Multigram amounts of suitably protected b2 -amino acids with 17 of the 20 proteinogenic side chains are prepared by diastereoselective reactions of Li, B, or Ti enolates of the corresponding 3-acyl-4-isopropyl-5,5-diphenyloxazolidin-2-ones (acyl-DIOZ; 1) with appropriate electrophiles (amidomethylation, hydroxyalkylation, (benzyloxycarbonyl)methylation) in yields of 55 ± 90% and with diastereoselectivities of 80 to > 97% (Scheme). The primary products 2 ± 8 thus obtained are converted to protected b 2 -amino acids by standard procedures ( Table 1). Many of the DIOZ derivatives are highly crystalline compounds (31 X-ray crystal structures in Table 2). The chiral auxiliary DIOZ, readily prepared in either enantiomeric form, is recovered with high yield.b-Peptides, which consist of homologs of a-amino acids, have turned out to present a new world of peptide chemistry. While the functional groups in the chain (the amide bonds) and in the side chains (of Arg, Asp, Glu, His, Lys, Met, Ser, Thr, Trp, and Tyr) are identical, there is just an additional backbone CH 2 group in each amino acid moiety. Even this causes dramatic effects: secondary structures differ fundamentally (in number, shape, size, and polarity) and are more stable and predictable at short chain length [1] [2]; there is total enzymatic stability (against peptidases and proteases) [3], metabolic stability in rats has been demonstrated [4], even microbial degradation is slow [5]. On the other hand, the activities of an a-peptidic hormone and of an apeptidic amphipathic helix can be mimicked by b-peptides [6], and strong binding of certain b-peptides to DNA of mammalian cells has been detected [7].There are two ways of inserting CH 2 groups into the backbone of peptides: between the CO group and the a-C-atom ( 3 b 3 -amino acid) or between the a-C-atom and the N-atom ( 3 b 2 -amino acid), and it turns out that the latter change has the more intriguing effects, leading to turn structures [2] or to a novel type of helix, which consists of alternating ten-and twelve-membered H-bonded rings [1] [8].
Amphidinium species are an extremely prolific source of marine secondary metabolites.[1] Structurally unique polyketides such as amphidinolides, caribenolide I, and amphidinolactones have fostered the interest of chemists not only as challenging targets for total synthesis but also because of their potent anticancer activity.[2] Recently, the Amphidinium strain HYA024 was found to produce cytotoxic compounds such as iriomoteolides 1a-c, [3] and a rare 15-membered macrolide, iriomoteolide 3a (1).[4] With a novel carbon framework comprising eight stereogenic centers, four of them in allylic positions, compound 1 represents the first member of a unique and unprecedented 15-membered macrolide class. Compound 1 represents the first member of a unique and unprecedented 15-membered macrolide class. In addition, the preliminary physiological properties disclosed for 1 and its 7,8-O-isopropylidene derivative 2 are very promising, showing potent cytotoxicity against lymphoma cell lines in the low nanomolar range. [4] To confirm the assigned structure, further evaluate its biological activity, and determine whether its cellular targets are related to those of larger congeners such as amphidinolides, [5] substantial quantities of these compounds are required. Our retrosynthetic approach to 1 involved four major disconnections, which revealed key fragments 3-6 as summarized in Scheme 1. Fragment 6 was planned to be incorporated at the end of our synthetic sequence by a JuliaKocienski olefination because of its widely recognized performance in the elaboration of such sensitive settings and also to ensure a flexible late-stage diversification of the parent compound. An intermolecular esterification was envisioned to assemble fragments 3 and 4. Finally, we hypothesized that the C 2 -symmetry of the diol precursor of fragment 5 could be advantageously used to construct the 1,5-diene upon ring closure by a cross-metathesis (CM)/ringclosing metathesis (RCM) approach. We were relying on the excellent results achieved by the Grubbs-type carbene complexes in both CM and RCM processes with the expectation that the formation of a medium-sized ring would also be E,E stereoselective (Scheme 1).The required building block 3 (Scheme 2) was prepared by alkylation of the Evans oxazolidinone 7[6] with iodide 8.[7]Scheme 2. a) Na[N( , THF, 73 %; n) DDQ, CH 2 Cl 2 , pH 7 buffer, RT, 85 %. CSA = camphorsulfonic acid, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL-H = diisobutylaluminium hydride, DIPT = diisopropyl tartrate, DMF = N,N-dimethylformamide, DMSO = dimethylsulfoxide, MS = molecular sieves, PMB = para-methoxybenzyl, PPTS = pyridinium para-toluenesulfonate, TBAF = tetra-n-butylammonium fluoride, TBDPS = tert-butyldiphenylsilyl, TBS = tert-butyldimethylsilyl.Scheme 1. Retrosynthetic analysis for iriomoteolide 3a (1).
