Total Synthesis of (±)-Eucophylline. A Free-Radical Approach to the Synthesis of the Azabicyclo[3.3.1]nonane Skeleton

Abstract

The first total synthesis of eucophylline was reported in 10 steps and 10% overall yield. The naphthyridine core of eucophylline was prepared through the coupling between a strained azabicyclo[3.3.1]nonan-2-one and a trisubstituted benzonitrile, followed by a cyclization of the corresponding amidine. This coupling reaction was shown to proceed through a stable bicyclic chloroenamine intermediate. The azabicyclo[3.3.1]nonan-2-one skeleton was in turn accessible through a straightforward sequence including a free-radical three-component olefin carbo-oximation as a key step.

Twisted Amides: From Obscurity to Broadly Useful Transition‐Metal‐Catalyzed Reactions by N−C Amide Bond Activation

“…[25] The synthesis was accomplished by an Ir-catalyzed enantioselective allylic amination (> 90 % ee), followed by lactam formation by ring-closing metathesis and intramolecular Heck cyclization to afford as eries of bridged lactams. [27] At hree-component radical coupling was employeda sakey step to access the bicyclic lactam.I ntermolecular condensation of the twisted amide bond with functionalized aniline afforded ab ridged amidine with preservation of the bicyclic structure. This report showcases the intramolecular Heck reactioni nt he synthesis of bridged lactams.…”

Free‐Radical Carbocyanation of Olefins

“…[1] In this context, we have recently developed several radicalp rocessesr elying on such additions to provide compounds having two new CÀCb onds and two additionalf unctional groups. [3] However, further use of this carbo-oximation as af ormal carboformylation process with more hindereds ubstrates (e.g., 2a in Figure1)led to less satisfactory yields, and thus underlined the limitations of the process. [3] However, further use of this carbo-oximation as af ormal carboformylation process with more hindereds ubstrates (e.g., 2a in Figure1)led to less satisfactory yields, and thus underlined the limitations of the process.…”

“…[2] Amongt hese reactions, one-pot, three-component carbo-oximation of olefins proved to be particularly efficient, [2a, e] and allowed the incorporation on the carbon backbone of an oxime functional group, which was later hydrolyzed to an aldehyde or reduced to an aminomethyl group, as illustrated recently in the total synthesis of the alkaloid eucophylline. [3] In the search for ab etter formyl or aminomethyl surrogate,i tw as envisioned that ac yano group mightb ep articularly well suited, as it can be selectively reduced to an aldehyde with DIBAL-Ho r fully hydrogenated to an amine by using H 2 and Raney nickel underm ild conditions. [3] In the search for ab etter formyl or aminomethyl surrogate,i tw as envisioned that ac yano group mightb ep articularly well suited, as it can be selectively reduced to an aldehyde with DIBAL-Ho r fully hydrogenated to an amine by using H 2 and Raney nickel underm ild conditions.…”

Highly Efficient One‐Step Synthesis of N‐Trimethylsiloxy Alkyl Imidothioates

“…There are three classes of compounds that contain the N–OH bond: hydroxylamines (R 2 N–OH), oximes (R 2 C=N–OH), and hydroxamic acids (RCONH–OH) Oximes and their analogues alkyl imidothioates are highly important reagents in many of organic transformations, and these structural motifs are known for their biological activity . In spite of the many methods that have been developed for their synthesis, there are a lack of examples that involve the direct use of thiols to obtain alkyl imidothioates.…”

“…[1] Oximes and their analogues alkyl imidothioates are highly important reagents in many of organic transformations, and these structural motifs are known for their biological activity. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In spite of the many methods pands upon the knowledge of nitro compounds and demonstrates their importance not only as solvents but also as valuable organic reagents. This reaction proceeds under mild conditions and is characterized by excellent yields and a facile workup.…”