Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

Nicolaou, K. C.; Bunnage, Mark E.; Mcgarry, D. G.; Shi, Shuhao; Somers, Patricia K.; Wallace, Paul A. W.; Chu, Xin‐Jie; Agrios, Konstantinos A.; Gunzner, Janet L.; Yang, Zhen

doi:10.1002/(sici)1521-3765(19990201)5:2<599::aid-chem599>3.0.co;2-n

Cited by 93 publications

(25 citation statements)

References 22 publications

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“…Following the procedure described by Nicolaou et al [ 18 ] we attempted the opening of the epoxide to obtain a dihydroxylated compound in C-4 and C-5. Unexpectedly, the integrals of the 1 H-NMR of the product showed that there was only one hydrogen at C-6 at δ 4.77 (H-6), too high for hydrogens in α position to the carbonyl at C-1.…”

Section: Resultsmentioning

confidence: 99%

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships

et al. 2018

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(+)-epi-Epoformin (1), is a fungal cyclohexene epoxide isolated together with diplopimarane and sphaeropsidins A and C, a nor-ent-pimarane and two pimaranes, from the culture filtrates of Diplodia quercivora, a fungal pathogen for cork oak in Sardinia, Italy. Compound 1 possesses a plethora of biological activities, including antifungal, zootoxic and phytotoxic activity. The last activity and the peculiar structural feature of 1 suggested to carry out a structure activity relationship study, preparing eight key hemisynthetic derivatives and the phytotoxicity was assayed. The complete spectroscopic characterization and the activity in the etiolated wheat coleoptile bioassay of all the compounds is reported. Most of the compounds inhibited growth and some of them had comparable or higher activity than the natural product and the reference herbicide Logran. As regards the structure-activity relationship, the carbonyl proved to be essential for their activity of 1, as well as the conjugated double bond, while the epoxide could be altered with no significant loss.

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Section: Resultsmentioning

confidence: 99%

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships

et al. 2018

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“…The vinyliodide fragment 27 lacking the C‐11 methyl branch (amphidinolide X numbering) was obtained by alkylation of 2‐methyl‐1,3‐dithiane 20 with ( S )‐ 21 (>99 % ee )33 followed by opening of the epoxide in 22 with propynyl lithium in the presence of BF 3 (OEt 2 ) (Scheme ) 34. 35 Treatment of 23 with ethyleneglycol and iodine in MeCN gently swapped the thioketal for the corresponding 1,3‐dioxolane 24 ,36, 37 which served as the substrate for a subsequent hydrozirconation/iodination38 sequence once the free hydroxy group had been protected as PMB‐ether. For a regioselective hydrozirconation of a non‐symmetrical alkyne to occur, it is believed that thermodynamic conditions need to be operative 38.…”

Section: Resultsmentioning

confidence: 99%

“…[ α ]${{{20\hfill \atop {\rm D}\hfill}}}$ =−6.4 ( c =4.2, CH 2 Cl 2 ) [lit. :36 [ α ]${{{22\hfill \atop {\rm D}\hfill}}}$ =−4.9 ( c =4.7, CH 2 Cl 2 )]; 1 H NMR (400 MHz, CDCl 3 ): δ =3.20–3.16 (m, 1 H), 2.95–2.79 (m, 5 H), 2.52 (dd, J =5.0, 2.7 Hz, 1 H), 2.23 (dd, J =14.7, 4.8 Hz, 1 H), 2.10 (dd, J =14.7, 6.3 Hz, 1 H), 2.06–1.87 (m, 2 H), 1.71 ppm (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ): δ =48.7, 47.4, 46.3, 44.0, 28.1, 26.3, 26.2, 24.6 ppm; IR (film): $\tilde \nu $ =3045, 2920, 1446, 1422, 1277, 1258, 864 cm −1 ; MS (EI): m / z (%): 190 (41) [ M + ], 133 (100); HRMS (EI): m / z: calcd for C 8 H 14 OS 2 [ M + ]: 190.0486, found: 190.0488.…”

