Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis.

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.

Introduction

The synthesis of natural products defines the frontier of synthetic chemistry as it offers the practitioners the challenge of constructing complex and structurally diverse molecular frameworks. This wealth of synthetic challenges has been a valuable platform for expanding state-of-the-art synthetic methodology and discovering fundamentally new chemical protocols that can subsequently be implemented by the whole chemical community.[1−12]

Natural products that display biological activity often serve as vital targets for novel drug lead candidates.[13−17] Access to these complex and structurally diverse assemblies constitutes a multifaceted challenge for chemists, which requires efficient and powerful synthetic strategies.[18−20] The use of small-molecule libraries inspired by bioactive natural products is an essential part of drug discovery and is an attractive aspect of the early stages of drug development. Here, the transition from planar structures with a sp2-rich character to more structurally complex libraries that contain multiple sp3 centers may yield a higher probability of displaying selective biological activity.[21]

The increased attention to environmentally related issues has also led to the reassessment of several existing technologies, requiring the scientific community to devise novel and “green” methods. These processes should be energy-efficient, reduce the consumption of raw materials, and ultimately produce minimal amounts of waste.[22−25] Ideal methods would provide the opportunity to transform simple feedstocks into highly functionalized and complex molecules. An attractive approach would be to explore the potential of photochemical reactions, as they only involve the absorption of photons. In this sense, photoinduced reactions offer powerful and efficient strategies for designing diverse organic frameworks that might otherwise be difficult to access.[26,27]

A central feature of all light-promoted transformations is the involvement of electronically excited states, formed upon the absorption of photons. This excitation leads to the generation of transient reactive intermediates and significantly alters the reactivity of a chemical compound (Figure ), a process that can be controlled to generate the intended product in high yield and with excellent selectivity.[28,29] Compared to thermal reactions, a majority of the prevailing photochemical reactions do not require additional reagents for activation, such as metal catalysts, Brønsted acids, or bases. The selective input of energy provided by light offers a means to produce strained and unique target molecules that cannot be assembled using thermal protocols, thus allowing for the production of immense molecular complexity in a single chemical step. Rational and efficient synthetic methodologies can thereby be designed as a rapid entry to diverse molecular scaffolds containing various functional groups, often in shorter synthetic sequences with respect to alternative multistep procedures.[30,31]

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*).

As previously mentioned, the use of photochemistry is appealing for generating molecular complexity that may not be accessible by conventional methods. As a result, a number of fascinating total syntheses of natural products have been achieved, which highlight the remarkable power of UV light for constructing advanced polycyclic carbon skeletons.[27,32,33] The use of UV light for bond assembly has been known for a long period of time. Trommsdorff found in the early 19th century that crystals of the sesquiterpene santonin reacted upon exposure to sunlight, which may be considered the birth of photochemistry.[34,35] From the mid-20th century, myriad examples have been reported where photochemistry has been exploited for remarkable rearrangements and construction of complex molecular scaffolds.[27,36]Figure depicts some of the outstanding and now classic examples of natural product synthesis where photochemical reactions have been applied in key steps. These include the synthesis of α-cedrene (1),[37] ingenol (2),[38] estrone (3),[39−41] and ginkgolide B (4),[42] among others.

Figure 2

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

This review aims to demonstrate the importance of photochemical approaches for accessing complex chemotypes and its key role in the synthesis of advanced structures with relevance to biological systems. The review is organized by the different types of photochemical reactions, beginning with various [n + 2] photocycloadditions and then describing various photochemical rearrangements that can be achieved. The broader chemistry community has recently become well-aware of the virtues of photoredox catalysis to engage in an array of single-electron transfer (SET) events that have previously been elusive. The final chapter of this review therefore highlights the use of photoredox catalysis to trigger unique catalytic processes in natural product synthesis.

[2 + 2] Photocycloadditions

[2 + 2] Photocycloadditions of Olefins—A Versatile Method for Accessing Cyclobutanes

Ciamician and Silber reported on the [2 + 2] photocycloaddition in 1908 when they observed the formation of carvone camphor (6) when carvone (5) was exposed to light for 1 year (Scheme ).[43] In the [2 + 2] photocycloaddition of alkenes, α,β-unsaturated carbonyl compounds are generally employed, as they are more easily photoexcited. This produces an initial short-lived singlet state that decays by intersystem crossing (ISC) to produce a triplet state. The triplet exciplex that is formed with the ground state alkene moiety results in a triplet 1,4-biradical that undergoes spin inversion to the singlet biradical, thus allowing for generation of the desired cyclobutane (Scheme ).[44−46] The [2 + 2] photocycloaddition has the possibility of generating two different regioisomers, which are referred to as the head-to-tail and head-to-head products (Scheme , top). In general, head-to-tail products are formed when the R group is electron-donating, while head-to-head products are produced when the R group is electron-withdrawing (Scheme , bottom).[47−50]

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

[2 + 2] Photocycloaddition affords cyclobutanes, an important and common structural motif in a variety of natural products (Figure ). This makes the [2 + 2] photocycloaddition of two alkene units a powerful method in natural product synthesis for constructing precursors to either acyclic or cyclic systems, including carbo-, heterobi-, and oligocyclic structures. The utilization of the [2 + 2] photocycloaddition of olefins has, for example, been exploited in the total synthesis of (−)-biyouyanagin A (17, Scheme ),[51−53] (−)-littoralisone (20, Scheme ),[54] (−)-paeoniflorin (23, Scheme ),[55] (±)-punctaporonin C (26, Scheme ),[56,57] and (+)-solanascone (29, Scheme ).[58] Recent examples for use of the [2 + 2] photocycloadditions include the total syntheses of aquatolide (32, Scheme )[59] and an intramolecular [2 + 2] photocycloaddition for construction of the tricyclic core of solanoeclepin A (14, Scheme ).[60]

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[5.2.1.01,6]decane Core of Solanoeclepin A (14)

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

Optically active allenes appended to enones have also been shown to afford the cyclobutane photoadducts with high levels of asymmetric induction, thus providing access to optically active fused polycyclic structures that might otherwise be difficult to access (Scheme ).[61,62] A remarkable example for generation of molecular complexity from simple precursors can be encountered in the photocycloaddition/rearrangement sequence that converts pyrroles to aziridines (Scheme ).[63] Booker-Milburn and co-workers discovered that irradiation of pyrroles such as 37 could facilitate rearrangement from the initially produced [2 + 2] photocycloaddition adduct 38 to produce aziridine 39. This constitutes a novel photochemical sequence for conversion of substituted pyrroles into intricate tricyclic aziridines and was shown to be general for a variety of substituted pyrroles, ranging from mono- to tetrasubstituted.

Scheme 11

Intramolecular [2 + 2] Photocycloaddition of Optically Active Allene 35

Scheme 12

Photocycloaddition/Rearrangement of Pyrroles to Aziridines

From the aforementioned example it is obvious that the inherent ring strain in the cyclobutane ring system renders it amenable to strain-releasing reactions, making the cyclobutane products versatile substrates for further reactions. If the generated cyclobutane is fused to one or several rings, a tandem [2 + 2] photocycloaddition–fragmentation sequence offers powerful routes for accessing ring-expansion products and can thus be used as an intermediate for constructing more complex medium-sized ring systems (Scheme ). Typical fragmentation pathways for the generated [2 + 2] photoadducts include Grob fragmentations (Figure , top), radical fragmentations (Figure , middle), or De Mayo reactions (Figure , bottom). The robust and sterically tolerant nature of the [2 + 2] photocycloaddition makes it well-suited for constructing C–C bonds in a plethora of contexts.[64−66]

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.

The use of the [2 + 2] photocycloaddition for the chemoselective annulation of larger ring systems is a powerful concept and was utilized in the total synthesis of (±)-gibberellic acid (46, Scheme ),[67] (±)-pentalenene (53, Scheme ),[68,69] and linderol A (56, Scheme ).[70−72] The [2 + 2] photocycloaddition in combination with a retro-aldol reaction is known as the De Mayo reaction and will be discussed in detail in section .

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)

A Grob fragmentation[73] was employed in the synthesis of (±)-epikessane (62) to construct the hydroazulene skeleton via ring expansion.[74] Cyclobutane 60, produced from [2 + 2] photocycloaddition of 4-acetoxy-2-cyclopentenone (57) and 1-acetoxy-2-carbo-methoxycyclopentene (58), treated with p-toluenesulfonyl chloride (p-TsCl) in pyridine, thereby triggering Grob fragmentation to afford ketone 61 bearing the hydroazulene core of epikessane (62) (Scheme ). Epoxides can also be used as functional groups to achieve ring expansion through a Grob-type fragmentation and were utilized in the total synthesis of the hydroazulene sesquiterpene (+)-aphanamol I (see Scheme ).[75]

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.

Scheme 50

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

Isocomene (63) is a sesquiterpene that belongs to a family of tricyclic angular triquinane sesquiterpenes, initially isolated from the plant Isocoma wrigthii.[76,77] Tobe and co-workers used a [2 + 2] photocycloaddition approach using enone 66 to generate the tricyclic adduct 67.[78] Subjecting enone 66 to an excess of 1,2-propadiene (43) in CH2Cl2 at −78 °C (λ = 300 nm) successfully gave the desired head-to-head product 67 in high yield and excellent selectivity (Scheme ). Compound 67 was subsequently converted in two steps to epoxide 69, which under Lewis acid-mediated epoxide–carbonyl rearrangement conditions[79] afforded the triquinane core. Further manipulations of triquinane 70 resulted in (±)-β-isocomene (64, Figure ), which could undergo acid-catalyzed isomerization to furnish (±)-isocomene (63). A related ring expansion route by use of the epoxide-carbonyl rearrangement was also employed by Tobe and co-workers in the synthesis of (±)-modhephene (65).[80]

Scheme 18

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

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

Figure 5

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

Free radical fragmentations of the generated cyclobutanes to produce medium-sized ring systems represent a second class of essential cleavage reactions that have been widely exploited in organic synthesis.[81−86] Shipe and Sorensen employed an intramolecular [2 + 2] photocycloaddition/radical SmI2-mediated fragmentation sequence in the convergent enantioselective syntheses of both natural (+)- and unnatural (−)-guanacastepene E (73) and formal total syntheses of (+)- and (−)-guanacastepene A (71, Figure ).[87,88] Initial π-allyl Stille cross-coupling afforded photosubstrate 76, which underwent intramolecular [2 + 2] photocycloaddition to furnish cyclobutane 77 in 82% yield. The selective ring opening of the cyclobutane (77) was accomplished using SmI2-mediated ketyl radical formation and radical fragmentation. Subsequent trapping of the samarium enolate with phenylselenenyl bromide gave organoselenide 78. Selenoxide elimination with mCPBA produced the tricyclic compound 79, which could be elaborated to (+)-guanacastepene A (71) and (+)-guanacastepene E (73) (Scheme ).

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.

