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Revision as of 10:05, 2 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'StdInChI', 'StdInChIKey', 'CAS_number').← Previous edit Latest revision as of 01:45, 24 August 2024 edit undoGraeme Bartlett (talk | contribs)Administrators249,716 edits pubchem 
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{{Short description|Group of chemical compounds}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
⚫ | IUPAC_name = (2E,2'E)-4,4'-benzoxirenoisochromene-7a,11a(5H,11H)-diyl]bis(​2-met hylbut-2-enoic acid)
| Watchedfields = changed
| verifiedrevid = 470625291
⚫ | IUPAC_name = (2E,2'E)-4,4'-benzoxirenoisochromene-7a,11a(5H,11H)-diyl]bis(2-met hylbut-2-enoic acid)
| image = torreyanic_acid.png | image = torreyanic_acid.png
| width = 171 | width = 171


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename =


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 176260-42-7 --> | CAS_number = 176260-42-7
| ATC_prefix = none | ATC_prefix = none
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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 | StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = DQBVXDMPCDAQGS-YOWCJFHESA-N | StdInChIKey = DQBVXDMPCDAQGS-YOWCJFHESA-N
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 10307511 | ChemSpiderID = 10307511
| PubChem = 21722714


<!--Chemical data--> <!--Chemical data-->
| C=38 | H=44 | O=12 | C=38 | H=44 | O=12
| smiles = CCCCC12C3C(OC(24C(=CO1)C(=O)5(C4=O)(O5)C/C=C(\C)/C(=O)O)C6=C3C(=O)7((C6=O)O7)C/C=C(\C)/C(=O)O)CCCCC
| molecular_weight = 692.7488 g/mol
| smiles = O2\C=C/4(O)1O1(CO)42O3O((O)(O)3O)CO
| InChI = 1/C15H22O10/c16-3-6-9(19)10(20)11(21)14(23-6)24-13-7-5(1-2-22-13)8(18)12-15(7,4-17)25-12/h1-2,5-14,16-21H,3-4H2/t5-,6-,7-,8+,9-,10+,11-,12+,13+,14+,15-/m1/s1
| InChIKey = LHDWRKICQLTVDL-PZYDOOQIBS
}} }}


'''Torreyanic acid''' is a dimeric ] first isolated and by Lee ''et al.'' in 1996 from an endophyte, '']''. This endophyte is likely the cause of the decline of Florida torreya ('']''), an endangered species that is related to the taxol-producing Taxus brevifolia.<ref name="one">{{cite journal | author=Lee, J.C., ''et al.''|title=Torreyanic Acid: A Selectively Cytotoxic Quinone Dimer from the Endophytic Fungus Pestalotiopsis microspora.|journal=The Journal of Organic Chemistry|volume=61|pages=3232–3233|year=1996 | doi=10.1021/jo960471x | issue=10}}</ref> The natural product was found to be cytotoxic against 25 different human cancer cell lines with an average IC50 value of 9.4&nbsp;µg/mL, ranging from 3.5 (NEC) to 45 (A549) µg/mL.<ref name="one"/><ref name="two">{{cite journal | author=Mehta, G. and S.C. Pan|title=Total Synthesis of the Novel, Biologically Active Epoxyquinone Dimer (±)-Torreyanic Acid: A Biomimetic Approach|journal=Organic Letters|volume=6|pages=3985–3988|year=2004 | doi=10.1021/ol0483551 | pmid=15496080 | issue=22}}</ref> 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.<ref name="three"/> Torreyanic acid also promoted G1 arrest of G0 cynchronized cells at 1-5&nbsp;µg/mL levels, depending on the cell line.<ref name="one"/> It has been proposed that the eukaryotic translation intiation factor EIF-4a is a potential biochemical target for the natural compound.<ref name="three">{{cite journal | author=Li, C., R.P. Johnson, and J.A. Porco|title=Total Synthesis of the Quinone Epoxide Dimer Torreyanic Acid: Application of a Biomimetic Oxidation/Electrocyclization/Diels–Alder Dimerization Cascade|journal=Journal of the American Chemical Society|volume=125|pages=5095–5106|year=2003 | doi=10.1021/ja021396c | pmid=12708860 | issue=17}}</ref> '''Torreyanic acid''' is a dimeric ] first isolated and by Lee ''et al.'' in 1996 from an endophyte, '']''. This endophyte is likely the cause of the decline of Florida torreya ('']''), an endangered species that is related to the taxol-producing '']''.<ref name="one">{{cite journal | vauthors= Lee JC, Strobel GA, Lobkovsky E, Clardy J |title=Torreyanic Acid: A Selectively Cytotoxic Quinone Dimer from the Endophytic Fungus ''Pestalotiopsis microspora''.|journal=The Journal of Organic Chemistry|volume=61|pages=3232–3233|year=1996 | doi=10.1021/jo960471x | issue=10 }}</ref> The natural product was found to be cytotoxic against 25 different human cancer cell lines with an average IC50 value of 9.4&nbsp;μg/mL, ranging from 3.5 (NEC) to 45 (A549) μg/mL.<ref name="one"/><ref name="two">{{cite journal | vauthors = Mehta G, Pan SC | title = Total synthesis of the novel, biologically active epoxyquinone dimer (+/-)-torreyanic acid: a biomimetic approach | journal = Organic Letters | volume = 6 | issue = 22 | pages = 3985–8 | date = October 2004 | pmid = 15496080 | doi = 10.1021/ol0483551 }}</ref> 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.<ref name="three"/> Torreyanic acid also promoted G1 arrest of G0 synchronized cells at 1-5&nbsp;μg/mL levels, depending on the cell line.<ref name="one"/> It has been proposed that the eukaryotic translation initiation factor EIF-4a is a potential biochemical target for the natural compound.<ref name="three">{{cite journal | vauthors = Li C, Johnson RP, Porco JA | title = Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade | journal = Journal of the American Chemical Society | volume = 125 | issue = 17 | pages = 5095–106 | date = April 2003 | pmid = 12708860 | doi = 10.1021/ja021396c }}</ref>


== Biosynthesis == == Biosynthesis ==
There are over 150 natural products that are presumed to undergo a ] type ], belonging to classes such as: polyketides, terpenoids, phenylpropanoids, and alkaloids.<ref name="four">{{cite journal | author=Oikawa, H. and T. Tokiwano|title=Enzymatic catalysis of the Diels–Alder reaction in the biosynthesis of natural products|journal=Natural Products Reports|volume=21 | issue=3|pages=321–352|year=2004 | pmid=15162222 | doi=10.1039/b305068h}}</ref> The Diels–Alder cycloaddition involves the overlap of the p-orbitals of two unsaturated systems: a ] and ].<ref name="five">{{cite journal | author=Kagan, H.B. and O. Riant|title=Catalytic asymmetric Diels Alder reactions|journal=Chemical Reviews|volume=92|pages=1007–1019|year=1992 | doi=10.1021/cr00013a013 | issue=5}}</ref> 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. Natural products that are constructed biosynthetically via a Diels–Alder reaction occur both uncatalyzed and catalyzed by enzymes such as ] and ].<ref name="six">{{cite journal | author=Stocking, E.M. and R.M. Williams|title=Chemistry and Biology of Biosynthetic Diels–Alder Reactions|journal=Angewandte Chemie International Edition|volume=42 | issue=27|pages=3078–3115|year=2003 | pmid=12866094 | doi=10.1002/anie.200200534}}</ref> 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 cycloaddition with a Diels–Alder dimerization of 2H-pyran monomers 2a and 2b.<ref name="one"/> Key observations that indicate a natural product is biosynthesized via a Diels–Alder reaction include: (a) isolation of an adduct with its corresponding pre-cursor, (b) presence of adducts and their regio- and diastereoisomers, (c) a non-enzymatic feasibility of a likely cycloaddition and (d) chirality of the adducts.<ref name="four"/> There are over 150 natural products that are presumed to undergo a ] type ], belonging to classes such as: polyketides, terpenoids, phenylpropanoids, and alkaloids.<ref name="four">{{cite journal | vauthors = Oikawa H, Tokiwano T | title = Enzymatic catalysis of the Diels-Alder reaction in the biosynthesis of natural products | journal = Natural Product Reports | volume = 21 | issue = 3 | pages = 321–52 | date = June 2004 | pmid = 15162222 | doi = 10.1039/b305068h }}</ref> The Diels–Alder cycloaddition involves the overlap of the p-orbitals of two unsaturated systems: a ] and ].<ref name="five">{{cite journal | vauthors = Kagan HB, Riant O |title=Catalytic asymmetric Diels Alder reactions|journal=Chemical Reviews|volume=92|pages=1007–1019|year=1992 | doi=10.1021/cr00013a013 | issue=5}}</ref> 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. Natural products that are constructed biosynthetically via a Diels–Alder reaction occur both uncatalyzed and catalyzed by enzymes such as ] and ].<ref name="six">{{cite journal | vauthors = Stocking EM, Williams RM | title = Chemistry and biology of biosynthetic Diels-Alder reactions | journal = Angewandte Chemie | volume = 42 | issue = 27 | pages = 3078–115 | date = July 2003 | pmid = 12866094 | doi = 10.1002/anie.200200534 }}</ref> 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 cycloaddition with a Diels–Alder dimerization of 2H-pyran monomers 2a and 2b.<ref name="one"/> 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.<ref name="four"/>
]{{clear}} ]{{clear}}
The proposed biosynthetic pathway is thought to involve: (a) an electrocyclic ring closure of 3, followed by (b) an enzymatic oxidation to furnish ]s 2a and 2b, and finally (c) a cyclodimerization to generate torreyanic acid 1.<ref name="six"/> 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.<ref name="four"/> 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.<ref name="seven">{{cite journal | author=Li, J.Y., et al.|title=Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis spp. and Monochaetia sp|journal=Phytochemistry|volume=56|pages=463–468|year=2001 | doi=10.1016/S0031-9422(00)00408-8 | pmid=11261579 | issue=5}}</ref> 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 ] 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.<ref name="four"/> The proposed biosynthetic pathway is thought to involve: (a) an electrocyclic ring closure of 3, followed by (b) an enzymatic oxidation to furnish ]s 2a and 2b, and finally (c) a cyclodimerization to generate torreyanic acid 1.<ref name="six"/> 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.<ref name="four"/> 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.<ref name="seven">{{cite journal | vauthors = Li JY, Harper JK, Grant DM, Tombe BO, Bashyal B, Hess WM, Strobel GA | title = Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis spp. and Monochaetia sp | journal = Phytochemistry | volume = 56 | issue = 5 | pages = 463–8 | date = March 2001 | pmid = 11261579 | doi = 10.1016/S0031-9422(00)00408-8 | bibcode = 2001PChem..56..463L }}</ref> 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 ] carried out at 60&nbsp;°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.<ref name="four"/>
]{{clear}} ]{{clear}}


