Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle

Journal Pre-proof Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle Mikołaj Zgorzelak, Jakub Grajewski PII:

S0022-2860(19)31445-0

DOI:

https://doi.org/10.1016/j.molstruc.2019.127336

Reference:

MOLSTR 127336

To appear in:

Journal of Molecular Structure

Received Date: 1 July 2019 Revised Date:

25 October 2019

Accepted Date: 31 October 2019

Please cite this article as: Mikoł. Zgorzelak, J. Grajewski, Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle, Journal of Molecular Structure (2019), doi: https:// doi.org/10.1016/j.molstruc.2019.127336. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Graphical Abstract

The synthesis of rhombimine with enantiopure trans-1,2-diaminocyclohexane and racemic bisaldehyde with spiro carbon atoms yields single macrocyclic product with almost quantitative yield. This is possible by partial reverse hydrolysis and thus ring opening and the inversion of absolute configuration of the a conformationally stable spiro-acetal moiety.

Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle. Mikołaj Zgorzelak,a and Jakub Grajewski*a a

Department of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8,

61-614 Poznań, Tel: +48 829 1711, E-mail: [email protected] Abstract: The synthesis and conformational preferences of a novel chiral macrocyclic polyimine possessing spiro carbon atoms is described. The key feature of the synthesis is the incorporation of an axially chiral surrounding of quaternary carbon atom having four constitutionally identical substituents into the structure of the macrocycle. This is possible by partial hydrolysis, which enables the inversion of absolute configuration, of the spiro-acetal moiety. This approach allows to obtain the macrocyclic product with almost quantitative yield. Keywords: Rhombimines, Dynamic covalent chemistry, Chiral diacetals, Schiff-base macrocycles, Spiro atom, TDDFT calculations

1. Introduction Macrocyclic polyimines based on trans-1,2-diaminocyclohexane and various bisaldehydes of defined geometry are interesting group of compounds not only due to their relative ease of synthesis, based on rules of the dynamic covalent chemistry [1,2] but also due to their properties. The shape and size of particular macrocycle is strongly dependent on the geometry of the bisaldehyde linker [3-9]. The most commonly used linear aldehydes usually lead to [3+3] cyclocondensation (formation of trianglimines) [10-15] while the use of bent dialdehydes leads to [2+2] cyclocondensation (formation of rhombimines) [16-19] when carried out under thermodynamic conditions. In the most trianglimines and rhombimines known, the dialdehydes used as the linkers in the macrocyclization reaction are non chiral, however few examples of chiral mostly aromatic dialdehydes are known [20-22]. In the most cases, the source of chirality of macrocycle is trans-1,2-diaminocyclohexane (DACH).

1

On the base of the previously reported compounds, it is known that for the formation of trianglimines and rhombimines the chirality of diamine component (DACH) does not influence the formation of macrocycle when condensed with achiral dialdehyde. [23] Reaction of racemic DACH with terephtalaldehyde results in a mixture of cyclic diastereomeric products of [3+3] cyclocondensation. However when a chiral racemic dialdehyde is reacting with enantiomerically pure diamine only one enatiomer is incorporated into macrocyclic structure, while the other forms oligomeric mixture of products of helical structures [21-22]. Recently chiral romboidal macrocyclic structures of interesting conformational properties were synthesized in which the components introducing chirality to the molecule are non-racemic bis-naphthyl derivatives [24-25]. The synthesis of rhombimines from racemic bisaldehyde with the spiro carbon incorporated into macrocyclic framework can involve two mechanisms. When the bisaldehyde racemizes under reaction condition only macrocyclic product is found and if bisaldehyde is enantiomerically stable, one enantiomer forms macrocycle and the other reacts to produce a mixture of oligomeric products. Configuration of the spiro system [26] build of four constitutionally identical groups is presented on Figure 1. The helicity can be described by a sign of either of the two OCH2-C(spiro)-CH2 torsion angles involving oxygen atoms that are at the closest distance but belong to separate 1,3-dioxane rings. In the M-helical structure, each of the two torsion angles has a negative sign while in an P-helical structure both are positive. This description of helicity, based on oxygen atoms, does not depend on the conformation of the two condensed dioxane rings. In this paper we describe, to the best of our knowledge, the first example of diastereoselective opening and closure of acetal ring that is used in dynamic covalent chemistry approach.

