An Ultimate Stereocontrol in Supramolecular Photochirogenesis

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An Ultimate Stereocontrol in Supramolecular Photochirogenesis. Photocyclodimerization of 2-Anthracenecarboxylate Mediated by Sulfur-Linked #-Cyclodextrin Dimers Jiecheng Ji, Wanhua Wu, Wenting Liang, Guo Cheng, Ryohei Matsushita, Zhiqiang Yan, Xueqin Wei, Ming Rao, De-Qi Yuan, Gaku Fukuhara, Tadashi Mori, Yoshihisa Inoue, and Cheng Yang J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2019 Downloaded from http://pubs.acs.org on May 22, 2019

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Journal of the American Chemical Society 1

An Ultimate Stereocontrol in Supramolecular Photochirogenesis. Photocyclodimerization of 2Anthracenecarboxylate Mediated by Sulfur-Linked βCyclodextrin Dimers

Jiecheng Ji,† Wanhua Wu,† Wenting Liang,‡ Guo Cheng,† Ryohei Matsushita,§ Zhiqiang Yan,† Xueqin Wei,† Ming Rao,† De-qi Yuan,*, Gaku Fukuhara,‖ Tadashi Mori,§ Yoshihisa Inoue,*,§ and Cheng Yang*,†

†

Key Laboratory of Green Chemistry & Technology, College of Chemistry, State Key Laboratory of Biotherapy, West China Medical Center, and Healthy Food Evaluation Research Center, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China ‡ Institute of Environmental Sciences, Department of Chemistry, Shanxi University, Taiyuan 030006, China § Department of Applied Chemistry, Osaka University, Yamada-oka 2-1, Suita565-0871, Japan  Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe 650-8586, Japan ‖ Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku 1528551, Japan E-mails: [email protected]; [email protected]; [email protected]

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ABSTRACT: Stereoisomeric β-cyclodextrin (CD) dimers linked with a sulfur atom or an arene spacer were designed to create a tethered dual CD capsule for precisely manipulating the regioand enantio-selectivities of the photocyclodimerization of 2‑anthracenecarboxylate (AC) to four stereoisomeric classical 9,10:9’,10’-cyclodimers and two nonclassical 5,8:9’,10’cyclodimers. Among the dimeric CD hosts prepared, exo-3-thia-β-CD dimer formed 1:1 and 1:2 host-guest complexes with AC in aqueous solutions, the former of which hindered but the latter facilitated the AC photocyclodimerization with regio- and enantioselectivities much higher than those obtained with native β-CD or the rest of the β-CD dimers. The stereochemical outcomes turned out to be highly sensitive to and hence critically manipulable by the linking position and configuration of the connected saccharide units and the linker length, as well as the external variants, such as temperature, pH, and added salt. Eventually, the photocyclodimerization of AC mediated by the dimeric β-CD host gave enantiopure syn-headto-tail-9,10:9’,10’-cyclodimer in 97-98% yield in a pH 5.1 buffer solution at 0.5 °C and also in an aqueous CsCl solution at -20 °C.


