Echinopine
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| IUPAC names
(A): 2-[(1R,2R,4R,7R,12R)-8-methylidene-2-tetracyclo[5.3.2.02,4.04,12]dodecanyl]acetic acid (B): methyl 2-[(1R,2R,4R,7R,12R)-8-methylidene-2-tetracyclo[5.3.2.02,4.04,12]dodecanyl]acetate | |
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3D model (JSmol) |
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| Properties | |
| (A): C15H20O2 (B): C16H22O2 | |
| Molar mass | (A): 232.32 g/mol (B): 246.34 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Echinopines A and B are sesquiterpenoids isolated from the roots of the Moroccan plant Echinops spinosus by Kiyota et al.[1] They are characterized by a [3-5-5-7] tetracyclic carbon framework, designated as the echinopane skeleton. Echinopines A and B represent the first known natural products to possess this particular ring structure.
Structure
[edit]Echinopine A is chemically designated as echinop-10(14)-en-12-oic acid, with echinopine B characterized as its corresponding methyl ester.[1]
Both compounds contain five contiguous stereocenters at positions C1, C5, C4, C7, and C13. Conformational analysis indicates that the seven-membered ring adopts a flat chair conformation, while the two five-membered rings (C4-C5-C6-C7-C13 and C1-C2-C3-C4-C5) adopt envelope conformations.[1] The naturally occurring isolates were assigned as the (+)-enantiomers.[2]
Biosynthesis
[edit]The biosynthesis of echinopines A and B begins with a guaiane-type precursor (guaia-4(15),10(14),11(13)-trien-12-oic acid) under acidic conditions.[1] First, protonation at C13 initiates migration of the C7-C11 bond to C13. Subsequent deprotonation at C13 regenerates the hydroxonium ion catalyst, yielding a C11-C13 double bond conjugated to the carboxyl group. Under the ongoing acidic conditions, the carboxylic acid is protonated, promoting the double bond at C4-C15 to act as a nucleophile and attack the C11-C13 double bond, forming a [5-6-7] tricyclic carbocation intermediate via C15-C13 cyclization. Finally, the formation of the [3-5-5-7] tetracyclic echinopane skeleton is concluded with a cyclization at C13-C4 driven by the elimination of the C13 proton.
Laboratory synthesis
[edit]Despite their lack of uncovered biological activity, echinopines A and B have motivated considerable synthetic interest.[2][3][4][5][6][7][8]
Magauer (2009)
[edit]Echinopine A and B were first synthesized by Magauer, Mulzer, and Tiefenbacher in 2009 in 21 steps, starting from 1,5 cyclooctadiene.[2] Their approach featured a Myers [3.3]-sigmatropic rearrangement to form a substituted bicyclooctane intermediate that could subsequently be transformed into the echinopane skeleton via ring-closing metathesis.
Chen (2010,2011)
[edit]In 2010 and 2011, Chen et al. developed three generations of bioinspired total and formal syntheses.[3][4][5]Their strategies were refined with the goal of emulating the biosynthetic pathway to echinopine.
Vanderwal (2012)
[edit]In 2012, Vanderwal and co-workers completed a 13-step total synthesis of racemic echinopine B starting from ethyl 4-oxocyclohexanecarboxylate.[6] The route utilized a platinum(II)-catalyzed 5-exo-dig cycloisomerization of a propargylic ether precursor to construct the tricyclic [3-5-5] core.
Liang (2013)
[edit]Liang et al. achieved an 18-step synthesis of racemic echinopines A and B in 2013.[7] The pathway included an aldol-Henry reaction cascade to produce a trans-decalin intermediate, a Tiffeneau-Demjanov rearrangement for ring expansion, and an intramolecular 1,3-cycloaddition.
Misra (2015)
[edit]In 2015, Misra et al. executed a formal synthesis starting with a photochemical, Cr(0)-promoted [6π + 2π] cycloaddition between an alkynoate and cycloheptatriene to form a bicyclo[4.2.1]nonane intermediate.[8] This intermediate was subsequently converted to a tricyclic ester intermediate previously established by Magauer, Mulzer, and Tiefenbacher.
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References
[edit]- 1 2 3 4 Dong M, Cong B, Yu SH, Sauriol F, Huo CH, Shi QW, et al. (March 2008). "Echinopines A and B: sesquiterpenoids possessing an unprecedented skeleton from Echinops spinosus". Organic Letters. 10 (5): 701–704. doi:10.1021/ol702629z. PMID 18251544.
- 1 2 3 Magauer T, Mulzer J, Tiefenbacher K (November 2009). "Total syntheses of (+)-echinopine A and B: determination of absolute stereochemistry". Organic Letters. 11 (22): 5306–5309. doi:10.1021/ol902263k. PMID 19824621.
- 1 2 Nicolaou KC, Ding H, Richard JA, Chen DY (March 2010). "Total synthesis of echinopines A and B". Journal of the American Chemical Society. 132 (11): 3815–3818. Bibcode:2010JAChS.132.3815N. doi:10.1021/ja9093988. PMID 20184316.
- 1 2 Peixoto PA, Severin R, Tseng CC, Chen DY (March 2011). "Formal asymmetric synthesis of echinopine A and B". Angewandte Chemie International Edition. 50 (13): 3013–3016. Bibcode:2011ACIE...50.3013P. doi:10.1002/anie.201008000. PMID 21404388.
- 1 2 Peixoto PA, Richard JA, Severin R, Chen DY (November 2011). "Total synthesis of echinopines A and B: exploiting a bioinspired late-stage intramolecular cyclopropanation". Organic Letters. 13 (21): 5724–5727. doi:10.1021/ol202053m. PMID 21882829.
- 1 2 Michels TD, Dowling MS, Vanderwal CD (2012-06-18). "A Synthesis of Echinopine B". Angewandte Chemie. 124 (30): 7690–7694. Bibcode:2012AngCh.124.7690M. doi:10.1002/ange.201203147. ISSN 0044-8249.
- 1 2 Xu W, Wu S, Zhou L, Liang G (April 2013). "Total syntheses of echinopines". Organic Letters. 15 (8): 1978–1981. doi:10.1021/ol400645v. PMID 23540437.
- 1 2 De S, Misra S, Rigby JH (July 2015). "Formal Total Synthesis of Echinopines A and B via Cr(0)-Promoted [6π + 2π] Cycloaddition". Organic Letters. 17 (13): 3230–3232. doi:10.1021/acs.orglett.5b01326. PMID 26070029.