Total Synthesis of (−)-Flueggeacosine C

Abstract

Herein we describe a total synthesis of the heterodimeric securinega alkaloid (−)-flueggeacosine C (8). The convergent synthetic strategy is based on a Liebeskind−Srogl cross-coupling reaction that combines a benzoquinolizidine fragment with a securinine-type alkaloid. An acyloxy nitroso ring-expansion was employed as the key step in accessing benzoquinolizidine 9 and a novel intramolecular Diels-Alder reaction of an allenic acid-containing pyridone expeditiously delivers the skeleton of the securinine-type fragment (16). Finally, a Cu-catalyzed hydroboration/oxidation sequence was employed to regio- and diastereoselectively introduce the secondary alcohol found in 8.

Graphical Abstract

As part of an ongoing program in the total synthesis of securinega alkaloids, we reported successful syntheses of (±)-securinine (1) and (±)-allosecurinine (2) by employing a highly efficient rhodium-catalyzed O-H insertion/Claisen rearrangement/1,2-allyl migration domino process (Figure 1).¹ In subsequent efforts we completed the total synthesis of (±)-phyllantidine (3) via a route that employed the ring expansion of an acyloxy nitroso-containing cyclopentanone to furnish the requisite hydroxamic acid.² In addition to our own work and relevant to this report, we note that Han and coworkers recently reported a completed semisynthesis of flueggeacosine B (7) from allosecurinine.³ The latter synthesis highlighted a visible-light-mediated copper-catalyzed cross-dehydrogenative coupling of an aldehyde and an electron-deficient olefin. To date, there have been no reported total syntheses of these dimeric family members isolated from flueggea suffruticosa. Accordingly, we turned our attention to the synthesis of flueggeacosine C (8), which includes a remote stereogenic benzoquinolizidine fragment and a novel A-ring-opened securinine-type alkaloid moiety. Along with these interesting densely-functionalized subunits, flueggeacosine C (8) also exhibits biologically-relevant neuronal differentiation activity.^4–6 Thus, we endeavored to develop a modular route that would enable structure-activity studies.

Figure 1.

Representative Members of Securinega Alkaloids.

Illustrated retrosynthetically in Scheme 1 is the modular/convergent strategy that was eventually developed and entails disconnection of the C-15’ and C-3 bond, which could be formed via Liebeskind-Srogl coupling between aryl stannane 9 and thioester 10. As for the synthesis of 9, the benzoquinolizidine tricycle would be completed by a reductive cyclization sequence applied to ester 11 wherein the lactam moiety was seen as arising from a Beckmann-type ring expansion of the corresponding oxime 12. An intermediate indanone poised for conversion to 12 would derive from hydroboration/oxidation of indene 13 which, in turn, would be produced via a Wittig olefination/isomerization sequence applied to indanone 14. Regarding the azabicyclic fragment (Scheme 1, bottom), acetate protection of the secondary alcohol in 15 followed by late-stage thioester formation would generate the desired coupling partner 10. A copper-mediated and directed hydroboration/oxidation sequence applied to the internal alkene in 16 was envisioned as providing regio- and diastereoselective access to 15 and the [2,2,2]-azabicyclooctane skeleton would be constructed through an intramolecular Diels-Alder reaction (IMDA) of allenic ester 17. The latter would derive from Steglich esterification of the corresponding N-alkyl hydroxy pyridone. Known benzyloxypyridone 18 would serve as our point of departure and be subjected to simple N-alkylation to introduce the estercontaining sidechain.⁷

Scheme 1.

Retrosynthetic Analysis.

As detailed in Scheme 2,⁸ the synthesis began with Wittig ofefination of commercially available bromo indanone 14 using the ylide derived from phosphonium bromide (19).⁹ The derived inseparable mixture of olefin isomers 20 (E/Z=1:1) was subjected to TFA which promoted migration of the alkene and furnished endocyclic indene 13 in excellent yield.¹⁰ A hydroboration/oxidation sequence applied to 13 produced secondary alcohol 21 which, upon treatment with the Dess–Martin periodinane, cleanly produced the corresponding indanone (22).

Scheme 2.

Transformation from 1-Indanone to 2-Indanone.

Turning to the planned ring expansion (Scheme 3), brief exposure of indanone 22 to hydroxylamine with gentle heating provided oxime 12, which appeared well suited for regioselective conversion to the corresponding lactam. In initial studies, we explored traditional Beckmann-type reactions for the direct conversion of 12 to lactam 11. Unfortunately, the oxime proved to be unexpectedly sensitive to a variety of conditions and failed to produce any of the desired material.

Scheme 3.

Ring Expansion to Obtain Hydroxamic Acid 24.

Turning toward less traditional methods, we postulated that oxime 12 might be a suitable substrate for conversion to an acyloxy nitroso intermediate that would, in turn, undergo ring expansion. This notion was clearly inspired by our recently developed synthesis of phyllantidine wherein a similar reaction played a key role.² In exploring this transformation, we found that exposure of oxime 12 to phenyliodine(III) diacetate (PIDA) in AcOH rapidly produced acyloxy nitroso 23 as a single diastereomer (Scheme 3). Although the observed level of diastereoselectivity was not anticipated, the relative stereochemistry, which was unambiguously confirmed by single crystal X-ray analysis (See SI), is consistent with acetate attack from the sterically less encumbered alpha-face. With 23 in hand, we began optimizing conditions for its conversion to hydroxamic acid 24. After screening several reagents (See SI for details), methanolic lithium methoxide solution was found to be most efficient in promoting the ring expansion, furnishing hydroxamic acid 24 in modest yield over two steps. As we had observed in our phyllantidine efforts, the more substituted alkyl group displayed greater migratory aptitude, providing the desired regioisomer as the only isolable product.

Efforts to complete the synthesis of stannane fragment 9 began with an efficient three-step sequence for conversion of 24 to benzoquinolizidine 26 (Scheme 4). In the event, cleavage of the N-O bond in 24 was achieved using zinc in acetic acid to provide lactam 11.¹¹ Subsequent reduction of 11 with DIBALH led to 25 which could be further reduced to benzoquinolizidine 26 using boron trifluoride diethyl etherate and triethylsilane.¹² Having secured tricycle 26, the aryl bromide was converted to the required aryl stannane (9) via Pd(PPh₃)₄-mediated aryl stannylation with hexabutyldistannane.¹³

Scheme 4.

Synthesis of the Benzoquinolizidine 9

With 9 in hand, we turned our attention to preparing the securine-type alkaloid fragment by advancing commercially available 2,3-dihydroxypyridine 27 via a selective mono-benzyl protection that delivers pyridone 18 (Scheme 5).^7,14 Alkylation of 18 was performed with sodium hydride and tert-butyl 4-bromobutanoate (28) to furnish pyridone 29 which,¹⁴ upon catalytic hydrogenolysis of the benzyl ether afforded hydroxypyridone 30. The known tosyl-protected pyridone 31 was also prepared to allow comparison of its reactivity in the subsequent intramolecular Diels-Alder reaction.¹⁵ Next, we explored the Diels-Alder chemistry of 30 and 31 by employing acid 32 as the dienophilic component (Scheme 6A). In the event, Steglich esterification proceeded smoothly between hydroxy pyridone 31 and acid 32.¹⁶ Heating a toluene solution of the resulting ester (33) and BHT in a microwave reactor for 48 h produced the butanolide-fused azabicycle 34 in excellent yield as a single diastereomer (stereochemistry unassigned), thus demonstrating the feasibility of our designed intramolecular Diels-Alder reaction.¹⁷ Unfortunately, attempted removal of the p-toluenesulfonyl protecting group in 34 under a variety of conditions was not fruitful. Accordingly, we turned to the more convergent IMDA approach wherein 35, possessing the requisite aliphatic side chain, serves as substrate. To this end, Steglich esterification of 30 afforded the requisite IMDA substrate (35). Unfortunately, upon microwave irradiation of 35, cycloaddition product 36 was not observed, even after either increasing temperature and greatly extending the reaction time or introducing Lewis acidic additives.

Scheme 5.

Preparation of Hydroxy-Pyridone

Scheme 6.

(A) Diels-Alder Reactions with But-3-enoic Acid (B) Diels-Alder Reactions with Allenic Acid

Given the challenges associated with advancing sulfonamide protected substrates such as 34 and the poor Diels-Alder reactivity of alkylated pyridone 35, we opted to investigate substrates possessing a more reactive dienophilic component. Specifically, as alluded to in the retrosynthetic analysis (vide supra) allenic acid 37 was seen as an attractive coupling partner since conjugation to the electron withdrawing ester would potentially enhance reactivity with the relatively electron-rich pyridone diene (Scheme 6B).¹⁸ An additional benefit to this strategy would be immediate introduction of the butenolide double bond, thereby avoiding the need for late-stage oxidation of an intermediate butanolide. As illustrated, our initial investigations with the allenic intermediate employed tosyl pyridone 31. To this end, esterification of pyridone 31 with allenic acid 37 was once again promoted by DCC. However, in contrast to previous reactions, we were surprised to find that the intermediate ester (38) could not be isolated in any appreciable quantity, but rather underwent a spontaneous Diels-Alder cycloaddition to provide 39 at greatly reduced temperature relative 33. The facility of the latter reaction gave some hope that the allenic component may engage the alkyl-substituted pyridone 30 in a similar fashion (Scheme 6B). Indeed, after optimizing the conditions (see SI), we found that this cascade reaction could be completed in a microwave reactor at 45 °C in CH₂Cl₂ to provide 42% yield of the requisite butenolide (16). To the best of our knowledge, this novel reaction represents the first reported pyridone/allene IMDA. Furthermore, this cycloaddition takes place under mild conditions at relatively low temperatures thus, this method could be easily extended to provide access to other fused azabicyclic scaffolds.

With 16 in hand, we turned toward regio- and stereoselective conversion of the internal alkene to alcohol 15. To this end, we implemented a directed hydroboration/oxidation strategy. After investigating a variety of conditions, we settled upon a copper-mediated process that was inspired by recent work from Sarpong and coworkers in their total synthesis of cephanolides and ceforalides. In the latter study it was postulated that bidentate coordination of the copper complex with an alkene and a lactone carbonyl served to direct hydroboration to a single diastereomer.¹⁹ To our delight, we found that applying this method to 16 (Scheme 7) led successfully to the desired diastereomer. As illustrated, the observed selectivity may arise via initial bidentate coordination of copper, thereby controlling the facial selectivity. Regioselective migratory insertion of the more electron rich olefin then affords a borane-inserted intermediate which, upon proto-decupration and oxidation of the remaining boronic ester, delivers alcohol 15.

Scheme 7.

Regioselective and Diastereoselective Hydroboration and Oxidation

Protection of 15 was necessary before the tert-butyl ester to thioester conversion (Scheme 8). To this end, exposure of 15 to pyridine and acetyl chloride produced acetate 40 which, upon treatment with TFA, led to cleavage of the tert-butyl ester to the corresponding acid 41. The derived acid was then advanced without purification to thioester 10 by employing a DCC/DMAP-mediated thioesterification with p-toluenethiol. The structure of 10 was unambiguously determined by single crystal X-Ray analysis, confirming the stereo- and regiochemical outcome of the hydration step. The coupling reaction between 10 and 9 via a Liebeskind−Srogl reaction afforded a pair of inseparable diastereomers 42 and 43 which,²⁰ upon subjection to methanolic potassium carbonate, led to (±)-flueggeacosine C (8) and its diastereomer 44. Unfortunately, we were unable to separate the derived mixture of diastereomers through either traditional or HPLC-based chromatographic methods. Our inability to obtain analytically pure samples of the final compounds dictated that we complete the synthesis with enantioenriched coupling fragments. In considering possible methods for accessing these latter materials, the availability of numerous chromatographic techniques for the resolution of enantiomers led us to explore chiral separation technology. To the latter end, we opted to explore the enantiomeric separation of intermediates 16 (Scheme 7) and 26 (Scheme 4).

Scheme 8.

Synthesis of (±)-Flueggeacosine C (8) and its Diastereomer

In the interest of step-economy and prior to committing more valuable enantioenriched intermediates, we hoped to obviate the need for protecting alcohol 15 (Scheme 8) by performing the olefin hydration step (Scheme 7) after the Liebeskind−Srogl coupling. This strategic shift was proved feasible a model study (See SI). Thus, we turned to chiral separation and found that 26 and 16 could be resolved into their respective enantiomers via chiral-SFC-HPLC methods (see SI). The absolute stereochemistries of (+)- and (−)-26 were established through a chemical correlation study (see SI),²¹ where it was found that (−)-26 possessed the desired S-configuration necessary for the completion of (−)-flueggeacosine C (8). To this end, (−)-26 was converted to aryl stannane (−)-9. Coupling of (−)-45 with (−)-9 via the coupling reaction produced the corresponding enantioenriched intermediate (−)-46 (Scheme 9). Exposure of (−)-46 to the copper-mediated hydroboration/oxidation furnished (−)-8. Structural assignment of the latter was based upon comparison of optical rotation and proton/carbon-NMR data to that reported for (−)-flueggeacosine C (8).²²

Scheme 9.

Completion of (−)-Flueggeacosine C (8).

In conclusion, we have completed the total synthesis of (−)-flueggeacosine C (8) via a convergent route that assembles two fragments. The synthesis of the benzoquinolizidine fragment features an acyl nitroso ring expansion to construct the requisite amide. Construction of the azabicyclic fragment involves a novel one-pot esterification/IMDA cascade wherein cycloaddition of an intermediate allenic ester butenolide-containing core. and a regio- and diastereoselective borocupration/oxidation was employed to complete the functional group installation. The resolution of the racemic fragments via HPLC allowed for enantioselective completion of the natural product.

Supplementary Material

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information