Azaphilones: Chemistry and Biology - ACS Publications - American

Review pubs.acs.org/CR

Azaphilonoids: Chemistry and Biology Jin-Ming Gao,*,† Sheng-Xiang Yang,‡ and Jian-Chun Qin§ †

Shaanxi Engineering Center of Bioresource Chemistry & Sustainable Utilization, Department of Chemistry and Chemical Engineering, College of Science, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China ‡ College of Science, Zhejiang A&F University, Lin’an, Hangzhou 311300, Zhejiang, China § College of Plant Sciences, Jilin University, Changchun, Jilin 130062, China 3.2. Synthesis of Citrinin 3.3. First Synthesis of (±)-Ascochitine by Galbraith and Whalley 3.4. Synthesis of (±)-Sclerotiorin by Whalley and Co-workers 3.5. Enantioselective Synthesis of (+)-Sclerotiorin and (+)-8-O-Methylsclerotiorinamine 3.6. Concise Synthesis of (+)-Sclerotiorin and 7epi-Sclerotiorin and Their Analogues 3.7. Synthesis of 3-Methylazaphilone 3.8. Total Synthesis of (±)-Mitorubrin 3.9. Total Synthesis of (±)-Mitorubrinic Acid 3.10. Asymmetric Syntheses of (−)-Mitorubrin and Related Azaphilones 3.11. Synthesis of Azaphilone (±)-S-15183a and Related Molecules 3.12. Biomimetic Synthesis of (−)-S-15183a and Unnatural Azaphilones Based on CopperMediated Enantioselective Oxidative Dearomatization 3.13. Enantioselective Synthesis of (+)-Harziphilone 3.14. Synthesis of Vinylogous γ-Pyridones Mediated by Sc(OTf)3 3.15. Diastereoselective IBX Oxidative Dearomatization of Phenols by Remote Induction: Toward the Epicocconone Core Framework 3.16. Synthesis of Chlorofusin 3.16.1. Total Synthesis of Chlorofusin 3.16.2. Total Synthesis of Chlorofusin Azaphilone and Its Chromophore Diastereomers 3.16.3. Synthesis of Chlorofusin Azaphilone and Its Diastereomers 3.17. Synthesis of Berkelic Acid 3.17.1. Enantioselective Formal Synthesis of Berkelic Acid 3.17.2. Scalable Total Synthesis of (−)-Berkelic Acid (234) by Using a ProtectingGroup-Free Strategy 4. Biological Activities of Azaphilones and Related Compounds 4.1. Inhibitors of the p53−MDM2 Interaction 4.2. Inhibitors of Heat Shock Protein 90 4.3. Anti-HIV Activity

CONTENTS 1. Introduction 2. Azaphilones 2.1. Citrinin and Its Derivatives 2.2. Spiciferinone and Its Derivatives 2.3. Austdiol and Its Derivatives 2.4. Helotialins and Deflectins 2.5. Bulgarialactones 2.6. Sequoiatones 2.7. O-Containing Monascus Pigments 2.8. Trichoflectin and Sassafrin Azaphilones 2.9. Hydrogenated Azaphilones 2.9.1. Hydrogenated Azaphilones Missing the Benzoyl Moiety 2.9.2. Mitorubrin with a 7-Benzoyl Group 2.9.3. Mitorubrins with a 6- or 8-Benzoyl Group 2.10. Ascochitine 2.11. Chaetoviridins and Chaetomugilins 2.12. Pulvilloric Acid-Type Azaphilones 2.12.1. Pulvilloric Acid Derivatives 2.12.2. Berkelic Acid 2.13. Chrysodin-Type Azaphilones 2.13.1. Chrysodins 2.13.2. Cytosporolides 2.14. Sclerotiorins and Related Azaphilones 2.15. Multiformins and Cohaerins 2.16. Hydrogenated Spiroazaphilones 2.17. Chlorofusin 2.18. Nitrogenated Azaphilones 2.18.1. N-Containing Monascus Pigments 2.18.2. Sclerotioramine Pigments 3. Chemical Syntheses of Azaphilones and Related Compounds 3.1. General Synthetic Protocol for Azaphilone Scaffolds Based on Transition-Metal-Catalyzed Cycloisomerization of o-Alkynylbenzaldehyde © XXXX American Chemical Society

B L L M N N N N O O O O P T U U U U V V V V V Y Y AB AB AC AC AC

AD AD AD AD AD AF AF AG AG AH

AH AH AH

AI AK AK

AK AL AL AL

AM AN AN AN AO

Received: October 3, 2012

AC A

dx.doi.org/10.1021/cr300402y | Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 4.3.1. HIV-1 gp120−CD4 Binding Inhibitors 4.3.2. Inhibitors of HIV REV−RRE Binding 4.3.3. HIV Inhibitors 4.4. Inhibitors of the Grb2−Shc Interaction 4.5. Enzyme Inhibition 4.5.1. Topoisomerase II Inhibitors 4.5.2. Protein Phosphatase Inhibitors 4.5.3. Inhibitors of Lipoxygenase and Aldose Reductase 4.5.4. Inhibitors of Lipase, HMG-CoA Reductase, α-Glucosidase, and Acyl-CoA:ACAT 4.5.5. Inhibitors of Sphingosine Kinase 4.5.6. Caspase-3 Inhibitors 4.5.7. Inhibitors of Telomerase 4.5.8. Inhibitors of DNA Polymerases 4.5.9. Inhibitors of CETP Activity 4.6. Inhibitors of PDGF Binding to Their Receptors 4.7. Cytotoxic and Anti-Cancer Effects 4.8. Anti-inflammatory Activity 4.9. Hypolipidemic and Antihypertense Effects 4.10. Antioxidative Activity 4.11. Antimicrobial Activity 4.12. Miscellaneous Activity 5. Biosynthesis of Azaphilones 5.1. Biosynthesis of Citrinin, Austdiol, and Ascochitine 5.1.1. Citrinin 5.1.2. Austdiol 5.1.3. Ascochitine 5.2. Biosynthesis of Ochrephilone, Chaetoviridin B, Chaetomugilin A, PP-V, and Monascin 5.2.1. Ochrephilone 5.2.2. Chaetoviridin B and Chaetomugilin A 5.2.3. PP-V 5.2.4. Monascusone B and Monascin 5.3. Chlorofusin 5.4. Asperfuranone 5.5. Berkelic Acid 5.6. Cytosporolide A 5.7. Perinadine A 5.8. Dicitrinones A−C 5.9. Ergophilones A and B 5.10. Azanigerones 6. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments References

Review

as pigments and mycotoxins, comprise a diverse group of secondary metabolites that play an important role for drug discovery.3,5,6 Azaphilones or azaphilonoids are a structurally variable family of fungal polyketide metabolites possessing a highly oxygenated pyranoquinone bicyclic core (Scheme 1), usually known as

AO AP AP AP AP AP AP

Scheme 1. Azaphilonoid Scaffold AP AP AQ AQ AQ AQ AQ

isochromene, and a quaternary carbon center. More interestingly, they belong to a large group of fungal pigments, which turn red in the presence of primary amines due to an exchange of the pyran oxygen for nitrogen, arising from their affinity of the 4H-pyran nucleus to undergo substitution with primary amines to form the corresponding vinylogous γ-pyridones.7,8 The colored and noncolored azaphilone compounds are produced by numerous species of ascomyceteous and basidiomyceteous fungi, in particular the former,9 including genera Aspergillus, Penicillium, Chaetomium, Talaromyces, Pestalotiopsis, Phomopsis, Emericella, and Epicoccum, as well as Monascus and Hypoxylon, where they are responsible for the bright yellow, red, or green colors of fruiting bodies or mycelia.10 Several azaphilones are unique to one species and constitute taxonomically important marker metabolites.11 In recent years, it has been reported that these azaphilone molecules exhibit a wide range of significant biological activities, such as inhibitions of gp120−CD4 binding,12 Grb2-SH2 interaction,13 MDM2−p53 interaction,14 heat shock protein 90 (Hsp90),15 and dihydrofolate reductase,16 as well as antimicrobial, antiviral, cytotoxic, anticancer, and anti-inflammatory activities.8,17 Many of these activities may be attributed to the reactions of azaphilones with amino group-containing compounds, such as amino acids, proteins, and nucleic acids, leading to the production of vinylogous γ-pyridones. In view of their promising biological activities and interesting structural features, azaphilones have increasingly received a great deal of research interest. Since the 1970s, a number of synthetic studies of azaphilones have been disclosed.14,18,19 The isolation, characterization, and chemistry of azaphilones, especially as pigments, of marine and terrestrial fungal sources, including macromycetes fungi (macrofungi)20 and filamentous fungi (Monascus),21,22 have been comprehensively reviewed. Turner and Aldridge’s monograph presented an extensive list of the secondary metabolites from fungi, including azaphilones, classified on the basis of their biosynthetic origin.23 These reviews deal primarily with the chemistry of coloring substances or more generally with all types of fungal metabolites, of which Osmanova et al. also provide an account.8 According to the literature, over 170 different azaphilones are produced by 23 genera of fungi.8 However, we found a significantly higher number of relevant fungal metabolites: Around 373 compounds are presented in this review. To illustrate the variety of azaphilones produced by fungi, Figures 1−14 and Table 1 show all the azaphilones discovered. A full list of structures published between the end of 1932 and September 2012 is also presented. In this review we survey the chemical and biological literature regarding the isolation, structure elucidation, biological activities, biosynthesis, and chemical synthesis of azaphilone

AQ AQ AR AR AS AS AS AT AT AT AU AU AU AU AV AW AW AW AW AX AX AX AX AX AX AX AY AY AY AY AY AY

1. INTRODUCTION Fungi have proved to be a rich and important source of a huge number of secondary metabolites with a large variety of chemical structures and diverse biological activities. Fungal metabolites are of considerable synthetic interest and dramatic importance as new lead compounds for medicine as well as for plant protection.1−3 Importantly, fungal polyketides are one of the largest and most structurally diverse classes of naturally occurring compounds, ranging from simple aromatic metabolites to complex macrocyclic lactones.4 Fungal polyketides, such B


Chemical Reviews

Review

Table 1. Azaphilones and Related Derivatives name (stereochemistry) (alternative name)

producing strain

molecular formula

Citrinin and Its Derivatives citrinin (monascidin A, 1) Penicillium citrinum Penicillium sp. GQ-7 (endophyte) Penicillium sp. SBE-8 (mangrove endophyte) Penicillium citrinum B-57 (halotolerant) Penicillium notatum B-52 Penicillium citrinum IFM 53298 Monascus purpureus Monascus ruber Penicillium citrinum MST-F10130 Penicillium sp. MFA446 (marine fungus) Penicillium citrinum HGY1-5 (volcano-ash-derived Penicillium sp. H9318 Penicillium citrinum Aspergilus carneus Penicillium corylophilum(entomopathogenic) Penicillium citrinum KCTC6549 Penicillium purpurogenum G59 dihydrocitrinin (2) Penicillium sp. GQ-7 (endophyte) Penicillium citrinum MST-F10130 Penicillium citrinum B-57 decarboxydihydrocitrinin (3) Aspergillus sydowi YH11-2 Penicillium citrinum IFM 53298 Cylindrocarpon sp. SC 0537 Penicillium citrinum PSU-F51 Penicillium citrinum HGY1-5 (volcano-ash-derived 1-acetonyl-7-carboxyl-6,8-dihydroxy-3,4,5-trimethylisochroman (4) Cylindrocarpon sp. SC 0537 Penicillium citrinum PSU-F51 7-carboxyl-6,8-dihydroxy- 1,1,3,4,5-pentamethylisochroman (5) Cylindrocarpon sp. SC 0537 (3R,4S)-6,8-dihydroxy-1,1-dimethyl- 3,4,5-trimethylisochroman (6) Penicillium citrinum PSU-F51 (marine fungus) citrinin H1 (7) Penicillium citrinum B-57 pennicitrinone A (dicitrinin A, 8) Penicillium citrinum IFM 53298 Penicillium citrinum MST-F10130 Penicillium citrinum B-57 Penicillium notatum B-52 Penicillium citrinum HGY1-5 (volcano-ash-derived Penicillium sp. H9318 Penicillium citrinum pennicitrinone B (9) Penicillium citrinum IFM 53298 pennicitrinone C (10) Penicillium citrinum B-57 pennicitrinone D ((3′R)-3′-hydroxypennicitrinone A, 11) Penicillium notatum B-52 penicitrinol A (12) Penicillium citrinum IFM 53298 Penicillium citrinum B-57 Penicillium sp. H9318 penicitrinol B (13) Penicillium citrinum B-57 Penicillium sp. H9318 penicitrinol F1 (14) Penicillium citrinum HGY1-5 (volcano-ash-derived dicitrinol A (15) Penicillium citrinum HGY1-5 (volcano-ash-derived dicitrinol B (16) Penicillium citrinum HGY1-5 (volcano-ash-derived penidicitrinin B (17) Penicillium citrinum HGY1-5 (volcano-ash-derived dicitrinone A (18) Penicillium citrinum HGY1-5 (volcano-ash-derived dicitrinone B (19) Penicillium citrinum HGY1-5 (volcano-ash-derived Penicillium citrinum dicitrinone C (20) Penicillium citrinum HGY1-5 (volcano-ash-derived Penicillium citrinum tricitrinol A (21) Penicillium citrinum HGY1-5 (volcano-ash-derived tricitrinol B (22) Penicillium citrinum HGY1-5 (volcano-ash-derived penicitrinol C (23) Penicillium citrinum penicitrinol D (24) Penicillium citrinum penicitrinol E (25) Penicillium citrinum penicitrinol F (26) Penicillium citrinum C

C13H14O5

fungus)

C13H16O5

C12H16O3

fungus) C16H20O6 C15H20O5 C14H20O3 C24H26O7 C23H24O5

fungus)

C23H22O5 C23H26O6 C23H24O6 C23H26O5

C24H28O6 fungus) fungus) fungus) fungus) fungus) fungus)

C24H28O6 C25H30O6 C25H30O6 C23H30O6 C28H35O6 C26H31O6

fungus)

C25H29O6

fungus) fungus)


ref 24 36 33 38 43 39 29 29 37 34 45 44 49 35 31 30 32 36 37 38 40 39 41 42 45 41 42 41 42 38 39 37 38 43 45 44 50 39 38 43 39 38 44 38 44 45 45 45 46 47 47 50 47 50 45 45 49 49 49 50


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name)

producing strain

molecular formula

Citrinin and Its Derivatives penicitrinol G (27) Penicillium citrinum penicitrinol H (28) Penicillium citrinum penicitrinol I (29) Penicillium citrinum penicillanthranin A (30) Penicillium citrinum PSU-F51 (marine fungus) penicillanthranin B (31) Penicillium citrinum PSU-F51 perinadine A (32) Penicillium citrinum N055 (marine fungus) aspergilone A (33) Aspergillus sp. ZJ-2008001 (marine fungus) aspergilone B (34) Aspergillus sp. ZJ-2008001 Spiciferinone and Its Derivatives spiciferinone (35) Cochliobolus spicifer Nelson D-5 (Pyrenophoraceae) cochliospicin A (36) Cochliobolus spicifer Nelson D-5 leptosphaerone (pseudohalonectrin A, (7S,8R)-7-ethyl-7,8-dihydro- Leptosphaeria sp. IV403 (endophyte) 8-hydroxy- 3,4,7-trimethyl-6H-[2]benzopyran-6-one, 37) Pseudohalonectria adversaria YMF1.01019 fusarone (38) Fusarium sp. LN-12 (endophyte) pseudohalonectrin B (39) Pseudohalonectria adversaria YMF1.01019 Austdiol and Its Derivatives austdiol ((7R,8S)-7,8-dihydroxy-3,7-dimethyl-6-oxo-7,8-dihydroAspergillus ustus (Bainier) 6H-isochromene-5-carbaldehyde, 40) dihydrodeoxy-8-epi-austdiol ((7R,8R)-7,8-dihydro-7,8-dihydroxyAspergillus ustus (Bainier) 3,5,7-trimethyl-2-benzopyran-6-one, 41) daldinin A (42) Daldinia concentrica (Xylariaceae) daldinin B (43) Daldinia concentrica (Xylariaceae) (3S)-4,6-dihydro-8-methoxy-3,5- dimethyl-6-oxo-3H-2-benzopyran Penicillium expansum (4) arohynapene C ((3S)-6-hydroxy-8-methoxy-3,5Penicillium expansum dimethylisochroman, 45) a hybrid strain ME 0004 derived from Penicillium citreo-viride B. IFO6200 and 4692 Penicillium sp. FO-2295 arohynapene D (46) Penicillium sp. FO-2295 8-hydroxy-6-methoxy-3,7-dimethylisochroman (47) Penicillium citrinum Penicillium steckii 6-hydroxy-3-methylisochroman-5-carboxylic acid (48) unidentified mangrove endophytic fungus no. 1893 penicisochroman D (49) Penicillium sp. PSU-F40 (marine fungus) penicisochroman E (50) Penicillium sp. PSU-F40 (3S*,4S*,5S*,6R*)-4,5,6-trihydroxy-3-methyl- 3,4,6,7-tetrahydroDelitschia corticola YMF 1.01111 (aquatic fungus) 1H-isochromen-8(5H)-one (51) bisbynin (52) Stachybotrys bisbyi (Srinivasan) Barron Helotialins and Deflectins helotialin A (53) Helotialean (Ascomycete) helotialin B (54) Helotialean sp. (Ascomycete) helotialin C (55) Helotialean sp. (Ascomycete) chermesinone A (56) Penicillium chermesinum ZH4-E2 chermesinone B (57) Penicillium chermesinum ZH4-E2 chermesinone C (58) Penicillium chermesinum ZH4-E2 monochaetin (59) Monochaetia compta PRL 1754 deflectin A-1a (60) Aspergillus deflectus Aspergillus deflectus CBS 109.55 deflectin A-1b (61) Aspergillus deflectus Aspergillus deflectus CBS 109.55 deflectin A-1c (62) Aspergillus deflectus Aspergillus deflectus CBS 109.55 deflectin B-2a (63) Aspergillus deflectus Aspergillus deflectus CBS 109.55 deflectin B-2b (64) Aspergillus deflectus Aspergillus deflectus CBS 109.55 Bulgarialactones bulgarialactone A (65) Bulgaria inquinans (Fr.) (Ascomycete) Bulgaria inquinans ICRM-184 bulgarialactone B (66) Bulgaria inquinans (Fr.)

D

ref

C15H20O4 C16H22O4 C15H20O4 C28H24O10 C28H24O11 C28H37NO7 C26H26O3 C39H40O6

50 50 50 42 42 51 52 52

C14H16O3 C17H22O6 C14H18O3

53 54 55

C15H24O5 C16H21O3

56 57 56

C12H12O5

58, 60

C12H14O4

59

C12H14O3

61 61 62

C12H16O3

62 63

C11H14O3 C12H16O3

64, 65 65 66

C11H12O4 C10H12O2 C10H12O3 C10H14O5

67 68 68 69

C15H22O5

70

C23H30O6 C22H30O4 C23H32O6 C17H22O4 C18H20O5 C18H22O6 C18H20O5 C21H24O5

71 71 71 72 72 72 73, 74 75, 15

C23H28O5

75 15 75 15 75 15 75 15

C25H32O5 C24H30O5 C26H34O5

C26H28O6 C26H28O7

76 15 76


Chemical Reviews

Review


bulgarialactone C (67) bulgarialactone D (68) pitholide A (69) pitholide B (70) pitholide C (71) pitholide D (72) epicocconone (73) acetosellin (74) sequoiatone A (75) sequoiatone B (sporogen-PF 1, 76)

sequoiatone sequoiatone sequoiatone sequoiatone

C (77) D (78) E (79) F (80)

rubropunctatin (81)

monascorubrin (82)

monascin (83)

ankaflavin (84)

yellow II (85) PP-O ((10Z)-12-carboxylmonascorubrin, 86) PP-Y ((10Z)-monascorubrin, 87) monapilol A (88) monapilol B (89) monapilol C (90) monapilol D (91) monascuspiloin (dihydromonascin, 92) monascusone B (93) monascusazaphilol (94) sequoiamonascin C (95) monarubrin (96) rubropunctin (97) monaphilone A (98) monaphilone B (99) monapurone A (100) monapurone B (101) monapurone C (102) biscogniazaphilone A (103)

producing strain

molecular formula

Helotialins and Deflectins Bulgaria inquinans ICRM-184 Bulgaria inquinans (Fr.) Bulgaria inquinans ICRM-184 Bulgaria inquinans ICRM-184 Pithomyces sp. (marine-derived fungus) Pithomyces sp. Pithomyces sp. Pithomyces sp. Epicoccum nigrum Cercosporella acetosella Ell Aspergillus parasiticus RDWD1−-2 (endophyte) Penicillium sp. JP-1 (endophyte) Penicillium funiculosum NOY-237 Aspergillus parasiticus RDWD1-2 Penicillium sp. JP-1 (endophyte) Aspergillus parasiticus RDWD1-2 Aspergillus parasiticus RDWD1-2 Aspergillus parasiticus RDWD1-2 Aspergillus parasiticus RDWD1-2 Monascus Pigments Monascus purpureus (Eurotiaceae) Monascus pilosus Monascus purpureus CBS 285.34 Monascus purpureus Monascus Monascus Monascus Monascus Monascus

pilosus purpureus CBS 285.34 purpureus BCRC 38113 kaoliang KB20M10.2 purpureus

C26H30O7 C22H26O7 C22H26O6 C21H26O6 C21H26O5 C23H22O7 C23H22O6 C23H30O6 C22H30O5

C22H30O5 C22H30O6 C22H30O6 C22H32O5 C21H22O5

C23H26O5

C21H26O5

Monascus pilosus Monascus purpureus NTU 568 Monascus purpureus CBS 285.34 Monascus anka Monascus purpureus BCRC 38113 Monascus purpureus Monascus pilosus Monascus purpureus NTU 568 Monascus purpureus CBS 285.34 Monascus sp. Penicillium sp. AZ Penicillium sp. AZ Monascus purpureus NTU 568 Monascus purpureus NTU 568 Monascus purpureus NTU 568 Monascus purpureus NTU 568 Monascus pilosus M93 Monascus kaoliang KB20M10.2 Monascus pilosus BCRC 38072 Aspergillus parasiticus RDWD1-2 (endophyte) Monascus ruber ATCC 96218 Monascus ruber ATCC 96218 Monascus purpureus NTU 568 Monascus purpureus NTU 568 Monascus purpureus Monascus purpureus Monascus purpureus Biscogniauxia formosana BCRC 33718 (Xylariaceae) (endophytic)

E

C26H26O6

C23H30O5

C23H28O5 C23H24O7 C23H26O5 C23H28O5 C21H24O5 C26H32O6 C24H28O6 C21H28O5 C17H18O5 C25H36O5 C23H30O7 C20H26O4 C22H30O4 C22H32O4 C20H28O4 C20H26O4 C21H28O4 C21H28O4 C24H34O4

ref 15 76 15 15 77 77 77 77 78, 79 80 81 84 83 81 84 82 82 82 82 22, 85 91 15 86, 88, 22 91 15 92 93 22, 87 −89 91 94 15 90 92 22 91 94 15 95 96 96 97 97 97 97 98 93 99 100 101 101 94 94 102 102 102 103


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) trichoflectin (104) 9-hexanoyl-3-(2-hydroxypropyl)-6a-methyl-9,9a-dihydro-6H-furo [2,3-h]isochromene-6,8(6aH)-dione (R3, 105) monasfluore A (106) monasfluore B (107) sassafrin A (108) sassafrin B (109) sassafrin C (110) monascuskaolin (111) biscogniazaphilone B (112)

FK17-P2b1 (113) FK17-P2b2 (114) FK17-P3 (115) monascusone A (116) berkazaphilone A (117) (−)-lunatoic acid A (118) rubiginosin C (119) (−)-mitorubrin (120) (−)-(R)-mitorubrin

(−)-mitorubrinol (121)

(−)-mitorubrinal (122) (−)-mitorubrinic acid (123)

(+)-mitorubrin (124)

(+)-mitorubrinol (125)

(+)-mitorubrinol acetate (126)

(+)-mitorubrinic acid (127)

producing strain

molecular formula

Trichoflectin/Sassafrins Trichopezizella nidulus A73-95 Monascus purpureus IB1 Monascus purpureus HP14 (mutant) Monascus AS3.4444 Monascus purpureus BCRC 38113 Monascus AS3.4444 Monascus purpureus BCRC 38113 Creosphaeria sassafras (Xylariaceae) Creosphaeria sassafras Creosphaeria sassafras Monascus kaoliang BCRC 31506 Biscogniauxia formosana BCRC 33718 (Xylariaceae) (endophyte) Hydrogenated Azaphilones Aspergillus sp. FK17 Aspergillus sp. FK17 Monascus kaoliang KB20M10.2 Aspergillus sp. FK17 Monascus kaoliang KB20M10.2 Penicillium rubrum Stoll Cochliobolus lunata IFO 5997 Curvularia sp. MF6369 Hypoxylon rubiginosum Penicillium rubrum Penicillium funiculosum Talaromyces flavus (Klöcker) Stolk and Samson MF6954 Talaromyces austrocalifornicus Talaromyces convolutus Penicillium purpurogenum JS03-21 Penicillium rubrum Penicillium funiculosum Talaromyces austrocalifornicus Talaromyces convolutus Penicillium vermiculatum Dang Talaromyces austrocalifornicus Talaromyces convolutus Talaromyces austrocalifornicus Talaromyces convolutus Penicillium funiculosum IFO 6345 Penicillium funiculosum CCM F-8080 Cochliobolus lunatus Penicillium vermiculatum IV/5 Penicillium rubrum Talaromyces emodensis Talaromyces hachijoensis Talaromyces wortmannii var.sublevisporus Hypoxylon fragiforme Emericella falconensis Emericella fruticulosa Talaromyces sp. T1BF (endophyte) Talaromyces emodensis Talaromyces wortmannii var. sublevisporus Hypoxylon fragiforme Talaromyces emodensis Talaromyces hachijoensis Talaromyces wortmannii var. sublevisporus Hypoxylon fragiforme Entonaema splendens Hypoxylon fragiforme F

ref

C17H14O5 C21H26O6

104 105

C21H24O5

106 107 106 107 108 108 108 109 103


C13H16O4 C13H16O4 C13H15O4Cl C13H18O5 C13H16O3

C28H38O6 C21H18O7

C21H18O8

C21H16O8 C21H16O9

C21H18O7

C21H18O8

C23H20O9

C21H16O9

110 110 93 110 93 111 112, 113 114 115 116 117 114 118 118 137 116 117 118 118 119 118 118 118 120 121 113 122 116 118 118 118 123 124 124 125 118 118 123 118 118 118 123 141 123


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) monomethylmitorubrin (128) monomethyl-(S)-mitorubrin 4′-hydroxy-3′-methoxy-(+)-(S)-mitorubrin (129) 6′-Hydroxy-3′-methoxymitorubrin (130) wortmin (131) hypomiltin (132)

kasanosin B (133) kasanosin C (134) pinophilin A (Berkazaphilone B, 135) falconensin A (136) falconensin falconensin falconensin falconensin

B (137) C (138) D (139) E (140)

falconensin F (141)

falconensin G (142)

falconensin H (143) falconensin I (144)

falconensin J (145) falconensin K (146) falconensin L (147) falconensin M (148) falconensin N (149) monomethyldihydromitorubrin (150) rubiginosin B (151) comazaphilone A (152) comazaphilone B (153) comazaphilone C (154) purpurquinone A (155) purpurquinone B (156) purpurquinone C (157) (−)-diazaphilonic acid (158) rutilin A (159) rutilin B (160) ergophilone A (161) ergophilone B (162) deacetylisowortmin (163) rubiginosin A (164) entonaemin A (165)

producing strain

molecular formula

Hydrogenated Azaphilones Talaromyces tardifaciens Emericella falconensis Penicillium radicum FKI-3765-2 Penicillium citrinum Thom. MF6409 Penicillium radicum FKI-3765-2 Penicillium radicum FKI-3765-2 Penicillium wortmanni Klöcker Hypoxylon hypomiltum Hypoxylon intermedium, Hypoxylon perforatum Hypoxylon trugodes, Pulveria porrecta Talaromyces sp. KA02K3 Talaromyces sp. T1BF (endophytic) Penicillium pinophilum Hedgcok Penicillium rubrum Stoll Emericella falconensis Horie, Miyaji, Nishimura, and Udagawa NHL 2999 Emericella falconensis Horie Emericella falconensis Horie Emericella falconensis Horie Emericella falconensis Emericella fruticulosa (Raper and Fennell) Malloch and Cain strain IFO 30841 Emericella falconensis Emericella fruticulosa (Raper and Fennell) Malloch and Cain strain IFO 30841 Emericella falconensis Emericella fruticulosa (Raper and Fennell) Malloch and Cain strain IFO 30841 Emericella falconensis Emericella falconensis Emericella fruticulosa (Raper and Fennell) Malloch and Cain strain IFO 30841 Emericella falconensis Emericella fruticulosa Emericella falconensis Emericella fruticulosa Emericella falconensis Emericella fruticulosa Emericella falconensis Emericella fruticulosa Emericella falconensis Emericella fruticulosa Emericella falconensis Emericella fruticulosa Hypoxylon rubiginosum Hypoxylon rutilum Penicillium commune QSD-17 Penicillium commune QSD-17 Penicillium commune QSD-17 Penicillium purpurogenum JS03-21 Penicillium purpurogenum JS03-21 Penicillium purpurogenum JS03-21 Talaromyces flavus PF1195 Hypoxylon rutilum (Xylariaceae) Hypoxylon rutilum Penicillium sp. BM-99 Penicillium sp. BM-99 Trichoderma sp. MFF-1 (endophyte) Hypoxylon rubiginosum Hypoxylon rutilum Hypoxylon rubiginosum G

C22H20O7

C22H20O8 C22H20O8 C24H28O8 C23H22O9

C22H24O8 C22H24O7 C21H22O7

ref 126 124 127 114 127 127 128 129

C23H24O7Cl2

130 125 131 111 132

C23H26O7Cl2 C25H26O8Cl2 C25H28O8Cl2 C23H25O7Cl

132 132 132 133

C23H26O7

133

C25H28O8

133

C22H19ClO7 C22H24O7

134 124

C22H26O7

124

C22H23O7Cl

124

C22H25O7Cl

124

C22H22O7Cl2

124

C22H24O7Cl2

124

C22H22O7

124

C21H22O8

115 135 136 136 136 137 137 137 138 135 135 139 139 140 115 135 115

C22H26O7 C22H26O8 C22H24O8 C21H20O9 C21H20O10 C21H20O8 C42H32O18 C44H40O16 C44H40O16 C50H60O10 C49H58O10 C21H24O7 C23H24O9 C21H22O8


Chemical Reviews

Review


entonaemin B (166) entonaemin C (167) comazaphilone D (168) comazaphilone E (169) comazaphilone F (170) kasanosin A (171) (+)-mitorubrinic acid B (172) Sch725680 (berkazaphilone C173)

Sch1385568 (174) pinophilin B (175) 3-[(2S)-butan-2-yl]-7-(dihydroxymethylidene)-4methylisochromene-6,8-dione ascochitine (176) chaetoviridin A (177)

chaetoviridin B (178) chaetoviridin C (179) chaetoviridin D (180) chaetoviridin E (181) chaetoviridine E (182) chaetoviridine F (183) epi-chaetoviridin A (4′-epi-chaetoviridin A, 184) 5′-epi-chaetoviridin A (185) 4′-epi-chaetoviridin F (186) 12β-hydroxychaetoviridin C (187) chaetoviridine G (188) chaetoviridine H (189) chaetoviridine I (190) chaetomugilin S (191) 7,5′-bis-epi-chaetoviridin A (192) 7-epi-chaetoviridin E (193) chaetomugilin A (194) chaetomugilin B (195) chaetomugilin C (196) chaetomugilin D (197) chaetomugilin E (198) chaetomugilin F (199) 11-epi-chaetomugilin A (200) 4′-epi-chaetomugilin A (201) chaetomugilin G (202) chaetomugilin H (203) seco-chaetomugilin A (204) seco-chaetomugilin D (205) chaetomugilin I (206) chaetomugilin J (207) chaetomugilin K (208)

producing strain

molecular formula

Hydrogenated Azaphilones Hypoxylon rutilum Entonaema splendens (Xylariaceae) Talaromyces sp. T1BF (endophytic) Entonaema splendens Entonaema splendens Penicillium commune QSD-17 Penicillium commune QSD-17 Penicillium commune QSD-17 Talaromyces sp. KA02K3 Penicillium funiculosum IFO 6345 Aspergillus sp. SPRI-0814 Penicillium pinophilum Hedgcok Penicillium rubrum Stoll Aspergillus sp. SPRI-0814 Penicillium pinophilum Hedgcok Ascochyta pisi Lib.

