Mohammad Movassaghi

Total Synthesis of (+)-11,11'-Dideoxyverticillin A

The fungal metabolite (+)-11,11′-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly 4 decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)-11,11′-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids.

General approach to epipolythiodiketopiperazine alkaloids: total synthesis of (+)-chaetocins A and C and (+)-12,12'-dideoxychetracin A.

A highly stereoselective and systematic strategy for the introduction of polysulfides in the synthesis of epipolythiodiketopiperazines is described. We report the first total synthesis of dimeric epitri- and epitetrathiodiketopiperazines.

A Versatile Cyclodehydration Reaction for the Synthesis of Isoquinoline and β-Carboline Derivatives

The direct conversion of various amides to isoquinoline and beta-carboline derivatives via mild electrophilic amide activation, with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine, is described. Low-temperature amide activation followed by cyclodehydration upon warming provides the desired products with short overall reaction times. The successful use of nonactivated and halogenated phenethylene derived amides, N-vinyl amides, and optically active substrates is noteworthy.

Concise total synthesis of (+)-WIN 64821 and (-)-ditryptophenaline.

Many of these alkaloids, including the closely related ( )-N(2-phenylethylene)ditryptophenaline (3), contain vicinal quaternary stereocenters that connect two hexahydropyrroloindole substructures (Scheme 1). Bioactivity-guided studies led to the identification of (+)-1 as a potent competitive substance P antagonist with submicromolar potency for the human neurokinin 1 and the cholecystokinin B receptors, whereas alkaloids ( )-2 and ( )-3 were found to be weaker inhibitors for the former receptor. Many closely related and potently biologically active epidithiodiketopiperazine derivatives are known, including (+)-chaetocin (Scheme 1), the first inhibitor of a lysine-specific histone methyltransferase, and (+)-11,11’-dideoxyverticillin A (Scheme 1), a tyrosine kinase inhibitor with potent antitumor activity. Based on the pioneering work of Hino, Nakagawa et al. reported the first synthesis of ( )-2 through a thallium(III)-promoted oxidative dimerization reaction (in 3% yield). In 2001, Overman and Paone reported an elegant total synthesis of ( )-ent-WIN 64821 and ( )-2 in which alkylation reactions were employed for the introduction of the quaternary stereocenters. Herein we describe a concise enantioselective total synthesis of naturally occurring alkaloids (+)-1 and ( )-2 in six and seven steps, respectively, from commercially available amino acid derivatives. Additionally, we report the conversion of ( )-2 into N-styrenyl derivatives as well as the structural confirmation of ( )-3. The retrosynthetic analysis of (+)-WIN 64821 (1) illustrates our planned approach to preparing these dimeric diketopiperazine alkaloids (Scheme 2). We envisioned simul-

New Strategies for the Synthesis of Pyrimidine Derivatives

Recent advances in pyrimidine synthesis are described. Modification of conventional strategies involving N-C-N fragment condensation with 1,3-dicarbonyl derivatives remains a common theme in current literature. Other methods, including N-C fragment condensation strategies, provide reactive intermediates capable of intramolecular cyclization and formation of pyrimidine derivatives. These recently developed methodologies offer a valuable addendum to azaheterocycle synthesis.

A Concise and Versatile Double‐Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

The monoterpene indole alkaloids represent the largest family of alkaloid natural products whose more than 2,000 members display a broad range of chemical diversity and potent biological activity.1 The structural challenges presented by this family have long been a source of interest, resulting in the development of a variety of inventive synthetic strategies to access various family members. The biogenetically related natural alkaloids N-methylaspidospermidine (1), N-methylquebrachamine (2), and tabernaebovine (3) represent the aspidosperma subfamily of monoterpene indole alkaloids (Figure 1).2-5 The dimeric alkaloid 3, isolated from Tabernaemontana bovina in 1998,2e has a fascinating molecular constitution that exhibits a unique C2–C15′ linkage between two pentacyclic aspidosperma skeletons. While elegant strategies for synthesis of other dimeric monoterpene indole alkaloids have been reported,5 no synthetic solution to the distinctive C2–C15′ union present in 3 exists. As an outgrowth of our laboratorys studies concerning electrophilic amide activation,6 we report a concise and convergent strategy for the enantioselective synthesis of alkaloids (–)-1, (+)-2, and dimeric (+)-dideepoxytabernaebovine (4).

Synthesis of highly epimerizable N-protected α-amino aldehydes of high enantiomeric excess

Abstract The Dess–Martin periodinane was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N -protected α-amino aldehydes from the corresponding N -protected β-amino alcohols. Highly racemization-prone products, including N -Fmoc phenylglycinal and N -trifluoroacetyl α-amino aldehydes, were prepared in ≥95% yield with ≤1% epimerization.

Concise total synthesis and stereochemical revision of all (-)-trigonoliimines.

The concise and enantioselective total syntheses of (-)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (-)-trigonoliimines A, B, and C.

Direct dehydrative N-pyridinylation of amides.

Electrophilic activation of secondary amides with trifluoromethanesulfonic anhydride in the presence of 2-fluoropyridine followed by introduction of a pyridine N-oxide derivative and warming affords the corresponding N-pyridinyl tertiary amide derivatives. A mechanism supported by in situ monitoring and deuterium labeling experiments is discussed.

Directed Heterodimerization: Stereocontrolled Assembly via Solvent-Caged Unsymmetrical Diazene Fragmentation

A general strategy for the directed and stereocontrolled assembly of carbon-carbon linked heterodimeric hexahydropyrroloindoles is described. The stepwise union of complex amines in the form of mixed diazenes followed by photoexpulsion of dinitrogen in a solvent cage provides completely guided assembly at challenging C(sp(3))-C(sp(3)) and C(sp(3))-C(sp(2)) connections.