Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis

Abstract

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.

Figure 1

Reaction pathways in (a) a thermal reaction with reagent R yielding product P catalyzed by a catalyst (cat.) via intermediate I′ and (b) in a photochemically induced reaction where the chemical reaction commences from the excited state of the reagent (R*).

Figure 2

Representative examples where photochemical reactions have been exploited for construction of complex natural products with polycyclic frameworks.

Scheme 1. Ciamician and Silber’s early [2 + 2] Photocycloaddition of Carvone (5)

Scheme 2. Photoexcitation of Enones

ISC = intersystem crossing.

Scheme 3. Regioselectivity in [2 + 2] Photocycloadditions

Figure 3

Examples of natural products containing the cyclobutane scaffold.

Scheme 4. Intermolecular [2 + 2] Photocycloaddition in the Synthesis of (−)-Biyouyanagin A (17)

Scheme 5. Application of the Intramolecular [2 + 2] Photocycloaddition in the Total Synthesis of (−)-Littoralisone (20)

Scheme 6. [2 + 2] Photocycloaddition of Enone 21 in the Total Synthesis of (−)-Paeoniflorin (23)

Scheme 7. Intramolecular [2 + 2] Photocycloaddition for Synthesis of the (±)-Punctaporonin C (26) Core

TIPS = triisopropylsilyl.

Scheme 8. Intramolecular [2 + 2] Photocycloaddition in the Synthesis of (+)-Solanascone (29)

Scheme 9. Photochemical [2 + 2] Cycloaddition in the Total Synthesis of Aquatolide (32)

Scheme 10. Intramolecular [2 + 2] Photocycloaddition for Construction of the Tricyclo[5.2.1.0^1,6]decane Core of Solanoeclepin A (14)

Bpin = (pinacolato)boron. TBS = tert-butyldimethylsilyl.

Scheme 11. Intramolecular [2 + 2] Photocycloaddition of Optically Active Allene 35

Scheme 12. Photocycloaddition/Rearrangement of Pyrroles to Aziridines

Scheme 13. Formation of Cyclobutanes via [2 + 2] Photocycloaddition, Followed by Ring-Opening To Generate Medium-Sized Rings

Figure 4

Fragmentation strategies for [2 + 2] photocycloaddition adducts: (top) Grob fragmentation, (middle) radical fragmentation, and (bottom) De Mayo reaction.

Scheme 14. Application of the [2 + 2] Photocycloaddition/Ozonolysis/Retro-Dieckmann Reaction Sequence in the Synthesis of (±)-Gibberellic Acid (46)

MOM = methoxymethyl. SEM = 2-(trimethylsilyl)ethoxymethyl.

Scheme 15. Allene–Enone [2 + 2] Photocycloaddition with Subsequent Lewis Acid-Catalyzed Rearrangement in the Synthesis of (±)-Pentalenene (53)

Scheme 16. Dimethylsulfoxonium Methylide Mediated Rearrangement of Cyclobutane 54 in the Synthesis of Linderol A (56)

Scheme 17. Grob Fragmentation for Generation of the Hydroazulene Skeleton in the Synthesis of (±)-Epikessane (62)

p-TsOH = p-toluenesulfonic acid; p-TsCl = p-toluenesulfonyl chloride.

Figure 5

Structures of isocomene (63), β-isocomene (64), and modhephene (65).

Scheme 18. Tobe’s Approach for Construction of the Tricyclic Core of (±)-Isocomene (63)

HMPA = hexamethylphosphoric triamide. m-CPBA = m-chloroperoxybenzoic acid.

Figure 6

Structures of guanacastepenes A (71), C (72), and E (73).

Scheme 19. Use of the Intramolecular Enone–Olefin [2 + 2] Photocycloaddition and Stereoelectronically Controlled, Reductive, SmI₂-Mediated Fragmentation in the Syntheses of (+)-Guanacastepene A (71) and (+)-Guanacastepene E (73)

mCPBA = m-chloroperoxybenzoic acid. DIPEA = diisopropylethylamine. HMPA = hexamethylphosphoric triamide. PMP = p-methoxyphenyl.

