Personal Account
THE CHEMICAL RECORD
Total Synthesis of the Congested Propellane Alkaloid (−)-Acutumine Steven L. Castle Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602 (USA) E-mail: [email protected]
Received: January 31, 2014 Published online: May 23, 2014
ABSTRACT: The enantioselective total synthesis of (−)-acutumine is described. The synthetic strategy was inspired by the premise that the cyclohexenone ring could be derived from an aromatic precursor. After successful construction of a propellane model system, an initial attempt to prepare the spirocyclic subunit was thwarted by incorrect regioselectivity in a radical cyclization. A secondgeneration approach involving a radical–polar crossover reaction was successful, and the chemistry developed in the aforementioned model system was then applied to synthesize the natural product. Key reactions included a phenolic oxidation, a diastereoselective ketone allylation utilizing Nakamura’s chiral allylzinc reagent, an anionic oxy-Cope rearrangement, an acid-promoted cyclization of a secondary amine onto an α,β-unsaturated ketal, and a regioselective methyl enol etherification of a 1,3-diketone. DOI 10.1002/tcr.201400005 Keywords: anionic oxy-Cope rearrangements, asymmetric ketone allylations, natural products, radical–polar crossover reactions, total synthesis
Introduction In 1929, Goto and Sudzuki isolated a new alkaloid named acutumine (1, Figure 1) from Sinomenium acutum, a climbing vinelike plant native to Japan and China.[1] Several years passed before Tomita and co-workers also isolated acutumine from another vine known as Menispermum dauricum, or Asian moonseed. In 1967, these researchers used X-ray crystallography to determine that 1 possesses the unusual tetracyclic architecture shown in Figure 1.[2] Other alkaloids containing the acutumine skeleton such as acutumidine (2),[2] dechloroacutumine (3),[3] and the epimeric alcohols dauricumine (4),[4] dauricumidine (5),[4] and dechlorodauricumine (6)[5] were subsequently discovered. Additionally, a derivative of 4 known as hypserpanine (7) was obtained from the woody vine Hypserpa nitida.[6] The analgesic and fever-reducing properties of the plants that produce the acutumine alkaloids[6,7] have prompted studies of
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the bioactivity of the natural products themselves. Interestingly, it was discovered that 1 is endowed with selective T-cell cytotoxicity[7] as well as antiamnesic activity in mice.[8] Acutumine possesses a unique structure consisting of a spirocyclic subunit that is merged with a propellane core.[9] Its highly congested cyclopentane ring incorporates two contiguous all-carbon quaternary stereocenters, a tert-alkyl amine, and a neopentylic secondary chloride. These striking architectural features have inspired studies of its biosynthesis. Barton and co-workers posited that 1 could be produced from a benzylisoquinoline alkaloid via oxidative phenolic coupling, oxidation, and rearrangement steps (Figure 2).[10] Wipf and co-workers conducted synthetic studies designed to probe Barton’s hypothesis, and subsequently introduced a modified biosynthetic proposal.[11] Sugimoto and co-workers established
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of (−)-1.[19] In this account, we describe the evolution of our preliminary ideas regarding the construction of acutumine into a viable synthetic strategy. During the course of this work, several synthetic methods with the potential for broad utility were developed and refined.
Propellane Model Studies
Fig. 1. Selected members of the acutumine family of alkaloids.
that 1 is assembled from two molecules of tyrosine,[12] and that different combinations of chlorination, epimerization, and N-demethylation steps transform dechlorodauricumine (6) into its congeners 1–5.[13] Despite its intriguing structure and potential for novel bioactivity, acutumine was ignored by the synthesis community for many years. In 2005, our group reported the first stage of our efforts targeting 1, in which a model system representing the propellane core was prepared.[14] This laid the foundation for additional studies[15] that culminated in the enantioselective total synthesis of (−)-1.[16] Subsequent to our initial disclosure, the Sorensen[17] and Reisman[18] groups devised creative synthetic approaches toward acutumine. Recently, Herzon and co-workers completed a concise and innovative total synthesis
Steven L. Castle was born in 1971 in Albuquerque, New Mexico, USA. His first exposure to chemistry came during summers in high school, when he worked in the laboratory of his grandfather, Prof. Raymond N. Castle of the University of South Florida. He received his B.S. with Honors in Chemistry from Brigham Young University in 1995, where he performed research with Prof. Jerald S. Bradshaw. He earned his Ph.D. in 2000 from The Scripps Research Institute under the direction of Prof. Dale L. Boger. Upon completing a National Institutes of Health postdoctoral fellowship in the laboratory of Prof. Larry E. Overman at the University of California, Irvine, in 2002 he began his independent career at Brigham Young University. His research interests encompass the development of new synthetic methods and strategies targeting complex bioactive natural products, and studies of their modes of action. He is the recipient of a Research Innovation Award from Research Corporation and a Long-Term Invitation Fellowship from the Japan Society for the Promotion of Science.
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As we contemplated the synthesis of 1, we recognized that its highly oxygenated cyclohexenone ring could be derived from an aromatic precursor. Given the ready availability of numerous aromatic starting materials and the wealth of known methods for the regioselective functionalization of arenes, the construction of a key aromatic intermediate followed by an oxidative dearomatization became an important aspect of our plan. Inspired by reports from the Sorensen,[20] Ciufolini,[21] and Honda[22] groups describing the participation of tethered nitrogen nucleophiles in phenolic oxidations, we wondered if amines would be viable nucleophiles in a related intermolecular process (cf. 8 + 9→10, Figure 3). An intramolecular conjugate addition of intermediate 10 would then furnish the propellane core of acutumine. Unfortunately, attempts to employ either secondary amines or tosyl-protected primary amines as nucleophiles in phenolic oxidations of 8 promoted by PhI(OAc)2 or PhI(OTFA)2 were fruitless. In the case of the secondary amines, it is likely that protonation by the acetic acid or trifluoroacetic acid that is liberated during the reaction prevents the desired nucleophilic addition from occurring.[23] The failure of amines and amine derivatives to participate in the phenolic oxidation required us to modify our approach to the propellane core of 1. Fortunately, we were able to retain oxidative dearomatization as a key strategic element. Thus, exposure of 8 to PhI(OAc)2 in MeOH[24] afforded masked o-benzoquinone 12 in excellent yield (Scheme 1). Masked o-benzoquinones are extremely versatile synthetic intermediates that present several different opportunities for functionalization.[25] In our case, we desired to perform a conjugate allylation of 12, but the extremely hindered nature of the β-carbon precluded this transformation. We were gratified to discover that a 1,2-allylation–anionic oxy-Cope rearrangement sequence furnished ketone 14, which possesses vicinal quaternary carbon atoms, in good yield. Ozonolysis of the terminal alkene was plagued by competitive oxidation of the electron-rich methyl enol ether, but by halting the reaction after ca. 50% conversion and subjecting the crude mixture of aldehyde and alkene to a reductive amination, suitable quantities of amine 15 could be obtained. Based on a report by Matsumoto and co-workers,[26] we anticipated that treatment of 15 with a Lewis or Brønsted acid would promote ionization of the dimethyl ketal and trigger cyclization of the secondary amine onto the α,β-unsaturated oxocarbenium ion
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Fig. 2. Biosynthetic proposals related to acutumine.
