Letter pubs.acs.org/OrgLett
Absolute Stereochemical Determination of Asymmetric Sulfoxides via Central to Axial Induction of Chirality Hadi Gholami, Jun Zhang, Mercy Anyika, and Babak Borhan* Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States S Supporting Information *
ABSTRACT: The absolute configuration of chiral sulfoxides is determined by means of host−guest complexation that leads to the induction of axial chirality in an achiral host. The central to axial induction of helicity is rationalized by a simple recognition of the relative length and size of the substituents attached to the S-center. This technique is used to determine the absolute configuration of chiral sulfoxides, requiring micrograms of sample, without the need for prefunctionalization.
T
the electric dipole transition moments of two or more independently conjugated chromophores, has been utilized by a number of groups to address the absolute stereochemical determination of organic molecules (the reader is referred to the referenced reviews for numerous examples in the literature for the use of ECCD in stereochemical assignment).8 Our approach to this problem originates from our interest in utilizing host systems capable of adopting either the P or M helicity as the consequence of predictable interactions of a bound chiral guest molecule. The host/guest interactions are such that the point chirality of the guest is translated to the axial chirality of the host, which in turn leads to an observable ECCD signal. To this end, we envisioned the use of our recently developed host molecule, MAPOL 1,9 as a receptor that binds sulfoxides. Our constraints for success were to develop a methodology that is sensitive, highly reproducible, and operationally simple for chemists not necessarily versed in spectroscopic techniques. Herein, we demonstrate the utility of Zn-MAPOL 2 to address a long-standing problem in the assignment of absolute stereochemistry of chiral sulfoxides with the specific goals addressed above. We have recently demonstrated that MAPOL 1 (non metalated porphyrin) is capable of binding monoamines via hydrogen bonding to the core biphenol moiety. The ensuing interactions lead to a preferred helical disposition of the two porphyrin chromophores as the result of an induced axial chirality of the host molecule (Figure 1a).9 The zincated analog, ZnMAPOL 2, was optimized for binding cyanohydrins in a bidentate fashion (alcohol binding with the biphenol hydroxyl groups and the cyano binding with the metallozinc center, Figure 1b).10 Although sulfoxides have putatively two sites of coordination (the O-atom and the S lone pair), the geometric constraints of the host system would preclude bidentate binding. We first hypothesized that sulfoxides could bind via hydrogen bonding to the biphenol and thus provide a mechanism for
he ubiquitous nature of the chiral C-atom, in every facet of science as it relates to the structure of an organic molecule, has led to tremendous activity for assigning its absolute stereochemistry. The chiral S-atom has enjoyed much less attention, although one can argue it is no less important. In its oxide form, the S-atom can be asymmetric, with similarly profound impact on its chemical and spectroscopic characteristics, as well as its biological activity. From a substantial list of biologically active sulfoxide containing molecules,1 Nexium (one of the world’s highest selling drugs), oxisurane, and armodafinil are examples of important pharmaceuticals that share the same commonality; the sulfoxide is the only asymmetric center in these molecules.2 Chiral sulfoxides as ligands and auxiliaries are also important contributors in asymmetric synthesis.3 The importance of this functionality necessitates a robust, reliable, efficient, preferably microscale and direct method for the assignment of absolute configuration. Nonetheless, the structural features of sulfoxides (lack of a suitable derivatizing site) have posed a challenge to port over the prototypical procedures used for the absolute stereochemical assignment of carbon substituted functionalities. A modified Mosher ester analysis was an early attempt in this regard. Typical ester derivatization of the sulfoxide oxygen results in racemization. Yabuuchi and Kusumi circumvented this problem via an initial oxidation of the sulfoxide to generate an iminosulfanone, which was then derivatized as an MPA-amide.4 Limited use of chiral solvating agents for NMR analysis has been reported, although this strategy has not delivered a comprehensive solution.5 An electronic CD method to address aryl sulfoxides has been reported by Rosini et al.6 Alternatively, the most successful chiroptical technique has been vibrational circular dichroism (VCD),7 although this has not yet become a routine and common methodology for the synthetic community. Our goal was to develop a simple and microscale procedure that enables the facile determination of absolute stereochemistry of chiral sulfoxides using Exciton Coupled Circular Dichroism (ECCD). ECCD, the product of the through-space coupling of © XXXX American Chemical Society
Received: February 17, 2017
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DOI: 10.1021/acs.orglett.7b00495 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Table 1. Predicted and Observed ECCD for Sulfoxides Complexed with 2a
Figure 1. Three different modes of binding to MAPOL: (A) amines bind MAPOL via hydrogen bonding to the bisphenol core; (B) bidentate binding of cyanohydrins with Zn-MAPOL; (C) putative binding of sulfoxides with the metallocenter of Zn-MAPOL.
