)‐Isomerization of 3′‐Epilutein

3′‐Epilutein (=(all‐E,3R,3′S,6′R)‐4′,5′‐didehydro‐5′,6′‐dihydro‐β,β‐carotene‐3,3′‐diol; 1 ), isolated from the flowers of Caltha palustris, was submitted to both thermal isomerization and I₂‐catalyzed photoisomerization. The structures of the main products (9Z)‐ 1 , (9′Z)‐ 1 , (13Z)‐ 1 , (13′Z)‐ 1 , (15Z)‐ 1 , and (9Z,9′Z)‐ 1 were determined based on UV/VIS, CD, ¹H‐NMR, and MS data.     

Molecular Switching: A Fully Reversible,Optically Active Photochemical Switch Based on a Tetraethynylethene‐1,1′‐Binaphthalene Hybrid System

The synthesis, characterization, and physical properties of a novel, fully reversible, light‐driven molecular switch, (R,R)‐ 1 /(R,R)‐ 2 , based on a tetraethynylethene‐1,1′‐binaphthalene hybrid system are presented. trans‐Configured (R,R)‐ 1 was synthesized in 57% yield by Stille cross‐coupling between stannylated tetraethynylethene 3 and 3‐iodo‐1,1′‐binaphthalene derivative (R)‐ 4 (cf. Scheme 2). The cis‐isomer (R,R)‐ 2 was prepared from (R,R)‐ 1 by photoisomerization. X‐Ray crystal‐structure analyses were obtained for both cis‐ and trans‐forms of the photoswitch (Figs. 1 and 2). In the crystalline state, molecules of the cis‐isomer (R,R)‐ 2 exhibit intramolecular edge‐to‐face (C−H⋅⋅⋅π) interactions between naphthalene rings of the two 1,1‐binaphthalene moieties (Fig. 3). The switching properties were investigated by electronic absorption spectroscopy (Table and Fig. 4): irradiation at λ=398 nm converts trans‐isomer (R,R)‐ 1 into cis‐isomer (R,R)‐ 2 , whereas switching occurs in the opposite direction upon irradiation at λ=323 nm. No thermal interconversion between the two isomers was observed in CH₂Cl₂ at room temperature over a period of 2 – 3 months, and the system possesses good resistance against photofatigue (Fig. 5). Investigations of the circular dichroism of (R,R)‐ 1 and (R,R)‐ 2 in CH₂Cl₂ solution showed that the chiral binaphthalene moieties induce a weak Cotton effect in the achiral tetraethynylethene core (Fig. 6). System (R,R)‐ 1 /(R,R)‐ 2 represents one of the rare switches allowing two‐way photochemical interconversions, not perturbed by thermal‐isomerization pathways.     

Helical Structures of Bicyclic α‐Amino Acid Homochiral Oligomers with the Stereogenic Centers at the Side‐Chain Fused‐Ring Junctions

Chiral bicyclic α‐amino acid (R,R)‐Ab_5,6=c with stereogenic centers at the γ‐position of fused‐ring junctions, and its enantiomer (S,S)‐Ab_5,6=c, were synthesized. The CD spectra of (R,R)‐Ab_5,6=c oligomers indicated that the (R,R)‐Ab_5,6=c hexapeptide formed a mixture of right‐handed (P)‐ and left‐handed (M)‐3₁₀‐helices, while, in the (R,R)‐Ab_5,6=c nonapeptide, a right‐handed (P)‐3₁₀‐helix slightly dominated over the (M)‐helix. X‐Ray crystallographic analyses of (S,S)‐tripeptide and (R,R)‐hexapeptide revealed that both the tripeptide and hexapeptide formed a mixture of (P)‐ and (M)‐3₁₀‐helices, respectively. These results indicated that the side‐chain environments around the stereogenic centers are particularly important to control the helical‐screw handedness of foldamers.     

Isomerization of (all‐E)‐Cucurbitaxanthin A

Cucurbitaxanthin A (=(all‐E,3S,5R,6R,3′R)‐3,6‐epoxy‐5,6‐dihydro‐β,β‐carotene‐5,3′‐diol; 1 ) was submitted to thermal isomerization and to I₂‐catalysed photoisomerization. The structure of the main reaction products (9Z)‐ ( 2 ), (9′Z)‐ ( 3 ), (13Z)‐ ( 4 ), and (13′Z)‐cucurbitaxanthin A ( 5 ) was determined by their UV/VIS, CD, ¹H‐NMR, and mass spectra.     

Enantioselectivity in Odor Perception

The 3‐methyl‐4‐(tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ylidene)butan‐2‐ols (=Fleursandol^®; rac‐ 10 ), a new class of sandalwood odorants, were synthesized in their enantiomerically pure forms by use of tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ones 17 and ent‐ 17 and (tetrahydro‐2H‐pyran‐2‐yl)‐protected 4‐bromo‐3‐methylbutan‐2‐ols 22 and ent‐ 22 as starting materials (Schemes 2–4). Only four of 16 possible stereoisomers of rac‐ 10 possess the typical, very pleasant, long‐lasting sandalwood odor (Table 1). The (2S,3R,4E,1′R,2′R,6′R,7′R)‐isomer ent‐ 10a is by far the most important representative, with an odor threshold of 5 μg/l in H₂O.     