C21H20O8 C44H44O16 C21H22O7 C22H24O8 C22H26O8 C22H24O8 C21H18O9 C21H22O7

C21H20O7 C21H22O8 C15H16O5

Ascochyta fabae Speg. Ascochyta salicorniae Chaetoviridins/Chaetomugilins Chaetomium globosum var. flavo-viridae TRTC 66.631a (Chaetomiaceae) Chaetomium cochliodes VTh01 Chaetomium cochliodes CTh05 Chaetomium globosum var. flavo-viridae Chaetomium sp. Chaetomium globosum var. flavo-viridae Chaetomium globosum OUPS-T106B-6 Chaetomium globosum var. flavo-viridae Chaetomium sp. Chaetomium cochliodes CTh05 Chaetomium cochliodes CTh05 Chaetomium cochliodes CTh05 Chaetomium globosum Chaetomium globosum Chaetomium globosum Chaetomium globosum Chaetomium globosum Chaetomium globosum Chaetomium globosum Chaetomium elatum no. 89-1-3-1 (lichen fungus) Chaetomium elatum no. 89-1-3-1 (lichen fungus) Chaetomium elatum no. 89-1-3-1 (lichen fungus) Chaetomium globosum OUPS-T106B-6 (marine fungus) Chaetomium globosum (endophyte) Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum (endophyte) Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 H

ref 135 141 125 141 141 136 136 136 130 120 142 131 111 143 131 144 145 147

C23H25ClO6

C23H29ClO7 C23H27ClO6 C23H29ClO8 C23H25ClO6 C23H23ClO5 C23H25ClO5 C23H25ClO6 C23H25ClO6 C23H25ClO5 C23H27ClO7 C23H25ClO5 C23H26O6 C23H27ClO8 C23H29ClO5 C23H25ClO6 C23H23ClO5 C23H27ClO7 C24H29ClO7 C23H25ClO6 C23H27ClO6 C24H29ClO6 C23H25ClO5 C23H27ClO7 C23H27ClO7 C24H29ClO7 C24H29ClO6 C24H31ClO8 C24H31ClO7 C22H27ClO5 C22H27ClO4 C23H29ClO5

148 150 150 148 149 148 156 148 149 150 150 150 151 151 151 151 151 151 151 152 152 152 153 160 153, 154 153, 154 154 160 154 154 155 155 156 156 157 157 158 158 158


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) chaetomugilin L (209) chaetomugilin M (210) chaetomugilin N (211) chaetomugilin O (212) chaetomugilin Q (213) chaetomugilin R (214) chaetomugilin P (215) (11S)-epi-chaetomugilin I (216) chaetomugilin S1 (217) chaetomugilin T (218) chaetomugilin U (219) pulvilloric acid (220)

phomoeuphorbin A (221) phomoeuphorbin B (222) phomoeuphorbin C (223) phomoeuphorbin D (224) T22 azaphilone (225) harziphilone (226) cyathusal A (227) cyathusal B (228) cyathusal C (229) cyathuscavin A (230) cyathuscavin B (231) cyathuscavin C (232) pulvinatal (233) berkelic acid (234) chrysodin (235) patulodin (236) CT2108A (237) CT2108B (238) S-15183a (239) S-15183b (240) CJ-12,373 (241) pseudoanguillosporin A (242) pseudoanguillosporin B (243) cytosporolide A (244) cytosporolide B (245) cytosporolide C (246) sclerotiorin (247) (+)-(7R,13S)-sclerotiorin (+)-sclerotiorin

producing strain

molecular formula

Chaetoviridins/Chaetomugilins Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Chaetomium globosum OUPS-T106B-6 Pulvilloric Acid Type Penicillium pulvillorum Penicillium araracuarense, Penicillium elleniae, Penicillium penarojense, Penicillium vanderhammenii, Penicillium wotroi Phomopsis euphorbiae Phomopsis euphorbiae Phomopsis euphorbiae Phomopsis euphorbiae Trichoderma harzianum T22 and T39 Trichoderma harzianum WC47695 Cyathus stercoreus (Basidiomycete) Cyathus stercoreus Cyathus stercoreus Cyathus stercoreus Cyathus stercoreus Cyathus stercoreus Cyathus stercoreus (Basidiomycete) Nidularia pulvinata (Schw.) Fr. Penicillium sp. Chrysodin Type Sepedonium chrysospermum Penicillium urticae Penicillium solitum strain CT2108 Penicillium solitum strain CT2108 Penicillium solitum strain CT2108 Zopfiella inermis SANK15 183 Zopfiella inermis SANK15 183 Penicillium sp. CL22557 Pseudoanguillospora sp.6577 (endophyte) Pseudoanguillospora sp.6577 (endophyte) Cytospora sp. XZ014 (Coelomycetes) Cytospora sp. XZ014 Cytospora sp. XZ014 Sclerotiorin Type Penicillium sclerotirium Van Beyma Penicillium multicolor NRRL 2060 Penicillium sclerotiorum X11853 Penicillium frequentans (mycobionts of the lichen Pyrenula japonica) Penicillium multicolor F1753 Penicillium frequentans CFTRI A-24 Penicillium sclerotiorum PSU-A13 (endophyte) Penicillium citreonigrum AF033418 Penicillium sclerotiorum van Beyma Penicillium multicolor FO-2338 Penicillium sp. FO-4164 Cephalotheca faveolata Yaguchi, Nishim., and Udagawa (endophytic) unidentified fungus ZJ27 (seaweed)

I

ref

C23H29ClO4 C23H27ClO7 C23H25ClO6 C23H25ClO5 C22H29ClO6 C16H21ClO5 C22H27ClO5 C22H27ClO5 C23H27ClO6 C23H28O7 C23H28O6

158 158 158 158 159 159 159 159 161 161 161

C15H18O5

162 163− 165 166 166 166 166 167, 168 169 170 170 170 171 171 171 170, 171 172 173

C15H16O6 C15H18O4 C15H20O6 C15H20O6 C19H20O6 C15H18O4 C17H14O7 C17H14O8 C20H20O8 C17H14O8 C18H16O9 C17H14O9 C18H16O8 C29H40O9 C19H18O5 C23H26O8 C21H22O7 C21H22O6 C25H36O5 C27H40O5 C17H24O6 C17H26O3 C17H26O4 C33H48O9 C32H46O8 C35H50O10 C21H23ClO5

178 179 180 180 180 181 181 182 183 183 184 184 184 186, 187 188 190 191 192 193, 194 195 196 197 198 199 200 201


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) isochromophilone III (248) isochromophilone IV (249)

isochromophilone V (250) isochromophilone VII (251) isochromophilone VIII (252) penicilazaphilone A (253) penicilazaphilone B (254) dechloroisochromophilone III (255)

dechloroisochromophilone IV (8-acetyldechloroisochromophilone III, 256) (−)-sclerotiorin (7-epi-sclerotiorin, 257)

(8R)-7-deacetyl-O8,8-dihydro-7-epi-sclerotiorin (luteusin A) (258) luteusin B (259) helicusin A (260) helicusin B (261) helicusin C (262) helicusin D (263) (8S,8α-R)-7-deacetyl-1,O8,8,8a-tetrahydro-7-epi-sclerotiorin (264) (8S,8α-R)-5-dechloro-7-deacetyl-1,O8,8,8a-tetrahydro-7-episclerotiorin (265) RP-1551-7 (266) RP-1551-M2 (267) RP-1551-2 (268) isochromophilone II (269) epi-isochromophilone II (270) rubrorotiorin (7-epi-5-chloroisorotiorin, 5-chloroisorotiorin, 271)

ochrephilone (272)

isochromophilone I (273) isorotiorin (274) 5-bromoochrephilone (275) RP-1551-3 (276) RP-1551-4 (277) luteusin E (278) luteusin C (279) luteusin D (280) RP-1551−1 (281) RP-1551-M1 (282) RP-1551-6 (283) RP-1551-5 (284) rotiorin (285)

producing strain

molecular formula

Sclerotiorin Type Penicillium multicolor FO-3216 Penicillium multicolor FO-3216 Penicillium sp. FO-4164 Penicillium multicolor F1753 Penicillium multicolor FO-3216 Penicillium sp. FO-4164 Penicillium sp. FO-4164 Penicillium sclerotiorum PSU-A13 (endophytic) Penicillium sclerotiorum PSU-A13 (endophytic) Penicillium multicolor FO-2338 Penicillium sclerotiorum PSU-A13 (endophyte) Penicillium citreonigrum AF033418 Penicillium multicolor FO-2338 Penicillium citreonigrum AF033418 Penicillium hirayamae Udagawa Penicillium hirayamae NHL 6046 unidentified marine fungus 98F134 Talaromyces luteus IFM42239 (Ascomycete) Penicillium sclerotiorum X11853 Talaromyces luteus IFM42239 Talaromyces helius IFM 42241 Talaromyces helius IFM 42241 Talaromyces helius IFM 42241 Talaromyces helius IFM 42241 Penicillium sclerotiorum X11853 Penicillium sclerotiorum X11853 Penicillium Penicillium Penicillium Penicillium

sp. SPC-21609 sp. SPC-21609 sp. SPC-21609 multicolor FO-2338

C19H23ClO4 C21H25ClO6 C21H27ClO5 C22H32O6 C19H28O6 C19H26O4

C21H28O5

C21H23ClO5

C19H23ClO4 C19H23ClO4 C25H27ClO7 C25H27ClO7 C25H27ClO7 C25H27ClO7 C19H25O4Cl C19H26O4 C19H23ClO4 C19H25ClO4 C24H31ClO5 C22H27ClO4

Chaetomium cupreum CC3003 Penicillium hirayamae Udagawa Penicillium hirayamae Van Beyma Penicillium multicolor FO-2338 Penicillium sp. FO-4164 Penicillium sclerotiorum X11853 Chaetomium cupreum CC3003 Penicillium multicolor NRRL 2060 Penicillium sp. FO-4164 Penicillium multicolor FO-2338 Penicillium sclerotiorum X11853 Penicillium citreonigrum AF033418 unidentified fungus ZJ27 (seaweed, endophytic) Penicillium multicolor FO-2338 Penicillium multicolor FO-2338 penicillium multicolor FO-2338 Penicillium sp. SPC-21609 Penicillium sp. SPC-21609 Talaromyces luteus Talaromyces luteus Talaromyces luteus Penicillium sp. SPC-21609 Penicillium sp. SPC-21609 Penicillium sp. SPC-21609 Penicillium sp. SPC-21609 Penicillium sclerotiorum Van Beyma Penicillium multicolor NRRL 2060 J

C19H25ClO4 C21H27ClO5

C22H27ClO4 C23H23O5Cl

C23H26O5

C23H25O5Cl C23H24O5 C23H25O5Br C25H27O5Cl C25H29O6Cl C25H27O6Cl C25H29O6Cl C25H29O6Cl C25H29O6Cl C26H31O6Cl C25H29O6Cl C25H33O5Cl C23H24O5

ref 202 202 199 192 202 199 199 195 195 12 195 196 12 196 203, 204 205 206 207, 208 209, 190 208, 209 210 210 210 210 190 190 211 211 211 212, 198, 213 214 204 205 198 199 190 214 215 199 198, 213 1990 196 201 212, 213 12 12 211 211 216 216 216 211 211 211 211 205 215


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) rotiorinol A (286) rotiorinol B (287) rotiorinol C (288) (−)-rotiorin (289) asperfuranone (290) multiformin A (291) multiformin B (292) multiformin C (293) multiformin D (294) cohaerin C (295) cohaerin D (296) cohaerin E (297) cohaerin F (298) longirostrerone A (299) longirostrerone B (300) longirostrerone C (301) longirostrerone D (302) cohaerin A (303) cohaerin B (304) daldinin C (305)

daldinin D (306) daldinin E (307) daldinin F (308) decipinin A (309) pestafolide A (310) peneciraistin A (311) peneciraistin B (312) peneciraistin C (313) cochliodone A (314) cochliodone B (315) cochliodone C (316) cochliodone D (317) sequoiamonascin A (318) sequoiamonascin B (319) fusidilactone C (320) chlorofusin (321) rubropunctamine (322)

monascorubramine (323)

N-glutarylrubropunctamine GTR (324) N-glutarylmonascorubramine GTM (325) N-glucosylrubropunctamine GCR (326) N-glucosylmonascorubramine GCM (327) monascorubrin L-alanine (328) rubropunctatin L-alanine (329) monascorubrin L-aspartate (330) rubropunctatin L-aspartate (331) monascorubrin D-alanine (332) rubropunctatin D-alanine (333)

producing strain

molecular formula

Sclerotiorin Type Chaetomium cupreum CC3003 Chaetomium cupreum CC3003 Chaetomium cupreum CC3003 Chaetomium cupreum CC3003 Aspergillus nidulans Multiformin and Cohaerins Hypoxylon multiforme (Xylariaceae) Hypoxylon multiforme Hypoxylon multiforme Hypoxylon multiforme Annulohypoxylon cohaerens (Xylariaceae) Annulohypoxylon cohaerens Annulohypoxylon cohaerens Annulohypoxylon cohaerens Chaetomium longirostre (soil fungus) Chaetomium longirostre Chaetomium longirostre Chaetomium longirostre Hypoxylon cohaerens Hypoxylon cohaerens Hydrogenated Spiroazaplilones Daldinia concentrica (Xylariaceae) Hypoxylon rubiginosum Hypoxylon fuscum Penicillium thymicola IBT5891 Hypoxylon fuscum Hypoxylon fuscum Podospora decipiens JS 270 (coprophilous fungus) (Lasiosphaeriaceae) Pestalotiopsis foedan L436 Penicillium raistrickii HQ717799 (saline-soil-derived fungus) Penicillium raistrickii HQ717799 Penicillium raistrickii HQ717799 Chaetomium cochliodes VTh01 Chaetomium cochliodes VTh01 Chaetomium cochliodes CTh05 Chaetomium cochliodes CTh05 Aspergillus parasiticus RDWD1-2 Aspergillus parasiticus RDWD1-2 Fusidium sp. (endophyte) Microdochium caespitosum (initial name Fusarium sp. 22026) Nitrogenated Azaphilones Monascus purpureus Monascus pilosus Monascus purpureus DSM1379 Monascus purpureus Monascus pilosus Monascus purpureus DSM1379 Monascus ruber Monascus purpureus Monascus ruber Monascus purpureus Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber K

ref

C23H26O5 C23H26O6 C23H26O6 C23H24O5 C19H24O5

214 214 214 214 217

C24H26O6 C24H24O6 C24H22O6 C24H26O7 C28H34O7 C28H32O7 C28H30O6 C27H36O6 C32H40O7 C31H42O6 C32H38O6 C32H38O7 C26H28O6 C26H30O7

218 218 218 218 219 219 219 219 220 220 220 220 221 221

C22H26O9

C21H24O10 C24H28O9 C24H28O9 C31H36O12

61 115 224 223 224 224 225

C15H22O5 C15H20O5 C15H20O5 C19H26O9 C34H38O12 C34H38O12 C38H42O16 C38H42O16 C23H30O7 C23H30O7 C22H30O9 C63H99O19ClN12

226 227 227 227 150 150 150 150 100 100 228 230

C21H23NO4

241 91 250 241, 242 91 252 29 243 29 243 243 243 244 244 244 244 244 244

C23H27NO4

C26H29NO8 C28H33NO8 C27H33NO9 C29H37NO9 C26H31NO6 C24H27NO6 C27H31NO8 C25H27NO8 C26H31NO6 C24H27NO6


Chemical Reviews

Review

Table 1. continued name (stereochemistry) (alternative name) monascorubrin D-aspartate (334) rubropunctatin D-aspartate (335) monascorubrin l-tryptophane (336) rubropunctatin l-tryptophane (337) monascorubrin D-tyrosine (338) rubropunctatin D-tyrosine (339) monascorubrin ethyl L-leucine (340) rubropunctatin ethyl L-leucine (341) monascorubrin ethyl L-tyrosine (342) rubropunctatin ethyl L-tyrosine (343) monascorubrin L-threonine (344) rubropunctatin L-threonine (345) rubropunctatin arginine (346) monascorubrin arginine (347) rubropunctatin glycine (348) monascorubrin glycine (349) H-Nle (350) H-Cha (351) L-t-Bg (352) H-Pen (353) monascopyridine A (354) monascopyridine B (355) monascopyridine C (356) monascopyridine D (357) red pigment (358) PP-V ((10Z)-12-carboxylmonascorubramine, 359)

PP-R ((10Z)-7-(2-hydroxyethyl)monascorubramine, 360) sclerotioramine (361) (+)-isochromophilone VI (362)

isochromophilone IX (363) isochromophilone X (364) isochromophilone XI (365) isochromophilone XII (366) 8-O-methylsclerotiorinamine (367) chaetoglobin A (368) chaetoglobin B (369) fleephilone (370) sequoiamonascin D (371) (5S)-3,4,5,7-tetramethyl-5,8-dihydroxyl-6(5H)-isoquinolinone (isoquinocitrinin A, 372) 3-((R)-sec-butyl)-7-carboxy-6,8-dihydroxy-2-(2-hydroxyethyl)-4methylisoquinolinium (fusarimine, 373)

producing strain

molecular formula

Nitrogenated Azaphilones Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus ruber Monascus purpureus Monascus purpureus Monascus sp. Monascus sp. Monascus sp. Monascus sp. Monascus purpureus DSM1379 Monascus purpureus DSM1379 Monascus purpureus Monascus kaoliang BCRC 31506 Monascus purpureus Monascus kaoliang BCRC 31506 Monascus ruber van Tieghem Penicillium sp. AZ

C27H31NO8 C25H27NO8 C34H38N2O6 C32H34N2O6 C32H37NO7 C30H33NO7 C31H43NO6 C29H39NO6 C34H41NO7 C32H37NO7 C26H33NO6 C25H29NO7 C27H34N4O8 C29H38N4O8 C23H25NO8 C25H29NO6 C28H35NO6S C32H41NO6 C29H37NO6 C29H37NO6 C21H25NO4 C23H29NO4 C20H27NO3 C22H31NO3 C19H28N2O5 C23H25NO6

Penicillium sp. AZ Penicillium citreonigrum Diaporthe sp. IFB-3lp-10 (endophytic) Penicillium multicolor FO-3216 Penicillium sp. MINAP9902 Penicillium sclerotiorum van Beyma Diaporthe sp. IFB-3lp-10 (endophytic) Penicillium sp. MINAP9902 Diaporthe sp. IFB-3lp-10 (endophytic) Diaporthe sp. IFB-3lp-10 (endophytic) Diaporthe sp. IFB-3lp-10 (endophytic) Penicillium multicolor Chaetomium globosum IFB-E019 (endophytic) Chaetomium globosum IFB-E019 Trichoderma harzianum WC47695 Aspergillus parasiticus RDWD1-2 (endophyte) Penicillium sp. JP-1 Penicillium sp. H9318 Fusarium sp. LN12 (endophytic)

C25H31NO5 C21H24ClNO4

ref 244 244 245 245 245 245 246, 247 246, 247 246 246 248 248 249 249 22 22 245 245 245 245 250 250 251, 252 109 251, 252 109 249 96, 253, 254

C13H15NO3

255 196 259 202 258 197 259 258 259 259 259 13 260 260 169 100 84 44

C17H21NO5

261

C23H28ClNO5

C25H30ClNO6 C29H32ClNO4 C27H30ClNO3 C31H33N2ClO4 C22H26ClNO4 C34H40N2O10 C36H44N2O11 C24H27NO7 C26H33NO7

2. AZAPHILONES

derivatives from nature. In addition, the general methods for

2.1. Citrinin and Its Derivatives

the synthesis of some natural azaphilone-like scaffolds are

Citrinin (1; Figure 1), the best known fungal mycotoxin, was first isolated from Penicillium citrinum in 1931.24 The structure was elucidated by the groups of Whalley and Cram at the end of the 1940s by extensive degradation studies.25 Subsequently, the absolute stereochemistry26 and tautomeric configuration27

described. We focus on work that has appeared in the literature up to September 2012. L


Chemical Reviews

Review

Citrinin (1), produced by several fungal species of genera Penicillium, Monascus, and Aspergillus, is widely considered as a hazardous contaminant of foods and feeds.29−35 Recently, 33 various derivatives of the citrinin family have been isolated from different P. citrinum strains and two Aspergillus species (Table 1 and Figure 1). On the basis of the degree of polymerization of the citrinin core, the derivatives can be classified into four different categories: (i) monomeric citrinin congeners 2−6, such as dihydrocitrinin (2)36−38 and decarboxydihydrocitrinin (3);39−42 (ii) citrinin dimers containing four to five rings, e.g., citrinin H1 (7),38 pennicitrinones A−D (8−11),39,43 pennicitrinols A and B (12, 13),37−39,44 penicitrinol F1 (14),45 and penidicitrinin B (17);46 (iii) 7,7′-carbon-bridged citrinin dimers, e.g., dicitrinones A−C (18−20);47 (iv) citrinin trimers containing six to seven rings, including unprecedented tricitrinols A (21) and B (22).45 Interestingly, 7, a newly isolated metabolite from a halotolerant fungus, P. citrinum B57,38 had been reported as an artifact in early 1993 as this was produced by the decomposition of 1 under aqueous conditions on heating.48 These studies indicated that citrinin might be a latent precursor of novel active compounds. 7 was found to be 10-fold more toxic than 1.48 Among the citrinin dimers, the dicitrinones A−C (18−20) were unprecedented 7,7′-carbon-bridged compounds, which were isolated from a volcano-ash-derived fungus, P. citrinum HGY1-5.47 18 and 19 were verified as two atropisomeric mixtures by both NMR and quantum chemical calculations.47 In addition, from the same fungal strain, three novel Diels− Alder coupling citrinin dimers, penicitrinol F1 (14) and dicitrinols A (15) and B (16) were also obtained.45 Seven new citrinin derivatives, penicitrinols C−E (23−25) and penicitrinols F−I (26−29), were produced by P. citrinum.49,50 Their structures were determined by X-ray diffraction analysis. Furthermore, two rare anthraquinone− citrinin derivatives, penicillanthranins A (30) and B (31), were isolated from P. citrinum PSU-F51.42 Perinadine A (32), a novel uncommon tetracyclic alkaloid isolated from P. citrinum N055, was elucidated by spectroscopic methods, including 2D NMR experiments.51 Aspergilones A (33) and B (34), two novel benzylazaphilone derivatives with an unprecedented carbon skeleton, were isolated from a marine-derived fungus Aspergillus sp.52 Their relative stereochemistries were elucidated by NMR spectroscopy and X-ray crystallography.52 2.2. Spiciferinone and Its Derivatives

Compounds of this type include five azaphilones, 35−39 (Table 1 and Figure 2). They have unique structural features in

Figure 2. Spiciferinone and related derivatives.

common: (i) a quaternary carbon bearing an ethyl, a methyl, and a ketonic carbonyl and (ii) vicinal methyls except pseudohalonectrin B (39). Two new phytotoxins, spiciferinone (35) and cochliospicin A (36), were produced by the phytopathogenic fungus Cochliobolus spicifer Nelson.53,54 The stereostructure of 36 was determined by X-ray analysis. Leptosphaerone (37) was extracted from Leptosphaeria sp. IV403, an endophytic fungus

Figure 1. Citrinin and its derivatives.

were resolved and confirmed in 1971 by X-ray diffraction studies. The tautomeric equilibrium of 1 in the solid state and in solutions was defined by 13C NMR analysis.28 M


Chemical Reviews

Review

Figure 3. Austdiol and its derivatives.

found in Artemisia annua55 and later from the aquatic fungus Pseudohalonectria adversaria YMF1.01019,56 together with a nematicidal azaphilone, pseudohalonectrin B (39). Fusarone (38) was isolated from an endophyte Fusarium sp. in Melia azedarach,57 and the absolute configurations of 37 and 38 were determined by means of CD spectroscopy.55,57

mangrove endophytic fungus Penicillium chermesinum (ZH4E2), and the absolute configuration of 56 was determined by Xray crystallography.72 By NMR techniques, Steyn and Vleggaar reinvestigated the structure of monochaetin (59),73 a metabolite previously produced by the fungus Monochaetia compta PRL 1754 in 197074 and revised to its new structure (Figure 4). Five angular azaphilones, deflectins A1a−1c (60− 62), B2a (63), and 2b (64), were isolated from the mycelia of Aspergillus deflectus.75

2.3. Austdiol and Its Derivatives

There are 13 compounds, 40−52, within this type (Table 1 and Figure 3). Austdiol (40), the main phytotoxin elaborated by Aspergillus ustus (Bainier) Thom and Church, was first isolated in 1974 by Vleggaar et al.,58 and subsequently dihydrodeoxy-8epi-austdiol (41) was also obtained.59 The structure, including the absolute configuration, of 40 was deduced by X-ray crystallographic data60 and possesses an aldehyde group at C-5, while the absolute configuration of 41 was established by CD spectra.59 Daldinins A (42) and B (43) were isolated from the fruiting bodies of the ascomycete Daldinia concentrica, and both contain a mixture of four fatty acid esters. Their absolute configurations were elucidated by CD spectra.61 A new antifungal compound, (3S)-4,6-dihydro-8-methoxy-3,5-dimethyl-6-oxo-3H-2-benzopyran (44), was isolated from Penicillium expansum.62 Two anticoccidial agents, arohynapenes C (45) and D (46), were produced by Penicillium sp. FO-2295.63−65 The major mycotoxin 3,7-dimethyl-8-hydroxy-6-methoxyisochroman (47) was produced by a marine-derived strain of Penicillium steckii.66 A new isochroman, 6-hydroxy-3-methylisochroman-5-carboxylic acid (48), was isolated from the culture of marine-derived mangrove fungus no. 1893.67 Penicisochromans D (49) and E (50) were isolated from the sea-fan-derived fungus Penicillium sp. PSU-F40.68 Another new metabolite, 4,5,6-trihydroxy-3-methyl-3,4,6,7-tetrahydro-1Hisochromen-8(5H)-one (51), was isolated from the culture broth of the aquatic fungus Delitschia corticola YMF 1.01111.69 Bisbynin (52) was a novel C-prenylated pentaketide isolated from the fungus Stachybotrys bisbyi (Srinivasan) Barron and structurally characterized by X-ray diffraction analyses.70

2.5. Bulgarialactones

This group of 10 compounds 65−74 (Table 1 and Figure 4) features an extensively conjugated or saturated aliphatic chain at C-3 and a linear γ-lactone ring on the azaphilone nucleus. From the ascomycete Bulgaria inquinans, bulgarialactone A−D (65− 68) were obtained.15,76 Four fungal pigments, pitholides A−D (69−72), were isolated from the culture of the tunicate-derived fungus Pithomyces sp.77 The absolute stereochemistry of 69 was determined by the modified Mosher method.77 Epicocconone (73) was isolated by Bell and Karuso from the fungus Epicoccum nigrum Link through bioassay-directed fractionation,78 using the ability of column fractions to fluorescently (λex = 365 nm) stain yeast cells. Its structure has been determined by 2D NMR, as well as molecular modeling of the (6R*,9aS*)-azaphilone nucleus. Compound 73 represents a new class of natural fluorescent probes and is a cell-permeable long Stokes shift fluorescent stain for live cell imaging and multiplexing applications.79 Acetosellin (74), a naphtopyrane derivative with a novel carbon skeleton, is a phytotoxic pigment of the phytopathogenic fungus Cercosporella acetosella Ell.80 The absolute configuration was determined by CD correlations. 2.6. Sequoiatones

This class of six compounds, 75−80, represent a new carbon skeleton that possesses a five-membered ring and lacks a γlactone ring except sequoiatone A (75) (Table 1 and Figure 4). Six antitumor compounds, sequoiatones A−F (75−80), were isolated from the redwood endophyte Aspergillus parasiticus.81,82 The absolute configuration of 75 was provided by X-ray crystallography, and the stereochemistry of 76 was determined by using both molecular mechanics geometry optimization and HyperChem PM3 semiempirical geometry optimization. 76 is a blue light-induced sporogenic substance that was isolated previously in 1989 from Penicillium funiculosum by Katayama et al., but not chemically charac-

2.4. Helotialins and Deflectins

This subgroup of azaphilones with 12 members is characterized by a ketone aliphatic chain at C-8, as in helotialins A−C (53− 55), as well as by an angular γ-lactone ring with a ketone aliphatic chain, as in deflectins 60−64 (Table 1 and Figure 4). The absolute configurations of 53−55, purified by bioassayguided fractionation of the culture of a helotialean ascomycete fungus, were assigned by the CD excitation chirality method.71 Chermesinones A−C (56−58) were isolated from the N


Chemical Reviews

Review

1926 by Eijiro Nishikawa from Monascus purpureus Mentii,88 and subsequent structural characterizations were achieved.86 Yellow II (85), a yellow pigment with a high content, was produced by a submerged culture of a mutant of Monascus sp.95 Two novel pigments, monascorubrin homologues PP-O (86) and PP-Y (87), were purified from a newly isolated strain of Penicillium sp. AZ.96 Red mold dioscorea is a fermented product of M. purpureus NTU 568 using dioscorea as the culture substrate, from which four new azaphilones with yellow fluorescence, monapilols A−D (88−91), were isolated.97 An azaphilone pigment, monascusone B (93), was isolated from a yellow mutant of Monascus kaoliang grown on rice.93 Monascuspiloin (92) and monascusazaphilol (94) were the new metabolites of two different strains of Monascus pilosus.98,99 Sequoiamonascin C (95) was isolated from a redwood endophyte, A. parasiticus.100 Two new yellow pigments with blue fluorescence, named monarubrin (96) and rubropunctin (97), were identified from the Monascus pigments and from the broth of Monascus ruber.101 Two new antiproliferative azaphilone derivatives, monaphilones A (98) and B (99), were isolated from the red mold rice fermented by mutant strain M. purpureus NTU 568.94 Three new cytotoxic azaphilones with a C20 skeleton, designated monapurones A− C (100−102), were obtained from M. purpureus-fermented rice. Their absolute configurations were determined by CD spectra.102 Two azaphilone derivatives, namely, biscogniazaphilones A (103) and B (112, Figure 6), were obtained from the endophytic fungus Biscogniauxia formosana BCRC 33718.103 2.8. Trichoflectin and Sassafrin Azaphilones

This subgroup of azaphilones with nine members is characterized by an angular lactone fused to a dihydroisochromenone ring (Table 1 and Figure 6), with a propenyl side chain and an acyl chain from the acetyl to the decanoyl unit. Trichoflectin (104) is a new deflectin derivative that was isolated by Anke et al. from submerged cultures of the ascomycete Trichopezizella nidulus A73-95.104 From M. purpureus pigments of hexanoic-supplemented cultures, R3 (105) was isolated and characterized by NMR data.105 Red yeast rice obtained as cultures of Monascus AS3.4444 on rice produced two new metabolites with strong blue fluorescence, monasfluores A (106) and B (107).106,107 Sassafrins A−C (108−110) are three antimicrobial metabolites of the stromata of the fungus Creosphaeria sassafras.108 The yellow mutant of M. kaoliang afforded one new compound, monascuskaolin (111), as a racemate, and its structure was elucidated by spectroscopic analyses.109

Figure 4. Deflectins and related azaphilones.

