Synthesis of the proposed structure of queenslandon

The proposed structure of the benzolactone queenslandon (6) was synthesized utilizing a triol containing building block prepared from d-ribose. While a ring-closing metathesis approach did not lead to the macrocycle, alkylation of a benzyl(phenyl)selane, elimination to generate the styrene double bond, followed by Mitsunobu macrolactonization proved to be successful. Spectral data suggest that the structure of queenslandon should be revised, probably to the C11 epimer.     

Synthesis of the proposed structure of phaeosphaeride A

The first total synthesis of the proposed structure of phaeosphaeride A has been achieved via six-membered-ring formation by means of an intramolecular vinyl-anion aldol reaction as the key step. This synthesis suggests a revised configurational assignment for phaeosphaeride A.     

Synthesis of nonactin and the proposed structure of trilactone

[reaction: see text] An efficient enantioselective route to nonactin using a novel beta-inversion of an Evans syn aldol to construct the THF ring is presented. Through total synthesis, the structure for trilactone proposed in the literature is shown likely to be incorrect.     

Synthesis of the proposed structure of plakevulin A: revised structure of plakevulin A

A total synthesis of the proposed structure of plakevulin A was accomplished. However, the NMR spectral data of the synthetic plakevulin A were not identical of those of the reported compound. We next converted the synthetic plakevulin A into 1-dihydrountenone A. The ¹H and ¹³C NMR spectral data of 1-dihydrountenone A were identical with those of reported plakevulin A except for the peaks derived from levulinic acid. Thus, we repurified sample of the natural product and confirmed that the natural sample contained 1-dihydrountenone A and levulinic acid in the ratio of one to one. We also found that not plakevulin A but 1-dihydountenone A possessed the inhibitory activity against mammalian DNA polymerases α and β.     

Synthesis of the proposed structure of fudecalone, an anticoccidial drimane terpenoid

[formula: see text] The proposed structure of fudecalone (1), an anticoccidial drimane sesquiterpene, was synthesized as a racemate in six steps starting from a known phthalide (5). Interestingly, our synthetic 1 showed conformation 1b, while the natural one was reported as 1a, and the NMR spectral data were not identical.     

Synthesis of the structures proposed for natural butanolides piliferolides A and C

The structures proposed for natural butanolides piliferolides A and C have been synthesized. The allylic and lactone stereogenic centers in the target structures were derived from d-mannitol, while that near the side-chain terminal was taken from (R)-propylene oxide. The synthetic samples helped to reveal that a signal at around δ 2.0 ppm was missing in the ¹H NMR data listing for the structures proposed for natural piliferolides, whereas the δ 29.7 ppm signal in the ¹³C NMR reported for the structure proposed for natural piliferolide C most likely stemmed from the impurities in the chromatography solvent.     

Synthesis of the proposed structure of mucoxin via regio- and stereoselective tetrahydrofuran ring-forming strategies

An enantioselective total synthesis of the proposed structure of mucoxin (1) is described. Mucoxin, an annonaceous acetogenin isolated from bioactive leaf extracts of Rollinia mucosa, is the first acetogenin containing a hydroxylated trisubstituted tetrahydrofuran (THF) ring. This natural product is a highly potent and specific antitumor agent against MCF-7 (breast carcinoma) cell lines (ED50 = 3.7 x 10(-3) microg/mL compared to adriamycin, ED50 = 1.0 x 10(-2) microg/mL). The total synthesis described herein features two regio- and stereoselective THF ring-forming reactions. The 2,3,5-trisubstituted THF portion (C13-C17) was accessed using a highly regioselective cyclization of a methylene-interrupted epoxydiol, and the 2,5-disubstituted THF ring (C8-C12) was conveniently assembled via a 1,2-n-triol cyclization strategy. The spectral data of the synthetic material and two of its diastereomers did not match the reported data for the natural product. On the basis of detailed spectroscopic analysis of the synthesized molecule, we reason that the spectral discrepancies are due to stereochemical misassignment of the natural product.     

Stereoselective synthesis of the published structure of feigrisolide A. Structural revision of feigrisolides A and B

The total synthesis of the proposed structure of feigrisolide A is reported. Ethyl (S)-3-hydroxybutyrate was the chiral starting material. A Brown asymmetric allylation and an Evans aldol reaction were key steps of the synthesis. The NMR data of the synthetic product are different from those of the natural product. The published structure of feigrisolide A is therefore erroneous. A subsequent comparison of spectral data strongly suggests that feigrisolides A and B are identical with (-)-nonactic acid and (+)-homononactic acid, respectively.     

Total synthesis of the proposed structure of xylarolide

A total synthesis of a proposed structure of xylarolide is described. The key features of the synthesis include Sharpless asymmetric reaction, Wittig olefination, Sharpless asymmetric dihydroxylation, Still-Gennari olefination and Yamaguchi lactonization. The differences in the spectroscopic data of the synthetic and natural product indicate a revision of the assigned structure.     