==Total synthesis== ==Total synthesis==
The first total synthesis of torreyanic acid was reported by Porco an co-workers in 2000.<ref name="three"/> This total synthesis aimed to employ and confirm the Diels–Alder genesis proposed by Lee et al.<ref name="one"/> To synthesize the monomers required for Diels–Alder dimerization, ] intermediate 4 was lithiated with ], brominated with BrCF<sub>2</sub>CF<sub>2</sub>Br, and underwent acid hydrolysis to afford ] 5. Upon selective methylation of 5 with ], ] 6 was produced in 52% yield. Phenol 6 first underwent an allylation with ], then a ], and finally a protection with a silyl group to furnish 7. ] 8 was furnished upon thermal ] of 7, which afforded an unstable allyl phenol that directly underwent a ] with PhI(OAc)<sub>2</sub> in methanol. 8 was then subjected to an ] exchange with ] to afford 1,3-dioxane 9, which was smoothly ] 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 ] with (E)-tributyl-1-heptenyl stannane, subsequently subjected to TBAF/AcOH for silyl removal and acetal hydrolysis to afford ] epoxide 12. Treatment of 12 with ] initiated a tandem oxidation-6p-]-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.<ref name="three"/> The first total synthesis of torreyanic acid was reported by Porco an co-workers in 2000.<ref name="three"/> This total synthesis aimed to employ and confirm the Diels–Alder genesis proposed by Lee et al.<ref name="one"/> To synthesize the monomers required for Diels–Alder dimerization, ] intermediate 4 was lithiated with ], brominated with BrCF<sub>2</sub>CF<sub>2</sub>Br, and underwent acid hydrolysis to afford ] 5. Upon selective methylation of 5 with ], ] 6 was produced in 52% yield. Phenol 6 first underwent an allylation with ], then a ], and finally a protection with a silyl group to furnish 7. ] 8 was furnished upon thermal ] of 7, which afforded an unstable allyl phenol that directly underwent a ] with {{chem2|PhI(OAc)2}} in methanol. 8 was then subjected to an ] exchange with ] to afford 1,3-dioxane 9, which was smoothly ] with Ph3COOH, KHMDS, −78&nbsp;°C to −20&nbsp;°C over 6 hours to afford 10. A 2-methyl-2-butenoic acid moiety was installed to afford 11. Intermediate 11 underwent a ] with (E)-tributyl-1-heptenyl stannane, subsequently subjected to TBAF/AcOH for silyl removal and acetal hydrolysis to afford ] epoxide 12. Treatment of 12 with ] initiated a tandem oxidation-6p-]-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.<ref name="three"/>
] ]


==References== == References ==
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