Tailor-Made Supramolecular Chirogenic System Based on Cs

Publication Date (Web): January 19, 2016 ... A Cs-symmetric, rigid, achiral organophosphoric acid host with differentiable tautomeric structures has b...
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Tailor-Made Supramolecular Chirogenic System Based on Cs‑Symmetric Rigid Organophosphoric Acid Host and Amino Alcohols: Mechanistic Studies, Bulkiness Effect, and Chirality Sensing Mohammed Hasan,† Vaibhav N. Khose,† Anita D. Pandey,† Victor Borovkov,*,‡ and Anil V. Karnik*,† †

Department of Chemistry, University of Mumbai, Vidayanagari, Santacruz (East), Mumbai 400098, India Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia

‡

S Supporting Information *

ABSTRACT: A Cs-symmetric, rigid, achiral organophosphoric acid host with differentiable tautomeric structures has been developed for induced circular dichroism (ICD) studies of vicinal amino alcohols. The structural features of the host and the substituent bulkiness of the guest, together, decide the preferred mode of hydrogen binding on equilibration with a resultant ICD signal. An unequivocal rule correlating the absolute configuration of the guest amino alcohol with the ICD outcome is proposed.

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onempirical methods for the absolute configuration determination based on induced circular dichroism (ICD) technique have emerged as a superior analytical procedure for various organic compounds.1 In recent years, stereodynamic probes comprising flexible biaryl and porphyrin hosts have acquired considerable attention for ICD studies.2 In general, a point chirality of the guest generates specific axial or helical arrangements in probes, resulting in chirality induction. Chirality generation via ICD relies on the electronic transition exciton coupling, which depends on the distance between the corresponding chromophores and their relative orientation.3 Except parallel and planar orientations, any oblique arrangement of chromophores can be viewed as positive or negative helical orientation. Based on these geometrical requirements, we tailormade a Cs-symmetric, rigid organophosphoric acid (PA) host with two obliquely arranged naphthalene chromophores for degenerate exciton coupling, suitable for metal-free ICD studies. The naphthalene chromophores tend to display weak 1La transition of the short axis at 270−350 nm and a more intense 1 Bb transition of the long axis at 224−250 nm, which are suitable for ICD studies.4 So far, PA’s hosts have found wide applicability in catalytic asymmetric transformations5a,b and chiral molecular recognition.5c−e High acidity, ability to protonate, and donor−acceptor hydrogen bonding characteristics are the key features of its successful use. However, in the field of chirogenic processes, application of nonpolymeric PA hosts as ICD sensors has not been advanced.6 For example, a stereodynamic biaryl PA host, 1, developed by Feringa et al. exhibited chirality amplification for enantiopure amines only in the presence of liquid-crystalline media, with poor results in organic solvent.6a To fill this gap and to develop an effective chirality sensor on the basis of a PA host, we designed a new PA-containing compound, 3, capable of discriminating between its two tautomeric structures for ICD studies (Figure 1). This report aims to elucidate the structural requirements for a PA host to act as a successful ICD sensor. For © XXXX American Chemical Society

Figure 1. Different bisnaphthalene hosts 1−4.

this purpose, a Cs-symmetric rigid dihydrofurofuran-fused bisnaphthol 27 was synthesized on a gram scale by a modified synthetic protocol. Diol 2 was conveniently converted to PA 3 using the standard procedure6a (Scheme 1). Scheme 1. Synthesis of PA 3

In diol 2, both of the naphthalene rings are in close proximity, separated by a short covalent methylene bridge with an angle of ∼113.5°. The NOESY correlation between the tertiary benzylic proton at 6.52 ppm to one of the bridge methylene protons at 5.06 ppm in 2 proves their proximity in space, apparently due to the boat conformation of an eight-membered carbocyclic C ring.7 This conformationally locked, oblique arrangement is perfectly suitable for degenerate exciton coupling.3a The rigid PA 3 consists of two cis-fused dihydrofurofuran D rings, one eightmembered carbocyclic C ring, and one dioxaphosphocine H ring. The newly formed H ring can adopt either boat−boat or boat− Received: December 7, 2015