Figure 1. The definition of helicity at a spiro carbon atom in two condensed 1,3dioxane rings.

2. Materials and Methods 2

2.1 General methods 1

H and

13

C NMR spectra were recorded on a Bruker 400 MHz or Varian Mercury 300

MHz apparatus at ambient temperature. All 1H NMR spectra are reported in parts per million (ppm) downfield of TMS and were measured relative to the signals for CDCl3 (7.27 ppm). All 13C NMR spectra were reported in ppm relative to residual CDCl3 (77.0 ppm) and were obtained with 1H decoupling. MS spectra were recorded on impact HD Bruker apparatus. CD spectra were recorded on JASCO J810 spectropolarimeter. Melting points were measured using open glass capillaries in a Buchi Melting Point B545 apparatus.

2.2 Reagents All commercially available reagents used in this study, except for (R,R)-1,2diaminocyclohexane, were obtained from Sigma-Aldrich and used in reactions without further purification. The organic solvents were obtained from commercial suppliers.

2.3 Synthesis of 3,9-bis(3-formylphenyl)-2,4,8,10-tetraoxaspiro[5.5]undecane (3) Isophthalic aldehyde (0.400 g, 2.98 mmol), pentaerythritol (0.202 g, 1.48 mmol), pTSA (0.021 g, 0.12 mmol) and 150 mL of chloroform was placed in 250 mL round bottom flask. The mixture was heated with stirring for 2 h. The reaction mixture was extracted with 10% K2CO3 solution and organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient: 0–10% EtOAc in DCM) to give 0.182 g of pure dialdehyde in 33% yield. Melting point: 142-144 °C. 1

H NMR (400 MHz, CDCl3) δ 10.04 (s, 2H), 8.03 (t, J = 1.7 Hz, 2H), 7.90 (dt, J = 7.6,

1.4 Hz, 2H), 7.77 (dt, J = 7.7, 1.3 Hz, 2H), 7.57 (t, J = 7.7 Hz, 2H), 5.55 (s, 2H), 4.87 (dd, J = 11.6, 2.4 Hz, 2H), 3.89 (d, J = 11.7 Hz, 2H), 3.88 (dd, J = 11.7, 2.6 Hz, 2H), 3.71 (d, J = 11.7 Hz, 2H). 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 2H), 7.99 (t, J = 1.7 Hz, 2H), 7.92 (dt, J = 7.6, 1.5 Hz, 2H), 7.78 (dt, J = 7.8, 1.5 Hz, 2H), 7.62 (t, J = 7.6 Hz, 2H), 5.64 (s, 2H), 4.62 (dd, J = 11.5, 2.5 Hz, 2H), 3.97 (d, J = 11.3 Hz, 2H), 3.86 (dd, J = 11.6, 2.3 Hz, 2H), 3.74 (d, J = 11.6 Hz, 2H).

13

C NMR (75 MHz, CDCl3) δ

191.96, 139.00, 136.44, 132.10, 130.09, 129.09, 127.68, 101.22, 101.18, 71.00, 70.51, 32.59.

13

C NMR (75 MHz, DMSO-d6) δ 193.53, 139.75, 136.58, 132.70, 130.26, 3

129.58, 127.60, 100.76, 100.73, 70.40, 69.89, 32.60. MS ESI (M+H)+=369.1341, calc.=369.1260 for C21H20O6. 2.4 Synthesis of Diacetal spirorhombimine (5) The mixture of dialdehyde 3 (0.293 g, 0.8 mmol), (R,R)-1,2-diaminocyclohexane 4 (0.091 g, 0.8 mmol) and chloroform (50 mL) was placed in round-bottom flask (under argon). The mixture was stirred for seven days and then the solvent was removed under reduced pressure to give macrocycle 5 in almost quantitative yield. Melting point: 285 °C (decomposition). 1

H NMR (300 MHz, CDCl3) δ 8.19 (s, 4H), 7.69 (s, 4H), 7.55 (d, J = 6.2 Hz, 4H), 7.46

(d, J = 6.9 Hz, 4H), 7.30 (t, J = 7.6 Hz, 4H), 5.38 (s, 4H), 4.77 (d, J = 11.0 Hz, 4H), 3.75 (d, J = 11.5 Hz, 8H), 3.55 (d, J = 11.7 Hz, 4H), 3.40 (s, 4H), 1.83 (s, 12H), 1.48 (s, 4H).

