Unified Total Syntheses of Structurally Diverse Akuammiline Alkaloids

Letter pubs.acs.org/OrgLett

Unified Total Syntheses of Structurally Diverse Akuammiline Alkaloids Xiaoni Xie, Bei Wei, Guang Li, and Liansuo Zu* School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China S Supporting Information *

ABSTRACT: The unified total syntheses of structurally diverse akuammiline alkaloids deformylcorymine (1), strictamine (2), and calophyline A (3) are reported. The strategy mimics the biosynthesis in nature at a strategic level, which allows for structural diversification from a common synthetic precursor by late-stage ring migrations.

T

Structurally, according to the ring connectivity around N4, these natural products can be divided into three subclasses with N4−C2, N4−C3, and N4−C14 linkages (Figure 1). These N− C linkages along with varied oxidation states result in different polycyclic ring systems of the akuammiline natural products. Owing substantially to the efforts of leading chemists in this area, several members of this alkaloid family have been successfully synthesized, highlighting the power of a variety of novel bond-forming strategies.2 While synthetic chemists typically build individual linkages around N4, leading to the total synthesis of natural products with “single connectivity”, biosynthesis in nature provides an appealing alternative involving structural diversification from a common biogenetic precursor. In the context of akuammiline alkaloid biosynthesis, nature generates all of the ring connectivities (N4−C2, N4− C3, and N4−C14) from rhazimal (Figure 1).1d,3 For example, direct deformylation of rhazimal leads to strictamine (2) with a N4−C3 linkage; the N4 migrations from C3 to C2 and C14 in rhazimal generate the polycyclic ring system of deformylcorymine (1) and calophyline A (3), respectively. The beauty of such an approach endorsed by nature is remarkable. Inspired by the brevity of nature’s way of making this class of natural products, we envisioned that an advanced intermediate 4 could serve as a potential common synthetic precursor to several structurally diverse akuammiline alkaloids if the selective migrations of N4 from C14 to C2 and C3 could be realized (Figure 1). While this concept features totally different modes of ring migrations compared to nature’s biosynthesis, it mimicks the biosynthesis at the strategic level, namely, structural diversification from a common precursor by latestage ring migrations. Herein, we report the unified total

he akuammiline natural products are a family of structurally intricate and bioactive monoterpene indole alkaloids that have become a popular research area in recent years (Figure 1).1 The fascinating structural features of these natural products, including their rigid and cagelike framework, the bridged polycyclic ring system, and multiple stereogenic centers, have presented significant challenges to chemical synthesis and attracted the attention of synthetic chemists for many years.1

Figure 1. Representative akuammiline alkaloids: biogenetic precursor and proposed synthetic precursor. © 2017 American Chemical Society

Received: August 30, 2017 Published: September 27, 2017 5430

DOI: 10.1021/acs.orglett.7b02698 Org. Lett. 2017, 19, 5430−5433

Letter

Organic Letters syntheses of three structurally diverse akuammiline alkaloids deformylcorymine (1), strictamine (2), and calophyline A (3). We chose three akuammiline alkaloids (1−3) with different ring connectivities (N4−C2, N4−C3, and N4−C14) as our targets to demonstrate our strategy via bioinspired ring migrations. Our retrosynthetic analysis of natural alkaloids 1− 3 is depicted in Scheme 1. We envisioned accessing calophyline

Scheme 2. Synthesis of the Common Synthetic Precursor 4

Scheme 1. Retrosynthetic Analysis of Akuammiline Alkaloids 1−3

carbonylation reaction for the introduction of the signature C16 methyl ester in akuammiline alkaloid total synthesis. The common synthetic precursor 4 was then successfully prepared from 7 by deprotection of the methyl carbamate and two site oxidations using iodosobenzene and manganese oxide. Calophylina A (3) was isolated by Li, Zou, and co-workers in 2012.6 This is the only member of the alkaloid family that contains a unique N4−C14 linkage and an inner salt, which resulted in a distinct polycyclic ring system associated with this member of the family. Our group reported the first, and so far only, total synthesis of this natural product in 2016.4 We envisioned that the identification and utilization of 4 as the key intermediate would minimize several unnecessary functional group transformations in our previous synthetic route and thus realize an improved total synthesis of this challenging natural product. Structurally, calophyline A (3) has the same ring connectivity as that of 4 (N4−C14, Scheme 3). The remaining task was to

