Dihydro-10H-indeno[1,2-b]benzofurans and Tetrahydroindeno[1,2-c]isochromenes via Stereoselective Intramolecular Carbocation Cascade Cyclization.

Nazarov cyclization of the (E)-(2-stilbenyl)methanols under the catalysis of p-TsOH immobilized on silica (PTS-Si) proceeded to give the corresponding indanyl cation with the exclusive trans relationship at the two newly formed adjacent stereogenic centers. The ensuing intramolecular nucleophilic addition by the MOM-protected phenol (m = 0) or benzyl alcohol (m = 1) furnished the Indane-fused benzofuran [5/5] or isochroman [5/6] system, respectively, with the exclusive cis stereocontrol at the two-carbon ring junction. Thus, in a single step, from nonchiral starting materials, the intramolecular cascade carbocation cyclization (CCC) furnished the [5/5] or [5/6] oxygen-containing Indane fused-ring systems in moderate to good yields with excellent stereoselectivity on all three contiguous stereogenic centers.

Total Synthesis of Palodesangrens A and C.

Palodesangrens A and C along with the common tetracyclic core are prepared from simple benzaldehyde and acetophenone derivatives in a 10-step longest linear sequence which featured the Diels-Alder reaction forming the cyclohexene moiety, LiAlH4 isomerization, stereoselective acid-catalyzed cyclization forming the chroman moiety, regioselective iodination/vinyl Suzuki cross-coupling reaction, and ring-closing metathesis (RCM) forming the 2H-pyran-2-one. Overall, the desired palodesangrens A and C are obtained in 6.1% and 6.4% yields, respectively.

Chemoselective acid-catalyzed [4 + 2]-cycloaddition reactions of ortho-quinone methides and styrenes/stilbenes/cinnamates.

ortho-Quinone methides (o-QMs) generated from the corresponding benzyl acetate precursors chemoselectively underwent the formal [4 + 2]-cycloadditions with the olefin of styrene, stilbene, or cinnamate derivatives by using different transition metal salts or Brønsted acids. Such selectivity was obtained when these olefins either separately acted as the dienophiles or were simultaneously present on the same dienophiles. Complete selectivity was also achieved between the stilbene olefin and acetylene to furnish the key chroman intermediate for the subsequent ring-closing metathesis (RCM), affording the corresponding tetracyclic 5H-dihydronaphtho[1,2-c]chromene.

Total Synthesis of Palodesangren B Trimethyl Ether and D Dimethyl Ether via a Late-Stage Formation of 2H-Pyran-2-one of the Tetrahydrobenzo[c]pyranochromenone Core.

In four steps from the tricyclic core, palodesangren B trimethyl ether and palodesangren D dimethyl ether could be synthesized in 29 and 18% overall yields, respectively. A reaction sequence comprising the regioselective MgCl2-mediated Casnati-Skattebøl ortho-formylation of phenol, Wittig methylenation, acryloylation, and Ru(II)-catalyzed ring-closing metathesis (RCM) led to the formation of the final 2H-pyran-2-one ring of the desired tetracyclic core.

Divergent Strategy for the Diastereoselective Synthesis of the Tricyclic 6,7-Diaryltetrahydro-6H-benzo[c]chromene Core via Pt(IV)-Catalyzed Cycloaddition of o-Quinone Methides and Olefin Ring-Closing Metathesis.

A divergent strategy for the synthesis of the tricyclic 6,7-diaryltetrahydro-6H-benzo[c]chromene core was successfully developed. The 2,3-trans, 2,4-cis trisubstituted chroman moiety was formed via highly efficient and stereoselective Pt(IV)-catalyzed cycloaddition reactions of the corresponding quinone methides with chalcones. Subsequent steps provided the common diene alcohol, which underwent BF3·Et2O-mediated Et3SiH reduction and olefin ring-closing metathesis (RCM) using Ru(II) catalysts. The sequence of the final two steps provided a handle to diversify the stereochemical outcomes at C6 as well as C10a.

Synthesis of C4 - C5 cycloalkyl-fused and C6-modified chromans via ortho-quinone methides.

Starting from 3,5-dimethoxybenzaldehyde, some functionalized 2,3,4-trisubstituted tricyclic 4,5-cycloalkyl-fused and 6-modified chromans could be prepared via ortho-quinone methides (o-QMs)/hetero-Diels-Alder (HDA) reactions of the appropriate precursors. The bromide at C6 served as a handle for introducing other substituents through palladium-catalyzed cross-coupling reactions and other functional-group transformations. Moderate to high yields (up to 80%) and diastereoselectivities (up to >99:1) could be obtained under [PtCl4 ] catalysis. The preferred endo transition state during the cycloaddition reaction played an important role in governing the stereochemical outcomes at C2 - C3 - C4. The configurationally fixed E geometry of the bicyclic o-QMs influenced the cycloaddition reactions to favor the C2 - C4 cis relationship.

Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products.

Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.