2.9. Hydrogenated Azaphilones

This group of compounds can be classified into four subgroups (Table 1 and Figure 7). They possess a benzoyl substitution on the C-6, C-7, or C-8 position, and some of them lack a benzoyl substitution on the same position. Table 1 indicates that this family of hydrogenated azaphilones are produced mainly by manifold species of genera Emericella, Hypoxylon, Penicillium, and Talaromyces. 2.9.1. Hydrogenated Azaphilones Missing the Benzoyl Moiety. Three UV-absorbing compounds, FK17-P2b1 (113), FK17-P2b2 (114), and FK17-P3 (115), from an Aspergillus sp. were previously patented.110 One azaphilone pigment, monascusone A (116), together with 114, was isolated from a yellow mutant of the fungus M. kaoliang.93 The absolute configuration of 116 was addressed by the use of Mosher’s ester.93

terized.83 More recently, 75 and 76 were also identified from a mangrove-derived endophyte, Penicillium sp. JP-1.84 2.7. O-Containing Monascus Pigments

This group of 23 azaphilones, also known as Monascus pigments, are usually composed of a 1H-isochromene skeleton connected with a propenyl side chain and an acyl chain from the acetyl to the decanoyl unit (Table 1 and Figure 5). Filamentous fungi of the genus Monascus are rich in azaphilone pigments.21 There are six major colorants, including two orange pigments, rubropunctatin (81)85 and monascorubrin (82),86 two yellow pigments, monascin (83)87,88 and ankaflavin (84), and two red pigments, rubropunctamine (322) and monascorubramine (323) (Figure 14). 21 82 and monascoflavin (83, also called monascin) were isolated in O


Chemical Reviews

Review

Figure 5. Rubropunctatin and monascorubrin azaphilones.

2.9.2. Mitorubrin with a 7-Benzoyl Group. This subclass of compounds, 120−162, features a benzoyl substitution on C7 (Figure 7). They include (−)-mitorubrin (120),116−118 (−)-mitorubrinol (121),118,119 (−)-mitorubrinal (122),118 and (−)-mitorubrinic acid (123).118,121,122 In addition, (+)-mitorubrin (124), (+)-mitorubrinol (125), (+)-mitorubrinol acetate (126), and (+)-mitorubrinic acid (127) and their derivatives have also been isolated from a variety of sources, such as Hypoxylon fragiforme.123,118 (−)- and (+)-Mitorubrin and related molecules have (R)- and (S)-configurations at C-7, respectively. Three potentiators of antifungal miconazole activity, monomethyl-(S)-mitorubrin (128), 4′-hydroxy-3′methoxy-(S)-mitorubrin (129), and 6′-hydroxy-3′-methoxymitorubrin (130), were obtained from the culture broth of Penicillium radicum FKI-3765-2.127 The structure of wortmin (131) is assigned as a new member of the mitorubrin group of metabolites, produced by Penicillium wortmanni,128 and a novel mitorubrin derivative named hypomiltin (132) was obtained from Hypoxylon hypomiltum.129 Kasanosins B (133) and C (134) are two novel azaphilones from cultures of a Talaromyces sp. isolated from seaweed130 and the plant endophyte Talaromyces sp. T1BF,125 respectively.125 Pinophilins A (135) and B (175), new inhibitors of mammalian A-, B-, and Y-family DNA polymerases, were reported from a fungus, Penicillium pinophilum Hedgcok, derived from a seaweed.131 Four new hydrogenated azaphilones named falconensins A− D (136−139) were obtained from the mycelia of a new ascomycetous fungus, Emericella falconensis, from Venezuelan soil.132 In 1996, Kawai and co-workers further isolated three new azaphilones, falconensins E−G (140−142), from the mycelia of E. falconensis and Emericella fruticulosa IFO 30841.133

Figure 6. Trichoflectin and sassafrin azaphilones.

Berkazaphilones A (117), B (135), and C (173) were newly discovered metabolites from an extremophilic fungus, Penicillium rubrum Stoll.111 (−)-Lunatoic acid A (118) was isolated as a chlamydospore-like cell inducer from Cochliobolus lunata113 and later as an inhibitor of GGTase I from Curvularia sp.114 118 and rubiginosin C (119), bearing an aliphatic ester side chain instead of an aromatic group, have been reported.112,115 The absolute configuration of 119 was established by CD spectroscopy.115 P


Chemical Reviews

Review

Figure 7. continued

Q


Chemical Reviews

Review

Figure 7. Hydrogenated azaphilones. R


Chemical Reviews

Review

Figure 8. continued

S


Chemical Reviews

Review

Figure 8. Chaetoviridins and chaetomugilins.

mitorubric acid, (−)-diazaphilonic acid (158), was reported from Talaromyces flavus, whose stereochemistry has not been determined.138 Two unprecedented dimeric azaphilones, named rutilins A (159) and B (160), were isolated from the stromata of Hypoxylon rutilum.135 Two novel phospholipase A2 inhibitors, ergophilones A (161) and B (162), were isolated from the culture broth of Penicillium sp. BM-99.139 They consisted of the ergostane skeleton and the azaphilone chromophore moieties. Their stereochemistries were established on the basis of CD analysis. 2.9.3. Mitorubrins with a 6- or 8-Benzoyl Group. The benzoyl substitution on C-6 or C-8 for azaphilones 163−175 is relatively rare (Table 1 and Figure 7); nine examples are benzoyl-substituted at C-6, whereas only four C-8 benzoylsubstituted examples have been encountered, such as

Reinvestigations of the antibacterial components of this fungus led to the isolation of an additional new metabolite, falconensin H (143).134 Subsequently, they reisolated another six minor dihydroazaphilones, namely, falconensins I−N (144−149), and a new relative, monomethyldihydromitorubrin (150), from two Emericella species.124 Their absolute configurations were confirmed by CD spectra and Mosher’s methods.132−134 Chemical investigation of the marine-sediment-derived fungus Penicillium commune yielded six new azaphilones, including 7-benzoylated comazaphilones A−C (152−154) and 6-benzoylated comazaphilones D−F (168−170).136 An acid-tolerant fungus, Penicillium purpurogenum, contained three new metabolites, purpurquinones A−C (155−157), and (−)-mitorubrin (120).137 Their absolute configurations were assigned on the basis of CD spectra. Additionally, a dimer of T


Chemical Reviews

Review

Ascochitine (176; Figure 7), a phytotoxic fungal metabolite, first isolated from cultures of Ascochyta pisi Lib. by Bertini,144 was later obtained from Ascochyta fabae Speg. by Oku and Nakanishi.145 The structure has been confirmed by spectroscopic analysis, chemical transformations, and synthesis.146 More recently, this compound was identified from the marine fungus Ascochyta salicorniae.147

Several series of chlorinated azaphilones have been reported recently from marine-fish-derived Ch. globosum OUPS-T106B6, including chaetomugilins A−F (194−199),153,154 11-epichaetomugilin A (200) and 4′-epichaetomugilin A (201),155 chaetomugilins G (202) and H (203),156 seco-chaetomugilins A (204) and D (205),157 chaetomugilins I−O (206−212),158 chaetomugilins Q (213) and R (214), and 11-epi-chaetomugilin I (216).159 The structures, including absolute configurations, of these chaetomugilins were elucidated on the basis of NMR techniques, CD spectra, X-ray analysis, and various chemical transformations. Interestingly, 194 and 197 were also obtained from the plant endophyte Ch. globosum by our group.160 The absolute stereostructure of 195 was determined through single-crystal X-ray analysis, CD spectra, and the modified Mosher method.153 In addition, the absolute configurations of C-8, C-8a, and C-12 in 214 were determined by the modified Mosher method to be all (S).158 200 is the first azaphilone that has an opposite absolute configuration at C-11 compared to that of other natural compounds of this class to date.159 Most recently, three metabolites, chaetomugilins S1 (217), T (218), and U (219), were produced by the same strain, and their absolute stereostructures were elucidated on the basis of CD spectra and degradation analysis. 161 Chaetomugilin P (215) was also discovered as a new unique skeleton with a methyl group at C-5 and no substituent at C7.158 In addition, the absolute configuration of chaetoviridin C (179) was established by derivatization from 194.156

2.11. Chaetoviridins and Chaetomugilins

2.12. Pulvilloric Acid-Type Azaphilones

These azaphilones include chaetoviridins or chaetomugilins that are characterized by a chlorine atom at C-5 except dechlorochaetomugilin A (218) and dechlorochaetomugilin D (219) and a methyl group at C-7 as well as a branched pentenyl side chain at C-3. There are 43 members within this family (Table 1 and Figure 8) that are widespread in Chaetomium sp.2c In 1990, Takahashi and co-workers first reported the isolation and identification of four new angular-type azaphilones, named chaetoviridins A−D (177−180), from the culture of the fungus Chaetomium globosum var. flavo-viride.148 The absolute stereochemistry of 177 was determined by CD spectra and single-crystal X-ray diffraction analysis. Chaetoviridins E (181) and B (178), antibiotic components from the mycelia of a cultured coprophilous fungus, Chaetomium sp.,149 were discovered, and structural revisions of 178 and 180 were made on the basis of detailed spectroscopic analysis by Kingsland and Barrow in 2009.149 From two strains of Chaetomium cochliodes, three new azaphliones, chaetoviridines E (182) and F (183) and epi-chaetoviridin A (184), were described.150 Six new chaetoviridin analogues, 5′-epichaetoviridin A (185), 4′-epichaetoviridin F (186), 12β-hydroxychaetoviridin C (187), and chaetoviridins G−I (188−190), were isolated from the plant endophyte Ch. globosum.151 The absolute configurations of chaetoviridin D (180), 185, 4′-epichaetoviridin A (184), and 189 were determined using the modified Mosher method.151 The dihydropyran ring of 190 could be produced in acidic conditions through the cyclization of the hydroxyl group attached to C-3′ at the C-1 of chaetoviridin A (177).151 Another three azaphilones, chaetomugilin S (191), 7,5′-bis-epi-chaetoviridin A (192), and 7-epi-chaetoviridin E (193), are the first examples with a (7R)-configuration from the lichen-derived fungal strain Chaetomium elatum.152 Their absolute configurations were assigned by CD experiments and X-ray crystallography.

This group of at least 15 compounds are characterized by an npentyl side chain at C-3 on an azaphilone skeleton (Table 1 and Figure 9).

(+)-mitorubrinic acid B (172). Deacetylisowortmin (163) was a new mitorubrin derivative from the culture of Trichoderma sp. MFF-1, an endophytic fungus inside the insecticidal plant Pyrethrum cinerariifolium.140 The fruit bodies of Hypoxylon rubiginosum contained three new azaphilone derivatives named rubiginosins A (164), B (151), and C (119).115 Three new azaphilones, entonaemins A−C (165−167), were isolated from the fruiting body of the rare inedible fungus Entonaema splendens.141 Although not stated explicitly in the literature,141 their absolute configurations were assumed on the basis of their co-occurrence with (+)-mitorubrinol acetate (126). Interestingly, 167 contains two different moieties of mitorubrin-like monomers that are not linked by a C−C bond as in the rutilins, but rather an ester bond.141 A new azaphilone, Sch725680 (173), was identified from the culture of an Aspergillus sp., and its absolute configuration was determined by the exciton chirality method.142 Sch 1385568 (174) was isolated from another Aspergillus sp., SPRI-0814.143 2.10. Ascochitine

Figure 9. Pulvilloric acid-type azaphilones.

2.12.1. Pulvilloric Acid Derivatives. Pulvilloric acid (220), a yellow antibiotic, was isolated in 1957 from acidified culture filtrates of Penicillium pulvillorum.162 Nine years later, its structure was elucidated on the basis of NMR data and chemical transformations.163,164 It is commonly produced by phylogenetically related Penicillium species.165 U


Chemical Reviews

Review

Figure 10. Chrysodin-type azaphilones.

Phomoeuphorbins A−D (221−224) are four azaphilone congeners isolated from cultures of Phomopsis euphorbiae, an endophytic fungus residing inside the petioles of the herbal medicine “maytansinoids-producing” Trewia nudiflora L.166 The structures of 221−224 were established by means of spectroscopic analyses, including 2D NMR techniques. T22 azaphilone (225) was the most abundant antibiotic of a commercial biopesticide, Trichoderma harzianum T22.167,168 Two novel azaphilones, harziphilone (226) and fleephilone (370; see Figure 14), were obtained by bioassay-guided fractionation of the broth from another fungal strain of Tr. harzianum.169 Six new antioxidative agents, cyathusals A−C (227−229) and cyathuscavins A−C (230−232), along with pulvinatal (233), were isolated from the culture of the basidiomycete Cyathus stercoreus.170,171 Compound 233 was previously reported from another basidiomycete, Nidularia pulvinata.172 2.12.2. Berkelic Acid. Berkelic acid (234; Figure 9), an architecturally unique isochroman spiroketal with selective anticancer activity, was isolated recently by Stierle and coworkers from an acid mine waste extremophilic Penicillium species.173 The structure was determined from the analysis of the NMR data and the analogous methyl ester of 234. The relative stereochemistry at C-22 and the absolute stereochemistry remained undetermined. However, subsequent total syntheses established this stereocenter as (S) and reassigned the absolute stereochemistry at C-18 and C-19 as shown.174−177

new azaphilone epoxide, was isolated from Penicillium urticae.179 2.13.1. Chrysodins. Two antifungal metabolites, CT2108A (237) and CT2108B (238), were discovered in Penicillium solitum CT2108.180 The structures of these new metabolites were determined using NMR experiments, as well as CD spectra. Two sphingosine kinase inhibitors, S-15183a and S15183b (239 and 240), were isolated from the broth of the fungus Zopfiella inermis SANK15 183.181 A novel isochroman carboxylic acid, CJ-12,373 (241), was isolated from Penicillium sp. CL22557. 182 Two new antimicrobial isochromans, pseudoanguillosporins A (242) and B (243), were produced by the red-algae-derived endophytic fungus Pseudoanguillospora sp. 6577.183 The absolute configurations of these two compounds were deduced from their CD spectrum, TDDFT CD calculations, and the Mosher NMR method.183 2.13.2. Cytosporolides. Cytosporolides A−C (244−246; Figure 10), three meroterpenoids, were isolated in 2010 from cultures of the fungus Cytospora sp. (Coelomycetes) isolated from a soil sample that was collected on the Qinghai-Tibetan plateau.184a The absolute configuration of the 5,6-diol moiety in 244 was assigned using Snatzke’s method.184b Very recently, the structure revision of 244−246 was supported by a biomimetic synthetic study, featuring a [4 + 2] cycloaddition reaction between a presumed o-quinone methide intermediate and β-caryophyllene and reinterpretation of spectroscopic data.185

2.13. Chrysodin-Type Azaphilones

2.14. Sclerotiorins and Related Azaphilones

There are 13 compounds of this chrysodin type (Table 1 and Figure 10), featuring a C7 side chain at C-3 on the azaphilone skeleton. Chrysodin (235) was the first example of this series produced by Sepedonium chrysospermum.178 Patulodin (236), a

The presence of a γ-lactone, a conjugated ketone, a chlorine atom at C-5, and a branched C7 side chain, namely, 3,5dimethyl-1,3-heptadiene, at C-3 on the isochromane skeleton was common in sclerotiorin-like compounds (Table 1 and V


Chemical Reviews

Review

Figure 11. continued

W


Chemical Reviews

Review

Figure 11. Sclerotiorin-type azaphilones.

natural acetonide unit, which was not an artifact. Its presence was determined by 2D NMR experiments. Chemical epigenetic manipulation of Atlantic-forest-soilderived Penicillium citreonigrum produced profound changes in the secondary metabolite profile of its guttate (fungal exudates), representing at least three distinct biosynthetic families.196 A combination of NMR and HRMS data facilitated the rapid dereplication of several azaphilones in solid-state fungal cultures, namely, sclerotiorin (247), ochrephilone (272), dechloroisochromophilone III (255), and dechloroisochromophilone IV (256).196 Moreover, from the culture broth of P. multicolor FO-2338, fermented in a KBr-containing medium, novel brominated and dehalogen azaphilone analogues 5bromoochrephilone (275) and 256 and the known derivatives 255 and isorotiorin (274) were isolated and identified.203 In addition to the major metabolite of Penicillium hirayamae, (−)-sclerotiorin (257), this organism also produced a red pigment, rubrorotiorin (271), which has been characterized by degradation and synthesis.204

Figure 11). Sclerotiorin and structurally related compounds were found to be isolated mostly from Penicillium species. Sclerotiorin (247) was first isolated in 1940 from Penicillium sclerotirium Van Beyma as a chlorine-containing fungal pigment by Curtin and Reilly,186,187 and its structure was established in 1959 by Waalley and co-workers.188 The absolute stereochemistry of (+)-sclerotiorin had until 1976 been defined by means of X-ray crystallographic analysis of its derivative Nmethylsclerotioramine.189 Interestingly, from the cultures of the spore-derived mycobionts of the lichen Pyrenula japonica, 247 was also obtained by Takenaka et al.191 Isochromophilones III−V (248−250) were isolated from the culture broth of Penicillium multicolor FO-3216,202 while isochromophilones VII (251) and VIII (252) were obtained from the culture broth of Penicillium sp. FO-4164.199 Two new azaphilone derivatives, penicilazaphilones A (253) and B (254), together with dechloroisochromophilone III (255) and (+)-sclerotiorin (247), were isolated from the endophytic fungus Penicillium sclerotiorum PSU-A13 found inside Garcinia atroviridis.195 Interestingly, 253 contained a X


Chemical Reviews

Review

From ascomycete Talaromyces luteus, five new azaphilones, named luteusins A (258), B (259), E (278), C (279), and D (280), were isolated by several groups.207−209 Furthermore, four new (7S,13S)-7-epi-sclerotiorin derivatives, named helicusins A−D (260−263), were separated from an EtOAc extract of Talaromyces helius.210 A series of azaphilones, isolated from P. sclerotiorum X11853, including two novel epi-sclerotiorin analogues, 264 and 265, as well as sclerotiorin (247), 258, rubrorotiorin (271), and ochrephilone (272), have been identified.190 Isochromophilones I (273) and II (269), the first novel gp120−CD4 binding inhibitors of microbial origin, isolated from a cultured broth of a soil fungus, P. multicolor FO2338, were elucidated by NMR experiments.212,198,213 During biosynthetic studies with [1,2-13C2]acetate on metabolites of P. multicolor NRRL 2060, 272 was first discovered by Seto and Tanabe.215 Interestingly, this pigment failed to react characteristically with ammonia, unlike other azaphilones. The structure was further supported by using the 13C−13C coupling in the labeled metabolite.215 From the culture broth of Penicillium sp. SPC-21609, nine azaphilones, RP-1551s, RP-1551-7 (266), RP1551-M2 (267), RP-1551-2 (268), RP-1551-3 (276), RP-15514 (277), RP-1551-1 (281), RP-1551-M1 (282), RP-1551-6 (283), and RP-1551-5 (284), were isolated.211 Three new azaphilones named rotiorinols A−C (286−288), two new stereoisomers, (−)-rotiorin (289) and epi-isochromophilone II (270), and rubrorotiorin (271) were isolated from the fungus Chaetomium cupreum CC3003.214 The absolute configuration of 286 was determined by the modified Mosher method214 along with an X-ray analysis of its acetate derivative, as well as by chemical transformation. Wang and co-workers have used a genomic mining approach to identify a new azaphilone-like polyketide,217 named asperfuranone (290), together with its intermediate from the culture of the Aspergillus nidulans AN1033.3 deletant. A gene cluster containing two fungal polyketide synthases in combination with five additional genes encodes the biosynthetic pathway of 290. Its absolute configuration was determined by a modified Mosher method.217

Figure 12. Multiformin and cohaerin azaphilones.

crystal X-ray diffraction.61 Daldinin D (306) is a new peracetylated spiroazaphilone derivative that was isolated from an isolate of Penicillium thymicola.223 Two additional antioxidative cyclic azaphilones, daldinins E (307) and F (308), were produced by the fruit bodies of Hypoxylon fuscum, in addition to daldinin C (305). Their structures were determined by 2D NMR and CD spectroscopy.224 Decipinin A (309), a new antimicrobial derivative of daldinin C, was obtained from liquid cultures of the coprophilous fungus Podospora decipiens JS 270. The structure of 309 was elucidated by analysis of 1D and 2D NMR data.225 Pestafolide A (310) is a new member of the reduced spiroazaphilone family that was purified by bioassay-guided fractionation of the solid cultures of the plant endophytic fungus Pestalotiopsis foedan. The absolute configuration of 310 was determined by application of the CD excitation chirality method.226 Compound 310 showed modest antifungal activity. Quite recently, three new spiroketals, named peneciraistins A−C (311−313), were isolated from the salinesoil-derived fungus Penicillium raistrickii.227 Among them, compounds 311 and 312 are rare benzannulate 6,6-spitoketals. Their absolute configurations were assigned by the modified Mosher method and CD excitation chirality method.227 Four new dimeric spiroazaplilones, cochliodones A−D (314−317), in addition to chaetoviridins E and F and epichaetoviridin A (184) were isolated from the fungi Ch. cochliodes VTh01 and Ch. cochliodes CTh05.150 The structures and stereochemistry of atropisomers 314−316 were deter-

2.15. Multiformins and Cohaerins

These compounds constitute a unique group of azaphilones with 14 members (Table 1 and Figure 12), bearing a 6methylcyclohexenone or a 6-methylphenol moiety at C-3, while some lack a γ-lactone ring, with varying aliphatic side chains at C-8 on an isochromane ring. Four new azaphilones, named multiformins A−D (291−294), were purified from the stromatal extract of Hypoxylon multiforme.218 Their absolute stereostructures were characterized by CD spectroscopy. Furthermore, four unprecedented azaphilones, named cohaerins C−F (295−298), were identified from Annulohypoxylon cohaerens.219 Four new cytotoxic azaphilones, designated longirostrerones A−D (299−302), have been isolated from the soil fungus Chaetomium longirostre.220 Two azaphilones, named cohaerins A (303) and B (304), were produced by Hypoxylon cohaerens. Their absolute structures were determined by CD spectroscopy.221,222 2.16. Hydrogenated Spiroazaphilones

This group of 17 compounds are characterized by an (O)N,Ospiroketal five- or six-membered ring system at C-3 on an azaphilone skeleton (Table 1 and Figure 13). Daldinin C (305), the first hydrogenated spiroazaphilone, was isolated from the fruiting bodies of the fungus D. concentrica61 and later from H. rubiginosum.115 Its structure was confirmed by singleY


Chemical Reviews

Review

Figure 13. Hydrogenated spiroazaphilones.

structures of sequoiamonascins A and B were deduced by interpretation of their spectral data and chemical reactions. Fusidilactone C (320), a structurally highly oxygenated unusual polycyclic lactone, with an oxoadamantane skeleton, a spiroacetal structure, and two ether-bridged hemiacetals was

mined by single-crystal X-ray diffraction analysis. 316 showed antimycobacterial activity against Mycobacterium tuberculosis. Another series of compounds with a new carbon skeleton, sequoiamonascins A (318) and B (319), have been isolated from the redwood tree endophyte A. parasiticus.100 The Z


Chemical Reviews

Review

Figure 14. continued

AA


Chemical Reviews

Review

Figure 14. Nitrogenated azaphilones.

Scheme 2. Proposed Mechanism for N-Containing Azaphilone Formation238−240

isolated from the fungal endophyte Fusidium sp. found in the leaves of Mentha arvensis. The structure of 320 was established by analysis of major 2D NMR experiments.228

that the protons attached to C-8, C-10, and C-13 all lie on the same side of the chromophore. Yao and co-workers accomplished the first total synthesis of chlorofusin (321) and by using all four unambiguous diastereomeric model chromophores as references revised the absolute stereochemistry of the chromophore unit to be (7S,4R,3S) by 1H NMR studies and asymmetric synthesis.233 The complete structure of natural chlorofusin was assigned for the first time. Recently, Boger and co-workers have assigned the (7R,4S,3R)-configuration of the chromophore by synthesis of 321 and its eight diastereomers of the chromophore−dipeptide conjugate and spectroscopic properties.234,235 Evidently, uniform consensus was lacking on the absolute stereochemistry of the azaphilone-derived chromophore in the molecule.

