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Total Synthesis of C-α-Mannosyl Tryptophan via Palladium-Catalyzed C–H Glycosylation

2020; Chinese Chemical Society; Volume: 3; Issue: 6 Linguagem: Inglês

10.31635/ccschem.020.202000380

2096-5745

Quanquan Wang, Yue Fu, Wanjun Zhu, Shuang An, Qian-Yi Zhou, Shou‐Fei Zhu, Gang He, Peng Liu, Gong Chen,

Studies on Chitinases and Chitosanases

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jun 2021Total Synthesis of C-α-Mannosyl Tryptophan via Palladium-Catalyzed C–H Glycosylation Quanquan Wang, Yue Fu, Wanjun Zhu, Shuang An, Qianyi Zhou, Shou-Fei Zhu, Gang He, Peng Liu and Gong Chen Quanquan Wang State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Yue Fu Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 , Wanjun Zhu State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Shuang An State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Qianyi Zhou State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Shou-Fei Zhu State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Gang He *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Peng Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 and Gong Chen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.020.202000380 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail The C2-α-mannosyl-tryptophan amino acid is produced by a unique posttranslational modification (PTM) of proteins and poses a significant synthetic challenge. A new strategy based on Pd-catalyzed auxiliary-directed remote C–H glycosylation of tryptophan was developed, which generates the C2-α-mannopyranose (Man)-Trp unit in a highly efficient and stereoselective fashion. Density functional theory (DFT) computational studies support a concerted oxidative addition mechanism for the stereospecific functionalization of a Pd(II) palladacycle intermediate with an α-mannosyl chloride donor. The utility of this method was demonstrated in the first total synthesis of insect C-glycopeptide hormone Cam-HrTH-I. Download figure Download PowerPoint Introduction Enzyme-catalyzed glycosylation provides one of the most sophisticated means for posttranslational modification (PTM) of proteins.1–4 Besides typical glycosylations of nucleophilic functional groups such as OH and NH2, nature has evolved to modify more inactive sites of metabolites and biopolymers via C-glycosylation, in which the C1 atom of a sugar ring is appended to a carbon atom of substrate.5,6 In 1992, Gade et al. reported the isolation of Cam-HrTH-I 1, a decamer glycopeptide hormone, from the stick insect Carausius morosus. They noted that 1 carried a very unusual hexose modification on the tryptophan residue, although the identity of the hexose and the structure of the glyco-linkage was unclear.7,8 Soon afterwards, Hofsteenge et al.9,10 reported a related glycosylation-modified tryptophan in ribonuclease II and determined the glycol linkage was an α-mannopyranose (Man) at the indole C2 position of tryptophan (Scheme 1a). Since these groundbreaking studies, C2-α-Man-Trp has been gradually recognized as a widespread PTM of proteins, observed in the thrombospondin type-1 repeat (TSR) superfamily, type I cytokine receptor family, and many others.11,12 While significant data about the sequence selectivity of C-mannosylation of tryptophan in various proteins have been gathered over the years, the biological function of this PTM remains elusive. The lack of sufficient homogenous C-mannosyl-peptide or protein materials may have hampered functional studies. Scheme 1 | (a and b) Structure and synthesis of C2-α-mannosyl-Trp. Download figure Download PowerPoint The uniquely challenging structure of the glycosyl-amino acid building block C-Man-Trp 2 has attracted a number of synthetic studies.13–18 Most notably, Manabe and Ito14 reported the first total synthesis featuring a key step of BF3OEt2-mediated stereoselective ring opening of the epoxide 1,2-anhydro-mannose 4 by C2-lithiated tryptophan-derived indole 3 (Scheme 1b). However, to accommodate the high reactivity of 3, protection of the amine and carboxylic acid groups of tryptophan were required, resulting in diminished step and redox economy. Nishikawa et al.17 prepared C-mannosyl indole moiety 7 from C-alkynyl mannose precursor 6 via Castro indole cyclization under Cu catalysis. Subsequent installation of the amino acid backbone with serine-derived aziridine 8 completed the scaffold of 2. However, the three key bonds at the glyosidic, indolyl C–N, and Cα–Cβ positions were made in a stepwise fashion, resulting in a long linear sequence. Herein, we report a streamlined stereoselective synthesis of C-α-mannosyl tryptophan via palladium-catalyzed