Chiroptical Protocol for the Absolute Configurational Assignment of

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Chiroptical Protocol for the Absolute Configurational Assignment of Alkyl-Substituted Epoxides Using Bis(zinc porphyrin) as a CD-Sensitive Bidentate Host Shiori Takeda, Satoshi Hayashi, Masahiro Noji, and Toshikatsu Takanami J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02469 • Publication Date (Web): 14 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018

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Chiroptical Protocol for the Absolute Configurational Assignment of AlkylSubstituted Epoxides Using Bis(zinc porphyrin) as a CD-Sensitive Bidentate Host Shiori Takeda, Satoshi Hayashi, Masahiro Noji and Toshikatsu Takanami* Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

R3

R2 C 6F 5

p-Tol

R1

R4

O

C 6F 5

N N p-Tolp-Tol N N Zn Zn N N N N O

O  (M-1cm-1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

p-Tol (S)

80

O

0

(R)

-80 380

400 420 440 Wavelength (nm)

O

ABSTRACT: The absolute configurations of simple alkyl-substituted chiral epoxides not bearing other ligating groups are readily determined via the exciton-coupled circular dichroism (ECCD) protocol using a bidentate bis(zinc porphyrin) host system BP1 as a CD-sensitive chirality probe. In this situation, chiral epoxides can successfully be incorporated into the cleft of the V-shaped host BP1 by double coordination of both oxygen lone pairs of the guest to the two central zinc ions of the host. We also propose a working model based on an MM2 optimized structure of the substrates that enables nonempirical prediction of the chirality of the bound epoxide.

INTRODUCTION Optically active epoxides are important and highly useful chiral building blocks in synthetic chemistry,1 and consequently, much effort has been devoted to the development of novel and efficient methods for their preparation, such as the catalytic asymmetric epoxidation reactions of olefins.2 The most commonly used technique for the determination of the absolute stereochemistry of optically active epoxides includes NMR analysis3 and exciton-coupled circular dichroism (ECCD)4 of appropriate derivatives of the corresponding ring-opened alcohols such as the Mosher esters and dibenzoates. However, with the exception of those methods based on vibrational circular dichroism

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(VCD),5 which is yet to be established as a routine and common tool for the synthetic community, very little is known about the direct and nonempirical determination of the absolute stereochemistry of chiral epoxides that do not require analyte derivatization.6 Among the few relevant reports, Borhan et al. reported on a fluorinated porphyrin tweezer7 that is capable of undergoing noncovalent coordination with chiral epoxy alcohols, leading to induced asymmetry in the host that gives rise to ECCD spectra, which can be nonempirically and unambiguously correlated to the absolute configuration of the bound guest chiral epoxy alcohols (Figure 1(a)).7a However, to the best of our knowledge, the extension of this sophisticated tweezer methodology to simple alkyl-substituted chiral epoxides not bearing additional functional groups has not yet been addressed. This is mainly because, in order to create a helical disposition of the two porphyrin chromophores forming the tweezer-like structure that produces the ECCD spectra, the guest molecule needs to contain at least two functional groups that can bind to the metalated porphyrin, whereas simple alkyl-substituted chiral epoxides have only one site available for coordination.8 Therefore, further derivatization of simple alkyl-substituted epoxides will still be inevitable. Very recently, Jiang and coworkers used endo-functionalized molecular tubes as an efficient chirality sensor, which can effectively incorporate and recognize chiral epoxides without other functional groups (Figure 1(b)).9 Although this method requires no chemical derivatization, unfortunately, the resulting chiral host–guest complexes lack chromophores that can interact to form exciton couplets, which forces one perform an empirical assignment of the absolute configuration of the guest chiral epoxides instead of the desired nonempirical version. As a consequence, no direct and microscale method that ensures a derivatization-free and nonempirical determination of the chirality of simple alkyl-substituted epoxides has been reported to date. (a) C6F5

C6F5

C6F5 N N Zn N N C6F5 O O

(b)

O O

O

C6F5

O O

O

O O

RO RO

O

O

N HH N OR O OR

C6F5

N N Zn N N

N HH N RO RO

OR O OR

RO

O O

R = CH2CO2NH4, n-Bu

Figure 1. Structures of reported host molecules: (a) Borhan’s fluorinated porphyrin tweezer; (b) Jiang’s


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endo-functionalized molecular tubes.