2.17. Chlorofusin

Inhibitors of key protein−protein interactions are emerging as exciting therapeutic targets for the treatment of cancer.229 In an effort to screen for inhibitors of p53−MDM2 interaction, Williams and co-workers isolated an architecturally complex cyclopeptide chlorofusin (321; Figure 13) as the most abundant inhibitor from the fungal strain Microdochium caespitosum, and its structure was identified on the basis of spectroscopic and chemical degradation methods.230 Chlorofusin (321) is structurally characterized by a cyclic peptide of nine amino acid residues containing an L-ornithine side chain that incorporates a densely functionalized azaphilone-derived chromophore.230 The original absolute stereochemistry of the cyclic peptide moiety was recently elucidated by chemical synthesis and NMR studies.231,232 However, the absolute stereochemistry assignment of the chromophore still remains unclear, although its relative configuration was deduced from spectroscopic studies, showing

2.18. Nitrogenated Azaphilones

This family of colorants includes 52 N-containing azaphilones (Table 1 and Figure 14), which can be mainly divided into (i) Monascus pigments and (ii) sclerotioramine colorants. These compounds were generated as a consequence of azaphilones reacting with endogenous ammonia or exogenous diverse amino compounds during the culture process.236,237 The reaction mechanism takes place with strong aminophiles, AB


Chemical Reviews

Review

effects on five human cancer cell lines. A new metabolite, 8-Omethylsclerotiorinamine (367), was isolated from a strain of P. multicolor, and its structure was established using NMR spectroscopy and chemical evidence.13 Chaetoglobins A (368) and B (369), two unprecedented azaphilone alkaloid dimers, were isolated from the extract of Ch. globosum IFBE019, an endophytic fungal isolate from the stem of Imperata cylindrical. The absolute configurations of the two metabolites were assigned by a combination of Mosher’s reaction and CD methods.260 Bioassay-guided fractionation of the Tr. harzianum broth led to isolation of a novel compound, fleephilone (370).169 Sequoiamonascin D (371), with a new carbon skeleton, was isolated from a redwood tree endophyte, A. parasiticus RDWD1-2,100 and later from a mangrove-derived endophyte, Penicillium sp. JP-1.84 More interestingly, two rare polyketide isoquinoline alkaloids, isoquinocitrinin A (372)44 and isoquinochitine A (373),261 were produced by the marine fungus Penicillium sp. H9318 and the plant endophyte Fusarium sp. LN-12, respectively. They are possibly biosynthesized via mixed routes.261 The absolute configuration of 373 was confirmed by X-ray crystallographic analysis.

amino acids, and dipeptides via a Schiff base formation and dehydration reaction (Scheme 2).22,238−240 2.18.1. N-Containing Monascus Pigments. N-containing Monascus pigments commonly consist of an isoquinoline skeleton with an n-octanoyl or an n-hexanoyl side chain, a 1propenyl chain, and a γ-lactone ring. Most of the pigments are various amino acid derivatives of monascorubrin (82) and rubropunctatin (81),236 of which rubropunctamine (322) and monascorubramine (323) were earlier discovered as major components in the genus Monascus.241,242 The culturing of both M. ruber and M. purpureus A on a chemically defined medium using glutamic acid as a nitrogen source yielded two pigments, N-glutarylrubropunctamine (324) and N-glutarylmonascorubramine (325), which were linked to glutamic acid by amino groups.29 Similarly, the fungus M. ruber in a submerged culture produced two water-soluble red pigments, N-glucosylrubropunctamine (326) and N-glucosylmonascorubramine (327).243 Eight major pigments (328−335), which contain L- and Damino acid residues, have been isolated from commercial Monascus pigments. These pigments were identified as alanine or aspartate derivatives of monascorubrin (82) and rubropunctatin (81).244 Further cultivations of Monascus pigments made with aromatic and nonpolar aliphatic L- and D-amino acids afforded eight red pigments, 336−343.245−247 The Monascus pigment threonine derivatives 344 and 345 and arginine derivatives 346 and 347 were identified as new red pigments produced by M. ruber.248,249 Furthermore, cultivation of M. purpureus resting cells with glycine has been found to give the dark red substances 348 and 349.22 In addition, new derivatives of Monascus pigments were formed during fermentation by the addition of unnatural amino acids. For example, the derivatives containing penicillamine (H-Pen, 353), cyclohexylalanine (H-Cha, 351), butylglycine (L-t-Bg, 352), and norleucine (H-Nle, 350) were reported.245 Recently, four unique homologues, monascopyridines A−D (354−357), were obtained from M. purpureus DSM1379fermented rice in addition to pigments and citrinin (1).250−252 The latter two compounds have the same general chromophores and differ in a missing γ-lactone ring only. Another new red pigment (358) from M. ruber, which was linked to lysine, lacks a lactone unit as well.249 Two novel pigments, monascorubramine homologues PP-V (359) and PP-R (360), were isolated from a strain of Penicillium sp. AZ.96,253−255 2.18.2. Sclerotioramine Pigments. This group of pigments are composed of an isoquinoline skeleton with a branched heptyl side chain. Chemical epigenetic manipulation of an Atlantic-forest-soil-derived P. citreonigrum produced a highly colored substance, sclerotioramine (361),196 which was reported previously as a semisynthetic derivative of sclerotiorin (247).256,257 In particular, 361 was first obtained as a natural product.196 One new azaphilone, namely, isochromophilone VI (362), was isolated from the culture broth of P. multicolor FO-3216, in addition to isochromophilones III−V (348−350),202 and later from an isolate of P. sclerotiorum van Beyma.197 The antibiotic isochromophilone IX (363), obtained from the mycelia of Penicillium sp., represents the first novel metabolite containing a γ-aminobutyric acid unit.258 Most recently, three additional new azaphilone compounds, isochromophilones X−XII (364−366), together with sclerotioramine (361) and 362, were isolated from the culture of an endophytic fungus, Diaporthe sp. IFB3lp-10.259 Compound 364 alone showed moderate inhibitory

3. CHEMICAL SYNTHESES OF AZAPHILONES AND RELATED COMPOUNDS Because of the interesting structural features and biological properties of azaphilones, a number of synthetic efforts concerning azaphilones have been reported. In general, pyronoquinones and pyrylium salts have been employed as highly important intermediates or precursors for the synthesis of azaphilones.18,19,262,263 3.1. General Synthetic Protocol for Azaphilone Scaffolds Based on Transition-Metal-Catalyzed Cycloisomerization of o-Alkynylbenzaldehyde

A general synthetic route for the azaphilone 374 is outlined in Scheme 3. This approach makes use of readily available alkynes Scheme 3. General Synthetic Method for the Azaphilone Core Structure263−265

to construct azaphilones with different side chains at C-3. Sonogashira coupling of 2-bromobenzaldehyde 375 with alkynes may provide o-alkynylbenzaldehyde 376.263 Transition metal as a Lewis acid (Au(III) and Cu(II)) catalyzed cycloisomerization of the resulting 376 to 2-benzopyrylium salts 377 and subsequent oxidation by using o-iodoxybenzoic acid (IBX) yielded the desired isochromene ring systems 378.264−266 Finally, acylation of tertiary carbinol 378 afforded azaphilone derivative 374. There are two methods for the AC


Chemical Reviews

Review

oxidation of 2-benzopyrylium salts 377 to form the azaphilone nuclei: lead tetraacetate262,263 and IBX.264,265 The general synthetic method for azaoxaspirane 379 is shown in Scheme 4. Generally, the intermediate pyrylium salts

Scheme 5. First Synthesis of (±)-Ascochitine by Galbraith and Whalley272,a

Scheme 4. General Synthetic Method of Azaoxaspirane267,268

Reagents and conditions: (a) Na, liquid NH3, Fe(NO3)3, C6H6− ether, then MeI; (b) concd H2SO4, then KOH, EtOH−H2O; (c) (COCl)2, C6H6; (d) MeCH2(Me)CHMgBr, ether, reflux; (e) HBr (48%), AcOH, reflux; (f) KHCO3, CO2, glycerol, 150 °C; (g) CH(OEt)3. a

382 are derived from the formyl ketones 381, which were prepared from appropriately substituted benzylic halides 380 in the presence of acid catalysts HCl (g), P2O5, concd H2SO4, pTsOH, and HClO4.216,268 The intermediates can be transformed into the isochromene ring systems 383 by oxidations.262,263 Vinylogous γ-pyridone 384 could be easily prepared through treatment of 383 with a primary amine. The five-membered N,O-spiroketal azaoxaspiranes 379 could be formed from 384 by a cyclization reaction, such as an oxidative spirocyclization (AgNO3, H2O−DMSO, and I2) or an intramolecular electrophile-mediated cyclization.235

lation, to provide bromoacetone 394. The Wittig reaction as a critical step gave dienone 396, which went through deacetylation and condensation with CH(OEt)3 in p-TsOH, followed by chlorination with SO2Cl2 in methylene chloride, to furnish the keto formyl 397. Treatment of 397 with P2O5 in ethanol followed by oxidation of pyronoquinone 398 with Pb(OAc)4 in acetic acid afforded 247 in poor yield (Scheme 6). Similarly, the reaction of tetrahydro formyl ketone 399 with HCl in ether, followed by Pb(OAc)4 oxidation of the resultant pyrylium salt 400 in acetic acid in poor yield, provided 392 (Scheme 6).273

3.2. Synthesis of Citrinin

In 1986, a stereoselective synthesis of (±)-citrinin (1) using toluate anion chemistry was published by Barber et al.,269 and an asymmetric total synthesis of the unnatural enantiomer (+)-citrinin was announced by Regan and Staunton in 1987.270 The first enantioselective total synthesis of (−)-citrinin was not achieved until Rodel and Gerlach reported their Grignard approach in 1995.271 These studies on the synthesis of 1 were recently reviewed by Brase et al. in 2009.6

3.5. Enantioselective Synthesis of (+)-Sclerotiorin and (+)-8-O-Methylsclerotiorinamine

Most recently, Porco and co-workers have reported the first enantioselective syntheses of (+)-sclerotiorin (247) and (+)-8O-methylsclerotiorinamine (367).274 Treatment of 401 with N,N,N′-trimethylethylenediamine, followed by ortho-lithiation of the amino alkoxide intermediate with n-BuLi and subsequent treatment with 1,2-diiodoethane, yielded the protected iodobenzaldehyde. Deprotection with BBr3 proceeded to produce iodobenzaldehyde 402 in three steps. Sonogashira coupling of 402 with (trimethylsilyl)acetylene, followed by silyl deprotection, gave o-alkynylbenzaldehyde 403 in 80% yield. oAlkynylbenzaldehyde 403 was subjected to Sonogashira conditions with vinyl iodide 404 to afford benzaldehyde 405 in 55% yield. Copper-mediated asymmetric dearomatization of 405 followed by cycloisomerization using bis-μ-oxocopper complex 406 prepared from (+)-sparteine surrogate and acylation and chlorination of the resultant azaphilone 407 provided 247 in 49% yield over four steps. Notably, siteselective O-methylation of vinylogous pyridone 408 with (trimethylsilyl)diazomethane in a mixture of CH2Cl2−MeOH (9:1) led to quantitative formation of (+)-8-O-methylsclerotiorinamine (367) (Scheme 7).

3.3. First Synthesis of (±)-Ascochitine by Galbraith and Whalley

The first synthesis of racemic (±)-ascochitine (176) was published by Galbraith and Whalley in 1971.272 Methylation of 3,5-dimethoxybenzyl cyanide (385) with methyl iodide− sodium−liquid ammonia afforded the benzyl cyanide 386, which underwent successive acidic and basic hydrolysis to give the acid 387. Interaction of the acid chloride 388 with 2butylmagnesium bromide in dry ether provided the ketone 389, which was demethylated with HBr to the phenol 390. Further conversion into the acid 391, which was treated with CH(OEt)3, afforded 176 (Scheme 5). 3.4. Synthesis of (±)-Sclerotiorin by Whalley and Co-workers18

In the early 1970s, Whalley and co-workers developed a route to the syntheses of (±)-sclerotiorin (247) and (±)-tetrahydrosclerotiorin (392).18 The synthesis of 247 began with starting material 3,5-dihydroxy-4-methylbenzoic acid (393), which underwent a series of reactions, including benzylation, the Arndt−Eistert reaction, diazotization, hydrolysis, and debenzy-

3.6. Concise Synthesis of (+)-Sclerotiorin and 7-epi-Sclerotiorin and Their Analogues

Wang and co-workers developed a two- to three-step semisynthetic route to access (+)-sclerotiorin (247) and its AD


Chemical Reviews

Review

Scheme 6. Synthesis of (±)-Sclerotiorin by Whalley and Co-workers18,a

Reagents and conditions: (a) ref 18; (b) PPh3, propene oxide, CH2Cl2, under N2, then 1,2-dichlorobenzene, 130 °C; (c) 5% NaOH, MeOH, N2; (d) (i) CH(OEt)3, p-TsOH, benzene−ether (3:1), N2; (ii) ether−propene oxide, SO2Cl2, CH2Cl2; (e) P2O5, EtOH; (f) Pb(OAc)4, AcOH; (g) HCl, ether.

a

Scheme 7. Synthesis of (+)-Sclerotiorin (247) and (+)-8-O-Methylsclerotiorinamine (367) by Porco et al.274,a

Reagents and conditions: (a) N,N,N′-trimethylethylenediamine, n-BuLi, THF, 0 °C, 30 min; n-BuLi, THF, −20 °C, then 1,2-diiodoethane; BBr3, CH2Cl2; (b) CuI, (trimethylsilyl)acetylene, (t-Bu)3P−HBF4, PdCl2 (MeCN)4, diisopropylamine, rt, then K2CO3, MeOH, rt; (c) Pd(PPh3)4, CuI, Et3N, rt; (d) Cu(CH3CN)4PF6, N-ethyl-(+)-sparteine mimic 406, DIEA, DMAP, O2, −78 to −10 °C; (e) aq H2PO4/K2HPO4 buffer (pH 7.2), CH3CN, rt; (f) Ac2O, DMAP, DIEA, 0 °C, 30 min; (g) NCS, CH3CN, rt; (h) NH4OAc, MeOH; (i) (TMS)CHN2, CH2Cl2−MeOH (9:1). a

AE


Chemical Reviews

Review

Scheme 8. Short Synthesis of (+)-Sclerotiorin (247) and 7-epi-Sclerotiorin (257) and Their Analogues by Wang and Coworkers275,a

a

Reagents and conditions: (a) p-TsOH, AcOH, 95−100 °C; (b) Pb(OAc)4, AcOH; (c) NCS, NBS, or NIS, MeCN.

3.8. Total Synthesis of (±)-Mitorubrin

analogues starting from an advanced, putative azaphilone intermediate, 409, overproduced by an engineered strain of A. nidulans.275 Treatment of 409 with p-TsOH gave the 2benzopyrilium salt 410, which was then oxidized by Pb(OAc)4 to generate the nonhalogenated azaphilone 411. Electrophilic chlorination of azaphilone 411 introduced a chlorine atom at C-5 by using NCS to afford the natural products 247 and 7-episclerotiorin (257) (1:1) in 61% yield (Scheme 8), which were separated by chiral HPLC.

In the early 1970s, Whalley and co-workers reported the total synthesis of (±)-mitorubrin (120) in 11 steps.262 Reaction of bromoketone 423 with acetaldehyde through the Wittig process gave conjugate ketone 424, which was treated with aq HCl followed by debenzylation with BCl3 at −70 °C to furnish ketone 425. Percolation of the chloroketone via alumina yielded an enone which was rapidly converted by treatment with CH(OEt)3−HCl followed by precipitation with ether to aldehyde 426. This aldehyde was transformed into the pyronoquinone 427 with P2O5 followed by oxidation with Pb(OAc)4 in AcOH to give azaphilone 428. Exposure of 428 to 2,4-(dibenzyloxy)-6-methylbenzoic acid in TFA and subsequent debenzylation with BCl3 at −70 °C afforded 120 (Scheme 10).

3.7. Synthesis of 3-Methylazaphilone

Suzuki and co-workers reported an efficient synthesis of four 7(alkanoyloxy)azaphilones, 414−417, in poor yield over seven steps (overall yields of 6−26%).263 The synthesis started from 2-methylresorcinol (418). Ketone 419 was obtained via five steps in 53% overall yield. Formylation of 419 with CH(OEt)3 using ACl3 as a catalyst in dry toluene gave formyl ketone 420 in 72% yield. The reaction of 420 with p-TsOH followed by Pb(OAc)4 oxidation in various carboxylic acids via the key intermediate 2-benzopyrylium salt 421 and/or pyronoquinone 422 afforded 3-methylazaphilones 414−417 (Scheme 9). In contrast, in solvent oleic acid (±)-daldinin A (42) was not obtained.

Scheme 10. Total Synthesis of (±)-Mitorubrin (120) by Whalley and Co-workers262,a

Scheme 9. Synthesis of 3-Methylazaphilone by Suzuki and Co-workers263,a

a Reagents and conditions: (a) Ph3P; (b) HCl, then BCl3, CH2Cl2; (c) Al2O3, then CH(OEt)3, HCl; (d) P2O5, then Pb(OAc)4, AcOH; (e) EtONa; (f) (CF3CO)2O; (g) BCl3, −70 °C.

a

Reagents and conditions: (a) CH(OEt)3 (triethyl orthoformate), ACl3, toluene; (b) p-TsOH, RCOOH; (c) Pb(OCOR)4, AcOH. AF


Chemical Reviews

Review

Scheme 11. Concise Route to the Azaphilone Core of (±)-Mitorubrinic Acid (123) by Pettus and Co-workers19,a

a Reagents and conditions: (a) (i) Boc2O, DMAP, i-Pr2NEt; (ii) DIAD, PPh3, HO(CH2)2(TMS), 92%; (b) LDA,THF, TMEDA, Weinreb acetamide (431), −78 °C; (c) NaH, THF, 0 °C, 1 drop of t-BuOH; (d) (i) DIBAL-H, THF, −78 °C; (ii) ZnBr2, MeNO2; (e) (i) p-TsOH, AcOH; (ii) IBX, TBAI, 57% (two steps).

Scheme 12. Total Synthesis of (±)-Mitorubrinic Acid (123) by Pettus and Co-workers19,a

Reagents and conditions: (a) (i) SeO2, anhydrous dioxane, reflux; (ii) Ph3PCHCO2-t-Bu, CH2Cl2; (b) (i) DIBAL-H, THF, −78 °C; (ii) pTsOH, MeOH; (iii) TBAF, THF; (c) (ClCH2)2−TFA (20:1), °C; (d) IBX, TBAI; (e) (i) Yamaguchi conditions; (ii) 3 M HCl−dioxane, reflux. a

3.9. Total Synthesis of (±)-Mitorubrinic Acid

employing IBX/TBAI, esterification, and global deprotection to yield 123 (Scheme 12).

Pettus and co-workers reported a total synthesis of (±)-mitorubrinic acid (123) in 12 steps.19 The key steps involved elaboration and oxidative dearomatization of an isocoumarin intermediate to provide the azaphilone core with a disubstituted, unsaturated carboxylic acid side chain. The synthesis began with the methyl benzoate 429 via two protections to afford the ester 430. Introduction of N,N,N′,N′-tetramethylethylenediamine prior to the Weinreb acetamide (431) provided the ketoester 432 in 81% yield, which underwent cyclization to give the intermediate 433. Subsequent selective reduction of 433 with DIBAL-H in THF at −78 °C followed by global deprotection gave the keto 434. Treatment of 434 with p-TsOH followed by IBX oxidation in the presence of tetrabutylammonium iodide (TBAI) yielded the azaphilone core 436 (Scheme 11). The preparation of (±)-mitorubrinic acid (123) started from the intermediate 433. Allylic oxidation of 433 with selenium dioxide and subsequent homologation with Wittig’s reagent afforded (E)-tert-butyl ester 437, which underwent selective reduction using DIBAL-H and subsequent desilylation with TBAF to give the ketal 438 in 80% yield over the three steps. Conversion of 438 with TFA led to the benzopyrylium salt 439, which was subjected to oxidative dearomatization

3.10. Asymmetric Syntheses of (−)-Mitorubrin and Related Azaphilones

Zhu and Porco reported the asymmetric syntheses of (−)-mitorubrin (120) and related natural products276 (−)-mitorubrinol (121), (−)-mitorubrinal (122), and (−)-mitorubrinic acid (123). This synthesis involved the use of enantioselective copper-mediated oxidative dearomatization methodology to assemble the azaphilone nucleus 446 and olefin cross-metathesis to install the side chains. Mitorubrin core 446 was prepared from a key intermediate enyne benzaldehyde, 443, that was produced by two Sonogashira couplings starting from the readily available aryl bromide 442 using [(−)-sparteine]2Cu2O2 (444)-mediated, enantioselectively oxidative dearomatization followed by Cu(I)-catalyzed cycloisomerization. Treatment of 446 with protected orsellinic acid utilizing DMAP as the catalyst yielded the precursor 448, which was submitted to global deprotection using BCl3, affording 120 in 70% yield (Scheme 13). Furthermore, syntheses of (−)-mitorubrinol (121), (−)-mitorubrinal (122), and (−)-mitorubrinic acid (123) were successfully achieved from 448 via side chain installation utilizing olefin cross-metathesis (Scheme 14). Unfortunately, AG


Chemical Reviews

Review

3.12. Biomimetic Synthesis of (−)-S-15183a and Unnatural Azaphilones Based on Copper-Mediated Enantioselective Oxidative Dearomatization

Scheme 13. Asymmetric Syntheses of (−)-Mitorubrin (120) and Related Azaphilones by Zhu and Porco276,a

More recently, Porco and co-workers reported the biomimetic synthesis of the azaphilones employing copper-mediated enantioselective oxidative dearomatization of o-alkynylbenzaldehydes.278 The methodology was successfully applied to the synthesis of (−)-S-15183a (239) and several unnatural azaphilones. The enantioselective oxidative dearomatization mediated by Cu2[(−)-sparteine]2O2 (444) with o-alkynylbenzaldehyde 460 as a substrate afforded the vinylogous acid 466. After aq KH2PO4/K2HPO4 buffer-mediated cycloisomerization, azaphilone core structure 467 of 239 was obtained in 98% ee (84% yield) (Scheme 17). Likewise, copper-mediated asymmetric oxidation−cycloisomerization of diverse o-alkynylbenzaldehydes 468−472 yielded the corresponding azaphilones 473−477 (Table 2).278 In addition, o-alkynylbenzaldehyde 472 containing a terminal NH-Boc substituent was used to convert to tricyclic aminoazaphilone 477 after Boc deprotection. 3.13. Enantioselective Synthesis of (+)-Harziphilone

Sorensen and co-workers have developed an enantioselective synthesis of (+)-harziphilone (226) based on the biomimetic pathway of polyenes, using DABCO-catalyzed cycloisomerization (Scheme 18).279a To secure a doubly activated unsaturated diketone, 478, its preferred pathway commences with an asymmetric reduction of commercially available 2-methyl-2-cyclopenten-1-one (479) by the method of Corey, Bakshi, and Shibata (CBS).279b Through multiple reactions, including silylation of the secondary alcohol, highly diastereoselective dihydroxylation of the ring alkene, acetonide protection of the vicinal diol, an oxidative ring cleavage, chemoselective reaction of the aldehyde group, and Dess−Martin oxidation, the desired enone 478 was thus produced (Scheme 19).279a Compound 478 contains two additional electron-deficient carbon atoms that could cause undesired reactivity. Fortunately, however, the direct transformation of an acyclic polyene diketone, 478, to (+)-harziphilone (226) was achieved in the presence of a nucleophilic catalyst, 1,4-diazabicyclo[2.2.2]octane (DABCO), in 70% yield (Scheme 20).279 The process of this assisted bicycloisomerization is rationalized as follows: The nucleophilic catalyst DABCO adds reversibly to the highly reactive enone moiety of 478 to yield a Baylis−Hillman-like zwitterion, 484. Formation of an intramolecular C−C bond could then produce an allenolate ion and subsequently the putative zwitterion 485 via a proton transfer. After a simple β-elimination reaction, a final 6πelectrocyclization of the resulting 486 affords (+)-harziphilone (226). Alternatively, the oxacyclic ring of 226 could result from 485 by an intramolecular substitution of a DABCO neutral molecule.

Reagents and conditions: (a) Pd(PhCN)2Cl2, CuI, P-t-Bu3·HBF4·iPr2NH, (trimethylsilyl)acetylene, THF, 90%; (b) K2CO3, MeOH, 90%; (c) Pd(PPh3)4, CuI, trans-1-bromo-1-propene, Et3N, THF, 86%; (d) [(−)-sparteine]2Cu2O2 (444), i-Pr2NEt, DMAP, CH2Cl2, −78 to −10 °C; (e) CuI, i-Pr2NEt, CH2Cl2, 58% for two steps, 97% ee; (f) protected orsellinic acid, (COCl)2, cat DMF, then i-Pr2NEt, DMAP, CH2Cl2, 56%; (g) BCl3, CH2Cl2, −78 to −20 °C, 70%. a

however, an exception is that cross-metathesis of 448 with protected cis-2-butene ether 449 in the presence of Grubbs catalyst 450 or 451 failed to give the desired product 453. 3.11. Synthesis of Azaphilone (±)-S-15183a and Related Molecules

Pettus and co-workers have developed a concise route to diverse azaphilone scaffolds by using a gold-mediated cycloisomerization of o-alkynylbenzaldehydes.277 Synthesis of the oalkynylbenzaldehyde 460 was accomplished in six steps starting from commercially available 3-methylbenzaldehyde 456, including a key Sonogashira coupling of 442 with 1-nonyne (Scheme 15). The cycloisomerization reaction of o-alkynylbenzaldehyde 460 in the presence of gold(III) acetate gave rise to rapid formation of 2-benzopyrylium salt 461 at room temperature in 1,2-dichloroethane/TFA. Oxidation of the 2-benzopyrylium salt 461 with IBX in the presence of TBAI formed the azaphilone nucleus 462. Acylation of 462 afforded (±)-S-15183a (239) (Scheme 16). Furthermore, halogenation of 462 was investigated by Porco and co-workers since a number of natural azaphilones contain bromine or chlorine at C-5. Treatment of azaphilone 462 with NCS afforded chloroazaphilone 463a in MeCN, whose structure was confirmed by single-crystal X-ray analysis. Similarly, bromoazaphilone 463b and iodoazaphilone 463c were also obtained from the corresponding halogenation of alcohol 462. Acylation of 463a generated acetate 464 or angular azaphilone 465, which is a derivative of the natural trichoflectin (104) (Scheme 16).

3.14. Synthesis of Vinylogous γ-Pyridones Mediated by Sc(OTf)3

Recently, Chruma et al. prepared a series of azaphilone αbromoacetates (AzαB’s) on the basis of Porco’s procedures278 and the vinylogous γ-pyridones (Scheme 21).280 Direct treatment of AzαB 487a with benzylamine in MeCN afforded the vinylogous γ-pyridone 488 in low yield. However, after the addition of acid Sc(OTf)3 in MeCN in the presence of a nucleophilic thiol, e.g., dodecylthiol, transformation of AzαB 487a to 488 was performed in 10 min in good yield (Table 3). AH


Chemical Reviews

Review

Scheme 14. Asymmetric Syntheses of (−)-Mitorubrinol (121), (−)-Mitorubrinal (122), and (−)-Mitorubrinic Acid (123) by Zhu and Porco276,a

a

Reagents and conditions: (a) 20 mol % Grubbs second-generation catalyst 450 or Hoveyda−Grubbs catalyst 451, CH2Cl2, reflux; (b) DIBAL-H, BF3·Et2O, CH2Cl2, −78 °C; (c) BCl3, CH2Cl2, −78 to −20 °C; (d) MnO2, acetone, rt.

Scheme 15. Synthesis of o-Alkynylbenzaldehyde (460) by Pettus and Co-workers277,a

Scheme 16. Synthesis of Azaphilone (±)-S-15183a (239) and Related Molecules by Pettus and Co-workers277,a

Reagents and conditions: (a) Cu(NO3)2·3H2O, Ac2O, rt; (b) Pd/C, H2, THF, rt; (c) Br2, HOAc, rt; (d) NaNO2, concd HCl, THF/H2O, −5 °C; H3PO2, 0−40 °C; (e) BBr3, CH2Cl2, −78 °C to rt; (f) [PdCl2(PPh3)2], 1-nonyne, CuI, Et3N, DMF, 60 °C. a

3.15. Diastereoselective IBX Oxidative Dearomatization of Phenols by Remote Induction: Toward the Epicocconone Core Framework

Reagents and conditions: (a) Au(OAc)3 (5 mol %), (ClCH2)2−TFA (10:1), rt; (b) IBX, 5 mol % Bu4NI, rt, then satd Na2S2O3; (c) CH3(CH2)6COCl, i-Pr2NEt, DMAP, CH2Cl2, rt; (d) NCS, MeCN, rt; (e) NBS, MeCN, rt; (f) NIS, MeCN, rt; (g) Ac2O, Et3N, DMAP, CH2Cl2, rt; (h) Ac2O, Et3N, DMAP, rt, CH2Cl2; (i) Ac2O, Et3N, DMAP, CH2Cl2, rt. DMAP = 4-(dimethylamino)pyridine, NCS = Nchlorosuccinimide, NBS = N-bromosuccinimide, NIS = N-iodosuccinimide.

Most recently, Franck and co-workers described the first IBXmediated diastereoselective oxidative dearomatization of phenols with remote induction and showed the dramatic effect of water on this reaction for synthesis of the epicocconone (73)

core framework.281 The retrosynthetic pathway of dihydropyranic azaphilones of 73 is outlined in Scheme 22.

a

AI


Chemical Reviews

Review

Scheme 17. Biomimetic Synthesis of (−)-S-15183a (239) by Porco and Co-workers278,a

Scheme 19. Transformation of Polyene Diketone 478 by Sorensen and Co-workers279,a

a Reagents and conditions: (a) Cu(CH3CN)4PF6, (−)-sparteine, DIEA, DMAP, O2, CH2Cl2, −78 to −10 °C; (b) aq KH2PO4/ K2HPO4 buffer (pH 7.2), CH3CN, rt.

a

Reagents and conditions: (a) (S)-2-methyl-CBS-oxazaborolidine, BH3·SMe2, THF, 0 °C, 90% ee; (b) TBS, imidazole, 4-DMAP, CH2Cl2; (c) OsO4, 4-methylmorpholine N-oxide, i-PrOH, 0 °C, 98% ee; (d) 2-methoxypropene, 10-camphorsulfonic acid, CH2Cl2; (e) nBu4NF, THF; (f) SO3·pyridine, DMSO, Et3N, CH2Cl2; (g) Ac2O, pyridine, 4-DMAP, 80 °C; (h) K2OsO2(OH)4, NaIO4, t-BuOH/H2O; (i) Me3SiCHN2, MeOH/benzene; (j) K2CO3, MeOH, CH3COC(N2)PO(OMe)2; (k) lithium diisopropylamide (LDA), THF, −78 °C; sorbaldehyde, −78 °C to rt; (I) Et3SiCl, imidazole, CH2Cl2, rt; (m) LiN(OMe)Me, THF, −78 °C; (n) vinylmagnesium bromide, THF; (o) n-Bu4NF, AcOH, THF; (p) Dess−Martin periodinane, NaHCO3, CH2Cl2; (q) TFA/H2O (1:1), 0 °C.

Table 2. Enantioselective Synthesis of Diverse Azaphilones278

Scheme 20. Nucleophile-Catalyzed Cycloisomerization Permits a Concise Synthesis of (+)-Harziphilone (226) by Sorensen and Co-workers279,a

a

Isolated yield for two steps. bIsolated yield for three steps. a

Scheme 18. DABCO-Catalyzed Cycloisomerization of Polyene 478 by Sorensen and Co-workers279a

Reagents and conditions: DABCO, CHCl3, rt.

Scheme 21. Synthesis of Vinylogous γ-Pyridones Mediated by Sc(OTf)3 by Chruma et al.280,a

The synthesis of phenol 497 commenced from 1,3dimethoxytoluene (491), which reacts with i-PrNCO in the presence of AlCl3 to provide the amide 492 and the subsequent trapping of the organometallic species with epoxide 493. The resulting alcohol 494 was subjected to lactonization in the presence of camphorsulfonic acid, followed by deprotection

a

Reagents and conditions: (a) ref 278, alkyne; (b) (BrCH2CO)2O; (c) BnNH2, Sc(OTf)3, MeCN.

