Larry E. Overman

Catalytic enantioselective synthesis of quaternary carbon stereocentres

Quaternary carbon stereocentres—carbon atoms to which four distinct carbon substituents are attached—are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

A Concise Synthesis of (−)-Aplyviolene Facilitated by a Strategic Tertiary Radical Conjugate Addition

Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products.[1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8–C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8.[3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 (Figure 1A),[4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B).[5] In this latter effort, the key C8–C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6.[6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization.

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.

Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors.

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11) in 10 steps and 11% overall yield from isatin is reported. In addition, the epipolythiodioxopiperazine (ETP) natural product (+)-gliocladine C (6) has been prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of 6 constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.

Total Synthesis of (−)-Spirotryprostatin B and Three Stereoisomers

A catalytic intramolecular Heck reaction, followed by capture of the resulting η(3)-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (-)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η(3)-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.

Oxalates as Activating Groups for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling.

Alkyl oxalates are new bench-stable alcohol-activating groups for radical generation under visible light photoredox conditions. Using these precursors, the first net redox-neutral coupling of tertiary and secondary alcohols with electron-deficient alkenes is achieved.

Facile aminolysis of epoxides with diethylaluminum amides

Abstract Treatment of an epoxide with a diethylaluminum amide in dichloromethane at room temperature affords the corresponding β-amino alcohol in good yield.

Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates.

A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported.

Total Synthesis of (±)- and (−)-Actinophyllic Acid

Development of efficient sequences for the total syntheses of (+/-)-actinophyllic acid (rac-1) and (-)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (+/-)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to beta-hydroxyester intermediate rac-53, which is directly transformed to (+/-)-actinophyllic acid upon exposure to HCl and paraformaldehyde. This concise second-generation total synthesis of (+/-)-actinophyllic acid is realized in 22% overall yield from commercially available di-tert-butyl malonate and o-nitrophenylacetic acid by a sequence that proceeds by way of only six isolated intermediates. The first enantioselective total synthesis of (-)-actinophyllic acid (1) is accomplished by this direct sequence from tricyclic keto malonate (S)-35. Catalytic enantioselective reduction of alpha,beta-unsaturated ketone 66 is the key step in the preparation of intermediate (S)-35 from the commercially available Boc-amino acid 65. Discussed also is the possibility that the aza-Cope/Mannich reaction might be involved in the biosynthesis of (-)-actinophyllic acid.

Synthesis studies directed toward gelsemine. Preparation of an advanced pentacyclic intermediate

Abstract Pentacyclic gelsemine intermediate 2 was prepared from 3 by a six step sequence whose key steps are (a) intramolecular Mannich cyclization of an N-acyliminium ion intermediate to form the azatricyclo [4.4.0.0 2,8 ] decane ring system, and (b) palladium catalyzed intramolecular alkene arylation to elaborate the spirooxindole.