Recently, our group has developed a direct nonempirical ECCD protocol to determine the absolute configurations of chiral monoalcohols with no chemical derivatization that employs a bidentate bis(zinc porphyrin) host system BP1 having a V-shaped structural motif as a circular dichroic (CD)-sensitive chirality probe (Figure 2).10 The binding affinity of the V-shaped host molecule BP1 with monoalcohols can effectively be enhanced by double coordination of both oxygen lone pairs of the hydroxyl group to the two central zinc ions. By parallel thinking, we envisioned that similar double coordination with both oxygen lone pairs of epoxides would also promote their incorporation into the cleft of the V-shaped host BP1. The resulting host–guest complexes with one favored conformation would provide the corresponding ECCD spectra reflecting the absolute configuration of the guest chiral epoxides. As a new application of this bidentate host system BP1, we herein wish to report a facile, direct assignment of the absolute stereochemistry of simple alkyl-substituted epoxides without other ligating functional groups based on a chemical derivatization-free supramolecular ECCD protocol. A simple working model based on an MM2 optimized structure of the substrates is also proposed, which effectively enables the nonempirical prediction of the chirality of a variety of bound epoxides.

(a) C 6F 5

porphyrin ring

p-Tol

Zn

N N Zn N N

binding site

C 6F 5

p-Tol N N Zn N N p-Tol

Zn

O

p-Tol O

porphyrin ring

Previous work

Zn

R1 R2

BP1

R

O 3

H

Zn

(b) This work: double coordination of the oxygen lone pairs of epoxide Zn

Zn O complexation

Zn

O Zn

Figure 2. (a) Structure of bis(zinc porphyrin) BP1 and schematic of its simultaneous double coordination with monoalcohol (dashed box). (b) Conceptual diagram of the complexation between bidentate host molecule BP1 and simple epoxides.



RESULTS AND DISCUSSION At the outset of this work, (rac)-1,2-epoxybutane 2a was selected as the model substrate to explore the binding between a simple alkyl-substituted epoxide without other functionalities and the bisporphyrin host BP1, which was synthesized using a previously reported procedure.10 1H-NMR binding experiments and UV–vis spectroscopic titration revealed that the binding behavior of BP1 with epoxide 2a was quite similar to that found previously with monoalcohols,10 which allows concluding that the epoxide was also sandwiched in the bisporphyrin cavity of BP1. Thus, the firm confinement of the epoxide guest 2a within the cleft between the two porphyrin units of the bisporphyrin host BP1 was confirmed from the following data: (1) A 1:1 complex stoichiometry for binding epoxide 2a with BP1 was established by Job’s continuous analysis11 (Figure 3); (2) upon titration of bisporphyrin BP1 with epoxide 2a at 298 K in 1% CH2Cl2/hexane, the Soret absorption band underwent a small bathochromic shift12 from 411 to 413 nm, whereas a larger bathochromic shift from 414 to 420 nm was observed upon epoxide 2a binding with the monomeric counterpart Zn-3 (Figures 4 and 5); (3) the association constant for the complex of epoxide 2a with BP1 (Kassoc = 753 M-1) was about 6 times greater than that of the monomeric counterpart Zn-3 (Kassoc = 120 M-1) (Figures 4 and 5); (4) in the 1H-NMR studies, the protons of the epoxide 2a after complexation with the monomeric zincated porphyrin Zn-3 showed upfield shifts (Δδ = 0.11–0.04 ppm) compared with those of the free epoxide, whereas larger upfield shifts (Δδ = 0.22–0.09 ppm) were observed when 2a was bound to the bisporphyrin host BP1 because of the stronger ring current of the two porphyrins of the latter (Figure 6).

Figure 3. Job’s diagram. Solution of bidentate host molecule BP1 and rac-1,2-epoxybutane 2a (guest molecule) in 1% CH2Cl2/n-hexane were prepared with a fixed total concentration of host and guest molecule (3.4 μM). The UV–vis spectra were recorded at 0 °C and ΔAbs was monitored at 413 nm. Peaking at 0.5 mol fraction corresponds to a 1:1 BP1: epoxide 2a complex.


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Figure 4. (a) Spectral change upon titration of BP1 with epoxide 2a in 1% CH2Cl2/n-hexane at 25 °C. (b) Changes in ΔAbs at 400 nm for evaluating Kassoc. [BP1] = 1.2 μM; [2a]/[BP1] = 0‒4000).