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DOI: 10.1021/acs.orglett.5b03477 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters chair conformation.8 Combination of C and H rings in boat and boat−chair conformations (Figure 2a) is preferred over boat and

outcome.10 As an additional proof of this assumption, the use of 1% TEA as an additive in chloroform enhances the solubility of PA 3 with the disappearance of the ICD signal (see Supporting Information), hence indicating that the phosphate anion does not form the rigid supramolecular complex with amino alcohols. Further, addition of 10% 1,2-dimethoxyethane in chloroform also diminishes the ICD signal by disturbing the cyclic hydrogenbonded S ring by assisting in complete proton transfer between the host and guest due to increased polarity (see Supporting Information). Both experiments exclude the possibility of complete proton transfer to the amine group of an amino alcohol. Interaction of PA 3 with amino alcohol was further investigated by 1 H NMR, indicating formation of the corresponding supramolecular complex between 3 and 9 (see Supporting Information). The 31P NMR signal for the complex appeared as a singlet at δ = −12.5 ppm, with a chemical shift difference of Δδ = 3.0 ppm from the free 3 host. A single peak with an obvious shift in 31P NMR indicates that even though both tautomers (Figure 3) participate in the self-assembly process, the resultant fast equilibrium displays a singlet peak in 31P NMR. The NMR results indicate the 1:1 binding stoichiometry, which was further supported by a Job plot using UV−vis spectroscopy, and the equilibration of tautomeric forms of PA 3 is the resulting supramolecular complex (see Supporting Information). Chloroform was chosen as an appropriate nonpolar solvent for the ICD studies due to the facilitation of cyclic hydrogen-bonded complexation between 3 and amino alcohols. For ICD studies, we used a series of structurally diverse enantiopure amino alcohols, 5−12 (Figures 5 and 6). The corresponding amino alcohol was mixed with the host 3 to have an equimolar complex in solution. All enantiopure amino alcohols 5−12 induced bisignate ICD signals in the region of PA 3 absorption (Figure 3). We observed a similar trend of a bisignate ICD pattern for 5−8, for which all the R-configurations yielded first negative and second positive Cotton effects (CEs). The S-configuration displayed a mirror image ICD pattern. Herein, we propose a nonempirical rule for predicting the CD sign of guest amino alcohols 5−8 based on a mechanism of exciton coupling in the supramolecular complex, upon considering the following structural factors of the PA 3 host. PA 3 exists as an equilibrium mixture of two possible conformational tautomeric forms, namely, 3A and 3B, differing in the positions of P−OH and PO bonds on a rigid, fused dioxophosphocine H ring (Figure 3). In 3A, the P−OH bond occupies a pseudoaxial position, whereas the PO bond lies at a pseudoequatorial position; the situation is reversed in the case of the 3B tautomer. Literature reports on fused eight-membered dioxaphosphocine derivatized at −OH with a bulky phenyl group as in 138b show that it occupies a pseudoaxial position. The presence of bulky groups, such as t-butyl, at the 2-positon on aromatic rings as in 148c tends to favor the stability of a bulky group at the pseudoequatorial position (Figure 4). Thus, in

Figure 2. Possible conformation of the dioxaphosphocine H ring in PA 3.

boat−boat conformations (Figure 2b) to decrease transannular steric clashes8a between the oxygen on the P atom with the H atom at the methylene carbon. The purity of 3 was established by 31 P NMR, showing a single peak at δ = −15.5 ppm. The 1H NMR showed long-range 5JP−H coupling8a for the proton at δ = 4.83 ppm, with the P atom revealing coupling at J = 2.4 Hz, further confirming the boat−chair conformation of the H ring.8 The σplane of Cs-symmetric PA 3 passes through the center of the molecule via the P atom (Figure 2c). The corresponding CD measurements reveal that while the PA host 3 is CD silent, in the presence of enantiopure amino alcohols, there is induction of CD signals in the region of naphthalene electronic transitions (Figure 3). This indicates

Figure 3. Enantiopure guests (5−12) screened for ICD studies with 3, with their preferred mode of interaction and expected results.