Fig. 3. Initial plan for propellane core synthesis.
intermediate. A survey of acids revealed that TMSOTf mediated the desired cyclization, affording propellane 16 as its enol tautomer in moderate yield along with a byproduct 17 generated by cleavage of the methyl enol ether.[14] This result gave us confidence that our revised strategy offered a feasible route to the propellane core of acutumine; nevertheless, we recognized that the ozonolysis–reductive amination and cyclization steps were likely to be very challenging in the context of the total synthesis.
First-Generation Synthetic Plan Buoyed by the successful construction of model compound 16, we embarked upon the total synthesis of acutumine. Our firstgeneration retrosynthesis is shown in Figure 4. We reasoned that the cyclopentenone ring of the natural product could be
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generated in the final stages of the synthesis by functional group manipulation. Accordingly, we envisioned tetracycle 18 as a viable precursor to 1. The regioselective methyl enol etherification of a 1,3-diketone was projected to be the most challenging transformation in this section of the route. Then, disconnection of the pyrrolidine ring of 18 to reveal aromatic spirocycle 19 was inspired by our successful model studies. We posited that the spirocyclic ring system of 19 could be fashioned from iodide 20 via 5-exo-trig aryl radical cyclization followed by trapping of the resulting radical by TEMPO.[27] The silyl-ether-bearing stereocenters located in the cyclopentene ring of 20, both of which would be destroyed during the endgame, would presumably direct the cyclization to the bottom face of the alkene. Finally, a convergent dissection of 20 identified enantiopure vinyl iodide 21 and Weinreb amide 22 as key building blocks. Our enthusiasm for this plan
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Scheme 1. Synthesis of propellane core model system.
Fig. 4. First-generation retrosynthesis.
was high, but we were concerned about potential complications in the radical cyclization of 20, such as the stability of the allylic chloride and the regioselectivity of the process (i.e., 5-exo versus 6-endo). Enantiopure vinyl iodide 21 was prepared via a nine-step sequence from cis-3,5-diacetoxycyclopentene (23) featuring an enzymatic desymmetrization (Scheme 2).[28,29] The construction of Weinreb amide 22 was accomplished in nine steps from 2,3-dimethoxyphenol (24) and involved homologation of an aldehyde that was synthesized previously in our laboratory.[30] The coupling of 21 and 22 could only be achieved using Knochel’s protocol, which enlists i-PrMgCl·LiCl and 15-crown-5 for vinyl Grignard generation.[31] The resulting ketone 25 was then transformed into cyclization substrate 20 via a moderately diastereoselective CBS reduction[32] followed by SN2 chlorination[33] of allylic alcohol 26. Unfortunately, the
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radical cyclization of 20 did not proceed in the presence of TEMPO. A cyclized product was obtained by exposing 20 to Et3B, air, and Bu3SnH,[34] but NMR data indicated that fused tricycle 27 had been formed instead of the required spirocycle.[16b] Presumably, the high degree of steric hindrance inherent in the 5-exo pathway caused the cyclization to occur in a 6-exo fashion instead. This result was disappointing, but we were pleased that the allylic chloride was stable under the reaction conditions.
Modified Synthetic Plan Featuring a Radical–Polar Crossover Reaction Fortunately, a simple adjustment to the spirocyclization step enabled us to formulate a viable plan that retained the main
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Scheme 2. Synthesis of 20 and undesired 6-endo radical cyclization.
Fig. 5. Second-generation retrosynthesis.
strategic elements present in our initial retrosynthesis. From our studies of radical conjugate additions,[35,36] we recognized that otherwise unfeasible transformations can often be achieved by pairing a nucleophilic radical with an electrophilic radical acceptor. Thus, we reasoned that employing an α,βunsaturated ketone as the radical acceptor would control the regioselectivity of the cyclization by directing the electron-rich aryl radical to attack the electron-deficient β-carbon of the enone. In this way, the steric barrier associated with the 5-exo cyclization could be overcome by changing the electronic nature of the substrate. Inspired by seminal work from the Oshima[37] and Kunz[38] groups, we were aware that an α-keto radical resulting from a radical conjugate addition could be converted into an enolate capable of participating as a nucleophile in a polar process. Accordingly, we proposed a novel radical–polar crossover reaction[39] for construction of the acutumine spirocycle. We envisioned that the aryl radical generated from substrate 29 (Figure 5) would undergo 5-exo cyclization onto the neighboring enone to generate a spirocyclic α-keto radical. Exposure of this species to a suitable alkylmetal
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reagent (e.g., Et3B,[40] Et2Zn,[41] or Et3Al[42]) would furnish an enolate that could be trapped with an electrophilic oxygen source, delivering α-hydroxy ketone 28. Importantly, our original strategy for the endgame of the synthesis could be applied to 28 with virtually no changes. Moreover, the synthesis of radical–polar crossover substrate 29 would require only minor modifications to the route we had already employed to construct 20. As a result, the second-generation retrosynthesis closely resembled our original plan. Enantiopure vinyl iodide 30 possessing differentially protected alcohols was synthesized via the same route used to access vinyl iodide 21. As with 21, the Knochel protocol[31] was critical to generating a Grignard reagent from 30, and this reagent was then coupled with Weinreb amide 22 to afford enone 31 (Scheme 3). By carefully optimizing the CBS reduction of 31, we obtained allylic alcohol 32 in good yield and acceptable dr. In contrast to the chlorination of alcohol 26, exposure of 32 to NCS and Me2S furnished low yields of the desired chloride. Although the byproducts generated in this reaction were not characterized, it is likely that elimination of
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Scheme 3. Synthesis of radical–polar crossover reaction substrate 29.