13

C NMR (75 MHz, CDCl3) δ 160.57, 138.15, 136.37, 128.69, 128.45, 127.76,

125.63, 101.77, 73.70, 70.93, 70.86, 70.42, 70.36, 32.92, 32.39, 24.45. MS ESI (M+H)+=893.4497, calc.=893.4411 for C54H60N4O8.

3 Results and Discussion

3.1 Synthesis The synthesis of a macrocycle involved two steps. The first one was the synthesis of chiral racemic dialdehyde 3. The isophthalic aldehyde (1) and pentaerythritol (2) with catalytic amount of p-toluenesulfonic acid were refluxed in CHCl3 for two hours and resulted in bisaldehyde 3 along with longer oligocondensation products. The crude mixture was purified by the column chromatography which resulted in isolation of rac-3 in moderate 33% yield. This reaction was also carried out under reflux with the DeanStark apparatus, but under this conditions a branch of polymeric product was predominant. Having in hand bisaldehyde 3, series of condensation reactions with diamine 4 were performed. The usual conditions of macrocyclizations (stirring at RT overnight in CHCl3 or heating in toluene under the Dean-Stark apparatus) resulted in a very complicated mixture of products. This situation did not change significantly when reaction was carried under high dilution conditions. This could be explained as formation of a mixture of diastereomeric products and also by the possible different 4

positions of formyl groups in bisaldehyde 3 as the similar reaction with terephtalic aldehyde-based bisaldehyde analog of 3 resulted the macrocyclic product in 45% yield (based on diamine compound) [21]. Finally the reaction was stirred in chloroform, in a closed flask for seven days to give macrocycle 5 in almost quantitative yield. The NMR and MS spectra confirmed the single product of [2+2] cyclocondensation with molecular weight of 893.4497 (M+H)+. OH O

OH

O +

p-TSA CHCl3

O

O

∆ OH 1

O

OH

2

3

O

O O NH 2 3 + NH 2

O

N

CHCl3 7 days

N N N

O O

4

O

O O

O O

5

Scheme 1. Synthesis of macrocycle 5.

Full characterization of the new compounds can be found in Supporting Information.

3.2 Conformational analysis Structure of bisaldehyde 3 was established with the aid of MS and NMR spectra. The 1H and

13

C NMR spectra indicate C2 symmetry of 3. Separation of signals of the

CH2O groups proves the earlier studies of restricted conformation of similar cyclic pentaerythritol diacetals (Figure 2).

5

Figure 2. Characteristic pattern of conformationally stable spiro bicyclic bisacetals in CDCl3 (upper panel) and DMSO-d6 (lower panel).

Figure 3. Calculated preferred arrangements of aromatic ring neighboring to 2,4,8,10tetraoxaspiro[5.5]undecane linker and two main arrangements of aromatic rings.

6

Rotation of phenyl rings in 3 may result in different mutual arrangements of aldehyde groups. Conformational flexibility of 3 might lead to multiple products of macrocyclization reaction. In this case, to find a preferred conformation of 3 we performed conformational search. Both phenyl rings were rotated with step of 30o which led to 144 conformers. Their total energies were calculated by PM3 methods. The lowest energy conformers were refined with the use of DFT (B3LYP/6-31G**) [27]. Results of these calculations indicates three conformers of almost equal energies with differences in energy below 0.3 kcal*mol-1. In all low-energy conformers, acetal hydrogen atoms are located in syn conformations to one of orto protons of aromatic rings. It was found that the rotation of one phenyl ring does not influence the other (Figure 3). The small differences in energy between calculated conformers and the analysis of the 1H NMR spectrum of 3 suggest that the conformation of bisaldehyde during the macrocyclization reaction can be changed to form macrocycle. The synthesis of macrocycle 5 from 3 and enantiopure (R,R)-4 was initially carried out in usual conditions resulted in a complicated mixture of oligomeric products. The 1H NMR spectra of the crude mixture of products displayed more than ten different signals originating from diagnostic imine protons appeared in the range 8.0 – 8.5 ppm. The reaction was then carried out to achieve thermodynamic equilibrium. It was stirred at RT in chloroform, in a sealed flask for seven days. After solvent was removed under reduced pressure, macrocycle 5 was isolated in almost quantitative yield (Figure 4). This indicates that during the reaction not only the conformation of phenyl ring has changed but also the helicity of the spiro group. As this group is known to be stable, such result was possible only by partial reverse hydrolysis of acetal moiety. This reaction requires more time and was not completed in the reaction carried out only one day. Because the water has not been added, the water molecules come from the reaction of imination, which occurs first. This has not been observed before for similar macrocycles. The comparison the 1