formation of a chiral supramolecular complex between PA 3 and amino alcohol. In general, due to the nature of functional groups, there are two possible pathways for host−guest interactions: the phosphoryl group transfer reaction9 and cyclic hydrogen bonding between the phosphoric acid group of the host and the amine and hydroxyl groups of the guest. The 1H NMR of PA 3 in DMSO-d6 in the presence of excess amino ethanol remained symmetrical, ruling out the possibility of a phosphoryl group transfer reaction, as such a reaction is expected to desymmetrize the host (see Supporting Information). In general, the PA group favors the formation of a cyclic hydrogen-bonded complex with amino alcohols in nonpolar solvent,5c−e resulting in a cyclic spatially locked species suitable for ICD studies. In contrast, the single-point electrostatic interaction between PA and an amino group via proton transfer produces a conformationally flexible structure, which hinders the rationalization of a chiroptical

Figure 4. Different conformations of the dioxaphosphocine ring, which depend on the bulkiness around the P atom. B

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hydrogen-bonded S ring favors the bulk to be at a pseudoequatorial position, which is possible only by favoring 3B tautomer complexation. Similarly, a reversely induced CD pattern based on the bulkiness of the guests related to the A value of substituents has been observed in porphyrin tweezer systems.11 Further, different modes of binding of chiral PA to the reactants to induce opposite enantioselectivity during asymmetric synthesis have been reported.12 When a bulky substituent is present at the chiral center, the amino group of the hydrogen bond with an acidic P−O−H group occupies a pseudoequatorial position, and an −OH group acts as hydrogen bond donor to the PO group of 3B and occupies a pseudoaxial position (Figure 6). The bisignate ICD spectra of all R-

comparison to 13 and 14, host 3 is expected to have a more stable tautomer such as 3A for complexation with amino alcohols, due to a lack of any bulky group close to the P atom on the naphthalene ring and further possible (P)−OH/π attractive forces. The two tautomeric forms 3A and 3B upon complexation with amino alcohol equilibrate in favor of more energetically stable species. The overall stability of these species depends on two factors. First, it relies on the preferred tautomer 3A available for the binding event, which is governed by the structural features of host 3. The second factor considers the stability of a newly formed nine-membered spirocyclic hydrogen-bonded S ring, which in turn is based on the substituent’s bulkiness at the stereogenic center of the guest molecule. In 5−8, where the steric bulk is not available, these two factors favor the binding mode with tautomer 3A. However, on complexation in 9−12, the substituents on the guest provide steric bulk in the vicinity of the P atom. In this situation, the second factor relating to the bulkiness of the guest controls the mode of binding to favor the formation of energetically more stable species via complexation with tautomer 3B. Tautomer 3A is preferred over 3B to bind with amino alcohols 5−8, having a small substituent such as −CH3, −C2H5, or −CH2CH(CH3)2 at the stereogenic center. The free amino group accepts the acidic hydrogen P−O−H of 3A, occupying a pseudoaxial position, whereas the alcohol part of the chiral guest acts as a hydrogen bond donor to PO of the PA group, with a pseudoequatorial position on the H ring. This cooperative hydrogen bonding in a nonpolar solvent generates a ninemembered spirocyclic hydrogen-bonded S ring. Therefore, the information on the R/S-configuration at the stereogenic center of the guest transfers to the host via the S ring to the H ring, which is directly attached to the chromophores, thus resulting in the corresponding ICD signal. The following model with tautomer 3A explains the nonempirical path of a negative exciton coupling for the R-configuration of 5−8 guests (Figure 5).

Figure 6. Proposed exciton coupling model for amino alcohols 9−12 having a bulky −R group, binding with tautomer 3B.

configurations of amino alcohols 9−12 resulted in a positive and then a second negative CE, being exactly opposite to amino alcohols 5−8 with small groups at the stereogenic center. Hence, amino alcohols 5−8 favored the complexation equilibrium with 3A, whereas 9−12 preferred tautomer 3B. In the complexation with the 3A mode, 5 (2-AP) gave the highest Δε value at 498.65 cm−1 M−1. Similarly, the 3B mode resulted in highest Δε value of 641.13 cm−1 M−1 for 10 (2-AMB) (Table 1). Table 1. ICD Results for Amino Alcohols 5−12 with PA 3 guests

first CE

second CE

Δε (cm−1 M−1)

g = Δε/ε × 10−3 (at first CE)

binding mode

− − − − + + +

+ + + + − − −

498.65 121.10 85.48 7.12 124.66 641.13 4.63

35.9 15.16 10.8 10.0 10.5 9.3 0.1

A A A A B B B

+

−

3.21

0.4

B

Figure 5. Proposed exciton coupling model for amino alcohols 5−8 having a small −R group, binding with tautomer 3A.