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INTRODUCTION Inducing molecular chirality in the ground state through (organo)catalytic, enzymatic, and photoredox reactions has been one of the most intensively investigated subjects in modern chemistry. The compiled results and insights derived therefrom greatly facilitate the elucidation of the controlling factors and plausible stereodifferentiation mechanisms operative in related reactions and also provide universal, powerful implements for designing reasonable synthetic routes and choosing suitable catalysts, substrates, and conditions for gaining optimal stereochemical outcomes.1 In keen contrast, similar attempts to induce chirality in the electronically excited state, or photochirogenesis, have met major challenges in obtaining satisfactory chemical and optical yields due to the highly energetic, short-lived, reactive, and hence less-selective nature of excited-state molecules.2 However, some of the difficulties have been demonstrated to be removable or circumventable by employing the supramolecular approach that allows the dual use of chiral host environment in the ground and excited states.3 In a typical supramolecular photochirogenic reaction, the overall stereochemical outcome is governed in principle by three factors: (1) the thermodynamics upon interaction of prochiral guest substrate (G) with chiral host (H) in the ground state to form a pair of diastereomeric HG complexes with different association constants, (2) the spectroscopy upon photoexcitation of the H-G complex pair to the excited state with different extinction coefficients, and (3) the kinetics upon photochemical transformation of the excited complex pair at different rates. Over the past two decades, supramolecular photochirogenesis has been demonstrated promising in efficiently controlling the stereoselectivity of photoreactions.3 Chiral molecular hosts,4 templates,5 liquid crystals,6 molecular aggregates,7 and biomacromolecules8 have been exploited for this purpose to achieve good to excellent optical yields. As external influencers, the environmental variants, such as solvent, temperature, pressure, and irradiation wavelength, have also been employed to augment the stereoselectivity.9 Nevertheless, rational systematic approaches, beyond the trial-and-error basis, have rarely been proposed or executed for enhancing the stereochemical outcomes of supramolecular photochirogenic reactions, most probably due to the diversity and complexity of the host-guest systems as well as the labile



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nature of the excited states involved, all of which make it elusive to extract common features and establish general concepts or guiding principles. Photocyclodimerization of 2-anthracenecarboxylate (AC, X = CO2‒ in Scheme 1) is one of the most comprehensively investigated supramolecular photochirogenic reactions by several research groups and now becomes a sort of benchmark reaction for evaluating the supramolecular photochirogenic ability or performance of a given chiral host.6-10 So far, the most successful stereochemical control of excited-state reaction was attained in the photocyclodimerization of AC included in the hydrophobic binding pocket of canine serum albumin, affording syn-head-to-tail-cyclodimer (2) of 97% enantiomeric excess (ee) in 77% yield.8a,11 However, the origin of the excellent photochirogenic performance displayed by the protein of 66 kDa with a highly sophisticated 3D structure,12 though speculated, is not straightforward to unambiguously elucidate in detail. On the contrary, no artificial or semisynthetic chiral hosts have ever reached such a level of stereoselectivity in mediating excitedstate reactions, which makes the rational design of unsophisticated chiral host that achieves a comparable or higher level of stereocontrol a great challenge. Upon photoirradiation in aqueous media, AC cyclodimerizes to 9,10:9’10’-dimers 1-4 (Scheme 1). γ-Cyclodextrin (γ-CD) is known to significantly accelerate the photocyclodimerization by simultaneously accommodating two ACs in its cavity, but the level of stereocontrol is not satisfactory even after the optimization of reaction conditions, affording all of the anti/syn-isomeric head-to-tail (HT) and head-to-head (HH) cyclodimers 1-4 in varying ratios and chiral 2 and 3 in modest enantioselectivities (0-42% ee).9d,13 Recently, we found that smaller-sized β-CD also expedites the photocyclodimerization by forming a 2:2 complex with AC, in which two ACs are sled-parallel stacked in an in-situ capsule composed of two facing β-CDs and upon irradiation afford unprecedented 5,8:9’10’-cyclodimers 5 and 6 (Scheme 1), along with classical 9,10:9’10’-cyclodimer 1 and much smaller amounts of 2-4.14 Despite the significant endeavors to suppress the formation of the classical cyclodimers, for example, by introducing cationic substituents on the primary rim of β-CD (for electrostatically pulling each of the already sled ACs pair out of the CD capsule in the opposite directions), the anti/syn (or


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5/6) selectivity of the nonclassical cyclodimers and the ee of the major product (5) remained far from the perfection even under the optimized conditions (i.e., 80% yield and 71% ee).14

Scheme 1. Supramolecular Photocyclodimerization of 2-Anthracenecarboxylate (AC) to Classical 9,10:9’,10’-Cyclodimers (1-4) and Nonclassical Slipped 5,8:9’,10’-Cyclodimers (5 and 6) via 2:2 Complexation with β-Cyclodextrin (β-CD) X