The radical fragmentation of [2 + 2] photocycloadducts involving Sn reagents has also been exploited in natural product synthesis. Lange and Gottardo utilized Bu3SnH in combination with azobis(isobutyronitrile) (AIBN) to affect the ring expansion of cyclobutylcarbinyl iodide 83 in the formal synthesis of pentalenene (53) (Scheme ).[89] A related radical fragmentation/elimination sequence has also been applied in the total synthesis of the sesquiterpenoid alismol (92) to afford the bicyclo[5.3.0]decane ring system 90 using a Bu3SnH/AIBN reagent combination (Scheme ).[90,91]

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).

Laurenene (99) is a diterpene initially isolated by Corbett and co-workers in 1979 from Dacrydium cupressinum and contains the unique fenestrane motif (see Figure ). The tetracyclic [5.5.5.7]fenestrane core was seen as a challenge that photocycloaddition chemistry was suited to address.[92,93] To generate the sterically crowded quaternary carbon center, a [2 + 2] photocycloaddition of enone 94 furnished the essential cyclobutane intermediate 95 in 87% yield and established the three contiguous quaternary centers required for the central core of laurenene (99). Further manipulations transformed cyclobutane 95 to the unsaturated keto ester 96, where the cyclobutane underwent reductive ring opening under Birch reduction conditions (Na/NH3) at −33 °C, followed by hydrogenation using Pd/C to afford keto ester 97. A reduction–oxidation sequence generated the keto–aldehyde containing substrate, which underwent an intramolecular aldol condensation to give enone 98 containing the essential cycloheptane ring and core structure of (±)-laurenene (99) (Scheme ).[94] A related [2 + 2] photocycloaddition approach has also been reported for the synthesis of the sesquiterpene (±)-silphinene (105) (Scheme ).[95]

Figure 30

Numbering of the fenestrane framework.

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.

Merrilactone A (106, Figure ) is a sesquiterpene containing a bicyclo[3.3.0]octane core, two lactone moieties, an oxetane ring, and seven contiguous stereogenic centers, making it an alluring synthetic target.[96,97] Originally isolated from the pericarps of Illicium merrillianum, merrilactone A (106) displays neurotrophic activity in cultures of fetal rat cortical neurons[98,99] and is a promising potential therapeutic agent for the neurodegeneration associated with Alzheimer’s and Parkinson’s diseases.[100−106] Several total syntheses of merrilactone A (106) have been reported following its isolation. The groups of Mehta[107] and Inoue[108] both employed a [2 + 2] photocycloaddition of the acetylene surrogate 1,2-dichloroethylene in the synthesis of (±)-merrilactone A and in the asymmetric synthesis of (−)-merrilactone A, respectively. In addition to the two syntheses by Mehta and Inoue, Greaney and co-workers have also reported on the total synthesis of (±)-merrilactone A, which relied on an initial [2 + 2] photocycloaddition of 4,5-dimethylmaleic anhydride and dimethylketene acetal.[109] The photocycloaddition was chosen to produce the challenging syn angular methyl groups given the reactions robust nature in sterically encumbered environments.

Figure 7

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

In Mehta and Singh’s approach[107] toward the synthesis of (±)-merrilactone A (Scheme ), photochemical [2 + 2] cycloaddition of enone 109 and trans-1,2-dichloroethylene (110) afforded cyclobutane (111) in 43% yield, which was subsequently converted to enol ether 112 through a four-step procedure involving eliminative dehalogenation, acetonide deprotection, oxidation, and homologation. Acid-mediated intramolecular hemiacetal formation and oxidation furnished lactone 114. Ozonolysis and in situ reduction of the fused cyclobutene produced lactol 115, which was further elaborated into epoxide 116. Exposure of epoxide 116 to p-TsOH allowed for the homo-Payne rearrangement, yielding the target compound (±)-merrilactone A (106).

Scheme 24

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

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

For the asymmetric total synthesis of (−)-merrilactone A (106), Inoue and co-workers utilized the [2 + 2] photocycloaddition of the enantiomerically pure lactone 117 and cis-1,2-dichloroethylene (118) to afford cyclobutene 120 after Zn-promoted dehalogenation and LiAlH4 reduction. Cyclobutene 120 was subsequently converted into diene 121, which underwent ring-closing metathesis to yield a bicyclo[4.2.0]octane system that upon subjection to Pb(OAc)4 underwent oxidative ring expansion to give the cyclooctanedione 122. After some optimization, it was found that reacting cyclooctanedione 122 with NaN(TMS)2 allowed for site-selective deprotonation and diastereoselective C–C bond formation through a transannular aldol reaction, producing the desired bicyclo[3.3.0]octane system 124 with only small amounts of the other diastereomers. Further manipulations completed the asymmetric synthesis of (−)-merrilactone (106) in 31 steps with an overall yield of 1.1% (Scheme ).

Scheme 25

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

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

The ginkgolides are a family of polycyclic oxygenated compounds obtained from the ginkgo tree (Ginkgo biloba). Extracts from the ginkgo tree have been used as herbal medicines for 5000 years for alleviating disorders such as coughs, bronchitis, and asthma.[110−113] These therapeutic effects were shown to originate from five different compounds, called the ginkgolides, which differ only in the number and position of the hydroxyl groups (Figure ). The ginkgolides were originally isolated by Furukawa[114−116] in 1932, but their structures were not established until 1967, when X-ray crystallography studies confirmed the structure and absolute stereochemistry of the ginkgolides.[117−121] Bilobalide (129)[122] and ginkgolide J (127)[123] were subsequently discovered and added as members of the ginkgolide family. The five ginkgolides (A, B, C, J, and M) all share an identical carbon skeleton, consisting of 6 rings, 11 stereogenic centers, and an uncommon tert-butyl moiety. The syntheses of ginkgolides A (125)[124] and B (4)[125] as well as bilobalide (129)[126,127] were initially accomplished by Corey and co-workers.[128]

Figure 8

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

A remarkable example where [2 + 2] photocycloaddition has been employed to access complex polycyclic carbon skeletons is the total synthesis of ginkgolide B (4) reported by Crimmins and co-workers, where they made use of a [2 + 2] photocycloaddition in order to establish the two vicinal quaternary stereocenters.[42,129] Previously, the same group reported the synthesis of the structurally related compound bilobalide (129) using a stereoselective, intramolecular [2 + 2] photocycloaddition as the key step for assembling the core of bilobalide (129) (Scheme ).[130,131] Here the [2 + 2] photocycloaddition of photosubstrate 130 gave the desired photoadduct 131 in 50% yield where both the (trimethylsilyl)oxy and the tert-butyl groups occupy pseudoequatorial positions on the generated five-membered ring. Hydroxylation of photoadduct 131 with MoOPH {(hexamethylphosphoric triamide)oxodiperoxy(pyridine)molybdenum(VI) [MoO5·pyr·HMPA][132,133]} produced hydroxy ketone 132 in 80% yield. Oxidative cleavage of hydroxy ketone 132 afforded aldehyde 133 in 94% yield, which could subsequently be converted into acetal 134 in three steps. A regioselective Baeyer–Villiger oxidation of cyclobutanone 134 furnished lactone 135 in 95% yield. After construction of the basic skeleton of bilobalide, a three-step oxidation sequence involving Jones’ reagent[134]/dimethyldioxirane/Jones’ reagent furnished the target compound bilobalide (129) in excellent yield.

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.

As previously shown for the ginkgolides, the introduction of the functional groups and the correct orchestration of the C5 and C9 quaternary carbon centers have been recognized as the crucial steps and certainly constitute a significant challenge for synthetic chemists. A resourceful synthetic approach was taken by Crimmins and co-workers, who made use of the enone–furan 138 as the key building block in the total synthesis of ginkgolide B (4, Scheme ).[42,129] The important photocycloaddition substrate 138 was prepared using a previously established homoenolate approach for the construction of carboalkoxycyclopentenones.[135,136] Reacting the acetylenic ester 137 with the appropriate zinc–copper homoenolate gave the photosubstrate 138 in 82% yield. Subsequent irradiation of enone 138 in hexanes resulted in the formation of the tetracyclic photoadduct 139 in quantitative yield and in >98:2 diastereoselectivity, thus establishing the two quaternary centers of the ginkgolide skeleton. Conversion of cyclobutane 139 to the bridged lactone 140, accompanied by treatment with dimethyldioxirane, provided bis-hemiacetal 141, which was further transformed to lactone 142. Acid-catalyzed methanolysis of lactone 142 facilitated ring closure to construct the E ring of the ginkgolides, affording the pentacyclic lactone 143 in 88% yield. Finally, ring closure and additional functionalization of the F ring provided ginkgolide B (4).[42,129]

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.

Ring expansion by use of the Cargill rearrangement[137−141] is an attractive way to produce bridged ketones from cyclobutenyl ketones (Scheme ). Pirrung took advantage of this rearrangement in the synthesis of (±)-isocomene (63) (Scheme ). Intramolecular [2 + 2] photocycloaddition of 144 generated tricyclo[6.3.0.01,6]undecanone 145. Subsequent Cargill rearrangement of cycloadduct 145 afforded the two bicyclo[3.3.0]octane and bicyclo[3.2.1]octane products 146 and 147 in a 1:5 ratio. Finally, bicyclo[3.2.1]octane 147 was transformed to (±)-isocomene via acid-catalyzed rearrangement.[142,143] Additional routes to (±)-isocomene (63) include the use of the Paternò–Büchi reaction,[144,145] the meta-photocycloaddition,[146] and the oxa-di-π-rearrangement,[147] and they will be discussed in more detail in the upcoming sections.

Scheme 28

Ring Expansion of Cyclobutanes via Cargill Rearrangement

Scheme 29

Pirrung’s Approach to (±)-Isocomene (63)

p-TsOH = p-toluenesulfonic acid.

The [2 + 2] photocycloaddition can also be accompanied by a thermally induced ring opening. This route was exploited by Schreiber and Santini in the synthesis of the sex pheromone periplanone-B (154, Scheme ).[148−150] The synthesis commenced with a [2 + 2] photocycloaddition of allene (43) and alkene 148 to afford a mixture of the syn and anti head-to-head photoproduct 149. It was revealed that the diastereomeric mixture converged to the same end product; thus, addition of vinylmagnesium bromide provided a mixture of allyl carbinols 150. Subsequent anion-accelerated oxy-Cope rearrangement followed by electrocyclic ring opening produced a mixture of s-cis diene 152 and s-trans diene 153. Cis/trans photoisomerization of the dienes showed a photostationary equilibrium in a 15:1 ratio with the s-trans isomer 153 being favored, which could be converted to periplanone B (154).

Scheme 30

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

An intramolecular aza-Prins reaction with a guided fragmentation of a cyclobutylcarbinyl cation was used as the key step for assembling the bicyclo[3.3.1]nonene core of the nootropic alkaloid (−)-huperzine A (160).[151] Here, the necessary photoadduct 156, generated from intramolecular [2 + 2] photocycloaddition in 58% yield from 155, was converted to cyclohexanone 157. Condensation of ketone 157 with NH2CO2Me in the presence of p-TsOH initiated the aza-Prins reation sequence, presumably via carbamate 158, to afford the desired fragmentation product 159, which is a known precursor to (−)-huperzine A (160) (Scheme ).

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.