AJ


Chemical Reviews

Review

Table 3. γ-Pyridone Formation280

azaphilone (500) and cyclic peptide (501) components (Scheme 24). Scheme 24. Disconnection of Chlorofusin (321)

AzαB

R1NH2

solvent

time

yield (%)

487a (R = C7H15) 487a (R = C7H15) 487b (R = Ph)

BnNH2 NH2-Gly-Phe-OMe NH2-Gly-Phe-OMe

MeCN MeCN THF

10 min 2−3 h 3h

86 95 93

Scheme 22. Retrosynthetic Pathway of Dihydropyranic Azaphilones

3.16.1. Total Synthesis of Chlorofusin. Yao and coworkers reported the first total synthesis of chlorofusin (321).233 Synthesis of 502 started from o-alkynylbenzaldehyde 503, which was prepared from 2-bromobenzaldehyde 442. The enantioselective copper-mediated oxidation of the aldehyde 503 with Cu2-[(−)-sparteine]2O2 (444) and subsequent treatment with aq NH4Cl in MeCN afforded azaphilone 504 (91% ee). Acylation of the tertiary alcohol of 504 followed by selective chlorination with SO2Cl2 at room temperature provided chloroester 506. Basic hydrolysis of 506 was conducted using K2CO3 in MeOH, resulting in chloroazaphilone 502 in 80% yield. Next, treatment of (S)-chloroazaphilone 502 with free peptide 501 smoothly afforded 321 (Scheme 25). 3.16.2. Total Synthesis of Chlorofusin Azaphilone and Its Chromophore Diastereomers. Boger and co-workers also reported the total synthesis of chlorofusin (321) and the establishment of its chromophore absolute stereochemistry.234 They developed the approach to the chloroazaphilones 507 and 508, beginning with the one-carbon elongation of commercially

with AlCl3, leading to diphenol 495 in 95% yield. Reprotection of compound 495 with (MOM)Cl provided MOM ether 496, followed by a DIBAL-H reduction to lactol 497. Oxidative dearomatization of lactol 497 was then carried out with IBX in the presence of TFA/water (7:20) afforded diketone alcohol 490 in 48% yield with excellent diastereoselectivity (dr up to 90:10). In the presence of Et3N, lactol 490 was heated with dioxin-4-one 498 to generate acylfuranone 499 as the major diastereomer in 86% yield (Scheme 23). Scheme 23. Diastereoselective Synthesis of the Epicocconone Core Framework by Franck and Coworkers281,a

Scheme 25. Total Synthesis of Chlorofusin (321) by Yao and Co-workers233,a

a

Reagents and conditions: (a) i-PrNCO, AlCl3; (b) t-BuLi/TMEDA, then 3; (c) CSA (camphorsulfonic acid)−toluene, reflux; (d) AlCl3; (e) NaH, (MOM)Cl (methyl chloromethyl ether); (f) DIBAL-H, toluene, −78 °C; (g) CH2Cl2, TFA/H2O, then IBX; (h) toluene, 100 °C, then Et3N.

3.16. Synthesis of Chlorofusin

In 2009, Boger and co-workers presented an overview of the isolation, total synthesis, and structure elucidation of chlorofusin (321).14 Herein, we provide some representative synthetic examples of 321 as follows. 321 is disconnected into

a

Reagents and conditions: (a) Cu(CH3CN)4PF6, (−)-sparteine, DIEA, DMAP, O2, CH2Cl2; (b) MeCN, aq NH4Cl; (c) n-PrCOCl, DMAP, pyridine, CH2Cl2; (d) SO2Cl2, CH2Cl2, rt; (e) K2CO3, MeOH; (f) cyclopeptide 501, NBS, MeCN, rt. AK


Chemical Reviews

Review

available benzoic acid 509. Alkylation of the chloride of the acid 509 with BtCH2(TMS) followed by treatment with 2,6-lutidine and Tf2O produced the triflate 510 in high yield, which was treated with NaOMe to yield methyl ester 511, with subsequent acidic hydrolysis of the resulting ynamine in 95% yield. After transformation to Weinreb amide 512 in excellent yield with NHMe(OMe), addition of the lithium reagent derived from 513 to the amide 512 provided ketone 514 in 90% yield. Selective demethylation of 514 using BBr3, BF3·Et2O, AlCl3, LiI, (TMS)I, or PhSH failed since cleavage of the silyl ether took place preferentially. However, on treatment of 514 with (TMS)I under microwave irradiation, the methyl ethers were removed and the TIPS-protected primary hydroxyl group was replaced with iodide to obtain the ketone 515 in high yields. Formylation of 515 generated ketone−benzaldehyde 516 in good yield, and one-pot oxidative cyclization of 516 in HOAc provided the azaphilone 517 in the presence of p-TsOH and Pb(OAc)4. Similarly, conducting the same reaction in butyric acid produced 518. Displacement of the iodide of 517 and 518 with AgOAc afforded 519 and 520, whose chlorination at C-6 with NCS yielded the chloroazaphilones 507 and 508 (Scheme 26).

Scheme 27. Synthesis of Chlorofusin Diastereomers by Boger and Co-workers235,a

a

Reagents and conditions: (a) BnNH2, CH2Cl2; (b) K2CO3, MeOH− H2O, 0 °C; (c) I2, AgNO3, DMSO, H2O.

Scheme 28. Synthesis of Chlorofusin Diastereomers by Boger and Co-workers235,a

Scheme 26. Synthesis of Chlorofusin Chloroazaphilones 507 and 508 by Boger and Co-workers234,a

a

Reagents and conditions: (a) butylamine, CH2Cl2; (b) K2CO3, MeOH−H2O, 0 °C; (c) I2, AgNO3, DMSO, H2O. a Reagents and conditions: (a) (i) SOCl2; (ii) BtCH2(TMS), THF, reflux; (iii) 2,6-lutidine, Tf2O, CH2Cl2, 0−23 °C; (b) (i) NaOMe, MeCN, reflux; (ii) HCl, MeOH, reflux; (c) i-PrMgCl, NH(OMe)Me, THF, −20 °C; (d) t-BuLi, −78 °C, Et2O−THF; (e) (TMS)I, MeCN, 120 °C, microwave; (f) AlCl3, CH(OEt)3, toluene, −45 to −15 °C; (g) p-TsOH, Pb(OAc)4, HOAc or butyric acid; (h) AgOAc, HOAc, 55 °C; (i) NCS, HOAc, 23 °C, 24 h. Bt = benzotriazole.

of the methyl ester by Furstner,174 the first total synthesis of berkelic acid was reported by Snider.175 Further total and formal syntheses have since been reported by the groups of De Brabander,176 Pettus,282 and Brimble.283 In 2010, Brimble et al. presented an excellent review on the synthesis of benzannulated spiroketal natural products, including 234.284 We herein present two examples of the synthesis of this molecule. 3.17.1. Enantioselective Formal Synthesis of Berkelic Acid. The retrosynthetic strategy of Snider’s berkelic acid advanced intermediate 523 is outlined in Scheme 29, in which deprotection of the benzyl and TBS ethers of isochroman 524 under acidic conditions would result in spiroketalization to form 523. In 2011, Brimble and co-workers reported an enantioselective formal synthesis of berkelic acid (234). This was completed by preparation of Snider’s advanced intermediate 523. The key steps involve a silyl enol ether−oxonium coupling followed by debenzylation under acidic conditions to afford the

3.16.3. Synthesis of Chlorofusin Azaphilone and Its Diastereomers. Oxidative azaspirocyclization of chlorofusin azaphilone 507 or 508 using Porco’s methodology277 with I2 assisted by AgNO3 in the presence of H2O−DMSO provided all four diastereomers (520A−D or 522A−D) of a simplified chlorofusin chromophore (Schemes 27 and 28). 3.17. Synthesis of Berkelic Acid

The potent biological activity and remarkable structural architecture of an extremophile natural product, berkelic acid (234), have led to a number of efforts toward its total synthesis. After reassignment of the relative stereochemistry by synthesis AL


Chemical Reviews

Review

Scheme 29. Retrosynthetic Strategy of Snider’s Berkelic Acid (234)

Scheme 30. Synthesis of Lactol 525 and Ether 526 by Brimble and Co-workers285,a

desired thermodynamically favored tetracyclic spiroketal configuration as a single diastereoisomer (Scheme 30). Synthesis of lactol 525 commenced from the known benzoic acid 527 by benzyl protection of the carboxylic acid and two phenolic groups in seven steps. The preparation of silyl enol ether 526 was completed from amide 532 through synthesis of the key lactone 533 (Scheme 30). Then addition of methyllithium to lactone 533 and treatment of the resulting adduct with KO-t-Bu and (TBS)Cl gave methyl ketone 534. The formation of silyl enol ether with (TMS)OTf and Hunig’s base proceeded smoothly to afford 526. Under these conditions, debenzylation, spiroketalization of the lactol 525, and thermodynamic equilibration occurred in one pot to afford spiroketal 536 as a single diastereoisomer in 58% yield from 534. Finally, the formal synthesis of berkelic acid (234) was completed by reaction of 537 with allyl bromide (Scheme 31). 3.17.2. Scalable Total Synthesis of (−)-Berkelic Acid (234) by Using a Protecting-Group-Free Strategy. Fañanás et al. reported a scalable total synthesis of (−)-berkelic acid (234) by using a protecting-group-free strategy in a sevenstep linear sequence.286 In this synthesis, the tetracyclic core of 234 was constructed in just one step from very simple starting materials and all but the last step were performed on a gram scale. Preparation of the key building blocks 538 and 539 was achieved in a concise way from commercially available starting materials. Specifically, fragment 538 was synthesized from chiral alcohol 540 in just three conventional conversions (Scheme 32). Thus, initial mesylation of alcohol 540 yielded the corresponding product 541, which was subjected to an SN2 displacement reaction by diethyl malonate in the presence of cesium fluoride to furnish the diester 542. Finally, reduction with LAH afforded diol 538 (2.8 g) in 70% overall yield and 96% ee. Preparation of fragment 539 was also achieved in three steps (Scheme 32). Namely, treatment of ester methyl 2,4,6trihydroxybenzoate (543) with triflic anhydride provided compound 544. A Sonogashira-type cross-coupling reaction of this intermediate with the potassium trifluoroborate salt derived from 1-heptyne led to alkyne 545 in high yield. Finally,

a

Reagents and conditions: (a) BnBr, K2CO3, acetone, reflux; (b) LiOH, THF/H2O, 0 °C to rt; (c) EDC, DMAP, NEt3, HCl− HN(Me)(OMe), CH2Cl2, rt; (d) n-pentenylmagnesium bromide, THF, rt; (e) (i) (R)-2-methyl-CBS-catecholborane, EtNO2, −78 °C, (ii) H2, PtO2, EtOAc, rt; (iii) Amberlyst-15, CH2Cl2, rt; (f) DIBAL, CH2Cl2, −78 °C; (g) MeLi, THF, −78 °C; (h) KO-t-Bu, (TBS)Cl, THF rt; (i) (TMS)OTf, i-Pr2NEt, CH2Cl2, 0 °C.

Scheme 31. Formal Synthesis of (−)-Berkelic Acid (234) by Brimble and Co-workers285,a

Reagents and conditions: (a) BF3·Et2O, CH2Cl2, −78 to 0 °C, then 526, −78 °C; (b) H2, Pd/C, HCl, MeOH−EtOAc, rt; (c) allyl bromide, K2CO3, DMF, rt. a

introduction of an initial hydroxymethylation with formaldehyde in the presence of CaCl2 followed by oxidation with MnO2 afforded the fragment 539 (4.8 g) in 60% overall yield. AM


Chemical Reviews

Review

new reactive pyran ring, hydrogenation of the C−C double bond of this pyran ring was directly conducted in the presence of Pd/C. Notably, the desired product 549 (2.4 g) was obtained as the major diastereoisomer (dr = 2:1) in just one step with 83% yield. Further treatment of alcohol 549 with PPh3 and I2 gave the iodide 550 (1.6 g) in 52% yield and enantiomerically pure form. Finally, reaction of 550 with cyanohydrin 551 furnished the diester 552 (1.2 g) in 88% yield. The diester was treated by using (Bu3Sn)2O on a small scale for the selective cleavage of the benzylic ester, providing 25 mg of 234 in one batch (Scheme 33).

Scheme 32. Preparation of the Key Building Block 538 by Fañanás et al.286,a

4. BIOLOGICAL ACTIVITIES OF AZAPHILONES AND RELATED COMPOUNDS As stated above, azaphilones of this family are known to exhibit a wide variety of significant biological activities,8 such as inhibitions of gp120−CD4 binding,12 Grb2− SH2 interaction,13 MDM2−p53 interaction,14 Hsp90,15 and dihydrofolate reductase,16 as well as antimicrobial, antiviral, cytotoxic, anticancer, and anti-inflammatory activities.8,17,287 Their potent biological activities may be related to the reaction of the 4Hpyran nucleus with amines to produce the corresponding vinylogous 4-pyridones. Here we briefly survey the bioactivities of this class of compounds, as well as structure-activity relationships (SARs) and mechanisms of action.

Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b) diethyl malonate, CsF, THF, 45 °C; (c) LAH, THF, 75 °C; (d) Tf2O, 2,6lutidine, CH2Cl2, rt; (e) potassium trifluoro(hept-1-yn-1-yl)borate, DIPEA, [PdCl2(dppf)] (5 mol %), MeOH, 65 °C; (f) CHO, CaCl2·2H2O, KOH, MeOH, rt, and then MnO2, CH2Cl2, rt. DIPEA = N-ethyl-N,N-diisopropylamine, dppf = 1,1′-bis(diphenylphosphino)ferrocene, LAH = lithium aluminum hydride, Ms = methanesulfonyl, Tf = (trifluoromethyl)sulfonyl. a

Next, the new silver-catalyzed cycloisomerization of fragments 538 and 539 by AgOTf and subsequent formal cycloaddition reaction between the in situ formed intermediates 546 and 547 proceeded to give product 548 (Scheme 33). To avoid possible decomposition of 548 due to the presence of the

4.1. Inhibitors of the p53−MDM2 Interaction

Inhibiting the key MDM2−p53 protein−protein interaction is emerging as exciting therapeutic targets for the treatment of cancer.288 Williams and co-workers reported chlorofusin (321) inhibits the p53−MDM2 interaction from Mi. caespitosum.230 321 antagonized p53−MDM2 binding (IC50 = 4.7 μM) by directly binding to the N-terminal domain of MDM2,289 but was inactive against the TNFα−TNFα protein−protein interaction and showed no cytotoxicity against Hep G2 cells at 4 μM. As such, chlorofusin represents an exciting lead for antineoplastic intervention that acts by a disruption of a protein−protein interaction.14,290 Significant SAR studies on the inhibition of p53−MDM2 binding showed the following (Table 4):231,232,291,292 (i) the relative or absolute stereochemistry of the chromophore (e.g., 321, 553−559) played little or no role in inhibition of this binding; (ii) the chromophore moiety in 321 was removed (e.g., 560) or replaced by bulky hydrophobic amine protecting groups (e.g., 561−563), which led to a marked reduction in activity (IC50 > 100 μM); (iii) replacement of the chlorofusin cyclic peptide with a smaller dipeptide (e.g., L-Orn9-L-Thr1 of chlorofusin) resulted in a loss of activity (e.g., 564−567) (IC50 > 150 μM).

Scheme 33. Scalable Total Synthesis of (−)-Berkelic Acid (234) by Fañanás et al.286,a

4.2. Inhibitors of Heat Shock Protein 90

Interest in the Hsp90 molecular chaperone as a therapeutic target is related to its central role in correct folding and stabilization of proteins involved in malignant behavior and tumor progression.293 A series of 12 natural products, bulgarialactones A−D (65− 68), rubropunctatin (81), monascorubrin (82), monascin (83), ankaflavin (84), deflectins 60, 61, 63, and 64, and 11 semisynthetic derivatives, 568−577 (Figure 15) and 327, were found to be a new class of heat shock protein Hsp90 inhibitors.15 Among them, 66 showed high affinity for Hsp90 by interacting with the 90−280 region of the N-terminal

Reagents and conditions: (a) AgOTf (5 mol %), THF, 0 °C, and then H2, Pd/C (5 mol %), MeOH, −5 °C; (b) I2, PPh3, imidazole, Et2O− MeCN (3:1), rt; (c) (i) 551, LDA, DMPU, THF, −78 °C, and then 550; (ii) TBAF·3H2O, MeOH, rt; (d) (Bu3Sn)2O, toluene, 115 °C. a

AN


Chemical Reviews

Review

Table 4. Inhibition of p53−MDM2 Binding (IC50, μM) by Chlorofusin (321) Derivatives

Figure 15. Structures of synthetic compounds 568−577.

isomer chlorofusin (321) 553 554 555 560, R = NH2 561, R = NHCbz 564, R1 = Bu 565, R1 = H2N-Orn-ThrOBn

IC50 8 10 8 24 >100 140 250 150

isomer 556 557 558 559 562, R = NHBoc 563, R = NHSES 566, R1 = Bu 567, R1 = H2N-Orn-ThrOBn

and 576, with the same tricyclic system and the same N-benzyl moiety, exerted enhanced Hsp90 binding, 576 showing the highest data (IC50 = 4 nM). The reduced potency for 66 in antiproliferation was in agreement with a low affinity for Hsp90. Interestingly, 81 and 82 showed strong binding to Hsp90 (IC50 = 0.27 and 0.04 μM, respectively). Compounds 569−577 and 327 were generally stronger than the natural products in the Hsp90 inhibitory potency. Also, the deflectins 60, 61, 63, and 64 and their analogue 577, all possessing an angular structure, gave a deleterious effect on Hsp90 binding and antiproliferative properties. Compound 66 was shown to give in vivo activity against an ascitic ovarian carcinoma xenograft, thereby confirming this new series of Hsp90 inhibitors as potential therapeutic agents.

IC50 8 18 16 8 150 150 170 150

4.3. Anti-HIV Activity

4.3.1. HIV-1 gp120−CD4 Binding Inhibitors. Blocking of human immunodeficiency virus (HIV) entry, which begins with highly specific binding of the HIV gpl20 envelope protein with cellular CD4 receptors on the surface of most susceptible cells, is one of the most important targets for HIV therapies.294 Isochromophilones I (273) and II (269) were the first novel gp120−CD4 binding inhibitors of microbial origin, from P. multicolor (IC50 = 6.6 and 3.9 μM, respectively).212,198,213 Isochromophilone II (269) at 25 μM significantly inhibited HIV replication in peripheral human lymphocytes. Subsequently, a series of natural and synthesized sclerotiorin analogues were evaluated for the inhibition of gp120−CD4 binding.213 5-Bromoochrephilone (275) is the strongest inhibitor (IC50 = 2.5 μM). These results indicated that a 5halogen atom, an 8-proton, and a conjugated diene moiety in the C-3 side chain of the 6-oxoisochromane ring are important for gp120−CD4 binding12 and that a 7-hydroxyl group may be

domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR.15 In addition, all the natural azaphilones tested had various antiproliferative effects on a panel of human tumor cell lines (IGROV-1, JR8, A431, and STO),15 of which 65 and 66 and hexahydrobulgarialactone B (568) were the most potent (IC50 ≤ 10 μM). Synthezied analogues 569−577 and 327 led to an increase in the antiproliferative activity. Among the open-ring analogues 569−573, compound 569, containing an N-benzyl group, was the most potent (IC50 = 0.3 μM for A431 and 0.2 μM for IGROV-1), whereas 569−573 produced modest binding to Hsp90, comparable to that of 66.15 Notably, 575 AO


Chemical Reviews

Review

suppresses DNA gyrase at a stage distinct from the religation step. This compound inhibits not only prokaryotic DNA gyrase, but also eukaryotic topoisomerase II-mediated relaxation and shows an antimicrobial efficacy attributable to its DNA gyrase inhibition.182 4.5.2. Protein Phosphatase Inhibitors. Protein phosphatases have emerged as promising drug targets for a wide range of diseases. For example, protein tyrosine phosphatase 1B (PTP1B) is involved in type 2 diabetes.300 Inhibition of the My. tuberculosis protein tyrosine phosphatase B (mPTPB) reduces mycobacterial survival in IFN-γ-activated macrophages and in guinea pigs, which is considered to be a promising target for a pulmonary tuberculosis cure.301 In silico screening identified ascochitine (4) from the marine fungus As. salicorniae as a potential inhibitor of protein phosphatases.147 It was found to inhibit the enzymatic activity of mPTPB (IC50 = 11.5 μM) and PTP1B (IC50 = 38.5 μM). 4.5.3. Inhibitors of Lipoxygenase and Aldose Reductase. Sclerotiorin (247) was found to be a potent reversible, uncompetitive inhibitor against soybean lipoxygenase-1 (LOX1) (IC50 = 4.2 μM).193 It also exerted an antioxidant property by scavenging free radicals (ED50 = 0.12 μM) and inhibited nonenzymatic lipid peroxidation (PD50 = 64 μM), but showed no metal chelation. 247 was revealed to inhibit LOX by two possible pathways, by interacting with the enzyme−substrate complex and by quenching or trapping the free radical intermediates produced in the enzyme reaction.193 In screening for LOX-1 inhibitors, sclerotiorin analogues dechlorosclerotiorins 578 and 581 exhibited the highest LOX-1 inhibition (Table 5), while 579 and 580 showed similar inhibition activities,275 in low micromolar potency. A preliminary SAR study indicates the importance of the C-8 ketone for the activity.

effective for the inhibition, but that an 8-carbonyl group is inactive.295 4.3.2. Inhibitors of HIV REV−RRE Binding. HIV-1 REV protein regulates the transport of viral RNA to the cytoplasm, and thereby, it is indispensable for HIV replication.169 REV function is depentent upon the interaction between REV and the REV-responsive element (RRE) in the envelope region. Inhibitions of this interaction could be a new target in the discovery of anti-HIV agents.296 Harziphilone (226) and fleephilone (370) from Tr. harzianum have been demonstrated to block the interaction of the REV proteins−RRE RNA complex (IC50 = 2.0 and 7.6 μM, respectively).169 4.3.3. HIV Inhibitors. Of the isolated helotialins A−C (53− 55), identified from a helotialean fungus, compounds 53 and 54 in vitro displayed inhibitory effects on HIV-1 replication in C8166 cells (EC50 = 8.01 and 27.9 μM, respectively), but 55 is inactive. It has been suggested that the C-13/C-14 olefin could play an important role in activity.71 4.4. Inhibitors of the Grb2−Shc Interaction

The growth factor receptor-bound protein-2 (Grb2) is an important adaptor protein in the mitogenic Ras signaling pathway of receptor tyrosine kinases, consisting of one Src homology 2 (SH2) domain and two SH3 domains. The SH2 domain binds to specific phosphotyrosine motifs on receptors or adaptor proteins such as Shc.297 The SH2 domain antagonists may lead to blocking of the oncogenic Ras signals and to development of new antitumor agents. During a search for SH2 domain antagonists from natural sources, the first nonpeptidic inhibitors, slerotiorin (247) and isochromophilone IV (249), from P. multicolor F1753, significantly antagonized the binding between the Grb2-SH2 domain and phosphopeptide derived from the Shc protein (IC50 = 22 and 48 μM, respectively).192 Meanwhile, 8-Omethylsclerotiorinamine (367) from the same fungus strongly inhibited the binding between the Grb2-SH2 domain and the phosphopeptide derived from the Shc protein and also disrupted the Grb2−Shc interactions in cell-based assays (IC50 = 5.3 and 50 μM, respectively).13

Table 5. Lipoxygenase-1 Inhibitory Activity275

4.5. Enzyme Inhibition

compound

4.5.1. Topoisomerase II Inhibitors. Type II topoisomerases are key enzymes involved in transcription, DNA replication, and nucleoid segregation.298 Prokaryotic topoisomerase II (DNA gyrase) is an important target for developing antibacterial agents; the eukaryotic topoisomerase II is a clinically proven target for more effective anticancer agents.299 Fifteen citrinin analogues from P. citrinum HGY1-5 were evaluated for their cytotoxicity.46 The six-membered ring A system of dimers dicitrinols A (15) and B (16) and trimers tricitrinols A (21) and B (22) is crucial for the cytotoxicity. 22 displayed cytotoxic activity against 17 cancer cells (IC50 = 1−10 μM) and potential anti-multi-drug-resistance abilities and caused cell apoptosis in HL60 and HCT116 cells through primarily extrinsic pathways and G2/M arrest. Further studies revealed that 22 acts as an intercalating topoisomerase IIα poison, which suppresses the enzymatic activity of topoisomerase IIα and induces DNA damage.46 22 constitutes a novel family of topoisomerase IIα-inhibitory skeletons for development of new chemotherapeutic agents. CJ-12,373 (241) from Penicillium sp. has suppressed both DNA gyrase-mediated supercoiling and relaxation without the formation of a cleavage intermediate. This indicates that 241

(+)-sclerotiorin (247) asperfuranone (290) dechlorosclerotiorin (578) 7-epi-sclerotiorin (257) 5-bromosclerotiorin (579) deacetylsclerotiorin (580) deacetyl-5-bromosclerotiorin (581)

IC50 (μM) 7.8 ± >100 4.9 ± 2.3 ± 6.8 ± 7.9 ± 3.2 ±

2.4 3.3 0.9 4.5 3.9 1.5

Aldose reductase, the first key enzyme in the polyol pathway, is involved in complications of diabetes. Sclerotiorin (247) potently suppressed aldose reductase (IC50 = 0.4 μM).194 4.5.4. Inhibitors of Lipase, HMG-CoA Reductase, αGlucosidase, and Acyl-CoA:ACAT. Compounds containing penicillamine (H-Pen, 353), cyclohexylalanine (H-Cha, 351), butylglycine (L-t-Bg, 352), and norleucine (H-Nle, 350) were reported to have strong inhibitory activities against lipase.245 Among them, H-Pen showed the strongest inhibitory activity (IC50 = 24.0 μM). The four compounds all displayed noncompetitive inhibition patterns against lipase. H-Pen also highly inhibited α-glucosidase (IC50 = 50.9 μM). The inhibition profile of H-Pen against α-glucosidase appeared to be of a mixed type. Chermesinone A (56) from P. chermesinum showed a mild inhibitory effect on α-glucosidase (IC50 = 24.5 μM).72 AP


Chemical Reviews

Review

sclerotiorin (247) (IC50 = 19.4 μM). Rotiorin (285), chaetoviridin A (177), and rubrorotiorin (271) had moderate inhibitory activity (IC50 = 30−40 μM), but others showed little activity. The SAR studies indicated that the presence of an electrophilic ketone(s) and/or enone(s) at both C-6 and C-8 positions in the isochromane ring is essential for eliciting activity.