X

X

h

X

-CD

AC (X=CO2-)

X

1 anti-9,10:9',10'-HT

X

+

X

2

X

+

X

+

3

X

X

+

X

4

syn-9,10:9',10'-HT anti-9,10:9',10'-HH syn-9,10:9',10'-HH

+

X

5

6

anti-5,8:9',10'-HT

syn-5,8:9',10'-HT

Later consideration has led us to an idea that the rotatable top/bottom hemisphere structure, as well as the temporal nature, of the dual CD capsule formed in situ, which allows flexible fitting to multiple stereoisomeric AC pairs to produce the corresponding precursor complexes of comparable energies (vide infra), is a major origin of the rather random product distribution obtained with native β-CD and the imperfect anti/syn- and enantio-selectivities even with the cation-modified β-CDs under the optimized conditions. To substantiate this hypothesis and derive guiding principles therefrom, we designed and synthesized a series of stereoisomeric βCD dimers (7-13) with various tethers, in which two out of endo-2-glucosyl (2Gn), exo-2altrosyl (2Ax), endo-3-altrosyl (3An), and exo-3-glucosyl (3Gx) units were linked together with a sulfur atom (as the shortest tether) or an arene spacer (to extend the capsule size) in order to scrutinize the effects of the tethering itself and the pivot position, angle, and configuration as well as the tether length on the photo- and stereochemical consequences (Figure 1). This systematic study enabled us indeed to reveal the factors and mechanism operative in the supramolecular photochirogenesis, to achieve the ultimate stereocontrol of the supramolecular photocyclodimerization of AC, and further to establish the reliable guiding principles potentially applicable to a broader range of supramolecular photochirogeneses.



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OH OH O O

O

O O

O

O

O HO HO

O O

O

O OH

OH HO OH OH HO HO OH m

OO

HO

O O

HO

OO

HO HO

HO OH OH

HO OH

O

HO

O

O HO O HO O HO O O O

OH OH

OH

O O OO

HO

HO

O

O

O O O O

HO

OH

HO O

OH

HO

OH

O

O

OH OH OH

OO

O

OH

OO

O O OO

HO

OH

O

HO

HO HO

O O OO

HO

HO

O O OO O

HO

OH O

OH

HO HO HOHO

S

OH HO

OH OH

O O

O O HO HO O HO HO

O

OH O

O

OH OH

OH O

OH

OH OO OH HO HO O OH O HO O O OHOH O OH OH

9 (2Gn-N-2Gn) O

O OO

HO

HO O HO O OH HOHO O OH OO HO OH HO OO OH O HO O O OH HO HO OO OH OH HO HO O O O HO HO

OH

HO

HO O O O HO HO

OH OH O OH

OH

HO O O HO HO

OH

8 (2Gn-B-2Gn) HO HO

HO

OH OH OH O O

O

OH

HO

OHOH OH OH

OH

7 (2Gn-2Gn)

HO HO HOHO

OH

HO HO HO

OH OH O OH

OH

OH

OH OH OH OH

O

-CD (m = 1) -CD (m = 2)

HO HO

OH O HO OH HO O OH O OH O OH S HO O O OH OH O OH O OH HO HO

O

OO

OH OH OH OH

HO O

O OH OO OH HO HO OH HO OO OH HO O OH O OH HO HO O HO O O O O OH OH HO O OH HO OH

HO

O OH

OO O

OO

HO HO O HO O O O

S

O HO

O

OH HO HO O O

OH

O

HO

O

OH

OO

HO HO

OH HO HO OH

OH OH OH

OH OH OH OH

HO

O

OH OH OH

O O

HO O O

OH OH O O

HO HO O OO HO HO

OH OH

HO HO

10 (2Ax-3Gx)

11 (3An-3An)

OH HO O OH HO O OH O OH HOHO O OH OH O O O O OH OH S HO HO O O O OH O HO OH HO HO O O OH O O OH OH HO O HO O OH HO HO O OH O HO O O OH OHOH HO HO O O O O OH HO OH HO

