Stereochemical elucidation of streptorubin B

Streptorubin B is a structurally remarkable member of the prodiginine group of antibiotics produced by several actinobacteria, including the model organism Streptomyces coelicolor A3(2). Transannular strain within the pyrrolophane structure of this molecule causes restricted rotation that gives rise to the possibility of (diastereomeric) atropisomers. Neither the relative nor the absolute stereochemistry of streptorubin B is known. NOESY NMR experiments were used to define the relative stereochemistry of the major atropisomer of streptorubin B·HCl in solution as anti. We exploited this finding together with our knowledge of streptorubin B biosynthesis in S. coelicolor to determine the absolute stereochemistry of the anti atropisomer. 2-Undecylpyrrole stereoselectively labeled with deuterium at C-4' was synthesized and fed to a mutant of S. coelicolor, which was unable to produce streptorubin B because it was blocked in 2-undecylpyrrole biosynthesis, and in which the genes responsible for the last two steps of streptorubin B biosynthesis were overexpressed. (1)H and (2)H NMR analysis of the stereoselectively deuterium-labeled streptorubin B·HCl produced by this mutasynthesis strategy allowed us to assign the absolute stereochemistry of the major (anti) atropisomer as 7'S. HPLC analyses of streptorubin B isolated from S. coelicolor on a homochiral stationary phase and comparisons with streptorubin B derived from an enantioselective synthesis showed that the natural product consists of an approximately 88:7:5 mixture of the (7'S, anti), (7'S, syn), and (7'R, anti) stereoisomers.     

Synthesis of streptorubin B core

A straightforward synthesis of streptorubin B core structure has been established starting from trans-4-hydroxyproline. The core structure of streptorubin B is constructed in an intramolecular ring-closing metathesis as the key step.     

Elucidation of the Streptomyces coelicolor pathway to 2-undecylpyrrole, a key intermediate in undecylprodiginine and streptorubin B biosynthesis

The red gene cluster of Streptomyces coelicolor directs production of undecylprodiginine. Here we report that this gene cluster also directs production of streptorubin B and show that 2-undecylpyrrole (UP) is an intermediate in the biosynthesis of undecylprodiginine and streptorubin B. The redPQRKL genes are involved in UP biosynthesis. RedL and RedK are proposed to generate UP from dodecanoic acid or a derivative. A redK(-) mutant produces a hydroxylated undecylprodiginine derivative, whereas redL(-) and redK(-) mutants require addition of chemically synthesized UP for production of undecylprodiginine and streptorubin B. Fatty acid biosynthetic enzymes can provide dodecanoic acid, but efficient and selective prodiginine biosynthesis requires RedPQR. Deletion of redP, redQ, or redR leads to an 80%-95% decrease in production of undecylprodiginine and an array of prodiginine analogs with varying alkyl chains. In a redR(-) mutant, the ratio of these can be altered in a logical manner by feeding various fatty acids.     

Synthesis and Configuration of Neomaclafungin A

The relative and absolute configuration of neomaclafungins were impossible to establish by spectroscopic analyses alone because of the lack of exploitable ¹H‐¹H couplings and nOes between the upper and the lower subunits. This very difficult task now is finally completed by an enantioselective total synthesis of neomaclafungin A (revised) and its diastereomer (reported). The results also provided a key reference for the complete structures for other neomaclafungins and the long‐known closely related natural product maclafungin.     

Enantioselective total synthesis of (+)-salvileucalin B

An enantioselective total synthesis of the diterpenoid natural product (+)-salvileucalin B is reported. Key findings include a copper-catalyzed arene cyclopropanation reaction to provide the unusual norcaradiene core and a reversible retro-Claisen rearrangement of a highly functionalized norcaradiene intermediate.     

First enantioselective synthesis and determination of the absolute configuration of natural (+)-dehydro-β-monocyclonerolidol

The enantioselective synthesis and determination of the absolute configuration of (+)-dehydro-β-monocyclonerolidol, a natural product isolated from the liverwort P. subobtusa, has been achieved starting from (+)-karahana lactone as an enantiopure building block. Furthermore, the methodology applied provided a new approach towards the known (+)-γ-cyclohomocitral, a key intermediate in the sequence, and natural (+)-pallescensone.     

The catalytic asymmetric total synthesis of elatol

Described in this report is the first total synthesis of elatol, a halogenated sesquiterpene in the chamigrene natural product family. The key disconnections in our synthetic approach include an enantioselective decarboxylative allylation to form the all-carbon quaternary stereocenter and a ring-closing olefin metathesis to concomitantly form the spirocyclic core as well as the fully substituted chlorinated olefin. This strategy represents a general platform for accessing the chamigrene natural product family, as demonstrated by the synthesis of (+)-laurencenone B as an intermediate in our route.     

The direct and enantioselective organocatalytic alpha-oxidation of aldehydes

The first direct enantioselective catalytic alpha-oxidation of carbonyls has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective oxyamination of aldehydes, to generate alpha-oxyaldehydes, important chiral synthons for natural product and medicinal agent synthesis. The use of l-proline as the asymmetric catalyst has been found to mediate the oxidation of a large variety of aldehyde substrates with nitrosobenzene serving as the electrophilic oxidant. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 2 mol % were generally employed in this study, successful oxidations conducted using catalyst loadings as low as 0.5 mol % are described.     