Eight red pigments containing amino acid residues had strong inhibitory activities against a porcine pancreatic lipase,245−247 with low IC50 data (61.2 and 103 μM) for L -Trp and D-Tyr derivatives 336 and 337, and 338 and 339, respectively, and with lower IC50 data (12.2 and 13.8 μM) for LLeu-OEt and L-Tyr-OEt derivatives 340 and 341, and 342 and 343, respectively. The L-Leu-OEt analogues 340 and 341 revealed some specificity for porcine pancreatic lipase, but no high activities with other digestive enzymes. The Monascus pigment threonine derivatives 345 and 344, and rubropunctatin (81) and monascorubrin (82), had high inhibitory activities of 38% and 36% on HMG-CoA reductase, respectively, and regulated the cholesterol level in mice.248 Isochromophilones III−V (248−250) and isochromophilone VI (362) from P. multicolor were shown to be inhibitors of acylCoA:cholesterol acyltransferase (ACAT), which is thought to be one of the promising inhibition sites for the treatment of atherosclerosis and hypercholesterolemia.202 The L-Leu-OEt analogues 340 and 341 exhibited higher in vitro inhibitory activities against HMG-CoA reductase and lipoprotein lipase than the L-Trp analogues 336 and 337. An in vivo test showed the L-Trp derivative to exert higher antiobesity effects than the L-Leu-OEt derivative.302 Jou et al. recently studied the effect of Monascus metabolites monascin (83) and ankaflavin (84) on adipogenesis and lipolysis activity in 3T3-L1 and demonstrated their antiobesity effects by inhibiting differentiation of preadipocytes, and by promoting lipolysis of mature adipocytes.303 4.5.5. Inhibitors of Sphingosine Kinase. In the course of screening for inhibitors of sphingosine kinase, two active compounds named S-15183a and S-15183b (239 and 240) were discovered in Z. inermis.181 They inhibited sphingosine kinase from rat liver (IC50 = 2.5 and 1.6 μM, respectively). In addition, 239 also inhibited endogenous sphingosine (SPH) kinase activity in intact platelets. 239 is a potent and specific inhibitor of mammalian SPH kinase.181 S-l5183a may be an effective tool in understanding the role of SPP in cellular physiological functions. 4.5.6. Caspase-3 Inhibitors. Three new caspase-3 inhibitors, chaetomugilin S (191), 7,5′-bis-epi-chaetoviridin A (192), and 7-epi-chaetoviridin E (193), from Ch. elatum, showed inhibitory activity in the cysteine aspartyl-specific protease-3 (caspase-3) enzymatic assay (IC50 = 20.6, 10.9, and 7.9 μM, respectively).152 4.5.7. Inhibitors of Telomerase. Diazaphilonic acid (158), produced by Ta. flavus, inhibited DNA amplification (IC50 = 2.6 μg/mL) by polymerase chain reaction with Tth DNA polymerase. In addition, this compound also dosedependently inhibited telomerase activity of MT1 (human leukemia) and almost completely inhibited activity at 50 μM.138 4.5.8. Inhibitors of DNA Polymerases. Kasanosins A (171) and B (133) from a Talaromyces sp. elicited extremely selective inhibition of eukaryotic DNA polymerases β and λ (pols β and λ) in family X of pols.130 The high specificity for families of pols might be attributable to the azaphilone structure. The inhibition of 171 was stronger than that of 133. The compounds could be useful molecular tools as pols βand λ-specific inhibitors to develop a drug design strategy for immunosuppressive and/or anticancer chemotherapy agents. 4.5.9. Inhibitors of CETP Activity. The effects of 13 fungal azaphilones were tested on cholesteryl ester transfer protein (CETP) activity in vitro.304 Chaetoviridin B (178) showed the best inhibitory activity (IC50 < 6.2 μM), followed by

4.6. Inhibitors of PDGF Binding to Their Receptors

Recent studies showed that drugs which block the activation of the platelet-derived growth factor (PDGF) receptor would have potential as antitumor agents or for treatment of atherosclerosis. In an effort to search for inhibitors of the binding of the PDGFs to their receptors, RP-1551’s produced by Penicillium sp. were found to inhibit the binding of PDGF AA to the extracellular domain of PDGF α-receptor (IC50 = 0.1−2 μM) without affecting PDGF BB binding to the extracellular domain of PDGF β-receptor.211 RP-1551-1 (281) may block PDGF AA binding by reacting with amino groups on the α-receptor extracellular domain. This finding reveals that 281 may irreversibly interact with the PDGF αreceptor.211 4.7. Cytotoxic and Anti-Cancer Effects

Citrinin (1) and dicitrinin A (8) were found to show moderate cytotoxicity in the mouse NS-1 assay (LD99 = 25 and 6.3 μg/ mL, respectively).37 Decarboxydihydrocitrinin (3) from Aspergillus sydowi was cytotoxic against the P388 cell line (IC50 = 1.95 μM).40 Various chaetomugilins had moderate to strong cytotoxic activity against the human cancer cell lines. For example, chaetomugilins A (194), C (196), and F (199) exhibited significant cytotoxic activities against the P388 and HL-60 cell lines which were equal to that of 5-fluorouracil.153,154 In addition, chaetomugilins A (194), C (196), F (199), and I (206) showed selective cytotoxic activities against 39 human cancer cell lines.158 Ankaflavin (84) was found to be cytotoxic to human cancer cell lines Hep G2 and A549 (IC50 = 15 μg/mL) and induced apoptosis of Hep G2 cells.305 Monapurones A−C (100−102) from M. purpureus exhibited selective in vitro cytotoxicity against A549 cells (IC50 = 3.8, 2.8, and 2.4 μM, respectively).102 However, none of these compounds caused toxicity to normal MRC-5 and WI-38 cells. Monascopyridines A−D (354−357) displayed cytotoxic effects (EC50 = 11−43 μM) using immortalized human kidney epithelial cells, but none of the compounds induced apoptosis. The compounds caused mitotic arrest and the formation of structural damages such as c-mitosis through interaction with the mitotic spindle. These properties point to an aneuploidyinducing potential, which is associated with cancer formation.251,252 Monascin (83) exhibited marked inhibitory activity on both peroxynitrite- and ultraviolet-light-B-induced mouse skin carcinogenesis. Compound 83 may be regarded as a potential tumor chemopreventive agent in chemical and environmental carcinogenesis.306 Sclerotiorin (247) was potently antiproliferative against several different cancer cells (ACHN, Panc-1, Calu-1, HCT116, and H460), with IC50 = 0.63−2.1 μM, and showed the most potent activity in HCT-116 (IC50 = 0.63 μM), but posed toxicity to normal breast epithelium cells (MCF10A) (IC50 > 10 μM). 247 induced apoptosis in colon cancer (HCT-116) cells via the activation of BAX, and down-regulation of BCL-2, AQ


Chemical Reviews

Review

4.8. Anti-inflammatory Activity

which further activated cleaved caspase-3, inducing apoptosis of the cancer cells.200 Six pigments from Monascus product and some semisynthesized derivatives were evaluated for their cytotoxicity to various human cancer cells (SH-SY5Y, HepG2, HT-29, BGC823, AGS, and MKN45).307,308 Among the compounds tested, rubropunctatin (81) exerted the greatest anticancer effect.307 The inhibition effect of 81 was higher than that of paclitaxel on the growth of the human gastric cancer cells SH-SY5Y, BGC823, AGS, and MKN45.307 Further in vitro studies demonstrated that 81 had an antiproliferation effect on BGC-823 cells (IC50 = 12.6 μM) through a dose- and time-dependent apoptosis. The in vivo test revealed that 81 could have therapeutic effects on BGC-823 cells similar to those of paclitaxel.308 The SAR analysis307 showed that 6-internal ether, 4-carbonyl, and conjugated double bonds in 81 were structural requirements for the anticancer effect, whereas the length of the side chain gave rise to little influence. Recent studies with in vitro and in vivo models have shown that monascuspiloin (92) at 50 μM effectively inhibits the growth of both androgen-dependent LNCaP and androgenindependent PC-3 human prostate cancer cells.98 It has been further demonstrated that 92 induces apoptosis and autophagic cell death in human prostate cancer cells through the PI3K/Akt and AMPK signaling pathways.98 Additional in vitro studies showed that 92 enhances the radiation sensitivity of PC-3 cells by stimulating endoplasmic reticulum stress and inducing autophagy via inhibition of the Akt/mTOR signaling pathways.309 Of dicitrinones A−C (18−20),47 isolated from P. citrinum, 19 was found to display more potent cytotoxic effects in the leukemia cell lines HL-60 and MOLT-4 (IC50 = 6.5 and 6.0 μM, respectively). 20 inhibited the MOLT-4 cell viability (IC50 = 6.0 μM), while 18 only exhibited moderate cytotoxicity against four tumor cell lines (HL-60, MOLT-4, A-549, and BEL-7402). 19 arrested the HL-60 cell cycle at the G2/M phase. Aspergilone A (33) displayed in vitro selective cytotoxicity toward HL-60, MCF-7, and A-549 cell lines (IC50 = 3.2, 25.0, and 37.0 μg/mL, respectively).52 Monaphilones A (98) and B (99) from M. purpureus inhibited proliferation in both HEp-2 and WiDr cell lines.94 The pyran ring in these azaphilones may play a crucial role in their antiproliferative effect. Berkazaphilones B (135) and C (173) from P. rubrum Stoll exhibited selective activity against leukemia cancer cell lines in the National Cancer Institute 60 human cell line assay.111 (−)-Berkelic acid (234) displays strong anticancer activity toward OVCAR-3 in the NCI-60 panel screen (GI50 = 91.0 nM) and inhibits MMP-3 and caspase-1 (GI50 = 1.87 and 98.0 μM, respectively).173 Chaetoglobin A (268) remarkably inhibited the proliferation ability of MCF-7 and colon cancer cell line SW1116 and expressions of tumor-related genes bcl-2, c-myc, and βcatenin.260 Longirostrerones A−D (299−302) from Ch. longirostre exhibited strong cytotoxicity against KB cancer cell lines (IC50 = 0.23−6.38 μM), while only 299 exerted potent cytotoxicity against MCF7 and NCI-H187 cell lines (IC50 = 0.24 and 3.08 μM, respectively).220 Peneciraistin C (313) from P. raistrickii showed significant cytotoxicity against A549 and MCF-7-60 cell lines (IC50 = 3.2 and 7.6 μM, respectively).227

It was demonstrated that falconensins 136−149, but not monomethylmitorubrin (128), exerted inhibitory effects against TPA-induced inflammation in the ears of mice, comparable to the control moascorubrin (82) and indomethacin.310 Asakawa and co-workers showed that 15 azaphilones from mushrooms suppressed lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells.311 The dimeric azaphilones rutilins A (159) and B (160) were found to be the greatest inhibitors of NO production (IC50 = 1.76 and 1.80 μM, respectively). In addition, rubiginosin A (164) (IC50 = 2.56 μM) showed potent inhibitory activity against NO production stimulated by LPS via the inhibition of inducible nitric oxide synthase (iNOS) protein synthesis. The acetyl group plays an important role in inhibition, and the position of the orsellinic acid unit retained the activity. Monapilols A−D (88−91) from M. purpureus significantly inhibited NO production on LPS-stimulated RAW 264.7 cells (IC50 = 1.0−3.8 μM) and also exhibited antiproliferative activities against HEp-2 and WiDr cell lines (IC50 = 8.6−15.7 μM). The length of the saturated side chain and the ketonic carbonyl group of azaphilones may play a crucial role in the activities. The results revealed that the compounds could prevent tumor formation by anti-inflammatory and antiproliferative effects.97 Monascuskaolin (111), monascopyridine C (356), and monascopyridine D (357) from M. kaoliang showed inhibition of NO production in LPS-stimulated RAW 264.7 macrophages in vitro (MIC = 7.62, 18.78, and 26.72 μg/mL, respectively).109 Cohaerins C−F (295−298) from An. cohaerens showed similar activity in RAW cells.219 Ergophilones A (161) and B (162) from Penicillium sp. were demostrated to inhibit the rat platelet PLA2 (IC50 = 0.44 and 0.56 μM, respectively), but were weak on the porcine pancreatic PLA2.139 In addition, sclerotiorin (247) was previously reported as a phospholipase A2 inhibitor.312 Monascusazaphilol (94) from M. pilosus inhibited the production of tumor necrosis factor (TNF-α) induced by LPS in U937 cells in vitro (IC50 = 1.24 μg/mL).99 4.9. Hypolipidemic and Antihypertense Effects

Recent studies have shown that monascin (83) and ankaflavin (84) serve as novel and potent hypolipidemic and high-density lipoprotein cholesterol (HDL-C)-raising ingredients by using hyperlipidemic hamsters.313 Importantly, 83 and 84, unlike monacolin K, were able to perform up-regulation rather than down-regulation of HDL-C levels in serum. Monascus-fermented rice metabolites monascin (83) and ankaflavin (84), in addition to monacolin K, impaired TNF-αstimulated endothelial adhesiveness as well as down-regulated intracellular ROS (reactive oxygen species) generation, nuclear factor (NF)-κB activation, and VCAM-1 (vascular cell adhesion molecular-1)/E-selectin expression in HAECs (human aortic endothelial cells). This result supports the notion that the Monascus metabolites might have potential implications in clinical atherosclerosis disease.314 It has been demonstrated that 83 and 84 have potential means to attenuate TNF-α-stimulated endothelin-1 activation, inhibit eNOS expression, and reduce NO generation in human umbilical endothelial cells (HUVECs), and thus may help to abate the risk of vascular disease associated with inflammation, thereby exerting antihypertension.315 AR


Chemical Reviews

Review

and 3.12 μg/mL, respectively). Sch725680 (173) and Sch1385568 (174) from Aspergillus sp. were shown to present inhibitory activity against Saccharomyces cerevisiae (PM503) (MIC = 8 and 32 μg/mL, respectively).142,143 Among comazaphilones A−C (152−154) and comazaphilones D−F (168−170) from P. commune,136 compounds 154, 169, and 170 displayed potent inhibitory activities against several bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) (MIC = 16−32 μg/mL), while 168−170 showed moderate cytotoxic activities against human pancreatic tumor cell line SW1990 which are stronger than that of the positive control 5-fluorouracil.136 The double bond at C-10 and the position of the orsellinic acid unit at C-6 in these azaphilones are important for these activities.136 Multiformins A−D (291−294) from H. multiforme have been found to exhibit potent nonselective in vitro antimicrobial activity for a panel of human pathogenic microorganisms.218 Four compounds, rotiorinol A (286), rotiorinol C (288), (−)-rotiorin (289), and rubrorotiorin (271), from Ch. cupreum, exhibited an antifungal activity against Ca. albicans (IC50 = 10.5, 16.7, 24.3, and 0.6 μg/mL, respectively).214 Sch725680 (173) from the culture of Aspergillus sp. showed inhibitory activity against S. cerevisiae and Ca. albicans (MIC = 8 and 64 μg/mL, respectively).142 Cytosporolides A−C (244−246) from the fungus Cytospora sp. showed significant antimicrobial activity against Gram-positive bacteria.184 246 is the most potent compound among these metabolites tested (IC50 = 1.98 and 1.16 μg/mL, respectively).

4.10. Antioxidative Activity

Seven antioxidative agents, cyathusals A−C (227−229), cyathuscavins A−C (230−232), and pulvinatal (233), from Cy. stercoreus,170,171 were found to possess significant antioxidant activities similar to those of reference antioxidants BHA and Trolox in the ABTS+, DPPH, and superoxide anion radical scavenging bioassays. In addition, 230−232 protected supercoiled plasmid DNA from Fe2+/H2O2-induced breakage. Some citrinin congeners, such as pennicitrinone C (10), penicitrinol B (13), citrinin H1 (7), and dihydrocitrinin (2), identified from P. citrinum B-57, were found to possess an antioxidative property against DPPH radicals (IC50 = 0.8−59 μM).38 4.11. Antimicrobial Activity

The antifungal activities of the newly synthesized sclerotiorin derivatives were evaluated against seven phytopathogens.316,317 Some tested compounds, 582−588 (Figure 16), had higher

Figure 16. Synthesized sclerotiorin derivatives 582−588.

activity and simpler structures than the parent sclerotiorin (247). Preliminary SAR data revealed the following results:316,317 (i) the presence of the chlorine or bromine atom at C-5 and the phenyl group at C-3 improved the activity; (ii) introducing a methyl substituent at C-1 led to a reduction in activity; (iii) the free hydroxyl group at the C-7 center of azaphilones plays an important role in activity. Isochromenone 51 from De. corticola showed in vitro antimicrobial activities against a panel of plant bacteria and fungi at 50 μg/disk.69 Deflectins A-1b (61) and B-2a (63) as major components from A. deflectus showed antibacterial activity with MIC < 1 μg/mL.75 Of chaetoviridins A (177) and B (178) from Ch. globosum F0142, 177 exerted a higher antifungal efficacy in vitro and in vivo against rice blast (Magnaporthe grisea) than 178.318 T22 azaphilone (225) from a commercial biopesticide, Tr. harzianum T22,167 has been shown to elicit distinguished in vitro inhibition of Rhizoctonia solani, Pythium ultimum, and Gaeumannomyces graminis var. tritici (1−10 μg/plug). Pseudoanguillosporins A (242) and B (243) from Pseudoanguillospora sp. showed a broad spectrum of antimicrobial activities, and 242 gave the strongest activity. The best inhibition of Phytophthora infestans was shown for 242.183 Sclerotiorin (247) and isochromophilone VI (362) from P. sclerotiorum van Beyma were found to produce bacteriostatic activity against all Gram-positive and Gram-negative bacteria tested.197 (−)-Sclerotiorin (257) inhibited the maturation of starfish oocytes induced by 1-methyladenine (IC50 = 0.50 μM) and also suppressed several plant pathogenic fungi (IC50 < 20 μg/mL).206 Sassafrins A−C (108−110) from Cr. sassafras showed a moderate antibacterial property and strong antifungal activity.108 Two potential antifungal agents, CT2108A (237) and CT2108B (238), from P. solitum were found to inhibit fungal fatty acid synthase (FAS), but did not suppress human FAS activity.180 Additionally, these two compounds exhibited reversible growth inhibition of Candida albicans, (MIC90 = 6.25

4.12. Miscellaneous Activity

Biscogniazaphilones A (103) and B (112) from B. formosana exhibited the strongest antimycobacterial activities against My. tuberculosis strain H37Rv (MIC = 5.12 and 2.52 μg/mL, respectively).103 Longirostrerones A−C (299−301) showed antimalarial activity against Plasmodium falciparum (IC50 = 0.62−3.73 μM).220 Chaetoviridin E (181) presented an antimalarial activity against Pl. falciparum (IC50 = 2.9 μg/ mL),149 whereas chaetoviridins E (181) and F (183) exterted an antimycobacterial activity against My. tuberculosis.150 Purpurquinones B (156) and C (157) from P. purpurogenum exhibited significant antiviral activity against H1N1 (IC50 = 61.3 and64.0 μM, respectively).137 Pseudohalonectrins A (37) and B (39), isolated from the aquatic fungus Ps. adversaria, were found to display moderate nematicidal activity against the pine wood nematode Bursaphelenchus xylophilus.56 Bulgarialactone A (65) and B (66) possess nematicidal activity toward Caenorhabditis elegans (LD50 = 5 and 10−25 μg/mL, respectively) and block the binding of 3H-SCH 23390 to the dopamine D1 receptor in rat brain striatal homogenates (IC50 = 34 and 19 μM, respectively).15,76 Aspergilone A (33) also exhibited potential antifouling activity against the larval settlement of barnacle Balanus amphitrite at a nontoxic dose (EC50 = 7.68 μg/mL), being lower than the standard requirement (EC50 = 25 μg/mL) established by the U.S. Navy program.52 Acetosellin (74) from Ce. acetosella Ell at 6.4 × 10−4 M suppressed Lepidium sativum and Zea mais using the root elongation assays,80 but not any antifungal activity. Trichoflectin (104) from T. nidulus A73-95 inhibited dihydroxynaphthalene melanin biosynthesis in fungi.104 The biological activity of (−)-mitorubrinic acid (123) as a trypsin inhibitor was determined (IC50 = 41 μM).113 AS


Chemical Reviews

Review

5. BIOSYNTHESIS OF AZAPHILONES

Scheme 36. Biosynthetic Pathway of Austdiol (40) from Pentaketide328,329

5.1. Biosynthesis of Citrinin, Austdiol, and Ascochitine

Early labeling experiments provided evidence for a polyketidetype biosynthesis for citrinin (1), austdiol (40), and ascochitine Scheme 34. Biosynthesis of Citrinin (1) from Pentaketide320−324

Scheme 37. Biosynthetic Pathway of Ascochitine (176) from Hexaketide330,331

Scheme 35. 13C Labeling Pattern and Biosynthesis of Citrinin (1) from Tetraketide326

Scheme 38. Biosynthesis of Ochrephilone (272)215

(176) that involves one acyl-CoA and three or four malonylCoA units. 5.1.1. Citrinin. The biosynthesis of citrinin (1) has been recently reviewed.6,319 It is known that, in Aspergillus or Penicillium species, 1 results from a pentaketide produced by AT


Chemical Reviews

Review

Scheme 42. 13C Labeling Patterns of Chlorofusin (321)336

Scheme 39. 13C Labeling Patterns of Chaetoviridin B (178)148 and Chaetomugilin A (194)335

This biosynthesis involved the formation of methylated pentaketide, followed by condensation and reduction, to obtain the ketoaldehyde 591. The keto group of 591 underwent reduction and then formed the hemiacetal 593. Dehydration of 593 and subsequent oxidation of the methyl C-7 of the resulting 594 to COOH afforded (−)-citrinin.34,325 Carbon isotope distribution of 13C-enriched citrinin from M. ruber incubated with [1,2-13C2]acetate revealed that the biosynthesis of citrinin (1) resulted from a tetraketide (Scheme 35), instead of a pentaketide as had been shown for Penicillium and Aspergillus species.320,3,4 Then an additional acetyl-CoA unit is introduced to the tetraketide to provide the intermediate 595. Subsequent reactions encompass O-alkylation and single bond cleavage. Thus, the production of 1 by M. ruber may be regulated at the level of the tetraketide branch point. Interestingly, the enzymatic reactions at the tetraketide branch point need to be further characterized.326 In addition, Pisareva et al. have shown that the biosynthesis of 1 appears to be strainspecific and does not correlate with the pigments’ biosynthesis by the genus Monascus.327 5.1.2. Austdiol. A 13C NMR analysis of [1,2-13C2]acetateand L-[methyl-13C]methionine-derived austdiol (40) is consistent with the symmetrical aldehyde 604 being a biosynthetic precursor of 40 (Scheme 36).328 Interpretation of the incorporation data of 18O2 into austdiol in A. ustus suggests a mono-oxygenase mechanism.329 5.1.3. Ascochitine. Feeding experiments330 with [1-13C]and [1,2-13C2]acetate- and L-[methyl-13C]methionine-enriched 589 have shown that the skeleton of ascochitine (176) resulted from a single hexaketide chain and three Cl units (Scheme 37). Enzymic trap experiments show that the main biosynthetic pathway to 176 involves the direct reduction of the enzymebound ester into the aldehyde 605.331

Scheme 40. 13C Labeling Pattern of PP-V (359) and Monascorubrin (82)252

Scheme 41. Possible Biosynthesis of Monascusone B (93) and Monascin (83)93

5.2. Biosynthesis of Ochrephilone, Chaetoviridin B, Chaetomugilin A, PP-V, and Monascin

Biosynthetic studies conducted with 13C-labeled acetate tracer experiments on several azaphilones, e.g., monascorubrin (82), monascin (83), ochrephilone (272),215 chaetoviridin B (178), and chaetomugilins A (194) and M (210), revealed that they were assembled via a common polyketide pathway.148,320,335 The main polyketide chain of these compounds has been reported to be assembled from acetate plus malonate in a conventional way, but the β-oxolactone systems are derived from condensation of hexanoate and octanoate with acetate.332−334 5.2.1. Ochrephilone. Seto and Tanabe reported the biosynthesis of ochrephilone (272) from sodium [1,2-13C2]acetate in P. multicolor.215 This biosynthesis involves the use of

the condensation of one acetyl-CoA with four malonyl-CoA molecules, followed by the addition of three methyl units arising from SAM (S-adenosylmethionine, 589) (Scheme 34).320−324 Furthermore, the biosynthetic pathway for 1 in Penicillium sp. has been recently elucidated by incorporation studies with advanced precursors such as redoxcitrinin (591).34 AU


Chemical Reviews

Review

Scheme 43. Proposed Biosynthesis Pathway for Asperfuranone (290)217

Scheme 44. Proposed Biosynthesis of Berkelic Acid (234) and Spiciferinone (35)176,177

5.2.2. Chaetoviridin B and Chaetomugilin A. A biosynthetic study of chaetoviridin B (178) with sodium [1,2-13C2]acetate substantiated the angular structures.148 The 13 C−13C coupling constants indicated a labeling pattern arising from two polyketide chains (Scheme 39). Most recently, feeding experiments with [1,2-13C2]acetate by Watanabe et al. further confirmed that the entire molecule of chaetomugilin A (194) is derived from a polyketide backbone (Scheme 39).335

two polyketide chains (Scheme 38). One long polyketide chain arises from the condensation of seven malonyl-CoA molecules with one acyl-CoA molecule, accompanying the insertion of three SAM molecules, while the other short chain results from that of two sodium acetate molecules. These two ketides are coupled to form 272 via a series of reactions, such as condensation, reduction, and oxidation. AV


Chemical Reviews

Review

Scheme 45. Proposed Biosynthesis of Cytosporolide A (244)185

Scheme 48. Proposed Biogenesis of Ergophilones A (161) and B (162)139

Scheme 46. Postulated Biosynthetic Pathway of Perinadine A (32)51

5.3. Chlorofusin

The biosynthesis of chlorofusin (321) has been investigated by the utilization of sodium [1-13C]acetate feeding experiments.336 The acetogenic origin of the chlorofusin chromophore 606 backbone as well as of an aminodecanoic acid residue, 607, is established (Scheme 42). The formation of chlorofusin is similar to that of the fungal N-azaphilones, such as rubropunctamine (322). 5.4. Asperfuranone

Wang and co-workers proposed the biosynthetic pathway for asperfuranone (290) through genome mining (Scheme 43).217 AN1036.3 (AfoG), a HR-PKS, is responsible for forming the 3,5-dimethyloctadienone moiety from acetyl-CoA, three molecules of malonyl-CoA, and two SAMs. The 3,5dimethyloctadienone moiety is then loaded onto the SAT (starter unit: acyl carrier protein transacylase) domain of AN1034.3 (AfoE) and extended with four molecules of malonyl-CoA and one SAM. The benzylic hydroxylation of the side chain of compound 409 is catalyzed by AN1033.3 (AfoD) to benzylic alcohol 608. Then a furan ring, 609, is generated after formation of a fivemembered ring hemiacetal followed by loss of water. The oxidation of the α-diketone active proton of 610 and reducation of the unconjugated carbonyl group of 611 are catalyzed by two enzymes, AN1035.3 (AfoF) and AN1032.3 (AfoC), respectively, affording 290. Therefore, a gene cluster containing two fungal PKS genes in combination with five

5.2.3. PP-V. The biosynthetic pathway of pigment PP-V (359) has been elucidated by 13C-labeled acetate incorporation experiments by Ogihara et al.252 These incorporation patterns are consistent with those reported in the biosynthesis of a Monascus azaphilone pigment, monascorubrin (82) (Scheme 40); namely, 359 is derived from the condensation of a decanoate and a monomethylated dodecanoate, but the origin of the only angular methyl residue has not yet been clarified. 5.2.4. Monascusone B and Monascin. Possible biogenetic routes to several metabolites, monascusones A (116) and B (93), monascin (83), and FK17-P2b2 (114), from the fungus M. kaoliang, are shown in Scheme 41.93 It is known that the hexaketide chromophore of azaphilone pigments is derived from the condensation of acetate and malonate by polyketide synthases (PKSs) while the side chain of these pigments arises from a medium-chain fatty acid synthesized via a fatty acid synthetic pathway.

Scheme 47. Proposed Biosynthetic Pathway of Dicitrinones A−C (18−20)47

AW


Chemical Reviews

Review

Scheme 49. Proposed Biosynthetic Pathway of Azanigerones 636−641 by Tang and Co-workers338

was probably derived from methionine and incorporated into the azaphilone unit 634 before the Diels−Alder reaction. Biogenetically, the new six-membered ring formation between ergosterol (635) and a putative azaphilone intermediate, 634, and (−)-mitorubrinic acid (123) was responsible for the enzymatic catalysis of the Diels−Alder reaction (Scheme 48).139

additional genes encodes the asperfuranone (290) biosynthetic route. 5.5. Berkelic Acid

Both De Brabander’s and Snider’s groups thought that berkelic acid (234) might be biosynthesized by the nucleophilic addition of ketone 618 to pulvilloric acid (220) (Scheme 44).176,177 In this pathway a single pentaketide chain bearing two C-methyls from C1 units and one ethyl unit is modified into the possible precursor 618 via the known metabolite spiciferinone (35) by a sequence of biological reactions, including an aldol condensation. Alteratively, participation of enol ether 619 in a [4 + 2] cycloaddition with the o-quinone methide tautomer 620 of 220 would generate 234. The ketone 618 is related to spicifernin (617) in the same strain of C. spicifer.53,337 Moreover, it has been suggested that the biosynthetic origin of cochliospicin A (36) would be a mixed pathway of polyketide and a C3 unit in this fungus.337

5.10. Azanigerones

Activation of a silent (aza) gene cluster in Aspergillus niger ATCC 1015 has led to the isolation of six previously unreported compounds, azanigerones A−F (636−641).338 The biosynthesis of 636 begins with the benzaldehyde 642. This compound results from a methylated hexaketide that can be synthesized by an NR-PKS, which undergoes a product template (PT)-mediated cyclization and reductive release to provide a 1,3-diketobenzaldehyde, 643.339 Further ketoreduction of the terminal ketone by putative ketoreductase AzaE affords 642. Most importantly, in vitro reaction of AzaH, a key flavin-dependent monooxygenase encoded in the cluster, with the benzaldehyde 642 revealed its critical roles in hydroxylation-mediated pyran ring formation to afford the typical bicylic core 640 of azanigerones.338 In parallel, the 2,4dimethylhexanoyl chain may be offloaded from the HR-PKS as a carboxylic acid and converted to an acyl-CoA by AzaF. The resulting acyl-CoA molecule could then be regarded as a substrate by the acyltransferase AzaD340 to form 637. Next, hydroxylation at C-10 of 637, possibly catalyzed by the two monooxygenases AzaG and AzaL, gave the vicinal diol 638. Subsequently, this putative intermediate 638 undergoes consecutive oxidation by the P450 enzyme AzaI to yield 636 (Scheme 49).338 Additionally, 641 is the 7-O-acetylated version of 640, while 639 is derived from amination of 636.

5.6. Cytosporolide A

Biogenetically, dehydration of the known fungal metabolite CJ12,373 (241) could generate the o-quinone methide 623. Cycloaddition of this putative reactive intermediate to the cooccurring fuscoatrol A (624) would then produce the revised structure of cytosporolide A (244) (Scheme 45).185 5.7. Perinadine A

Biogenetically, perinadine A (32) may be derived from citrinin (1) and a decarboxylic analogue, 626, of the scalusamide A-type pyrrolidine alkaloid 625 isolated from Penicillium brevicompactum through a Diels−Alder reaction (Scheme 46).51 5.8. Dicitrinones A−C

Condensation of citrininyl-CoA (628) with one or two malonyl-CoA units via Claisen reactions followed by decarboxylation could afford the intermediates 630 and 631.47 Enzymatic reduction of the intermediates and citrinin (1) could produce benzyl intermediates 632a and 632b, respectively, which could be further subjected to a Friedel− Crafts reaction with decarboxycitrinin (633), affording dicitrinones A−C (18−20), respectively (Scheme 47).

6. CONCLUSIONS In the present review we demonstrate the structural and biological diversity of fungal polyketide azaphilones excreted from various ascomycetous fungi, which have a characteristic isochroman scaffold. The scaffold may be modified by a γlactone ring or spirocyclic moieties and a variety of acyclic or cyclic side chains, generating structural diversity. In this review we survey the isolation, structure elucidation, biological

5.9. Ergophilones A and B

Ergophilone A (161) possessed one more carbon at the C-13′ position compared to ergophilone B (162). The C-13′ carbon AX


Chemical Reviews

Review

activities, including structure−activity relationships, biosynthesis, and total synthesis of azaphilones and their derivatives. Additionally, the general protocols for the synthesis of complex substituted nitrogenous azaphilones and some natural azaphilone-like scaffolds have been developed. On the basis of the accumulated information and the advancement in synthetic methods, the future prospect is bright for the development of drugs (fungicides) and/or drug candidates of antitumor, antiinflammary, and antifungal azaphilonoids. The comprehensive and intensive understanding of biochemical pathways concernSheng-Xiang Yang received his Ph.D. degree from Northwest A&F University in 2011. Thereafter, he joined Zhejiang A&F University. From 2010 to 2011, he worked at the University of Goettingen under the supervision of Professor H. Laatsch. His research interests include discovery and structure modification of natural products from fungi and Chinese herbal medicines with potent bioactivity.

ing both production and metabolism of these fungal metabolites is still needed.

AUTHOR INFORMATION Corresponding Author

*Fax/phone: +86 29 87092515. E-mail: jinminggao@nwsuaf. edu.cn. Notes

The authors declare no competing financial interest. Biographies

Jian-Chun Qin was born in 1977. He completed his B.Sc. degree in 2001 and his M.Sc. degree in 2006 at Northwest A&F University. In 2009, he acquired his Ph.D. degree at Northwest A&F University and the University of Gottingen in Germany, under the supervision of Prof. Jin-Ming Gao and Hartmut Laatsch, where he worked on the search for bioactive substances from higher fungi, endophytic fungi, and marine microbial species. In 2011, he carried out postdoctoral research on natural product biosynthesis with Prof. Xiang-Li. At present, he works as a vice professor at Jilin University. His current research interests focus on microbial natural product chemistry and biosynthesis. He has received several research awards and authored over 17 scientific publications in international journals.

Jin-Ming Gao received his B.Sc. in chemistry in 1986 from Shaanxi Normal University and M.Sc. in plant chemistry in 1998 from Northwest A&F University, China. He studied for his Ph.D. degree under the supervision of Prof. J. K. Liu at the Kunming Institute of

ACKNOWLEDGMENTS We acknowledge funding support from the National Natural Science Foundation of China (Grants 30370019, 30670221, and 30770237) and from the Program for New Century Excellent Talents in University (Grant NCET-05-0852). We thank Dr. Clay C. C. Wang and the reviewers for critical review of the manuscript.