Section: Methodsmentioning

confidence: 99%

Molecular Editing and Biological Evaluation of Amphidinolide X and Y

Fürstner

Kattnig

Kelter³

et al. 2009

Chemistry A European J

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Scarce and precious: A collection of compounds with deep-seated structural "point mutations" within the framework of the marine natural products amphidinolide X and Y was prepared by "diverted total synthesis". The resulting products provided first insights into the cytotoxicity profile of these extremely scarce macrolides.Deliberate deviations from the previously described total syntheses of amphidinolide X (1) and Y (2) allowed a collection of seven designed analogues of these extremely scarce marine natural products to be obtained. These fully synthetic "natural product-like" compounds enabled first insights into the previously unknown structure-activity relationships governing this series. Although the average cytotoxicity is moderate, it was found that certain bladder, colon and prostate cancer cell lines are fairly sensitive, and that the best synthetic analogues are more active than the natural products themselves. The syntheses rely on the 9-MeO-9-BBN variant of the Suzuki coupling for the formation of the carbon frameworks, as well as on Yamaguchi lactonization reactions for the cyclization of the macrocyclic rings.

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“…By using this gap in methodology as an opportunity for discovery, we developed a series of synthetic reactions based on the power of heteroatoms (i.e., sulfur and phosphorous) to drive these entropically disfavored ring closures; four of these methods are shown in Scheme 2. Apart from finding widespread applicability to a range of other synthetic problems, these unique approaches were critical to the completion of both of these formidable targets, accomplishments that have more recently inspired a host of researchers to attempt the total synthesis of other cyclic polyethers, some of even greater size and complexity (14)(15)(16)(17)(18)(19)(20).…”

Section: Selected Total Synthesis Endeavorsmentioning

confidence: 99%

The Essence of Total Synthesis

Nicolaou¹,

Snyder²

2005

ChemInform

Self Cite

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For the past century, the total synthesis of natural products has served as the flagship of chemical synthesis and the principal driving force for discovering new chemical reactivity, evaluating physical organic theories, testing the power of existing synthetic methods, and enabling biology and medicine. This perspective article seeks to examine this time-honored and highly demanding art, distilling its essence in an effort to ascertain its power and future potential.Essence (és'ns) n. the most significant part of a thing's nature; the sum of the intrinsic properties without which a thing would cease to be what it is, and which are not affected by accidental modifications. (The New Lexicon Webster's Dictionary) A lthough the practice of total synthesis and the rationale behind its pursuit have changed throughout the course of its history, its most fundamental property has not. At its core, in its most essential form, natural product total synthesis is a vehicle for discovery, one that is perhaps unparalleled by any other endeavor in the realm of chemical synthesis (1-3). The reason follows: every natural product type isolated from the seemingly limitless chemical diversity in nature provides a unique set of research opportunities deriving from its distinctive three-dimensional architecture and biological properties. For instance, in the early part of the 20th century, efforts directed toward the synthesis of the antimalarial agent quinine (1) (Fig. 1) led to a sizeable body of knowledge regarding the construction of heteroaromatic systems and the unique physical properties of quinoline and piperidine rings. In more recent times, its structure has served as the basis for the design of several new classes of antimalarial drugs that have saved thousands of lives (4). Similarly, attempts to construct steroids such as progesterone (2) before World War II provided insights into how carbon-carbon bonds could both be forged and cleaved, with their partial or total synthesis ultimately rendering them available in quantities that are sufficient to propel them into useful drugs, such as the birth control pill, which is now used by millions of women around the world (5). In the 1950s, the highly sensitive ␤-lactam ring of penicillin (3) served as the impetus for John Sheehan (6) to develop carbodiimide-based reagents for the formation of peptide bonds. This discovery capped the first practical synthesis of this essential medicinal agent, enabled the synthesis of designed penicillins with activity profiles superior to the parent natural product, and revolutionized the entire peptidesynthesis field. In the 1960s and 1970s, members of the eicosanoid family of natural products, such as prostaglandin F 2a (4), served as the artistic canvas on which E. J. Corey was inspired to create the first catalysts capable of orchestrating asymmetric Diels-Alder reactions. It also was the arena in which he and his group developed the now ubiquitous family of silyl-based protecting groups, one of the most general and powerful methods for ...

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Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

Cited by 93 publications

References 22 publications

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships

Molecular Editing and Biological Evaluation of Amphidinolide X and Y

The Essence of Total Synthesis

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