Catalytic Enantioselective Alkylative Dearomatization-Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K

Abstract

The asymmetric total synthesis of the polyprenylated acylphloroglucinol hyperibone K has been achieved using an enantioselective alkylative dearomatization-annulation process. NMR and computational studies were employed to probe the mode of action of a chiral phase-transfer (ion pair) catalyst.

The polyprenylated acylphloroglucinols (PPAP’s) are a unique natural product class bearing the highly substituted and oxygenated bicyclo[3.3.1]nonane-1,3,5-trione framework (Figure 1). Clusianone (1) and its C7 epimer 2, isolated from the floral resins of the Clusia species, have been shown to have cancer chemopreventive activity ¹ as well as inhibit HIV infection. ² Hyperibone K (3)³ and its structural isomer plukenetione A (4)⁴ (absolute stereochemistries unassigned) possess highly functionalized and unusual adamantane cores. In light of their challenging structures and promising biological activities, the PPAP family has garnered significant interest. Recently, asymmetric syntheses of (+)-clusianone (1)⁵ and (−)-hyperforin (3) ⁶ were reported. In a previous study, ⁷ we reported the synthesis of (±)-clusianone (1) employing a tandem alkylative dearomatization-annulation process. In this Communication, we report development of an enantioselective dearomatization-annulation protocol employing chiral phase-transfer (ion pair) catalysis and its application to the enantioselective synthesis of hyperibone K.

Figure 1.

Polyisoprenylated Acylphloroglucinol Natural Products

Our approach to hyperibone K (Figure 1, 3) leverages a concise access to adamantane 5⁷ (Scheme 1). We envisioned that 3 may be derived from allylic alcohol 6 by Lewis acid-promoted intramolecular cation cyclization. ⁸ Allylic alcohol 6 may be derived from base-promoted retroaldol/vinyl metal addition⁹ of adamantane 5, the latter which may be derived from alkylative dearomatization of clusiaphenone B (7).

Figure 3.

Determination of the Absolute Configuration of 5

Scheme 1.

Retrosynthetic Analysis for Hyperibone K

Enantioselective approaches to clusianone, hyperibone K, and other PPAPs required development of an asymmetric alkylative dearomatization-alkylation process. A number of enantioselective dearomatization processes have been reported, chiefly involving oxidation chemistry, ¹⁰ with more limited studies reported involving alkylative dearomatization. ¹¹ Our approach was inspired by a recent report from O’Donnell and coworkers ¹² involving tandem conjugate addition-elimination using a chiral phase-transfer catalyst¹³ derived from Cinchona alkaloids. We focused our initial studies on enantioselective dearomatization/alkylation of 7 with α-acetoxy enal 9.⁷ We first evaluated a number of chiral catalysts (8a–g, Figure 2) which were prepared from readily available Cinchona alkaloids. In initial experiments, we found that the desired dearomatization-annulation process using O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (8a, ¹⁴ Figure 2) (CsOH·H₂O, 4Å MS, CH₂Cl₂, −50 °C) proceeded smoothly to afford adamantane 5 in moderate yield (68%) and ee (75%) (Table 1, Entry 1). ¹⁵ However, a stoichiometric amount of catalyst 8a was required to promote the reaction at −50 °C.

Figure 2.

Dearomatization/Alkylation Using Cinchona Alkaloid-Derived Catalysts Using Various Phase Transfer Catalysts

Table 1.

Enantioselective Dearomatization of Clusiaphenone B Using Various Phase Transfer Catalysts

entry	aldehyde (1.05 equiv.)	catalyst (25 mol%)	time (h)	yield (%)	ee (%)
1	9	8a (1 equiv.)	15	68	75 (27R)
2	9	8b	22	41	68 (27R)
3	9	8c	22	22	11 (27R)
4	9	8d	22	~10	20 (27R)
5	9	8e	22	48	84 (27R)
6	10	8b	10	65	76 (27R)
7	10	8e	10	61	86 (27R)
8	10	8f	10	71	90 (27R)
9	10	8g	10	53	−60 (27S)

Recently, dimeric Cinchona alkaloid-derived phase-transfer catalysts have been reported,¹⁶ which show very high reactivity and enantioselectivity in transformations including asymmetric alkylations^16a,d and nucleophilic epoxidation.^16c Accordingly, we first evaluated several reported dimeric catalysts (8b–d, Figure 2). Interestingly, we found that reactions catalyzed by the meta-substituted dimer 8b (entry 2) afforded 5 in promising enantiomeric excess (68% ee) at a catalyst loading of 25 mol%. Catalysts with ortho- and para-substitution (8c and 8d) showed poor enantioselectivity (11% ee and 20% ee). Through extensive structural modifications of the meta-dimeric catalyst, we identified the benzyl ether dimer 8e which afforded 5 in moderate yield and good enantiomeric excess (48% yield, 84% e.e.).

We also evaluated heptanoate aldehyde 10 which displayed better reactivity having improved yields and shorter reaction times (Table 1, Entries 6–9). Further modification of catalyst 8e by replacing the vinyl group with a 2-methylpropenyl moiety (catalyst 8f, entry 8) led to improvement of enantioselectivity (90% ee). Use of (+)-cinchonine-derived catalyst 8g afforded the opposite enantiomeric product (27S), albeit with lower enantioselectivity (−60% ee). We were able to unambiguously determine the absolute configuration of adamantane (−)-5 by single crystal X-ray analysis after conversion to p-bromobenzoate ester 11 (Figure 3).^{15, 17}

Our synthetic approach to hyperibone K (3) features a retroaldol/addition process and is shown in Scheme 2. Dearomatization-annulation of 7 and aldehyde 10 proceeded smoothly to produce (−)-5 (71%, 90% ee). Treatment of 5 with LDA, followed by addition of 2-methyl-1-propenyl magnesium bromide,¹⁸ afforded allylic alcohol 6 which was produced from the retroaldol intermediate 12 followed by addition of 2-methyl-propenyl magnesium bromide. Intramolecular cation cyclization of 6 catalyzed by Sc(OTf)₃ successfully afforded (−)-3 in moderate yield (50% yield, two steps),⁸ thus establishing the absolute configuration of natural (+)-3. The high (>20:1) diastereoselectivity observed in the cyclization may be explained by analysis of cationic intermediate 13 which indicates a likely preference for conformation 13a wherein the allylic cation is situated away from the gem-dimethyl moiety (Figure 4).

Scheme 2.

Total Synthesis of (−)-Hyperibone K

Figure 4.

Allylic Cation Intermediate 13

Although we developed an efficient catalyst system for enantioselective dearomatization-annulation, the mechanism and mode of action for the phase-transfer (ion pair) catalyst remained unsolved. To further understand catalyst mode of action, we considered a two-stage approach which would utilize both experimental and computational information. Stage 1 involved understanding the identity of the reactive substrate and relevant conformation(s) for the catalyst. Stage 2 involved elucidation of the substrate and catalyst complex leading to the observed enantiomer (−)-5.

Accordingly, initial ¹H NMR studies were conducted which indicated that, under standard reaction conditions (both achiral and chiral phase transfer catalysts), 80–90 % of clusiaphenone B 7 exists in a dearomatized enolate form (cf. 14–17, Figure 5).^{15, 19} Accordingly, we propose that an enolate is likely the reactive species interacting with the catalyst.

Figure 5.

Dearomatized Acyl Phloroglucinols 14–17

We next turned our attention to elucidating the catalyst conformation. ¹H and ¹³C NMR analysis of dimeric catalyst 8e indicated that the catalyst adopts a C2 symmetrical conformation which is in agreement with a previously reported crystal structure of a related dimeric Cinchona alkaloid-derived catalyst.^16c We utilized NOESY experiments in conjunction with conformational analysis (mixed Monte Carlo Multiple Minimum (MCMM)/Low-Mode Conformational Search (LMCS)) to determine likely conformations of catalyst 8e in solution. By surveying the generated low energy conformations corresponding to key nOe interactions, we identified a single conformation (Figure 6) which was further optimized using DFT (B3LYP-63-1g). We also compared NOESY data of 8e both alone and with substrate 7 allowing us to ascertain that the catalyst conformation did not shift significantly upon substrate complexation.¹⁵

Figure 6.

Optimized Conformation of Catalyst 8e with Key nOe’s

Stage 2 relied on use of computational molecular docking to generate binding poses of the catalyst substrate complex. Literature reports have indicated the possibility of this approach highlighted by an example from Deslongchamps and coworkers who have utilized reverse docking to explore the configurational space of a flexible organocatalyst around a rigid catalyst-free transition state. ²⁰ We utilized CDOCKER (a CHARMM-based docking program) to systematically pose the flexible substrate (acylphloroglucinol) within a static catalytic site and conduct low-level energy calculations for each pose. We also combined these studies with ROESY data of the substrate catalyst complex which illuminated key intermolecular interactions.¹⁵

As there are several possible enolates which may be operative (cf. Figure 5), we conducted docking studies on each. Docking experiments provided over 100 poses for enolates 14 – 17 bound to 8e which were quickly reduced to a single pose for each enolate through a series of criteria: 1) correlation with ROESY data; 2) potential for ion-pair interactions (2 – 4 Å); and 3) substrate availability for Michael addition. The selected pose for each enolate was further optimized by DFT (B3LYP-63-1g).¹⁵ Poses meeting most of these criteria for each substrate were very similar regarding placement of the dearomatized enolate in the catalyst cavity.

Utilizing a pose which meets all of the criteria above, we developed a working model for the phase-transfer (ion pair) catalyst-mediated dearomatization-annulation with 8e and enolate 15 (Figure 7). The preferred binding mode appears to be one in which the para-enolate oxygen is placed near a quaternary nitrogen center to form a tight ion pair and the dearomatized cyclohexadienone is aligned near the top of the aromatic linker. The lower energy poses situate the substrate such that the pseudo-axial proton derived from dearomatization is oriented away from the catalyst (Figure 7, a).¹⁵ In this orientation, substrates 15 and 17 appear to have more optimal ion pairing (Figure 7, a) with the more accessible ammonium center while substrates 14 and 16 are situated such that the charge bearing oxygen is paired with the less accessible ammonium center.¹⁵ The pose illustrated in Figure 7 also satisfies the major intermolecular interactions identified by ROESY experiments (Figure 7, a).¹⁵ Furthermore, poses utilizing substrates 15 and 17 may lead to the correct stereochemical outcome ((−)-5) while poses with 14 and 16 would afford the opposite configuration.¹⁵ Based on the model of catalyst 8e and substrate 15, it is apparent that a key binding element involves hydrophobic interaction of a substrate prenyl group in a hydrophobic cleft of the catalyst formed by the vinyl and O-benzyl groups (Figure 7, b), both of which were shown to be critical for enantioselectivity (cf. Table 1). ¹⁷

Figure 7.

Proposed Binding Model of Catalyst 8e and 15.

a) Key interactions of 8e and 15. b) 1.4 Å Connolly surface.

In summary, we have developed an enantioselective alkylative dearomatization annulation process using dimeric chiral phase-transfer (ion pair) catalysts. The total synthesis and absolute configuration assignment of hyperibone K have been achieved by application of the asymmetric dearomatization process. NMR and computational studies were employed to illuminate the mode of action for the phase-transfer (ion pair) catalyst. Further studies utilizing molecular docking for mechanistic understanding of phase-transfer catalysis are ongoing and will be reported in due course.