Scheme 20. Bu₃SnH-Mediated Fragmentation of Cyclobutane 83 in the Formal Synthesis of (±)-Pentalenene (53)

AIBN = azobis(isobutyronitrile).

Scheme 21. [2 + 2] Photocycloaddition with Subsequent Bu₃SnH-Mediated Fragmentation in the Total Synthesis of Alismol (92)

AIBN = azobis(isobutyronitrile).

Scheme 22. Synthesis of (±)-Laurenene (99) via Intramolecular [2 + 2] Photocycloaddition Followed by Reductive Cleavage

p-TsOH = p-toluenesulfonic acid.

Scheme 23. Construction of the Core in Silphinene (105) By [2 + 2] Photocycloaddition

LDA = lithium diisopropylamide.

Figure 7

Structures of merrilactones A (106) and B (107).

Scheme 24. Mehta and Singh’s Approach to (±)-Merrilactone A (106)

PCC = pyridinium chlorochromate. TBS = tert-butyldimethylsilyl. p-TsOH = p-toluenesulfonic acid.

Scheme 25. Inoue and Co-Workers’ Approach toward (−)-Merrilactone A (106)

BTB = 2,6-bis(trifluoromethyl)benzyl.

Figure 8

Structures of ginkgolides A, B, C, M, and J (125, 4, 126–128) and bilobalide (129).

Scheme 26. Use of Intramolecular [2 + 2] Photocycloaddition in the Synthesis of Bilobalide (129)

m-CPBA = m-chloroperoxybenzoic acid. LDA = lithium diisopropylamide. MoOPH = (hexamethylphosphoric triamide)oxodiperoxy(pyridine)molybdenum(VI) (MoO₅·pyr·HMPA). Piv = pivaloyl.

Scheme 27. Total Synthesis of Ginkgolide B (4) via Stereoselective Intramolecular [2 + 2] Photocycloaddition and Cyclobutane Ring-Opening Methodology

CSA = camphorsulfonic acid. TES = triethylsilyl. p-TsOH = p-toluenesulfonic acid; HMPA = hexamethylphosphoric triamide.

Scheme 28. Ring Expansion of Cyclobutanes via Cargill Rearrangement

Scheme 29. Pirrung’s Approach to (±)-Isocomene (63)

p-TsOH = p-toluenesulfonic acid.

Scheme 30. [2 + 2] Photocycloaddition with Subsequent Thermal Ring Opening in the Synthesis of Periplanone B (154)

Scheme 31. Synthesis of the Nootropic Alkaloid (−)-Huperzine A (160) Using a [2 + 2] Photocycloaddition/Cyclobutane Fragmentation Sequence through an Aza-Prins Reaction

p-TsOH = p-toluenesulfonic acid.

Figure 9

Compounds containing the oxetane motif.

Scheme 32. Illustration of the Paternò–Büchi Reaction

ISC = intersystem crossing.

Scheme 33. Total Synthesis of the Pyrrolidinol Alkaloid (+)-Preussin (167) by a Diastereoselective Paternò–Büchi Approach

Scheme 34. Synthesis of (±)-Oxetanocin (171) Using the Paternò–Büchi Reaction

Scheme 35. Synthesis of (±)-1,13-Herbertendiol (176)

LDBB = lithium di-tert-butylbiphenylide.

Scheme 36. Intramolecular Paternò–Büchi Reaction To Produce Oxetane 184 Bearing the Tetracyclic Core of Merrilactone A (106)

PDC = pyridinium dichromate. TBAF = tetra-n-butylammonium fluoride.

Scheme 37. Rawal’s Synthesis of (±)-Isocomene (63) By an Intramolecular Paternò–Büchi Reaction

LDA = lithium diisopropylamide. LDBB = lithium 4,4′-di-tert-butylbiphenylide. MOM = methoxymethyl. DMPU = N,N′-dimethylpropyleneurea.

