Total Synthesis of (+)-Laurencin. Use of Acetal-Vinyl Sulfide Cyclizations for Forming Highly Functionalized Eight-Membered Cyclic Ethers

Abstract

The enantioselective total synthesis of (+)-laurencin (1) is accomplished in 24 steps from allyl alcohol.The synthesis features an acetal-vinyl sulfide cyclization that forms the oxocene ring and introduces, with complete control, the * 1234 unsaturation and requisite functionality at carbons 3, 4, and 9. Starting with allyl alcohol, mixed acetal 17 is constructed in seven steps and 38% overall yield (Scheme 2). Exposure of 17 to excess Bp3<)Et2 in f-BuOMe at -70 -* -40 °C affords A4-oxocene 27 in 55-65% yield (Scheme 4). Removal of the phenylthio group, followed by elaboration of the C(9) side chain and introduction of bromine at C(4), completes the construction of (-l-)-laurencin (Schemes 4 and 5).Red algae produce a breathtaking diversity of secondary metabolites.2 Distinctive members of this marine natural products group are the C15 acetogenins, many of which are halogen-containing cyclic ethers of diverse ring sizes. The prototypical member of the eight-membered cyclic ether subgroup is (+)-laurencin (1), which was first isolated from methanol extracts of Laurencia glandulifera by Irie and Masamune in 1965.3 On the basis of chemical degradation and spectroscopic studies, these researchers proposed that laurencin was a bromine-containing A4-oxocene. Four years later this proposal was confirmed and the stereochemistry and absolute configuration of (+)-laurencin were fully defined by singlecrystal X-ray analysis.4The pioneering synthetic investigations in this area were carried out also in Hokkaido and culminated in the Masamune group's total synthesis of (±)-laurencin in 1977.5 Recently, the

Halogenated Organic Molecules of Rhodomelaceae Origin: Chemistry and Biology

“…438 The synthesis features an acetal-vinyl sulfide cyclization that forms the oxocene ring directly, and introduces, with complete control, the Δ 4 unsaturation and requisite functionality at C 3 , C 4 , and C 9 .…”

Synthesis of Disubstituted Dithioethers: tert-Butoxide Promoted Elimination/Ring Opening of 1,3-Dithianes Followed by Palladium-Catalyzed C–S Bond Formation

“…Synthesis of 2-Benzyl-1,3-dithiane (5). A dry 100 mL roundbottom flask fit with a stir bar was capped with a septum and flushed with dry nitrogen gas.…”

Heterogeneous Hydrothiolation of Alkynes with Thiols Catalyzed by Diphosphino-Functionalized MCM-41 Anchored Rhodium Complex

“…For example, the preparation of (E)-1-(4-methylphenyl)-2-phenylthioethene (3b) was successful using 3 mol% MCM-41-2P-RhCl(PPh 3 ) as catalyst in ethanol at 40°C and gave a 93% yield after 24 h (entry 2), the same reaction catalyzed by 3 mol% RhCl(PPh 3 ) 3 gave a 94% yield after 20 h. The procedure can be applied to a variety of aliphatic alkynes, the corresponding (E)-vinyl sulfides 3h-r was obtained in good yields (entries [8][9][10][11][12][13][14][15][16][17][18]. Similarly, arenethiols bearing 4-methyl, 4-methoxy and 4-chloro groups can add to terminal alkynes regio-and stereoselectively, but the reactivity of arenethiols with electron-donating substituents was lower than that of arenethiols with electron-withdrawing substituents (entries 6,7,9,10). In contrast, the hydrothiolation reaction of terminal alkynes with alkanethiols such as butanethiol and cyclohexanethiol did not occur at all under the same conditions and most of the starting materials were recovered unchanged.…”

“…Vinyl sulfides are important synthetic intermediates in total synthesis and are versatile building blocks for many functionalized molecules owing to the versatile reactivity of the sulfonyl group and the carbon-carbon double bond [6][7][8][9]. The addition of thiols to alkynes is one of the most straightforward routes to vinyl sulfides.…”