Rearranged Lindenane Sesquiterpenoid Trimers from Chloranthus fortunei: Target Discovery and Biomimetic Conversion

Abstract

Seven lindenane-type sesquiterpenoid trimers, including four new ones (1−4) and three known analogues (5− 7), were isolated from Chloranthus fortunei guided by highperformance liquid chromatography with photodiode array detection with characteristic absorption at 210 and 350 nm. Their structures, including absolute configurations, were achieved by high-resolution mass spectrometry, nuclear magnetic resonance, electronic circular dichroism, and quantum chemical calculations. Compound 1 was the first example of two lindenane units connected by a C-15−C-15′ bond. The 5/7/5-fused ring system in 2 was presumably formed biogenetically by key keto−enol tautomerism and Cope rearrangement from 5. The 5/3/6 carbon skeleton in 3−5 and epi-cyclopropane in 3 and 6 might have originated from trishizukaol A (7) with a normal 3/5/6-fused ring system through vinylcyclopropane rearrangement. The biomimetic conversion from 7 to 3−6 was successfully achieved by adding a 365 nm ultraviolet lamp and a free radical initiator, and 2 was also spontaneously converted to 5 in methanol and CDCl 3 , which proved the correctness of the structural identification and the speculation described above. Compounds 1−7 exhibited antiinflammatory activity with IC 50 values in the range of 2.90−22.80 μmol/L.

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

“…Trishizukaol A ( 336 ), consisting of three lindenane units connected by [4 + 2] cycloaddition and apparent C linear linkage, was firstly isolated from the roots of C. japonicus in 1998, 66 and also from C. spicatus and C. fortunei . 89,173 Recently, diverse derivatives of 336 , trichloranoids A–D ( 337–340 ) and chlofortunins B–D ( 341–343 ) were likely formed biogenetically via key vinylcyclopropane and Cope rearrangement and keto–enol tautomerism (Scheme 7), which was confirmed by their biomimetic conversion from 336 to 337 , 338 , 342 , and 343 by adding a 365 nm ultraviolet lamp and a free radical initiator. 89,173 Chlofortunin A ( 344 ) was the first trimer linked by an unprecedented C-15–C-15′ bond.…”

“…89,173 Recently, diverse derivatives of 336 , trichloranoids A–D ( 337–340 ) and chlofortunins B–D ( 341–343 ) were likely formed biogenetically via key vinylcyclopropane and Cope rearrangement and keto–enol tautomerism (Scheme 7), which was confirmed by their biomimetic conversion from 336 to 337 , 338 , 342 , and 343 by adding a 365 nm ultraviolet lamp and a free radical initiator. 89,173 Chlofortunin A ( 344 ) was the first trimer linked by an unprecedented C-15–C-15′ bond. 89 Inspired by recent biomimetic synthesis, 174 the C linear linkage in these compounds may originate from breaking of the C–C bond by [4 + 2] cycloaddition (Scheme 8).…”

“…Among the numerous oligomers, only nineteen trimers ( 336–354 ) have been identified to date. 32,33,66,67,72,89,173 It is noteworthy that all the homo-trimers were discovered in the Chloranthaceae family, 66,67,72,89,173 while all the hetero-trimers were isolated from the Lindera genus. 32,33…”

“…89,173 Chlofortunin A ( 344 ) was the first trimer linked by an unprecedented C-15–C-15′ bond. 89 Inspired by recent biomimetic synthesis, 174 the C linear linkage in these compounds may originate from breaking of the C–C bond by [4 + 2] cycloaddition (Scheme 8). 89,174 Spirolindemer B ( 345 ), 72 as the first example of a homo-trimer through C–C and C–O [4 + 2] cycloaddition, can be recognized as the hybrid of chlotrichene B ( 253 ) 27 and spirolindemer A ( 254 ) and form a complex oxaspiro[4.5]decane and spiro[4.5]decane skeleton.…”

“…5,12,13 Plants from the genus Chloranthus are characterized by homo-[4 + 2] and homo-[6 + 6] dimers, which are especially abundant in roots 14,16,17,59 and have been studied extensively, including Chloranthus japonicus 87,88 and C. fortune . 89,90 Sarcandra plants have been widely studied for their use in traditional Chinese medicine formulations, 91 and almost every type of LS has been reported. 10,59,82 Oxygen-involved [2 + 2 + 2] cycloaddition-type dimers and homo- O -linear oligomers are the characteristic metabolites of this genus.…”