It is clear that the wide range of natural products that can be accessed by the [2 + 2] photocycloaddition makes the reaction a highly useful tool in total synthesis. The prominent structures that have successfully been accessed utilizing a [2 + 2] photocycloaddition strategy are frameworks with multiple stereocenters and quaternary carbon centers. The ability to create several C–C bonds in hindered environments, in a single transformation, highlights the powerful features of the [2 + 2] photocycloaddition. The accessible fragmentation strategies that can subsequently be used allow for creative and effective construction of a multitude of complex natural products and their derivatives.

[2 + 2] Photocycloadditions between Olefins and Carbonyls—Oxetane Synthesis through the Paternò–Büchi Reaction

The [2 + 2] photocycloaddition of an alkene and a carbonyl compound—the Paternò–Büchi reaction—is a powerful method for construction of oxetanes, which are versatile intermediates in organic synthesis and occurring motifs in pharmaceutical compounds as well as in natural products (Figure ).[152,153] In these reactions the carbonyl motif usually serves as the light-absorbing species. Excitation of the nπ* state thus results in a singlet state that readily undergoes ISC to the triplet state, from which a majority of the Paternò–Büchi reactions occur. The diastereoselectivity is dictated by the lifetimes of the generated triplet 1,4-biradicals, as a consequence of the stepwise mechanism, and is connected with the mode of spin inversion events that allows for closed-shell products to be formed (Scheme ). The regioselectivity can usually be predicted by formation of the most stable biradical upon addition of the carbonyl compound to the alkene moiety.[154−159] A requirement for the Paternò–Büchi reaction to occur is that the alkene cannot have a lower triplet energy state than the carbonyl entity; if this would be the case, energy transfer is the major reaction pathway, with oxetane formation occurring slowly.[160−165]

Figure 9

Compounds containing the oxetane motif.

Scheme 32

Illustration of the Paternò–Büchi Reaction

ISC = intersystem crossing.

Although the Paternò–Büchi reaction has been less frequently employed in natural product synthesis than the cyclobutane [2 + 2] photocycloaddition reaction, it has for example been utilized in the synthesis of (+)-preussin (167, Scheme ),[166] (±)-oxetanocin (171, Scheme ),[167] and (±)-1,13-herbertendiol (176, Scheme ).[168]

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.

An intramolecular version of the Paternò–Büchi reaction was applied by Greaney and co-workers in a six-step approach to the tetracyclic core intermediate 184 of merrilactone A (106).[169] Starting from TBS-protected 3-hydroxycyclopentenone (177), nucleophilic addition of 178 afforded alcohol 179, which was subsequently desilylated and oxidized to generate hydroxy enone 180. A domino oxy/carbopalladation reaction with Pd(OAc)2 produced the bicyclic acetal 182 as a 1:1 mixture of diastereoisomers. Oxidative cleavage of alkene 182 gave ketone 183, which upon irradiation underwent [2 + 2] photocycloaddition to the tetracyclic oxetane 184 in 93% yield (Scheme ). In addition to creating two new rings, the intramolecular Paternò–Büchi reaction also establishes three stereocenters, thus forming the oxa[3.3.3]propellane motif present in merrilactone A (106).

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.

Rawal and co-workers also utilized an intramolecular Paternò–Büchi reaction as the key step in the stereocontrolled syntheses of the angular triquinane (±)-isocomene (63).[144,145] It was envisioned that diquinane enone 192, which has three of the stereocenters correctly in place, would be a key intermediate in the synthesis. The synthesis of the desired methyl ketone substrate 188 for the Paternò–Büchi reaction was synthesized from norbornene 185 by alkylation with the methoxymethyl (MOM) ether of 3-iodopropan-1-ol (186) followed by reaction with dimsyl lithium and Zn. Irradiation of methyl ketone 188 produced the desired oxetane 189 in 92% yield, which was subsequently cleaved using an excess of iPr2NMgI. Oxidation of the resulting homoallylic alcohol under Swern conditions[170] provided fragmentation precursor 190. Treatment of ketone 190 with lithium di-tert-butylbiphenylide (LDBB)[171,172] as a one-electron reducing agent yielded the desired reductive fragmentation product 191, which was subsequently methylated at the bridgehead position and converted to diquinane 192. Treatment of iodide 192 with nBuLi allowed for anionic cyclization and in situ trapping of the resulting enolate to afford enol triflate 194, which upon treatment with Me2CuLi gave (±)-isocomene (63) (Scheme ). The synthesis of (±)-isocomene (63) illustrates the advantages of the Paternò–Büchi photocycloaddition–reductive fragmentation strategy for access to intricate triquinane-based natural products.

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.

(−)-Sarracenin (202) is a tricyclic highly oxygenated monoterpene originally isolated from Sarracenia flava.[173] In the synthesis of (±)-sarracenin, Hoye and Richardson employed the Paternò–Büchi photocycloaddition of cyclopentadiene (195) and acetaldehyde (196) to access the exo diastereomeric oxetane 197. Acid-catalyzed methanolysis followed by exposure to TsCl in pyridine allowed for oxetane opening and formation of tosylate 198. Treating tosylate 198 with KOtBu and dimethyl β-styrenylmalonate (199) provided malonate 200, which underwent decarbomethoxylation followed by demethylation to yield alcohol 201. Methanolic ozonolysis followed by reductive workup with dimethyl sulfide (DMS) and subsequent acetic acid treatment produced (±)-sarracenin (202) in a nine-step sequence in an overall yield of 2% (Scheme ).[174]

Scheme 38

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

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

The Paternò–Büchi reaction can also be carried out with thiocarbonyl compounds.[175] An intramolecular Paternò–Büchi reaction has for example been reported for the synthesis of spirocyclic pyrrolizinone 205.[176] Here, irradiation of thioxasuccinimide system 203 afforded the tetracyclic thietane 204 as the major photoproduct in 74% yield. Reduction of photoproduct 204 with Raney-Ni gave the spiro pyrrolizinone 205 in 55% yield (Scheme ), showing that carrying out the Paternò–Büchi with thiocarbonyl compounds can be used to access complex assemblies.

Scheme 39

Intramolecular Paternò–Büchi Reaction of Thiocarbonyl 203

[2 + 2] Photocycloadditions Followed by Retro-Aldol Reaction—The De Mayo Reaction

An important contribution to the field of photochemistry was made in 1962 by De Mayo and co-workers when they observed that irradiation of alkenes with acetylacetone afforded 1,5-diketones in good yields. Subjecting the produced 1,5-diketones to catalytic amounts of acid or base subsequently led to cyclization to give cyclohexenones (Scheme ).[177] The first step in the De Mayo reaction involves tautomerization of the 1,3-dicarbonyl compound to the enol. For β-diketone 212 this affords the corresponding keto enol 213, which allows for [2 + 2] photocycloaddition with alkene 214 and thus generates a β-acylcyclobutanol (215). Subsequent retro-aldol condensation of the formed cyclobutanols produces the 1,5-dicarbonyl species 216 (Scheme ), which can be further transformed into cyclooctadiones (see Scheme ) and cyclohexenones.[178,179] The poor regioselectivity that is sometimes observed in the De Mayo reaction can be explained by formation of a triplet 1,4-biradical from the keto enol reaction partner, which needs to undergo spin inversion to a singlet biradical for cyclobutane formation to occur (cf. Schemes and ).[180,181]

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[182]

The synthetic utility of the De Mayo reaction in natural product synthesis has been readily explored and early examples include hirsutene (222),[183,184] loganin (223),[185−187] reserpine (224),[188,189] and zizaene (225) (Figure ).[190,191] Another classical example employing an intramolecular [2 + 2] photocycloaddition followed by a retro-aldol reaction was reported in the total synthesis of (±)-longifolene (232),[192,193] a tricyclic sesquiterpene containing a bicyclo[5.4.0]undecane scaffold.[194−201] Here, the design of the complex carbon skeleton of this sesquiterpene was centered on a photoaddition/retro-aldolization sequence. Irradiation of benzyloxycarbonyl derivative 228 afforded cyclobutane 229 regioselectively, which upon hydrogenolysis underwent retro-aldol cleavage to give the bicyclo[5.4.0]undecane core. Subsequent functionalization of bicyclo[5.4.0]undecane 230 through a regioselective Wittig reaction/Simmons–Smith cyclopropanation sequence, followed by additional manipulations, produced (±)-longifolene (232) in ∼25% overall yield (Scheme ).[192,193] The expedient construction of the sesquiterpene (±)-longifolene (232) exemplifies the synthetic utility of the intramolecular De Mayo reaction in natural product synthesis.

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)

Daucene (233) is a member of the carotane-type sesquiterpenes and has an unusual hydroazulene skeleton. The daucane (carotane) sesquiterpenes all share a bicyclo[5.3.0]decane core with diverse functionality and varied degrees of oxidation (Figure ) and have been shown to exhibit diverse biological activities.[202−205] During the years, several total syntheses of daucene (233) have been reported.[206−211] Seto and co-workers employed a highly regioselective intramolecular [2 + 2] photocycloaddition followed by a retro-aldol reaction to access a variety of carotane-type terpenes, including (±)-daucene.[212] Irradiation of enone 239 resulted in efficient and regioselective photocyclization to afford photoproduct 240 in 88% yield (Scheme ). Subsequent alkaline hydrolysis of the acetate group in photoproduct 240 resulted in retro-aldolization and ring expansion to provide the tricyclic ketol 242, which was subsequently transformed to monotosylate 243. Treating 243 with iPrLi initiated Grob fragmentation, followed by alkylation of the produced ketone to furnish the tertiary alcohol 244. Subjecting alcohol 244 to HCO2H at room temperature provided the dehydrated product (±)-daucene (233) in 28% yield together with two other regioisomeric products.

Figure 11

Representative examples of daucane (carotane) sesquiterpenes.

Scheme 44

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

The direct use of β-keto esters and β-keto acids in photocycloadditions can generate oxetanes through the Paternò–Büchi reaction (vide infra) instead of the desired cyclobutane. However, the use of dioxenones as β-keto ester and β-keto acid surrogates circumvents this problem by covalently locking the 1,3-dicarbonyl compound in the enol form and was originally reported by Baldwin and Wilkinson.[213] Dioxenones have, after this observation, been applied to a number of natural product syntheses, such as the tricyclic skeleton of taxane diterpenes (Scheme ).[214,215]

Scheme 45

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

Another example of employing dioxenones can be found in the synthesis of perhydrohistrionicotoxin (249). Histrionicotoxin (248) and its derivatives (Figure ) are powerful neurotoxic alkaloids initially isolated from the Columbian frog Dendrobates histrionicus.[216−218] Initial attempts of synthesizing perhydrohistrionicotoxin (249) by Smith and Koft employed a [2 + 2] photocycloaddition methodology as the key step for assembling the core of perhydrohistrionicotoxin (249).[219] Here, the cyclobutene fragment 251 was recognized as a potential intermediate in the synthesis of the natural product. Unfortunately, the outlined synthetic approach by the authors was not viable for converting the generated cyclobutene photoproduct 251 to perhydrohistrionicotoxin (249) (Scheme ). However, a few years later, Winkler and co-workers reported the total synthesis of (−)-perhydrohistrionicotoxin, where the absolute configuration was derived from l-glutamic acid (253).[220] For establishing the relative configuration, the authors employed an intramolecular De Mayo reaction between a vinylogous amide and a dioxenone to afford the necessary keto-lactone intermediate 257, which could be converted to (−)-perhydrohistrionicotoxin (249) (Scheme ).