interaction with MAPOL 1. Nonetheless, binding of a number of chiral sulfoxides with 1 failed to produce a discernible ECCD signal. We had also envisioned the possibility of a different binding paradigm with the MAPOL family of analogs. This is depicted in Figure 1c, resulting from the binding of the sulfoxide O-atom with the metallocenter of Zn-MAPOL 2. Gratifyingly, complexation of R-4d with 2 led to a strong ECCD signal centered on the Soret band (420 nm, see Figure 2a). A simple screen of conditions (see Supporting Information) led to the choice of hexane as the optimal solvent, with measurements at 0 °C. These conditions lead to a high binding affinity for complexation of R-4d with 2 measured in excess of 14 500 M−1 (see Figures S9−S10 for Kd measurements). With the initial results in hand, a number of chiral sulfoxides, with varied alkyl and aryl substituents, were synthesized via previously reported procedures (Table 1).7c,11 Using a standard protocol (1 μM Zn-MAPOL 2 and 50 equiv of sulfoxide dissolved in hexane), strong ECCD signals were obtained for host/guest complexes in all cases. Not surprisingly, enantiomers (see Table S1 for enantiomeric pairs) yield signals of opposite sign with equal intensities when correction for enantiopurity is applied (Acorr).12 The ECCD amplitudes are large, enabling lower detection limits by reducing the sulfoxide to 5 equiv (4.5) than the phenyl substituent (3.0). Nonetheless, the length of the phenyl group is longer (4.6 Å for Ph, 2.8 Å for tertbutyl), thus dictating the population difference that leads to the observed negative ECCD. In cases where the measured L is identical for both groups, then A-values are used as the secondary consideration to decide size priority. An example of this is S-4k, where L1 and L2 for tert-butyl and isopropyl are the same, yet the A-value for tert-butyl (>4.5) is substantially larger than the Avalue for isopropyl (2.15). Considering that the A-value is a predictor of “volume”, it stands to reason that when the lengths of the substituents are the same, the volume of the substituents can exert a stereodefining role. Notably, the same analysis can be used for the absolute determination of S-4l. The slightly larger perdeuterated benzene ring leads to the anticipated ECCD signal, albeit in small amplitude, reflective of the slightly larger volume of the perdeuterated phenyl vs phenyl.17 Nonetheless, the latter observation demonstrates the sensitivity of the current system. The sulfinamide S-4m (entry 13) produced the largest amplitude (see Figures S16−S17 for CD titration curves), presumably as a result of the sulfoxide’s highly polarized nature that leads to superior binding affinity (Kd = 35 236 M−1, Figure S15) for the zincated porphyrin. Gratifyingly, the crystal structure of S-4m, bound to Zn-tetraphenylporphyrin (Zn-TPP), provides clear evidence for the anticipated binding of the O-atom to the metallocenter (see Figure S38 for crystal structure).18 Having demonstrated the efficacy of the methodology with a variety of chiral sulfoxides, we next challenged the system with a more complex molecular structure containing ancillary groups that could alter or abolish coordination of the sulfoxide moiety
Figure 2. (A) Binding of R-4d (50 equiv) with Zn-MAPOL 2 leads to a strong negative ECCD spectrum (A = −419). (B) Putative model for binding of sulfoxides to Zn-MAPOL 2. The nonequal population distribution of the two diastereomeric complexes is the result of steric interactions of the two groups on the S-atom, projected toward the porphyrin not bound to the sulfoxide. The longer aryl substituent disfavors the P helicity (as shown bound to R-4d) in favor of the Mhelical orientation, resulting in a negative ECCD.