auxiliary-directed remote C–H glycosylation of tryptophan with simple mannosyl chloride. The utility of this method was demonstrated in the first total synthesis of Cam-HrTH-I 1. Computational Methods Geometry optimizations and single-point energy calculations were carried out using Gaussian 16 (Gaussian, Inc; Wallingford, Ct) (see Supporting Information for details). Geometries of intermediates and transition states were optimized using dispersion-corrected B3LYP-D3 functional with a mixed basis set of LANL2DZ for Pd and 6-31G(d) for other atoms in the gas phase. Vibrational frequency calculations were performed for all the stationary points to confirm if each optimized structure is a local minimum or a transition state structure. All optimized transition-state structures had only one imaginary (negative) frequency, and all minima (reactants, products, and intermediates) had no imaginary frequencies. The M06 functional with a mixed basis set of SDD for Pd and 6-311+G(d,p) for other atoms was used for single-point energy calculations in solution. Solvation energy corrections were calculated in toluene solvent with the SMD continuum solvation model based on the gas-phase optimized geometries. The reported Gibbs free energies and enthalpies include zero-point vibrational energies and thermal corrections at 298 K. The three-dimensional (3D) images of structures were prepared using CYLview and POV-Ray. Results and Discussion The conventional strategies for synthesis of aryl C-glycosides often rely on the coupling or addition reactions of properly functionalized aryl partners.19–29 We previously reported a new synthetic strategy based on Pd-catalyzed auxiliary-directed glycosylation of the ortho C–H bonds of arene substrates.30 Arylcarboxamide or 2-arylacetamide substrates equipped with an N,N-bidentate 8-aminoquinoline (AQ) auxiliary react with various glycosyl chloride donors to give the corresponding aryl C-glycosides in good to excellent yield and with excellent diastereoselectivity.31–42 Previously, the Ye group36 reported the first Pd-catalyzed AQ-directed ortho C–H alkenylation of arenes with 1-iodoglycals to generate C1-aryl-substituted glycals. This Pd-catalyzed C–H alkenylation was recently extended to alkyl substrates for synthesis of C1-alkyl-substituted glycals.37,38 These Pd-catalyzed reactions start with C–H palladation at the ortho position of arene to form a five- or six-membered PdII palladacycle intermediate.43–51 Due to the stabilizing effect of the auxiliary, this PdII palladacycle intermediate reacts with chloro glycosyl donors via oxidative addition (OA) and reductive elimination (RE) to give C-glycosylated product.30 Reactions of arylcarboxamides through kinetically favored five-membered palladacycle intermediates exhibited higher reactivity than 2-arylacetamides through six-membered palladacycle intermediates. Encouraged by these results, we investigated whether auxiliary-directed mannosylation of C2–H of the tryptophan indole could give the desired Cα-Man-Trp product. As shown in Scheme 2a, our investigation commenced with the model substrate AQ-coupled, benzyl-protected 2-indolylacetamide 9. Reaction of 9 with tetrabenzyl-protected mannosyl chloride 10 (2 equiv) under the optimized conditions of 10 mol % of Pd(OAc)2, 1.5 equiv of KOAc, and 30 mol % of Ac-Ile-OH additive in toluene at 110 °C for 12 h gave the desired product 11 in 11% yield and with exclusive α selectivity.52,a,b This reaction presumably proceeds through a six-membered PdII palladacycle intermediate 9-0. In comparison, the reaction of 12 without the N-benzyl protecting group under the same conditions gave N-mannoside 13-N as the only major product.c Unsurprisingly, C–H glycosylation of AQ-coupled tryptophan 14 with 10 through the higher energy seven-membered palladacycle intermediate 14-0 did not give any desired product 15 under the various conditions tested. As shown in Scheme 2b, model substrate 3-methylindole 16 bearing a urea-linked AQ auxiliary on N1 underwent C–H glycosylation with 10 at the C2 position under standard conditions to give product 17-2 in moderate yield (57%) and with excellent α selectivity.d Notably, the C7 regioisomer of 17-2, formed through a similar six-membered palladacycle intermediate, was not observed. Unfortunately, the reaction of more complex tryptophan substrate 18 did not give any desired product 19, likely due to complexation of Pd by the ester or phthalamide groups. Scheme 2 | (a and b) C–H glycosylation of Trp using a Cα or N1 linked auxiliary. Download figure Download PowerPoint The failure of Pd-catalyzed C–H mannosylation of tryptophan using Cα or N1 linked auxiliary compelled us to investigate the use of auxiliaries