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)

A related fragmentation strategy employing dioxenones has also been employed in the total synthesis of (±)-saudin (267, Scheme ).[221,222] Here, irradiation of dioxenone 261 afforded photoadduct 262 as a single diastereomer in 80% yield. Introduction of the furan motif was accomplished in a two-step sequence by first reacting 262 with nBuLi and Tf2O in the presence of TMEDA to produce enol triflate 263. Subsequent Stille coupling of enol triflate 263 with 3-furyltributylstannane (264) gave the furyl enol ether 265 in almost quantitative yield, which upon exposure to LiOH resulted in fragmentation. Cyclization to (±)-saudin (267) was carried out by treating the fragmented product with pyridinium tosylate. This 15-step route afforded (±)-saudin (267) in 5% overall yield and illustrates the potential of the intramolecular dioxenone photocycloaddition for the efficient construction of complex carbocyclic motifs.

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.

A related retro-aldol approach was also utilized by Winkler and co-workers in the first total synthesis of (±)-ingenol (2, Figure ).[38] Ingenol (2) is a complex diterpenoid originally isolated from Euphorbia ingens in 1968 by Hecker.[223] However, its structure was not determined until 1970, when the crystal structure of the triacetate compound was derived.[224] The Euphorbia species contains a variety of diterpenoids with complex carbon skeletons, some of which are shown in Figure .[225−229] Of the various diterpenoids, the ingenanes display several interesting biological activities, such as antileukemic and anti-HIV.[230−233] In particular, ingenol 3-angelate (ingenol mebutate, 274, Figure ) has received a great deal of attention since its approval by the Food and Drug Administration (FDA) in 2012 for treatment of actinic keratosis, a precancerous skin condition.[234−236]

Figure 14

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

Figure 13

Skeletal types of Euphorbia diterpenes.

The biological activity and the structural complexity of ingenol (2) have motivated interest from synthetic organic chemists for several decades. The polyoxygenated tetracyclic core of ingenol (2) features several challenges, including the stereogenic triol unit of the A and B rings and a quaternary carbon stereocenter. However, the unusual in/out stereochemistry,[237] or trans intrabridgehead stereochemical configuration, of the bicyclo[4.4.1]undecane motif represents a particularly daunting difficulty.[238−250] In light of these challenges, a number of total syntheses of ingenol (2) have been reported.[38,251−261]

In the first total synthesis of ingenol (2),[38] Winkler and co-workers established the rare and challenging trans intrabridgehead configuration of the BC ring system by employing inside–outside stereoisomerism methodologies previously developed in their laboratory.[262] Initial attempts to use the De Mayo reaction on allylic alcohol 279, obtained from the bicyclic enone 275, resulted in a low yield (16%) of the desired photoadduct. However, irradiation of the corresponding allylic chloride (280) afforded photoadduct 281 with the important bicyclo[5.3.0]decane motif in 60% yield. Fragmentation of cyclobutane 281 with methanolic potassium carbonate followed by LiAlH4 reduction, chloride elimination, and silylation of the primary alcohol gave bicyclo[4.4.1]undecanone 282 in 35% yield over four steps. Cyclopropanation and reductive methylation subsequently produced cyclopropane 283, which allowed for further manipulations into (±)-ingenol (2) (Scheme ).[38]

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.

Modifications of the De Mayo reaction have also been developed and have for example been utilized in the synthesis of (+)-aphanamol I (291)[75] and for constructing the 3,12-dioxatricyclo[8.2.1.06,13]tridecane skeleton of terpenoid natural products.[263] Hansson and Wickberg’s strategy for accessing (+)-aphanamol I (291) depended upon a De Mayo-type sequence where the opening of the generated cyclobutane ring was achieved through a base-induced opening with concomitant β-elimination of a properly oriented oxirane.[75] Here, the essential photosubstrate 286 was derived from (+)-(R)-limonene (284). Irradiation of photosubstrate 286 and cyclopentenone 287 afforded a 1:1 mixture of the regioisomeric photoadducts 288 and 289. Reacting photoadduct 289 with dimethyloxosulfonium methylide yielded the endo-epoxide 290, which upon alkaline hydrolysis by refluxing with LiOMe in MeOH produced (+)-aphanamol I (291) in 70% yield through fragmentation of the intermediate γ,δ-epoxy alcohol (Scheme ).

Bach and co-workers explored an unusual fragmentation pathway for constructing 3,12-dioxatricyclo[8.2.1.06,13]tridecane skeletons.[263] [2 + 2] Photocycloadditions of tetronate 292 gave photoproduct 293 in 65% yield as a single diastereoisomer. Facile ring expansion occurred upon treatment with KOH in aqueous MeOH to give the seven-membered ketolactone 295 via the intermediate tricyclic hemiacetal 294 (Scheme ). The ring strain present in the tetracyclic compound 293 apparently facilitates nucleophilic substitution by hydroxide, thus resulting in cleavage of the cyclobutane ring.

Scheme 51

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

Recent work by Minter and Winslow involves the use of an unusual De Mayo approach for constructing the tetracyclic galanthan ring system (296, Figure ),[264] which is the core of the lycorine-type Amaryllidaceae alkaloids.[265,266] Minter and Winslow utilized photosubstrate 305, synthesized in three steps from isocarbostyril (300), as the precursor to the galanthan skeleton. Irradiation of the De Mayo substrate 305 afforded a single product, which was shown to be photoproduct 307 with the correct cis stereochemistry of the vicinal tertiary ring protons. Subsequent ring closure was achieved under basic conditions using piperidine in refluxing benzene to afford the galanthan derivative 309 in five steps with 35% overall yield (Scheme ).

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.

[2 + 2] Photocycloadditions of Vinylogous Amides—Formation of Nitrogen-Containing Ring Systems

In analogy to the De Mayo reaction, which utilizes 1,3-dicarbonyl compounds, [2 + 2] photocycloaddition adducts of vinylogous amides (enaminones) can undergo subsequent fragmentation. The fragmentation gives ketoimines or ketoiminium ions, which can be recyclized in a domino sequence. This photocycloaddition/retro-Mannich fragmentation sequence provides a powerful route for the construction of nitrogen-containing ring systems and has since its initial observation by Tamura and co-workers[267] (Scheme ) been exploited in natural product synthesis.[268]

Scheme 53

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

Similarly to Tamura and co-workers’ initial work, Schell and Cook investigated the use of secondary vinylogous amides. Irradiation of the secondary vinylogous amide 313 afforded ketoimine 315, which is presumably generated from cyclobutane intermediate 314 upon retro-Mannich fragmentation (Scheme ).[269] Pete and co-workers employed the intramolecular [2 + 2] photocycloaddition of N-alkenoyl β-enaminones to produce valuable synthons for synthesis of triquinanes or various sesquiterpenes (Scheme ).[270] Related photocycloaddition/retro-Mannich sequences have also been reported for 3-aminocyclopentenones[271] and for the synthesis of 6-aza-bicyclo[3,2,1]octan-3-ones[3,2,1]octan-3-ones via Vinylogous Imide Photochemistry: An Approach to the Synthesis of the Hetisine Alkaloids. J. Am. Chem. Soc.. 2001 ">272] and pyrroles.[273,274]

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

Examples of the application of the photocycloaddition/retro-Mannich reaction can be found in studies toward the synthesis of taxane skeletons by Swindell and co-workers.[275−278] Photocycloaddition of vinylogous amide 321 generated photoproduct 322, which was converted to silyloxy ketone 323 through a Rubottom-type oxidation. Subsequent fragmentation and additional manipulations converted silyloxy ketone 323 to enone 324 having the basic BC subunit of the taxane diterpenoids (Scheme ).

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.

The intramolecular photocycloaddition of vinylogous amides has also been exploited in the Sceletium alkaloid[279] mesembrine (328) by Winkler and co-workers.[280] Similarly to the alkaloids pretazettine (326) and sceletium A-4 (327), mesembrine (328) also features a functionalized cis-3a-aryloctahydroindole core (Figure ). The desired photosubstrate 330 was accessible from veratrole (329) in four steps. Intramolecular photocycloaddition of 330 led to the photocycloaddition/reto-Mannich product 332 in 74% yield. Subsequent methylation using Me3OBF4 followed by treatment with DMAP facilitated ring closure, affording mesembrine (328) in 84% yield (Scheme ).[280] The efficient access to the alkaloid mesembrine (328) in merely seven steps with an overall yield of 33% from veratrole (329) illustrates the power of the synthetic utility of the photocycloaddition/retro-Mannich fragmentation/Mannich closure cascade sequence.

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.

White and Ihle have employed β-aminoalkylidene malonates for accessing spiropyrrolines and the tetracyclic core of the indolenine alkaloid koumine (339).[281] The strategy for assembling the nonindolenine fragment 338 of koumine (339) was believed to be accessible through a photocycloaddition/retro-Mannich approach from β-aminoalkylidene malonate 333. Irradiation of malonate 333 indeed furnished cyclobutane 334, which upon removal of the Boc group caused spontaneous retro-Mannich fragmentation to spiroimine 335. Methylation of the imine nitrogen and subsequent treatment with MeNH2 triggered initial aminal formation, followed by intramolecular acylation to give lactam 337, which could be converted to ketone 338, a precursor for koumine (339) (Scheme ). A related [2 + 2] photocycloaddition/retro-Mannich fission approach for tryptamine-based vinylogous amides was also employed by White and co-workers in the total syntheses of (±)-coerulescine (340), (±)-horsfiline (341), and (±)-elacomine (342) (Figure ).[282]

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.

The formal synthesis of vindorosine (349), starting from l-tryptophan (343), is another example where the intramolecular vinylogous amide photocycloaddition/retro-Mannich fragmentation/Mannich closure sequence has been applied for construction of nitrogen-containing ring systems (Scheme ).[283] By starting from l-tryptophan (343), Winkler and co-workers showed that photosubstrate 344 afforded the highest stereoselectivity in photocycloaddition, providing photoproduct 346 in 91% yield as a single diastereomer. Treatment of keto imine 346 with LDA followed by TBSOTf and nBu4NF produced the desired tetracyclic ketone 347 in 51% yield. The latter intermediate could be converted to 348, a precursor to vindorosine (349), highlighting the efficiency of the vinylogous amide photocycloaddition approach to the synthesis of the aspidosperma alkaloids.

Scheme 59

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

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

The application of this methodology to the construction of more complex alkaloids is exemplified by Winkler and co-workers in the syntheses of the marine alkaloids ircinol (350), ircinal (351), manzamine A (352), and manzamine D (353) (Figure ).[284,285] [2 + 2] Photocycloaddition of vinylogous amide 354 afforded aminal 357. Exposure of aminal 357 to pyridinium acetate produced manzamine tetracycle 358 in 20% yield as a single stereoisomer from photosubstrate 354. Macrocyclization to produce the 13-membered D ring and subsequent manipulations allowed for conversion of precursor 358 to the four marine alkaloids ircinol (350), ircinal (351), manzamine A (352), and manzamine D (353) (Scheme ). The establishment of all of the stereogenic centers in the manzamine skeleton from the single stereogenic center present in photosubstrate 354 validates the remarkable levels of stereochemical control that are possible using the photocycloaddition/fragmentation/Mannich closure cascade sequence in organic synthesis.