Botany, Chinese Academy of Sciences, China, and was awarded the Excellent Graduate Prize of the President of the Chinese Academy of Sciences in 2001. After finishing his Ph.D., he moved back to Northwest A&F University as a postdoctoral fellow, where he worked on biopesticidal chemistry. Then he worked as a visiting scholar in 2005 and as a postdoctoral fellow with Prof. Y. Konishi in 2007 at the

REFERENCES

Biotechnology Research Institute, National Research Council Canada.

(1) (a) Hoffmeister, D.; Keller, N. P. Nat. Prod. Rep. 2007, 24, 393. (b) Cichewicz, R. H. Nat. Prod. Rep. 2010, 27, 11. (c) Gunatilaka, A. A. L. J. Nat. Prod. 2006, 69, 509. (2) (a) Zhang, H. W.; Song, Y. C.; Tan, R. X. Nat. Prod. Rep. 2006, 23, 753. (b) Gao, J. M. Curr. Org. Chem. 2006, 10, 849. (c) Zhang, Q.;

Currently, he is a professor of chemical biology at Northwest A&F University, researching structure−activity relationships in pharmacology and natural product chemistry. AY


Chemical Reviews

Review

Zong, S.-C.; Li, H.-Q.; Gao, J.-M.; Zhang, A.-L. Mini-Rev. Med. Chem. 2012, 12, 127. (3) (a) Demain, A. L.; Sanchez, S. J. Antibiot. 2009, 62, 5. (b) Kim, B. S.; Hwang, B. K. J. Phytopathol. 2007, 155, 641. (4) (a) O’Hagan, D. The Polyketide Metabolites; Ellis Horwood: Chichester, U.K., 1991. (b) Thomas, R. A ChemBioChem 2001, 2, 612. (5) (a) Thomas, R. Nat. Prod. Rep. 2004, 21, 224. (b) Schuemann, J.; Hertweck, C. Biosynthesis of Fungal Polyketides, The Mycota; Springer: Berlin, Heidelberg, 2009; Vol. 15, p 331. (6) Brase, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem. Rev. 2009, 109, 3903. (7) (a) Nakanishi, K. J. Nat. Med. 2006, 60, 2. (b) Mapari, S. A.; Thrane, U.; Meyer, A. S. Trends Biotechnol. 2010, 28, 300. (8) Review: Osmanova, N.; Schultze, W.; Ayoub, N. Phytochem. Rev. 2010, 9, 315. (9) (a) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod. 1987, 51, 1. (b) Quang, D. N.; Hashimoto, T.; Asakawa, Y. Chem. Rec. 2006, 6, 79. (10) Mapari, S. A. S.; Meyer, A. S.; Thrane, U. J. Agric. Food Chem. 2006, 54, 7027. (11) (a) Stadler, M.; Fournier, J. Rev. Iberoam. Micol. 2006, 23, 160. (b) Frisvad, J. C.; Andersen, B.; Thrane, U. Mycol. Res. 2008, 112, 231. (c) Stadler, M.; Ju, Y.-M.; Rogers, J. D. Mycol. Res. 2004, 108, 239. (12) Matsuzaki, K.; Tahara, H.; Inokoshi, J.; Tanaka, H.; Masuma, R.; Omura, S. J. Antibiot. 1998, 51, 1004. (13) Nam, J. Y.; Kim, H. K.; Kwon, J. Y.; Han, M. Y.; Son, K. H.; Lee, U. C.; Choi, J. D.; Kwon, B. M. J. Nat. Prod. 2000, 63, 1303. (14) Clark, R. C.; Lee, S. Y.; Searcey, M.; Boger, D. L. Nat. Prod. Rep. 2009, 26, 465. (15) Musso, L.; Dallavalle, S.; Merlini, L.; Bava, A.; Nasini, G.; Penco, S.; Giannini, G.; Giommarelli, C.; De Cesare, A.; Zuco, V.; Vesci, L.; Pisano, C.; Dal Piaz, F.; De Tommasi, N.; Zunino, F. Bioorg. Med. Chem. 2010, 18, 6031. (16) Hayashi, K.; Hatsutori, N.; Donho, M.; Nakajima, H. Jpn. Pat. JP 08217673, 1996. (17) Wang, T. H.; Lin, T. F. Adv. Food Nutr. Res. 2007, 53, 123. (18) Chong, R.; King, R. R.; Whalley, W. B. J. Chem. Soc. 1971, 3566. (19) Marsini, M. A.; Gowin, K. M.; Pettus, T. R. Org. Lett. 2006, 8, 3481. (20) (a) Gill, M. Nat. Prod. Rep. 2003, 20, 615. (b) Zhou, Z. Y.; Liu, J. K. Nat. Prod. Rep. 2010, 27, 1531. (21) Review: (a) Jůzlová, P.; Martínková, L.; Křen, V. J. Ind. Microbiol. 1996, 16, 163. (b) Šturdíková, M.; Slugeň, D.; Lešová, K.; Rosenberg, M. Chem. Listy 2000, 94, 105. (c) Lin, Y. L.; Wang, T. H.; Lee, M. H.; Su, N. W. Appl. Microbiol. Biotechnol. 2008, 77, 965. (22) Martínková, L.; Patáková-Jůzlová, P.; Krent, V.; Kucerová, Z.; Havlícek, V.; Olsovský, P.; Hovorka, O.; Ríhová, B.; Veselý, D.; Veselá, D.; Ulrichová, J.; Prikrylová, V. Food Addit. Contam. 1999, 16, 15. (23) Turner, W. B.; Aldridge, D. C. Fungal Metabolites; Academic Press: New York, 1971 and 1983; Vols. 1 and 2. (24) Hetherington, A. C.; Raistrick, H. Philos. Trans. R. Soc. London, Ser. B 1931, 220, 269. (25) (a) Brown, J. P.; Cartwright, N. J.; Robertson, A.; Whalley, W. B. Nature 1948, 162, 72. (b) Brown, J. P.; Robertson, A.; Whalley, W. B.; Cartwright, N. J. J. Chem. Soc. 1949, 867. (c) Cram, D. J. J. Am. Chem. Soc. 1950, 72, 1001. (26) (a) Mehta, P. P.; Walley, W. B. J. Chem. Soc., Perkin. Trans. 1 1963, 3777. (b) Hill, R. K.; Gardella, L. A. J. Org. Chem. 1964, 29, 766. (27) (a) Kovac, S.; Nemec, P.; Betina, V.; Balan, J. Nature 1961, 190, 1104. X-ray: (b) Rodig, O. R.; Shiro, M.; Fernando, Q. J. Chem. Soc., Chem. Commun. 1971, 1553. (28) Poupko, R.; Luz, Z.; Destro, R. J. Phys. Chem. A 1997, 101, 5097. (29) Blanc, P. J.; Laussac, J. P.; Le Bars, J.; Le Bars, P.; Loret, M. O.; Pareilleux, A.; Prome, D.; Prome, J. C.; Santerre, A. L.; Goma, G. Int. J. Food Microbiol. 1995, 27, 201. (30) Park, S. Y.; Kim, R.; Ryu, C. M.; Choi, S. K.; Lee, C. H.; Kim, J. G.; Park, S. H. FEMS Microbiol. Ecol. 2008, 65, 229. (31) Dos Santos, C. M.; Costa, G. L.; Figueroa-Villar, J. D. Nat. Prod. Res. 2012, 26, 2316.

(32) Chai, Y. J.; Cui, C. B.; Li, C. W.; Wu, C. J.; Tian, C. K.; Hua, W. Mar. Drugs 2012, 10, 559. (33) Guo, Z.; Cheng, F.; Zou, K.; Wang, J.; She, Z.; Lin, Y. Nat. Prod. Commun. 2009, 4, 1481. (34) Zhang, D.; Li, X.; Kang, J. S.; Choi, H. D.; Jung, J. H.; Son, B. W. J. Microbiol. Biotechnol. 2007, 17, 865. (35) Chien, M. M.; Schiff, P. L., Jr.; Slatkin, D. J.; Knapp, J. E. Lloydia 1977, 40, 301. (36) Lin, Z. J.; Lu, Z. Y.; Zhu, T. J.; Fang, Y. C.; Gu, Q. Q.; Zhu, W. M. Chem. Pharm. Bull. 2008, 56, 217. (37) Clark, B. R.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. Org. Biomol. Chem. 2006, 4, 1520. (38) Lu, Z. Y.; Lin, Z. J.; Wang, W. L.; Du, L.; Zhu, T. J.; Fang, Y. C.; Gu, Q. Q.; Zhu, W. M. J. Nat. Prod. 2008, 71, 543. (39) Wakana, D.; Hosoe, T.; Itabashi, T.; Okada, K.; de Campos Takaki, G. M.; Yaguchi, T.; Fukushima, K.; Kawai, K. J. Nat. Med. 2006, 60, 279. (40) Li, D. H.; Cai, S. X.; Tian, L.; Lin, Z. J.; Zhu, T. J.; Fang, Y. C.; Liu, P. P.; Gu, Q. Q.; Zhu, W. M. Arch. Pharm. Res. 2007, 30, 1051. (41) Xu, L.; Xue, J.; Xu, H.; Liu, X.; Ma, W.; Wei, X. Heterocycles 2006, 68, 1955. (42) Khamthong, N.; Rukachaisirikul, V.; Phongpaichit, S.; Preedanon, S.; Sakayaroj, J. Tetrahedron 2012, 68, 8245. (43) Xin, Z. H.; Wang, W. L.; Zhang, Y. P.; Xie, H.; Gu, Q. Q.; Zhu, W. M. J. Antibiot. 2009, 62, 225. (44) Yao, G.; Sebisubi, F. M.; Voo, L. Y. C.; Ho, C. C.; Tan, G. T.; Chang, L. C. J. Braz. Chem. Soc 2011, 22, 1125. (45) Du, L.; Liu, H. C.; Fu, W.; Li, D. H.; Pan, Q. M.; Zhu, T. J.; Geng, M. Y.; Gu, Q. Q. J. Med. Chem. 2011, 54, 5796. (46) Liu, H.-C.; Du, L.; Zhu, T.-J.; Li, D.-H.; Geng, M,-Y.; Gu, Q.-Q. Helv. Chim. Acta 2010, 93, 2224. (47) Du, L.; Li, D.; Zhang, G.; Zhu, T.; Ai, J.; Gu, Q. Tetrahedron 2010, 66, 9286. (48) Trivedi, A. B.; Hirota, M.; Doi, E.; Kitabatake, N. J. Chem. Soc., Perkin Trans. 1 1993, 2167. (49) Chen, L.; Liu, W.; Hu, X.; Huang, K.; Wu, J. L.; Zhang, Q. Q. Chem. Pharm. Bull. 2011, 59, 515. (50) Chen, L.; Liu, W.; Huang, K.; Hu, X.; Fang, Z.-X.; Wu, J.-L.; Zhang, Q.-Q. Heterocycles 2011, 83, 1853. (51) Sasaki, M.; Tsuda, M.; Sekiguchi, M.; Mikami, Y.; Kobayashi, J. Org. Lett. 2005, 7, 4261. (52) Shao, C.-L.; Wang, C.-Y.; Wei, M.-Y.; Gu, Y.-C.; She, Z.-G.; Qian, P.-Y.; Lin, Y.-C. Bioorg. Med. Chem. Lett. 2011, 21, 690. (53) Nakajima, H.; Kimura, Y.; Hamasaki, T. Phytochemistry 1992, 31, 105. (54) Nakajima, H.; Nakamura, S.-I.; Fujimoto, H.; Fukuyama, K.; Hamasaki, T. J. Nat. Prod. 1997, 60, 414. (55) Liu, J.-Y.; Liu, C.-H.; Zou, W.-X.; Tian, X.; Tan, R.-X. Helv. Chim. Acta 2002, 85, 2664. (56) Dong, J.; Zhou, Y.; Li, R.; Zhou, W.; Li, L.; Zhu, Y.; Huang, R.; Zhang, K. FEMS Microbiol. Lett. 2006, 264, 65. (57) Yang, S.-X.; Gao, J.-M.; Laatsch, H.; Tian, J.-M.; Pescitelli, G. Chirality 2012, 24, 621. (58) Vleggaar, R.; Steyn, P. S.; Nagel, D. W. J. Chem. Soc., Perkin Trans. 1 1974, 45. (59) Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Perkin Trans. 1 1976, 204. (60) Lo Presti, L.; Soave, R.; Destro, R. Acta Crystallogr., C 2003, 59 (Part 4), O199. (61) Hashimoto, T.; Tahara, S.; Takaoka, S.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull. 1994, 42, 2397. (62) He, G.; Matsuura, H.; Takushi, T.; Kawano, S.; Yoshihara, T. J. Nat. Prod. 2004, 67, 1084. (63) Lai, S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Terada, Y.; Furukawa, H. Chem. Lett. 1990, 589. (64) Masuma, R.; Tabata, N.; Tomoda, H.; Haneda, K.; Iwai, Y.; Omura, S. J. Antibiot. 1994, 47, 46. (65) Tabata, N.; Tomoda, H.; Iwai, Y.; Omura, S. J. Antibiot. 1995, 48, 83. AZ


Chemical Reviews

Review

(66) Malmstrøm, J.; Christophersen, C.; Frisvad, J. C. Phytochemistry 2000, 54, 301. (67) Chen, G.; Lin, Y.; Vrijmoed, L. L. P.; Fong, W.-F. Chem. Nat. Compd. 2006, 42, 138. (68) Trisuwan, K.; Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit, S.; Preedanon, S.; Sakayaroj, J. Tetrahedron 2010, 66, 4484. (69) Sun, R.; Gao, Y.-X.; Shen, K.-Z.; Xu, Y.-B.; Wang, C.-R.; Liu, H.Y.; Dong, J.-Y. Phytochem. Lett. 2011, 4, 101. (70) De Silva, L. B.; Herath, W. H. M. W.; Gunawardena, D. S. S.; Wijesundera, R. L. C.; Medis, S. A.; Choudhary, M. I.; Clardy, J. Tetrahedron Lett. 1995, 36, 1997. (71) Zou, X.-W.; Sun, B.-D.; Chen, X.-L.; Liu, X.-Z.; Che, Y.-S. Chin. J. Nat. Med. 2009, 7, 140. (72) Huang, H.; Feng, X.; Xiao, Z.; Liu, L.; Li, H.; Ma, L.; Lu, Y.; Ju, J.; She, Z.; Lin, Y. J. Nat. Prod. 2011, 74, 997. (73) Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Perkin Trans. 1 1986, 1975. (74) Spencer, H.; Mo, Y. K.; Tertzakian, G.; Slater, G. P.; Haskins, R. H.; Nesbitt, L. R. Can. J. Chem. 1970, 48, 3654. (75) Anke, H.; Kemmer, T.; Hofle, G. J. Antibiot. 1981, 34, 923. (76) Stadler, M.; Anke, H.; Dekermendjian, K.; Reiss, R.; Sterner, O.; Witt, R. Nat. Prod. Res. 1995, 7, 7. (77) Wang, G. Y. S.; Borgeson, B. M.; Crews, P. Tetrahedron Lett. 1997, 38, 8449. (78) Bell, P. J. L.; Karuso, P. J. Am. Chem. Soc. 2003, 125, 9304. (79) Choi, H. Y.; Veal, D. A.; Karuso, P. J. Fluoresc. 2006, 16, 475. (80) Nasini, G.; Arnone, A.; Assante, G.; Candiani, G.; Vajna de Pava, O. Tetrahedron Lett. 2002, 43, 1665. (81) Stierle, A. A.; Stierle, D. B.; Bugni, T. J. Org. Chem. 1999, 64, 5479. (82) Stierle, A. A.; Stierle, D. B.; Bugni, T. J. Nat. Prod. 2001, 64, 1350. (83) Katayama, M.; Yanagi, M.; Marumo, S. Agric. Biol. Chem. 1989, 53, 3379. (84) Lin, Z.; Zhu, T.; Fang, Y.; Gu, Q.; Zhu, W. Phytochemistry 2008, 69, 1273. (85) Haws, E. J.; Holker, J. S. E.; Kelly, A.; Powell, A. D. G.; Robertson, A. J. Chem. Soc. 1959, 3598. (86) (a) Ohashi, M.; Kumasaki, S.-I.; Yamamura, S.; Nakanishi, K.; Koike., H.; Monascorubrin, I. J. Am. Chem. Soc. 1959, 81, 6339. (b) Nakanishi, K.; Ohashi, M.; Kumasaki, S.-I.; Yamamura, S. J. Am. Chem. Soc. 1959, 81, 6339. (c) Fielding, B. C.; Haws, E. J.; Holker, J. S. E.; Powell, A. D. G.; Robertson, A.; Stanway, D. N.; Whalley, W. B. Tetrahedron Lett. 1960, 1, 24. (d) Kumasaki, S.; Nakanishi, K.; Nishikawa, E.; Ohashi, M. Tetrahedron 1962, 18, 1171. (87) Fielding, B. C.; Holker, J. S. E.; Jones, D. F.; Powell, A. D. G.; Richmond, K. W.; Roberston, A.; Whalley, W. B. J. Chem. Soc. 1961, 4579. (88) (a) Chen, F. C.; Manchand, P. S.; Whalley, W. B. J. Chem. Soc. 1971, 3577. (b) Nishikawa, H. J. Agric. Chem. Soc. Jpn. 1932, 5, 1007. (89) (a) Ohashi, M.; Yamamura, S.; Terahara, A.; Nakanishi, K. Bull. Chem. Soc. Jpn. 1960, 33, 1630. (b) Inouye, Y.; Nakanishi, K.; Nishikawa, H.; Ohashi, M.; Terahara, A.; Yamamura, S. Tetrahedron 1962, 18, 1195. (90) Manchand, P. S.; Whalley, W. B.; Chen, F.-C. Phytochemistry 1973, 12, 2531. (91) Akihisa, T.; Tokuda, H.; Yasukawa, K.; Ukiya, M.; Kiyota, A.; Sakamoto, N.; Suzuki, T.; Tanabe, N.; Nishino, H. J. Agric. Food Chem. 2005, 53, 562. (92) Cheng, M. J.; Wu, M. D.; Chen, I. S.; Chen, C. Y.; Lo, W. L.; Yuan, G. F. Nat. Prod. Res. 2010, 24, 1719. (93) Jongrungruangchok, S.; Kittakoop, P.; Yongsmith, B.; Bavovada, R.; Tanasupawa, S.; Lartpornmatulee, N.; Thebtaranonth, Y. Phytochemistry 2004, 65, 2569. (94) Hsu, Y. W.; Hsu, L. C.; Liang, Y. H.; Kuo, Y. H.; Pan, T. M. J. Agric. Food Chem. 2010, 58, 8211. (95) Yongsmith, B.; Krairak, S.; Bavavoda, R. J. Ferment. Bioeng. 1994, 78, 223. (96) Ogihara, J.; Oishi, K. J. Biosci. Bioeng. 2002, 93, 54.

(97) Hsu, Y.-W.; Hsu, L.-C.; Liang, Y.-H.; Kuo, Y.-H.; Pan, T.-M. J. Agric. Food Chem. 2011, 59, 4512. (98) Chen, R. J.; Hung, C. M.; Chen, Y. L.; Wu, M. D.; Yuan, G. F.; Wang, Y. J. J. Agric. Food Chem. 2012, 60, 7185. (99) Cheng, M.-J.; Wu, M.-D.; Yuan, G.-F.; Su, Y.-S.; Yanai, H. Phytochem. Lett. 2012, 5, 567. (100) Stierle, D. B.; Stierle, A. A.; Bugni, T. J. Org. Chem. 2003, 68, 4966. (101) Loret, M. O.; Morel, S. J. Agric. Food Chem. 2010, 58, 1800. (102) Li, J. J.; Shang, X. Y.; Li, L. L.; Liu, M. T.; Zheng, J. Q.; Jin, Z. L. Molecules 2010, 15, 1958. (103) Cheng, M.-J.; Wu, M.-D.; Yanai, H.; Su, Y.-S.; Chen, I.-S.; Yuan, G.-F.; Hsieh, S.-Y.; Chen, J.-J. Phytochem. Lett. 2012, 5, 467. (104) Thines, E.; Anke, H.; Sterner, O. J. Nat. Prod. 1998, 61, 306. (105) Campoy, S.; Rumbero, A.; Martín, J. F.; Liras, P. Appl. Microbiol. Biotechnol. 2006, 70, 488. (106) Huang, Z.; Xu, Y.; Li, L.; Li, Y. J. Agric. Food Chem. 2008, 56, 112. (107) Cheng, M. J.; Chen, J. J.; Wu, M. D.; Yang, P. S.; Yuan, G.. F. Nat. Prod. Res. 2010, 24, 979. (108) Quang, D. N.; Hashimoto, T.; Fournier, J.; Stadler, M.; Radulović, N.; Asakawa, Y. Tetrahedron 2005, 61, 1743. (109) Cheng, M.-J.; Wu, M.-D.; Su, Y.-S.; Yuan, G.-F.; Chen, Y.-L.; Chen, I.-S. Phytochem. Lett. 2012, 5, 262. (110) Takayuki, A., Hiroshi, S. Jpn. Pat. JP 6329576, 1994. (111) Stierle, A. A.; Stierle, D. B.; Girtsman, T. J. Nat. Prod. 2012, 75, 344. (112) Nukina, M.; Marumo, S. Tetrahedron Lett. 1977, 18, 2603. (113) Natsume, M.; Takahashi, Y.; Marumo, S. Agric. Biol. Chem. 1988, 52, 307. (114) Singh, S. B.; Kelly, R.; Guan, Z.; Polishook, J. D.; Dombrowski, A. W.; Collado, J.; González, A.; Pelaez, F.; Register, E.; Kelly, T. M.; Bonfiglio, C.; Williamson, J. M. Nat. Prod. Res. 2005, 19, 739. (115) Quang, D. N.; Hashimoto, T.; Stadler, M.; Asakawa, Y. J. Nat. Prod. 2004, 67, 1152. (116) Buchi, G.; White, J. D.; Wogan, G. N. J. Am. Chem. Soc. 1965, 87, 3484. (117) Locci, R.; Merlini, L.; Nasini, G.; Locci, J. R. G. Microbiol. 1967, 15, 93. (118) Suzuki, S.; Hosoe, T.; Nozawa, K.; Yaguchi, T.; Udagawa, S.; Kawai, K. J. Nat. Prod. 1999, 62, 1328. (119) Proksa, B.; Uhrin, D.; Fuska, J.; Michalkova, E. Collect. Czech. Chem. Commun. 1992, 57, 408. (120) Natsume, M.; Takahashi, Y.; Marumo, S. Agric. Biol. Chem. 1985, 49, 2517. (121) Lesova, K.; Sturdikova, M.; Rosenberg, M. J. Basic Microbiol. 2000, 40, 369. (122) Proksa, B.; Sturdikova, M.; Mojumdar, S. C.; Fuska, J. Folia Microbiol. 1997, 42, 133. (123) (a) Steglich, W.; Klaar, M.; Furtner, W. Phytochemistry 1974, 13, 2874. (b) Stadler, M.; Quang, D. N.; Tomita, A.; Hashimoto, T.; Asakawa, Y. Mycol. Res. 2006, 110, 811. (c) Quang, D. N.; Hashimoto, T.; Asakawa, Y. Chem. Rec. 2006, 6, 79. (124) Ogasawara, N.; Kawai, K. Phytochemistry 1998, 47, 1131. (125) Li, L. Q.; Yang, Y. G.; Zeng, Y.; Zou, C.; Zhao, P. J. Molecules 2010, 15, 3993. (126) Nozawa, K.; Saito, R.; Udagawa, S.-I.; Nakajima, S.; Kawai, K.-I. Phytochemistry 1995, 39, 719. (127) Yamazaki, H.; O̅ Mura, S.; Tomoda, H. Chem. Pharm. Bull. 2010, 58, 829. (128) Merlini, L.; Mondelli, R.; Nasini, G.; Hesse, M. Helv. Chim. Acta 1973, 56, 232. (129) Hellwig, V.; Ju, Y.-M.; Rogers, J. D.; Fournier, J.; Stadler, M. Mycol. Prog. 2005, 4, 39. (130) Kimura, T.; Nishida, M.; Kuramochi, K.; Sugawara, F.; Yoshida, H.; Mizushina, Y. Bioorg. Med. Chem. 2008, 16, 4594. (131) Myobatake, Y.; Takeuchi, T.; Kuramochi, K.; Kuriyama, I.; Ishido, T.; Hirano, K.; Sugawara, F.; Yoshida, H.; Mizushina, Y. J. Nat. Prod. 2012, 75, 135. BA


Chemical Reviews

Review

(132) Itabashi, T.; Nozawa, K.; Miyaji, M.; Udagawa, S.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1992, 40, 3142. (133) Itabashi, T.; Ogasawara, N.; Nozawa, K.; Kawai, K. Chem. Pharm. Bull. 1996, 44, 2213. (134) Itabashi, T.; Nozawa, K.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1993, 41, 2040. (135) Quang, D. N.; Hashimoto, T.; Stadler, M.; Asakawa, Y. Tetrahedron 2005, 61, 8451. (136) Gao, S. S.; Li, X. M.; Zhang, Y.; Li, C. S.; Cui, C. M.; Wang, B. G. J. Nat. Prod. 2011, 74, 256. (137) Wang, H.; Wang, Y.; Wang, W.; Fu, P.; Liu, P.; Zhu, W. J. Nat. Prod. 2011, 74, 2014. (138) (a) Tabata, Y.; Ikegami, S.; Yaguchi, T.; Sasaki, T.; Hoshiko, S.; Sakuma, S.; Shin-Ya, K.; Seto, H. J. Antibiot. 1999, 52, 412. (b) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321. (139) Hyodo, S.; Fujita, K.; Kasuya, O.; Takahashi, I.; Uzawa, J.; Koshino, H. Tetrahedron 1995, 51, 6717. (140) Li, G.-H.; Wang, X.-B.; Liu, F.-F.; Dang, L.-Z.; Li, L.; Yang, Z.S.; Xin, X.; Zhang, K.-Q. Chem. Biodiversity 2010, 7, 1790. (141) Hashimoto, T.; Asakawa, Y. Heterocycles 1998, 47, 1067. (142) Yang, S. W.; Chan, T. M.; Terracciano, J.; Patel, R.; Patel, M.; Gullo, V.; Chu, M. J. Antibiot. 2006, 59, 720. (143) Yang, S. W.; Chan, T. M.; Terracciano, J.; Loebenberg, D.; Patel, M.; Gullo, V.; Chu, M. J. Antibiot. 2009, 62, 401. (144) (a) Bertini, S. Ann. Stn. Chim.-Agrar. Sper. Roma 1956, 11, 545. (b) Nakanishi, T.; Oku, H. Phytopathology 1969, 59, 1563. (c) Marcinkowska, J.; Klos, B.; Shcherbakova, A. J. Phytopathol. 1991, 131, 253. (145) (a) Oku, H.; T. Nakanishi, T. Phytopathology 1963, 53, 1321. (b) Beed, F. D.; Sue, R. E.; Strange, R. N. Mycol. Res. 1994, 98, 1069. (146) (a) Iwai, I.; Mishima, H. Chem. Ind. 1965, 186. (b) Galbraith, M. N.; Whalley, W. B. J. Chem. Soc. 1971, 3557. (147) Seibert, S. F.; Eguereva, E.; Krick, A.; Kehraus, S.; Voloshina, E.; Raabe, G.; Fleischhauer, J.; Leistner, E.; Wiese, M.; Prinz, H.; Alexandrov, K.; Janning, P.; Waldmann, H.; König, G. M. Org. Biomol. Chem. 2006, 4, 2233. (148) Takahashi, M.; Koyama, K.; Natori, S. Chem. Pharm. Bull. 1990, 38, 625. (149) Kingsland, S. R.; Barrow, R. A. Aust. J. Chem. 2009, 62, 269. (150) Phonkerd, N.; Kanokmedhakul, S.; Kanokmedhakul, K.; Soytong, K.; Prabpai, S.; Kongsearee, P. Tetrahedron 2008, 64, 9636. (151) Borges, W. S.; Mancilla, G.; Guimarães, D. O.; Durán-Patrón, R.; Collado, I. G.; Pupo, M. T. J. Nat. Prod. 2011, 74, 1182. (152) Chen, G. D.; Li, Y. J.; Gao, H.; Chen, Y.; Li, X. X.; Li, J.; Guo, L. D.; Cen, Y. Z.; Yao, X. S. Planta Med. 2012, 78, 1683. (153) Yamada, T.; Doi, M.; Shigeta, H.; Muroga, Y.; Hosoe, S.; Numata, A.; Tanaka, R. Tetrahedron Lett. 2008, 49, 4192. (154) Yasuhide, M.; Yamada, T.; Numata, A.; Tanaka, R. J. Antibiot. 2008, 61, 615. (155) Muroga, Y.; Yamada, T.; Numata, A.; Tanaka, R. Helv. Chim. Acta 2010, 93, 542. (156) Yamada, T.; Yasuhide, M.; Shigeta, H.; Numata, A.; Tanaka, R. J. Antibiot. 2009, 62, 353. (157) Yamada, T.; Muroga, Y.; Tanaka, R. Mar. Drugs 2009, 7, 249. (158) Muroga, Y.; Yamada, T.; Numata, A.; Tanaka, R. Tetrahedron 2009, 65, 7580. (159) Yamada, T.; Muroga, Y.; Jinno, M.; Kajimoto, T.; Usami, Y.; Numata, A.; Tanaka, R. Bioorg. Med. Chem. 2011, 19, 4106. (160) Qin, J. C.; Zhang, Y. M.; Gao, J. M.; Bai, M. S.; Yang, S. X.; Laatsch, H.; Zhang, A. L. Bioorg. Med. Chem. Lett. 2009, 19, 1572. (161) Yamada, T.; Jinno, M.; Kikuchi, T.; Kajimoto, T.; Numata, A.; Tanaka, R. J. Antibiot. 2012, 65, 413. (162) Brian, P. W.; Curtis, P. J.; Hemming, H. G.; Norris, G. L. F. Trans. Br. Mycol. Soc. 1957, 40, 369. (163) (a) McOmie, J. F. W.; Turner, A. B.; Tute, M. S. J. Chem. Soc. 1966, 1608. (b) Tanenbaum, S. W.; Nakajima, S. Biochemistry 1969, 8, 4622. (164) Tanenbaum, S. W.; Nakajima, S. Biochemistry 1969, 8, 4626.