Scheme 4. Radical–polar crossover reaction.
the sensitive allylic chloride to afford a conjugated diene was at least partially responsible for the poor result. Fortunately, MsCl and Et3N[43] facilitated a reliable and reproducible SN2 chlorination, delivering 33 in reasonable yield. Selective TES deprotection followed by oxidation afforded enone 29, substrate for the key radical–polar crossover reaction. For the intended transformation to occur, it was imperative to avoid reduction of the radical intermediates. Accordingly, hexabutylditin was employed instead of tributyltin hydride. We were pleased to discover that the reaction proceeded at 0°C when a solution of 29, hexabutylditin, and an alkylmetal reagent in THF was irradiated by a sunlamp. While reactions conducted with Et3B and Et2Zn were successful, the best results were obtained with Et3Al. A variety of electrophilic oxygen sources were examined, and 3-phenyl-2(phenylsulfonyl)oxaziridine[44] emerged as the optimal hydroxylating agent. In addition to the desired product 28, an α-iodinated byproduct (35) and a reduced byproduct (36)
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were also produced (Scheme 4). Fortunately, under the optimized conditions 28 was obtained in significantly greater quantities than the byproducts (62% vs. 7% and 3%). We also found that iodide 35 could be transformed into 28 in 62% yield by treatment with Et2Zn, O2, and the oxaziridine, thereby raising the overall yield of 28 to 66% from 29. Excitingly, each of the products was furnished as a single detectable diastereomer. NOE experiments performed on a derivative of 28 allowed the configuration of the two newly formed stereocenters to be assigned.[15] A proposed mechanism for the radical–polar crossover reaction that is consistent with the observed stereoselectivity is depicted in Figure 6. Abstraction of the iodine atom of 29 by a tin radical produces an electron-rich aryl radical, which then engages the neighboring enone in a 5-exo cyclization. The bulky silyl ether steers this radical to the bottom face of the alkene, and the electron-withdrawing ketone directs the cyclization to occur at the hindered but electron-deficient β-carbon.
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Fig. 6. Mechanistic rationale.
Scheme 5. Synthesis of masked o-benzoquinone 40.
Then, a homolytic substitution process involving the resulting α-keto radical and Et3Al generates an aluminum enolate and an ethyl radical, the latter of which is presumably converted into a benign byproduct. The oxaziridine undergoes attack from the less-hindered top face of the enolate, ultimately furnishing α-hydroxy ketone 28. A few additional details related to the radical–polar crossover reaction are worthy of mention. It is surprising that the transformation occurs in the absence of a sensitizer, as hexabutylditin does not absorb visible light (λmax = 236 nm).[45] We considered the possibility that the C–I bond might be directly cleaved by light, and that the ditin reagent might simply be functioning as a trap for iodine radicals. However, the reaction did not proceed in the absence of hexabutylditin, indicating that this reagent is playing a crucial role in aryl radical generation.[16b] It is possible that the enone moiety of 29 could function as a sensitizer and facilitate homolysis of the Sn–Sn bond in the ditin reagent. Alternatively, coordination of the iodine atom of 29 to the ditin reagent might weaken the C–I and/or Sn–Sn bonds sufficiently to enable photolysis to occur. Ketone byproduct 36 presumably results from protonation of the enolate intermediate by adventitious moisture or reduction of the α-keto radical intermediate. However, the origin of α-iodo ketone 35 is unclear. This byproduct might be formed by reaction of I• or I2 with the α-keto radical intermediate. Another possibility involves attack of the α-keto radical or enolate on either Bu3SnI or an electrophilic species formed by in situ oxidation of Bu3SnI.[46] The mechanism of this intriguing transformation is clearly worthy of further study.
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Pyrrolidine Annulation Including Asymmetric Ketone Allylation With the spirocyclic subunit of acutumine in hand, we turned our attention to construction of the propellane system. We were anxious to test our pyrrolidine annulation strategy[14] in a more challenging setting than the simple model system (see Scheme 1). However, a few functional group manipulations were required before the key phenolic oxidation could be performed. Although the carbonyl carbon of 28 is maintained at the same oxidation state as 1, the incompatibility of a ketone at this position with an upcoming allylation reaction required us to perform a reduction–protection sequence. Thus, reduction of 28 with L-Selectride produced diol 37 in good yield and high diastereoselectivity (Scheme 5). A stereoselective reduction was unnecessary due to reoxidation of the alcohol later in the route, but the convenience of isolating and characterizing pure compounds instead of diastereomeric mixtures was welcomed. Selective silylation of the less hindered alcohol moiety of 37 and subsequent debenzylation furnished phenol 38. At this point, the strategic oxidative dearomatization was accomplished by exposing a solution of 38 in MeOH to PhI(OAc)2. After benzylation of the remaining free alcohol, masked o-benzoquinone 40 was obtained in good yield. The next step in our planned route was a diastereoselective ketone allylation of 40. After studying molecular models of this compound, we were pessimistic about the prospects of achieving synthetically useful levels of substrate-directed stereocontrol in this reaction. Consequently, we believed that a
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Fig. 7. Hasubanan alkaloids.
chiral reagent or catalyst would be required for the allylation to be successful. At the time, a number of enantioselective ketone allylation protocols were available;[47] however, to the best of our knowledge none of these methods had been utilized in a complex molecule synthesis. Concurrent with the acutumine total synthesis, we were also engaged in studies targeting the hasubanan alkaloids, which resemble 1 due to the presence of a propellane ring system (Figure 7). Application of our pyrrolidine annulation strategy to the construction of alkaloids 41–43 required the enantioselective allylation of masked o-benzoquinones that were structurally related to 40. A comprehensive investigation revealed that Nakamura’s chiral allylzinc reagent (S,S)-45[47b] facilitated highly enantioselective allylations of ketones of type 44 (Scheme 6). Most other methods that were examined either delivered racemic product or returned unreacted starting material, underscoring the sluggish reactivity of these bulky masked o-benzoquinones.[30b] An experimental and theoretical study of enantioselective ketone allylations mediated by 45 established the high reactivity of this reagent and suggested that it is most useful with relatively bulky substrates.[48] Excitingly, treatment of masked o-benzoquinone 40 with (S,S)-45 triggered a highly selective allylation, furnishing homoallylic alcohol 47 in good yield and 93:7 dr (Scheme 7).[16a] By recovering the bisoxazoline ligand from the reaction mixture,[49] we could mitigate the negative impact of using a small excess (1.6 equiv) of the chiral reagent. A tentative configurational assignment of the newly formed stereocenter in 47 was made by considering the transition state proposed by Nakamura and co-workers for asymmetric ketone allylations utilizing 45.[47b] This assignment was ultimately confirmed by our synthesis of (−)-acutumine from 47. In an attempt to determine the relative importance of reagent-derived and substrate-derived stereocontrol in the diastereoselective allylation of 40, this ketone was reacted with allylmagnesium bromide and with the enantiomeric Nakamura reagent (R,R)45. The former reaction produced 47 in modest (70:30) dr, whereas the latter favored the epimer of 47 (87:13 dr).[16b] These experiments demonstrated that the high selectivity in the diastereoselective allylation of 40 is primarily due to
