Letter pubs.acs.org/OrgLett
Total Synthesis of TAN1251C via Diastereoselective Construction of the Azaspiro Skeleton Yosuke Nagasaka, Sayaka Shintaku, Kosuke Matsumura, Akitaka Masuda, Tomohiro Asakawa, Makoto Inai, Masahiro Egi, Yoshitaka Hamashima, Yoshinobu Ishikawa, and Toshiyuki Kan* School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan S Supporting Information *
ABSTRACT: An efficient total synthesis of TAN1251C was accomplished by employing a Ugi four-component accumulation reaction and a Dieckmann condensation to construct the spiro-fused cyclohexanone and γ-lactam ring. Diastereoselective reduction by side-chain-controlled hydrogenation of enamide 15 or Zn reduction of oxime 23 enabled construction of the amino group with the desired stereochemistry. by this success, we expected that an efficient and flexible synthesis of 1c could be accomplished by means of similar methodology. The heart of our synthetic strategy for 1c is illustrated in Scheme 1. The tricyclic skeleton of 1c would be constructed by intramolecular dienamine formation of N-methyl amino aldehyde 3 based on the biosynthetic hypothesis. Although the combination of the Ugi 4CC reaction4 and the Dieckmann condensation allowed for facile construction of the spirolactam in the total synthesis of 2, the late-stage incorporation of the monomethylamine unit onto the spirolactam ring required a
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n 1991, researchers at the Takeda Pharmaceutical Company reported the isolation of the TAN1251 series of compounds (A−D) (Figure 1) from a culture of Penicillium thomii RA-89.1
Scheme 1. Retrosynthetic Analysis of TAN1251C (1c)
Figure 1. Structures of TAN1251A−D (1a−d) and FR901483 (2).
These compounds possess a unique tricyclic skeleton with 1,4diazabicyclo[3.2.1]octane and spiro-fused cyclohexanone moieties and are muscarinic antagonists with potential value as antispasmodic or antiulcer agents.1 Considering their unique structure and potent biological activities, they have attracted considerable interest, and several total syntheses have been reported.2 For example, Snider accomplished an efficient total synthesis of TAN1251C (1c) and also obtained the analogues TAN1251A (1a), -B (1b), and -D (1d) from synthetic intermediates. Therefore, 1c is considered a key target for preparation of the TAN1251 series. During the course of our synthetic studies on natural products with a nitrogen atom on the tetrasubstituted carbon,3 we accomplished the total synthesis of biosynthetically related (−)-FR901483 (2)4 using a Ugi four-component condensation (4CC) reaction.5 Inspired © 2017 American Chemical Society
Received: June 7, 2017 Published: June 29, 2017 3839
DOI: 10.1021/acs.orglett.7b01718 Org. Lett. 2017, 19, 3839−3842
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Organic Letters tedious five-step sequence. We envisioned that the Ugi 4CC reaction with glycine derivatives 7b−d (R1 = NHCO2R) instead of acetic acid (7a, R1 = H) would enable easy incorporation of the amine group into the Ugi adduct, accomplishing one-step accumulation of all of the atoms required for the ring system of 1c. Furthermore, the use of our odorless isonitrile 86 would be favorable in the Dieckmann condensation. The Ugi 4CC reaction of ketone 5, amine 6, carboxylic acids 7, and isonitrile 8 was investigated, as shown in Scheme 2. In
with 5 equiv of LiHMDS, the desired cyclization proceeded smoothly to give β-keto lactam 12. Selective reduction of the ketone followed by mesylation and β-elimination afforded the desired α,β-unsaturated lactam 13. Subsequently, dimethyl acetal 13 was converted to the more stable ethylene ketal 14 after hydrolysis according to Noyori’s protocol.8 Removal of the TBDPS group of 14 was carried out by treatment with TBAF to give primary alcohol 15. Next we investigated the stereoselective reduction of the double bonds of 14 and 15, as shown in Table 1. While the
Scheme 2. Synthesis of α,β-Unsaturated Lactams 14 and 15
Table 1. Diastereoselective Reduction of Enamides 14 and 15
entry enamide 1 2 3 4 5 a
14 15 15 15 15
pressure
catalyst
time (h)
yield (%)
selectivity (a:b)a
500 psi 1 atm 1 atm 1 atm 1 atm
Pd/C Pd/C Pd(OH)2 PtO2 Pt/C
4.5 8 24 96 24
89 83 67 80 66
1:1 1:1 1:1 4:1 1:1
The selectivity was determined by 1H NMR analysis.
reduction of TBDPS ether 14 required high-pressure conditions (entry 1), the reduction of primary alcohol 15 proceeded under atmospheric pressure (entries 2−5). Since the selectivity was not satisfactory, several catalysts were tested (entries 3−5). Among them, the best result was obtained with PtO2 (entry 4). Interestingly, hydrogenation with Pt/C gave a 1:1 mixture of the diastereomers. However, separation of isomers 17a and 17b was difficult. Since the ene carbamate unit within 14 and 15 can potentially be converted to an oxime group, we decided to employ Zn reduction of the oxime, which gave excellent results in our synthesis of FR901483 (2).4 As shown in Scheme 3, the Ugi 4CC reaction was carried out using the combination of ketone 5, amine 6, acid 7d, and isonitrile 189l to provide 19a. Among recently reported convertible isonitriles for the Ugi reaction,9 we selected isonitrile 18.9l As expected, methanolysis of the bromopyridine amide of 19a proceeded smoothly to afford 20 through the subsequent Dieckmann condensation of the corresponding methyl ester 19b. However, reduction of the enol moiety of 20 was difficult, in contrast to 12. Thus, we decided to convert 20 to the corresponding enol triflate 21. Upon treatment of 20 with excess KHMDS and sequential addition of triflic imidate, the desired enol triflate 21 was obtained. Next, reductive removal of the triflate group was achieved by treatment with Et3SiH in the presence of PdCl2(dppf) to afford 22 in good yield. After removal of the Cbz group of 22, treatment with excess hydroxylamine gave the desired oxime 23. Reduction of 23 with Zn in acetic acid in the presence of NH4Cl proceeded smoothly to give 24 as a single diastereomer. In order to clarify the stereoselectivity observed in this reaction, we calculated the most stable conformers of 25 and 23.10
our previous investigation, the Ugi 4CC reaction with a less bulky (2-aryl-1-vinyl)ethylamine component4a proceeded smoothly upon simple mixing of the four components in methanol. In the case of the bulkier amine component 6, the undesired Passerini reaction occurred predominantly. Since the reactivity of the bulky amine was not sufficient for imine formation, the reaction was examined under anhydrous conditions. After treatment of ketone 5 with amine 6 in the presence of 4 Å molecular sieves (MS4A) to form the imine intermediate, subsequent addition of carboxylic acids 7 and isonitrile 8 furnished the desired Ugi products 10a−d in high yields. Initially we envisioned a one-step conversion to the corresponding β-keto lactam from Ugi adducts 10b and 10c under basic conditions, but nucleophilic attack at the neopentyl imide carbonyl group proved difficult.7 Thus, methanolysis of the secondary amide bond and concomitant conversion to the dimethyl acetal were carried out under acidic conditions to provide the corresponding methyl ester 11 in 60% yield. Next, construction of the spirolactam ring was performed by means of a Dieckmann condensation. Upon treatment of methyl ester 11 3840
DOI: 10.1021/acs.orglett.7b01718 Org. Lett. 2017, 19, 3839−3842
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Organic Letters
proceeded through the chelating intermediate 27 generated after reduction of the oxime double bond. Since the Zn atom of 27 would be located at the less hindered β-side of the spirolactam, sequential protonation would occur from the αside to provide 24 with the desired stereochemistry. The interesting induction of this stereochemistry might arise from the constrained conformation of the side chain of the rigid spiro skeleton. Finally, dienamine formation was performed according to Snider’s method,2a as shown in Scheme 4. After incorporation
Scheme 3. Stereoselective Reduction of Oxime 23
Scheme 4. Completion of the Total Synthesis of TAN1251C (1c)
After detailed conformational analysis,10 the most stable forms of 25 and 23 were simulated as shown in Figure 2. Since
of a methoxycarbonyl group and a prenyl ether into 24, treatment with LiAlH4 allowed simultaneous reduction of the lactam and methyl carbamate, and concomitant deprotection of the TBDPS ether provided 28, which was fully identical with the synthetic intermediate in Snider’s total synthesis. Upon treatment of 28 with trifluoroacetic anhydride, dimethyl sulfoxide, and triethylamine, trifluoroacetamide formation and oxidation of the primary alcohol occurred smoothly. Construction of the 1,4-diazabicyclo[3.2.1]octane skeleton was achieved by treatment with K2CO3 through hydrolysis of the trifluoroacetoamide unit and aminal formation. Finally, removal of the ketal group by treatment with 1 M HCl afforded TAN1251C (1c). The spectroscopic data for synthetic 1c were in good agreement with those of natural product. In conclusion, we have accomplished a stereoselective total synthesis of TAN1251C (1c) from ketone 5 in 13 steps with an overall yield of 5.2%. Our synthesis features a Ugi 4CC reaction and a diastereoselective incorporation of amine functionality by Zn-mediated oxime reduction. Considering the applicability of the Ugi 4CC reaction for obtaining various amine and carboxylic acid derivatives, this protocol should provide ready access to a variety of spiro compounds. Further investigations are underway in our laboratory.