(R)-5 (R)-6 (R)-7 (R)-8 (R)-9 (R)-10 (1R,2S)11 (1R,2S)12

Based on the preferred binding mode 3A, the resultant complex gave rise to a counterclockwise orientation of the 1La coupling transitions to give a negative sign in the ICD spectrum for the R-configuration of amino alcohols. In contrast, as expected, upon complexation with the S-enantiomer, a mirror image ICD spectrum was obtained experimentally due to the opposite orientation of coupling transitions in the resulting supramolecular complex. Interestingly, in the case of guest 10 (2AMB), having a more bulky isopropyl group, we obtained a reverse ICD pattern. Here, the stability of the host:guest complex is favored via tautomer 3B, indicating that the binding mode of the substituents is bulk dependent at the stereogenic center. Due to the rigid, conformationally locked H ring, the newly formed

In general, aliphatic guests offered greater amplitudes compared to the guest (8, 11, and 12), having directly attached aromatic rings to the chiral center. It possibly indicates that the overall stability of the hydrogen-bonded S ring decreases with directly attached aromatic rings at the stereogenic center. The Cs-symmetry and rigid geometry of PA 3 were due to the presence of cis-fused dihydrofurofuran D rings. The absence of such rings will lead to the absence of an eight-membered boatshaped C ring. Consequently, this will allow the system to have a conformationally flexible H ring. The dynamically flexible H ring will flip and result in an equivalent tautomeric structure with nondifferentiable pseudoaxial and pseudoequatorial positions even for the supramolecular complex. Thus, we anticipated that C

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the JRF and SRF awards. We thank National Centre for Nanoscience and Nanotechnology, Mumbai University, for providing CD machine facility. V.B. acknowledges funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant Agreement No. 621364 (TUTIC-Green).

the changes in the rigid geometric features of the H ring of 3 will diminish its efficiency as an ICD sensor. To support this assumption, we prepared host PA 4 with a flexible H ring from pamoic acid ethyl ester (see Supporting Information). As expected, host 4 did not show any ICD signals for amino alcohols 5−12 under similar conditions, further supporting our model. Additionally, we performed DFT calculations at B3LYP/631G(d,p) for the supramolecular complexes between tautomers 3A and 3B with 5 (2-AP), 10 (2-AMB), and 8 (2-PG). It revealed that 5 favors the formation of a complex with 3A, with 2.6 kcal/ mol energy less compared to 3B. In contrast, 10 preferred the complexation with 3B over 3A by 12.0 kcal/mol energy. Surprisingly, 8 with a bulky phenyl group preferred the complexation with 3A, with an energy difference 4.6 kcal/mol, apparently via π−CH interaction between the host and guest. As the differences in energies are trivial, both the tautomeric forms may participate in the binding event. On equilibration, the preferred tautomer is expected to result in ICD signals that depend on the bulk of the group attached at the stereogenic center of the guest. Modification of host 3 around the close vicinity of the PA group (i.e., at the 3-position of aromatic rings or at the bridge methylenic benzylic position) should be able to influence this equilibrium, favoring one tautomer for complexation. These hypotheses will be investigated in due course. Host 3 also exhibited ICD activity with other classes of chiral compounds, such as natural product cinchonine, a few amines, and diamines (see Supporting Information).13 In conclusion, a novel nonpolymeric achiral bisnaphthol-based Cs-symmetric rigid PA 3 host was successfully applied for supramolecular ICD sensing of chiral vicinal amino alcohols via two-point cyclic hydrogen bonding interactions in nonpolar organic solvent. The combination of the cis-fused dihydrofurofuran D ring, one eight-membered carbocyclic C ring, and one eight-membered heterocyclic dioxaphosphocine H ring results in the rigid structural feature. This spatially fixed geometry leads to differentiable 3A and 3B tautomers, making 3 a successful ICD sensor for 1,2-amino alcohols based on the selective binding mode. High efficiency of this system offers further development of a variety of new Cs-symmetric, rigid hosts with obliquely arranged chromophores having suitable functional groups for configurational correlations of a wide range of chiral organic molecules.

