MacMillan OrganoCatalyst

Serotonin (8) mimics have been used effectively as treatments for a variety of psychiatric illnesses [199-201]. Homotryptamines could be constructed by multistep routes. One-pot synthesis of homotryptamines 277a-k was achieved by the conjugate addition of indoles with acrolein in the presence of the MacMillan organocatalysts (118a, 274) followed by reductive amination (Scheme 60) [201]. 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

In Communications submitted two weeks apart, David W.C. MacMillan of Caltech (7. Am. Chem. Soc. 2004,126,4108) and Karl Anker Jorgensen of Aarhus University, Denmark (7. Am. Chem. Soc. 2004, /26,4790) reported the enantioselective a-chlorination of aldehydes, using organocatalysts 14 and 15 respectively. The chloro aldehydes are promising precursors to, inter aliay enantiomerically-pure epoxides. 

In addition, immobilized catalysts related to the MacMillan imidazolidinone-type organocatalyst 5 have been used for the asymmetric Diels-Alder reaction (Section... 

MacMillan s organocatalyst, 56a, which was used typically for electrophilic activation, was seen also to be efficient in promoting conjugate addition via enamine formation (Scheme 2.52) [42]. The proof of the enamine pathway was furnished by extended NMR studies. Gellman and colleagues noted an interesting dependence of selectivity on the catalyst structure improved conversion and ee-value can occur with the spirocyclopentane derivative 56b, and by the addition of a catechol derivative as acid additive (Scheme 2.52). The cyclohexane-derived catalyst 56c was unreactive, however. 

A limitation of MacMillan s approach towards iminium-activated Diels-Alder reactions has been the use of a-substituted a,/ -unsaturated aldehydes as dieno-philes. Recently, Ishihara and Nakano [31] succeeded in partially overcoming this problem by identifying a novel primary amine organocatalyst for this type of... 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Chiral nonracemic enamines formed in situ by reaction of aldehydes and ketones with proline-based organocatalysts also undergo stereoselective a-oxygenation. MacMillan and coworkers have achieved enantioselective a-oxidation of a range of aliphatic aldehydes such as (5.87) with 97-99% ee using proline in combination with nitrosobenzene (5.85). This method can be applied to the aminoxylation of six-membered cyclic ketones such as 1,4-cyclohexanedione monoethylene ketal (5.88). 59... 

The organocatalyst-based a-functionalisation strategy has been applied with much success to the asymmetric halogenation of aldehydes. The imidazolidi-none salt (5.110) has been used by MacMillan and coworkers, in combination with NFSI, to effect enantioselective fluorination of a range of aldehydes, for example (5.111). ... 

The iminium strategy, elegantly illustrated by MacMillan, using chiral imidazolidinones as organocatalysts in a Diels-Alder reaction was then... 

Owing to their structural complexity, Strychnos alkaloids, especially strychnine itself, are a benchmark in synthetic organic chemistry and have been prepared numerous times ]92]. Another alkaloid of the Strychnos family that enjoys increasing popularity nowadays is (+)-minfiensine. It was isolated from Strychnos minfimsis and features a l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole motif, and hence is closely related to echitamine and vincorine [93]. A total synthesis of this beautiful structure was accomplished by MacMillan and coworkers [94]. Their key step was a highly efficient enantioselective domino Diels-Alder/isomerization/amine cycHzation reaction (Scheme 14.35). In this process, the chiral organocatalyst 226-TBA (TBA, tribromoacetic acid) was used, which reacted first with propargyl aldehyde 225 to form i minium ion 229 as intermediate, which underwent an endo-selective Diels-Alder reaction with 224... 

---