Total Synthesis Of Amphidinolide Research Articles

Allyl Alcohol as an Acrolein Equivalent in Enantioselective C-C Coupling: Total Synthesis of Amphidinolides R, J, and S.

The first systematic study of catalytic enantioselective 1,2-additions to acrolein is described. Specifically, using allyl alcohol as a tractable, inexpensive acrolein proelectrophile, iridium-catalyzed acrolein allylation is achieved with high levels of regio-, anti-diastereo-, and enantioselectivity. This process delivers 3-hydroxy-1,5-hexadienes, a useful compound class that is otherwise challenging to access via enantioselective catalysis. Two-fold use of this method unlocks concise total syntheses of amphidinolide R (9 vs 23 steps, LLS) and amphidinolide J (9 vs 23 or 26 steps, LLS), which are prepared in fewer than half the steps previously possible, and the first total synthesis of amphidinolide S (10 steps, LLS).

Toward a total synthesis of amphidinolide N: convergent synthesis of the C1–C13 segment

A convergent synthesis of the C1–C13 segment of amphidinolide N, a potent cytotoxic marine macrolide isolated from the dinoflagellate Amphidinium sp., was achieved. The key features of the synthesis involve vinylogous Mukaiyama and Evans aldol reactions to form the C1–C7 and C8–C13 fragments, and convergent union of the two fragments by means of an aldol reaction to construct the C1–C13 segment.

Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8-C29 Fragment.

A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9-C15 and C16-C29 fragments by Steglich esterification and the construction of a pyran unit through a Tebbe methylenation/ring-closing metathesis sequence.

Studies toward the Total Synthesis of Amphidinolide N: Stereocontrolled Synthesis of the C13–C29 Segment

Studies toward the Total Synthesis of Amphidinolide N: Stereocontrolled Synthesis of the C13–C29 Segment

ChemInform Abstract: Toward the Total Synthesis of Amphidinolide O: An Enantioselective Synthesis of C3—C8 Fragment.

AbstractTitle fragment (X) is synthesized enantioselectively starting from L‐(‐)‐malic acid (I) via 11 steps in 14 % overall yield.

Toward the Total Synthesis of Amphidinolide O: An Enantioselective Synthesis of C3-C8 Fragment

Wedescribe herein the enantioselective synthesis of C3-C8fragment of amphidinolide O (1).Retrosynthetic analysis was described in Figure 1. Amphi-dinolide O (1) might be assembled from two intermediates 2and 3 via esterification and ring closing metathesis as keysteps. Intermediate 4, a precursor to 3 as well as the targetmolecule in this paper, involves the γ,δ-unsaturated estermoiety along with α,β-chiral substituents with anti-stereo-chemical relationship. Those structural features could beavailable by Ireland-Claisen rearrangement of the corre-sponding (E)-enolate derived from the propionate ester 5.The ester 5 was prepared from the commercially available

Exploiting hidden symmetry in natural products: total syntheses of amphidinolides C and F.

The total synthesis of amphidinolide C and a second-generation synthesis of amphidinolide F have been accomplished through the use of a common intermediate to access both the C1-C8 and the C18-C25 sections. The development of a Ag-catalyzed cyclization of a propargyl benzoate diol is described to access both trans-tetrahydrofuran rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl addition strategy to incorporate C9-C11 diene as well as C8 stereocenter is detailed. Key controlling aspects in the sulfone alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the C18 carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have been developed for the rapid construction of the C26-C34 subunit. A Tamura/Vedejs olefination to introduce the C26 side arm of amphidnolides C and F is employed. The late-stage incorporation of the C15, C18 diketone motif proved critical to the successful competition of the total syntheses.

Total Synthesis of Amphidinolide F

Total Synthesis of Amphidinolide F

Total Synthesis of Amphidinolide F

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13−C14 bond was achieved by the “9-MeO-9-BBN” variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.

Total Synthesis of Amphidinolide F

Geglücktes Zusammenspiel: Das charakteristische „umgepolte“ 1,4-Dioxygenierungsmuster im Polyketidgerüst von Amphidinolid F wurde durch eine Alkin-Ringschlussmetathese mit anschließender dirigierter transannularer Hydratisierung unter Anwendung eines carbophilen π-Säure-Katalysators im späten Synthesestadium eingeführt. Auf dieser Strategie beruht eine kurze Totalsynthese des faszinierenden marinen Naturstoffs.

