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. Author manuscript; available in PMC: 2013 Aug 16.
Published in final edited form as: Angew Chem Int Ed Engl. 2012 Mar 16;51(17):4080–4084. doi: 10.1002/anie.201107730

Total Syntheses of Hopeanol and Hopeahainol A Empowered by a Chiral BrØnsted acid-Induced Pinacol Rearrangement**

Scott A Snyder 1,*, Stephen B Thomas 1, Agathe C Mayer 1,+, Steven P Breazzano 1,+
PMCID: PMC3744884  NIHMSID: NIHMS413326  PMID: 22431237

Although the stilbene resveratrol is simple in terms of its size and functional group array, it possesses high chemical reactivity, a property that enables its conversion into hundreds of architecturelly diverse bioactive oligomeric natural products.[1–3] Among recent dimeric isolates, hopeanol and hopeahainol A (1 and 2, Scheme 1) are two of the most intriguing given their constrained, partially dearomatized bicyclic cores and potent activity in antitumor and acetyl-cholinesterase inhibition assays.[4] Indeed, these molecules have already been the subject of synthetic interest, with reports by Nicolaou, Chen, and co-workers describing racemic and enantioselective syntheses of 1 and 2 in 15 linear steps.[5] Their route featured several cascade-based bond constructions[6] and the discovery that hopeahainol A (2) could be converted into hopeanol (1) upon treatment with base, an idea counter to the original biosynthetic proposal.[4b] In this communication, we describe a distinct approach for the total synthesis of these natural products empowered by a unique, reagent-driven pinacol rearrangement and substrate-specific oxidation chemistry. Significantly, it has potential for scaleability as well as biogenetic implications.

Scheme 1.

Scheme 1

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Structures of hopeanol (1) and hopeahainol A (2) and retrosynthetic analysis based on a pinacol rearrangement and site-specific oxidations inspired by a potential biogenesis from 8–10.

Our retrosynthetic analysis is shown in the lower portion of Scheme 1, wherein our key disconnnections were focused on rapidly constructing the 7-membered ring and attendant quaternary carbon (C-7b) found in both natural products as best noted by a redrawing of 1 and 2. Critical insights came following a change in the oxidation state of 2 to that of 3, in that we anticipated that its all carbon-based quaternary center (C-7b) could potentially arise from diol 5 through a pinacol rearrangement.[7] Although such events often possess modest selectivity due to ambiguity in the site of carbocation formation and/or migrating group, we hoped that the specific patterning of 5 could avoid such issues. And, assuming that such a rearrangement could proceed with any stereoisomeric variant of 5, then issues of diastereocontrol would not be a relevant concern since all isomers of 3 should be able to be funneled to racemic 2 through oxidation chemistry. Issues in diastereocontrol occurred several times in the Nicolaou/Chen approach to this same ring system,[5] eroding overall efficiency and material throughput since such flexibility was not part of their design. Additionally, we felt the complete route should be concise if the materials needed for this key rearrangement step could arise from ketone 6, variants of which we synthesized previously through acid-induced cyclizations of alcohol 7.[8] These materials have already enabled controlled syntheses of nearly 20 dimeric and higher-order natural products within the resveratrol class through several distinct, cascade-based constructions of diverse C–C and C–O bonds.[8,9] Finally, the route had two additional appealing elements. First, it is redox economic.[10] Second, it might possess biogenetic relevance given the structures of other 7-membered ring natural products. For example, if reactive compounds 8–10 were precursors[11] for natural products 11–14[12] via proton cyclizations, then the same starting materials could lead to the C-7b quaternary carbon of 1 and 2 by initial oxidation (to generate 5 or a related congener) followed by acid treatment as likely needed to initiate pinacol rearrangement.[13]

We began our efforts by synthesizing diols of type 5. As shown in Scheme 2, that goal was accomplished through a unique protocol starting from ketone 15 (prepared in 5 steps from commercial resveratrol in 48% overall yield, see Supporting Information),[14] a methyl ether protected version of 6 (cf. Scheme 1) redrawn with three-dimensional structure.[15] Following Corey–Chaykovsky epoxidation,[16] which afforded 16 with complete relative stereocontrol, subsequent dissolution in CH2Cl2 and stirring with AcOH at 25 °C generated what we believe to be acetate-opened epoxide and/or an intermediate diol with inverted chirality at the C-7b position;[17] subsequent exposure to Dess–Martin periodinane, followed by Grignard attack, afforded separable diols 19 and 20 in a 1:1.3 ratio.[18] Critically, the two ring-based chiral centers were formed with complete relative stereocontrol, an outcome that can be rationalized via the steric bulk of the remote aryl ring within 17[19] and one that proved essential to the success of the later sequence (vide infra). Worth noting is that other routes towards pinacol-type precursors were attempted, largely by trying to add nucleophiles to the ketone in 15. However, none provided the expected materials with the exception of the Tebbe reagent; in this case, the resultant methylene could not be functionalized further.

Scheme 2.

Scheme 2

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Synthesis and pinacol rearrangement of 19 and 20. a) Me3SI (10 equiv), n-BuLi (8.0 equiv), THF, 0 °C, 1 h; d) AcOH, CH2Cl2, 25 °C, 30 min; b) Dess-Martin periodinane (1.2 equiv), 25 °C, 1 h, 45% over two steps; c) 4-OMePhMgBr (5.0 equiv), THF, 0 25 °C, 1.5 h, 87%, ~1.3:1 of 20:19; d) (R)-21 (1.0 equiv), CHCl3, µwave, 100 °C, 1 h, 56% 22:23 as a >18:1 mix of diastereomers.

Nevertheless, with 19 and 20 in hand, explorations into the critical pinacol rearrangement could begin. Pleasingly, many protic and Lewis acids (such as p-TsOH, PPTS, and TMSOTf) could generate the desired quaternary carbon of 22 and 23, though there were some (such as benzoic acid) that did not. However, those that worked did so in low to moderate yield and modest diastereocontrol, a critical issue since only 22 proved competent in later chemistry. Several side-products were also observed in varying amounts, the most significant and consistent of which was epoxide 24, a material whose structure was confirmed by X-ray analysis and which could not be converted into a pinacol rearranged product under any conditions.[20] A small subset of these initial results are collated within Table 1 in entries 1–3. However, the most important and consistent observation in all experiments was that diol diastereomer 19 transformed into 22 quickly and with high diastereoselectivity (typically >10:1), while 20 reacted much more slowly, provided more side-products, and required increased reaction temperatures for any conversion (leading to 22 and 23).[21]

Table 1.

Exploration of the key pinacol cyclization step.

graphic file with name nihms413326t1.jpg
Entry Acid Equivalents Solvent Temperature [°C] Time [h] Yield [%] d.r.
1 p-TsOH 5.0 toluene 25 24 40–60[a] 2.5:1[a]
2 PPTS 3.0 toluene 100 1 39 3.3:1
3 H3PO4 3.0 THF 25 24 38 5.5:1
3 H3PO4 3.0 THF 25 24 38 5.5:1
4 (R)-BINOL•HPO4 1.0 CHCl3 100[b] 1 63 3.9:1
5 (S)-BINOL•HPO4 1.0 CHCl3 100[b] 1 62 3.9:1
6 rac-BINOL•HPO4 1.0 CHCl3 100[b] 1 55 3.0:1
7 (R)-BINOL•HPO4 1.0 CHCl3 25 24 32 >10:1
8 (R)-BINOL•HPO4 1.0 DMSO 25 24 33 1.8:1
9 (R)-BINOL•HPO4 1.0 CHCl3/MeOH (5:1) 25 24 41 5.0:1
10 (R)-BINOL•HPO4 0.7 CHCl3 100[b] 1 55 4.5:1
11 (S)-BINOL•HPO4 0.7 CHCl3 100[b] 1 54 4.6:1
12 rac-BINOL•HPO4 0.7 CHCl3 100[b] 1 50 3.1:1
13 (R)-21 1.0 CHCl3 100[b] 1 56 18.4:1
14 (S)-21 1.0 CHCl3 100[b] 1 56 18.9:1
15 rac-21 1.0 CHCl3 100[b] 1 59 13.6:1
16 (R)-CSA 2.0 CHCl3 50 2 54 4.0:1
17 (S)-CSA 2.0 CHCl3 50 2 56 4.1:1
18 rac-CSA 2.0 CHCl3 50 2 53 4.0:1
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[a]

Both yield and d.r. proved highly variable between runs; d.r. as high as 4:1 for 22:23 were observed, but 2.5:1 was more common, especially on scale;

[b]

under microwave irradiation.

PPTS = pyridinium p-toluenesulfonate, CSA = camphorsulfonic acid.

As such, the goal for optimization became finding an acid source with a suitable pKa capable not only of rearranging 19 smoothly, but also improving the throughput of 20. Our first significant advance based on this analysis occurred when a mixture of both 19 and 20 was stirred with 1.0 equivalents of (R)-BINOL•HPO4[22] in CHCl3 at 100 °C under microwave irradiation for 1 h. These conditions led to pinacol-rearranged products 22 and 23 in 63% yield and 3.9:1 diastereocontrol in favor of 22 (Table 1, entry 4) alongside varying amounts of epoxide 24 (~10–15%).[23] Other solvents and conditions with this promoter afforded decreased selectivity and/or yield (entries 7–9) for 22. Interestingly, while use of the opposite enantiomer of promoter [(S)-BINOL•HPO4] under these conditions afforded nearly identical results, its racemic form provided inferior stereoselection (entries 5 and 6).[24] The same phenomenon was also observed when decreased quantities of phosphoric acid were used, though these cases afforded improved diastereoselectivity (4.5:1) at the price of yield (entries 10–12). It was also observed when the promoter size was changed to that of VAPOL•HPO4 (21, entries 13–15).[25] In these cases, high diastereoselection (>18:1) and similar throughput efficiency (56% yield of 22 and 23; trace 24) was achieved when a single enantiomer was used. At present, it is too preliminary to provide a rationale for these unexpected outcomes between the use of racemic or single enantiomer forms of these promoters other than to state that it is a reproducible result over several runs. We do note, however, that this effect may be specific to materials of the BINOL and VAPOL scaffolds in that both chiral and racemic CSA gave nearly identical results (entries 16–18).[26] Current work is directed at understanding the parameters of this event more fully, especially determining whether chiral acids have value in other pinacol rearrangements where incongruities exist in diastereomer reactivity and stereoselection. What we can state is that, to the best of our knowledge, this event constitutes the first use of a chiral BrØnsted acid for this rearrangement in a total synthesis.

With this key quaternary carbon forged with good efficiency, our next goal was to effect the remaining oxidations needed to the access the natural products. These steps had to install the missing ketone located at C-8a, convert the hindered aldehyde into a carboxylic acid, and generate the C–C bond leading to the dearomatized p-quinone ring essential to hopeanol (1). After an exhaustive screen of oxidants [including DDQ, hyperveralent iodine, and Pd(OAc)2/H2O2],[27] we discovered that the Jones reagent could uniquely accomplish two of these tasks when it was added to an acetone solution of 22 (Scheme 3) at 0 °C and stirred for 30 min. This step leading to 26 proceeded in 27% overall yield, with only the drawn diastereomer of 22 reacting productively.[28] Equally intriguing, this event appears to proceed via the initial formation of 25, as a trace amount of this material was obtained when insufficient Jones reagent was available to drive the reaction to completion; this material (i.e. 25) was quickly converted into 26 following re-exposure to the Jones reagent. Surprisingly, the aldehyde within 22 was not oxidized in this step; thus, a different oxidant (NaOCl) proved necessary. Then, following treatment with TMSCHN2, protected hopeanol (27) was obtained in 75% yield (4.3% overall from 15). Despite much effort, however, this material could not be deprotected,[29] including use of the Nicolaou/Chen conditions.[5]

Scheme 3.

Scheme 3

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Completion of hopeanol (1) and hopeahainol A (2). a) Jones reagent (20 equiv), acetone, 0 °C, 30 min, 27%; b) resorcinol (15 equiv), NaH2PO4•H2O (10 equiv), NaClO2 (5 equiv), THF/t-BuOH/H2O (1/1/2), 25 °C, 3 d, 70%; c) TMSCHN2 (5 equiv), THF/MeOH (4/1), 0 °C, 15 min, 98%; d) resorcinol (15 equiv), NaH2PO4•H2O (10 equiv), NaClO2 (5 equiv), THF/t-BuOH/H2O (1/1/2), 25 °C, 3 d; e) BBr3 (18 equiv), CH2Cl2, −78 0 °C, 3 h; f) BnBr (20 equiv), K2CO3 (20 equiv), n-Bu4NI (1.0 equiv), acetone, 25 °C, 12 h, 29% over 3 steps; g) CAN (8.0 equiv), DMSO, 25 °C, 12 h, 65–89%; h) BCl3 (12 equiv), CH2Cl2, −78 °C, 15 min, 75%; i) NaOMe (1.2 equiv), MeOH, 25 °C, 4 d, 69%. CAN = ceric ammonium nitrate.

As such, efforts were made to deprotect the phenolic methyl ethers earlier in the sequence, such as at the stage of aldehyde 26 and intermediate 22. Unfortunately, in both cases (as well as many others not explicitly described here), these attempts consistently led to rearrangement reactions and/or decomposition, one of which is denoted in the Supporting Information section. Pleasingly, when carboxylic acid 28 was treated with BBr3 in CH2Cl2, methyl ether cleavage was attended by lactone formation to afford 29; a small amount of decarboxylated material was also observed. Although all attempts at oxidizing this material directly to 1 or 2 failed, its benzyl ether analog could be oxidized with CAN to afford the structure of hopeahainol A in 65–89% yield depending on the scale. No other oxidant succeeded. Finally, deprotection with BCl3 then delivered the natural product (2) in 75% yield, a portion of which was converted to hopeanol (1) following the exact conditions developed by Nicolaou, Chen, and co-workers.[5] In total, the route to hopeahainol A (2) is 14 steps long, and as one reflection of its overall efficiency (4.0% overall from 15), we have prepared over 60 mg of it along with 180 mg of its protected precursor to date.

In conclusion, we have accomplished an efficient total synthesis of both hopeanol (1) and hopeahainol (2) from our key precursor for the controlled preparation of the resveratrol family (i.e. 7) through a pathway that traces both of these structures to a more common manifold within this fascinating oligomer family. Critical steps involved a pinacol rearrangement empowered by a chiral phosphoric acid and multi-stage, substrate specific oxidation processes. Current efforts are directed towards developing asymmetric syntheses of these materials and probing their chemical biology.

Supplementary Material

Supporting Information

Footnotes

**

We thank the NSF (CHE-0619638) for an X-ray diffractometer and Prof. Gerard Parkin, Mr. Wesley Sattler, Mr. Aaron Sattler, and Ms. Ashley Zuzek for performing the crystallographic analyses. We thank Mr. Adel ElSohly for NMR assistance and Mr. Jason Pflueger for early work. Financial support was provided by Columbia University, the National Institutes of Health (R01-GM84994), Bristol-Myers Squibb, Eli Lilly, the NSF (Predoctoral Fellowships to S.B.T. and S.P.B.), the DFG (Postdoctoral Fellowship to A.C.M.) and the Research Corporation for Science Advancement (Cottrell Scholar Award to S.A.S.).

Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.

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Supplementary Materials

Supporting Information
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