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.

[3 + 2] Photocycloadditions

Apart from the meta-photocycloaddition reaction that is discussed in section , [3 + 2] photocycloadditions have been rarely applied in natural product synthesis. Several structurally interesting natural products have been isolated from the plant genus Aglaia (Figure ).[286−289] Porco and co-workers developed a biomimetic approach involving a [3 + 2] photocycloaddition/ketol shift rearrangement/reduction sequence using 3-hydroxyflavone and methyl cinnamate derivatives to access (−)-rocaglamide and related natural products.[290−293] In the synthesis of methyl rocaglate (366), irradiation of 3-hydroxyflavone 362 produced oxidopyrylium intermediate 364, which undergoes a [3 + 2] photocycloaddition with methyl cinnamate (363) to furnish aglain core structure 365. Subsequent treatment with NaOMe/Me4NBH(OAc)3 was the basis for a ketol rearrangement/reduction sequence to provide methyl rocaglate (366) (Scheme ).[290,292] A related approach has also been employed to accomplish enantioselective photocycloaddition and was used in the asymmetric synthesis of rocaglamides.[291,293]

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

The groups of Porco and Stephenson have also reported a tandem dienone photorearrangement–cycloaddition reaction of cyclohexadienones tethered with various 2π and 4π functional groups that afforded polycyclic, bridged scaffolds.[294] Photoirradiation of alkenyl ether-tethered cyclohexadienones, such as 367, resulted in the bridged tricyclic ketone 371, presumably via the photorearranged oxyallyl intermediate 368, which upon [3 + 2] photocycloaddition resulted in the observed product (Scheme ). Using cyclohexadienone 372 containing a furfuryl alkyne ether tether led to the production of the polycyclic ketone 374 (Scheme ). This tandem dienone photorearrangement/cycloaddition/[4 + 2] cycloaddition sequence generates four new bonds where the final hexacyclic framework 374 contains seven stereogenic centers, thus highlighting the complex architectures that can be created in this tandem process.

Scheme 62

Tandem Dienone Photorearrangement–Cycloaddition of Cyclohexadienone 367

Scheme 63

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

Photochemical [4 + 2] Cycloadditions in Natural Product Synthesis

Photochemical Generation of Dienes—Combining Photoenolization with [4 + 2] Cycloadditions

o-Quinodimethanes are fundamental intermediates in total synthesis and are in general produced from o-alkyl-substituted aromatic carbonyl compounds.[295−299] The high reactivity associated with the photochemically generated o-quinodimethanes can be utilized by subsequently trapping them in a Diels–Alder reaction (Figure ).[300−302]

Figure 20

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

A classic example where the photochemically produced o-quinodimethanes subsequently underwent [4 + 2] cycloaddition can be found in the total synthesis of (+)-estrone (3) by Quinkert and co-workers. Here, photochemically triggered formation of dienol 380 from precursor 379 allowed for [4 + 2] cycloaddition to afford alcohol 381, which could subsequently be converted to estrone (3) via already known transformations (Scheme ).[303−305] Other early examples where the photoenolization/[4 + 2] cycloaddition sequence had been employed include the formal total synthesis of podophyllotoxin (385, Scheme )[306] and the synthesis of 6-methylpretetramid (389, Scheme ).[307,308]

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)

The hamigerans are a family of natural products isolated from the poecilosclerid sponge Hamigera tarangaensis. The framework of hamigerans A–C (390–392) contains a substituted benzenoid core fused onto either a [4.3.0] or a [5.3.0] bicyclic ring system, three or four contiguous stereogenic centers, and an isopropyl group (Figure ).[309,310] In the total syntheses of hamigerans A (390) and B (391), Nicolaou and co-workers employed the photoinitiated [4 + 2] cycloaddition as the key step for assembling the hamigeran core.[311−313] It was envisioned that incorporating an oxygen functionality at C6 would allow for the enantioselective synthesis of the targeted compounds. Irradiation of photosubstrate 394, derived from benzamide 393 as a 3:1 E/Z mixture, indeed triggered o-quinodimethane formation and afforded the tricyclic hydroxyl ester 396 in 92% yield as a mixture of C10 epimers (∼3:1; see Scheme ). Subsequent epimerization at C5 and additional manipulations produced hamigeran A (390), which could be expediently converted to hamigeran B (391) in 82% yield through a Ba(OH)2-mediated cascade reaction involving saponification, decarboxylation, and auto-oxidation. A related photoenolization/Diels–Alder strategy was also applied by Nicolaou and Gray in the total synthesis of the lichen-derived antitumor agent hybocarpone (402) (Scheme ) and analogues thereof.[314]

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)

A hetero-Diels–Alder reaction with the photochemically produced dienol 404 was utilized by Prabhakar and co-workers in the total synthesis of the alkaloid (±)-cis-alpinigenine (405).[315,316] Here, photolysis of bis-aldehyde 403 led to the formation of at least seven photoproducts. The desired tetracyclic (±)-cis-alpinigenine (405) was presumably formed from o-quinodimethane intermediate 404, affording 405 in 20–30% yield (Scheme ).

Scheme 69

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

Photoisomerization Approaches for Triggering [4 + 2] Cycloadditions

The photoisomerization of cis-cycloalkenones to trans-cycloalkenones is a well-established procedure.[317−323] An early example of this effect can be found in the photoisomerization of cis-2-cycloheptenone (406) to trans-2-cycloheptenone (407), where irradiation of a mixture of cis-2-cycloheptenone and excess cyclopentadiene (195) at −50 °C gave a single adduct (408) in 95% yield (Scheme ).[324] Intramolecular Diels–Alder trapping of photochemically generated trans-cyclic enones have also been reported as a rapid entry to complex polycyclic structures (Scheme ).[325]

Scheme 70

Photoisomerization of cis-2-Cycloheptenone (406)

Scheme 71

Intramolecular Diels–Alder Reaction of Photochemically Generated trans-Cycloheptenone

The diterpene vibsanin E (413) was initially isolated by Kawazu from the Japanese fish poison plant Viburnum odoratissimum and was among the first vibsane natural products to be isolated (Figure ).[326] Its highly oxygenated cycloheptane ring and the 3-oxatricyclo[6.3.2.05,10]tridecane core make vibsanin E (413) a considerable synthetic challenge.[327,328] Davies and co-workers’ approach to (±)-5-epi-10-epivibsanin E (423) centered on three different cycloaddition steps: a Rh-catalyzed [4 + 3] cycloaddition, a heteronuclear [4 + 2] cycloaddition, and a photochemically induced [4 + 2] cycloaddition.[329,330] The synthesis commenced with Rh-catalyzed [4 + 3] cycloaddition between diene 414 and vinyldiazoacetate 415 to afford cycloheptadiene 416 in 69% yield. The subsequent step involved reduction of ester 416 and oxidation of the resulting alcohol under Swern conditions to furnish aldehyde 417 in 90% yield. BF3·OEt2-assisted heteronuclear [4 + 2] cycloaddition of aldehyde 417 constructed the tricyclic vibsanin E core with the desired relative configuration. Further manipulations of tricycle 418 gave the conjugated ketone 419, which was shown to be resistant to a tandem conjugate addition/alkylation strategy that would have completed the synthesis of vibsanin E (413). Furthermore, thermal Diels–Alder reactions were also conducted but failed to give any product, highlighting the limited reactivity of 419 due to the sterically encumbered environment. An alternate strategy therefore had to be examined that increased the reactivity of enone 419. Intrigued by the possibility of exploiting a tandem photoisomerization/[4 + 2] cycloaddition sequence, the authors irradiated enone 419 in the presence of isoprene (421) to efficiently generate alkene 422 in 61% yield with the desired anti fusion across the enone moiety. This was further advanced to (±)-5-epi-10-epivibsanin E (423) (Scheme ).

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.

Baldwin and co-workers employed the photoisomerization of (E,E,E,E)-tetraene 424 to produce the (E,E,E,Z)-tetraene intermediate 425. Tetraene 425 undergoes a radical cascade, ultimately revealing compound 427 (Scheme ), which contains the crispatene core,[331] similar to that reported by Padwa and co-workers in their studies of 1,3,5-hexatrienes.[332,333] A recent example of the use of photoisomerization is encountered in Tang and co-workers’ synthesis of xanthanolide dimers.[334] Xanthanolides are sesquiterpenoids with over a hundred members having been identified to date. A majority of the members in the xanthanolide family feature a butyrolactone moiety that is trans- or cis-fused to a seven-membered carbocycle, as in xanthatin (429, Figure ).[335−339] Although Tang and co-workers were not initially attempting to access dimeric products, they discovered that irradiation of xanthatin (429) under a N2 atmosphere led to a mixture of 3-epimogolide A (435) and mogolide A (436) in a combined yield of 74% (Scheme ). The authors proposed that the reaction proceeded via photoinduced C1–C5 double bond isomerization to generate trans-cycloheptene 432, which rapidly undergoes Diels–Alder dimerization via 433 to produce the pentacyclic product 434. From intermediate 434, a subsequent [2 + 2] photocycloaddition gives the two dimerization products, 3-epimogolide A (435) and mogolide A (436).[334] Although the photoisomerization strategy has not received significant attention in natural product synthesis, the examples discussed in this section highlight the synthetic utility of the photoisomerization of cis-cycloalkenes to trans-cycloalkenes to trigger subsequent reactions.

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)

Norrish-Type Photoreactions

The Norrish type I reaction refers to a photochemical reaction where the C–C bond between a carbonyl group and an α-carbon is homolytically cleaved. Several reaction modes are available for the generated 1,4-diradical and are dependent on the exact nature of the molecule (Scheme ). One pathway involves decarbonylation with subsequent cyclization to furnish interesting cyclic products. Alternative pathways include formation of ketenes or aldehydes or a simple recombination of the 1,4-diradical, resulting in racemization of the α-carbon center.[340−343]

Scheme 75

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

The Norrish type II photoreaction involves an intramolecular γ-hydrogen abstraction of an excited carbonyl compound and was first reported by Ronald Norrish in the early 1930s.[344−347] The primary 1,4-diradical that is formed can subsequently undergo further cleavage to produce alkenes and enols as the initial products (pathway A in Scheme ). Alternatively, the produced 1,4-diradical can recombine to form cyclobutanols, a process that is called Norrish–Yang cyclization (pathway B in Scheme ).[348,349] The competition between fragmentation and cyclization is strongly dependent on the nature of the substituents.

