Torreyanic acid

Torreyanic acid

Clinical data
ATC code	none
Identifiers
IUPAC name (2E,2'E)-4,4'-[(1aR,5R,5aS,7aS,8aR,10aS,11aS)-2,7,9,11-tetraoxo-5,13-dipentyl-1a,2,5a,6,7,8a,9,10-octahydro-10,6-(epoxymethano)bis[1]benzoxireno[3,4-d:3',4'-g]isochromene-7a,11a(5H,11H)-diyl]bis(2-met hylbut-2-enoic acid)
CAS Number	176260-42-7  N
PubChem CID	21722714
ChemSpider	10307511  N
Chemical and physical data
Formula	C38H44O12
Molar mass	692.758 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCCCC[C@@H]1[C@H]2C3C(OC([C@@]24C(=CO1)C(=O)[C@H]5[C@@](C4=O)(O5)C/C=C(\C)/C(=O)O)C6=C3C(=O)[C@@]7([C@H](C6=O)O7)C/C=C(\C)/C(=O)O)CCCCC
InChI InChI=1S/C38H44O12/c1-5-7-9-11-21-23-24-25(28(40)32-36(49-32,29(24)41)15-13-18(3)33(42)43)30(48-21)38-20(17-47-22(26(23)38)12-10-8-6-2)27(39)31-37(50-31,35(38)46)16-14-19(4)34(44)45/h13-14,17,21-23,26,30-32H,5-12,15-16H2,1-4H3,(H,42,43)(H,44,45)/b18-13+,19-14+/t21?,22-,23?,26+,30?,31+,32+,36-,37+,38-/m1/s1 N Key:DQBVXDMPCDAQGS-YOWCJFHESA-N N
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Torreyanic acid is a dimeric quinone first isolated and by Lee et al. in 1996 from an endophyte, Pestalotiopsis microspora . This endophyte is likely the cause of the decline of Florida torreya ( Torreya taxifolia ), an endangered species that is related to the taxol-producing Taxus brevifolia . ^[1] The natural product was found to be cytotoxic against 25 different human cancer cell lines with an average IC50 value of 9.4 μg/mL, ranging from 3.5 (NEC) to 45 (A549) μg/mL. ^{[1] [2]} Torreyanic acid was found to be 5-10 times more potent in cell lines sensitive to protein kinase C (PKC) agonists, 12-o-tetradecanoyl phorbol-13-acetate (TPA), and was shown to cause cell death via apoptosis. ^[3] Torreyanic acid also promoted G1 arrest of G0 synchronized cells at 1-5 μg/mL levels, depending on the cell line. ^[1] It has been proposed that the eukaryotic translation initiation factor EIF-4a is a potential biochemical target for the natural compound. ^[3]

Biosynthesis

There are over 150 natural products that are presumed to undergo a [4+2] Diels–Alder type cycloaddition, belonging to classes such as: polyketides, terpenoids, phenylpropanoids, and alkaloids. ^[4] The Diels–Alder cycloaddition involves the overlap of the p-orbitals of two unsaturated systems: a 1,3-diene and dienophile. ^[5] The conjugated diene reacts with the dienophile to form a cyclic product in a concerted fashion. This reaction is widely used in synthesis due to its facile nature and reio- and stereoselectivity under mild conditions. This reaction is very useful for forming carbon-carbon bonds, four-chiral centers, and quaternary stereogenic centers.[4,5] Natural products that are constructed biosynthetically via a Diels–Alder reaction occur both uncatalyzed and catalyzed by enzymes such as Diels–Alderase and RNA Diels-Alderase. ^[6] In their report of the isolation and structural characterization of the natural product, Lee and co-worker proposed that the biosynthesis of torreyanic acid proceeded via an endo-selective [4+2] cycloaddition with a Diels–Alder dimerization of 2H-pyran monomers 2a and 2b. ^[1] Key observations that indicate a natural product is biosynthesized via a Diels–Alder reaction include: (a) isolation of an adduct with its corresponding precursor, (b) presence of adducts and their regio- and diastereoisomers, (c) a non-enzymatic feasibility of a likely cycloaddition and (d) chirality of the adducts. ^[4]