Figure 5. (a) Spectral change upon titration of Zn-3 with epoxide 2a in 1% CH2Cl2/n-hexane at 25 °C. (b) Changes in ΔAbs at 420 nm for evaluating Kassoc. [Zn-3] = 1.0 μM; [2a]/[ Zn-3] = 0‒83000).



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C 6F5

H H

2

3

O

H

4

C(H1)3

N

H 3C

Zn

N

CH3

N

N

2a

OEt O

‡

Zn-3

† † H4

(a) [2a] : [BP1] = 1:1

2.52

2.66

(b) [2a] : [Zn-3] = 1:1

2.31

H

3

H3

H

H4 (c) 2a 2.88

2.9

2.72

H4 2.8

H

2.7

0.95

0.99

H

2.5

H1

2

2.46 3

2.6

H1

H2

2.39

2.62

2.77

0.90

H1

2

2.4 ppm

2.3

1.0

0.9

Figure 6. 1H NMR spectra (CDCl3, 25 °C) of 2a in the presence of (a) BP1 († = methyl proton of the ptolyl group in BP1), (b) monomeric zincated porphyrin Zn-3 (‡ = methyl proton of the p-tolyl group in Zn3), and (c) in the absence of zinc porphyrins. The epoxide signals have been color-coded.

Next, we investigated the helicity of bisporphyrin BP1 when complexed with chiral epoxides. As shown in Figure 7, strong and consistent ECCD signals centered about the Soret band of porphyrin were observed in the CD spectra of chiral 1,2-epoxybutane ((S)2a and (R)-2a), with the bisporphyrin BP1 in 1% CH2Cl2/hexane at 1:100 host/guest ratio.13,14 The positive ECCD spectrum corresponds to (S)-2a, whereas a negative signal can be observed for enantiomer (R)-2a. Not surprisingly, there is a linear correlation between the enantiomeric excess (ee) of the epoxides and the measured amplitude. As shown in Figure 8, the ECCD amplitude of BP1 was plotted against various ee values of epoxides (S)-2a and (R)-2a, which provided a linear fit with high regression (R2 = 0.998).


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The resulting ee calibration carve could be used to measure the ee of unknown samples. To gain stereochemical insights into the present host–guest complexation, we briefly explored the structures of epoxide 2a by MM2 calculations. Figure 9 shows the optimized structure of (R)-2a. Examination of its Newman projection drawn with the methylene carbon (C3) of the substituent at the front and the stereogenic carbon (C2) of the oxirane ring at the back reveals that the methyl group on the C3 carbon is arranged at 180° with respect to the oxygen atom, and that one oxygen lone pair (Lp 1) points to the front-left corner of the paper plane, while the other lone pair (Lp 2) tilts to the right rearward (Figure 10(a)). As a consequence, porphyrin rings P1 and P2 in BP1 selectively bind lone pairs Lp1 and Lp2, respectively, and thus, P1 adopts a counterclockwise (M) helicity relative to P2, producing a negative ECCD spectrum.15,16 As expected, the binding between BP1 and enantiomer (S)-2a yields the corresponding host–guest complex with clockwise (P) helicity, thus leading to the opposite ECCD spectrum (Figure 10(b)).

C 6F5

*

BP1

p-Tol

O

*

C 6F5

O N N N N p-Tol Zn Zn p-Tol p-Tol N N N N

BP1+(S)-2a BP1+(R)-2a

80

(S)-2a (77% ee) O O

BP1  (S)-2a C 6F5

*

BP1

O (R)-2a (99% ee)

p-Tol

*

C 6F5

O N N N N p-Tol Zn Zn p-Tol p-Tol N N N N

 (M-1cm-1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0

-80

O O

BP1  (R)-2a

390 420 450 Wavelength (nm)

Figure 7. ECCD spectra of host molecule BP1 (1.5 μM) in the presence of chiral epoxides 2a (100 equiv) in 1% CH2Cl2/n-hexane at 0 °C.



Figure 8. (a) ECCD spectra of BP1 (2.0 × 10‒6 M) complexed with 2a (100 equiv.) at different enantio excess (ECCD spectra were recorded in 1% CH2Cl2/n-hexane at 0 °C). (b) The plot of ECCD amplitude (A = Δε(429 nm) – Δε(414 nm)) versus % ee of (S)-2a in complex with BP1.


