Longest Linear Sequence Research Articles

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4.

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.

Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores.

The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.

Convergent Assembly of Highly Oxygenated Natural Products Enabled by Intermolecular Radical Reactions.

Natural products with a high ratio of sp3-hybridized atoms and oxygen-substituted stereogenic centers represent privileged structures for the development of pharmaceuticals and chemical probes. The multiple oxygen functionalities of these natural products endow their potent and selective biological activities, although they significantly heighten the challenge of their chemical assemblies. We focused on developing efficient strategies for the total syntheses of this biologically and chemically important class of molecules. A convergent strategy is more advantageous than a linear strategy for designing a shorter synthetic route because a convergent strategy enables direct coupling of functionalized fragments whereas a linear strategy involves stepwise construction of a molecule from its terminus. Radical reactions are preferred over polar reactions for the coupling of heavily functionalized and sp3-rich fragments, as they allow for C(sp3)-C(sp3) coupling without damaging diverse polar functional groups. With these considerations in mind, we designed radical-based convergent strategies for assembling highly oxygenated natural products. Here we summarize the concise total syntheses of asimicin (1, antibiotic activity), 1-hydroxytaxinine (2, cytotoxicity), polyoxins (3, antifungal activity), and hikizimycin (4, anthelmintic activity) as representative examples. Retrosynthetic disconnection at the central part of these molecules produces highly substituted α-alkoxy radicals as synthons. In the synthetic direction, the α-alkoxy radicals were generated from the corresponding α-alkoxyacyl tellurides in a unified fashion, and then utilized for four distinct coupling reactions. Formation of the Et radical from Et3B and O2 homolytically cleaves the C-Te bond of α-alkoxyacyl telluride, and the facile expulsion of carbon monoxide from the acyl radical leads to the α-alkoxy radical. Dimerization of the stabilized α-alkoxy radical resulted in the core structure of 1 with 10 contiguous stereocenters. The coupling adduct was derivatized to 1 through the attachment of two different carbon chains (17 steps as the longest linear sequence). Alternatively, intermolecular addition reactions of the α-alkoxy radicals to electron-deficient C═C, C═N, and C═O bonds, followed by Et3B-mediated radical termination, led to the core structures of 2, 3, and 4, respectively. Intermolecular coupling between the α-alkoxy radical and the cyclohexenone derivative and intramolecular pinacol coupling gave rise to the 6/8/6-fused ring system of 2, which was transformed to 2 (26 steps). The two amino acid moieties of 3 were prepared by combining the α-alkoxy radical and the oxime and were then condensed to complete the synthesis of 3 (11 steps). Furthermore, a combination of α-alkoxyacyl telluride and Et3B/O2 realized a novel addition reaction of α-alkoxy radicals to aldehydes. This method was incorporated in the construction of the core 4-amino-5-deoxyundecose with 10 contiguous stereocenters, which was fabricated with two appendage structures to deliver 4. The four total syntheses described here demonstrate the versatility and robustness of intermolecular radical reactions. These syntheses will also provide new insights for retrosynthetic analyses in the field of organic chemistry and streamline synthetic routes to various bioactive natural products with multiple oxygen functionalities.

Asymmetric Synthesis of ent-Fissistigmatin C.

The asymmetric synthesis of ent-fissistigmatin C is successively accomplished in 12 steps (longest linear sequence (LLS)). Relying on the enantioselective coupling of aliphatic aldehyde with 2-hydroxychalcone promoted by cooperative organocatalysts, the pivotal linkage of ent-fissistigmatin C between the flavonoid and the sesquiterpenoid fragment was stereoselectively established. An unprecedented final-stage radical cascade was also featured in this synthesis, which enabled the simultaneous establishment of the trans-decalin framework via forging two consecutive C-C bonds in one step.

An updated asymmetric total synthesis of (+)-tronocarpine

An updated route for the asymmetric total synthesis of (+)-tronocarpine is presented. By a careful modification of the synthetic strategies and methods for the construction of azepanone ring and for the incorporation of acetyl side group at C 20 based on our experiences for the synthesis of chippiine-dippinine type indole alkaloids, the synthesis of (+)-tronocarpine could be shortened from 15 longest linear sequences (LLSs) to 11 LLSs starting from an easily prepared intermediate. The new synthetic route presented herein would provide a more efficient synthesis of (+)-tronocarpine as well as its analogues for biological evaluation which remained unexplored due to the paucity of natural sources. To create your abstract, type over the instructions in the template box below.Fonts or abstract dimensions should not be changed or altered. Leave this area blank for abstract info.

A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2

AbstractA new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

Concise Diastereoselective Total Synthesis of (±)-Parvistemonine A

AbstractWe have developed a concise diastereoselective total synthesis of (±)-parvistemonine A. By using a Mukaiyama–Michael addition, an aza-Wittig reaction, a Paal–Knorr pyrrole synthesis, an acid-mediated annulation, and a Mitsunobu reaction as key steps, we achieved a total synthesis in which the longest linear sequence was ten steps and the overall yield was 19.6%. Additionally, the relative stereochemistry of parvistemonine A was confirmed by X-ray crystallographic analysis for the first time.

Next-Generation Total Synthesis of Vancomycin.

A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation-Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room-temperature atroposelective intramolecular SNAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large-scale synthetic preparation of pocket-modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.

Total Synthesis of Ajudazol A by a Modular Oxazole Diversification Strategy.