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reagent-derived stereocontrol, and that Nakamura’s reagent is capable of delivering excellent results in mismatched allylations. Treatment of alcohol 47 with KOt-Bu and 18-crown-6 induced a rapid and facile anionic oxy-Cope rearrangement, delivering ketone 48 in 92% yield after just 1 hour at 0°C (Scheme 8). This was a pleasantly surprising outcome, as we had anticipated some difficulty in forming an extremely crowded C–C bond. Presumably, the anionic oxy-Cope rearrangement of 47 is accelerated by the methyl enol ether moiety, which is conjugated to one of the alkenes that participates in the reaction.[50] When viewed together, the ketone allylation and anionic oxy-Cope rearrangement accomplish a formal conjugate allylation of ketone 40. Recently, Taber and co-workers established the generality of an enantioselective 1,2-allylation– anionic oxy-Cope sequence as a method for the conjugate allylation of cyclic enones.[51] In preparation for the upcoming cyclization, it was necessary to convert the terminal alkene of 48 into a secondary amine via oxidative cleavage and reductive amination. The analogous transformation in the model system was low yielding (see 14→15, Scheme 1), so we expected difficulties with a more complex substrate. These expectations were realized, as ozonolysis of 48 under standard conditions (i.e., bubbling of O3 through the reaction mixture) produced a complex mixture with several byproducts. In an attempt to improve the yield and reproducibility of the reaction, we searched for a means of controlling the stoichiometry of O3. Fortunately, while we were addressing this problem Wender and co-workers described a protocol for generating and employing standard solutions of O3.[52] We were excited to find that treatment of an EtOAc solution of 48 with 1.5 equivalents of O3 in the form of a 0.007 M EtOAc solution provided ca. 30% of the desired aldehyde, along with some recovered starting material. Disappointingly, increasing the amount of O3 resulted in lower yields due to the formation of byproducts. Fortuitously, a timely paper by Donohoe and co-workers[53] drew our attention to the fact that pyridine can modulate the reactivity of O3.[54] By including pyridine in the ozonolysis reaction mixture and conducting the subsequent reductive amination in the same pot, we obtained a respectable 54% yield of amine 49 along with 27% of unreacted alkene 48 that could be readily separated and recycled. Although stopping the reaction at partial conversion was not ideal, it resulted in fewer byproducts and allowed us to accumulate sufficient quantities of 49 to attempt the critical cyclization. Our earlier model study, which culminated in construction of the propellane core of acutumine, identified TMSOTf as a suitable acid for promoting the key cyclization reaction.[14] Thus, we were dismayed to find that exposure of amine 49 to this reagent induced decomposition. The desired tetracyclic product was detected by mass spectrometry, but it was likely
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Scheme 6. Enantioselective allylations of masked o-benzoquinones with Nakamura’s reagent.
Scheme 7. Reagent-controlled diastereoselective allylation of ketone 40.
Scheme 9. Lewis acid promoted cyclization of 49.
facilitated the cyclization of 49, but reactions employing BCl3 were cleaner and higher yielding (Scheme 9).[16] Although the yield of tetracycle 50 was relatively modest, it is noteworthy that this cyclization fashioned a highly congested C–N bond at a low temperature (−40°C).
Completion of the Total Synthesis
Scheme 8. Anionic oxy-Cope rearrangement and ozonolysis–reductive amination.
produced in only trace quantities. Presumably, one or more of the array of acid-sensitive functional groups in 49 was degrading more rapidly than the cyclization was occurring. With limited amounts of the precious substrate in hand, we elected to screen a wide range of Lewis and Brønsted acids for their ability to mediate cyclization of the readily accessible model compound 15 (see Scheme 1 for structure). The Lewis acid BCl3 and the Brønsted acid TFA emerged from this study as promising alternatives to TMSOTf. Both of these acids also
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With the tetracyclic framework of acutumine in hand, only a few functional group manipulations stood between us and completion of the total synthesis. The three steps that transformed tetracycle 50 into 1,3-diketone 52 (desilylation, oxidation, and debenzylation) proceeded uneventfully, although it is worth noting that no reduction of the tetrasubstituted alkene or the alkyl chloride occurred during the debenzylation (Scheme 10). We approached the final reaction with concern, as we were uncertain about the prospects for a regioselective methyl enol etherification of 52. Although a variety of protocols spanning basic,[55] Lewis acidic,[56] and neutral conditions[57] are available for this transformation, the small quantities of 52 available at this late stage in the synthesis prevented us from exhaustively screening them. Accordingly, we carefully considered the merits and disadvantages of each enol etherification method before selecting two of them for evaluation. The procedure of Porta and co-workers, which utilizes catalytic amounts of TiCl4 in MeOH, was attractive due to its reported selectivity for producing the less hindered enol ether from an unsymmetrical 1,3-diketone.[56a] Addition-
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Scheme 10. Completion of the total synthesis of 1.
ally, CH2N2 was appealing because of its mild and neutral nature.[57] Disappointingly, treatment of 52 with CH2N2 yielded a ca. 1:1 mixture of 1 and its constitutional isomer 53, albeit in good combined yield (ca. 75%). Excitingly, TiCl4 and MeOH delivered a favorable outcome, producing a 52% yield of 1 along with only 14% of 53, which was separable.
Conclusions Guided by recognition that the highly oxygenated cyclohexenone ring of acutumine could be derived from an aromatic precursor, we initiated a program targeting the enantioselective synthesis of (−)-1. Although our initial plan underwent several modifications, the oxidative dearomatization strategy was retained in the successful synthetic route. During the course of the work, several transformations were developed that have the potential for broad utility in other synthetic endeavors. Specifically, the good yields and excellent stereoselectivities of the radical–polar crossover reaction (Scheme 4), the asymmetric ketone allylation employing Nakamura’s chiral allylzinc reagent (Scheme 7), and the anionic oxy-Cope rearrangement (Scheme 8) testify to the power of these methods. The Lewis acid promoted cyclization (Scheme 9), while low yielding, is also impressive due to the complex nature of the substrate. It is interesting to note that the recent total synthesis of (−)-1 by Herzon and co-workers showcases an entirely different set of transformations, including an enantioselective Diels–Alder reaction, a diastereoselective alkynylation of an iminium ion, and an intramolecular Hosomi–Sakurai allylation.[19] Clearly, the complex and unique molecular architecture of the acutumine alkaloids has inspired
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the discovery of diverse synthetic strategies and reactions. It is our hope that the methods we have developed in the context of this work will be of value to the chemistry community.
Acknowledgements I would like to express my sincere gratitude to the talented and enthusiastic co-workers who performed the work that is described in this account: Fang Li, Matthew D. Reeder, Samuel S. Tartakoff, G. S. C. Srikanth, Spencer B. Jones, Daniel K. Nielsen, Laura L. Nielsen, A. George Johnson, Brad M. Loertscher, Adam R. Moeck, and Sam S. Matthews. I also thank the National Science Foundation (CHE-716991), Research Corporation (Research Innovation Award), and Brigham Young University for financial support.
