An alkoxide anion-triggered tert-butyloxycarbonyl group migration. Mechanism and application

Abstract

We report a fast N→O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (2) via a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual nine-membered cyclic transition state. Keywords N to O migration; Boc group migration; intramolecular migration; crossover experimentIn the course of research on the development of chiral pyrrolidine-based inhibitors for neuronal nitric oxide synthase (nNOS), we evaluated various methods for the synthesis of compounds 1a and 1b, the key intermediates to prepare drug candidates for different kinds of neurodegenerative diseases. 1-3 Given the poor efficiency of benzyl deprotection during the reported synthetic route to 1a ,2 we attempted to use bis-Boc protection of the amino group on the pyridine ring (1b); these groups could be removed in one step during the late stage deprotection of the synthesis in excellent yields, providing a much more practical preparation of the final products on a multigram scale. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. To generate 1b, allylation of alcohol 2 was attempted by treating a solution of 2 in DMF with NaH (2 equiv) at room temperature, followed by the addition of allyl bromide (2 equiv). The reaction was quenched with H 2 O to form the product with 93% isolated yield (Scheme 1). To our surprise, mass spectrum and 1 H NMR data for this product did not match the anticipated product (1b). The isolated product has only an (M + H + ) peak at 448, which is 100 less than the calculated molecular weight of 1b, implying a possible lost of one Boc group from the desired product. This was further confirmed by the fact that there were two distinctive singlets at 1.46 and 1.52 ppm (each integrating to nine protons) in the 1 H NMR spectrum (in CDCl 3 ) of the product. The instability of the Boc protecting group under strong basic conditions has been documented. 5-6 Interestingly however, one broad singlet in the 1 H NMR spectrum was found from 2.30 to 2.40 ppm, indicating the presence of a hydroxyl group in the product. Further NOSEY NMR data showed that the allyl group was connected through the nitrogen atom of the amino functionality to the pyridine ring. 7 On the basis of these results, we assigned the product as (3R,4R)-tert-butyl 3-((6-(allyl(tertbutoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (3). 8 It was also noted that: 1) compound 2 showed significant stability in aqueous NaOH even at accelera...

Synthesis of Raputimonoindoles A–C and Congeners

“…SEM‐protection, reduction with LiAlH 4 , methylation and deprotection gave rise to raputimonoindole C ( 33 ) in 64 % yield over 4 steps. Interestingly, alternative N ‐Boc or N ‐TIPS protection led to undesired protecting group migration during the methylation . The use of N ‐TBS protection and methylation with Ag 2 O in MeI at 45 °C followed by deprotection with TBAF also led to raputimonoindole C ( 33 ), albeit in lower yield (29 % over 4 steps).…”

Improved Synthesis of Chiral Pyrrolidine Inhibitors and Their Binding Properties to Neuronal Nitric Oxide Synthase

“…Di-Boc protection of 10 also was fruitless because one of the Boc groups is transferred to the oxyanion of 11 upon condensation of di-Boc- 9 with tert -butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate, as described earlier. 10a The hydroxyl group of 11 was first protected with t -butyldimethylsilyl chloride (TBSCl) in the presence of imidazole to give the silyl ether ( 12 ) in excellent yields. Next, the NH of the carbamate group on the pyridine ring was further protected with another Boc protecting group using (Boc) 2 O in the presence of 4-dimethylaminopyridine (DMAP) to yield 13 in high yields, then the silyl ether was cleaved using tetrabutylammonium fluoride (TBAF) to provide the tri-Boc protected alcohol ( 14 ) in very high yields.…”

“…10–11 Alkene 16 was treated with ozone, followed by dimethyl sulfide to generate 17 in excellent yields. Aldehyde 17 underwent a reductive amination reaction with the corresponding amines in the presence of NaHB(OAc) 3 to give 18, 19a–e in high yields.…”

Acid-facilitated debenzylation of N-Boc, N-benzyl double protected 2-aminopyridinomethyl pyrrolidine derivatives

“…Our recent study demonstrated that di-Boc deprotected 4′-[(6-aminopyridin-2-yl)methylpyrrolidin]-3′-ol ( 5b ) can cause a fast N → O Boc migration via a base-generated alkoxide. 16 The mechanism of the migration is intramolecular, implicating an unusual nine-membered cyclic transition state.…”