SYNLETT0936-52141437-2096 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2021, 32, 1024–1028 letter 1024 en Synlett N. Shimada et al. Letter Direct Synthesis of N-Protected Serine- and Threonine-Derived Weinreb Amides via Diboronic Acid Anhydride-Catalyzed Dehy- drative Amidation: Application to the Concise Synthesis of Garner’s Aldehyde Naoyuki Shimada* 0000-0002-0143-7867 HO O OH B B Naoki Ohse Br Br • 5 examples • 89%–95% yields Naoya Takahashi • gram scale synthesis Sari Urata O Br Br O O Boc Masayoshi Koshizuka BocHN (2.0–5.0 mol%) BocHN OMe N OH N H Kazuishi Makino 0000-0001-8518-6593 HNMe(OMe) Me OH DCE, reflux OH O Garner’s aldehyde Laboratory of Organic Chemistry for Drug Development and – H2O 93% yield 89% yield over 3 steps Medical Research Laboratories, Department of Pharmaceutical without racemization Sciences, Kitasato University, Tokyo 108-8641, Japan Catalytic synthesis of serine- and threonine-derived Weinreb amides [email protected] Corresponding Author Received: 22.03.2021 Recently, some condensation conditions using EDCI,9 Accepted after revision: 10.04.2021 HBTU,10 HATU,11 CDI,12 and T3P13 as coupling reagents were Published online: 04.05.2021 DOI: 10.1055/s-0037-1610773; Art ID: st-2021-r0109-l applied to the synthesis of -hydroxy--amino acid derived Weinreb amides. However, these conditions require stoi- Abstract An efficient method for the direct synthesis of Weinreb am- chiometric amounts of reagents, resulting in cumbersome ides derived from serine and threonine derivatives via diboronic acid an- workup and purification procedures and poor atom econo- hydride-catalyzed hydroxy-directed amidation is described. This is the first successful example of the synthesis of serine- or threonine-derived my. Therefore, the development of an environmentally be- Weinreb amides using catalytic dehydrative amidations. The methodol- nign catalytic version of the dehydrative amide condensa- ogy could be applied to the concise synthesis of Garner’s aldehyde. tion reaction is highly demanded (Scheme 1a). Starting with Yamamoto’s pioneering report on the catalytic dehy- Key words dehydrative amidation, Weinreb amide, Garner’s aldehyde, organoboron catalysis, diboronic acid anhydride, hydroxy-directed re- drative amide condensation of carboxylic acids with amines 14 action using electron-deficient aromatic boronic acids, a variety of amidations and peptide synthesis utilizing organoboron catalysts, such as modified aromatic boronic acids,15–18 di- N-Methoxy-N-methylamides, commonly called Weinreb boron,19 borate esters,20 DATB,21 and gem-diboronic acid,22 amides,1 are useful functional groups that can be easily have been developed. In this context, we disclosed that a di- converted into aldehydes or modified ketones in organic boronic acid anhydride possessing the B–O–B motif23 is a synthesis.2 Especially, Weinreb amides derived from -hy- highly efficient catalyst for the dehydrative amidation of - droxy--amino acids such as serine or threonine have been or -hydroxycarboxylic acids24a or -hydroxy--amino ac- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. widely used as chiral building blocks for the synthesis of ids.24b More recently, we found that this hydroxy-directed complex products.3 Moreover, N-tert-butoxycarbonyl (Boc) amidation reaction could be also applied to the reaction of protected serine-derived Weinreb amide is an important - or -hydroxycarboxylic acids with weakly nucleophilic synthetic intermediate for Garner’s aldehyde,4,5 which is, in N,O-dimethylhydroxylamine, demonstrating the first cata- turn, a versatile chiral intermediate in the synthesis of nat- lytic synthesis of Weinreb amides from carboxylic acids ural products and biologically active chiral compounds (Fig- ure 1).6,7 Although Weinreb amides have been synthesized O O O from various precursors such as esters, amides, imides, al- Boc PGHN OMe PGHN OMe N dehydes, alcohols, aryl halides, and acid chlorides,2 the N N H Me Me condensation reaction of carboxylic acids with N,O-di- OH OH O N methylhydroxylamine is the most straightforward meth- N-protected serine- -protected threonine-derived Garner’s aldehyde od. To this end, a number of coupling reagents have been derived Weinreb amides Weinreb amides developed.8 Figure 1 Structures of Weinreb amides and Garner’s aldehyde © 2021. Thieme. All rights reserved. Synlett 2021, 32, 1024–1028 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 1025 Synlett N. Shimada et al. Letter (Scheme 1b).24c Herein, we report an efficient method for ronic anhydride 1 for the preparation of N-Boc-protected