Scheme 76

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

Norrish Type I Photoreactions

The utilization of the Norrish type I reaction can be found in the synthesis of α-cuparenone (439). Here, irradiation of diketone 438 produced α-cuparenone (439) in 85% yield via a decarbonylation/cyclization sequence (Scheme ).[350] A related approach was also used by the authors in the total synthesis of the sesquiterpene (±)-herbertenolide (442), where a Norrish type I reaction was employed to produce the essential cyclopentane core (Scheme ).[351]

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)

In Nicolaou and co-workers’ studies on the hamigerans, a Norrish type I homolysis reaction was observed for hydroxy ketoester 443. Irradiation of a benzene solution containing hydroxy ketoester 443 produced an equilibrium mixture of C10 epimers. The authors speculated that this equilibration originates from a Norrish type I cleavage reaction of the C10–C11 bond, resulting in diradical 444. This diradical can either reclose, regenerating the hydroxyl ketoester 443, or undergo inversion prior to recombination to produce the C10 epimer 445 (Scheme ). Furthermore, peculiar ring-contracted products were also derived from diketone 446. These ring-contraction products presumably proceed through a Norrish type I fragmentation, generating diradical 447. Subsequent expulsion of CO and intramolecular recombination of diradical 448 produces the observed ring-contracted product 449 (Scheme ).[312,313]

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

Bicyclo[2.2.1]heptanones and related derivatives are prone to undergo Norrish type I cleavage. The resulting acyl radicals can subsequently abstract a hydrogen atom, leading to the formation of γ,δ-unsaturated aldehydes. Vandewalle and co-workers employed such an approach in the synthesis of (±)-boschnialactone (454).[352] Irradiation of bicyclo[2.2.1]heptanone 450 promoted Norrish type I photoinduced α-cleavage to afford the 1,5-diradical 451. Subsequent hydrogen atom abstraction by the produced acyl radical gave the γ,δ-unsaturated aldehyde 452, which underwent facile ring closure to form lactol 453 in 90% yield. Oxidation with PCC followed by double bond hydrogenation using Pd/C gave (±)-boschnialactone 454 in 75% yield (Scheme ). Additional applications of this photoinduced α-cleavage/hydrogen abstraction sequence can be found in the synthesis of (+)-juvabione (459, Scheme )[353] and (±)-hop ether.[354]

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

The formation of tetrahydrofuryl ethers upon irradiation of cyclobutanones in the presence of alcohols or other protic solvents is believed to proceed via initial formation of an oxacarbene species, which is subsequently inserted into the O–H bond.[355−357] Molander and co-workers utilized this oxacarbene/insertion sequence in the synthesis of deacetoxyalcyonin acetate (465).[358] The photochemical rearrangement of cyclobutanone 460 generated oxacarbene 461, which could be trapped with AcOH to afford the mixed acetal ring expansion product 462 in high yield and with complete retention of the stereocenter adjacent to the carbonyl. The mixed acetal 462 subsequently underwent a TiCl4-mediated [4 + 3] annulation at −80 °C to give the ester 464, which could be advanced to deacetoxyalcyonin acetate (465) (Scheme ).

Scheme 83

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

Norrish–Yang Cyclizations

(−)-Punctaporonin A (470), originally isolated from the fungus Poronia punctata, is a trihydroxylated tricyclic sesquiterpene containing a trans-cyclobutanol unit.[359,360] For construction of the strained four-membered cyclobutanol scaffold, Sugimura and Paquette applied Norrish type II photochemistry.[361] The synthesis commenced with diketone 466, which was converted to the essential photosubstrate 467. Irradiation of a benzene solution of ketone 467 generated diradical 468 via γ-hydrogen abstraction from the proximal isopropyl moiety, which produced the desired key Norrish–Yang cyclized product 469 in 49% yield along with approximately 20% of the Norrish β-fragmentation product (cf. Scheme ). Removal of the SEM group and subsequent manipulations completed the synthesis and afforded (−)-punctaporonin A (470) (Scheme ).

Scheme 84

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

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

Ouabain (471) and ouabagenin (472) belong to a class of steroids known as cardenolides and exhibit positive inotropic acitivity (Figure ).[362−364] The steroidal skeleton of ouabagenin (472), an aglycon of ouabain (471), possesses several characteristic features, such as cis-fused A/B and C/D rings, an angular hydroxyl unit at the C14 position, and a β-oriented butenolide group at C17, and poses a formidable synthetic challenge. In light of the need for a scalable and economically viable route to the cardenolides and derivatives thereof, Baran and co-workers’ synthesis commenced with cortisone acetate (473).[365,366] Conversion of cortisone acetate (473) to adrenosterone with subsequent ketalization afforded ketone 474. Functionalization of the angular C19 methyl group was realized through a Norrish type II photochemical event (Scheme ). Precedent for such a strategy can be found in the work of Jeger’s[367] and Thomson’s[368] groups on C19 functionalization of steroid scaffolds. Irradiation of ketone 474 efficiently provided the desired cyclobutanol 476 in 68% yield on a multigram scale after ring closure of diradical 475. Subsequent oxidative fragmentation employing N-iodosuccinimide as oxidant gave iodide 477. This process presumably proceeds via a transient hypoiodite species, which undergoes a chemoselective homolysis of the C11–C19 bond followed by recombination with an iodine radical to furnish the fragmentation product 477, which could be further transformed into ouabagenin (472).

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.

Booker-Milburn and co-workers recently applied the Norrish–Yang cyclization for the synthesis of aza-fuzed tricyclic lactones.[369,370] It was realized that alkoxy-substituted maleimides such as 478 underwent a [5 + 2] cycloaddition/Norrish–Yang cyclization cascade sequence of the major initial photoadduct 479 to provide the complex azepine-fused alkylidene-oxetanol 482 in a single photochemical operation. The produced oxetane derivatives, such as 482, were shown to afford the tricyclic lactone 483, a result of acid-catalyzed rearrangement (Scheme ). The rearrangement was proposed to proceed via initial oxetane ring-opening, followed by transannular amide cleavage. The resulting amine cyclizes to produce an aminol, which upon elimination of water forms the tricyclic lactone 483.

Scheme 86

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

A recent application of the Norrish–Yang cyclization can be found in Inoue and co-workers’ synthesis of (+)-lactacystin (490).[371] The C5–C9 core skeleton of (+)-lactacystin (490) was provided by commercially available (S)-pyroglutaminol (484), which was converted to diketone 485. Subjecting diketone 485 to UV light (λ < 360 nm) gave a complex product mixture, presumably due to unselective photoexcitation. As an alternative, the authors turned their attention to blue LEDs (λ ≈ 460 nm). Using the longer-wavelength-emitting blue LEDs led to smooth conversion to the cis-fused cyclobutanone 488. The observed chemoselective hydrogen abstraction in the Norrish type II reaction is presumed to originate from the more electron-rich nature of the ethereal C(sp3)–H bond in comparison to the aliphatic C–H bond. Subsequent oxidative ring-opening using Pb(OAc)4 generated ketoester 489 as a single isomer in 66% yield over two steps (Scheme ), which could be converted to (+)-lactacystin (490) through homologation at C10, construction of C6 and C7 stereocenters, and attachment of the cysteine moiety.

Scheme 87

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

Substrates lacking γ-hydrogens are also prone to undergo Norrish-Yang cyclization. Examples of this type have been applied in the synthesis of (±)-paulownin (493, Scheme )[372] and the structurally related (+)-phrymarin I and (+)-phrymarin II.[373]

Scheme 88

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

The Oxa-di-π-methane Rearrangement—Access to Complex Molecular Frameworks

Substrates housing β,γ-unsaturated ketone motifs are generally competent in undergoing the oxa-di-π-methane rearrangement. The reaction involves triplet-sensitized irradiation and is the reason why the reaction is conducted in the presence of a sensitizer, usually by employing acetone as the solvent. The oxa-di-π-methane rearrangement ultimately furnishes an α-cyclopropyl ketone, where photochemical excitation brings about a 1,2-acyl migration, resulting in bond formation between what were formerly the α and γ atoms.[374]Scheme depicts typical cyclic and acyclic substrates that undergo the oxa-di-π-methane rearrangement.

Scheme 89

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

The first reported example of the oxa-di-π-methane rearrangement dates back as far as 1966. Here, the authors discovered that a β,γ-unsaturated ketone underwent rearrangement to afford a cyclopropyl ketone.[375] After this initial report, there have been a multitude of synthetic examples that address the photochemistry of substrates containing β,γ-unsaturated ketone scaffolds.[376] The synthetic advantages of using the oxa-di-π-methane rearrangement as a tool in synthesis can be attributed to its feature of accessing molecular frameworks with significantly increased structural complexity that might be difficult to obtain via other routes. The relatively easily accessed starting materials, β,γ-unsaturated ketones, and the high tolerance of functional groups certainly increase the synthetic potential of the photochemical rearrangement.[377]

Stevens and Yates reported one of the initial applications of the oxa-di-π-methane rearrangement in total synthesis. The authors employed the oxa-di-π-methane rearrangement of bicyclo[2.2.2]octenone derivatives for the synthesis of cedrenoid sesquiterpenes.[378] Acetophenone-sensitized irradiation of the Diels–Alder adduct 494 afforded the oxa-di-π-methane rearranged product 495. The strained tricyclic compound 495 was subsequently subjected to Me2CuLi to give compound 496, which underwent Krapcho decarbomethoxylation to ketoester 497 in 74% yield. The introduction of the functionalized two-carbon substituent was carried out by treating 497 with lithium acetylide (498). This afforded the propargylic alcohol 499, where attack of the acetylide occurs at the β-face of 497. Propargylic alcohol 499 was subsequently transformed into the Stork–Clarke β-diketone 500 (Scheme ),[378,379] which had previously been reported as a key intermediate in the synthesis of (±)-cedrol (501).[436,380]

Scheme 90

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

Another example of employing the bicyclo[2.2.2]octenone skeleton for rearrangement into viable building blocks in total synthesis can be found in the synthesis of (±)-modhephene (65), which contains a carbocyclic [3.3.3]propellane framework (see Figure ).[381−394] Here, Mehta and Subrahmanyam applied a photochemical approach that involved the oxa-di-π-methane rearrangement for constructing the sesquiterpene hydrocarbon (±)-modhephene (65). In this route, diene 506 was converted to bicyclo[2.2.2]octenone 508 through a Diels–Alder cycloaddition. Irradiation of β,γ-unsaturated ketone 508, in the presence of acetone, afforded the tetracyclic strained cyclopropyl ketone 509 housing three quaternary carbon centers through a oxa-di-π-methane rearrangement. Conventional synthetic manipulations then converted the tetracyclic ketone 509 into the sesquiterpene (±)-modhephene (65) (Scheme ).[395,396]

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.

Uyehara and co-workers have also utilized the oxa-di-π-methane rearrangement in the synthesis of (±)-modhephene (65) and (±)-isocomene (63).[147] Here, oxa-di-π-rearrangement of bicyclo[2.2.2]oct-5-en-2-ones 512 and 514 afforded ketones 513 and 515, which could be further elaborated to (±)-modhephene (65) and (±)-isocomene (63), respectively (Scheme ).