H NMR of mixture of products and pure 5 after one day and seven days is displayed

in the Figure 4. The [2+2] stoichiometry of macrocycle 5 was confirmed by MS spectrum. NMR spectra show only one product of D2 symmetry. The

1

H NMR

spectrum of 5 displays a single signal from imine bond and preserves the clear characteristic pattern of acetal and CH2-O protons.

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Figure 4. 1H NMR of a mixture of products of macrocyclization reaction after one day (upper panel) and the pure 5 obtained after 7 days (lower panel).

Due to insufficient solubility of 5 in acetonitrile or cyclohexane the UV and CD spectra spectrum were recorded in dichloromethane. ECD spectrum of macrocycle 5 proved the usually encountered diequatorial positions of C=N bonds connected to cyclohexane ring with characteristic pattern of Cotton effects (CE). An exciton type negative CE (∆ε = -164, located at 258 nm) and positive CE (∆ε =131, located at 237 nm) origins from π-π* transitions within the substituted phenylimine chromophores (ε = 53 900 located at 243 nm) and reflects a negative torsion angle of the vicinal C=N bonds. Because chromophores attached to different cyclohexane rings are

Figure 5. Recorded UV (dotted line) and ECD (solid line) spectra of macrocycle 5 in dichloromethane c = 1.52*10-4 mol*L-1 and calculated ECD spectrum of 5 (dashed line).

8

remote (around 12 Å) their coupling does not contribute significantly to CD spectrum. The detailed structure of macrocycle 5 was also calculated by molecular modeling using Gaussian suite of programs [27]. Conformers of macrocycle 5 were initially calculated

with

semi-empirical

method

(PM6)

and

then

refined

by

DFT

(B3LYP/631G**). Due to the results of experimental spectra only the symmetric structures were taken into account. The calculations are in good agreement with experimental results indicating the presence of only one symmetric P stereoisomer (torsion angle Tors 1 = +74º) as the reaction product. The M isomer, which was not found in the reaction mixture tends rather to form a helix than a macrocycle, was of much higher energy and the dihedral angles were not of optimal values. The structure of calculated isomer of 5 is presented on the Figure 6.

Figure 6. Calculated structure of the lowest energy conformer of macrocycle 5.

ECD spectrum was calculated for the lowest energy conformer of macrocycle 5 by TD-DFT (B3LYP/631G**) method with 140 excited states taken into account due to covering the spectrum range (calculated spectrum was scaled in energy to fit the experimental spectra). Spectrum calculated for 5 shows the same sequence of CE's /+, what is in very good agreement with those obtained by ECD measurement (Figure 5).

Conclusion In summary, we have presented an efficient, non-templated method for synthesis of a new chiral polyimine macrocycle. The use of the thermodynamic condition of macrocyclization reaction was applied not only for the usual reasons – the reversible reaction of imine bond formation but also for the partial hydrolysis and therefore the

9

inversion absolute configuration located on the spiro atom of the 2,4,8,10tetraoxaspiro[5.5]undecane linker. This new approach allowed to increase significantly the yield of macrocyclic product comparing to the usual method using chiral discrimination and avoid a mixture of macrocyclic product with acyclic polyimine byproducts. The mechanism for the configuration inversion by partial acetal hydrolysis is proposed. Acknowledgements This work was supported by the National Science Centre, grant number: 2012/06/A/ST5/00230. Calculations were performed at the Poznan Supercomputing and Networking Centre (PCSS), grant number 406.

Supporting information Additional supporting information (copies of HRMS, carbon and proton NMR spectra) may be found in the Supporting Information.

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Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle. Mikołaj Zgorzelak,a and Jakub Grajewski*a a

Department of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego

8, 61-614 Poznań, Tel: +48 829 1711, E-mail: [email protected]

Highlights

- diastereoselective synthesis of spiro rhombimines - absolute configuration of spiro moiety changes during the reaction - new mechanism for adapting the racemic substrate in the macrocyclization reaction