Synthesis and Asymmetric Enantioselective Addition of Chiral Polybinaphthyl and Polybinaphthol I.igands

Four chiral polymers P-1, P-2, P-3 and P-4 were synthesized by the polymerization of （S）-2,2＇-dioctoxy-1,1＇- binaphthyl-6,6＇-boronic acid （S-M-3） with （S）-6,6＇-dibromo-1,1＇-binaphthol （S-M-1）, （R）-6,6＇-dibromo-1,1＇- binaphthol （R-M-1）, （S）-3,3＇-diiodo-1,1＇-binaphthol （S-M-2） and （R）-3,3＇-diiodo-1,1＇-binaphthol （R-M-2） under Pd-catalyzed Suzuki reaction, respectively. All four polymers can show good solubility in some common solvents due to the nonplanarity of the polymers in the main chain backbone and flexible alkyl groups in the side chain. The analysis results indicate that specific rotation and circular dichroism （CD） spectral signals of the alternative S-S chiral polymers P-1 and P-3 are larger than those of S-R chiral polymers P-2 and P-4, but their UV-Vis and fluorescence spectra are almost similar. The results of asymmetric enantioselectivity of four polymers for diethylzinc addition to benzaldehyde indicate that catalytically active center is （R） or （S）-1, 1＇-binaphthol moieties.     

Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2‐Methoxy‐2‐naphthylpropanoic Acids

The crystal structures of salt 8 , which was prepared from (R)‐2‐methoxy‐2‐(2‐naphthyl)propanoic acid ((R)‐MβNP acid, (R)‐ 2 ) and (R)‐1‐phenylethylamine ((R)‐PEA, (R)‐ 6 ), and salt 9 , which was prepared from (R)‐2‐methoxy‐2‐(1‐naphthyl)propanoic acid ((R)‐MαNP acid, (R)‐ 1 ) and (R)‐1‐(p‐tolyl)ethylamine ((R)‐TEA, (R)‐ 7 ), were determined by X‐ray crystallography. The MβNP and MαNP anions formed ion‐pairs with the PEA and TEA cations, respectively, through a methoxy‐group‐assisted salt bridge and aromatic CH???π interactions. The networks of salt bridges formed 2₁ columns in both salts. Finally, (S)‐(2E,6E)‐(1‐²H₁)farnesol ((S)‐ 13 ) was prepared from the reaction of (2E,6E)‐farnesal ( 11 ) with deuterated (R)‐BINAL‐H (i.e., (R)‐BINAL‐D). The enantiomeric excess of compound (S)‐ 13 was determined by NMR analysis of (S)‐MαNP ester 14 . The solution‐state structures of MαNP esters that were prepared from primary alcohols were also elucidated.     

Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

A Highly Efficient Synthesis of Optically Active Ferrocenylethylamines via Hydride Reduction of Chiral Ferrocenylketimines

Due to using (R)‐ or (S)‐α‐methylbenzylamine as a chiral auxiliary, and low‐temperature regime for reduction of the intermediate ferrocenyl‐mono‐ or 1,1′‐bis‐ketimines, the corresponding secondary mono‐ or 1,1′‐bis‐amines were prepared with high diastereoselectivity. Removal of the α‐methylbenzyl group afforded the optically active primary mono‐ and bis‐ferrocenylethylamines in high yields. The absolute configuration of (R,R)‐ 3a and (S,S)‐ 3b was determined by X‐ray single crystal diffraction.     

(E/Z)‐Isomerization of (all‐E)‐5,6‐Diepikarpoxanthin

(all‐E)‐5,6‐Diepikarpoxanthin (=(all‐E,3S,5S,6S,3′R)‐5,6‐dihydro‐β,β‐carotene‐3,5,6,3′‐tetrol; 1 ) was submitted to thermal isomerization and I₂‐catalyzed photoisomerization. The structures of the main products, i.e. (9Z)‐ ( 2 ), (9′Z)‐ ( 3 ), (13Z)‐ ( 4 ), (13′Z)‐ ( 5 ), and (15Z)‐5,6‐diepikarpoxanthin ( 6 ), were determined by their UV/VIS, CD, ¹H‐NMR, and mass spectra. In addition, (9Z,13′Z)‐ or (13Z,9′Z)‐ ( 7 ), (9Z,9′Z)‐ ( 8 ), and (9Z,13Z)‐ or (9′Z,13′Z)‐5,6‐diepikarpoxanthin ( 9 ) were tentatively identified as minor products of the I₂‐catalyzed photoisomerization.     