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Total Synthesis of the Congested Propellane Alkaloid (−)-Acutumine Steven L. Castle Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602 (USA) E-mail: [email protected]
Received: January 31, 2014 Published online: May 23, 2014
ABSTRACT: The enantioselective total synthesis of (−)-acutumine is described. The synthetic strategy was inspired by the premise that the cyclohexenone ring could be derived from an aromatic precursor. After successful construction of a propellane model system, an initial attempt to prepare the spirocyclic subunit was thwarted by incorrect regioselectivity in a radical cyclization. A secondgeneration approach involving a radical–polar crossover reaction was successful, and the chemistry developed in the aforementioned model system was then applied to synthesize the natural product. Key reactions included a phenolic oxidation, a diastereoselective ketone allylation utilizing Nakamura’s chiral allylzinc reagent, an anionic oxy-Cope rearrangement, an acid-promoted cyclization of a secondary amine onto an α,β-unsaturated ketal, and a regioselective methyl enol etherification of a 1,3-diketone. DOI 10.1002/tcr.201400005 Keywords: anionic oxy-Cope rearrangements, asymmetric ketone allylations, natural products, radical–polar crossover reactions, total synthesis
Introduction In 1929, Goto and Sudzuki isolated a new alkaloid named acutumine (1, Figure 1) from Sinomenium acutum, a climbing vinelike plant native to Japan and China.[1] Several years passed before Tomita and co-workers also isolated acutumine from another vine known as Menispermum dauricum, or Asian moonseed. In 1967, these researchers used X-ray crystallography to determine that 1 possesses the unusual tetracyclic architecture shown in Figure 1.[2] Other alkaloids containing the acutumine skeleton such as acutumidine (2),[2] dechloroacutumine (3),[3] and the epimeric alcohols dauricumine (4),[4] dauricumidine (5),[4] and dechlorodauricumine (6)[5] were subsequently discovered. Additionally, a derivative of 4 known as hypserpanine (7) was obtained from the woody vine Hypserpa nitida.[6] The analgesic and fever-reducing properties of the plants that produce the acutumine alkaloids[6,7] have prompted studies of
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the bioactivity of the natural products themselves. Interestingly, it was discovered that 1 is endowed with selective T-cell cytotoxicity[7] as well as antiamnesic activity in mice.[8] Acutumine possesses a unique structure consisting of a spirocyclic subunit that is merged with a propellane core.[9] Its highly congested cyclopentane ring incorporates two contiguous all-carbon quaternary stereocenters, a tert-alkyl amine, and a neopentylic secondary chloride. These striking architectural features have inspired studies of its biosynthesis. Barton and co-workers posited that 1 could be produced from a benzylisoquinoline alkaloid via oxidative phenolic coupling, oxidation, and rearrangement steps (Figure 2).[10] Wipf and co-workers conducted synthetic studies designed to probe Barton’s hypothesis, and subsequently introduced a modified biosynthetic proposal.[11] Sugimoto and co-workers established
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of (−)-1.[19] In this account, we describe the evolution of our preliminary ideas regarding the construction of acutumine into a viable synthetic strategy. During the course of this work, several synthetic methods with the potential for broad utility were developed and refined.
Propellane Model Studies
Fig. 1. Selected members of the acutumine family of alkaloids.
that 1 is assembled from two molecules of tyrosine,[12] and that different combinations of chlorination, epimerization, and N-demethylation steps transform dechlorodauricumine (6) into its congeners 1–5.[13] Despite its intriguing structure and potential for novel bioactivity, acutumine was ignored by the synthesis community for many years. In 2005, our group reported the first stage of our efforts targeting 1, in which a model system representing the propellane core was prepared.[14] This laid the foundation for additional studies[15] that culminated in the enantioselective total synthesis of (−)-1.[16] Subsequent to our initial disclosure, the Sorensen[17] and Reisman[18] groups devised creative synthetic approaches toward acutumine. Recently, Herzon and co-workers completed a concise and innovative total synthesis
Steven L. Castle was born in 1971 in Albuquerque, New Mexico, USA. His first exposure to chemistry came during summers in high school, when he worked in the laboratory of his grandfather, Prof. Raymond N. Castle of the University of South Florida. He received his B.S. with Honors in Chemistry from Brigham Young University in 1995, where he performed research with Prof. Jerald S. Bradshaw. He earned his Ph.D. in 2000 from The Scripps Research Institute under the direction of Prof. Dale L. Boger. Upon completing a National Institutes of Health postdoctoral fellowship in the laboratory of Prof. Larry E. Overman at the University of California, Irvine, in 2002 he began his independent career at Brigham Young University. His research interests encompass the development of new synthetic methods and strategies targeting complex bioactive natural products, and studies of their modes of action. He is the recipient of a Research Innovation Award from Research Corporation and a Long-Term Invitation Fellowship from the Japan Society for the Promotion of Science.
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As we contemplated the synthesis of 1, we recognized that its highly oxygenated cyclohexenone ring could be derived from an aromatic precursor. Given the ready availability of numerous aromatic starting materials and the wealth of known methods for the regioselective functionalization of arenes, the construction of a key aromatic intermediate followed by an oxidative dearomatization became an important aspect of our plan. Inspired by reports from the Sorensen,[20] Ciufolini,[21] and Honda[22] groups describing the participation of tethered nitrogen nucleophiles in phenolic oxidations, we wondered if amines would be viable nucleophiles in a related intermolecular process (cf. 8 + 9→10, Figure 3). An intramolecular conjugate addition of intermediate 10 would then furnish the propellane core of acutumine. Unfortunately, attempts to employ either secondary amines or tosyl-protected primary amines as nucleophiles in phenolic oxidations of 8 promoted by PhI(OAc)2 or PhI(OTFA)2 were fruitless. In the case of the secondary amines, it is likely that protonation by the acetic acid or trifluoroacetic acid that is liberated during the reaction prevents the desired nucleophilic addition from occurring.[23] The failure of amines and amine derivatives to participate in the phenolic oxidation required us to modify our approach to the propellane core of 1. Fortunately, we were able to retain oxidative dearomatization as a key strategic element. Thus, exposure of 8 to PhI(OAc)2 in MeOH[24] afforded masked o-benzoquinone 12 in excellent yield (Scheme 1). Masked o-benzoquinones are extremely versatile synthetic intermediates that present several different opportunities for functionalization.[25] In our case, we desired to perform a conjugate allylation of 12, but the extremely hindered nature of the β-carbon precluded this transformation. We were gratified to discover that a 1,2-allylation–anionic oxy-Cope rearrangement sequence furnished ketone 14, which possesses vicinal quaternary carbon atoms, in good yield. Ozonolysis of the terminal alkene was plagued by competitive oxidation of the electron-rich methyl enol ether, but by halting the reaction after ca. 50% conversion and subjecting the crude mixture of aldehyde and alkene to a reductive amination, suitable quantities of amine 15 could be obtained. Based on a report by Matsumoto and co-workers,[26] we anticipated that treatment of 15 with a Lewis or Brønsted acid would promote ionization of the dimethyl ketal and trigger cyclization of the secondary amine onto the α,β-unsaturated oxocarbenium ion
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Fig. 2. Biosynthetic proposals related to acutumine.
