Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epihapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scaleable, and protecting group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses. The syntheses are also characterized by an adherence to the concept of “redox economy”. Analogous to “atom economy” or “step economy”, “redox economy” minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.

Catalytic enantioselective a-amination reactions of bketo esters and b-keto lactones with dibenzyl azodicarboxylate are catalyzed by cinchona alkaloids, affording the products in up to 99% yield and 90% ee.In 1922, Otto Diels 1 and his group disclosed the first example of a reaction between a b-dicarbonyl compound (acetylacetone) and diethyl azodicarboxylate. Surprisingly, papers concerning modern a-amination methods rarely attribute this reaction to Diels' seminal discovery.In his original 1922 paper, Diels indicated that these reactions are promoted by catalytic amounts of bases such as potassium acetate. 1a Inspired by this, we reasoned that we should be able to develop an organocatalytic, asymmetric variant of the same reaction. Recently, Jørgensen and coworkers have employed chiral Lewis acid complexes as the catalyst for the a-amination reaction, affording the aamination products derived from a-monosubstituted b-ketoesters in up to 99% ee. 2 Other examples of catalytic, enantioselective direct a-aminations include the prolinecatalyzed a-aminations of aldehydes 3 and ketones, 4 both of which proceed in excellent yield and enantioselectivity.In this paper, we describe a simple organocatalytic and enantioselective protocol for the a-amination of b-keto esters and b-keto lactones using catalytic amounts of cinchona alkaloids. Importantly, both enantiomers of the product are readily accessible simply by changing the catalyst. 5The reaction between b-keto esters such as 1 and dibenzyl or di-t-butyl azodicarboxylate progressed without a catalyst in protic solvents (EtOH, i-PrOH: 30-45 min reaction time). However, this background reaction was nearly completely suppressed in less polar solvents such as CH 2 Cl 2 and toluene. The higher reactivity of the dibenzyl azodicarboxylate 2 encouraged us to select it as the nitrogen donor of choice. Its advantages include the presence of an aromatic chromophore in the product, facilitating HPLC analysis of the enantioselectivity.An initial screen of catalysts in CH 2 Cl 2 revealed that the acetate catalyst could increase the rate by at least three orders of magnitude (Table 1). With chiral amine catalysts, quinine and quinidine already gave the product in modest enantioselectivity. A slight improvement in ee was observed when the reaction was conducted at -25°C (entry 4). However, more dramatic results were obtained with the cinchona alkaloids cinchonine and cinchonidine (entries 5-8), affording the product in up to 88-90% ee and 95% yield, with reaction times of 5 minutes at -25°C! Remarkably, both enantiomers of the product were readily accessible simply by exchanging the catalysts. The catalyst could easily be recovered by simple extraction with 0.5 M HCl. 6

Enantioselective isoxazoline synthesis: A combination of 1) a catalytic enantioselective conjugate addition of oximes to alpha,beta-unsaturated aldehydes and 2) an acid-catalyzed intramolecular oxime-transfer reaction lead to the first asymmetric synthesis of 3-unsubstituted 2-isoxazolines (see scheme).

The formation of 3-unsubstituted 2-isoxazolines by means of condensation reactions between α,β-unsaturated aldehydes and oximes proceeds readily in the presence of catalytic amounts of anilinium salts. Mechanistically, the process involves a fast conjugate addition of the oxime and a slower intramolecular oxime-transfer reaction. The rate of oxime transfer was found to correlate with the acidity of the catalyst. This finding enabled us to discover an enantioselective process in which the fragile conjugate-addition product generated in the first stage is rapidly cyclized into the stable isoxazoline under acidic conditions, with conservation of enantiomeric excess. In summary, herein we describe synthetically useful protocols for accessing 3-unsubstituted 2-isoxazolines in both the enantioselective and racemic manner. The mechanism of the condensation reaction catalyzed by the anilinium salt was also investigated by NMR spectroscopy experiments in which the effect of differently substituted aldehydes and oximes as well as water on the reaction rate was studied. The results point to the rate-limiting elimination of water from the 3-hydroxy-2-isoxazolidine intermediate.

Optimized conditions render possible the highly selective C‐5 arylation of pyrazole (I) with a wide variety of aryl bromides.