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The longstanding challenge posed by the complex diterpene vinigrol has been answered for the first time. The notorious difficulty in synthesizing vinigrol stems from its unprecedented decahydro-1,5-butanonaphthalene ring system, eight contiguous stereocenters, and highly congested functionality. This communication delineates a stereocontrolled 23-step route to vinigrol that is scalable (>5 grams prepared of a late stage intermediate), minimally reliant on protecting group chemistry, and facilitated by a number of unique and chemoselective transformations.The total synthesis of the biologically significant diterpene vinigrol (1) 1 has stood for over two decades as a major unsolved challenge for organic synthesis. 2 The extreme difficulty in preparing this molecule stems from its unprecedented and highly congested decahydro-1,5-butanonaphthalene ring system containing eight contiguous stereocenters (shown in four different views in Figure 1A). In this Communication we report a solution to this longstanding problem in complex terpene synthesis. 3 Last year our laboratory reported a short route to the core skeleton of 1, featuring a simple sequence of classic transforms such as the Diels-Alder and Grob fragmentation, that proved to be capable of delivering structures similar to 2 ( Figure 1B) albeit lacking the C-9 methyl group. 2w In accord with the well-documented reluctance of late-stage intermediates to be converted to 1 ,2 many seemingly logical routes to 1 from 2 and related intermediates failed in our hands. The final route presented herein was formed from a detailed series of experiments.pbaran@scripps.edu. Supporting Information Available: Detailed experimental procedures, copies of all spectral data and full characterization. This material is available via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 December 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe route to 1 commences from 3 (Scheme 1), an intermediate available in decagram quantities in seven steps from commercially available materials. The C-9 methyl group was installed by alkylation (LDA, MeI) and, following silyl group removal (TBAF), the adjacent alcohol stereochemistry was established using Evans' Me 4 NBH(OAc) 3 -mediated, 4 hydroxyl-directed reduction to deliver 4 as a single diastereomer in 72% yield over the three step sequence. Nondirected reductions (i.e. DIBAL) afforded mainly the undesired alcohol diastereomer at C-11 due to the shielding effect of the C-9 methyl group. The correct stereochemistry is critical for the ensuing Grob fragmentation that furnished 2 (see Figure 1B for structure) after mesylation and treatment with KHMDS (85% yield over 2 steps).Installation of the C-8 methyl and C-8a hydroxyl group proved to be a challenge due to their cis orientation. The methyl group cannot arise from the simple hydrogenation of an exocyclic olefin because reagents approach from the less hindered (and wrong) diaste...

Cyclobutanones reacted with alkynes in the presence of nickel(0) catalysts to produce cyclohexenones. Oxidative cyclization of the carbonyl group of the cyclobutanone and the alkyne with the nickel(0) was followed by beta-carbon elimination from the resulting oxanickelacyclopentene and subsequent reductive elimination. This reaction achieves a formal alkyne insertion between the carbonyl carbon and the alpha-carbon, providing a six-membered carbocyclic skeleton.

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Cyclobutanones underwent a formal [4 + 2 + 2] annulation reaction with 1,6- and 1,7-diynes in the presence of nickel(0) catalysts to provide bicyclic eight-membered ring ketones. The annulation reaction proceeds through a ring-expansion of oxanickelacycloheptadiene via beta-carbon elimination to form a nine-membered nickelacycle. This reaction employing cyclobutanones as a C4 unit constructs cyclooctadienone cores in one synthetic step.

SummaryEffect of Ticlopidine, 5-(2-chlorobenzyl)-4, 5, 6, 7-tetrahydro[3,2-C]pyridine hydrochloride, on platelet aggregation was studied in the rat. Ticlopidine was found to be a potent, long-lasting inhibitor of platelet aggregation. It inhibited the aggregation induced by any of ADP, collagen, thrombin, arachidonic acid and prostaglandin endoperoxides and/or thromboxane A2-like substance. Ticlopidine was effective at doses as low as 30 mg/kg when orally given to rats, and the effect lasted as long as the life span of the circulating platelets (half time: about 48 hours).Ticlopidine inhibited also nucleotide release from and prostaglandin synthesis in the platelets, but did not significantly affect platelet adhesiveness to glass, platelet factor 3 availability and clot retraction.

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Chiral N-heterocyclic carbene (NHC) ligands having a 2,2'-bisquinoline-based C(2) symmetric skeleton were developed. The ligands exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.