Scheme 38. Access to (±)-Sarracenin (202) Using a Paternò–Büchi Reaction

CSA = camphorsulfonic acid. DMS = dimethyl sulfide. TsCl = p-toluenesulfonyl chloride.

Scheme 39. Intramolecular Paternò–Büchi Reaction of Thiocarbonyl 203

Scheme 40. Initial Photochemical Experiments Performed by De Mayo and Co-Workers

Scheme 41. Depiction of the De Mayo Reaction

Scheme 42. Formation of 1,5-Cyclooctadione 221 Using the De Mayo Reaction

Figure 10

Examples of natural products accessed using the De Mayo reaction.

Scheme 43. Use of a Photocycloaddition/Retro-Aldol Sequence (De Mayo Reaction) in the Total Synthesis of (±)-Longifolene (232)

Figure 11

Representative examples of daucane (carotane) sesquiterpenes.

Scheme 44. Synthesis of (±)-Daucene (233) by Use of the De Mayo Reaction

Scheme 45. Construction of the Taxane Skeleton (247) by Use of an Intramolecular Dioxenone Photocycloaddition–Fragmentation Strategy

Figure 12

Structures of histrionicotoxin (248) and perhydrohistrionicotoxin (249).

Scheme 46. Unsuccessful Approach toward the Synthesis of Perhydrohistrionicotoxin (249) via Cyclobutene Intermediate 251

DMAP = 4-dimethylaminopyridine.

Scheme 47. Fragmentation of Photoproduct 255 en Route to the Total Synthesis of (−)-Perhydrohistrionicotoxin (249)

Scheme 48. Access to (±)-Saudin (267) by Means of a [2 + 2] Photocycloaddition and Subsequent Retro-Aldol Reaction

PPTS = pyridinium p-toluenesulfonate. Tf₂O = trifluoromethanesulfonic anhydride. TMEDA = N,N,N′,N′-tetramethylethylenediamine.

Figure 13

Skeletal types of Euphorbia diterpenes.

Figure 14

Structures of ingenol (2) and FDA approved ingenol mebutate (274).

Scheme 49. Application of the De Mayo Reaction in the First Total Synthesis of (±)-Ingenol (2)

LDA = lithium diisopropylamide. p-MBOH = p-methoxybenzyl alcohol. TFA = trifluoroacetic acid. TFAA = trifluoroacetic anhydride. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.

Scheme 50. Synthesis of (+)-Aphanamol I (291) by Use of a Modified De Mayo Sequence

Scheme 51. Hydroxide-Mediated Ring Expansion of [2 + 2] Photocycloaddition Product 293

Figure 15

Structure of the galanthan skeleton (296) and examples of Amaryllidaceae alkaloids.

Scheme 52. Synthesis of Tetracyclic Compound 309 Bearing the Galanthan Skeleton

p-TsOH = p-toluenesulfonic acid.

Scheme 53. Tamura and Co-Workers’ Initial Observation of the Intramolecular Photocycloaddition/Retro-Mannich Fragmentation Sequence of Vinylogous Amides

Scheme 54. Intramolecular Photocycloaddition/Retro-Mannich Fragmentation of Secondary Vinylogous Amide 313

Scheme 55. Intramolecular [2 + 2] Photocycloaddition of N-Alkenoyl β-Enaminones with Subsequent Acid- or Trimethylsilyl Iodide-Catalyzed Cyclobutane Ring Opening

Scheme 56. Use of the Photocycloaddition/Retro-Mannich Sequence for the Construction of the BC Substructure of Taxanes

TBS = tert-butyldimethylsilyl. m-CPBA = m-chloroperoxybenzoic acid.

Figure 16

Examples of alkaloids containing the cis-3a-aryloctahydroindole motif.