Fig. 3. Initial plan for propellane core synthesis.
intermediate. A survey of acids revealed that TMSOTf mediated the desired cyclization, affording propellane 16 as its enol tautomer in moderate yield along with a byproduct 17 generated by cleavage of the methyl enol ether.[14] This result gave us confidence that our revised strategy offered a feasible route to the propellane core of acutumine; nevertheless, we recognized that the ozonolysis–reductive amination and cyclization steps were likely to be very challenging in the context of the total synthesis.
First-Generation Synthetic Plan Buoyed by the successful construction of model compound 16, we embarked upon the total synthesis of acutumine. Our firstgeneration retrosynthesis is shown in Figure 4. We reasoned that the cyclopentenone ring of the natural product could be
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generated in the final stages of the synthesis by functional group manipulation. Accordingly, we envisioned tetracycle 18 as a viable precursor to 1. The regioselective methyl enol etherification of a 1,3-diketone was projected to be the most challenging transformation in this section of the route. Then, disconnection of the pyrrolidine ring of 18 to reveal aromatic spirocycle 19 was inspired by our successful model studies. We posited that the spirocyclic ring system of 19 could be fashioned from iodide 20 via 5-exo-trig aryl radical cyclization followed by trapping of the resulting radical by TEMPO.[27] The silyl-ether-bearing stereocenters located in the cyclopentene ring of 20, both of which would be destroyed during the endgame, would presumably direct the cyclization to the bottom face of the alkene. Finally, a convergent dissection of 20 identified enantiopure vinyl iodide 21 and Weinreb amide 22 as key building blocks. Our enthusiasm for this plan
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Scheme 1. Synthesis of propellane core model system.
Fig. 4. First-generation retrosynthesis.
was high, but we were concerned about potential complications in the radical cyclization of 20, such as the stability of the allylic chloride and the regioselectivity of the process (i.e., 5-exo versus 6-endo). Enantiopure vinyl iodide 21 was prepared via a nine-step sequence from cis-3,5-diacetoxycyclopentene (23) featuring an enzymatic desymmetrization (Scheme 2).[28,29] The construction of Weinreb amide 22 was accomplished in nine steps from 2,3-dimethoxyphenol (24) and involved homologation of an aldehyde that was synthesized previously in our laboratory.[30] The coupling of 21 and 22 could only be achieved using Knochel’s protocol, which enlists i-PrMgCl·LiCl and 15-crown-5 for vinyl Grignard generation.[31] The resulting ketone 25 was then transformed into cyclization substrate 20 via a moderately diastereoselective CBS reduction[32] followed by SN2 chlorination[33] of allylic alcohol 26. Unfortunately, the
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radical cyclization of 20 did not proceed in the presence of TEMPO. A cyclized product was obtained by exposing 20 to Et3B, air, and Bu3SnH,[34] but NMR data indicated that fused tricycle 27 had been formed instead of the required spirocycle.[16b] Presumably, the high degree of steric hindrance inherent in the 5-exo pathway caused the cyclization to occur in a 6-exo fashion instead. This result was disappointing, but we were pleased that the allylic chloride was stable under the reaction conditions.
Modified Synthetic Plan Featuring a Radical–Polar Crossover Reaction Fortunately, a simple adjustment to the spirocyclization step enabled us to formulate a viable plan that retained the main
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Scheme 2. Synthesis of 20 and undesired 6-endo radical cyclization.
Fig. 5. Second-generation retrosynthesis.
strategic elements present in our initial retrosynthesis. From our studies of radical conjugate additions,[35,36] we recognized that otherwise unfeasible transformations can often be achieved by pairing a nucleophilic radical with an electrophilic radical acceptor. Thus, we reasoned that employing an α,βunsaturated ketone as the radical acceptor would control the regioselectivity of the cyclization by directing the electron-rich aryl radical to attack the electron-deficient β-carbon of the enone. In this way, the steric barrier associated with the 5-exo cyclization could be overcome by changing the electronic nature of the substrate. Inspired by seminal work from the Oshima[37] and Kunz[38] groups, we were aware that an α-keto radical resulting from a radical conjugate addition could be converted into an enolate capable of participating as a nucleophile in a polar process. Accordingly, we proposed a novel radical–polar crossover reaction[39] for construction of the acutumine spirocycle. We envisioned that the aryl radical generated from substrate 29 (Figure 5) would undergo 5-exo cyclization onto the neighboring enone to generate a spirocyclic α-keto radical. Exposure of this species to a suitable alkylmetal
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reagent (e.g., Et3B,[40] Et2Zn,[41] or Et3Al[42]) would furnish an enolate that could be trapped with an electrophilic oxygen source, delivering α-hydroxy ketone 28. Importantly, our original strategy for the endgame of the synthesis could be applied to 28 with virtually no changes. Moreover, the synthesis of radical–polar crossover substrate 29 would require only minor modifications to the route we had already employed to construct 20. As a result, the second-generation retrosynthesis closely resembled our original plan. Enantiopure vinyl iodide 30 possessing differentially protected alcohols was synthesized via the same route used to access vinyl iodide 21. As with 21, the Knochel protocol[31] was critical to generating a Grignard reagent from 30, and this reagent was then coupled with Weinreb amide 22 to afford enone 31 (Scheme 3). By carefully optimizing the CBS reduction of 31, we obtained allylic alcohol 32 in good yield and acceptable dr. In contrast to the chlorination of alcohol 26, exposure of 32 to NCS and Me2S furnished low yields of the desired chloride. Although the byproducts generated in this reaction were not characterized, it is likely that elimination of
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Scheme 3. Synthesis of radical–polar crossover reaction substrate 29.
