Mechanistic investigation on the remote stereocontrol in the chiral Lewis base-catalyzed, SiCl4-promoted kinetic resolution of chlorinated cis-vinyl epoxides
Graphical abstract
Introduction
Epoxide is one of the most versatile functional groups in organic synthesis, and thus a number of synthetic methods have been developed for the enantioselective formation of chiral epoxide [1]. Enantioenrichment can also be achieved by the enantioselective opening of optically inactive epoxide via either desymmetrization of meso-epoxide [2] or kinetic resolution of racemic epoxide [3], typically in the presence of chiral Lewis acid. Denmark and coworkers developed a chiral Lewis base catalysis for the generation of highly active chiral silicon Lewis acids by taking advantage of Lewis base activation of Lewis acids phenomenon [4], and the utility of such catalytic system was demonstrated in the desymmetrization of meso-epoxide with chiral phosphoramide catalyst and silicon tetrachloride [5]. Since this seminal report, various types of chiral Lewis base including N-oxides [6], phosphines [7], and phosphine oxides [8] were developed by several research groups, and highly selective epoxide desymmetrization was accomplished, illustrating the efficiency of the Lewis base-SiCl4 system [9]. Later, the scope of Denmark’s chiral phosphoramide-catalyzed, enantioselective epoxide opening has been successfully extended to the kinetic resolution of racemic cis-vinyl epoxide (1) by Vanderwal and coworkers during the enantioselective total synthesis of chlorosulfolipids (Fig. 1A) [10]. In this case, the dimeric bisphosphoramide 2 performed better than the monomeric catalyst even though it was an inferior catalyst for desymmetrization. Interestingly, the selectivity of the kinetic resolution is highly affected by the configuration of a relatively remote β-stereocenter. Under the identical catalytic conditions with 2, anti-α,β-dichloride (R = n-C6H13) was resolved much more effectively than the related syn-α,β-dichloride (R = n-C8H17). Recently, a preliminary mechanistic study on the stereo-controlling effect of these chlorine-bearing stereocenters was reported by our group (Fig. 1B) [11]. Through a systematic examination of α- or β-monochlorinated substrates 4–6, we have demonstrated that both α- and β-chlorine substituents are required for the high level of enantio-differentiation. In addition, computational analysis was performed for the aliphatic side chain conformation of α,β-dichlorinated vinyl epoxide in order to rationalize the cooperative action of the two stereocenters. It was suggested that the allylic 1,3-like strain at the α-stereocenter as well as the preferred gauche conformation between the α- and β-chlorine-bearing carbons result in a fairly well-defined spatial arrangement of the substituents. Then, upon examination of the ground state of a representative catalyst-substrate complex, it was proposed that the dichloroalkyl side chain could be placed near the chiral catalyst pocket depending on the epoxide configuration, and the conformationally rigid α-center would direct the aliphatic residue toward the catalyst. Thus, the enantiomer with its alkyl side chain in a less crowded space (i) is likely to be activated preferentially to result in the selective epoxide opening whereas the other enantiomer-catalyst complex (ii) is energetically less favorable because of the destabilizing steric interaction between the β-substituents of the side chain and the catalyst. The degree of such interaction appears to be finely controlled by the position and property of the substituents at the β-center. In the current study, the influence of the remote site was further evaluated by employing a substrate with two β-alkyl groups (Fig. 1C). This type of substrate can be considered as an alkyl analog of α,β-dichloro cis-vinyl epoxide, in which the β-chlorine is replaced by an alkyl group. Then, a more precise computational analysis was conducted via transition state calculation to support our stereochemical model and to rationalize the observed remote configuration-dependency. Herein, we describe the results from these mechanistic investigations that led to a plausible proposal on the nature of the catalyst-substrate interaction.
Section snippets
Kinetic resolution of α-chloro cis-vinyl epoxide with two β-alkyl substituents
To probe the role of the β-substituents, two alkyl moieties were installed at the β-position of α-chloro cis-vinyl epoxide (Scheme 1A). A cyclohexyl group was employed in order to avoid the creation of an additional stereocenter as well as to increase the molecular weight for convenient handling. First, commercially available 2-cyclohexylethanol (7) was oxidized to aldehyde 8 via the Swern oxidation [12]. Then, α-chlorination was accomplished with the combination of NCS and (±)-proline to give
Conclusions
In summary, we have conducted experimental and theoretical mechanistic investigations on the kinetic resolution of chlorinated cis-vinyl epoxides to elucidate the origin of the remarkable stereo-controlling effect of the remote β-stereocenter, which has been observed with α,β-dichloro cis-vinyl epoxides. Through a control experiment with a β,β-dialkyl analog, the site of predominant catalyst-substrate interaction was identified (X in Fig. 1B). Furthermore, DFT calculation of the transition
General experimental
All reactions were performed in oven-dried (140 °C) or flame-dried glassware under an atmosphere of dry argon unless otherwise noted. Purification of solvents and reagents are described in the Electronic Supporting Information. Filtration and column chromatography were performed using Merck silica gel (SiO2) 60 Å (0.040–0.063 mm). Analytical thin-layer chromatography (TLC) was conducted on Merck silica gel 60 F254 TLC plates. Visualization was accomplished with UV (254 nm) as well as KMnO4 and p
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science & ICT (NRF-2020R1F1A1076028) and by “GIST Research Institute (GRI)" grant funded by the GIST in 2020.
References (28)
- et al.
Eur. J. Org Chem.
(2020)Chem. Rev.
(2017)et al.Chem. Commun.
(2015)et al.Chem. Asian J.
(2015)et al.Angew. Chem. Int. Ed.
(2014)et al.Chem. Rev.
(2014)et al.Chem. Rec.
(2011)et al.Chem. Soc. Rev.
(2011)et al.Chem. Rev.
(2008)Coord. Chem. Rev.
(2008)et al.Chem. Rev.
(2005)et al.Chem. Rev.
(2005)et al.Org. React.
(1996)Chem. Rev.
(1989) - et al.
Angew. Chem. Int. Ed.
(2013)et al.J. Org. Chem.
(2014)et al.Acc. Chem. Res.
(2014) - et al.
Org. Lett.
(2006) - et al.
Chem. Eur J.
(2016)Beilstein J. Org. Chem.
(2013)Compreh. Chiral.
(2012)Eur. J. Org Chem.
(2006)Synthesis
(2006)et al.Chem. Soc. Rev.
(2002)Acc. Chem. Res.
(2000) - et al.
Adv. Synth. Catal.
(2001)et al.Angew. Chem. Int. Ed.
(2005) - et al.
Angew. Chem. Int. Ed.
(2008) - et al.
J. Org. Chem.
(1998)et al.Adv. Synth. Catal.
(2007)et al. - et al.
J. Am. Chem. Soc.
(2001)et al.Tetrahedron Lett.
(2002)et al.Tetrahedron
(2008)et al.Angew. Chem. Int. Ed.
(2008)et al.Org. Lett.
(2009) - et al.
J. Org. Chem.
(1997)et al.Synlett
(2003) - et al.
Tetrahedron: Asymmetry
(2005)et al.Adv. Synth. Catal.
(2008)et al.J. Am. Chem. Soc.
(2009)et al.Tetrahedron
(2013)et al.Angew. Chem. Int. Ed.
(2013)
Tetrahedron
Bull. Kor. Chem. Soc.
Angew. Chem. Int. Ed.
J. Am. Chem. Soc.
J. Am. Chem. Soc.
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