Scheme 92

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

The structurally related magellanine (516),[397−399] magellaninone (517),[397−399] and paniculatine (518)[400] are members of the Lycopodium alkaloids, which are a family of natural products that have attracted considerable interest from the synthetic community since their isolation in the 1970s due to their intriguing polycyclic skeleton and biological activity (Figure ).[401−404] These alkaloids share a diquinane core that is fused to a cyclohexenone or cyclohexanol and piperidine unit. Construction of the tetracyclic scaffolds of these alkaloids and also controlling the stereochemistry at a multitude of the carbon centers of the bicyclo[3.3.0]octane core certainly represent daunting synthetic challenges.[405−409]

Figure 26

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

The tetracyclic magellanine (516) with six contiguous stereogenic centers, one of which is a quaternary carbon center, was efficiently synthesized from commercially available acetovanillone 519 using the oxa-di-π-methane rearrangement as a key step.[410] Liao and co-workers found that irradiation of Diels–Alder cycloadduct 520 yielded the tetracyclic diketone 521 through the oxa-di-π-methane rearrangement. Cyclopropyl ring-opening resulted in a linear triquinane (523), which was subsequently transformed into (±)-magellanine (516) (Scheme ).

Scheme 93

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

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

A similar approach by Liao and co-workers was also applied in the synthesis of (±)-Δ9(12)-capnellene (525), which was accessed in nine steps with 20% overall yield from 2-methoxy-4-methylphenol (524) (Scheme ).[411] Additional examples of linear triquinanes that have been assembled utilizing the oxa-di-π-methane rearrangement are (−)-complicatic acid (526),[412,413] (−)-coriolin (527),[414−418] (−)-hirsutene (222),[419−422] (+)-hirsutic acid (528),[412,413,423,424] and (−)-phellodonic acid (529) (Figure ).[425]

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.

The examples highlighted here illustrate the power of the oxa-di-π-methane rearrangement for the elaborate functionalization of simple scaffolds into highly condensed skeletons for use in the total synthesis of natural products.

The Meta-Photocycloaddition Reaction—A Powerful Method for Accessing Polycyclic Skeletons

Aromatic compounds are known for their robustness; however, upon electronic excitation the aromatic ring can be activated and engaged in reaction pathways that are generally not possible from the ground state. Scheme a depicts the cycloaddition between an alkene (ethylene) and an arene (benzene) and the three pathways, ortho-, meta-, and para-photocycloaddition, that can be observed.[426] Ortho- and meta-photocycloadditions are the most frequently encountered outcomes, while para-photocycloaddition is rarely observed. The meta-photocycloaddition (Scheme b) is perhaps the most remarkable photochemical reaction, as it allows for the formation of three single bonds and up to six stereogenic centers in one step.[427,428] The reaction proceeds via the formation of a tricyclic scaffold from which fragmentation of the three-membered ring can produce several products (Scheme c). Cleavage of the C2–C8 bond is considered as the most common pathway and generates a bicyclo[3.3.0]octane framework. On the other hand, cleavage of the C1–C2 bond or the bond between C1 and C8 furnishes a bicyclo[3.2.1]octane skeleton. The extensive bond reorganization associated with the meta-photocycloaddition reaction makes it a powerful method for generating significant molecular complexity in a single synthetic step, and it lacks a thermal counterpart. The versatility of the different fragmentation routes creates various exotic frameworks and it is this feature that has rendered the meta-photocycloaddition a widely used tool in a number of synthetic routes for accessing natural products.[429,430]

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

Although Wilzbach and Kaplan reported the first example of a meta-photocycloaddition reaction in 1966,[431] it was Wender’s successful implementation of the meta-photocycloaddition in the total synthesis of a variety of natural products that began to attract significant attention.[432] In particular, Wender’s synthesis of α-cedrene (1) expanded the concept of the alkene–arene meta-photocycloaddition reaction and extended the chemical toolbox (Figure ).[37] The tricyclic α-cedrene (1) belongs to a family of naturally occurring sesquiterpenes. It was isolated[433,434] from Juniperus cedrus and Juniperus thurifera in 1841; however, its structure and the tricycle undecane skeleton were not verified until 1953 by Stork and Breslow.[435] The intriguing [5.3.1.01,5] tricyclic structure found in the cedranoids has attracted considerable interest among the synthetic community.[436−447]

Figure 28

Examples of cedranoids.

Wender’s concise synthesis of (±)-α-cedrene (1) in merely four steps (Scheme ) exemplified the ability of the meta-photocycloaddition reaction to provide the tricyclic sesquiterpene with the correct configuration at all four stereogenic centers. The high diastereo- and regioselectivity is dictated by 1,3-allylic (A1,3) strain between the aryl methoxy and the methyl group in 532. This favors a conformation for the ring closure step that gives the two products 533 and 534 in a 1:1 ratio. Subsequent fragmentation of the cyclopropane ring upon treatment with Br2, followed by reductive dehalogenation with nBu3SnH, provided convergent access to ketone 535 from the two cycloaddition products 533 and 534. Wolff–Kishner reduction of ketone 535 generated (±)-α-cedrene (1) in merely four steps.[37]

Scheme 96

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

As previously discussed in section , both (±)-isocomene (63)[78] and silphinene (105)[95] have been synthesized using the [2 + 2] photocycloaddition. However, the tricyclic cores of (±)-isocomene (63)[146] and silphinene (105)[448] can also be accessed by using a meta-photocycloaddition strategy and are depicted in Schemes and 98, respectively.

Scheme 97

Photochemical Approach for Synthesis of (±)-Isocomene (63)

Scheme 98

Route to Silphinene (105) Using Meta-Photocycloaddition

Pentacyclic (−)-retigeranic acid A (548), a structurally related natural product, was initially isolated from Himalayan lichen and is reported to have antibacterial activity.[449,450] It is a structurally unique member of the class of sesterterpene natural products and houses a triquinane subunit and eight stereocenters.[451,452] Due to retigeranic acid’s intriguing structure, several research groups have pursued its synthesis and related sesterterpenoids.[453−455] Early examples of the total synthesis of retigeranic acid include reports by the groups of Corey,[456] Hudlicky,[457−460] and Paquette.[461−463]

Wender and Singh’s convergent approach to (−)-retigeranic acid A (Scheme ) commenced with the preparation of the enantiomerically pure arene–alkene derivative 543 from commercially available 3-methylglutaric acid. Photolysis of the arene–alkene fragment 543 afforded a 1:2 mixture of photoadducts 544 and 545, which were found to be interconvertible vinylcyclopropane isomers, allowing them each to be converted to the Diels–Alder precursor 546. This precursor was then allowed to undergo an intramolecular Diels–Alder reaction to furnish the pentacyclic compound 547, which could be further transformed into (−)-retigeranic acid (548).[464]

Scheme 99

Synthesis of (−)-Retigeranic Acid A (548)

Subsequently, the Wender group reported on the total synthesis of rudmollin (554).[465] The pseudoguaianolide rudmollin (554) was initially isolated from a coneflower by Herz and co-workers and exhibits antileukemic activity.[466] It was realized by Wender and co-workers that the trans-fused perhydroazulene core of rudmollin (554) could be accessed through the use of an arene−olefin cycloaddition strategy. Their approach thus centered on accessing a seven-membered cyclic compound via intramolecular meta-photocycloaddition of substrate 549, which would establish the trans relationship between carbons C1 and C5. Furthermore, since these photocycloadditions generally preserve the geometry of the olefin moiety, this would also set the relative configuration between carbons C1 and C10 in the photocycloadduct. Performing the meta-photocycloaddition on substrate 549 afforded the two photocycloadducts 550 and 551 in a 7:3 ratio and hence established the relative configuration at the three carbon centers C1, C5, and C10. Here, the cyclopropane isomers 550 and 551 could be converted into a common product by employing a similar technique as with (±)-α-cedrene (1); see Scheme . However, instead of using Br2-induced cleavage of the cyclopropane bond, Hg(OAc)2-catalyzed hydrolysis was shown to convergently transform the cycloadducts 550 and 551 into compound 552, which could subsequently be used to access (±)-rudmollin (554) (see Scheme ).[465,467]

Scheme 100

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

Penifulvin A (555), an antiinsectan sesquiterpenoid, was originially isolated by Gloer and co-workers in 2006 from Penicillium griseofulvum.[468,469] The penifulvins (Figure ) contain an intricate dioxa[5.5.5.6]fenestrane skeleton where four rings are joined at a central quaternary carbon atom (Figure ). In addition to the two vicinal quaternary stereocenters, a total of five stereogenic centers exist within the 15-carbon atom framework.[470,471] The unique and complex molecular scaffold of penifulvins has made them an attractive target for total synthesis.[472−474]

Figure 29

Structure of penifulvins A–E.

Recently, the Mulzer group used the arene olefin meta-photocycloaddition to access the sesquiterpene (−)-penifulvin A (555).[475−477] The asymmetric synthesis of compound 566 was carried out by using Myers’ alkylation strategy (Scheme ).[478] Photoreaction of compound 566 resulted in a mixture of the two allylic regioisomers 569 and 570 in a 1:1 ratio. Subsequent cyclopropane ring opening using Birch-like reductive conditions afforded alcohol 571. This was followed by an oxidative cascade sequence to complete the concise synthesis of (−)-penifulvin A (555) (Scheme ). In addition to the photocyclization event, which furnishes separable regioisomers, the synthesis did not require any protecting groups.[475] The total syntheses of penifulvins B (556) and C (557) were subsequently accomplished using a similar meta-photocycloaddition approach as the key step to rapidly access the fenestrane-type carboskeletons.[476] Wender and co-workers have also disclosed a method for synthesizing cis,cis,cis,trans-[5.5.5.5]fenestranes using the meta-photocycloaddition.[479]

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.

Laurenene (99) is another natural product containing the fenestrane framework that has been synthesized using meta-photocycloaddition.[480] Wender and co-workers started with a Diels–Alder reaction of commercially available 575 and cyclohepta-1,3-diene (576) to afford the tricyclic arene 577, which was subsequently elaborated to give lactone 579 upon Grob fragmentation of keto tosylate 578. Hydrogenation of lactone 579 and alkylation with homoprenyl iodide furnished the desired stereoisomer 581 with a 8:1 preference. Photolysis of lactol 582, prepared by LiAlH4 reduction of lactone 581, through a BiCl3 filter solution allowed for 80% conversion and isolation of a single hexacyclic product (583) in 51% yield. Completion of the synthesis was then accomplished in three steps to afford (±)-laurenene (99) in 5% overall yield (Scheme ).

