Experimental and Computational Studies on Regiodivergent Chiral Phosphoric Acid Catalyzed Cycloisomerization of Mupirocin Methyl Ester

Abstract

This article presents a new strategy for achieving regiocontrol over the endo versus exo modes of cycloisomerizations of epoxide‐containing alcohols, which leads to the formation of five‐ or six‐membered cyclic ethers. Unlike traditional methods relying on achiral reagents or enzymes, this approach utilizes chiral phosphoric acids to catalyze the regiodivergent selective formations of either tetrahydrofuran‐ or tetrahydropyran‐containing products. By using methyl ester of epoxide‐containing antibiotic mupirocin as the substrate, it is demonstrated that catalytic chiral phosphoric acids (R)‐TCYP and (S)‐TIPSY could be used to achieve the selective formation of either the six‐membered endo product (95:5 r.r.) or the five‐membered exo product (77:23 r.r.), correspondingly. This cyclization was found to be unselective under the standard conditions involving various achiral acids, bases, or buffers. The subsequent mechanistic studies using state‐of‐the‐art quantum chemical solutions provided the description of the potential energy surface, which is fully consistent with the experimental observations. Based on these results, highly detailed reaction paths are obtained and a concerted and highly synchronous mechanism is proposed for the formation of both exo and endo products.

Identifying the true origins of selectivity in chiral phosphoric acid catalyzed N-acyl-azetidine desymmetrizations

“…67 Then, to study the mechanism of the transformation and the preferred conformations of the transition structures (TS) leading to the (R)-and (S)-products, we used dimethoxyphosphoric acid (5) as a model truncated catalyst, keeping a fixed conformation in line with the axial chirality of (R)-3. This approach has been used successfully in previous work, 51,54,62 and the lowest-energy TSs located with the small catalyst often mimicked those obtained with the large BINOL-(or SPINOL-) derived catalyst, indicating that low-energy TS arrangements are independent of the catalyst's cavity shape (see below). In agreement with the known catalytic behavior of CPAs which predominantly activate both nucleophile and electrophile simultaneously via bifunctional activation, 18 four possible activation modes were explored computationally.…”

“…Ad = adamantyl DFT geometry optimizations were performed with Gaussian 16 at the B97D3/6-31G(d,p) level of theory, 57 with the CPCM implicit solvation 58,59 model for toluene. This method has been shown to provide good results in previous DFT studies of CPA-catalyzed reactions [52][53][54][60][61][62] and accounts for both dispersive interactions and solvation issues. Conformational sampling of each stationary point was performed using Grimme's CREST algorithm 63 as implemented in the XTB code.…”

Synthesis and Evaluation of C2-Symmetric SPIROL-Based bis-Oxazoline Ligands

“…The general information about reagents and equipment and the copies of 1 H and 13 C NMR spectra for compounds 2-8 and HPLC traces for chiral product 4 are provided in Supplementary Materials. Enantiopure (R,R,R)-SPIROL (2) [15,16] (500.0 mg, 1.60 mmol, 1.0 equiv.)…”

“…1 H NMR (400 MHz, CD 3 OD) δ 7.85 (dd, J = 6.2, 2.6 Hz, 2H), 7.57-7.36 (m, 4H), 5.18 (dd, J = 7.6, 3.9 Hz, 2H), 1.96 (ddq, J = 11.0, 7.6, 3.8 Hz, 2H), 1.83 (dt, J = 14.3, 7.3 Hz, 2H), 1.02 (t, J = 7.4 Hz, 6H). 13 (332.4 mg, 2.14 mmol, 6.1 equiv.) were added to a round-bottom flask under nitrogen.…”

“…In particular, the developments in the design of C2-symmetric spirocyclic ligands has greatly impacted the field of asymmetric catalysis, and thousands of recent studies are focused on exploring such ligands in asymmetric synthesis and catalysis [5][6][7][8]. Powered by our long-term interests in chiral phosphoric acid catalysis [9][10][11][12][13][14], our group has been engaged in the development and exploration of new spiroketal-based C2-symmetric spirocyclic ligands (SPIROLs) [15,16]. Thus, in 2018 we described the one-step asymmetric synthesis of diastereomeric (S,S,S)-and (R,S,S)-SPIROL (2) cores from the readily available chiral alcohols (S)-1 (Scheme 1A).…”