two remaining groups as they project outward from the center of the porphyrin ring they are bound to, by placing the largest group, in this case the aryl substituent, in the least sterically demanding space. Considering both P and M helicities of the host, the M-(R) complex orients the aryl group away from the second porphyrin ring, while, in the P-(R) complex, the aryl group suffers from larger, undesired interactions. One would thus suggest that the M helicity is energetically favored. The prediction based on this model leads to a negative induced helicity in Zn-MAPOL 2, which indeed fits the observed ECCD spectrum for R-4d bound to 2. This simple mnemonic predicts the correct ECCD for all substrates listed in Table 1. The critical choice to be made for applying the latter mnemonic rests with determining which of the two groups attached to the asymmetric sulfur is larger. In systems described previously (amines and cyanohydrins), A-values, a thermodynamic measure of steric size,15 were used as determinants of size. A careful analysis of the data in Table 1, specifically correlation of the strength of the ECCD signal with the difference in steric size of the substituents, suggests that A-values alone are not sufficient to rationalize the data. For example, although the A-values of phenyl and 4-Me-Ph are expectedly similar, the ECCD observed for R-4f (Table 1, entry 6) is unexpectedly large (Acorr = −738). The greatest difference between the latter two substituents is in their length; i.e., measuring the distance L1 from the S-atom to the furthest heavy atom on 4-Me-Ph is 6.1 Å, while L2, measured from the S-atom to the furthest heavy atom on Ph, is 4.6 Å (Figure 3). The geometry dictated by the coordination of the sulfoxide with the zincated porphyrin projects the two substituents toward the plane of the opposite porphyrin ring. Thus, the difference in length of the two substituents is more significant than their bulk, C
DOI: 10.1021/acs.orglett.7b00495 Org. Lett. XXXX, XXX, XXX−XXX
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(2) (a) Bentley, R. Chem. Soc. Rev. 2005, 34, 609. (b) Wojaczyńska, E.; Wojaczyński, J. Chem. Rev. 2010, 110, 4303. (3) (a) Carreno, M. C. Chem. Rev. 1995, 95, 1717. (b) Pulis, A. P.; Procter, D. J. Angew. Chem., Int. Ed. 2016, 55, 9842. (c) Sipos, G.; Drinkel, E. E.; Dorta, R. Chem. Soc. Rev. 2015, 44, 3834. (4) Yabuuchi, T.; Kusumi, T. J. Am. Chem. Soc. 1999, 121, 10646. (5) (a) Donnoli, M. I.; Superchi, S.; Rosini, C. Mini-Rev. Org. Chem. 2006, 3, 77. (b) Buist, P. H.; Behrouzian, B.; MacIsaac, K. D.; Cassel, S.; Rollin, P.; Imberty, A.; Gautier, C.; Pérez, S.; Genix, P. Tetrahedron: Asymmetry 1999, 10, 2881. (c) Yang, L.; Wenzel, T.; Williamson, R. T.; Christensen, M.; Schafer, W.; Welch, C. J. ACS Cent. Sci. 2016, 2, 332. (6) Donnoli, M. I.; Giorgio, E.; Superchi, S.; Rosini, C. Org. Biomol. Chem. 2003, 1, 3444. (7) (a) Aamouche, A.; Devlin, F. J.; Stephens, P. J.; Drabowicz, J.; Bujnicki, B.; Mikołajczyk, M. Chem. - Eur. J. 2000, 6, 4479. (b) Devlin, F. J.; Stephens, P. J.; Scafato, P.; Superchi, S.; Rosini, C. Chirality 2002, 14, 400. (c) Drabowicz, J.; Zajac, A.; Lyzwa, P.; Stephens, P. J.; Pan, J.-J.; Devlin, F. J. Tetrahedron: Asymmetry 2008, 19, 288. (d) Petrovic, A. G.; He, J.; Polavarapu, P. L.; Xiao, L. S.; Armstrong, D. W. Org. Biomol. Chem. 2005, 3, 1977. (e) Stephens, P. J.; Aamouche, A.; Devlin, F. J.; Superchi, S.; Donnoli, M. I.; Rosini, C. J. Org. Chem. 2001, 66, 3671. (8) (a) Berova, N., Polavarapu, P. L., Nakanishi, K., Woody, R. W. Comprehensive Chiroptical Spectroscopy, Vol. 