Scheme 103

Total Synthesis of (±)-Laurenene (99)

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

Additional examples of natural products that have been accessed using the meta-photocycloaddition reaction as the key step are shown in Figure and include (±)-coriolin (527),[481] (±)-hirsutene (222),[482] (±)-isoiridomyrmecin (586),[483] (±)-modhephene (65),[484] (±)-silphiperfol-6-ene (588),[485] subergorgic acid (590),[486] and crinipellin B (592).[487]

Figure 31

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

Visible-Light Photoredox Catalysis—Single-Electron Transfer Approaches in Natural Product Synthesis

A central theme in photoinduced reactions is the excitation of an electron from an occupied molecular orbital to an antibonding orbital to generate a neutral π–π* excited state. A fundamentally different approach would be to use photosensitizer compounds for activation of organic compounds. Upon absorption of visible light, these photosensitizers form excited states that can function both as powerful oxidants and reductants, which would allow for the generation of radical cations or radical anions under remarkably mild reaction conditions.[488] Photoredox catalysis offers selective excitation of the organic compound, avoiding excitation of the whole organic network and decomposition, as can be the case with UV-light excitation. Visible-light photoredox catalysis is a rapidly emerging field that offers an attractive alternative to conventional methods of producing radical ion intermediates that are capable of engaging in a multitude of different pathways. This powerful method has enabled the development of novel reaction schemes and approaches for the controlled engineering of structurally complex and diverse frameworks through single-electron transfer (SET) reactions. In particular, transition-metal polypyridyl complexes based on Ru and Ir have proven to afford unique chemical reactivities when excited by visible light (Figure ). These photocatalysts are chemically robust, afford long-lived excited state lifetimes, and possess favorable redox properties that can be conveniently fine-tuned by modifying the polypyridyl ancillary ligands (Figure ).[489−493] These properties allow overall redox-neutral reactions to be carried out as both reductants and oxidants that can be transiently generated during different stages in the catalytic process. This reactivity pattern is beneficial since it might allow for the exploration of alternative pathways under benign reaction conditions.[494−504]

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).

A variety of cyclobutane-containing natural products have been accessed via photoinduced SET. The use of visible-light photoredox catalysis can, for example, be found in the synthesis of magnosalin (599, Scheme ),[505]ent-sceptrin (606, Scheme ),[506] (±)-epiraikovenal (614, Scheme ),[507] and (±)-cannabiorcicyclolic acid (619, Scheme ).[508] The synthesis of γ-butyrolactones from simple alkenes and unsaturated acids via polar radical crossover cycloaddition (PRCC) reactions was recently reported by Nicewicz and co-workers.[509] The mechanism was proposed to involve single-electron oxidation of the alkene (621) by the excited acridinium photocatalyst (620+*), which produces an electrophilic alkene cation radical (622). The carboxylic acid (623) can subsequently add to the generated radical cation 622 to furnish radical 624, which undergoes 5-exo-trig radical cyclization to give 625. Hydrogen atom transfer (HAT) to radical 625 produces the desired γ-butyrolactone (626) and completes the catalytic cycle (Scheme , top). The authors subsequently applied the PRCC method to the synthesis of protolichesterinic acid (630). Irradiation of styrene 627 and β-haloacrylic acid (628) in the presence of 2.5 mol% of acridinium photocatalyst 620(BF4) and substoichiometric quantities (25 mol%) of the redox-active cocatalyst PhSSPh afforded lactone 629 in 69% yield, which upon treatment with RuCl3/NaIO4 followed by K2CO3 produced protolichesterinic acid (630) as a single isomer in 54% yield (Scheme , bottom).

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.

The use of two electron-rich components in Diels–Alder cycloadditions typically requires harsher reaction conditions and prolonged reaction times as a result of the electronic mismatching. In contrast, radical cations generated from electron-rich olefins have been documented to react rapidly with electron-rich dienes in [4 + 2] cycloadditions, and the reactions typically occur with high chemo-, stereo-, and regioselectivity with rates that can be several orders of magnitude higher than the corresponding thermal process with the neutral species.[510−513] The essential radical cations are usually produced using high loadings of one-electron oxidants, such as aminium salts,[514] or photoinitiated electron transfer initiated by an organic photosensitizer.[515]

The Yoon group utilized visible-light photocatalysis as a means for the efficient generation of the vital radical cations.[516−518] This allowed for an operationally simple protocol for radical cation Diels–Alder cycloadditions that employed low loadings (0.5 mol%) of [Ru(bpz)3]2+ (595[519]) as photosensitizer.[516] Given the broad scope of this reaction, the authors became interested in heitziamide A (635), a natural product isolated as a racemate from the medicinal shrub Fagara heitzii.[520] Irradiation of styrene 631 and myrcene (632) in the presence of 2 mol% [Ru(bpz)3]2+ (595) produced [4 + 2] adduct 633 in 80% yield. This process can be best described as an umpolung process that reverses the intrinsic electronic character of the electron-rich olefin, thus producing the cycloadduct with the natural regiochemistry of heitziamide A (635). As a comparison, the thermal Diels–Alder reaction furnished the unnatural isomeric cycloadduct without any trace of 633. Deprotection of the TBS protecting group and subsequent oxidation afforded carboxylic acid 634, which could be converted to heitziamide A (635) by EDC coupling with isobutylamine (Scheme ).

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.

Given the high oxidation potential of the [Ru(bpz)3]2+ photosensitizer (1.4 V vs SCE), the visible-light-mediated radical cation Diels–Alder reaction is believed to proceed via reductive quenching of the excited state of the photosensitizer {[Ru(bpz)3]2+•} by the electron-rich olefin moiety 631. This results in a radical cation (631+•) that undergoes the [4 + 2] cycloaddition to generate a radical cycloadduct, which can either be reduced by the reduced photosensitizer {[Ru(bpz)3]+} or abstract an electron from another olefin molecule to initiate radical chain processes.[503,516,521] A related radical cation Diels–Alder approach has also been utilized in the synthesis of (±)-kingianic acid E (639) (Scheme ).[522]

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.

Aplyviolene (646) belongs to a class of spongian diterpene natural products and contains a cis-perhydroazulene unit.[523−525] For aplyviolene (646), formation of the bicyclic lactone subunit and the C8–C14 bond has been recognized as particularly challenging. In Schnermann and Overman’s synthesis of (−)-aplyviolene (646), the key step involved a photoredox-mediated fragmentation strategy, which allowed construction of the crucial C8–C14 bond.[526] The synthesis commenced with (+)-fenchone (640), which was converted to N-(acyloxy)phthalimide 641. Irradiation of cyclopentenone 642 and N-(acyloxy)phthalimide 641 in the presence of 1 mol% [Ru(bpy)3]2+ (594), Hantsch ester 643, and DIPEA efficiently provided the coupled product 644 in 61% yield with <5% of the reductively dechlorinated analogue. Reductive enol silylation of coupled product 644 using Me2CuCNLi2 in the presence of TBS-Cl at −20 °C delivered the tricyclic enol ether 645, which had previously been converted to (−)-aplyviolene (646) (Scheme ). The use of the photoredox-mediated fragmentation strategy thus allowed the construction of the C8–C14 bond and highlights the utility of using photoredox catalysis for generation of tertiary carbon radicals in the construction of quaternary stereocenters in a stereoselective fashion. A related strategy was also employed by Overman and co-workers in the synthesis of trans-clerodane natural products.[527]

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.

Pyrroloindoline alkaloids are a class of natural products that are formally derived from two molecules of tryptophan and have been shown to exhibit a broad range of biological activities. As a result of their structural complexity and broad biological activity, pyrroloindoline alkaloids have attracted attention from several research groups.[528−530] In the synthesis of (+)-gliocladin C (652), Stephenson and co-workers utilized a photoredox-mediated indole coupling reaction as the key step to access the C3–C3′ bisindole motif. Irradiation of bromopyrrolindoline 648, derived from Boc-d-tryptophan methyl ester (647), and aldehyde 649 using 1 mol% [Ru(bpy)3]Cl2 and Bu3N as reductive quencher successfully provided the C3–C3′ coupling product 650 in 82% yield. Subsequent decarbonylation of the aldehyde at the C2′ position using a combination of Rh(CO)(PPh3)3Cl, dppp, and DPPA in xylenes afforded the decarbonylated product 651 in 85% yield, which could be further advanced to (+)-gliocladin C (652) in merely 10 steps from Boc-d-tryptophan methyl ester (647) and in 30% overall yield (Scheme ).[531]

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.

Beatty and Stephenson identified (+)-catharanthine (653) as an entry point for the synthesis of a number of structurally related alkaloids.[532] Catharanthine has been reported to undergo a unique fragmentation of its C16–C21 bond[533,534] and it was envisioned that such an oxidative fragmentation could be exploited to produce a common α-aminonitrile intermediate (654), which could subsequently be converted to a variety of analogous alkaloids. Visible-light irradiation of catharanthine (653) in the presence of the fluorinated photocatalyst 610 and TMSCN indeed produced an α-aminonitrile fragmentation product (654) in 93% yield. Performing the reaction in a photochemical flow reactor[535−540] allowed for improved scalability, decreased reaction time, and the controlled generation of HCN, affording intermediate 654 in 96% yield. Refluxing a MeOH solution containing α-aminonitrile intermediate 654 and 1 equiv. of trifluoroacetic acid for 3 h gave (−)-pseudotabersonine (655) as the only observed product in 90% yield. Hydrogenation of the aminonitrile fragmentation product 654 followed by reflux in the presence of 1 equiv. of trifluoroacetic acid was anticipated to produce (−)-pseudovincadifformine (660). However, this yielded the natural product (+)-coronaridine (657) as the sole product in 48% yield over two steps and represents the highest yielding preparation of coronaridine from catharanthine reported thus far. An alternative approach to (−)-pseudovincadifformine (660) was therefore investigated and involved initial hydrogenation over Pd/C, followed by NaBH4 reduction to give 658. Exposing amine 658 to oxidative photoredox conditions employing malonate 659 as the terminal oxidant subsequently yielded (−)-pseudovincadifformine (660) in 58% yield (Scheme ).[532] This work demonstrates the synthetic utility of photoredox catalysis in natural product synthesis and the rapid access to structurally related alkaloid motifs from a common advanced intermediate.

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.

The examples described in this section highlight photoredox catalysis as a robust tool for the mild generation of radical species for potential access to a wide variety of complex molecular scaffolds, thus expanding the use of photochemistry en route to natural product targets.

Conclusions and Outlook

The purpose of this review has been to highlight some of the accomplishments that have been presented in natural product total synthesis using photochemistry. Photochemically mediated reactions have proven to be highly useful for construction of highly strained and complex molecular frameworks that can otherwise be challenging to access via conventional, thermal processes. However, the use of specialized equipment for performing these photochemical reactions could serve as a significant impediment for possible practitioners looking to implement these techniques. Although this may impede the advancement of photochemical transformations, continued triumphs in the total synthesis of natural products and biologically active compounds, along with further mechanistic studies to elucidate the general chemical reactivity of the electronically generated excited intermediates, will continue to inspire the development and application of photochemistry in organic synthesis.

The recent emergence of photoredox catalysis as a means to generate radical species in a controlled and mild fashion has further increased the ability of accessing complex molecular scaffolds. It is believed that such controlled redox manipulations will allow for chemoselective access to a wide array of novel structural motifs. Another important direction in modern photochemistry is its application to continuous flow processing. Compared to normal batch reactors, carrying out photochemical reactions in flow reactors can greatly improve the yields and selectivities due to the avoidance of unproductive reaction pathways.

On the whole, photochemistry serves as a useful tool for mastering new and environmentally benign transformations. In the future, it can also be used to expand our classical chemical toolbox by offering improved reaction conditions and can facilitate the discovery of new transformations for efficient bond construction. Thus, in combination with flow chemistry and other advanced techniques, photochemistry will continue to serve as an attractive option for accessing intricate chemotypes of biological and medicinal importance.