Total synthesis of the proposed structure of brevenal

Total synthesis of the proposed structure of brevenal, a natural marine polycyclic ether product, has been accomplished. The synthesis features (i) convergent synthesis of the pentacyclic polyether skeleton using our developed Suzuki-Miyaura coupling strategy and (ii) construction of the multi-substituted dienal side chain by CuTC-mediated Stille reaction. Comparison of the NMR data of the synthetic compound with those reported for the natural product revealed that the proposed structure of brevenal needs to be revised.     

Total synthesis of the proposed structure of macrocaffrine

A full account of the total synthesis of 18-demethyl-19-hydroxy-N_a-demethyl-N_b-methylsuaveoline (1), the structure assigned to macrocaffrine isolated from Rauwolfia caffra, is presented. The key steps involved are an intramolecular cycloaddition reaction of the oxazole-olefin 10 and a subsequent dehydration that generated the pentacyclic pyridine derivative 14. The spectral data and specific rotation of synthetic 1 were dissimilar to those reported for a natural sample, leaving the structure of this R. caffra alkaloid undefined.     

Enantioselective synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a

Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones.     

Total synthesis of the proposed structure for pyragonicin

[structure: see text] The total synthesis of acetogenin 1 reported for pyragonicin and its 10-epimer 32 is described. The common THP ring system was stereoselectively constructed through a SmI(2)-induced reductive cyclization of beta-alkoxy acrylate 5 followed by Mitsunobu inversion, and each chiral center at C-10 was created by Brown's asymmetric allylation. Compound 1 had spectroscopic data consistent with that of natural pyragonicin, but a different optical rotation.     

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.     

Synthesis of the fully functionalized core structure of the antibiotic abyssomicin C

[reaction: see text] The fully functionalized core structure 23 of abyssomicin C (6) containing an oxabicyclooctane ring and a tetronate was prepared via a Diels-Alder approach. After hydroxylation of lactone 10 to the alpha-hydroxylactone 12, lactone opening led to the hydroxy ester 16. A directed epoxidation furnished the desired syn-epoxide 20. Acetylation of the tertiary hydroxyl group, followed by intramolecular Claisen condensation, gave directly the core structure 23.     

Total synthesis of the proposed structure of briarellin J

The total synthesis of the originally proposed structure of briarellin J is reported in 15 steps from a known compound and in 23 steps from readily available materials. Key reactions include an exo-selective intramolecular Diels-Alder and a substrate-controlled hydroboration. Discrepancies in the spectroscopic data of the synthetic and natural material led to a revision of the assigned structure.     

Synthesis of a proposed 1,3,4-trisubstituted isoquinoline

The isoquinoline ring system is a reoccurring structural motif in alkaloids¹ and pharmaceuticals.² Consequently, the synthesis and functionalization of isoquinolines have attracted considerable attention from the synthetic community.³ We previously reported a facile synthesis of 1,3,4-trisubstituted isoquinolines from commercially available 1,3-dichloroisoquinoline 1 (Scheme 1).⁴ A key step in the process is the direct lithiation of 1 at C4. The resulting lithium species 2 was trapped with a variety of electrophiles to produce 4-substituted-1,3-dichloroisoquinoline 3, which was further elaborated to give1,3,4-trisubstituted isoquinoline 4 by exploiting the different reactivity of C1-Cl and C3-Cl bonds under Pd-catalysis.     

Synthesis of the C10-C32 core structure of spirangien A

The synthesis of the C10-C32 core structure of spirangien A is reported. The pivotal aldol coupling between both key intermediates provides a synthetic challenge in the synthesis of this complex natural product.     

Total synthesis of the proposed structure of iriomoteolide-1a

Full details of the total synthesis of the proposed structure of iriomoteolide-1a (1) are described. The key steps include (i) a Sakurai reaction between allylsilane 11 and aldehyde 10 that bears both a tertiary chiral center and vinyl iodide moiety (ii) an anti-aldol reaction to construct the C18/C19 chiral centers (iii) a B-alkyl Suzuki-Miyaura coupling reaction to assemble the C7-C23 fragment, and (iv) a macrocyclic ring-closing metathesis to complete the construction of the target molecule. Two different approaches to access penultimate precursor 2 are delineated. The NMR spectra of the synthetic iriomoteolide-1a (1) were found not to match those reported for the natural product bringing into question its true structural identity.     

Asymmetric catalytic synthesis of the proposed structure of trocheliophorolide B

A concise catalytic asymmetric synthesis of the proposed structure of trocheliophorolide B is reported. The synthetic sequence notably features an asymmetric acetaldehyde alkynylation, a Ru-catalyzed alder-ene reaction, and a Zn-ProPhenol ynone aldol condensation. Comparison with the reported data suggests a misassignment of the natural product structure.