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules; Wiley: Hoboken, NJ, 2012. (b) Lu, H.; Kobayashi, N. Chem. Rev. 2016, 116, 6184. (c) Pasini, D.; Nitti, A. Chirality 2016, 28, 116. (d) Wolf, C.; Bentley, K. W. Chem. Soc. Rev. 2013, 42, 5408. (e) You, L.; Zha, D.; Anslyn, E. V. Chem. Rev. 2015, 115, 7840. (9) Anyika, M.; Gholami, H.; Ashtekar, K. D.; Acho, R.; Borhan, B. J. Am. Chem. Soc. 2014, 136, 550. (10) Gholami, H.; Anyika, M.; Zhang, J.; Vasileiou, C.; Borhan, B. Chem. - Eur. J. 2016, 22, 9235. (11) (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93. (b) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637. (c) Fernandez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem. 1992, 57, 6789. (d) García Ruano, J. L.; Alemparte, C.; Aranda, M. T.; Zarzuelo, M. M. Org. Lett. 2003, 5, 75. (e) Lu, B. Z.; Jin, F.; Zhang, Y.; Wu, X.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2005, 7, 1465. (12) The amplitude A (not to be confused with A-value) in ECCD is the measure of intensity spanning the negative and positive Cotton effects, as shown in Figure 2a. (13) Vinodu, M.; Goldberg, I. Acta Crystallogr., Sect. E: Struct. Rep. Online 2004, 60, m579. (14) The structure of Zn-TPP bound to DMSO was determined by single crystal X-ray diffraction (CCDC 1511541). (15) Eilei, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; New York, 1994. (16) (a) The L parameter in sterimol analysis is the distance measured from the attachment point of the substituent to the furthest point along the primary bond. Although similar, we measure L1 and L2 from the Satom to the furthest heavy atom of the substituent to make the determination easier. (b) Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4, 366. (c) Verloop, A. IUPAC Pesticide Chemistry; Pergamon: 1983; Vol. 1. (d) Verloop, A. T. J. Biological Activity and Chemical Structure; Elsevier: 1977. (e) Verloop, A. T. J. In QSAR in Drug Dosing and Toxicology; Hadzi, B., Jerman-Blazic, B., Eds.; Elsevier: 1987; Vol. 97. (17) Dunitz, J. D.; Ibberson, R. M. Angew. Chem., Int. Ed. 2008, 47, 4208. (18) The structure of Zn-TPP bound to S-4m was determined by single crystal X-ray diffraction (CCDC 1518650).
with the metalloporphyrin. To address the latter concern, esomeprazole (Nexium), a highly effective proton pump inhibitor, with a number of potential coordinating functional groups was complexed with Zn-MAPOL 2 (Figure 4). Gratifyingly, a positive ECCD was observed, consistent with what was expected, considering the longer benzo-imidazole substituent as the determinant for helicity.
Figure 4. Complexation of esomeprazole (50 μM) with Zn-MAPOL 2 (1 μM) yields a positive ECCD spectrum, correctly predicting the S stereochemistry of the molecule. The assignment is based on considering the benzoimidazole side chain as the larger substituent (longer linear length as compared to the pyridyl side chain).
In summary, we report the first direct chiroptical method for the absolute stereochemical determination of chiral sulfoxides without the need for derivatizations or chemical transformations. The procedure is reliable, requiring a microgram quantity of chiral sulfoxides. Also, absolute stereochemistry is arrived at in a matter of minutes, with an operationally simple method that is amenable for researchers with little experience in chiroptical techniques. The mnemonic for correlating the observed ECCD sign to the actual stereochemistry at the S-center is straightforward, requiring the operator to only make a choice on the relative length and size of the substituents attached to the S-center.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00495. Experimental details, spectroscopic data, (PDF) Crystallographic data for Zn-TPP/DMSO (CIF) Crystallographic data for Zn-TPP/S-4m (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hadi Gholami: 0000-0001-6520-0845 Jun Zhang: 0000-0002-9986-0312 Babak Borhan: 0000-0002-3193-0732 Funding
We are grateful to the NSF (CHE-1213759) for funding. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to Dr. Richard Staples (MSU) for solving the crystal structures of the DMSO and S-4m bound to Zn-TPP. REFERENCES
(1) Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. D
DOI: 10.1021/acs.orglett.7b00495 Org. Lett. XXXX, XXX, XXX−XXX