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(1) Nakanishi, K.; Berova, N.; Woody, R. W. Circular Dichroism. Principles and Applications; VCH Publishers, Inc.: New York, 2000. (2) (a) Wolf, C.; Bentley, K. W. Chem. Soc. Rev. 2013, 42, 5408. (b) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008, 108, 1. (3) (a) Kasha, M.; Rawls, H. R.; Ashraf El-Bayoumi, M. Pure Appl. Chem. 1965, 11, 371. (b) Berova, N.; Bari, L. D.; Pescitelli, G. Chem. Soc. Rev. 2007, 36, 914. (4) Kodaka, M. J. Phys. Chem. A 1998, 102, 8101. (5) (a) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (b) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (c) Hulst, R.; Zijlstra, R. W. J.; Feringa, B. L.; de Vries, N. K.; ten Hoeve, W.; Wynberg, H. Tetrahedron Lett. 1993, 34, 1339. (d) Schuur, B.; Verkuijl, B. J. V.; Bokhove, J.; Minnaard, A. J.; de Vries, J. G.; Heeres, H. J.; Feringa, B. L. Tetrahedron 2011, 67, 462−470. (e) Pal, I.; Chaudhari, S. R.; Suryaprakash, N. New J. Chem. 2014, 38, 4908. (6) (a) Eelkema, R.; Feringa, B. L. Org. Lett. 2006, 8, 1331. (b) Riobe, F.; Schenning, A. P.H.J.; Amabilino, D. B. Org. Biomol. Chem. 2012, 10, 9152. (c) Miyagawa, T.; Furuko, A.; Maeda, K.; Katagiri, H.; Furusho, Y. J. Am. Chem. Soc. 2005, 127, 5018. (d) Yamada, H.; Maeda, K.; Yashima, E. Chem. - Eur. J. 2009, 15, 6794. (7) Hasan, M.; Pandey, A. D.; Khose, V. N.; Mirgane, N. A.; Karnik, A. V. Eur. J. Org. Chem. 2015, 2015, 3702. (8) (a) Arshinova, R. P.; Danilova, I.; Arbuzov, B. A. Phosphorus Sulfur Relat. Elem. 1987, 34, 1. (b) Reddy, C. D.; Reddy, R. S.; Reddy, M. S.; Krishnaiah, M.; Berlin, K. D.; Sunthankar, P. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 62, 1. (c) Pastor, S. D.; Rogers, J. S.; NabiRahni, M. A.; Stevens, E. D. Inorg. Chem. 1996, 35, 2157 and refs cited therein. (e) Prakasha, T. K.; Day, R. O.; Holmes, R. R. Inorg. Chem. 1992, 31, 1913. (9) Muche, M. S.; Gobel, M. W. Angew. Chem., Int. Ed. Engl. 1996, 35, 2126. (10) (a) Tsukagoshi, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4089. (b) Kondo, K.; Shiomi, Y.; Saisho, M.; Harada, T.; Shinkai, S. Tetrahedron 1992, 48, 8239. (c) Shiomi, Y.; Saisho, M.; Tsukagoshi, K.; Shinkai, S. J. Chem. Soc., Perkin Trans. 1 1993, 2111. (11) (a) Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson, R. T.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2002, 124, 10320. (b) Kurtán, T.; Nesnas, N.; Li, Y. Q.; Huang, X.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2001, 123, 5962. (c) Tanasova, M.; Borhan, B. Eur. J. Org. Chem. 2012, 2012, 3261. (12) (a) Wang, H.; Jain, P.; Antilla, J. C.; Houk, K. N. J. Org. Chem. 2013, 78, 1208. (b) Burns, A. R.; Madec, A. G. E.; Low, D. W.; Roy, I. D.; Lam, H. W. Chem. Sci. 2015, 6, 3550. (13) Hasan, M. Studies In Chiral Molecular Recognition. Ph.D. Dissertation, University of Mumbai, 2014.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03477. Experimental details, characterization data, and UV−vis and CD spectroscopic data (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grant-in-Aid SR/S1/OC-02/2007 from DST-India. M.H. thanks DST-India and UGC-MANF for D

DOI: 10.1021/acs.orglett.5b03477 Org. Lett. XXXX, XXX, XXX−XXX