Modified chiral triazolium salts for enantioselective benzoin cyclization of enolizable keto-aldehydes: synthesis of (+)-sappanone B

Asymmetric synthesis of (+)-sappanone B (1), a natural product with a 3-hydroxy chromanone structure, was achieved via enantioselective benzoin cyclization by using a modified Rovis catalyst and triethylamine. This catalyst enabled the successful benzoin cyclization of readily enolizable keto-aldehydes.     

Enantioselective formal synthesis of antitumor agent (+)-ottelione A

The enantioselective formal synthesis of a natural antitumor product, (+)-ottelione A, was achieved through a catalytic enantioselective Diels-Alder strategy. These endeavors have led to the synthesis of a variety of synthetic analogues of this biologically potent natural product.     

The catalytic enantioselective, protecting group-free total synthesis of (+)-dichroanone

Herein we report the first enantioselective total synthesis of (+)-dichroanone, confirming the absolute configuration of the natural product. This protecting group-free route features the first application of our enantioselective Tsuji allylation in the context of a natural product total synthesis. Additionally, this 11-step preparation of the molecule from commercial material features a novel Kumada-aromatization strategy and a rapid sequence for the conversion of a phenol to a hydroxy-p-benzoquinone.     

Short, enantioselective total synthesis of aflatoxin B2 using an asymmetric [3+2]-cycloaddition step

A highly enantioselective [3+2]-cycloaddition reaction of 2,3-dihydrofuran with 1,4-benzoquinones using a chiral oxazaborolidinium triflimidate as catalyst has been developed which allows rapid access to a variety of chiral phenolic tricycles (enantiomeric excesses ranging from 91 to 98%). The utility of this new methodology is demonstrated by a short synthesis of the important pentacyclic natural product, aflatoxin B2. This exploratory study indicates that an even broader application of these catalysts to enantioselective cycloadditions may be possible.     

Enantioselective Formal Syntheses of 11 Nuphar Alkaloids and Discovery of Potent Apoptotic Monomeric Analogues

Concise, scalable, and enantioselective formal syntheses of eight dimeric and three monomeric nuphar alkaloids were achieved, along with the construction of a stereochemically diverse collection of the first known monomeric analogues having apoptotic activity. The syntheses involved the development of highly enantioselective Brønsted acid catalyzed vinylogous Mukaiyama–Mannich reactions, which feature the unprecedented use of a supersilyl group to control the regio‐, enantio‐ and diastereoselectivity. Biological studies reveal that several of these novel nuphar analogues are even more potent than their dimeric natural product counterparts.     

A general enantioselective route to the chamigrene natural product family

Described in this report is an enantioselective route toward the chamigrene natural product family. The key disconnections in our synthetic approach include sequential enantioselective decarboxylative allylation and ring-closing olefin metathesis to form the all-carbon quaternary stereocenter and spirocyclic core present in all members of this class of compounds. The generality of this strategy is demonstrated by the first total syntheses of elatol and the proposed structure of laurencenone B, as well as the first enantioselective total syntheses of laurencenone C and α-chamigrene. A brief exploration of the substrate scope of the enantioselective decarboxylative allylation/ring-closing metathesis sequence with fully substituted vinyl chlorides is also presented.     

Direct Aldol Strategy in Enantioselective Total Synthesis of Thuggacin B

An enantioselective total synthesis of thuggacin B, a natural product exhibiting antibiotic activity against Mycobacterium tuberculosis, is described. Asymmetric direct aldol reactions promoted by Cu and Zn catalysts play a pivotal role in constructing four stereogenic centers. The use of direct aldol reactions as the initial steps for the synthesis of two key fragments allowed the construction of the other stereogenic centers through chirality transfer.     

Enantioselective total synthesis of isishippuric acid B via intramolecular Michael reaction

The first enantioselective total synthesis of isishippuric acid B bearing a novel 4,5-seco-6-norquadrane skeleton was accomplished from (R)-citronellal with use of a Diels-Alder cycloaddition and an intramolecular Michael addition as the ring-forming steps. Comparison of the optical rotation of the synthetic material with that of the natural product confirmed the absolute configuration of isishippuric acid B to be 1R, 2R, 8R, and 11R.     

A total synthesis prompts the structure revision of haouamine B

A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B has been revised.     

The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to alpha,beta-unsaturated aldehydes

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described.     

Total synthesis of the proposed structure of aldingenin B

The first enantioselective total synthesis of the proposed structure of aldingenin B is reported in 16 steps from known compounds. The stereochemistry at C5 and C6 were established by an asymmetric acetal aldol. Following a ring-closing metathesis, a selective, substrate-controlled hydrogen bond-mediated dihydroxylation provided control of the C2 and C3 stereocenters. Discrepancies in the spectroscopic data of the synthetic and natural material led to the conclusion that the structure of the natural sample was misassigned.     

Total Synthesis of the Proposed Structure of Neaumycin B

The total synthesis of the proposed structure of anti-glioblastoma natural product neaumycin B was achieved in 22 steps (longest linear sequence). The synthesis features HCl-mediated [6,6]-spiroketalization, a combination of Krische iridium-catalyzed crotylation, Marshall palladium-catalyzed propargylation, Fürstner nickel-catalyzed regio- and enantioselective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide-aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters.