Intramolecular Tricarbonyl‐Ene Reactions and α‐Hydroxy‐β‐Diketone Rearrangements Inspired by the Biosynthesis of Polycyclic Polyprenylated Acylphloroglucinols

Abstract

Structurally unique natural products pose biosynthetic puzzles whose solution can inspire new chemical reactions. Herein, we propose a unified biosynthetic pathway towards some complex meroterpenoids—the hyperireflexolides, biyoulactones, hybeanones and hypermonones. This hypothesis led to the discovery of uncatalyzed, intramolecular carbonyl‐ene reactions that are spontaneous at room temperature. We also developed an anionic cascade reaction featuring an α‐hydroxy‐β‐diketone rearrangement and an intramolecular aldol reaction to access four distinct natural product scaffolds from a common intermediate.

Chemical speculation on the biosynthesis of some complex meroterpenoids led to the discovery of intricate cascades that feature spontaneous intramolecular carbonyl‐ene reactions, α‐hydroxy‐β‐diketone rearrangements, and intramolecular aldol reactions. The combination of these transformations allowed divergent access to four distinct natural product scaffolds from a common intermediate, mimicking their proposed biosynthetic pathways.

Introduction

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a large family of highly oxygenated meroterpenoids produced almost exclusively by plants of the Hypericum and Garcinia genera. ^[1] Although most PPAPs contain a common bicyclo[3.3.1]nonane‐2,4,9‐trione core that can be linked to a mixed mevalonate‐polyketide biosynthetic pathway, there are several non‐canonical PPAP sub‐families whose biogenetic origins are more obscure. For example, hyperireflexolide A (1) and hyperireflexolide B (2, initially proposed structure) ^[2] are spirocyclic bislactone natural products ^[3] isolated as racemates ^[4] from Hypericum reflexum (Figure 1). Although 1 and 2 were originally considered to be oxidized derivatives of abietane terpenes, herein we propose a cryptic PPAP biosynthetic pathway that also explains their racemic nature. The structure of hyperireflexolide A (1) was determined by X‐ray crystallography, while hyperireflexolide B was assigned as 2 by NMR studies. Compared to 1, structure 2 has the opposite relative configuration at the C8, C12 and C13 stereocentres. However, our biosynthetic hypothesis predicts that the structure of hyperireflexolide B should be reassigned to 3, with the same relative configuration at the spirocyclic C8 stereocentre as in 1.

Figure 1.

Hyperireflexolides A and B.

Biyoulactones A, B and C (4, 5 and 6) are pentacyclic bislactone meroterpenoids ^[5] isolated from Hypericum chinense (Figure 2). The structure of 4 was determined by X‐ray crystallography, while 5 and 6 were assigned as the C4‐ and C23‐epimers of 4 via NMR spectroscopy. Although the biyoulactones were recognized as rearranged PPAPs on their isolation, we suggest a revised biosynthetic pathway that closely mirrors the origin of the hyperireflexolides. The distinctive tricyclic γ‐lactone ring system of the biyoulactones is shared by the biosynthetically related hybeanones A and B (7 and 8), isolated from Hypericum beanii, ^[6] and also hypermonones A, B, C and D (9, 10, 11 and 12) which were found in Hypericum monogynum. ^[7]

Figure 2.

The biyoulactone, hybeanone and hypermonone family.

Herein, we propose that the hyperireflexolide, biyoulactone, hybeanone and hypermonone polycyclic ring systems are all constructed in nature via sequences of intramolecular carbonyl‐ene reactions and α‐hydroxy‐β‐diketone rearrangements. Both these transformations are rare in biosynthetic pathways, but here they rationalise how simple acylphloroglucinol building blocks such as 13 and 14 undergo prenylation, dearomatization and fragmentation reactions to give complex natural products such as 1, 4, 8 and 12 (Figure 3). The diverse fate of the highlighted phloroglucinol carbon atoms exemplifies the power of dearomatization in natural product biosynthesis. ^[8]

Figure 3.

Comprehensive dearomatization of acylphloroglucinols in the biosynthesis of rearranged, non‐canonical PPAPs.

Results and Discussion

Our biosynthetic proposal for hyperireflexolides A and B (1 and 3), which asserts their meroterpenoid and PPAP origin, is outlined in Scheme 1. Acylphloroglucinol 13 is an aromatic polyketide commonly invoked in the biosynthesis of PPAPs, and it is the aglycone component of a recently isolated glycoside. ^[9] Di‐prenylation of 13 at C8 (hyperireflexolide numbering) gives the dearomatized β‐acid 15, which could undergo single electron oxidation at C10 to form the stabilized β‐diketo radical 16. Cyclization of 16 via a 5‐exo‐trig addition to one of the two equivalent prenyl side chains, followed by trapping of a tertiary radical intermediate with triplet oxygen and reduction of the resultant hydroperoxide, would give enaimeone A (17). ^[10] This bicyclo[3.2.1]octane PPAP natural product has been isolated from Hypericum papuanum. ^[11] Next, oxidative cleavage of the C1–C12 double bond, perhaps mediated by singlet oxygen, ^[12] would release a 1,2,3‐triketone motif and a carboxylic acid group, which could combine with the nearby tertiary alcohol to give the bicyclic lactone 18. Compound 18 is a key intermediate in this biosynthetic pathway, containing the fused γ‐lactone ring system of the hyperireflexolides and with the relative configurations at C5, C8 and C10 fixed. It is also at the same overall level of oxidation as the hyperireflexolides. We then propose a type I intramolecular carbonyl‐ene reaction ^[13] between the 1,2,3‐triketone ^[14] and the prenyl side chain of 18 to give cyclic α‐hydroxy‐β‐diketones 19 and 20 via two diastereomeric pericyclic transition states. Although carbonyl‐ene reactions typically require Lewis acid catalysis ^[15] or thermal activation, 1,2,3‐triketones are known to be highly reactive enophiles in intermolecular reactions. ^[16] We therefore proposed that an intramolecular carbonyl‐ene reaction such as 18→19/20 should be favourable, and indeed DFT calculations predict that it will occur spontaneously at room temperature (see later). The final step in the proposed biosynthetic pathway is the ring expansion of 19 and 20 to construct the spirocyclic δ‐lactones of hyperireflexolides A and B via an unusual α‐hydroxy‐β‐diketone rearrangement. First reported by Blatt and Hawkins in 1936, ^[17] the α‐hydroxy‐β‐diketone rearrangement to give ester or lactone products has only rarely been applied in total synthesis ^[18] or invoked in biosynthetic pathways. ^[19] As proposed by House, ^[20] the mechanism of the α‐hydroxy‐β‐diketone rearrangement can proceed via an anionic or a neutral, thermal pathway (as shown below) involving epoxide intermediates such as 21 and 22. Cleavage of the epoxide C−C bond of 21/22 followed by diastereoselective tautomerization of the resultant enols then gives 1 and 3. In addition to justifying the relative configuration of hyperireflexolides A and B, this biosynthetic proposal also rationalizes their racemic nature via cyclization of the achiral radical intermediate 16.

Scheme 1.

Proposed biosynthesis of hyperireflexolides A and B via an intramolecular carbonyl‐ene reaction and an α‐hydroxy‐β‐diketone rearrangement.

To gain insight into this unusual biosynthesis, we mimicked the intramolecular carbonyl‐ene reaction of the proposed biosynthetic intermediate 1,2,3‐triketone 18 in a simplified model spirocyclic system (Scheme 2). First, methyl cyclohexanecarboxylate (23) was α‐prenylated with LDA/prenyl bromide to give 24, followed by addition of MeLi to give methyl ketone 25. An intermolecular aldol reaction between the lithium enolate derived from 25 and isobutyraldehyde then gave the aldol adduct 26. Golec and co‐workers have shown that β‐hydroxycarbonyl compounds can be oxidized to 1,2,3‐tricarbonyl compounds in one step (via an intermediate β‐dicarbonyl compound) using Dess–Martin periodinane (DMP) in the presence of pyridine. ^[21] Meyer and Schreiber subsequently optimized this oxidation by the addition of 3 equiv of water. ^[22] Using these modified conditions, we were pleased to observe the oxidative cyclization of 26 to give the cyclopentyl α‐hydroxy‐β‐diketone 29 in high yield as a single diastereomer. The relative configuration of 29 (determined using X‐ray crystallography) supports a concerted, type I intramolecular carbonyl‐ene reaction of 1,2,3‐triketone 28. Although the β‐diketone intermediate 27 was observed as an isolable intermediate, 28 was not detected, which indicates that its intramolecular carbonyl‐ene reaction is spontaneous at room temperature. We are aware of only one previous example of an uncatalyzed, intramolecular carbonyl‐ene reaction at room temperature. ^[23]

Scheme 2.

Hyperireflexolide‐inspired oxidative intramolecular carbonyl‐ene reaction of an intermediate 1,2,3‐triketone. LDA=lithium diisopropylamide, THF=tetrahydrofuran, DMP=Dess–Martin periodinane.

While screening substrates for the oxidative intramolecular tricarbonyl‐ene reaction, we found three examples of stable 1,2,3‐triketones (Scheme 3). Firstly, DMP‐mediated oxidation of the more sterically hindered t‐Bu derivative 30 gave triketone 31 in good yield. On standing in CDCl₃ at room temperature, 31 gradually converted into 32 with a half‐life of 18 h via a slow type I intramolecular carbonyl‐ene reaction. Secondly, oxidation of the β‐methallyl derivative 33 gave a stable triketone 34 in high yield, which underwent a slow type II intramolecular carbonyl‐ene reaction to give the cyclohexyl α‐hydroxy‐β‐diketone 35 on heating in PhMe at 90 °C. Thirdly, oxidation of the homoprenyl derivative 36 gave triketone 37, which did not undergo the anticipated type I intramolecular carbonyl‐ene reaction to give cyclohexanol 38 under thermal conditions or Lewis acid catalysis.

Scheme 3.

Isolation of some stable 1,2,3‐triketone intermediates in the oxidative intramolecular tricarbonyl‐ene reaction.

The substrate scope of the oxidative intramolecular tricarbonyl‐ene reaction was further extended to allow the fully diastereoselective synthesis of a variety of spirocyclic α‐hydroxy‐β‐dicarbonyl compounds (Table 1). The reaction tolerates variation at R₁ to include β‐ketoesters (entry 1) and benzylic alcohols (entry 2), and at R₂ to include a geranyl side chain (entry 3). In addition to cyclohexyl substrates, the spirocyclization also works on cyclobutyl (entry 4), cyclopentyl (entry 5) and cycloheptyl (entry 6) substrates. In all of these cyclizations, the intramolecular carbonyl‐ene reaction was too fast to allow observation of 1,2,3‐triketone intermediates, and only one diastereomer of product was formed. In general, all of these examples show rapid consumption of starting material, with some of the lower yields possibly due to slow oxidation of the intermediate 1,3‐diketones, or else undesired over‐oxidation by DMP. Highest yields were obtained for the formation of the less strained spircocyclic products such as 29 and 50.

Table 1.

Further substrate scope of the oxidative intramolecular tricarbonyl‐ene reaction.

Entry	Substrate	Product	Yield [%]
1			52
2			34
3			52
4			41
5			45
6			71

Next, we explored some bioinspired α‐hydroxy‐β‐diketone rearrangements of 29, which could occur in either an endocyclic mode to give δ‐lactones 51 and 52 (as required in hyperireflexolide biosynthesis), or in an exocyclic mode to give cyclopentyl ester 53 (Table 2). On heating in PhMe at 110 °C (entry 1), 29 was converted into a separable mixture of 51 (major product) and 52 (minor product) via a neutral ring expansion mechanism analogous to that proposed in Scheme 1. Alternatively, on exposure of 29 to a hindered base such as KOt‐Bu in THF (entry 2), trans‐cyclopentyl ester 53 was formed in good yield in 9 : 1 d.r. alongside the proposed cis diastereomer (which was not fully characterized). Under these basic conditions, the initially formed alkoxide anion 54 attacks the carbonyl group outside the 5‐membered ring, giving epoxide 55, which fragments to give ester‐enolate 56 (Scheme 4a). Protonation of 56 then gives 53, which has a similar cyclopentanone ring system to hybeanones A and B (7 and 8). The endocyclic α‐hydroxy‐β‐diketone rearrangement of 29 is clearly disfavoured under basic conditions. Recent work by Kieslich and Christoffers has shown that cyanide catalyses the ring expansion of cyclic α‐hydroxy‐β‐oxoesters. ^[24] On exposure to 10 mol % KCN in PhMe at room temperature (entry 3), 29 was converted into a separable 2.5 : 1 mixture of spirocyclic δ‐lactones 51 and 52 in high overall yield. This ring expansion presumably proceeds via cyanide‐catalysed retro‐Dieckmann condensation of 29 to give 58 via 57, followed by lactonization and then protonation of enolate 59 (Scheme 4b). Use of hydroxide, which could plausibly act as either a base or a nucleophilic catalyst for the α‐hydroxy‐β‐diketone rearrangement of 29, gave a mixture of all three products in PhMe (entry 4), but only ester 53 in aqueous conditions (entry 5). We have therefore demonstrated that the carbonyl‐ene product 29 can be converted into the hyperireflexolide spirocyclic δ‐lactone ring system under simple reaction conditions via two distinct ring expansion mechanisms. However, since aqueous conditions exclusively favour the exocyclic rearrangement, the precise mechanism operating in the biosynthesis of hyperireflexolides A and B cannot be asserted at this stage.

Table 2.

α‐Hydroxy‐β‐diketone rearrangements of spirocycle 29.

Entry	Reagent	Solvent	T	Products
1	None	PhMe	110 °C	51 (42 %)+52 (7 %)
2	KOt‐Bu	THF	−78 °C	53 (71 %, 9 : 1 d.r.)
3	10 mol % KCN	PhMe	rt	51 (57 %)+52 (23 %)
4	KOH	PhMe	rt	complex mixture of 51/52/53
5	KOH	H2O	rt	53 (35 %, 12 : 1 d.r.)

Scheme 4.

Proposed mechanism of the α‐hydroxy‐β‐diketone rearrangement of spirocycle 29 under a) base catalysis and b) nucleophilic catalysis.

Having investigated the chemical viability of our proposed biosynthesis of the hyperireflexolides, we searched for PPAP meroterpenoids with similar δ‐lactone ring systems, leading to the biyoulactones, the hypermonones, and the biosynthetically related hybeanone cyclopentanones. ^[25] Our unified biosynthesis of this PPAP family (Scheme 5) is analogous to that of the hyperireflexolides, with key intramolecular carbonyl‐ene reactions and α‐hydroxy‐β‐diketone rearrangements. Firstly, prenylation and geranylation of acylphloroglucinol 14 ^[26] at C2 and C17, respectively (biyoulactone numbering), followed by oxidative cyclization of the geranyl group, would give the dearomatized natural product chinesin I (60). This PPAP meroterpenoid has been co‐isolated from Hypericum chinense alongside the biyoulactones. ^[27] Oxidative cyclization of 60 could then form 61, a diastereomer of chipericumin D ^[28] (another PPAP found in Hypericum chinense). The oxidative cyclization of 60 could proceed by a 6‐endo‐trig radical cyclization of a stabilized β‐diketo radical followed by trapping with molecular oxygen, or else via 6‐endo‐tet cyclization of an epoxide intermediate.

Scheme 5.

Proposed biosynthesis of biyoulactone, hypermonone and hybeanone natural products via divergent intramolecular carbonyl‐ene reactions, α‐hydroxy‐β‐diketone rearrangements and intramolecular aldol reactions.

Next, oxidative cleavage of the C5–C16 alkene of 61 and lactonization of the resultant carboxylic acid with the nearby tertiary alcohol at C24 would give the key 1,2,3‐triketone intermediate 62. The tricyclic γ‐lactone ring system of 62 is also found in related meroterpenoids such as furanmonogones A and B, ^[29] and hypercohone G. ^[30] A spontaneous intramolecular carbonyl‐ene reaction between the 1,2,3‐triketone and the prenyl side chain of 62 would then give the diastereomeric cyclopenantone intermediates 63 and 64. The cyclic α‐hydroxy‐β‐diketone motifs of 63 and 64 (which are perhaps undiscovered natural products ^[31] ) are now poised to undergo further rearrangements. Firstly, deprotonation of 63/64 could trigger endocyclic α‐hydroxy‐β‐diketone rearrangements to give lactone‐enolates 67/68 via fragmentation of the intermediate epoxides 65/66. The enediolates 67/68 are then primed for an intramolecular aldol reaction between the nucleophilic C5 position and the C6 ketone to form the bicyclic δ‐lactones of biyoulactones A and B (4 and 5). Alternatively, protonation of 68 at C5 would give hypermonone C (11). Finally, an exocyclic α‐hydroxy‐β‐diketone rearrangement of 64 could give ester‐enolate 70 via C−C bond cleavage of epoxide 69, followed by protonation to give hybeanone A (7).

We mimicked the key steps of the proposed biosynthesis of the biyoulactone/hypermonone/hybeanone PPAP family in a simplified model system (Scheme 6). Methylation of the commercially available β‐diketone 71 with NaH/MeI gave 72, which was prenylated with LDA/prenyl bromide to give 73. An intermolecular aldol reaction between the lithium enolate derived from 73 and isobutyraldehyde formed β‐hydroxyketone 74 as an inconsequential 1 : 1 mixture of diastereomers. DMP‐mediated oxidative intramolecular tricarbonyl‐ene reaction of 74 then gave the highly functionalized cyclopentanones 75 and 76 as an inseparable 3.4 : 1 mixture of diastereomers in favour of 75. The relative configurations of 75 and 76 were determined via NOESY correlations.

Scheme 6.

Biyoulactone‐inspired oxidative intramolecular tricarbonyl‐ene reaction. DMF=N,N‐dimethylformamide.

With 75 and 76 in hand, which are simplified models for the proposed biosynthetic intermediates 63 and 64, we could explore some further bioinspired cascade reactions (Table 3). Under thermodynamic, basic conditions of KOt‐Bu in THF room temperature (entry 1), the anionic α‐hydroxy‐β‐diketone rearrangement of 75/76 occurs exclusively outside the ring, to give hybeanone analogue 79 as the major product alongside significant decomposition. Use of lithium bis(trimethylsilyl)amide (LiHMDS) in THF at −78 °C (entry 2) gave a higher yield of 79, alongside a small amount of biyoulactone A analogue 80. Upon further lowering the temperature (LDA in THF at −98 °C, entry 3), we observed the formation of the biyoulactone substructures 77 and 80 (33 % combined yield) via an intricate cascade featuring an endocyclic α‐hydroxy‐β‐diketone rearrangement and an intramolecular aldol reaction that closely mirrors the proposed biosynthesis of the biyoulactones. The NMR spectra of 77 and 80 show strong similarity to biyoulactones A and B, and their structures were confirmed by X‐ray crystallography. Given that the biyoulactone A analogue 80 must derive from the minor α‐hydroxy‐β‐diketone diastereomer 76, its formation in 21 % yield in this reaction indicates that the anionic rearrangement and aldol reaction of this diastereomer is efficient and selective. A small amount of the hypermonone δ‐lactone 78 was also formed using LDA at at −98 °C. Use of KCN in PhMe (entry 4) allowed synthesis of the hypermonone analogue 78 in greater yield via an endocyclic α‐hydroxy‐β‐diketone rearrangement under nucleophilic catalysis. Finally, under thermal conditions 75/76 underwent extensive decomposition, although the ring expanded lactone 78 was isolated in low yield (entry 5). Although some of these cascade reactions are low yielding, the formation of four complex natural product scaffolds in two steps from the simple aldol adduct 74 gives some chemical evidence in favour of the unified biosynthetic pathway proposed in Scheme 5.

Table 3.

Anionic rearrangement of α‐hydroxy‐β‐diketones 75 and 76 to give four distinct natural product scaffolds.

Entry	Reagent	Solvent	T	Products
1	KOt‐Bu	THF	rt	79 (43 %)+decomposition
2	LiHMDS	THF	−78 °C	79 (50 %)+80 (8 %)
3	LDA	THF	−98 °C	77 (12 %)+78 (6 %)+79 (22 %)+80 (21 %)
4	10 mol % KCN	PhMe	rt	78 (41 %)
5	None	PhMe	110 °C	78 (13 %)+decomposition

Given the complex product distribution of the anionic cascade reactions of 75/76, we designed a slower, more diastereoselective oxidative intramolecular carbonyl‐ene reaction of a more sterically hindered substrate (Scheme 7). Thus, oxidation of the di‐t‐butylated aldol adduct 81 gave cyclic α‐hydroxy‐β‐diketone 82 in 20 : 1 d.r. via a now highly diastereoselective tricarbonyl‐ene reaction. Deprotonation of 82 with LDA then initiated an anionic α‐hydroxy‐β‐diketone rearrangement to give the hybeanone analogue 83 in 75 % yield, alongside trace quantities of isomeric by‐products. Alternatively, treatment of 82 with catalytic KCN triggered a nucleophilic α‐hydroxy‐β‐diketone rearrangement to give the ring‐expanded hypermonone analogues 84 and 85 in good overall yield. This sequence demonstrates the potential for the stereoselective synthesis of complex cyclopentanones and δ‐lactones via our bioinspired strategy.

Scheme 7.

A highly diastereoselective oxidative intramolecular tricarbonyl‐ene reaction and subsequent α‐hydroxy‐β‐diketone rearrangements.

To gain further insight into the bioinspired intramolecular tricarbonyl‐ene reactions and anionic α‐hydroxy‐β‐diketone rearrangements discovered in this work, we turned to computational modelling using density functional theory (DFT) calculations. Geometry optimizations and frequency calculations were conducted using the M06‐2X method ^[33] and 6‐31+G(d) basis set with single point energies calculated at 6‐311+G(d,p) using a SMD solvent continuum model ^[34] (in water or THF). As proposed in the biosynthesis of hyperireflexolides A and B (Scheme 1), our modelling reveals concerted pericyclic carbonyl‐ene reactions of 1,2,3‐triketone 18 to give 19 and 20, with remarkably low reaction barriers of 63 kJ mol⁻¹ and 62 kJ mol⁻¹, respectively (Scheme 8a). This result is consistent with the co‐isolation of both natural products, and supports our structure revision of hyperireflexolide B. Modelling of the carbonyl‐ene reaction of biyoulactone model 1,2,3‐triketone 86 (derived from oxidation of aldol adduct 74) also revealed low energy transition states leading to diastereomers 75 and 76, and correctly predicts 75 as the major product (Scheme 8b).

Scheme 8.

Computational analysis of the intramolecular tricarbonyl‐ene reaction of a) hyperireflexolide precursor 18 and b) model biyoulactone precursor 86.

The anionic α‐hydroxy‐β‐diketone rearrangement/aldol cascade of 75/76 models our proposed biosynthesis of the biyoulactones, hypermonones and hybeanones, with diverse reaction outcomes presenting a complex mechanistic and kinetic/thermodynamic scenario. Modelling of the anionic rearrangement pathways of 75 ⁻ and 76 ⁻ is presented in Scheme 9. Initially, the ground state anionic structures were modelled to predict their relative stabilities. For the reaction of 75 ⁻, the starting material, lactone‐enolate 78 ⁻ (−0.6 kJ mol⁻¹) and aldol adduct 77 ⁻ (−3.8 kJ mol⁻¹) are all very close in relative energy, with the ester‐enolate 79 ⁻ (−36.5 kJ mol⁻¹) representing the thermodynamic anionic product. In the reaction of 76 ⁻, the aldol product 80 ⁻ has greater relative stability (−26.6 kJ mol⁻¹), but with the ester‐enolate 88 ⁻ still the thermodynamic product (−50.2 kJ mol⁻¹). In both cases, the extra stability of the more conformationally flexible ester‐enolates compared to the rigid, bicyclic aldol products is due to a significant thermal (largely entropic) contribution of around 19 kJ mol⁻¹. The kinetic barriers to the intramolecular aldol reactions of lactone‐enolates 78 ⁻ and 87 ⁻ are both very low.

Scheme 9.

Computational analysis of the anionic α‐hydroxy‐β‐diketone rearrangement/aldol cascade of 75/76.

The key to reaction selectivity, therefore, is whether the initial α‐hydroxy‐β‐diketone rearrangement proceeds in an endo or exo sense relative to the five membered ring. For the endocyclic α‐hydroxy‐β‐diketone rearrangement of 75 ⁻, a low energy reaction path includes an epoxide intermediate 89 ⁻ (9.4 kJ mol⁻¹) as a local minimum, which then collapses to the lactone‐enolate 78 ⁻. A very similar reaction profile is evident for diastereomer 76 ⁻, but this endocyclic α‐hydroxy‐β‐diketone rearrangement is more favored as the transition states for the formation and collapse of the transient epoxide 90 ⁻ are remarkably low in energy due to less steric crowding between the tert‐butyl and isopropenyl substituents. For the exocyclic α‐hydroxy‐β‐diketone rearrangements of both 75 ⁻ and 76 ⁻, a concerted reaction mechanism is predicted, with a higher barrier than the endocyclic pathway. While the mechanism of the anionic α‐hydroxy‐β‐diketone rearrangement has traditionally been proposed to proceed via an epoxide intermediate, no direct evidence for this intermediate has been demonstrated. ^[35] Acyl substitution reactions generally proceed through a tetrahedral intermediate, although in some cases concerted substitution mechanisms have been established. ^[36] For our anionic α‐hydroxy‐β‐diketone rearrangements there appears to be a fine line between a stepwise (endocyclic) or concerted (exocyclic) mechanisms. However, the kinetic preference for the endocyclic pathway is critical in determining the reaction outcome. Under low temperature, basic reaction conditions (Table 3, entry 3), we expect the rapid formation of a mixture of alkoxide 75 ⁻, lactone‐enolate 78 ⁻ and aldol product 77 ⁻, as well as gradual formation of the thermodynamic ester‐enolate 79 ⁻. This is consistent with the experimental observations, and the preference for ester 79 at higher temperatures. From alkoxide 76 ⁻, we expect the rapid formation of aldol product 80 ⁻, which should offer some kinetic stability to the formation of the thermodynamic ester‐enolate 88 ⁻. Indeed, when aldol product 80 was treated with LDA and warmed to room temperature, an ester 88 derived from protonation of 88 ⁻ was isolated in low yield via a remarkable sequence of α‐hydroxy‐β‐diketone rearrangements (Scheme 10).

Scheme 10.

Anionic rearrangement of aldol product 80 to give ester 88.

Conclusion

In summary, we used speculation on the biosynthesis of some unusual meroterpenoids to discover a series of oxidative intramolecular tricarbonyl‐ene reactions and α‐hydroxy‐β‐diketone rearrangements. These predisposed cascade reactions can be combined in sequence to generate highly substituted cyclopentanones and δ‐lactones found in the hyperireflexolide, biyoulactone, hypermonone and hybeanone frameworks, with a remarkable increase in molecular complexity in each case. Our bioinspired model syntheses also provide compelling chemical support for the proposed biosynthesis of these complex PPAPs from simple acylphloroglucinol precursors via a cryptic dearomatization pathway.

Conflict of interest

The authors declare no conflict of interest.

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Supporting Information

A. B. zur Bonsen, R. A. Peralta, T. Fallon, D. M. Huang, J. H. George, Angew. Chem. Int. Ed. 2022, 61, e202203311; Angew. Chem. 2022, 134, e202203311.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.