Misplaced Pages

Torreyanic acid: Difference between revisions

Article snapshot taken from Wikipedia with creative commons attribution-sharealike license. Give it a read and then ask your questions in the chat. We can research this topic together.
Browse history interactively← Previous editContent deleted Content addedVisualWikitext
Revision as of 12:49, 14 December 2011 editMalcolma (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers145,247 edits added Category:Quinolones; removed {{uncategorized}} using HotCat← Previous edit Latest revision as of 01:45, 24 August 2024 edit undoGraeme Bartlett (talk | contribs)Administrators249,716 edits pubchem 
(29 intermediate revisions by 21 users not shown)
Line 1: Line 1:
{{Short description|Group of chemical compounds}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 458613030 | verifiedrevid = 470625291
| IUPAC_name = (2E,2'E)-4,4'-benzoxirenoisochromene-7a,11a(5H,11H)-diyl]bis(2-met hylbut-2-enoic acid) | 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
Line 8: Line 9:


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


<!--Identifiers--> <!--Identifiers-->
Line 14: Line 15:
| CAS_number = 176260-42-7 | CAS_number = 176260-42-7
| ATC_prefix = none | ATC_prefix = none
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | 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|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = DQBVXDMPCDAQGS-YOWCJFHESA-N | StdInChIKey = DQBVXDMPCDAQGS-YOWCJFHESA-N
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | 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&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"/> 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&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"/> 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 ==
{{Reflist}} {{Reflist|30em}}


]

]

]

]

] ]
]

]
]

Latest revision as of 01:45, 24 August 2024

Group of chemical compounds Pharmaceutical compound
Torreyanic acid
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • (2E,2'E)-4,4'-benzoxirenoisochromene-7a,11a(5H,11H)-diyl]bis(2-met hylbut-2-enoic acid)
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC38H44O12
Molar mass692.758 g·mol
3D model (JSmol)
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
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
  • Key:DQBVXDMPCDAQGS-YOWCJFHESA-N
  (what is this?)  (verify)

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. 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. 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. Torreyanic acid also promoted G1 arrest of G0 synchronized cells at 1-5 μg/mL levels, depending on the cell line. It has been proposed that the eukaryotic translation initiation factor EIF-4a is a potential biochemical target for the natural compound.

Biosynthesis

There are over 150 natural products that are presumed to undergo a Diels–Alder type cycloaddition, belonging to classes such as: polyketides, terpenoids, phenylpropanoids, and alkaloids. The Diels–Alder cycloaddition involves the overlap of the p-orbitals of two unsaturated systems: a 1,3-diene and dienophile. 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 Diels–Alderase and RNA Diels-Alderase. 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. 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.

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 cyclodimerization to generate torreyanic acid 1. 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. 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. 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.

Total synthesis

The first total synthesis of torreyanic acid was reported by Porco an co-workers in 2000. This total synthesis aimed to employ and confirm the Diels–Alder genesis proposed by Lee et al. 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.

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.
Categories: