Asymmetric Total Synthesis of Fasicularin by Chiral N-Alkoxyamide

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Asymmetric Total Synthesis of Fasicularin by Chiral N‑Alkoxyamide Strategy Shio Yamamoto,†,§ Yukinori Komiya,†,§ Akihiro Kobayashi,† Ryo Minamikawa,† Takeshi Oishi,‡ Takaaki Sato,*,† and Noritaka Chida*,† †

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Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan ‡ School of Medicine, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan S Supporting Information *

ABSTRACT: The asymmetric total synthesis of fasicularin is reported. The key to success is the use of a chiral N-alkoxyamide to control both reactivity and stereoselectivity. This functional group enables the aza-spirocyclization and the reductive Strecker reaction, which cannot be realized with an ordinary amide. In addition, use of the chiral alkoxy group establishes two consecutive stereocenters in the aza-spirocyclization through remote stereocontrol.

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In designing a synthetic route toward fasicularin (4), we employed a chiral N-alkoxyamide in order to control both the reactivity and the stereoselectivity and envisioned two crucial transformations (Scheme 1b). The first key step is the azaspirocyclization of acyclic ketoamide 5. Addition of an acid to ketoamide 5 would promote the generation of the transient Nacyliminium ion, which undergoes intramolecular allylation to give aza-spirocycle 6. In this reaction, the formation of a tertiary alcohol by the direct allylation of the ketone could compete with the desired pathway. However, the assistance of the alkoxy group as a reactivity control element would increase the nucleophilicity of the amide nitrogen (effect A) and facilitate the attack of the amide nitrogen to the ketone. We also expected that the two consecutive stereocenters of 6 could be established by remote stereocontrol of the chiral alkoxy group. The second key reaction is the reductive Strecker reaction of N-alkoxyamide 7.3,9−11 Hydride reduction of 7 would form the chelated intermediate 8, and then the acid-mediated Strecker reaction would give aminonitrile 9 via the N-oxyiminium ion in a one-pot process. This transformation also utilized the alkoxy group as a reactivity control element. The alkoxy group would increase the electrophilicity of the amide carbonyl (effect B) and allow for the first reduction under mild conditions. Additionally, the chelation effect of the alkoxy group would prevent over-reduction (effect C). The alkoxy group could be easily removed under reductive conditions to afford tricyclic compound 10, which is known to be transformed to fasicularin (4) by the Mitsunobu reaction with ammonium thiocyanate.8a,d Our total synthesis commenced with the catalytic asymmetric synthesis of N-alkoxyamine hydrochloride 14 (Scheme 2). The

ur research group has been exploring new synthetic strategies involving the heteroatom−heteroatom bond toward the total synthesis of biologically active natural products. Incorporation of another heteroatom onto an existing heteroatom imparts new reactivities that cannot be achieved with the single heteroatom. For example, installation of a methoxy group to amide 1 forms N-methoxyamide (the socalled Weinreb amide) 2, which is known to change the original reactivity by (A) increasing the nucleophilicity of the nitrogen atom,1 (B) increasing the electrophilicity of the amide carbonyl,2,3 and (C) the chelation effect.2,3 We took advantage of this methoxy group as a reactivity control element and developed a two-step synthesis of multisubstituted piperidines using the unique reactivities of N-methoxyamide 2.4 The method was successfully applied to the racemic total synthesis of gephyrotoxin.3b,5 In this communication, we developed chiral N-alkoxyamide 3 as an advanced form of N-methoxyamide 2. The chiral alkoxy group of 3 was utilized as a stereocontrol element in addition to a reactivity control element and resulted in the asymmetric total synthesis of fasicularin (4). Fasicularin (4) was isolated from the ascidian Nephteis fasicularis and has been shown to possess cytotoxic properties against Vero cells (IC50 of 14 μg/mL).6 The yeast strain with deletion of the RAD gene, involving repair of DNA, is known to be >20-fold more hypersensitive to fasicularin (4). Structurally, fasicularin (4) consists of a tricyclic framework including an azaspirocycle and a thiocyanate. The fascinating structure as well as its intriguing biological activity attracted considerable interest from synthetic chemists7,8 and culminated in the first total synthesis of fasicularin (4) by the Kibayashi group.8a,d After their report, Funk, 8b Dake, 8c,e Zhao, 8f Kim,8g Chiba, 8h and Robinson8i all achieved elegant total syntheses by original strategies. © XXXX American Chemical Society

Received: February 5, 2019

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DOI: 10.1021/acs.orglett.9b00478 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Table 1. Diastereoselective Aza-spirocyclization of NAlkoxyamides 16a

Scheme 1. (a) Chiral Alkoxy Group as a Reactivity and Stereocontrol Element. (b) Synthetic Strategy toward the Total Synthesis of Fasicularin

entry

16

acid

T (°C)

combined yieldb (%)

1 2 3 4 5 6 7 8 9 10 11d

16a 16b 16c 16d 16e 16f 16g 16a 16a 16a 16a

BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O SnCl4 TiCl4 CF3CO2H CF3CO2H

−78 to −20 −78 to −20 −78 to −20 −78 to −20 −78 to −20 −78 to −20 −78 to −20 −78 −78 −78 to −20 −85 to −60

71 70 72 76 79 0 79 0 0 73 78

6/17c 4.0:1 3.8:1 3.1:1 2.0:1 1.8:1 1.1:1

4.4:1 5.2:1

a 16 (50 μmol), acid (5 equiv), CH2Cl2 (0.02 M), T (°C), 3 h. bThe combined yields were reported. cThe ratio was determined by 1H NMR. d16a (668 mg, 1.65 mmol), CF3CO2H (5 equiv), CH2Cl2 (0.02 M), −85 °C, 24 h, then −60 °C, 18 h.

Scheme 2. A Catalytic Asymmetric Synthesis of the NAlkoxyamide

crystallographic analysis.14 The formation of the other two diastereomers 18a and 19a was not observed, probably due to the 1,3-diaxial repulsion of the axial N-alkoxyamine group. The substituent on the chiral alkoxy group affected the diastereoselectivity (Table 1, entries 1−6). While amides with electrondeficient substituents on the aryl group tended to show lower diastereoselectivities (Table 1, entries 3−5), amide 16f with an electron-rich methoxy group resulted in significant decomposition due to its instability under acidic conditions (Table 1, entry 6). The position of the substituent proved critical, and the reaction of 16g with the 2-methyl group showed almost no selectivity (Table 1, entry 7). We then investigated the nature of the acid. While use of SnCl4 and TiCl4 caused significant decomposition (Table 1, entries 8 and 9), the reaction with CF3CO2H improved the diastereoselectivity slightly (Table 1, entry 10). The best result was obtained when the reaction was conducted at −85 to −60 °C, giving the aza-spirocycles 6a and 17a in 78% combined yield with 5.2:1 diastereoselectivity (Table 1, entry 11). Thus, we succeeded in using the remote stereocontrol of the chiral alkoxy group and established two consecutive stereocenters embedded in the aza-spirocycle. To confirm the beneficial effects of the chiral alkoxy group in the aza-spirocyclization, the chiral alkoxy group was replaced with a simple methyl group (Scheme 3a). Interestingly, condensation of ketoacid 15 with N-methylamine resulted in isolation of the acyclic ketoamide 5h in 71% yield instead of the corresponding hemiaminal. The subsequent addition of BF3· Et2O to ketoamide 5h gave tertiary alcohol (±)-20 in 70% yield through direct intramolecular allylation. The same sequence with the N-methoxyamine showed similar reactivity to the chiral N-alkoxyamine. The condensation of 15 with N-methoxyamine

CBS reduction12 of 4-methylacetophenone 11 and subsequent Mitsunobu reaction with N-hydroxyphthalimide (NHPI) provided N-alkoxyphthalimide 13 in 96% ee. Removal of the phthaloyl group with methylamine provided chiral N-alkoxyamine hydrochloride 14 in 75% yield and 99% ee after recrystallization. Interestingly, condensation of 14 with ketoacid 15 (E/Z = 1.7:1), which was prepared from commercially available methyl 4-chloro-4-oxobutanoate in three steps,13 resulted in isolation of cyclic hemiaminal 16a, not acyclic Nalkoxyamide 5. With hemiaminal 16a in hand, we turned our attention to the aza-spirocyclization (Table 1). BF3·Et2O was added to a solution of 16a in CH2Cl2 at −78 °C, and the resulting solution was warmed to −20 °C to give two diastereomers 6a and 17a in 71% combined yield with 4.0:1 diastereoselectivity (Table 1, entry 1). The structure of 6a was unambiguously determined by X-ray B

DOI: 10.1021/acs.orglett.9b00478 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Control Experiments with N-Methyl- and NMethoxyamides

Scheme 4. Total Synthesis of Fasicularin (4)

formed hemiaminal 16i, which underwent BF3·Et2O-mediated allylation via the N-acyliminium ion to give aza-spirocycle (±)-6i in 86% yield. Diastereomer (±)-18i was also isolated in 9% yield probably due to the smaller 1,3-diaxial repulsion. Although the factors controlling both the reactivity and the diastereoselectivity are yet to be clarified, we have confirmed that the aza-spirocyclization was successfully achieved by taking advantage of the chiral alkoxy group. Cross metathesis15 of aza-spirocycle 6a with enone 2116 and subsequent hydrogenation of enone 22 in a one-pot process gave ketone 23, which was protected as a cyclic acetal under modified Noyori conditions17 (Scheme 4). With N-alkoxyamide 7 in hand, the stage was set for the crucial reductive Strecker reaction. Treatment of 7 with the Schwartz reagent [Cp2ZrHCl] at 0 °C generated five-membered chelated intermediate 24.18,19 Sc(OTf)3 (10 mol %) and TMSCN were added to 24 at −78 °C.3b The cyanide group approached the generated Noxyiminium ion from the side opposite to the large alkyl chain, giving aminonitrile 9 in 88% combined yield with 11:1 diastereoselectivity. We found that use of the iridium-catalyzed reduction resulted in better yield and diastereoselectivity. Hydrosilylation of N-alkoxyamide 720 with the Vaska complex [Ir(CO)Cl(PPh3)2] (10 mol %) and (Me2HSi)2O provided the transient N,O-acetal 25, which underwent the Sc(OTf)3catalyzed Strecker reaction in a one-pot process.11b In this case, the desired aminonitrile 9 was obtained in 92% combined yield with more than 20:1 diastereoselectivity. DIBAL-H reduction of the resulting cyanide group in 9, and subsequent reduction with NaBH4, provided primary alcohol 26 in 71% yield. Palladium-catalyzed hydrogenation of 26 under acidic conditions initiated removal of both the chiral alkoxy and acetal groups. After the formation of enamine 27 was confirmed by TLC analysis, the reaction mixture was basified with saturated aq NaHCO3. Subsequent hydrogenation of enamine 27 under basic conditions gave tricyclic intermediate 10 stereoselectively. Finally, the Kibayashi method with ammonium thiocyanate8a,d provided fasicularin (4), along with 28, which was isomerized to 4 in MeCN. Spectral data of our synthetic fasicularin were identical to those derived from the natural product. In summary, we have accomplished an asymmetric total synthesis of fasicularin (4) in 11 steps from commercially available 4-methylacetophenone in 7.9% total yield (12 steps, 10.2% total yield including isomerization of 28), representing

one of the most concise and efficient syntheses to date. The salient feature of our synthesis is the use of the chiral Nalkoxyamide to control reactivity and stereoselectivity. In the first key reaction, use of the N-alkoxyamide facilitated the formation of the cyclic hemiaminal, which underwent acidmediated aza-spirocyclization. In addition, two consecutive stereocenters of the aza-spirocycle were established by remote stereocontrol of the chiral alkoxy group. The resulting Nalkoxyamide then underwent the reductive Strecker reaction to provide the aminonitrile in high yield with high diastereoselectivity. We believe that the reaction sequence using the chiral N-alkoxyamide could be a general strategy for asymmetric syntheses of biologically active complex alkaloids.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00478. Experimental procedures; 1H NMR and 13C NMR spectra of new compounds (PDF) Accession Codes

CCDC 1580840 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. C

DOI: 10.1021/acs.orglett.9b00478 Org. Lett. XXXX, XXX, XXX−XXX

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Takaaki Sato: 0000-0001-5769-3408 Author Contributions §

S.Y. and Y.K. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a Grant-in-Aid for Scientific Research (C) from MEXT (15K05436), the Tobe Maki Foundation, and the JGC-S Scholarship Foundation.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b00478 Org. Lett. XXXX, XXX, XXX−XXX