Scheme 4. Radical–polar crossover reaction.
the sensitive allylic chloride to afford a conjugated diene was at least partially responsible for the poor result. Fortunately, MsCl and Et3N[43] facilitated a reliable and reproducible SN2 chlorination, delivering 33 in reasonable yield. Selective TES deprotection followed by oxidation afforded enone 29, substrate for the key radical–polar crossover reaction. For the intended transformation to occur, it was imperative to avoid reduction of the radical intermediates. Accordingly, hexabutylditin was employed instead of tributyltin hydride. We were pleased to discover that the reaction proceeded at 0°C when a solution of 29, hexabutylditin, and an alkylmetal reagent in THF was irradiated by a sunlamp. While reactions conducted with Et3B and Et2Zn were successful, the best results were obtained with Et3Al. A variety of electrophilic oxygen sources were examined, and 3-phenyl-2(phenylsulfonyl)oxaziridine[44] emerged as the optimal hydroxylating agent. In addition to the desired product 28, an α-iodinated byproduct (35) and a reduced byproduct (36)
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were also produced (Scheme 4). Fortunately, under the optimized conditions 28 was obtained in significantly greater quantities than the byproducts (62% vs. 7% and 3%). We also found that iodide 35 could be transformed into 28 in 62% yield by treatment with Et2Zn, O2, and the oxaziridine, thereby raising the overall yield of 28 to 66% from 29. Excitingly, each of the products was furnished as a single detectable diastereomer. NOE experiments performed on a derivative of 28 allowed the configuration of the two newly formed stereocenters to be assigned.[15] A proposed mechanism for the radical–polar crossover reaction that is consistent with the observed stereoselectivity is depicted in Figure 6. Abstraction of the iodine atom of 29 by a tin radical produces an electron-rich aryl radical, which then engages the neighboring enone in a 5-exo cyclization. The bulky silyl ether steers this radical to the bottom face of the alkene, and the electron-withdrawing ketone directs the cyclization to occur at the hindered but electron-deficient β-carbon.
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Fig. 6. Mechanistic rationale.
Scheme 5. Synthesis of masked o-benzoquinone 40.
Then, a homolytic substitution process involving the resulting α-keto radical and Et3Al generates an aluminum enolate and an ethyl radical, the latter of which is presumably converted into a benign byproduct. The oxaziridine undergoes attack from the less-hindered top face of the enolate, ultimately furnishing α-hydroxy ketone 28. A few additional details related to the radical–polar crossover reaction are worthy of mention. It is surprising that the transformation occurs in the absence of a sensitizer, as hexabutylditin does not absorb visible light (λmax = 236 nm).[45] We considered the possibility that the C–I bond might be directly cleaved by light, and that the ditin reagent might simply be functioning as a trap for iodine radicals. However, the reaction did not proceed in the absence of hexabutylditin, indicating that this reagent is playing a crucial role in aryl radical generation.[16b] It is possible that the enone moiety of 29 could function as a sensitizer and facilitate homolysis of the Sn–Sn bond in the ditin reagent. Alternatively, coordination of the iodine atom of 29 to the ditin reagent might weaken the C–I and/or Sn–Sn bonds sufficiently to enable photolysis to occur. Ketone byproduct 36 presumably results from protonation of the enolate intermediate by adventitious moisture or reduction of the α-keto radical intermediate. However, the origin of α-iodo ketone 35 is unclear. This byproduct might be formed by reaction of I• or I2 with the α-keto radical intermediate. Another possibility involves attack of the α-keto radical or enolate on either Bu3SnI or an electrophilic species formed by in situ oxidation of Bu3SnI.[46] The mechanism of this intriguing transformation is clearly worthy of further study.
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Pyrrolidine Annulation Including Asymmetric Ketone Allylation With the spirocyclic subunit of acutumine in hand, we turned our attention to construction of the propellane system. We were anxious to test our pyrrolidine annulation strategy[14] in a more challenging setting than the simple model system (see Scheme 1). However, a few functional group manipulations were required before the key phenolic oxidation could be performed. Although the carbonyl carbon of 28 is maintained at the same oxidation state as 1, the incompatibility of a ketone at this position with an upcoming allylation reaction required us to perform a reduction–protection sequence. Thus, reduction of 28 with L-Selectride produced diol 37 in good yield and high diastereoselectivity (Scheme 5). A stereoselective reduction was unnecessary due to reoxidation of the alcohol later in the route, but the convenience of isolating and characterizing pure compounds instead of diastereomeric mixtures was welcomed. Selective silylation of the less hindered alcohol moiety of 37 and subsequent debenzylation furnished phenol 38. At this point, the strategic oxidative dearomatization was accomplished by exposing a solution of 38 in MeOH to PhI(OAc)2. After benzylation of the remaining free alcohol, masked o-benzoquinone 40 was obtained in good yield. The next step in our planned route was a diastereoselective ketone allylation of 40. After studying molecular models of this compound, we were pessimistic about the prospects of achieving synthetically useful levels of substrate-directed stereocontrol in this reaction. Consequently, we believed that a
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Fig. 7. Hasubanan alkaloids.
chiral reagent or catalyst would be required for the allylation to be successful. At the time, a number of enantioselective ketone allylation protocols were available;[47] however, to the best of our knowledge none of these methods had been utilized in a complex molecule synthesis. Concurrent with the acutumine total synthesis, we were also engaged in studies targeting the hasubanan alkaloids, which resemble 1 due to the presence of a propellane ring system (Figure 7). Application of our pyrrolidine annulation strategy to the construction of alkaloids 41–43 required the enantioselective allylation of masked o-benzoquinones that were structurally related to 40. A comprehensive investigation revealed that Nakamura’s chiral allylzinc reagent (S,S)-45[47b] facilitated highly enantioselective allylations of ketones of type 44 (Scheme 6). Most other methods that were examined either delivered racemic product or returned unreacted starting material, underscoring the sluggish reactivity of these bulky masked o-benzoquinones.[30b] An experimental and theoretical study of enantioselective ketone allylations mediated by 45 established the high reactivity of this reagent and suggested that it is most useful with relatively bulky substrates.[48] Excitingly, treatment of masked o-benzoquinone 40 with (S,S)-45 triggered a highly selective allylation, furnishing homoallylic alcohol 47 in good yield and 93:7 dr (Scheme 7).[16a] By recovering the bisoxazoline ligand from the reaction mixture,[49] we could mitigate the negative impact of using a small excess (1.6 equiv) of the chiral reagent. A tentative configurational assignment of the newly formed stereocenter in 47 was made by considering the transition state proposed by Nakamura and co-workers for asymmetric ketone allylations utilizing 45.[47b] This assignment was ultimately confirmed by our synthesis of (−)-acutumine from 47. In an attempt to determine the relative importance of reagent-derived and substrate-derived stereocontrol in the diastereoselective allylation of 40, this ketone was reacted with allylmagnesium bromide and with the enantiomeric Nakamura reagent (R,R)45. The former reaction produced 47 in modest (70:30) dr, whereas the latter favored the epimer of 47 (87:13 dr).[16b] These experiments demonstrated that the high selectivity in the diastereoselective allylation of 40 is primarily due to