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top view

side view

* O

Lp2

C3

C2 (back)

C2

C2 Lp1

C3 Lp2 (front)

(R)-2a Lp1

C3

Figure 9. Energy minimized (MM2, ChemBio3D 14.0) structure of (R)-2a.

(a) Me H

H OH

H

BP1

Lp2

Lp1

Me

H

O

Lp1

Lp2

Zn

P1 Zn (up)

(R)-2a

H

P2 (down)

negative ECCD

counterclockwise (M)

(b) Me H

Me

H

BP1

HO Lp1

(S)-2a

Lp2

H

H

Lp1 Zn

P1 (down)

H

O

Lp2

Zn P2 (up)

positive ECCD

clockwise (P)

Figure 10. Newman projections of the MM2 optimized structures of chiral epoxides 2a and working models for assigning the absolute configuration of the chiral guests (dashed box). (a) The binding between BP1 and (R)-2a yields the host–guest complex with counterclockwise (M) helicity that produces a negative ECCD spectrum. (b) The binding between BP1 and (S)-2a yields the host–guest complex with clockwise (P) helicity that affords a positive ECCD spectrum.

To evaluate the scope of the present supramolecular chirogenesis utilizing the BP1 host system, various chiral terminal epoxides were synthesized as previously described and then subjected to ECCD measurement (Table 1). From this study, a general trend could be established, indicating that (S)-epoxides exhibit positive ECCD spectra upon complexation with bisporphyrin BP1, whereas (R)-epoxides give rise to negative spectra. In all cases, the predicted ECCD sign, which can readily be obtained using a working model same as that depicted in Figure 10 (Figures S1–S9, Supporting Information), was in complete agreement with the observed ECCD couplet of the complexes of BP1 and chiral



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terminal epoxides. The system was found to be tolerant to a variety of functional groups on the oxirane ring, including aryl, alkenyl, and halogenic groups as well as simple alkyl chains. Of note are the acceptable ECCD amplitudes obtained for guest substrates 2h and 2i containing the high electron-deficient Cl and CF3 groups.

Table 1. ECCD Data for Chiral Terminal Epoxide 2 with BP1a Predicted sign

λ nm (Δε)

Ab (Acorr)c

(S)-2a (77)

pos

429 (+78) 414 (-47)

+125 (+162)

(R)-2a (99)

neg

429 (-106) 414 (+61)

-167

(S)-2b (99)

pos

428 (+76) 414 (-45)

+121

(R)-2b (99)

neg

428 (-69) 414 (+44)

-113

(S)-2c (98)

pos

428 (+125) 414 (-78)

+203 (+207)

(R)-2c (97)

neg

428 (-125) 414 (+78)

-203 (-209)

Ph

(S)-2d (99)

pos

427 (+73) 414 (-50)

+123

Ph

(R)-2d (96)

neg

427 (-72) 414 (+49)

-121 (-126)

2

Ph

(S)-2e (99)

pos

429 (+18) 415 (-12)

+30

2

Ph

(R)-2e (99)

neg

429 (-22) 415 (+13)

-35

3 Ph

(S)-2f (99)

pos

429 (+114) 414 (-65)

+179

Ph

(R)-2f (99)

neg

429 (-107) 414 (+63)

-170

4

(S)-2g (99)

pos

428 (+21) 415 (-11)

+32

4

(R)-2g (99)

neg

428 (-22) 414 (+15)

-37

Chiral epoxide (% ee) * O * O

*

5

O *

5

O *

i-Pr

O *

i-Pr

O * O * O

* O * O * O * O

* O * O

3


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*

Cl

(R)-2hd (99)

pos

428 (+6) 415 (-5)

+11

Cl

(S)-2hd (99)

neg

428 (-8) 416 (+8)

-16

(R)-2id (99)

pos

428 (+32) 414 (-16)

+48

(S)-2id (99)

neg

429 (-29) 414 (+13)

-42

O * O

* CF3 O * CF3 O a

All CD measurements were performed with 1.5–2.7 μM of BP1 in 1% CH2Cl2/n-hexane at 0°C; 100 equiv.

of chiral epoxide was used. b A = Δε(upper) – Δε(bottom). c Acorr refers to amplitudes corrected for % ee for samples

Chiroptical Protocol for the Absolute Configurational Assignment of

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