Figure 2. Lowest-energy conformers of 25 and 23.
deprotection of the benzyl ether proceeded before hydrogenolysis of the enamide group of 15, optimization was carried out with 25. Presumably because of the sp2 nature of the amide carbonyl group or steric hindrance of the spiro skeleton, the side chain of the lactam ring of 25 and 23 was fixed in the same conformation in both the presence and the absence of the bulky TBDPS group. As shown in Figure 2, the aromatic ring was oriented at the β-face, and the hydroxyl group and the TBDPS ether were fixed on the α-side of the lactam ring. This orientation should play a key role in the selective reduction. Our hypothesis to explain induction of the stereochemistry is illustrated in Figure 3. Hydrogenation of 25 would proceed through coordination of the Pt catalyst with the primary alcohol, such as 26. On the other hand, Zn reduction of 23
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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.7b01718. Experimental procedures and conformational analysis (PDF) 1 H and 13C NMR spectra (PDF)
Figure 3. Plausible reduction intermediates 26 and 27. 3841
DOI: 10.1021/acs.orglett.7b01718 Org. Lett. 2017, 19, 3839−3842
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AUTHOR INFORMATION
However, it turned out that nucleophilic attack at the neopentyl imide carbonyl group of 30 was difficult.
Corresponding Author
(8) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357. (9) (a) Ugi, I.; Rosendahl, F. K. Justus Liebigs Ann. Chem. 1963, 666, 65. (b) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. (c) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574. (d) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64, 336. (e) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411. (f) Maison, W.; Schlemminger, I.; Westerhoff, O.; Martens. Bioorg. Med. Chem. Lett. 1999, 9, 581. (g) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128, 11772. (h) Pirrung, M. C.; Ghorai, S.; Ibarra-Rivera, T. R. J. Org. Chem. 2009, 74, 4110. (i) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631. (j) Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2008, 73, 4198. (k) Neves Filho, R. A. W.; Stark, S.; Morejon, M. C.; Westermann, B.; Wessjohann, L. A. Tetrahedron Lett. 2012, 53, 5360. (l) van der Heijden, G.; Jong, J. A. W.; Ruijter, E.; Orru, R. V. A. Org. Lett. 2016, 18, 984. (10) Several low-energy conformers of 25 and 23, generated by MM calculations, were geometry-optimized at the B3LYP/6-31G* level of theory using Gaussian 09. For details, see the Supporting Information.
*E-mail:
[email protected]. ORCID
Toshiyuki Kan: 0000-0002-9709-6365 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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REFERENCES
This work was financially supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Japan Society for the Promotion of Science (JSPS) through KAKENHI Grant JP17H03973 and by MEXT through Grant-in-Aid for Scientific Research on Priority Areas JP16H01160 and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science).
(1) Shirafuji, H.; Tsubotani, S.; Ishimaru, T. PCT Int. Appl. WO 91/ 13887, 1991. (2) (a) Snider, B. B.; Lin, H. Org. Lett. 2000, 2, 643. (b) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534. (c) Mizutani, H.; Takayama, J.; Honda, T. Synlett 2005, 328. (3) (a) Ikeuchi, K.; Hayashi, M.; Yamamoto, T.; Inai, M.; Asakawa, T.; Hamashima, Y.; Kan, T. Eur. J. Org. Chem. 2013, 2013, 6789. (b) Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y.; Furuta, T.; Asakawa, T.; Inai, M.; Wakimoto, T.; Fukuyama, T.; Kan, T. Org. Lett. 2014, 16, 1646. (c) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett. 2004, 6, 2729. (4) (a) Ieda, S.; Masuda, A.; Kariyama, M.; Wakimoto, T.; Asakawa, T.; Fukuyama, T.; Kan, T. Heterocycles 2012, 86, 1071. (b) Ieda, S.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 2010, 51, 4027. (5) For reviews of multicomponent reactions with isonitriles, see: (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (c) Gokel, G.; Lüdke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.; Academic Press: New York, 1971; p 145. (d) Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (6) (a) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Heterocycles 2007, 73, 403. (b) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Synlett 2004, 41. (7) The Ugi adduct 10 derived from our isonitrile 8 is easily converted to an oxazolidinone ring compound under basic conditions. Furthermore, the oxazolidinone group has good leaving group ability, so we envisioned the single-step formation of unsaturated lactam 31 from Ugi adduct 10 under the same basic conditions:
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