OH HO OH HO O HO O O O OH OH S HO HO OH O O O HO O O OH O HO OH HO HO O O OH OH OO OH HO O HO OH O OH HO O O OH HO O O HO OH HO OH HO OO OH O HO O O OH OH HO HO OH O OH OO HO

12 (3Gx-3Gx)

13 (6G-6G)

HO HO

O O

Figure 1. Native β- and γ-cyclodextrins (CDs) and sulfur- or arene-bridged β-CD dimers employed as chiral hosts for mediating the photocyclodimerization of 2-anthracenecarboxylate. Abbreviations of the saccharide units used for linking: 2Ax = exo-2-altrosyl; 2Gn = endo-2glucosyl; 3An = endo-3-altrosyl; 3Gx = exo-3-glucosyl; 6G = 6-glucosyl.

RESULTS AND DISCUSSION Syntheses of β-CD Dimers. A series of stereoisomeric sulfur-bridged β-CD dimers (Figure 1) were synthesized by reacting 2A,3A-mannoepoxy-β-CD or 2A,3A-alloepoxy-β-CD14 with sodium sulfide in N,N-dimethylformamide (DMF) under argon (Scheme S1, Figures S1S6, and S19-29).15 We have already shown that the reaction of 2A,3A-mannoepoxy-β-CD with


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sodium sulfide affords sulfur-bridged β-CD dimers 7 (2Gn-2Gn) and 11 (3An-3An),16 where the epoxy-ring opening caused by the backside attack of sulfur anion at the mannoepoxy’s 2- and 3-position converts the mannose unit to glucose and altrose unit, respectively. These sulfursubstituted intermediates were further reacted with 2A,3A-mannoepoxy-β-CD to selectively afford homo-linked CD dimers 7 and 11 as sole products without forming any cross-linked βCD dimer (2Gn-3An) for some steric reasons.16 In both of the CD dimers, two CD units are connected with an endo-thia-linkage at the saccharide’s 2- or 3-position. Since the linking position and configuration as well as the type of saccharide residue should shape the coupled CD cavities and hence the complexation and subsequent photochirogenic performances, we decided to expand the range of stereoisomeric β-CD dimers to exo-thia-bridged analogues. This was made possible by using 2A,3A-alloepoxy-β-CD as a starting material in the above-mentioned reaction under slightly modified conditions.15 Interestingly, only two out of the four possible CD dimers were isolated in 40% and 33% yield by reverse-phase HPLC. The sulfur-bridged β-CD dimers thus obtained gave the exact molecular masses assignable to the [M + Na]+ ions.15 One- and two-dimensional NMR spectral examinations15 allowed us to conclude that two β-CD units are connected with sulfur at the exo-2-position of the altrose residue of one β-CD unit and the exo-3-position of the glucose residue of the other unit in the former CD dimer, while at the exo-3-positions of the glucose residues in the latter. Thus, these two sulfur-bridged β-CD dimers obtained in higher and lower yields were assigned as 10 (2Ax-3Gx) and 12 (3Gx-3Gx), respectively. To the best of our knowledge, 10 is the first unsymmetrical CD dimer linked on the secondary rim. To

explore

how

the

inter-CD

distance

affects

the

stereoselectivities

of

photocyclodimerization, tether-elongated CD dimers 8 (2Gn-B-2Gn) and 9 (2Gn-N-2Gn), in which a p-xylylene or 2,6-naphthylenedimethylene spacer was inserted into the two CD units of 7 (2Gn-2Gn), were also synthesized by reacting β-CD with 1,4-bis(chloromethyl)benzene or 2,6-bis(bromomethyl)naphthalene, respectively, in the presence of sodium hydride in DMF. The CD dimers purified by reverse-phase column chromatography were characterized by HRMS and NMR spectral examinations. The HR-MS analyses gave the exact masses of m/z 2393.7023 and 2444.7904 assignable to the [M + Na]+ ions of 8 and 9, respectively, while their