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reagent-derived stereocontrol, and that Nakamura’s reagent is capable of delivering excellent results in mismatched allylations. Treatment of alcohol 47 with KOt-Bu and 18-crown-6 induced a rapid and facile anionic oxy-Cope rearrangement, delivering ketone 48 in 92% yield after just 1 hour at 0°C (Scheme 8). This was a pleasantly surprising outcome, as we had anticipated some difficulty in forming an extremely crowded C–C bond. Presumably, the anionic oxy-Cope rearrangement of 47 is accelerated by the methyl enol ether moiety, which is conjugated to one of the alkenes that participates in the reaction.[50] When viewed together, the ketone allylation and anionic oxy-Cope rearrangement accomplish a formal conjugate allylation of ketone 40. Recently, Taber and co-workers established the generality of an enantioselective 1,2-allylation– anionic oxy-Cope sequence as a method for the conjugate allylation of cyclic enones.[51] In preparation for the upcoming cyclization, it was necessary to convert the terminal alkene of 48 into a secondary amine via oxidative cleavage and reductive amination. The analogous transformation in the model system was low yielding (see 14→15, Scheme 1), so we expected difficulties with a more complex substrate. These expectations were realized, as ozonolysis of 48 under standard conditions (i.e., bubbling of O3 through the reaction mixture) produced a complex mixture with several byproducts. In an attempt to improve the yield and reproducibility of the reaction, we searched for a means of controlling the stoichiometry of O3. Fortunately, while we were addressing this problem Wender and co-workers described a protocol for generating and employing standard solutions of O3.[52] We were excited to find that treatment of an EtOAc solution of 48 with 1.5 equivalents of O3 in the form of a 0.007 M EtOAc solution provided ca. 30% of the desired aldehyde, along with some recovered starting material. Disappointingly, increasing the amount of O3 resulted in lower yields due to the formation of byproducts. Fortuitously, a timely paper by Donohoe and co-workers[53] drew our attention to the fact that pyridine can modulate the reactivity of O3.[54] By including pyridine in the ozonolysis reaction mixture and conducting the subsequent reductive amination in the same pot, we obtained a respectable 54% yield of amine 49 along with 27% of unreacted alkene 48 that could be readily separated and recycled. Although stopping the reaction at partial conversion was not ideal, it resulted in fewer byproducts and allowed us to accumulate sufficient quantities of 49 to attempt the critical cyclization. Our earlier model study, which culminated in construction of the propellane core of acutumine, identified TMSOTf as a suitable acid for promoting the key cyclization reaction.[14] Thus, we were dismayed to find that exposure of amine 49 to this reagent induced decomposition. The desired tetracyclic product was detected by mass spectrometry, but it was likely
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Scheme 6. Enantioselective allylations of masked o-benzoquinones with Nakamura’s reagent.
Scheme 7. Reagent-controlled diastereoselective allylation of ketone 40.
Scheme 9. Lewis acid promoted cyclization of 49.
facilitated the cyclization of 49, but reactions employing BCl3 were cleaner and higher yielding (Scheme 9).[16] Although the yield of tetracycle 50 was relatively modest, it is noteworthy that this cyclization fashioned a highly congested C–N bond at a low temperature (−40°C).
Completion of the Total Synthesis
Scheme 8. Anionic oxy-Cope rearrangement and ozonolysis–reductive amination.
produced in only trace quantities. Presumably, one or more of the array of acid-sensitive functional groups in 49 was degrading more rapidly than the cyclization was occurring. With limited amounts of the precious substrate in hand, we elected to screen a wide range of Lewis and Brønsted acids for their ability to mediate cyclization of the readily accessible model compound 15 (see Scheme 1 for structure). The Lewis acid BCl3 and the Brønsted acid TFA emerged from this study as promising alternatives to TMSOTf. Both of these acids also
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With the tetracyclic framework of acutumine in hand, only a few functional group manipulations stood between us and completion of the total synthesis. The three steps that transformed tetracycle 50 into 1,3-diketone 52 (desilylation, oxidation, and debenzylation) proceeded uneventfully, although it is worth noting that no reduction of the tetrasubstituted alkene or the alkyl chloride occurred during the debenzylation (Scheme 10). We approached the final reaction with concern, as we were uncertain about the prospects for a regioselective methyl enol etherification of 52. Although a variety of protocols spanning basic,[55] Lewis acidic,[56] and neutral conditions[57] are available for this transformation, the small quantities of 52 available at this late stage in the synthesis prevented us from exhaustively screening them. Accordingly, we carefully considered the merits and disadvantages of each enol etherification method before selecting two of them for evaluation. The procedure of Porta and co-workers, which utilizes catalytic amounts of TiCl4 in MeOH, was attractive due to its reported selectivity for producing the less hindered enol ether from an unsymmetrical 1,3-diketone.[56a] Addition-
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Scheme 10. Completion of the total synthesis of 1.
ally, CH2N2 was appealing because of its mild and neutral nature.[57] Disappointingly, treatment of 52 with CH2N2 yielded a ca. 1:1 mixture of 1 and its constitutional isomer 53, albeit in good combined yield (ca. 75%). Excitingly, TiCl4 and MeOH delivered a favorable outcome, producing a 52% yield of 1 along with only 14% of 53, which was separable.
Conclusions Guided by recognition that the highly oxygenated cyclohexenone ring of acutumine could be derived from an aromatic precursor, we initiated a program targeting the enantioselective synthesis of (−)-1. Although our initial plan underwent several modifications, the oxidative dearomatization strategy was retained in the successful synthetic route. During the course of the work, several transformations were developed that have the potential for broad utility in other synthetic endeavors. Specifically, the good yields and excellent stereoselectivities of the radical–polar crossover reaction (Scheme 4), the asymmetric ketone allylation employing Nakamura’s chiral allylzinc reagent (Scheme 7), and the anionic oxy-Cope rearrangement (Scheme 8) testify to the power of these methods. The Lewis acid promoted cyclization (Scheme 9), while low yielding, is also impressive due to the complex nature of the substrate. It is interesting to note that the recent total synthesis of (−)-1 by Herzon and co-workers showcases an entirely different set of transformations, including an enantioselective Diels–Alder reaction, a diastereoselective alkynylation of an iminium ion, and an intramolecular Hosomi–Sakurai allylation.[19] Clearly, the complex and unique molecular architecture of the acutumine alkaloids has inspired
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the discovery of diverse synthetic strategies and reactions. It is our hope that the methods we have developed in the context of this work will be of value to the chemistry community.
Acknowledgements I would like to express my sincere gratitude to the talented and enthusiastic co-workers who performed the work that is described in this account: Fang Li, Matthew D. Reeder, Samuel S. Tartakoff, G. S. C. Srikanth, Spencer B. Jones, Daniel K. Nielsen, Laura L. Nielsen, A. George Johnson, Brad M. Loertscher, Adam R. Moeck, and Sam S. Matthews. I also thank the National Science Foundation (CHE-716991), Research Corporation (Research Innovation Award), and Brigham Young University for financial support.
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