Remarkably Low Catalyst Loading in Brønsted Acid Catalyzed Transfer Hydrogenations: Enantioselective Reduction of Benzoxazines, Benzothiazines, and Benzoxazinones

Advances in catalytic metal-free reductions: from bio-inspired concepts to applications in the organocatalytic synthesis of pharmaceuticals and natural products

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).

Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids

Chiral six-membered nitrogen heterocycles, such as substituted piperazines, morpholines and piperidines, are found in many naturally occurring alkaloids as well as in pharACHTUNGTRENNUNGmaACHTUNGTRENNUNGceuACHTUNGTRENNUNGtiACHTUNGTRENNUNGcals and constitute an integral part of numerous important bioactive compounds. The biological and pharmacological properties of their aryl-fused analogues tetrahydroquinoxaline and dihydro-2 H-benzoxazine have been known for a long time. As early as 1947 various tetrahydroquinoxalines have already been synthesised to explore antimalarial activity, whereas the antituberculouses properties of dihydrobenzoxazines have been shown only ten years later. Since then, interest in tetrahydroquinoxalines and dihydro-2 H-benzoxazines has increased significantly and today optically active 2-substituted 1,2,3,4-tetrahydroquinoxalines and 3-substituted 3,4-dihydro2 H-1,4-benzoxazines constitute interesting building blocks in the drug discovery process and are an important motif of many naturally occurring alkaloids (Figure 1). More specifically, the chiral 1,2,3,4-tetrahydroquinoxaline A is a promising M2 acetylcholine receptor inhibitor, whereas B has been pursued as a potent V2 receptor antagonist. In addition, C is known to represent an active cholesteryl ester transfer protein inhibitor and the chiral 1,4-benzoxazine D is a promising candidate in atherosclerosis treatment. Levofloxacin is a commercialised highly potent antibacterial agent and obscurinervine and its related compounds are examples for naturally accruing alkaloids. With the growing importance of such chiral compounds in the life science industries, the development of efficient enantioselective methodologies continues to be interesting for organic chemistry and catalysis. Clearly, beside different multistep methods to synthesise chiral tetrahydroquinoxalines and dihydro-benzoxazines the most direct and atom-economic approach represents the enantioselective hydrogenation of quinoxalines and benzoxazines. Notably, virtually all of the known catalysts for the latter enantioselective hydro-

Cooperative Iron–Brønsted Acid Catalysis: Enantioselective Hydrogenation of Quinoxalines and 2 H‐1,4‐Benzoxazines

Geringste Katalysatormengen in der Brønsted‐Säure‐katalysierten Transferhydrierung: enantioselektive Reduktion von Benzoxazinen, Benzthiazinen und Benzoxazinonen

A new synthesis of the cylindrocarine group of alkaloids

An alternative approach to the synthesis of the trans-hydrindane ring system containing an angular methyl group, which forms rings C and D of paspalicine, is described.

Synthetic studies towards paspalicine. Part 2. An alternative approach to the synthesis of the C/D ring system

Publisher Summary The chapter discusses the synthesis of the Aspidosperma alkaloids. The Aspidosperma alkaloids include all those based on the aspidospermidine and vincadifformine ring systems, together with those, such as meloscine, which are derived by obvious rearrangement of one or other of these systems. The last summary of synthesis was published in 1979. During the past 16 years, these alkaloids have continued to exert a fascination on, and offer a challenge to, organic chemists engaged in the art of synthesis, and several notable and ingenious synthetic routes have been developed, either by the application of modern sophisticated synthetic methods or by brilliant attempts to mimic the presumed biosynthesis of these alkaloids in the laboratory. The most original approach to the Aspidosperma alkaloids is the tandem aza-Cope rearrangement—Mannich cyclization route developed by Overman et al. All of the major alkaloids have now yielded to synthesis, including those of the meloscine and kopsine groups, which, in terms of their ring systems, would appear to offer the greatest challenge.

Chapter 9 Synthesis of the Aspidosperma Alkaloids

Approaches to the synthesis of aspidosperma alkaloids : Part II. The synthesis of 18,19-didehydrotabersonine

The preparation of a hexacyclic aminoester, which lacks only the lactone ring of alalakine, is described.

J. Edwin Saxton

Papers

A new synthesis of the cylindrocarine group of alkaloids

Synthetic studies towards paspalicine. Part 2. An alternative approach to the synthesis of the C/D ring system

Chapter 9 Synthesis of the Aspidosperma Alkaloids

Approaches to the synthesis of aspidosperma alkaloids : Part II. The synthesis of 18,19-didehydrotabersonine

Total synthesis of heptacyclic Aspidosperma alkaloids. Part 3. Synthesis of an advanced intermediate in the synthesis of alalakine