Reassignment Of Configuration Research Articles

Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis.

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here we disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, we adopted an integrated strategy toward the structure elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

Synthesis of the Phormidolide A Macrocycle Supports the Proposed Configurational Reassignment.

We describe the successful synthesis of the phormidolide A macrocycle as a crucial step toward its total synthesis and configurational assignment. Exhaustive exploration of macrocyclization strategies revealed the detrimental effects of a bulky protecting group on the C17 hydroxyl function, leading to the successful use of a C17 p-methoxybenzyloxymethyl (PMBM) ether in the macrolactonization reaction. Further elaboration of the macrocycle with a truncated C18-C23 side chain afforded an advanced C1-C23 fragment of phormidolide A. Detailed comparison of spectroscopic data with those of phormidolide A supports the proposed configurational reassignment.

Enantioselective Total Syntheses of (-)-Caulamidine D and (-)-Isocaulamidine D and Their Absolute Configuration Reassignment.

The first enantioselective total syntheses of (-)-caulamidine D (5) and (-)-isocaulamidine D (6) were accomplished. Their absolute configurations were unambiguously elucidated through X-ray crystallography. The isolated natural samples of both 5 and 6 are determined to be the TFA salts instead of the neutral forms. It took 16 steps (longest linear sequence) to divergently access both 5 and 6 following a unified strategy. The key reactions include (1) development and application of an asymmetric Meerwein-Eschenmoser-Claisen rearrangement to construct the challenging C10, C23 consecutive stereocenters and (2) application of a cascade 6-exo-dig/6-exo-tet amine/nitrile cyclization reaction.

Reconsideration of the Structures of Stemara-13(14)-en-18-ol and Related Diterpene Natural Products: Vinylic Hydrogen Chemical Shifts Are Key.

The reported synthesis of stemara-13(14)-en-18-ol, which revealed that the structure of this natural product was misassigned, prompted an investigation using density functional theory methods into the structural reassignment of this natural product and related diterpenoids extracted from Calceolaria plants. 1H and 13C chemical shift predictions led to the reassignment of relative configuration, and in one case the carbon skeleton, of several diterpenoids from Calceolaria. In many of these cases, the chemical shift of the vinylic hydrogen was found to be diagnostic.

Re-visiting the diastereoselectivity of organocatalytic conjugate addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde

We describe the re-assignment of configuration previously ascribed to product diastereomers resultant from imidazolidinone-catalyzed conjugate addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde. A modified procedure that uses a diphenylprolinol catalyst was subsequently developed to selectively provide the ‘syn’ diastereomeric product in high enantiomeric excess on decagram scales.

Absolute Configuration Reassignment of Natural Products: An Overview of the Last Decade

The assignment of absolute configuration (AC) is a crucial step in the structural characterization of natural products, especially for those subjected to biological assays. Methods such as X-ray crystallography, stereocontrolled organic synthesis, nuclear magnetic resonance (NMR), and chiroptical spectroscopies are commonly used to determine the AC of chiral natural compounds. Even with these well-established techniques, however, unambiguous stereochemical assignments of natural products remain a challenge, resulting in an increasing number of structural misassignments being reported every year. Herein, we will present the main techniques that have been used in AC reassignments of natural products over the last 10 years, along with some selected examples. Special attention will be paid to the strengths and weaknesses of each approach. With this, we expect to provide the readers with critical information to help them to choose the appropriate methods for correct AC determinations.

Total Synthesis and Structural Revision of a Harziane Diterpenoid.

The first total synthesis of nominal harziane diterpenoid 1 is disclosed, whose spectral characteristics did not match those of the reported natural product. Stereochemical analysis and subsequent synthesis of the epimeric tertiary alcohol led to reassignment of configuration of the natural product as shown for 2. At the heart of the synthesis is an enyne cycloisomerization that sets a key quaternary stereocenter within a cyclobutane with high diastereocontrol. The route features strategies for the synthesis of the highly congested 6-5-7-4 carbon skeleton characteristic of the caged harziane diterpenoids.

Total Synthesis and Structural Revision of a Harziane Diterpenoid

AbstractThe first total synthesis of nominal harziane diterpenoid 1 is disclosed, whose spectral characteristics did not match those of the reported natural product. Stereochemical analysis and subsequent synthesis of the epimeric tertiary alcohol led to reassignment of configuration of the natural product as shown for 2. At the heart of the synthesis is an enyne cycloisomerization that sets a key quaternary stereocenter within a cyclobutane with high diastereocontrol. The route features strategies for the synthesis of the highly congested 6‐5‐7‐4 carbon skeleton characteristic of the caged harziane diterpenoids.