the direct preparation of N-protected serine- and thre- serine-derived Weinreb amide.26 To the best of our knowl- onine-derived Weinreb amides via diboronic acid anhy- edge, this is the first example of a catalytic synthesis of dride-catalyzed dehydrative amidations (Scheme 1c). The Weinreb amides derived from amino acids. synthetic utility of this catalytic system is demonstrated By using diboronic acid anhydride 1 as a catalyst, we by its application to the concise synthesis of Garner’s alde- then explored the dehydrative amidation of several serine- hyde. derivatives possessing different N-protected groups (Scheme 2). High product yields with minimum racemiza- (a) Weinreb amides synthesis from carboxylic acids tion were consistently observed with either N-Cbz-serine • conventional method: activation by using stoichiometric amount of reagent (2b) or N-Fmoc-serine (2c), giving the corresponding Wein- O coupling O O reb amides 4b and 4c in 95% and 92% yields, respectively. reagent HNMe(OMe) PGHN PGHN PGHN OMe OH Y N We next turned our attention to the reaction of threonine – YH Me derivatives, a residue that bears an additional methyl group R OH R = H: Ser R OH R OH R = Me: Thr active ester at the -position. Gratifyingly, N-Boc-threonine (2d) and N- catalyst HNMe(OMe) Cbz-threonine (2e) were applicable as substrates, and the corresponding Weinreb amides 4d and 4e were obtained in • ideal method: catalytic dehydrative amidation – H2O (b) Our previous work: catalytic synthesis of hydroxy Weinreb amides24c 89% and 90%, respectively; however, in this case, an in- O diboronic acid O creased catalyst loading of 5.0 mol% was necessary to ob- anhydride OMe R OH HNMe(OMe) R N tain satisfactory product yields. Me In this catalytic reaction, the desired Weinreb amide 4a nOH n OH α-hydroxycarboxylic acids (n = 0) n = 0 or 1 was obtained in 92% yield even when using a commercially β-hydroxycarboxylic acids (n = 1) available N,O-dimethylhydroxylamine hydrochloride (c) This work: catalytic synthesis of Ser/Thr-derived Weinreb amides O diboronic acid O PGHN anhydride PGHN OMe OH HNMe(OMe) N Table 1 Optimization of Dehydrative Amidation Conditionsa Me R OH R OH R = H (Ser) or Me (Thr) R = H or Me HO OH N-protected β-hydroxy-α-amino acids O Br B B Br Scheme 1 Synthesis of Weinreb amides O O BocHN BocHN OMe OH H OMe N N Br Br Me On the basis of our previous work, we initially explored OH Me 1 (x mol%) OH 2a 3 4a the dehydrative amidation of N-Boc-protected serine (2a) solvent (0.20 M) 1.0 equiv y equiv >99% ee with 3.0 equivalents of N,O-dimethylhydroxylamine (3) in 90 °C the presence of 2.0 mol% of diboronic acid anhydride 1 (Ta- ble 1). The reaction in toluene proceeded smoothly at 90 °C Entry 1 (x mol%) 3 (y equiv) Solvent Time (h) Yield (%)b to give serine-derived Weinreb amide 4a in 60% yield (entry 12.03.0toluene4 60 1). A survey of solvents revealed that 1,2-dichloroethane 22.03.0CH Cl 4 70 (DCE) was the optimal solvent for this transformation (en- 6 5 tries 2–4). We also performed a screening of the amount of 32.03.0C6H5CF3 463 amine 3, finding that a reduction to 2.0 equivalents 4 2.0 3.0 DCE 4 74 dropped the yield to 50% (entry 5), whereas an increase to 5 2.0 2.0 DCE 4 50 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 5.0 equivalents did not change the yield (entry 6). More- 6 2.0 5.0 DCE 4 74 over, prolonging the reaction time resulted in an improved 7 2.0 3.0 DCE 24 96 (93) yield of Weinreb amide 4a to 93% isolated yield (entry 7). It 8c 2.0 3.0 DCE 24 (82) is significant that 4a was obtained without any racemiza- tion at the -position of the amino acid, which was con- 9 1.0 3.0 DCE 24 84 firmed by chiral high-performance liquid chromatography 10 0.5 3.0 DCE 24 70 (HPLC) analysis. By using 1 as a catalyst, Weinreb amide 4a 11 – 3.0 DCE 24 3 was also successfully synthesized in a gram scale (entry a The reactions were performed in the presence of N-Boc serine (2a, 0.10 8).25 A high product yield of 84% was maintained even when mmol, 1.0 equiv), HNMe(OMe) (3), and catalyst 1 in a certain solvent (0.20 M, 1.0 mL) at 90 °C (bath temp). The optical purity of amide 4a was deter- reducing the catalyst loading to 1.0 mol% (entry 9), whereas mined by chiral HPLC analysis. a slight decrease in the yield (70%) was observed with 0.5 b Yields were determined by 1H NMR of the crude reaction mixture of prod- ucts using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yields mol% of catalyst 1 (entry 10). In the absence of catalyst 1, in parentheses. the reaction hardly proceeded, affording a low 3% yield (en- c Performed at 1 g scale.