Scheme 57. Synthesis of Mesembrine (328) via the Intramolecular Photocycloaddition of Vinylogous Amide 330

DMAP = 4-dimethylaminopyridine.

Scheme 58. Photocycloaddition/Retro-Mannich Approach for Construction of the Koumine Core

Boc = tert-butyloxycarbonyl. TFA = trifluoroacetic acid.

Figure 17

Synthesis of the spiro[pyrrolidine-3,3′-oxindole] alkaloids coerulescine (340), horsfiline (341), and elacomine (342) by use of the [2 + 2] photocycloaddition/retro-Mannich fragmentation process.

Scheme 59. Formal Synthesis of the Aspidosperma Alkaloid Vindorosine (349) by Photocycloaddition/Retro-Mannich Fragmentation

Cbz = carboxybenzyl. LDA = lithium diisopropylamide. TBS = tert-butyldimethylsilyl.

Figure 18

Structures of the marine alkaloids ircinol A (350), ircinal A (351), manzamine A (352), and manzamine D (353).

Scheme 60. Photocycloaddition/Fragmentation/Mannich Closure to Ketone 358, a Precursor to Ircinol A (350), Ircinal A (351), Manzamine A (352), and Manzamine D (353)

Boc = tert-butyloxycarbonyl.

Figure 19

Examples of natural products produced by the plant genus Aglaia.

Scheme 61. Synthesis of Methyl Rocaglate (366) Using a [3 + 2] Photocycloaddition/Ketol Shift Rearrangement/Reduction Sequence

Scheme 62. Tandem Dienone Photorearrangement–Cycloaddition of Cyclohexadienone 367

Scheme 63. Tandem Dienone Photorearrangement/Cycloaddition/[4 + 2] Cycloaddition To Afford Polycyclic Ketone 374

Figure 20

Schematic depiction of the photoenolization/[4 + 2] cycloaddition sequence.

Scheme 64. Application of the Photoenolization/[4 + 2] Cycloaddition Sequence in the Total Synthesis of Estrone (3)

Scheme 65. Tandem Photoenolization/Diels–Alder Reaction in the Synthesis of Podophyllotoxin (385)

Scheme 66. Photocyclization in the Total Synthesis of 6-Methylpretetramid (389)

Figure 21

Structures of hamigerans A–C (390–392).

Scheme 67. Photochemical Generation and Diels–Alder Trapping of o-Quinodimethane 395 in the Total Synthesis of Hamigerans A (390) and B (391)

Scheme 68. Photoenolization/[4 + 2] Cycloaddition in the Total Synthesis of Hybocarpone (402)

Scheme 69. Photolysis of Bis-aldehyde 403 for Generation of (±)-cis-Alpinigenine (405)

Scheme 70. Photoisomerization of cis-2-Cycloheptenone (406)

Scheme 71. Intramolecular Diels–Alder Reaction of Photochemically Generated trans-Cycloheptenone

Figure 22

Structures of vibsanin B (411), C (412), and E (413).

Scheme 72. Application of a Tandem Photochemical Isomerization/[4 + 2] Cycloaddition Sequence in the Total Synthesis of (±)-5-Epi-10-epivibsanin E (423)

DIBAL-H = diisobutylaluminum hydride.

Scheme 73. Photoisomerization of (E,E,E,E)-Tetraene 424

Figure 23

Examples of monomeric and dimeric xanthanolides.

Scheme 74. Synthesis of 3-Epimogolide A (435) and Mogolide A (436)

Scheme 75. Depiction of the Norrish Type I Reaction and the Possible Photoproducts That Can Be Generated

Scheme 76. Depiction of the Norrish Type II Reaction Involving γ-Hydrogen Abstraction

Scheme 77. Use of the Norrish Type I Reaction in the Synthesis of α-Cuparenone (439)

Scheme 78. Decarbonylation/Cyclization Sequence in the Total Synthesis of (±)-Herbertenolide (442)

Scheme 79. Photoinduced Epimerization of Hydroxy Ketoester 443 at C10 through Norrish Type I Fragmentation–Recombination

Scheme 80. Norrish Type I Fragmentation of Diketone 446 Observed in the Total Syntheses of the Hamigerans

Scheme 81. Norrish Type I Cleavage with Subsequent γ-Hydrogen Abstraction in Bicyclo[2.2.1]Heptanone 450

PCC = pyridinium chlorochromate.

