Total synthesis of salinosporamide A

The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction as key reactions.     

New synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues

[reaction: see text] A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4 --> 5.     

Propellane as a conformational device for the stabilization of the β-lactone of salinosporamide A

The synthesis of a propellane derivative of salinosporamide A having increased stability under physiological-like conditions is reported. The synthesis took advantage of a substrate-controlled stereoselective Ugi 4-center 3-component reaction to construct the required syn-bicyclic pyroglutamic acid framework.     

Formal synthesis of salinosporamide A via NHC-catalyzed intramolecular lactonization

An N-heterocyclic carbene (NHC) catalyzed intramolecular lactonization to prepare densely functionalized bicyclic γ-lactam-γ-lactone adducts from enals is reported. This method has been applied to the formal synthesis of salinosporamide A, a potent 20S proteasome inhibitor and anti-cancer therapeutic.     

Studies toward the synthesis of salinosporamide A, a potent proteasome inhibitor

An α-methylenepyrrolidinone bearing all the functionalities and relative configurations of an advanced intermediate in the synthesis of salinosporamide A and analogues has been synthesized from methyl pyroglutamate through regio- and stereoselective N-methylnitrone cycloaddition.     

New synthetic route to access (±) salinosporamide A via an oxazolone-mediated ene-type reaction

We report herein a racemic key intermediate in the synthesis of salinosporamide A via a tert-alkyl amino hydroxy carboxylic ester produced in an ene-type reaction of an oxazolone with an enol ether.     

Total synthesis of salinosporamide A

Total synthesis of potent proteasome inhibitor salinosporamide A (1) has been accomplished, which features strictly substrate-controlled operations starting with the only chiral center of (R)-pyroglutamic acid. The consecutive quaternary carbons within 1 have been efficiently constructed by manipulation of two intramolecular reactions: (1) carbonate-mediated internal acylation of imidate ester (4 --> 14) and (2) selenocyclization of aldehyde to exocyclic methylene group (5 --> 18).     

Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica

[structure: see text] Feeding experiments with stable isotopes established that the potent 20S-proteasome inhibitors salinosporamide A and B are biosynthesized in the marine bacterium Salinispora tropica from three biosynthetic building blocks, namely, acetate, beta-hydroxy-2'-cyclohexenylalanine, and either butyrate or a tetrose-derived chlorinated molecule. The unexpected observation that the chlorinated four-carbon residue in salinosporamide A is derived from a different metabolic origin than the non-chlorinated four-carbon unit in salinosporamide B is suggestive of a convergent biosynthesis to these two anticancer natural products.     

Total Synthesis of (−)‐Salinosporamide A via a Late Stage C−H Insertion

The synthesis of (?)‐salinosporamide A, a proteasome inhibitor, is described. The synthesis highlights the assembly of a densely decorated pyrrolidinone core via an aza‐Payne/hydroamination sequence. Central to the success of the synthesis is a late‐stage C?H insertion reaction to functionalize a sterically encumbered secondary carbon. The latter functionalization leads to an enabling transformation where most of the prototypical strategies failed.     

Proteasome inhibition by a totally synthetic beta-lactam related to salinosporamide A and omuralide

A new and effective proteasome inhibitor, beta-lactam 3, has been accessed enantioselectively by multistep synthesis from the readily prepared intermediates 7 and 8 which were joined by a [2 + 2]-cycloaddition reaction to form the spiro beta-lactam 9 stereoselectively. The intermediate 9 was converted to 3 in seven steps and 30% overall yield. The beta-lactam 3 is stable for many days in water at pH 7, in contrast to the natural beta-lactones salinosporamide A (1) and omuralide (2). In common with 1 and 2, the beta-lactam 3 effectively inhibits the mammalian proteasome.     

Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A

An important feature of the synthesis of salinosporamide A, a potent proteasome inhibitor, is the establishment of the quaternary stereocenter at C3. A new route has been developed based on the methylation of a functionalized pyrrolidinone. Direct methylation reaction led to the unwanted diastereomer; however, by means of a Corey–Chaykovsky reaction followed by LiAlH₄ epoxide opening, the desired alcohol was obtained. The pyrrolidinone was elaborated through a key allylation reaction between a tertiary allyltitanium reagent and an aldehyde bearing a spiroketal moiety in α-position.     

New cytotoxic salinosporamides from the marine Actinomycete Salinispora tropica

An extensive study of the secondary metabolites produced by the obligate marine actinomycete Salinispora tropica (strain CNB-392), the producing microbe of the potent proteasome inhibitor salinosporamide A (1), has led to the isolation of seven related gamma-lactams. The most important of these compounds were salinosporamide B (3), which is the deschloro-analogue of 1, and salinosporamide C (4), which is a decarboxylated pyrrole analogue. New SAR data for all eight compounds, derived from extensive testing against the human colon carcinoma HCT-116 and the 60-cell-line panel at the NCI, indicate that the chloroethyl moiety plays a major role in the enhanced activity of 1.     

Synthetic studies of salinosporamide A through the intramolecular hydroamidation of alkynes

Rhodium-catalyzed intramolecular hydroamidation of alkynes was carried out to construct the synthetic intermediates of a proteasome inhibitor, salinosporamide A. Several alkynyl formamides were synthesized and subjected to the hydroamidation reaction. Some derivatives with a methoxymethyl (MOM) or 2-methoxy-2-propyl (MOP) group near the reaction site were converted to the corresponding lactams in excellent yields.     

Stereoselective formal synthesis of the potent proteasome inhibitor: salinosporamide A

(2R,3S)-α-Methylenelactam 3, the key intermediate in Corey’s syntheses of salinosporamide A, has been synthesized from (S)-methyl 2-hydroxymethylpyroglutamate through chemoselective O-protection, regio- and stereoselective N-methylnitrone cycloaddition and quaternarization-elimination reactions as the main steps.     

Total Synthesis of Lactacystin and Salinosporamide A

Lactacystin and salinosporamide A are fascinating molecules with regard to both their chemical structures and biological activities. These naturally occurring compounds are potent and selective proteasome inhibitors. The molecular structures are characterized by their densely functionalized γ‐lactam cores. The structure and biological properties of these two compounds are attracting the attention of many chemists as challenging synthetic targets. We discuss their synthetic strategies in this review.     

Engineered biosynthesis of antiprotealide and other unnatural salinosporamide proteasome inhibitors

A new shunt in the phenylalanine biosynthetic pathway to the nonproteinogenic amino acid L-3-cyclohex-2'-enylalanine was exploited in the marine bacterium Salinispora tropica by mutagenesis to allow for the genetic engineering of unnatural derivatives of the potent proteasome inhibitor salinosporamide A (2) such as antiprotealide (1).     

Concise total synthesis of (+/-)-salinosporamide A, (+/-)-cinnabaramide A, and derivatives via a bis-cyclization process: implications for a biosynthetic pathway?

4-Alkylidene-beta-lactones (hetero ketene dimers) and alpha-amino acids are useful precursors for total syntheses of the beta-lactone-containing proteasome inhibitors salinosporamide A, cinnabaramide A, and derivatives. A key step is a nucleophile-promoted, bis-cyclization of keto acids that simultaneously generates the gamma-lactam and beta-lactone of these natural products. This reaction sequence may have implications for the biosynthesis of these natural products.     

Salinosporamide natural products: Potent 20 S proteasome inhibitors as promising cancer chemotherapeutics

Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized γ‐lactam‐β‐lactone pharmacophore, which is responsible for its irreversible binding to its target, the β subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure–activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering.