Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine,Mesembrine, and Δ7‐Mesembrenone

Although the Diels–Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6‐dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these—the complex amaryllidaceae alkaloid gracilamine—affording the shortest route to date in terms of linear step count.     

Total Synthesis of (−)‐Tetrodotoxin and 11‐norTTX‐6(R)‐ol

The enantioselective total synthesis of (−)‐tetrodotoxin [(−)‐TTX] and 4,9‐anhydrotetrodotoxin, which are selective blockers of voltage‐gated sodium channels, was accomplished from the commercially available p ‐benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]‐sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3‐dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11‐norTTX‐6(R )‐ol and 4,9‐anhydro‐11‐norTTX‐6(R )‐ol through late‐stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11‐norTTX‐6(R )‐ol without competing dehydration to their 4,9‐anhydro forms.     

Total Synthesis of (−)‐N‐Methylwelwitindolinone B Isothiocyanate

The asymmetric synthesis of (−)‐N ‐methylwelwitindolinone B isothiocyanate is reported. Critical challenges overcome through these studies include the stereoselective installation of the sterically congested C13 alkyl chloride and control of the wayward reactivity of the indole unit to standard oxidants. A Pt‐catalyzed hydrosilylation helped stymie unwanted rearrangements facilitated by vinyl group participation during the chloride installation step, and a new Fe^II‐catalyzed oxidation accomplished the problematic conversion of indole into 2‐indolinone.     

Organocatalytic,Asymmetric Total Synthesis of (−)‐Haliclonin A

The first total synthesis of the alkaloid (−)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI₂‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.     

Collective Synthesis of Cladiellins Based on the Gold‐Catalyzed Cascade Reaction of 1,7‐Diynes

The cladiellin family of natural products, which includes molecules with various biological activities, continues to invite new synthetic studies. A gold‐catalyzed tandem reaction of 1,7‐diynes to construct the 6‐5‐bicyclic ring systems that are present in a number of natural products was developed. This reaction was applied as the key step to realize the formal and total syntheses of nine members of the cladiellin family in an enantio‐ and diastereoselective manner. This modular and efficient approach could also be used for the construction of other cladiellins, as well as their analogues, for follow‐up studies.     

Total Synthesis of (−)‐Vindorosine

Outlined herein is a novel and scalable synthesis of (−)‐vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone‐derived lithium dienolates with indolyl N ‐tert‐butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza‐Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)‐vindorosine and related alkaloids.     

Total Syntheses of Aurachins A and B

Aurachins A and B are alkaloids having 3‐hydroxyquinoline N‐oxide cores. An efficient method for the synthesis of 3‐hydroxyquinoline N‐oxides was established and is amenable to the total syntheses of aurachins A and B. Alkylation of 1‐(2‐nitrophenyl)butan‐2‐one with farnesyl bromide took place selectively at the benzylic position, and subsequent treatment of the alkylated product with sodium tert‐butoxide in dimethyl sulfoxide gave aurachin B. Alkylation of 1‐(2‐nitrophenyl)butan‐2‐one with an epoxy iodide derived from farnesol was used to access aurachin A.