Amphidinium-Arten haben sich als sehr reichhaltige Quelle für marine Sekundärmetaboliten erwiesen.[1] Strukturell einzigartige Polyketide wie die Amphidinolide, Caribenolid-I und die Amphidinolactone sind wegen ihrer zytostatischen Wirkung und als anspruchsvolle Zielmoleküle für Synthesechemiker interessant.[2] Kürzlich wurden im AmphidiniumStamm HYA024 die zytotoxischen Produkte Iriomoteolid-1a bis Iriomoteolid-1c [3] und ein seltener 15-gliedriger Makrocyclus, Iriomoteolid-3a (1), [4] gefunden. 1 ist der erste Repräsentant einer Familie 15-gliedriger Makrocyclen mit einem neuartigen Kohlenstoffgerüst mit acht Stereozentren, insgesamt vier davon in Allylpositionen. Auch die bisher ermittelten physiologischen Eigenschaften von 1 und seinem 7,8-O-Isopropylidenderivat 2 sind mit einer hohen Zelltoxizität gegen Lymphoma-Zelllinien im niedrigen nanomolaren Bereich sehr verheissungsvoll. [4] Um die publizierte Struktur zu bestätigen und um zu bestimmen, ob die zellulären Ziele denen größerer Verwandter, wie der Amphidinolide, [5] ähneln, werden größere Mengen beider Substanzen benötigt. Unser retrosynthetischer Ansatz enthielt vier Hauptbindungsbrüche, die zu den in Schema 1 gezeigten Schlüsselfragmenten 3-6 führten. Fragment 6 sollte am Ende der Synthese mittels Julia-Kocienski-Olefinierung eingebaut werden, weil bekannt ist, dass diese Methode bei empfindlichen Systemen gute Ergebnisse erzielt, und um die Diversifizierung der Ausgangsverbindung zu erleichtern. Die Fragmente 3 und 4 sollten durch intermolekulare Veresterung zusammengefügt werden. Schlussendlich wurde die Hypothese aufgestellt, dass die C 2 -Symmetrie des Diolvorläufers von Fragment 5 genutzt werden könnte, um die 1,5-Dieneinheit durch Ringschluss mittels Kreuzmetathese (CM) und Ringschlussmetathese (RCM) herzustellen. Wir wussten um die guten Resultate der typischen Grubbs-Carbenkomplexe in den CM-und RCM-Reaktionen und hofften, dass die Bildung eines Rings mittlerer Größe ebenfalls E,E-stereoselektiv sein würde (Schema 1).Die Synthese von Fragment 3 ist in Schema 2 wiedergegeben. Zunächst wurde das Evans-Oxazolidinon 7[6] mit dem Iodid 8 [7] alkyliert; eine symmetrische Dihydroxylierung der Doppelbindung und spontane Lactonisierung unter Abspaltung des chiralen Hilfsstoffs lieferte 9 mit hervorragender Schema 2. a) Na[N(SiMe 3 ) 2 ], THF, À78 8C, 85 %; b) ADmix-a, MeSO 2 NH 2 , tBuOH/H 2 O, 0 8C, 83 % (94 % de); c) PMBNHCCl 3 , CSA, CH 2 Cl 2 , RT, 89 %; d) TBAF, THF, 89 %; e) TBSCl, Imidazol, DMF, 0 8C, 94 %; f) LiBH 4 , Et 2 O, 91 %; g) TBDPSCl, Imidazol, CH 2 Cl 2 , 08C, 90 %; h) TBSOTf, 2,6-Lutidin, CH 2 Cl 2 , 08C, 98 %; i) PPTS, EtOH, RT, 82 %; j) DMSO, (COCl) 2 , Et 3 N, CH 2 Cl 2 , À78 8C!RT, dann Ph 3 PCHCO 2 Me, CH 2 Cl 2 , RT, 91 %; k) DIBAL-H, CH 2 Cl 2 , À78 8C, 88 %; l) tBuOOH, Ti(OiPr) 4 , (+)-DIPT, CH 2 Cl 2 , MS (4 ), 94 %, (92 % de); m) DMSO, (COCl) 2 , Et 3 N, CH 2 Cl 2 , À78 8C!RT, dann [Ph 3 PCH 3 ]Br, Na[N(SiMe 3 ) 2 ], THF, 73 %; n) DDQ, CH 2 Cl 2 , pH-7-Puffer, RT, 85 %. CSA = Camphersulfonsäure, DDQ = 2,3-Dichlor-5,6-dicy...
Stereoselective access to 9-alkyl-10-hydroxy-9,10-dihydrophenanthrenes has been developed via the samarium(II) iodide mediated reductive cyclization of an ene-aldehyde appended to a biphenyl scaffold.
<p><i>A novel biocatalytic protocol enables the direct and selective introduction of nitrogen functionalities via activation of allylic C-H bonds. Utilizing an oxidase/peroxidase couple for the formal dehydrogenation of N-hydroxycarbamates and hydroxamic acids with air as terminal oxidant, acylnitroso species are generated under particularly mild aqueous conditions. The reactive intermediates undergo C-N bond formation through an ene-type mechanism and provide high yields both in intramolecular and intermolecular enzymatic aminations. Investigations on alternative reaction pathways and labelling studies provide more insights into this unprecedented biocatalytic promiscuity of classical oxidoreductases as catalysts for nitroso ene-based transformations.</i></p>
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