The total synthesis of the potent respiratory chain inhibitor ajudazol A was accomplished by a concise strategy in 17 steps (longest linear sequence). The modular approach was based on a direct oxazole functionalization strategy involving a halogen dance reaction for selective halogenation in combination with a challenging combination of sp2-sp2 and sp2-sp3 Negishi cross coupling reactions. The applicability of this strategy for analogue synthesis was demonstrated by the synthesis of a simplified as well as stabilized ajudazol analogue.

Total Synthesis of (+)-Raputindole A: An Iridium-Catalyzed Cyclization Approach.

This work describes the total synthesis of raputindole A (1) through a convergent approach that features (1) an iridium-catalyzed cyclization to assemble the tricyclic core of the northern part, (2) enzymatic resolution to secure the preparation of an enantiomerically pure benzylic alcohol intermediate, and (3) the installation of the isobutenyl side chain via methallylation of the corresponding benzylic carbocation and coupling of the northern and southern parts via the Heck reaction. (+)-Raputindole A (1) was prepared in 10 steps (longest linear sequence) in 3.3% overall yield.

Total synthesis of bryostatin 3.

Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.

Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)-Diastereoisomer.

The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2S)‐3‐benzyloxy‐2‐hydroxypropanoate (16 steps in the longest linear sequence). The cyclic depsipeptide was assembled from two building blocks of similar size and complexity in a modular, highly convergent approach. Peptide bond formation at the C‐terminal dehydrobutyrine amino acid of the northern fragment was possible via its (Z)‐diastereoisomer. After macrolactamization and formation of the thiazoline ring, the (Z)‐double bond of the dehydrobutyrine unit was isomerized to the (E)‐double bond of the natural product. The cytotoxicity of vioprolide D is significantly higher than that of its (Z)‐diastereoisomer.

Total Synthesis of Meayamycin B.

Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)‐Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

AbstractWe present the first asymmetric total synthesis and absolute configuration determination of (+)‐tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]‐bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven‐membered lactam. The side‐chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)‐tronocarpine was achieved through a 20‐step longest linear sequence from tryptamine.

Asymmetric Total Synthesis of the Complex Polycyclic Xanthone FD‐594

AbstractA highly convergent approach was developed to achieve the first asymmetric and scalable total synthesis of FD‐594, a complex polycyclic xanthone natural product from Streptomyces sp. TA‐0256, in a longest linear sequence (LLS) of 20 steps. The trans‐9,10‐dihydrophenanthrene‐9,10‐diol fragment (B‐C‐D ring) was generated through a new strategy involving asymmetric dihydroxylation followed by Cu‐mediated oxidative cyclization. Late‐stage stereoselective glycosylation assembled the angular hexacyclic framework with a β‐linked 2,6‐dideoxy trisaccharide fragment.

Asymmetric Total Synthesis of the Complex Polycyclic Xanthone FD-594.

A highly convergent approach was developed to achieve the first asymmetric and scalable total synthesis of FD-594, a complex polycyclic xanthone natural product from Streptomyces sp. TA-0256, in a longest linear sequence (LLS) of 20 steps. The trans-9,10-dihydrophenanthrene-9,10-diol fragment (B-C-D ring) was generated through a new strategy involving asymmetric dihydroxylation followed by Cu-mediated oxidative cyclization. Late-stage stereoselective glycosylation assembled the angular hexacyclic framework with a β-linked 2,6-dideoxy trisaccharide fragment.

Enantioselective synthesis and anti-parasitic properties of aporphine natural products

Chagas disease and visceral leishmaniasis are neglected protozoan diseases with significant impact in developing countries. Due to the limited number and toxicity of current therapies, new drug leads are urgently needed. In this work, four aporphine natural products were synthesized using an enantioselective, modular and convergent strategy, comprising eight steps in the longest linear sequence; key steps included Bischler-Napieralski cyclization/Noyori asymmetric reduction to construct the tetrahydroisoquinolines, and palladium-catalyzed arylation to close the C ring. Norglaucine, nordicentrine and dicentrine showed promising bioactivity against T. cruzi and L. infantum, suggesting potential for further development of these scaffolds as antiparasitic agents.

Total Synthesis of Clavatadine B.

The first total synthesis of clavatadine B (2), a natural product found to be a selective human blood coagulation factor XIa inhibitor, is described. A convergent approach that exemplifies the advantages of direct, early stage guanidinylation provided an immediate clavatadine B precursor, which was assembled in an efficient manner using known synthetic precursors of the structurally related natural product clavatadine A (1). Global deprotection cleanly provided clavatadine B in only four steps from a known derivative of homogentisic acid lactone (longest linear sequence, 75% overall yield).

Total Synthesis of (±)-Brazilin Using [4 + 1] Palladium-Catalyzed Carbenylative Annulation.

Palladium-catalyzed carbene insertion was utilized in a formal synthesis of (±)-picropodophyllone and a total synthesis of (±)-brazilin. All prior syntheses of brazilin have involved a Friedel-Crafts alkylation in the key carbon-carbon bond forming events. The palladium-catalyzed [4 + 1] reaction generates a 1-arylindane with all of the functionalities needed for formation of the indano[2,1-c]chroman ring system of brazilin. The synthesis of (±)-brazilin was achieved in 11 steps (longest linear sequence) with an overall 11% yield.

Total Synthesis of (-)-Himeradine A.

(-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.