The proposed biosynthetic pathway is thought to involve: (a) an electrocyclic ring closure of 3, followed by (b) an enzymatic oxidation to furnish diastereomers 2a and 2b, and finally (c) a [4+2] cyclodimerization to generate torreyanic acid 1. ^[6] The biosynthesis of torreyanic acid was studied extensively by Poroco et al. in their efforts to execute the first total synthesis of the natural product. ^[4] Given that monomer ambuic acid was also isolated from the same endophytic fungus Pestalotiopsis microspora, it is further evidence that a Diels–Alder reaction is involved in the biosynthesis of torreyanic acid. ^[7] The biomimetic synthesis of torreyanic acid involved the rapid conversion of aldehyde 3 to syn- and anti-pyrans 2a and 2b via an oxaelectrocyclization, with the pyrans existising as an equilibrium mixture. Next, a spontaneous Diels–Alder dimerization of 2a and 2b proceeded with complete and regio- and diastereoselectivity to furnish the endo-adduct, torreyanic acid 1. Further, a retro-Diels–Alder reaction carried out at 60 °C proved that torreyanic acid originated from 2a and 2b and ¹H-NMR spectra showed that no aldehyde 3 was observed. The stable transition state in the Diels–Alder reaction (shown with 2a and 2b) has an energy of 9.4kcal/mol, and coupled with the high reactivity of the diastereomers, it is indicated that the Diels–Alder reaction proceeds in a non-enzymatic manner. ^[4]

Total synthesis

The first total synthesis of torreyanic acid was reported by Porco and co-workers in 2000. ^[3] This total synthesis aimed to employ and confirm the Diels–Alder genesis proposed by Lee et al. ^[1] To synthesize the monomers required for Diels–Alder dimerization, 1,3-dioxane intermediate 4 was lithiated with BuLi, brominated with BrCF₂CF₂Br, and underwent acid hydrolysis to afford benzaldehyde 5. Upon selective methylation of 5 with sulfuric acid, phenol 6 was produced in 52% yield. Phenol 6 first underwent an allylation with allyl bromide, then a borohydride reduction, and finally a protection with a silyl group to furnish 7. Dimethoxyacetal 8 was furnished upon thermal Claisen rearrangement of 7, which afforded an unstable allyl phenol that directly underwent a hypervalent iodine oxidation with PhI(OAc)₂ in methanol. 8 was then subjected to an acetal exchange with 1,3-propanediol to afford 1,3-dioxane 9, which was smoothly monoepoxidized with Ph3COOH, KHMDS, −78 °C to −20 °C over 6 hours to afford 10. A 2-methyl-2-butenoic acid moiety was installed to afford 11. Intermediate 11 underwent a Stille vinylation with (E)-tributyl-1-heptenyl stannane, subsequently subjected to TBAF/AcOH for silyl removal and acetal hydrolysis to afford quinone epoxide 12. Treatment of 12 with Dess-Martin periodinane initiated a tandem oxidation-6p-electrocyclization-dimerization to afford two dimeric products 13 and 14. Upon treatment of 13 and 14 with TFA to remove the tert-butyl ester, iso-torreyanic acid 15 and torreyanic acid 1 were afforded, respectively. ^[3]

References

1. Lee JC, Strobel GA, Lobkovsky E, Clardy J (1996). "Torreyanic Acid: A Selectively Cytotoxic Quinone Dimer from the Endophytic Fungus Pestalotiopsis microspora". The Journal of Organic Chemistry. 61 (10): 3232–3233. doi:10.1021/jo960471x.
2. Mehta G, Pan SC (October 2004). "Total synthesis of the novel, biologically active epoxyquinone dimer (+/-)-torreyanic acid: a biomimetic approach". Organic Letters. 6 (22): 3985–8. doi:10.1021/ol0483551. PMID   15496080.
3. Li C, Johnson RP, Porco JA (April 2003). "Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade". Journal of the American Chemical Society. 125 (17): 5095–106. doi:10.1021/ja021396c. PMID   12708860.
4. Oikawa H, Tokiwano T (June 2004). "Enzymatic catalysis of the Diels-Alder reaction in the biosynthesis of natural products". Natural Product Reports. 21 (3): 321–52. doi:10.1039/b305068h. PMID   15162222.
5. Kagan HB, Riant O (1992). "Catalytic asymmetric Diels Alder reactions". Chemical Reviews. 92 (5): 1007–1019. doi:10.1021/cr00013a013.
6. Stocking EM, Williams RM (July 2003). "Chemistry and biology of biosynthetic Diels-Alder reactions". Angewandte Chemie. 42 (27): 3078–115. doi:10.1002/anie.200200534. PMID   12866094.
7. Li JY, Harper JK, Grant DM, Tombe BO, Bashyal B, Hess WM, Strobel GA (March 2001). "Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis spp. and Monochaetia sp". Phytochemistry. 56 (5): 463–8. Bibcode:2001PChem..56..463L. doi:10.1016/S0031-9422(00)00408-8. PMID   11261579.