installed on the N terminus (Nα). To our delight, C–H mannosylation of N1-benzyl-protected tryptophan 20 equipped with a picolinamide (PA) auxiliary under the standard conditions gave the desired product 21 in 82% yield and with exclusive α selectivity (Scheme 3a).31,45–51 The reaction likely proceeds through a six-membered palladacycle intermediate 20-0. C–H glycosylation of the C4 position of indole was not observed. However, the N1-benzyl protecting group of 21 was very difficult to remove under various hydrogenolysis conditions tested. In contrast, PA-directed C-mannosylation of N1-unprotected Trp substrate gave product 25-C in 54% yield along with 7% of undesired N-mannosylation product 25-N (Scheme 3b). Subsequent investigation of various analogs of the PA directing group revealed that the isoquinoline-1-carboxylic acid (i1QA) auxiliary is more effective, and the reaction of 23 gave the desired product 24-C in 85% yield with exclusive α selectivity and 5% of N-mannosylation product 24-N.46,e,f The stereochemistry of 24-C was confirmed by NMR analysis (see Supporting Information for details). No racemization of tryptophan was observed. Compound 23 was readily prepared in 76% yield via amide coupling of tryptophan methyl ester 20 and i1QA, both of which are commercially available at low cost. In contrast, substrates equipped with isoquinoline-3-carboxylic acid (i3QA) or quinoline-2-carboxylic acid (QA) auxiliaries (see 26 and 27) exhibited lower reactivity and chemoselectivity. Additionally, simpler PA derivatives bearing either electron-withdrawing or electron-donating groups on the pyridine ring did not improve results ( 28, 29). Scheme 3 | C–H glycosylation of Trp using Nα linked auxiliary. (a) i1QA, HATU, HOAt, N,N-Diisopropylethylamine (DIPEA), dimethylformamide (DMF), room temperature, 76%. Download figure Download PowerPoint Next, we performed density functional theory (DFT) calculations to probe the mechanism of this Pd-catalyzed C−H mannosylation reaction and the origin of the high α-selectivity (Figure 1). PA-coupled tryptamine 31 and tetramethyl mannosyl chloride 34 were used as model substrates in the calculations. C−H palladation of 31 via a concerted metalation–deprotonation mechanism ( TS1) gives palladacycle intermediate 33. Previously, we speculated that a stepwise OA of 33 to an oxocarbenium intermediate generated from the mannosyl chloride donor gives mannosyl Pd(IV) intermediate 35-α.30,g However, our DFT calculations revealed that the OA proceeds via a concerted three-membered cyclic transition state ( TS2-α), which directly leads to 35-α without the formation of oxocarbenium [see Supporting Information for intrinsic reaction coordinate (IRC) calculations that confirm the nature of this transition state] (Figure1b).53,h A concerted RE of 35-α via the three-membered cyclic transition state TS3-α gives α-mannosylation product 36-α.i While both the OA and RE transition states in the α-selective pathway possess relatively low barriers, the corresponding β-mannosylation pathway from β-mannosyl donor 34-β is significantly disfavored (shown in dark red, Figure1a). The 1,2-cis configuration of C2−OMe and C1−Pd causes severe steric destabilization of the β-mannosyl Pd(IV) intermediate 35-β: the 35-β-ax conformer with an axial C–Pd bond is destabilized by the 1,3-diaxial interactions between the basal plane of the square pyramidal Pd complex and the C3/C5 substituents, while the 35-β-eq conformer with an equatorial C−Pd bond is destabilized by the gauche repulsions with the C2−OMe group (Figure 1c). Overall, the concerted, stereospecific formation of the configurationally stable α-mannosyl Pd(IV) intermediate 35-α and the higher barrier to form the β-mannosylation product contribute to the high α-selectivity of this C−H mannosylation reaction. Figure 1 | (a–c) Computational studies of the Pd-catalyzed C−H mannosylation of PA-coupled tryptamine 31 with 34-α and 34-β. All energies are in kcal/mol with respect to 31 and 34-α/34-β in the black and dark red pathways, respectively. Bond distances are in Å. Download figure Download PowerPoint As shown in Scheme 4a, the amide-linked i1QA auxiliary group of 24-C was cleanly removed by brief treatment with 10 equiv of zinc powder in mixed solvent of 1N aq. HCl and THF at room temperature, giving amine product without any racemization of tryptophan.54,45–51 Protection of the amine with Boc2O and NEt3 in CH3CN gave compound 37 in 81% yield over two steps. A proton-coupled electron-transfer process might facilitate the reduction of the amide linkage of i1QA to a hemiaminal intermediate, which upon hydrolysis gives the amine product. Saponification of 37 with LiOH in a MeOH/H2O/THF mixture