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2D NMR spectra revealed that the two CD units are linked together at the endo-2-position of a glucose unit in both of the CD dimers (Figures S7-S18).15 Enantiodifferentiating Photocyclodimerization of AC with Stereoisomeric β-CD Dimers. For a quick grasp of the whole picture of the AC photocyclodimerization mediated by CD dimers, we first present the most plausible mechanism in Scheme 2, which was derived from the analyses of the experimental results obtained under a variety of conditions (vide infra). Briefly, in this mechanism, AC first forms a 1:1 complex with β-CD dimer (K1), which is photoinert and binds another AC (K2) or disproportionates (Kdisp) to afford a 1:2 complex. Upon irradiation, the AC pair in 1:2 complex cyclodimerizes to AC dimer, which is size-expanded and hence spontaneously decomplexed from the capsule, regenerating free CD dimer for the use in the next catalytic cycle.

Scheme 2. A Plausible Mechanism for the Supramolecular Photocyclodimerization of AC Mediated by β-CD Dimer via 1:1 and 1:2 Complexes disproportionation H

-

H+ +

K1

-

H+ +

K2

AC-

photoinert reservoir H

h H

-CD dimer

-

photoreactive H

h

2H+ +

AC dimer

H


Kdisp

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For a screening purpose, all of the β-CD dimers prepared above, as well as parent β-CD and reference γ-CD, were employed as chiral supramolecular hosts for mediating the photocyclodimerization of AC conducted under our standard conditions. Thus, the sample was irradiated at 365 nm in a pH 7.1 phosphate buffer at 0.5 C under Ar using a 100-mW LED as a monochromatic light source. The photolyzed sample was subjected to chiral HPCL analysis for determining the distribution of 1-6 and the ee’s of chiral 2, 3, 5, and 6;15 the reaction was clean without showing any side products in appreciable quantities and the yields based on conversion were essentially equivalent to the product distribution. The results are summarized in Table 1. Table 1. Supramolecular Photocyclodimerization of 2‑Anthracenecarboxylate (AC) Mediated by Native and Dimeric Cyclodextrin Hosts in Phosphate Buffer (pH 7.1) at 0.5 Ca yield/%

conversion/%

1

2

3

4

5

6

γ-CD

100

38

47

8

7

0

0

0

β-CDf

94

49

1

1

0

35

14

7 (2Gn-2Gn)

60

52

15

23

4

4

8 (2Gn-B-2Gn)

97

84

8

5

1

9 (2Gn-N-2Gn)

96

82

7

2

10 (2Ax-3Gx)

7

37

24

11 (3An-3An)

13

39

12 (3Gx-3Gx)

5

13 (6G-6G)

64

host

% non% HTc classicalb

% eed 2

3

5

6

85

42

1

e

e

49

99

8

-5

46

12

2

6

73

-6

12

-14

-40

1

1

2

94

7

-25

78

43

1

6

2

8

97

-22

-3

70

40

12

7

14

6

20

81

-20

-11

45

-29

25

27

9

0

0

0

64

6

23

e

e

32

59

8

1

0

0

0

91

-82

16

e

e

72

5

2

0

15

6

21

98

-25

-64

39

14

a [AC]

= 0.2 mM, [host] = 2 mM; irradiated at 365 nm for 30 min with a 100-mW LED, unless stated otherwise. b Nonclassical cyclodimer content: [(5 + 6)/(1 + 2 + 3 + 4 + 5 + 6)] x 100. c HT-cyclodimer content [(1 + 2 + 5 + 6)/(1 + 2 + 3 + 4 + 5 + 6)] x 100. d Enantiomeric excess determined by chiral HPLC analysis;15 the first/second elutes are given positive/negative signs, respectively. e Not determined due to the extremely low yield (

An Ultimate Stereocontrol in Supramolecular Photochirogenesis

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