(165) Houbraken, J.; López Quintero, C. A.; Frisvad, J. C.; Boekhout, T.; Theelen, B.; Franco-Molano, A. E.; Samson, R. A. Int. J. Syst. Evol. Microbiol. 2011, 61, 1462. (166) Yu, B. Z.; Zhang, G. H.; Du, Z. Z.; Zheng, Y. T.; Xu, J. C.; Luo, X. D. Phytochemistry 2008, 69, 2523. (167) Vinale, F.; Marra, R.; Scala, F.; Ghisalberti, E. L.; Lorito, M.; Sivasithamparam, K. Lett. Appl. Microbiol. 2006, 43, 143. (168) Vinale, F.; Ghisalberti, E. L.; Sivasithamparam, K.; Marra, R.; Ritieni, A.; Ferracane, R.; Woo, S.; Lorito, M. Lett. Appl. Microbiol. 2009, 48, 705. (169) Qian-Cutrone, J.; Huang, S.; Chang, L. P.; Pirnik, D. M.; Klohr, S. E.; Dalterio, R. A.; Hugill, R.; Lowe, S.; Alam, M.; Kadow, K. F. J. Antibiot. 1996, 49, 990. (170) Kang, H. S.; Jun, E. M.; Park, S. H.; Heo, S. J.; Lee, T. S.; Yoo, I. D.; Kim, J. P. J. Nat. Prod. 2007, 70, 1043. (171) Kang, H. S.; Kim, K. R.; Jun, E. M.; Park, S. H.; Lee, T. S.; Suh, J. W.; Kim, J. P. Bioorg. Med. Chem. Lett. 2008, 18, 4047. (172) Becker, U.; Erkel, G.; Kocksch, G.; Anke, T.; Sterner, O. Z. Naturforsch., C 1997, 52, 313. (173) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357. (174) (a) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450. (b) Snaddon, T. N.; Buchgraber, P.; Schulthoff, S.; Wirtz, C.; Mynott, R.; Furstner, A. Chem.Eur. J. 2010, 16, 12133. (175) (a) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009, 48, 1283. (b) Wu, X.; Zhou, J.; Snider, B. B. J. Org. Chem. 2009, 74, 6245. (176) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131, 11350. (177) Wu, X.; Zhou, J.; Snider, B. B. J. Org. Chem. 2009, 74, 6245. (178) Haraguchi, H.; Taniguchi, M.; Motoba, K.; Shibata, K.; Oi, S.; Hashimoto, K. Agric. Biol. Chem. 1990, 54, 2167. (179) Sakuda, S.; Otsuba, Y.; Yamada, Y. J. Antibiot. 1995, 48, 85. (180) Laakso, J. A.; Raulli, R.; McElhaney-Feser, G. E.; Actor, P.; Underiner, T. L.; Hotovec, B. J.; Mocek, U.; Cihlar, R. L.; Broedel, S. E., Jr. J. Nat. Prod. 2003, 66, 1041. (181) Kono, K.; Tanaka, M.; Ono, Y.; Hosoya, T.; Ogita, T.; Kohama, T. J. Antibiot. 2001, 54, 415. (182) Inagaki, T.; Kaneda, K.; Suzuki, Y.; Hirai, H.; Nomura, E.; Sakakibara, T.; Yamauchi, Y.; Huang, L. H.; Norcia, M.; Wondrack, L. M.; Sutcliffe, J. A.; Kojima, N. J. Antibiot. 1998, 51, 112. (183) Kock, I.; Draeger, S.; Schulz, B.; Elsässer, B.; Kurtán, T.; Á . Kenéz, Á .; Antus, S.; Pescitelli, G.; Salvadori, P.; Speakman, J.-B.; Rheinheimer, J.; Krohn, K. Eur. J. Org. Chem. 2007, 1427. (184) (a) Li, Y.; Niu, S.; Sun, B.; Liu, S.; Liu, X.; Che, Y. Org. Lett. 2010, 12, 3144. (b) Frelek, J.; Geiger, M.; Voelter, W. Curr. Org. Chem. 1999, 3, 117. (185) Spence, J. T. J.; George, J. H. Org. Lett. 2011, 13, 5318. (186) Curtin, T. P.; Reilly, J. Biochem. J. 1940, 34, 1419. (187) Curtin, T. M.; Reilly, J. Nature 1940, 3697, 335. (188) Dean, F. M.; Staunton, J.; Waalley, W. B. J. Chem. Soc. 1959, 3004. (189) Whalley, W. B.; Ferguson, G.; Marsh, W. C.; Restive, R. J. J. Chem. Soc., Perkin Trans. 1 1976, 1366. (190) Pairet, L.; Wrigley, S. K.; Chetland, I.; Reynolds, E. E.; Hayes, M. A.; Holloway, J.; Ainsworth, A. M.; Katzer, W.; Cheng, X. M.; Hupe, D. J.; Charlton, P.; Doherty, A. M. J. Antibiot. 1995, 48, 913. (191) Takenaka, Y.; Tanahashi, T.; Nagakura, N.; Hamada, N. Z. Naturforsch. 2000, 55, 910. (192) Nam, J. Y.; Son, K. H.; Kim, H. K.; Han, M. Y.; Kim, S. U.; Choi, J. D.; Kwon, B. M. J. Microbiol. Biotechnol. 2000, 10, 544. (193) Chidananda, C.; Sattur, A. P. J. Agric. Food Chem. 2007, 55, 2879. (194) Chidananda, C.; Rao, L. J.; Sattur, A. P. Biotechnol. Lett. 2006, 28, 1633. (195) Arunpanichlert, J.; Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit, S.; Tewtrakul, S.; Rungjindamai, N.; Sakayaroj, J. Chem. Pharm. Bull. 2010, 58, 1033. BB


Chemical Reviews

Review

(196) Wang, X.; Sena Filho, J. G.; Hoover, A. R.; King, J. B.; Ellis, T. K.; Powell, D. R.; Cichewicz, R. H. J. Nat. Prod. 2010, 73, 942. (197) Lucas, E. M. F.; Monteiro de Castro, M. C.; Takahashi, J. A. Braz. J. Microbiol. 2007, 38, 785. (198) Matsuzaki, K.; Ikeda, H.; Masuma, R.; Tanaka, H.; Omura, S. J. Antibiot. 1995, 48, 703. (199) Yang, D. J.; Tomoda, H.; Tabata, N.; Masuma, R.; Omura, S. J. Antibiot. 1996, 49, 223. (200) Giridharan, P.; Verekar, S. A.; Khanna, A.; Mishra, P. D.; Deshmukh, S. K. Indian J. Exp. Biol. 2012, 50, 464. (201) Xiao, B. H.; She, Z. G.; Lei, X. L.; Chen, B.; Huang, C. H.; Xu, J. Zhong Yao Cai 2011, 34, 544. (202) Arai, N.; Shiomi, K.; Tomoda, H.; Tabata, N.; Yang, D. J.; Masuma, R.; Kawakubo, T.; Omura, S. J. Antibiot. 1995, 48, 696. (203) (a) Udagawa, S. Chem. Pharm. Bull. 1963, 11, 366. (b) Gregory, E. M.; Turner, W. B. Chem. Ind. 1963, 1625. (204) Gray, R. W.; Whalley, W. B. J. Chem. Soc. 1971, 3575. (205) Jackman, G. B.; Robertson, A.; Travers, R. B.; Whalley, W. B. J. Chem. Soc. 1958, 1825. (206) Bao, L.; Xu, Z.; Niu, S. B.; Namikoshi, M.; Kobayashi, H.; Liu, H. W. Nat. Prod. Commun. 2010, 5, 1789. (207) Satoh, Y.; Yamazaki, M. Chem. Pharm. Bull. 1989, 37, 206. (208) Fujimoto, H.; Matsudo, T.; Yamaguchi, A.; Yamazaki, M. Heterocycles 1990, 30, 607. (209) Yoshida, E.; Fujimoto, H.; Yamazaki, M. Nat. Med. 1996, 50, 54. (210) Yoshida, E.; Fujimoto, H.; Baba, M.; Yamazaki, M. Chem. Pharm. Bull. 1995, 43, 1307. (211) Toki, S.; Tanaka, T.; Uosaki, Y.; Yoshida, M.; Suzuki, Y.; Kita, K.; Mihara, A.; Ando, Y.; Lokker, N. A.; Giese, N. A.; Matsuda, Y. J. Antibiot. 1999, 52, 235. (212) Omura, S.; Tanaka, H.; Matsuzaki, K.; Ikeda, H.; Masuma, R. J. Antibiot. 1993, 46, 1908. (213) Matsuzaki, K.; Tanaka, H.; Omura, S. J. Antibiot. 1995, 48, 708. (214) Kanokmedhakul, S.; Kanokmedhakul, K.; Nasomjai, P.; Louangsysouphanh, S.; Soytong, K.; Isobe, M.; Kongsaeree, P.; Prabpai, S.; Suksamrarn, A. J. Nat. Prod. 2006, 69, 891. (215) Seto, H.; Tanabe, M. Tetrahedron Lett. 1974, 15, 651. (216) Yoshida, E.; Fujimoto, H.; Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 284. (217) Chiang, Y. M.; Szewczyk, E.; Davidson, A. D.; Keller, N.; Oakley, B. R.; Wang, C. C. J. Am. Chem. Soc. 2009, 131, 2965. (218) Quang, D. N.; Hashimoto, T.; Stadler, M.; Radulović, N.; Asakawa, Y. Planta Med. 2005, 71, 1058. (219) Quang, D. N.; Stadler, M.; Fournier, J.; Tomita, A.; Hashimoto, T. Tetrahedron 2006, 62, 6349. (220) Panthama, N.; Kanokmedhakul, S.; Kanokmedhakul, K.; Soytong, K. J. Nat. Prod. 2011, 74, 2395. (221) Quang, D. N.; Hashimoto, T.; Nomura, Y.; Wollweber, H.; Hellwig, V.; Fournier, J.; Stadler, M.; Asakawa, Y. Phytochemistry 2005, 66, 797. (222) Hashimoto, T.; Tahara, S.; Takaoka, S.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull. 1994, 42, 2397. (223) Ariza, M. R.; Larsen, T. O.; Petersen, B. O.; Duus, J. Ø.; Christophersen, C.; Barrerof, A. F. J. Nat. Prod. 2001, 64, 1590. (224) Quang, D. N.; Hashimoto, T.; Tanaka, M.; Stadler, M.; Asakawa, Y. Phytochemistry 2004, 65, 469. (225) Che, Y.; Gloer, J. B.; Koster, B.; Malloch, D. J. Nat. Prod. 2002, 65, 916. (226) Ding, G.; Liu, S.; Guo, L.; Zhou, Y.; Che, Y. J. Nat. Prod. 2008, 71, 615. (227) Ma, L.-Y.; Liu, W.-Z.; Shen, L.; Huang, Y.-L.; Rong, X.-G.; Xu, Y.-Y.; Gao, X.-D. Tetrahedron 2012, 68, 2276. (228) Krohn, K.; Biele, C.; Drogies, K.-H.; Steingrover, K.; Aust, H.J.; Draeger, S.; Schulz, B. Eur. J. Org. Chem. 2002, 2331. (229) (a) Lane, D. P. Nature 1992, 358, 15. (b) Chen, J.-D.; Wu, X.W.; Lin, J.-Y.; Levine, A.-J. Mol. Cell. Biol. 1996, 16, 2445.

(230) Duncan, S. J.; Gruschow, S.; Williams, D. H.; McNicholas, C.; Purewal, R.; Hajek, M.; Geritz, M.; Martin, S.; Wrigley, S. V.; Moore, M. J. Am. Chem. Soc. 2001, 123, 554. (231) Desai, P.; Pfeiffer, S. S.; Boger, D. L. Org. Lett. 2003, 5, 5047. (232) Malkinson, J. P.; Zloh, M.; Kadom, M.; Errington, R.; Smith, P. J.; Searcey, M. Org. Lett. 2003, 5, 5051. (233) Qian, W. J.; Wei, W. G.; Zhang, Y. X.; Yao, Z. J. J. Am. Chem. Soc. 2007, 129, 6400. (234) Clark, R. C.; Lee, S. Y.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 12355. (235) Lee, S. Y.; Clark, R. C.; Boger, D. L. J. Am. Chem. Soc. 2007, 129, 9860. (236) Review: (a) Lin, T. F.; Yakushijin, K.; Buchi, G. H.; Demain, A. L. J. Ind. Microbiol. 1992, 9, 173. (b) Carvalho, J. C.; Pandey, A.; Babitha, S.; Soccol, C. R. Agro Food Ind. Hi-Tech 2003, 14, 37. (237) Jung, H.; Kim, C.; Kim, K.; Shin, C. S. J. Agric. Food Chem. 2003, 51, 1302. (238) Mapari, S. A. S.; Nielsen, K. F.; Larsen, T. O.; Frisvad, J. C.; Meyer, A. S.; Thrane, U. Curr. Opin. Biotechnol. 2005, 16, 231. (239) (a) Moll, H. R.; Farr, D. R. U.S. Patent 3,993,789, 1976. (b) Nakawa, N.; Watanabe, S.; Kobayashi, J. Jpn. Pat. JP 7009682, 1980. (240) Coghlan, D. R.; Mackintosh, J. A.; Karuso, P. Org. Lett. 2005, 7, 2401. (241) Hiroi, T.; Shima, T.; Isobe, A.; Kimura, S. J. Jpn. Soc. Food Nutr. 1975, 28, 497. (242) Powell, A. D. G.; Robertson, A.; Whalley, W. B. J. Chem. Soc. 1956, 5, 27. (243) Hajiaj, H.; Klaébé, A.; Loret, M. O.; Tzédakis, T.; Goma, G.; Blanc, P. J. Appl. Environ. Microbiol. 1997, 63, 2671. (244) Sato, K.; Goda, Y.; Sakamoto, S. S.; Shibata, H.; Maitani, T.; Yamada, T. Chem. Pharm. Bull. 1997, 45, 227. (245) Kim, J. H.; Kim, H. J.; Kim, C.; Jung, H.; Kim, Y. O.; Ju, J. Y.; Shin, C. S. Food Chem. 2007, 101, 357. (246) Kim, J. H.; Kim, H. J.; Park, H. W.; Youn, S. H.; Choi, D. Y.; Shin, C. S. FEMS Microbiol Lett. 2007, 276, 93. (247) Lin, T. F.; Demain, A. L. Arch. Microbiol. 1994, 162, 114. (248) Jeun, J.; Jung, H.; Kim, J. H.; Kim, Y. O.; Youn, S. H.; Shin, C. S. Food Chem. 2008, 107, 1078. (249) Lian, X.; Wang, C.; Guo, K. Dyes Pigm. 2007, 73, 121. (250) Wild, D.; Tóth, G.; Humpf, H. U. J. Agric. Food Chem. 2003, 51, 5493. (251) Knecht, A.; Cramer, B.; Humpf, H. U. Mol. Nutr. Food Res. 2006, 50, 314. (252) Knecht, A.; Humpf, H. U. Mol. Nutr. Food Res. 2006, 50, 406. (253) Ogihara, J.; Kato, J.; Oishi, K.; Fujimoto, Y.; Eguchi, T. J. Biosci. Bioeng. 2000, 90, 549. (254) Ogihara, J.; Kato, J.; Oishi, K.; Fujimoto, Y. J. Biosci. Bioeng. 2000, 90, 678. (255) Ogihara, J.; Kato, J.; Oishi, K.; Fujimoto, Y. J. Biosci. Bioeng. 2001, 91, 44. (256) Eade, R. A.; Page, H.; Robertson, A.; Turner, K.; Whalley, W. B. J. Chem. Soc. 1957, 4913. (257) Whalley, W. B. Pure Appl. Chem. 1963, 7, 565. (258) Michael, A. P.; Grace, E. J.; Kotiw, M.; Barrow, R. A. Aust. J. Chem. 2003, 56, 13. (259) Zang, L.-Y.; Wei, W.; Wang, T.; Guo, Y.; Tan, R.-X.; Ge, H.-M. Nat. Prod. Bioprospect. 2012, 2, 117. (260) Ge, H. M.; Zhang, W. Y.; Ding, G.; Saparpakorn, P.; Song, Y. C.; Hannongbua, S.; Tan, R. X. Chem. Commun. 2008, 45, 5978. (261) Yang, S.-X.; Xiao, J.; Holstein, J. J.; Dittrich, B.; Laatsch, H.; Gao, J.-M. Tetrahedron Lett. 2012, 53, 6372. (262) (a) Chong, R.; Gray, R. W.; King, R. R.; Whalley, W. B. J. Chem. Soc. 1971, 3571. (b) Chong, R.; Gray, R. W.; King, R. R.; Whalley, W. B. J. Chem. Soc., Chem. Commun. 1970, 101. (c) Chong, R.; King, R. R.; Whalley, W. B. J. Chem. Soc., Chem. Commun. 1969, 1512. (263) Suzuki, T.; Okada, C.; Arai, K.; Awaji, A.; Shimizu, T.; Tanemura, K.; Horaguchi, T. J. Heterocycl. Chem. 2001, 38, 1409. BC


Chemical Reviews

Review

(298) Sutcliffe, J. A.; Gootz, T. D.; Barrett, J. F. Antimicrob. Agents Chemother. 1989, 33, 2027. (299) Zhang, H.; D’Arpa, P.; Liu, L. F. Cancer Cells 1990, 2, 23. (300) Johnson, T. O.; Ermolieff, J.; Jirousek, M. R. Nat. Rev. Drug Discovery 2002, 1, 696. (301) (a) Singh, R.; Rao, V.; Shakila, H.; Gupta, R.; Khera, A.; Dhar, N.; Singh, A.; Koul, A.; Singh, Y.; Naseema, M.; Narayanan, P. R.; Paramasivan, C. N.; Ramanathan, V. D.; Tyagi, A. K. Mol. Microbiol. 2003, 50, 751. (b) Beresford, N. J.; Mulhearn, D.; Szczepankiewicz, B.; Liu, G.; Johnson, M. E.; Fordham-Skelton, A.; Adab-Zapatero, C.; Cavet, J. S.; Tabernero, L. J. Antimicrob. Chemother. 2009, 63, 928. (302) Kim, J. H.; Kim, Y. O.; Jeun, J.; Choi, D. Y.; Shin, C. S. Biosci., Biotechnol., Biochem. 2010, 74, 304. (303) Jou, P. C.; Ho, B. Y.; Hsu, Y. W.; Pan, T. M. J. Agric. Food Chem. 2010, 58, 12703. (304) Tomoda, H.; Matsushima, C.; Tabata, N.; Namatame, I.; Tanaka, H.; Bamberger, M. J.; Arai, H.; Fukazawa, M.; Inoue, K.; Omura, S. J. Antibiot. 1999, 52, 160. (305) Su, N. W.; Lin, Y. L.; Lee, M. H.; Ho, C. Y. J. Agric. Food Chem. 2005, 53, 1949. (306) Akihisa, T.; Tokuda, H.; Ukiya, M.; Kiyota, A.; Yasukawa, K.; Sakamoto, N.; Kimura, Y.; Suzuki, T.; Takayasu, J.; Nishino, H. Chem. Biodiversity 2005, 2, 1305. (307) Zheng, Y.; Xin, Y.; Shi, X.; Guo, Y. J. Agric. Food. Chem. 2010, 58, 9523. (308) Zheng, Y.; Xin, Y.; Shi, X.; Guo, Y. Appl. Microbiol. Biotechnol. 2010, 88, 1169. (309) Chiu, H. W.; Fang, W. H.; Chen, Y. L.; Wu, M. D.; Yuan, G.. F.; Ho, S. Y.; Wang, Y. J. PLoS One 2012, 7, e40462. (310) Yasukawa, K.; Itabashi, T.; Kawai, K.-I.; Takido, M. J. Nat. Med. 2008, 62, 384. (311) Quang, D. N.; Harinantenaina, L.; Nishizawa, T.; Hashimoto, T.; Kohchi, C.; Soma, G.; Asakawa, Y. Biol. Pharm. Bull. 2006, 29, 34. (312) Nakamum, K.; Kino, T.; Niko, K.; Kyotoo, S.; Okuhara, M. Jpn. Pat. JP 02255615 A2, 1990. (313) Lee, C. L.; Kung, Y. H.; Wu, C. L.; Hsu, Y. W.; Pan, T. M. J. Agric. Food Chem. 2010, 58, 9013. (314) Lin, C. P.; Lin, Y. L.; Huang, P. H.; Tsai, H. S.; Chen, Y. H. J. Sci. Food Agric. 2011, 91, 1751. (315) Hsu, W. H.; Lee, B. H.; Lu, I. J.; Pan, T. M. J. Agric. Food Chem. 2012, 60, 1666. (316) Lin, L.; Mulholland, N.; Wu, Q. Y.; Beattie, D.; Huang, S. W.; Irwin, D.; Clough, J.; Gu, Y. C.; Yang, G. F. J. Agric. Food Chem. 2012, 60, 4480. (317) Lin, L.; Mulholland, N.; Huang, S. W.; Beattie, D.; Irwin, D.; Gu, Y. C.; Clough, J.; Wu, Q. Y.; Yang, G. F. Chem. Biol. Drug Des. 2012, 80, 682. (318) Park, J. H.; Choi, G. J.; Jang, K. S.; Lim, H. K.; Kim, H. T.; Cho, K. Y.; Kim, J. C. FEMS Microbiol. Lett. 2005, 252, 309. (319) Review: Steyn, P. S. Pure Appl. Chem. 1980, 52, 189. (320) Birch, A. J.; Fitton, P.; Pride, E.; Ryan, A. J.; Smith, H.; Whalley, W. B. J. Chem. Soc. 1958, 4576. (321) Schwenk, E.; Alexander, G. J.; Gold, A. M.; Stevens, D. F. J. Biol. Chem. 1958, 233, 1211. (322) Colombo, L.; Gennari, C.; Scolastico, C.; Aragozzini, F.; Merendi, C. J. Chem. Soc., Chem. Commun. 1980, 1132. (323) Colombo, L.; Gennari, C.; Potenza, D.; Scolastico, C.; Aragozzini, F.; Merendi, C. J. Chem. Soc., Perkin Trans. 1 1981, 2594. (324) Barber, J.; Chapman, A. C.; Howard, T. D. J. Antibiot. 1987, 40, 245. (325) Curtis, R. F.; Hassall, C. H.; Nazar, M. J. Chem. Soc. 1968, 85. (326) Hajjaj, H.; Klaebe, A.; Loret, M. O.; Goma, G.; Blanc, P. J.; Francois, J. Appl. Environ. Microbiol. 1999, 65, 311. (327) Pisareva, E.; Savov, V.; Kujumdzieva, A. Z. Naturforsch., C 2005, 60, 116. (328) Colombo, L.; Gennari, C.; Ricca, G. S.; Scolastico, C.; Aragozzini, F. J. Chem. Soc., Chem. Commun. 1981, 575. (329) Colombo, L.; Scolastico, C.; Lukacs, G.; Dessinges, A.; Aragozzini, F.; Merendi, C. J. Chem. Soc., Chem. Commun. 1983, 1436.

(264) For recent examples of cycloisomerization of alkynyl substrates, see: Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (265) (a) Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem., Int. Ed. 2003, 42, 4399. (b) Achard, M.; Beeler, A. B.; Porco, J. A., Jr. ACS Comb. Sci. 2012, 14, 236. (266) For reviews on the chemistry of 2-benzopyrylium salts, see: Kuznetsov, E.; Shcherbakova, I. V.; Balaban., A. T. Adv. Heterocycl. Chem. 1990, 50, 157. (267) Coghlan, D. R.; Mackintosh, J. A.; Karuso, P. Org. Lett. 2005, 7, 2401. (268) Wei, W.-G.; Yao, Z.-J. J. Org. Chem. 2005, 70, 4585. (269) Barber, J. A.; Staunton, J.; Wilkinson, M. R. J. Chem. Soc., Perkin Trans. 1 1986, 2101. (270) Regan, A. C.; Staunton, J. J. Chem. Soc., Chem. Commun. 1987, 520. (271) Roedel, T.; Gerlach, H. Liebigs Ann. 1995, 885. (272) Galbraith, M. N.; Whalley, W. B. J. Chem. Soc. 1971, 3557. (273) Birchall, G. R.; Galbraith, M. N.; Gray, R. W.; King, R. R.; Whalley, W. B. J. Chem. Soc. 1971, 3559. (274) Germain, A. R.; Bruggemeyer, D. M.; Zhu, J.; Genet, C.; O’Brien, P.; Porco, J. A. J. Org. Chem. 2011, 76, 2577. (275) Somoza, A. D.; Lee, K. H.; Chiang, Y. M.; Oakley, B. R.; Wang, C. C. Org. Lett. 2012, 14, 972. (276) Zhu, J.; Porco, J. A., Jr. Org. Lett. 2006, 8, 5169. (277) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43, 1239. (278) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2005, 127, 9342. (279) (a) Stark, L. M.; Pekari, K.; Sorensen, E. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12064. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (280) Chruma, J. J.; Moon, S.-J.; Sanford, W. E., Jr. Lett. Org. Chem. 2009, 6, 367. (281) Boulange, A.; Peixoto, P. A.; Franck, X. Chem.Eur. J. 2011, 17, 10241. (282) (a) Wenderski, T. A.; Marsini, M. A.; Pettus, T. R. R. Org. Lett. 2011, 13, 118. (283) (a) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. J. Org. Chem. 2012, 77, 400. (b) Wilson, Z. E.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 1284. (284) Sperry, J.; Wilson, Z. E.; Rathwell, D. C. K.; Brimble, M. A. Nat. Prod. Rep. 2010, 27, 1117. (b) Wilson, Z. E.; Brimble, M. A. Nat. Prod. Rep. 2009, 26, 44. (285) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. Org. Lett. 2011, 13, 5382. (286) Fañanás, F. J.; Mendoza, A.; Arto, T.; Temelli, B.; Rodríguez, F. Angew. Chem., Int. Ed. 2012, 51, 4930. (287) Hsu, W. H.; Pan, T. M. Appl. Microbiol. Biotechnol. 2012, 93, 1831. (288) Chène, P. Nat. Rev. Cancer 2003, 3, 102. (289) Duncan, S. J.; Cooper, M. A.; Williams, D. H. Chem. Commun. 2003, 316. (290) Zheleva, D. I.; Lane, D. P.; Fischer, P. M. Mini-Rev. Med. Chem. 2003, 3, 257. (291) (a) Woon, E. C. Y.; Arcieri, M.; Wilderspin, A. F.; Malkinson, J. P.; Searcey, M. J. Org. Chem. 2007, 72, 5146. (b) Lee, S. Y.; Boger, D. L. Tetrahedron 2008, 49, 6585. (292) Clark, R. C.; Lee, S. Y.; Hwang, I.; Searcey, M.; Boger, D. L. Tetrahedron Lett. 2009, 50, 3151. (293) Whitesell, L.; Lindquist, S. L. Nat. Rev. Cancer 2005, 5, 761. (294) (a) Pierson, T. C.; Doms, R. W. Immunol. Lett. 2003, 85, 113. (b) Wyatt, R.; Sodroski, J. Science 1998, 280, 1884. (295) Sun, X. L.; Takayanagi, H.; Matsuzaki, K.; Tanaka, H.; Furuhata, K.; Omura, S. J. Antibiot. 1996, 49, 689. (296) (a) Cao, Y.; Liu, X.; De Clercq, E. Curr. HIV Res. 2009, 7, 101. (b) Cao, Y.; Liu, X. Y. Yao Xue Xue Bao 2007, 42, 347. (297) (a) Pawson, T.; Schlessinger, J. Curr. Biol. 1993, 3, 434. (b) Gay, B.; Suarez, S.; Weber, C.; Rahuel, J.; Fabbro, D.; Furet, P.; Caravatti, G.; Schoepfer, J. J. Biol. Chem. 1999, 274, 23311. BD


Chemical Reviews

Review

(330) Colombo, L.; Gennari, C.; Ricca, G. S.; Scolastico, C.; Aragozzini, F. J. Chem. Soc., Perkin Trans. 1 1980, 675. (331) Colombo, L.; Gennari, C.; Scolastico, C.; Aragozzini, F.; Merendi, C. J. Chem. Soc., Perkin Trans. 1 1980, 2549. (332) Birch, A. J.; Cassera, A.; Fitton, P.; Holker, J. S. E.; Smith, H.; Thompson, G. A.; Whalley, W. B. J. Chem. Soc. 1962, 3583. (333) (a) Kurono, M.; Nakanishi, K.; Shindo, K.; Tada, M. Chem. Pharm. Bull. 1963, 11, 359. (b) Sato, K.; Iwakami, S.; Goda, Y.; Okuyama, E.; Yoshihira, K.; Ichi, T.; Odake, Y.; Noguchi, H.; Sankawa, U. Heterocycles 1992, 34, 2057. (334) Hadfield, J. R.; Holker, J. S. E.; Stanway, D. N. J. Chem. Soc. 1976, 751. (335) Winter, J. M.; Sato, M.; Sugimoto, S.; Chiou, G.; Garg, N. K.; Tang, Y.; Watanabe, K. J. Am. Chem. Soc. 2012, 134, 17900. (336) Duncan, S. J.; Williams, D. H.; Ainsworth, M.; Martin, S.; Ford, R.; Wrigley, S. K. Tetrahedron Lett. 2002, 43, 1075. (337) (a) Nakajima, H.; Fujimoto, H.; Matsumoto, R.; Hamasaki, T. J. Org. Chem. 1993, 58, 4526. (b) Nakajima, H.; Fukuyama, K.; Fujimoto, H.; Baba, T.; Hamasaki, T. J. Chem. Soc., Perkin Trans. 1 1994, 1865. (338) Zabala, A. O.; Xu, W.; Chooi, Y. H.; Tang, Y. Chem. Biol. 2012, 19, 1049. (339) Bailey, A. M.; Cox, R. J.; Harley, K.; Lazarus, C. M.; Simpson, T. J.; Skellam, E. Chem. Commun. 2007, 39, 4053. (340) D’Auria, J. C. Curr. Opin. Plant Biol. 2006, 9, 331.

BE


Azaphilones: Chemistry and Biology - ACS Publications - American

Recommend Documents