Scheme 82. Synthesis of (+)-Juvabione (459) through a Norrish Type I Fragmentation Methodology

Scheme 83. Norrish Type I Cleavage with Subsequent Oxacarbene Trapping in the Total Synthesis of Deacetoxyalcyonin Acetate (465)

Scheme 84. Norrish–Yang Cyclization of Ketone 467 in the Total Synthesis of (−)-Punctaporonin A (470)

MOM = methoxymethyl. SEM = 2-(trimethylsilyl)ethoxymethyl.

Figure 24

Structures of ouabain (471) and ouabagenin (472).

Scheme 85. Photoinduced Norrish–Yang Cyclization in the Synthesis of Ouabagenin (472)

NIS = N-iodosuccinimide. SDS = sodium dodecyl sulfate.

Scheme 86. Maleimide [5 + 2] Photocycloaddition/Norrish Type II Cascade for Synthesis of Tricyclic Lactone 483

Scheme 87. Application of the Norrish–Yang Cyclization in the Total Synthesis of (+)-Lactacystin (490)

Scheme 88. Use of the Norrish–Yang Cyclization in the Total Synthesis of (±)-Paulownin (493)

Scheme 89. Illustrative Examples of the Oxa-di-π-methane Rearrangement for (top) an Acyclic and (bottom) a Cyclic β,γ-Unsaturated Ketone

Scheme 90. Use of the Oxa-di-π-methane Rearrangement in the Formal Total Synthesis of (±)-Cedrol (501)

Figure 25

Examples of carbocyclic propellanes.

Scheme 91. Construction of the Carbocyclic Framework of (±)-Modhephene (65) by Use of the Oxa-di-π-methane Rearrangement

PCC = pyridinium chlorochromate.

Scheme 92. Uyehara’s Approach to (±)-Modhephene (65) and (±)-Isocomene (63)

Figure 26

Structures of the Lycopodium alkaloids (−)-magellanine (516), (−)-magellaninone (517), and (+)-paniculatine (518).

Scheme 93. Synthesis of the Tetracyclic (±)-Magellanine (516) by Use of the Oxa-di-π-methane Rearrangement

AIBN = azobis(isobutyronitrile). TMSOTf = trimethylsilyl trifluoromethanesulfonate.

Scheme 94. Synthesis of (±)-Δ⁹⁽¹²⁾-Capnellene (525) from 2-Methoxy-4-methylphenol (524)

Figure 27

Examples of linear triquinanes that have been synthesized via the oxa-di-π-methane rearrangement.

Scheme 95. (a) Three Modes of Photocycloadditions of an Alkene to a Benzene Ring, (b) Pathway for the Meta-Photocycloaddition, and (c) Key Bond Fragmentations for the Meta-Photocycloaddition Adduct for Accessing Complex Cyclic Frameworks

Figure 28

Examples of cedranoids.

Scheme 96. Total Synthesis of (±)-α-Cedrene (1) Using Meta-Photocycloaddition

Scheme 97. Photochemical Approach for Synthesis of (±)-Isocomene (63)

Scheme 98. Route to Silphinene (105) Using Meta-Photocycloaddition

Scheme 99. Synthesis of (−)-Retigeranic Acid A (548)

Scheme 100. Total Synthesis of (±)-Rudmollin (554) Using an Intramolecular Meta-Photocycloaddition Approach

Figure 29

Structure of penifulvins A–E.

Figure 30

Numbering of the fenestrane framework.

