Stereocontrolled Synthesis of a Possible Stereoisomer of Laurenidificin and a Formal Total Synthesis of (+)-Aplysiallene Featuring a Stereospecific Ring Contraction

Abstract

We report a highly stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin. Highlights of the synthesis include the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by a stereospecific bromolactonization-α-bromination-ring contraction sequence, followed by a stereoselective propargylation, an insertion of the Z-enyne side chain by a hydroindation/cross coupling reaction, and ethylation at C13 with an organocuprate reagent. While the synthetic compound was not identical to the natural product, the absolute stereochemistry of the natural product was proposed on the basis of NMR analyses. Moreover, a formal total synthesis of (+)-aplysiallene was achieved by extending the ring contraction strategy.

4‐Methyltetrahydropyran (4‐MeTHP): Application as an Organic Reaction Solvent

“…After evaluating the potential of 4‐MeTHP in Grignard reactions, we undertook its utility in transition metal‐catalyzed coupling reactions with organometallic reagents. As shown in Scheme , conventional coupling reactions such as Sonogashira, Stille, and Suzuki coupling of α‐iodoenone 7 progressed in 71–96 % yields in 4‐MeTHP [Scheme , Eq. (1)–(3)].…”

“…After evaluatingt he potential of 4-MeTHP in Grignard reactions, we undertook its utility in transition metal-catalyzed coupling reactions with organometallic reagents. As shown in Scheme 7, conventionalc oupling reactions such as Sonogashira, [41,42] Stille, [17,43] and Suzuki coupling [44,45] (12), isoprenea nd methyl malonate, which was originally reported by Shimizue tal. in their synthetic study of mycophenolic acid.…”

Design and Synthesis of Backbone-Fused, Conformationally Constrained Morpholine-Proline Chimeras

“…Similar selectivities have also been reported in the literature for related reactions. 35,36 To compare relative basicities of the tertiary nitrogen of the bridged morpholine-proline chimeras 4 and 5, we conducted a DFT analysis using the N-methyl 2-oxa-5-azabicyclo[2.2.1]heptane motif (N-Me 1) as a reference compound. Unlike the bridged morpholine-proline chimeras 4 and 5, whose lone pair of electrons on nitrogen is spatially fixed by the introduction of an additional ring, the N-methyl group in the 2,5-bridged morpholine (N-Me 1) can adopt an equatorial or axial position with energies within 1 kcal•mol −1 between the two rapidly exchanging conformers at room temperature.…”

First Asymmetric Total Synthesis and Insight into the Structure of Laurenidificin

“…Among the natural products having fused bis‐THF skeletons, laurenidificin is the only compound whose relative relationships of the fused‐THF rings and the two side chains are all cis . Although Kobayashi et al synthesized stereoisomers of laurenidificin, in which the relative relationships of the fused bis‐THF rings and the two side chains were cis and trans , reports on the total synthesis and structure determination of the natural product have not appeared, and the structure of natural laurenidificin, including its absolute configuration, is still unknown. Although natural (+)‐laurenidificin has five stereogenic centers, only the R configuration of the chiral center at C6 and the cis orientation of H‐12, H‐10, H‐9, and H‐7 have been disclosed.…”

“…Of these, we synthesized stereoisomer 1 , which has an absolute configuration of (6 R ,7 R ,9 R ,10 R ,12 R ,13 S ). Compound 1 was also suggested to be a natural product by Kobayashi et al, although they did not synthesize it …”