New Diarylheptanoids and Kavalactone from Alpinia katsumadai Hayata

Two new diarylheptanoids, katsumains A ( 1 ) and B ( 2 ), and one new kavalactone, katsumadain ( 3 ), together with the three known compounds (4E,6E)‐1,7‐diphenylhepta‐4,6‐dien‐3‐one ( 4 ), (5R,6E)‐1,7‐diphenyl‐5‐hydroxyhept‐6‐en‐3‐one ( 5 ), and cardamonin ( 6 ), were isolated from the seeds of Alpinia katsumadai Hayata . Their structures were elucidated mainly by spectroscopic methods (1D‐ and 2D‐NMR) and by mass spectrometry (HR‐ESI‐MS). Besides, the erroneous nomenclatures for (+)‐linderatin and (+)‐neolinderatin as given in [10] [11] were corrected to be 2′,4′,6′‐trihydroxy‐3′‐[(3R,4R)‐4‐isopropyl‐1‐methylcyclohex‐1‐en‐3‐yl]dihydrochalcone for (+)‐linderatin and 2′,4′,6′‐trihydroxy‐3′,5′‐bis[(3R,4R)‐4‐isopropyl‐1‐methylcyclohex‐1‐en‐3‐yl]dihydrochalcone for (+)‐neolinderatin, respectively.     

Optically Active Cyclophane Receptors for Mono‐ and Disaccharides: The Role of Bidentate Ionic Hydrogen Bonding in Carbohydrate Recognition

A new family of optically active cyclophane receptors for the complexation of mono‐ and disaccharides in competitive protic solvent mixtures is described. Macrocycles (−)‐(R,R,R,R)‐ 1 – 4 feature preorganized binding cavities formed by four 1,1′‐binaphthalene‐2,2′‐diyl phosphate moieties bridged in the 3,3′‐positions by acetylenic or phenylacetylenic spacers. The four phosphodiester groups converge towards the binding cavity and provide efficient bidentate ionic H‐bond acceptor sites (Fig. 2). Benzyloxy groups in the 7,7′‐positions of the 1,1′‐binaphthalene moieties ensure solubility of the nanometer‐sized receptors and prevent undesirable aggregation. The construction of the macrocyclic framework of the four cyclophanes takes advantage of Pd⁰‐catalyzed aryl—acetylene cross‐coupling by the Sonogashira protocol, and oxidative acetylenic homo‐coupling methodology (Schemes 2 and 8 – 10). Several cleft‐type receptors featuring one 1,1′‐binaphthalene‐2,2′‐diyl phosphate moiety were also prepared (Schemes 1, 6, and 7). An undesired side reaction encountered during the synthesis of the target compounds was the formation of naptho[b]furan rings from 3‐ethynylnaphthalene‐2‐ol derivatives, proceeding via 5‐endo‐dig cyclization (Schemes 3 – 5). Computer‐assisted molecular modeling indicated that the macrocycles prefer nonplanar puckered, cyclobutane‐type conformations (Figs. 7 and 8). According to these calculations, receptor (−)‐(R,R,R,R)‐ 1 has, on average, a square binding site, which is complementary in size to one monosaccharide. The three other cyclophanes (−)‐(R,R,R,R)‐ 2 – 4 feature, on average, wider rectangular cavities, providing a good fit to one disaccharide, while being too large for the complexation of one monosaccharide. This substrate selectivity was fully confirmed in ¹H‐NMR binding titrations. The chiroptical properties of the cyclophanes and their nonmacrocyclic precursors were investigated by circular dichroism (CD) spectroscopy. The CD spectra of the acyclic precursors showed a large dependence from the number of 1,1′‐binaphthalene moieties (Fig. 9), and those of the cyclophanes were remarkably influenced by the nature of the functional groups lining the macrocyclic cavity (Fig. 11). Profound differences were also observed between the CD spectra of linear and macrocyclic tetrakis(1,1′‐binaphthalene) scaffolds, which feature very different molecular shapes (Fig. 10). In ¹H‐NMR binding titrations with mono‐ and disaccharides (Fig. 13), concentration ranges were chosen to favor 1 : 1 host−guest binding. This stoichiometry was experimentally established by the curve‐fitting analysis of the titration data and by Job plots. The titration data demonstrate conclusively that the strength of carbohydrate recognition is enhanced with an increasing number of bidentate ionic host−guest H‐bonds (Table 1) in the complex formed. As a result of the formation of these highly stable H‐bonds, carbohydrate complexation in competitive protic solvent mixtures becomes more favorable. Thus, cleft‐type receptors (−)‐(R)‐ 7 and (−)‐(R)‐ 38 with one phosphodiester moiety form weak 1 : 1 complexes only in CD₃CN. In contrast, macrocycle (−)‐(R,R,R,R)‐ 1 with four phosphodiester groups undergoes stable inclusion complexation with monosaccharides in CD₃CN containing 2% CD₃OD. With their larger number of H‐bonding sites, disaccharide substrates bind even more strongly to the four phosphodiester groups lining the cavity of (−)‐(R,R,R,R)‐ 2 and complexation becomes efficient in CD₃CN containing 12% CD₃OD. Finally, the introduction of two additional methyl ester residues further enhances the receptor capacity of (−)‐(R,R,R,R)‐ 3 , and efficient disaccharide complexation occurs already in CD₃CN containing 20% CD₃OD.