ChemInform Abstract: Studies on the Total Synthesis of Amphidinolide O. Part 4. A Stereoselective Synthesis of C1—C11 Fragment.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Studies on the Total Synthesis of Amphidinolide O (IV): A Stereoselective Synthesis of C1-C11 Fragment

Studies on the Total Synthesis of Amphidinolide O (IV): A Stereoselective Synthesis of C1-C11 Fragment

Total Synthesis of Amphidinolide Q

Asymmetric synthesis of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished with Julia coupling, Myers alkylation, and Yamaguchi lactonization. The absolute configuration of amphidinolide Q was confirmed to be 1 from comparison of the NMR data and [alpha](D) values of synthetic and natural amphidinolide Q.

Molecular Editing and Biological Evaluation of Amphidinolide X and Y

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.

Total Synthesis of Amphidinolide J

The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.

ChemInform Abstract: Total Synthesis of Amphidinolide O (III): A Stereoselective Synthesis of C1—C11 Fragment.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total Synthesis of Amphidinolide X and Its 12Z-Isomer by Formation of the C12-C13 Trisubstituted Double Bond via Ring-Closing Metathesis

Amphidinolide X, a 16-membered cytotoxic macro-diolide, and its 12 Z-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond. A 29:71 E/ Z mixture was obtained from the SECO substrate appended with a bulky C8-ODPS group in 50-65% combined yields by using 20 mol% of the second-generation Grubbs initiator and the corresponding indenylidene ruthenium complex. Amphidinolide X and 12 Z-isomer exhibit similar cytotoxicity (IC 50 : 7.6-13.9 μg/mL) against A549, KB, and HL60 cell lines.

Studies on the Total Synthesis of Amphidinolide O (III): A Stereoselective Synthesis of C1-C11 Fragment

The amphidinolides were isolated from the marine dinoflagellate Amphidinium sp., which produces a host of secondary metabolites endowed with potent cytotoxicity against various cancer cell lines. Amphidinolide O (1) displayed potent in vitro cytotoxicity against L1210 marine leukemia cells and human epidermoid carcinoma KB cells with 1.7 and 3.6 μg/mL of IC50s, respectively. In addition to our recent reports regarding to the synthesis of C12-C17 and C3-C11 fragments of amphidinolide O (1), we describe herein a new route to diastereoselective synthesis of C1-C11 fragment of 1. The retrosynthetic analysis of 1 led to the C1-C11 fragment 2 and C12-C17 fragment 3 (Scheme 1). The hemiketal 2 was expected from acyclic precursor 4 which, in turn, would be derived by diastereoselective aldol reaction between ketone 5 and aldehyde 6. The C1-C6 fragment 8 (equivalent to 5 in scheme 1) was prepared as summarized below (Scheme 2). Enolization of carboximide 7 with Bu2BOTf and EtN(i-Pr)2 was followed by reaction with aldehyde to provide the syn-aldol product in 86% yield (ds = > 97 : 3 by H NMR analysis) (Scheme 2). The aldol product was treated with N,O-dimethylhydroxylamine hydrochloride and Al(Me)3 to provide the Weinreb amide in 91% yield. The free hydroxyl group was protected as PMB ether, and finally Weinreb amide was converted to ketone 8 in 85% yield by reaction with MeMgCl. Synthesis of C7-C11 fragment 10 (equivalent to 6 in scheme 1) was completed via 5-step sequences (Scheme 3). Monoprotection of propane-1,3-diol (9), Swern oxidation of the remaining alcohol to aldehyde, and Wittig-olefination was undertaken to give α,β-unsaturated ester, which was subsequently reduced by DIBAL and oxidized to provide the C7-C11 fragment 10, another key intermediate in the next aldol reaction. Aldol-reactions of fragments 8 and 10 were investigated with four chiral boron reagents in ether at −78 C (Scheme 4), and the use of chlorodicyclohexylborane provided the desired product with the best diastereoselectivity (11a : 11b = 67 : 33) in 61% (11a) and 30% (11b) yield, respectively. Hydroxyl group-directed 1,3-anti reduction of either 11a or 11b with NaBH(OAc)3 provided the 5,7-anti diol 12a or 12b in 91% yield. The (5R,7S)-isomer 12a was treated with 2,2-dimethoxypropane in the presence of PPTS (Scheme 5). The PMB-

Total Syntheses of Amphidinolide H and G

Total Syntheses of Amphidinolide H and G

Total Syntheses of Amphidinolide H and G

Eureka! Die erste Synthese des außerordentlich zytotoxischen Amphidinolid H, das in pikomolaren Konzentrationen gegen humane Hautkrebszellen aktiv ist, war lange überfällig. Die erfolgreiche Route beruht auf gründlich optimierten Fragmentkupplungen (siehe Bild; RCM=Ringschlussmetathese) und sorgfältig ausgewählten peripheren Schutzgruppen. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2007/z704024_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.