Scheme 101. Synthesis of Enantiomerically Enriched Alcohol 566 Using Pseudoephedrine as a Chiral Auxiliary

DIC = diisopropylcarbodiimide. DMAP = 4-dimethylaminopyridine. LDA = lithium diisopropylamide.

Scheme 102. Use of the Arene Olefin Meta-Photocycloaddition in the Total Synthesis of (−)-Penifulvin A (555)

IBX = 2-iodoxybenzoic acid. PCC = pyridinium chlorochromate.

Scheme 103. Total Synthesis of (±)-Laurenene (99)

AIBN = azobis(isobutyronitrile). DMPU = N,N′-dimethylpropyleneurea. LDA = lithium diisopropylamide. NBS = N-bromosuccinimide.

Figure 31

Representative examples of natural products accessed by the meta-photocycloaddition reaction.

Figure 32

Examples of Ru- and Ir-based photosensitizers (bpy = 2,2′-bipyridine, bpz = 2,2′-bipyrazine, dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine, ppy = 2-phenylpyridine).

Figure 33

Properties of the [Ru(bpy)₃]²⁺ photocatalyst (594) (bpy = 2,2′-bipyridine, MLCT = metal-to-ligand charge transfer, A = sacrificial electron acceptor, D = sacrificial electron donor, S = substrate).

Scheme 104. Synthesis of Magnosalin (599) via Photoinduced Electron Transfer

p-OMeTPT = 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate.

Scheme 105. Visible-Light Photoredox Catalysis in the Synthesis of ent-Sceptrin (606)

BOM = benzyloxymethyl. TIPS = triisopropylsilyl. ppy = 2-phenylpyridine. fac = facial.

Scheme 106. Visible-Light-Promoted [2 + 2] Cycloaddition of 1,3-Diene 609 in the Synthesis of (±)-Epiraikovenal (614)

dF(CF₃)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine. dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. HMPA = hexamethylphosphoric triamide.

Scheme 107. Visible-Light-Sensitized [2 + 2] Cycloaddition of Olefin 617 in the Synthesis of (±)-Cannabiorcicyclolic Acid (619)

CFL = compact fluorescent light.

Scheme 108. (Top) Proposed Mechanism for Polar Radical Crossover Cycloaddition (PRCC) of Alkenes and Unsaturated Acids and (Bottom) Its Application in the Synthesis of Protolichesterinic Acid (630)

HAT = hydrogen atom transfer.

Scheme 109. Visible-Light Photocatalytic Radical Cation Diels–Alder Cycloaddition in the Synthesis of Heitziamide A (635)

EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. TBAF = tetra-n-butylammonium fluoride. TBS = tert-butyldimethylsilyl. NMO = N-methylmorpholine N-oxide. bpz = 2,2′-bipyrazine. DMAP = 4-dimethylaminopyridine.

Scheme 110. Synthesis of (±)-Kingianic Acid (639) via a Radical Cation Diels–Alder Approach

NMO = N-methylmorpholine N-oxide. TBAF = tetra-n-butylammonium fluoride. bpy = 2,2′-bipyridine. MV = methyl viologen.

Scheme 111. Photoredox-Mediated Tertiary Radical Generation in the Synthesis of (−)-Aplyviolene (646)

DIPEA = diisopropylethylamine. TBS = tert-butyldimethylsilyl. HMPA = hexamethylphosphoric triamide. bpy = 2,2′-bipyridine.

Scheme 112. Photoredox-Enabled Synthesis of (+)-Gliocladin (652)

Boc = tert-butyloxycarbonyl. Cbz = carboxybenzyl. DPPA = diphenylphosphoryl azide. dppp = 1,3-bis(diphenylphosphino)propane. bpy = 2,2′-bipyridine.

Scheme 113. Synthesis of Alkaloid Natural Products Enabled by Photoredox Catalysis in Flow

TFA = trifluoroacetic acid. dF(CF₃)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine. dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. bpy = 2,2′-bipyridine. TMS = trimethylsilyl.