Decahydroquinoline Ring 13C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (-)-Serralongamine A and Structural Reassignment and Synthesis of (-)-Huperzine K and (-)-Huperzine M (Lycoposerramine Y).

Analysis of 13C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the decahydroquinoline core to be established. A relatively simple predictive set of chemical shift combinations is reported, providing a tool for the challenging stereochemical assignment of phlegmarine-type alkaloids. Based on the chemical shifts in their NMR spectroscopic profiles, the alkaloids huperzine K and huperzine M, formally reported as cis derivatives, were structurally reassigned as trans-decahydroquinolines. The NMR spectroscopic data for huperzine M were identical to those reported for lycoposerramine Y and, hence, also implied the configurational reassignment of the latter. The revised structures of the above alkaloids were confirmed by enantioselective total synthesis. Additionally, the synthesis of (-)-serralongamine A via a common intermediate precursor is reported.

Asperfuranones A-C, 3(2H)-furanone derivatives from the fungus Aspergillus sp. and the configuration reassignment of their eighteen analogues

Three undescribed 3(2H)-furanone derivatives, asperfuranones A-C (1–3), along with one known compound (4) were isolated from the Aspergillus sp. strain obtained from the intestines of centipede. Their structures were determined by NMR and MS spectroscopic analyses, and the absolute configurations were established by the Snatzke's sector rules, modified Mosher's method and electronic circular dichroism (ECD) calculation. Meanwhile, the application of the sector rules led to the reassignment of the absolute configurations of 4 and other seventeen previously reported analogues (5–21).

A counterintuitive stereochemical outcome from a chelation-controlled vinylmetal aldehyde addition leads to the configurational reassignment of phormidolide A.

As part of our ongoing studies towards the total synthesis of phormidolide A (1), we explored the chelation-controlled vinylmetal addition of iodide 2 to aldehyde 3 to install the reported 17S configuration. While the stereochemical outcome of this reaction was opposite to that expected, detailed NMR comparisons with the previously reported triacetonide derivative of phormidolide A (18) highlighted that the major adduct was a better match to the natural product. The synthesis of three model acetonides and detailed spectroscopic comparisons to the triacetonide derivative of phormidolide A supports a reassignment of seven of the 11 stereocentres in phormidolide A (1a).

Total Synthesis of Repraesentin F and Configuration Reassignment by a Gold(I)-Catalyzed Cyclization Cascade.

The first total synthesis of repraesentin F has been accomplished by a highly diastereoselective gold(I)-catalyzed cyclization cascade as the key step. This cycloisomerization/Prins-type tandem transformation enabled direct access to the atypical tricyclic carbon skeleton of the natural product with the required syn/ anti/ syn ring fusion. This synthetic effort also allowed reassignment of the relative configuration of repraesentin F and determination of its absolute configuration.

Total synthesis and absolute configuration reassignment of mollenines A and B

The first total synthesis of mollenines A and B has been accomplished, and their absolute stereochemistry corrected.

Absolute Configuration of Menthene Derivatives by Vibrational Circular Dichroism.

The aerial parts of Ageratina glabrata afforded (-)-(3S,4R,5R,6S)-3,5,6-trihydroxy-1-menthene 3-O-β-d-glucopyranoside (1) and (-)-(3S,4S,6R)-3,6-dihydroxy-1-menthene 3-O-β-d-glucopyranoside (3). Acid hydrolysis of 1 yielded (+)-(1R,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (5) and (+)-(1S,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (6), while hydrolysis of 3 yielded (+)-(3S,4S,6R)-3,6-dihydroxy-1-menthene (10), (+)-(1R,4S,6R)-1,6-dihydroxy-2-menthene (11), and (+)-(1S,4S,6R)-1,6-dihydroxy-2-menthene (12). The structures of the new compounds 1, 2, 5-9, and 11 were defined by 1D and 2D NMR experiments, while the absolute configurations of the series of compounds were determined by comparison of the experimental vibrational circular dichroism (VCD) spectra of the 1,6-acetonide 5-acetate derived from 6 and of the 1,6-acetonide derived from 12 with their DFT-calculated spectra. In addition, Flack and Hooft X-ray parameters of 10 permitted the same conclusion. The results further led to the absolute configuration reassignment of 10 isolated from Brickellia rosmarinifolia, Mikania saltensis, Ligularia muliensis, L. sagitta, and Lindera strychnifolia, as well as of 11 from Cacalia tangutica, as ent-11.

Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product.

Apratoxin E provided the inspiration for the design of apratoxin A/E hybrids under preclinical development. Through total synthesis using two different strategies, it was determined that the originally proposed configuration of the thiazoline at C30 is opposite from that in apratoxin A, in contrast to previous assumptions on biosynthetic grounds. The epimer and true natural apratoxin E were synthesized, and the biological activities were evaluated.

Asymmetric Total Synthesis and Absolute Configuration Reassignment of Indole Alkaloid (+)-Alsmaphorazine D

The first asymmetric total synthesis of (+)-alsmaphorazine D has been achieved through a traceless chirality transfer strategy, which also enabled absolute configuration reassignment of the natural product. Key steps of this efficient approach entail a catalytic oxidative cyclization (To a solution of indoline ester 8 (5.82 g, 10 mmol) in AcOH (100 mL) were added CAN (550 mg, 1 mmol) and NaOAc (1.64 g, 20 mmol). The reaction vessel was exposed to air through a CaCl2 tube. The resulting mixture was stirred at 110 ℃ for 12 h before it was concentrated in vacuo. The residue was diluted with H2O, neutralized with NaHCO3 (sat. aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc, V∶V=4∶1) afforded δ-lactamindole 7 (4.34 g, 75%) as a white amorphous solid), a diastereoselective oxidative cyclic aminal formation (To a stirred solution of mono-ester 13 (5.20 g, 10 mmol, dr=1∶1) in acetone (100 mL) at 0 ℃ was added NaHCO3 (100 mL, sat. aq.). The resulting mixture was stirred for 0.5 h before it was added oxone (12.28 g, 20 mmol) slowly. The reaction mix- ture was stirred at 0 ℃ for an additional 2 h before it was diluted with H2O. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Flash column chromatog- raphy (silica gel, hexanes/EtOAc, V∶V=3∶1) afforded pyrroloindole 6' (1.61 g, 71%) as a white amorphous solid) and an intramolecular radical cyclization (To a stirred solution of ent-5 (250 mg, 0.47 mmol) in benzene (5 mL) at 80 ℃ were add- ed n-Bu3SnH (152 μL, 0.56 mmol) and AIBN (5 μL, 0.047 mmol). The resulting mixture was stirred for 0.5 h before it was concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc, V∶V=1∶1) afforded C(16)-epi-ent-4 (213 mg, 72%) as a colorless oil.). Keywords alkaloid; total synthesis; tetracyclic system; oxidative cyclization; radical reaction

Total Synthesis and Structural Reassignment of Aspergillomarasmine A

AbstractThe increase and spread of Gram‐negative bacteria that resistant are to almost all currently available β‐lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo‐β‐lactamases such as metallo‐β‐lactamase‐1 (NDM‐1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM‐1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM‐1‐expressing Gram‐negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo‐β‐lactamase inhibitors to potentiate β‐lactam antibiotics.

Total Synthesis and Structural Reassignment of Aspergillomarasmine A.

The increase and spread of Gram-negative bacteria that resistant are to almost all currently available β-lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo-β-lactamases such as metallo-β-lactamase-1 (NDM-1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM-1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM-1-expressing Gram-negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo-β-lactamase inhibitors to potentiate β-lactam antibiotics.

Total Synthesis and Structural Reassignment of Lyngbyaloside C Highlighted by Intermolecular Ketene Esterification.

Lyngbyaloside C, a classic macrolide, isolated from Lyngbya bouilloni, has shown moderate anticancer activity against several cancer cell lines. Here, we report the first total synthesis and stereochemical configuration reassignment of lyngbyaloside C. The synthesis highlights a one-pot intermolecular ketene esterification reaction to form the crucial tertiary ester and tetrahydropyran. In addition, a novel and concise synthetic pathway towards the 1,3-syn secondary, tertiary diol fragment is described using a regio- and stereospecific electrophilic ether transfer reaction.

ChemInform Abstract: First Total Synthesis and Reassignment of Absolute Configuration of Diosniponol A and B.

AbstractThe first enantioselective synthesis of the proposed structures of diosniponol A and B from vanillin via Wittig reaction, Keck allylation, and Prins cyclization is described.