gave free acid 39 in high yield. Hydrogenolysis of 37 with Pd(OH)2/C catalyst under 1 atm of H2 in mixed EtOAc, MeOH, and HCO2H at room temperature, followed by saponification with LiOH in MeOH/H2O/THF gave Boc-protected Trp(Man) 38 in 78% yield. Overall, 38 was prepared in approximately 40% yield in six linear steps from inexpensive starting material H-Trp-OMe 22. As outlined in Scheme 4b, a fragment peptide coupling strategy at the racemization-resistant proline site was adopted to assemble decamer glycopeptide Cam-HrTH-I. Amide coupling of 39 and side chain-blocked dipeptide H-Gly-Thr(Bn)-NH2 40 gave tripeptide 41 in 85% yield. The Boc-protected N terminus of 41 was then extended with an asparagine residue using the standard amide coupling and Boc deprotection procedure to give tetrapeptide 42. Hexamer peptide 43 was prepared via standard solid-phase peptide synthesis using Fmoc-protected building blocks. To our delight, coupling of 42 and 43 at the Pro-Asn termini under HATU/HOAt-mediated conditions proceeded cleanly to give the desired decamer product with negligible racemization. Global benzyl deprotection by hydrogenolysis with Pd(OH)2/C catalyst in mixed THF, MeOH, H2O, and HCO2H gave Cam-HrTH-I in good yield and high purity after HPLC purification. Scheme 4 | (a and b) Preparation of Boc-Trp(Man)-OH and synthesis of Cam-HrTh-I. Download figure Download PowerPoint Conclusion We have explored different Pd-catalyzed auxiliary-directed C–H glycosylation reactions to install a C-mannosyl group on the C2 position of tryptophan substrate. These efforts led to a highly efficient and stereoselective method for synthesis of C2-α-Man-Trp using a new isoquinoline acid auxiliary installed on the N terminus of tryptophan. Mechanistic studies revealed a concerted OA mechanism for the stereospecific functionalization of palladacycle intermediate with the α mannosyl chloride donor. Streamlined access to glycosylamino acid building block Boc-C-α-Man-Trp-OH enabled us to complete the first total synthesis of insect adipokinetic hormone Cam-HrTH-I in high efficiency. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information The experimental studies of this work were funded by NSFC-91753124, NSFC-21672105, NSFC-21421062, and NSFC-21725204 grants. Acknowledgments DFT calculations were performed at the Center for Research Computing at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by NSF. Footnotes a Many other carboxylic acid additives can also enhance this reaction albeit with slightly lower capacity than Ac-Ile-OH. For representative uses of amino acid ligands in Pd-catalyzed C–H reactions see Ref. 52. b C4 conformation of C-Man-Trp product was confirmed by NMR, see Supporting Information. c C4 conformation of N-Man-Trp product was confirmed by NMR, see Supporting Information. d Detailed study of Pd-catalyzed C–H glycosylation reactions using urea-linked auxiliaries will be reported in a future paper. e The functionalization step of palladacycle intermediate with glycosyl donor was shown to be the rate-limiting step in our AQ-directed C–H glycosylation system.10 We suspect that, in comparison to PA, the fused benzo group on i1QA may facilitate the functionalization step of the corresponding palladacycle intermediate, thus leading to higher reactivity and chemoselectivity (C vs N). f Most glycosyl chloride donors, except glucosyl chlorides, gave excellent diastereoselectivity in our Pd-catalyzed bidentate auxiliary-directed C–H glycosylation reactions.10 Most glycosyl chloride donors bearing electron-donating protecting groups showed good to excellent reactivity for reactions proceeding via five-membered palladacycle intermediates. In contrast, more remote C–H glycosylation reactions proceeding via the kinetically less favored six-membered palladacycle intermediate generally exhibited lower reactivity. While mannosyl chloride showed excellent yield of the desired C-glycosylation of the tryptophan substrate, the reactions of other donors such as galactose and ribofuranose chloride gave poorer yield of C-glycosylation product and formed significant amount of undesired N-glycosylation products. It is currently unclear why the α-diastereoselectivity of N-mannosylation side products 13-N and 24-N is strongly favored. g Pd(OAc)2 can also act as a Lewis acid to activate glycosyl chlorides to generate oxocarbenium intermediates.10 This observation led to the previous proposal of a stepwise OA of palladacycle intermediate to oxocarbenium for formation of a glycosyl Pd(IV) intermediate. h Our attempts to computationally locate the SN1-type oxidative addition transition state were not successful. 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