A (3) from 4 by a late-stage aldol-cyclization reaction with formaldehyde. Deformylcorymine (1) and strictamine (2) could be furnished from 5 and 6, respectively, which in turn could be generated from 4 by the selective ring migrations of N4 from C14 to C2 and C3. The common synthetic precursor 4 could be prepared by the oxidation-state adjustment of 7, which could be assembled from 8 by a highly efficient nickelmediated tandem Heck-carbonylation reaction. Finally, the synthesis of 8 could be traced back to 9, which we previously utilized for the first total synthesis of calophyline A.4 Our synthetic studies commenced with the preparation of the common synthetic precursor 4 (Scheme 2). From 9, vinyl triflate formation followed by palladium-catalyzed reduction furnished alkene 10, which was further attached to the vinyl iodide side chain to generate intermediate 8. At this stage, one of the key reactions in our synthesis would be the direct construction of the fused five-membered ring and installation of the required methyl ester in 7 by a tandem Heck-carbonylation reaction. Our initial attempts using palladium-based catalysts for this reaction proved fruitless under a variety of conditions. To our delight, the transformation of 8 to 7 could be achieved by the nickel-promoted Heck-carbonylation reaction developed by the group of Delgado.5a After further optimization of the reported reaction conditions, we were able to synthesize the polycycle 7 in 83% yield using MeCN/DMF (2:1) as the mixed solvents. This highly efficient process enabled the simultaneous generation of both the fused five-membered ring and a methyl ester at C16 without the prefunctionalization of alkene 8. To our knowledge, this is the first utilization of a tandem Heck-

Scheme 3. Total Synthesis of Calophyline A (3)

build the neopentyl quaternary stereocenter C16 and an additional oxygen-containing bridged [3.2.1] bicycle. Apparently, both could be achieved by a late stage aldol reaction with formaldehyde. However, the late stage decoration of C16 has been very challenging in akuammiline alkaloid synthesis due to the extremely congested architecture. Not surprisingly, the reaction of 4 with formaldehyde under a variety of conditions using different bases was unsuccessful. Gratifyingly, by using NaH as the base and DMF as the solvent, the formation of 11 was achieved in 34% yield involving A as the intermediate. 5431

DOI: 10.1021/acs.orglett.7b02698 Org. Lett. 2017, 19, 5430−5433

Letter

Organic Letters Finally, inner salt generation involving N-methylation and saponification delivered natural product calophyline A (3). Deformylcorymine (1)7 is structurally similar to vincorine (Figure 1) with an additional hydroxyl group at C3. While the total synthesis of vincorine8 has been elegantly accomplished by the groups of Qin, Ma, and MacMillan, the site-specific and stereoselective introduction of a hydroxyl group at C3 has been challenging. Most recently, the group of Li and Sun reported the creative total synthesis of another structurally related natural product corymine (Figure 1) in 21 steps from readily available starting materials.9 After the construction of the common synthetic precursor 4 and total synthesis of calophyline A (3), we next examined the selective ring migration of 4 (N4 from C14 to C2) to furnish the ring connectivity shown in deformylcorymine (1) (Scheme 4). We envisioned that this type of ring migration could be

the only epimer in 70% yield over two steps. Our synthesis represents the first total synthesis of this natural alkaloid. Strictamine (2) was first isolated in 196611 and had been a long-standing synthetic target for many years.12 The first total synthesis of strictamine was achieved by the groups of Garg and Zhu independently in 2016.12a,b Later, the groups of Fujii and Ohno, Gaich, and Snyder reported the formal total synthesis of this strained natural alkaloid.12c−f Except for Garg’s synthesis, all the other synthetic routes relied on a reductive Heck cyclization developed by Zhu to build the bridged 6-membered ring D (Scheme 5). However, the high strain associated with Scheme 5. Total Synthesis of Strictamine (2)

Scheme 4. Total Synthesis of Deformylcorymine (1) and the C3-Epimer of Demethyldeformylcorymine

the cagelike architecture of strictamine rendered the process very challenging (about 10% yield).12b We envisioned that our strategy could address this problem by first making the fused ring E in 4, which was then migrated to form the bridged ring D in strictamine. Then we turned to the construction of the ring connectivity of strictamine (2) by the ring migration of 4 (N4 from C14 to C3, Scheme 5). Our hypothesis was that 4 could be first reduced to 5 (Scheme 4) followed by the further reduction by SmI2 to form anionic intermediate F, which would facilitate the subsequent reductive cleavage of the N4−C2 bond and Ncyclization to C3 to furnish hemiketal 6. Thus, we carried out the reaction in the presence of large amounts of SmI2 (15.0 equiv); the direct transformation of 4 to 6 occurred smoothly in 68% yield. Thus, the successful ring migration of N4 from C14 to C3 built up the architecture of strictamine. Finally, reduction of the hemiketal by triethylsilane followed by the oxidation by iodosobenzene produced natural product strictamine (2). In summary, we have developed a unified strategy to structurally diverse akuammiline alkaloids by bioinspired ring migrations. The common synthetic precursor 4 served as a springboard to different ring connectivities of this class of natural products. Our approach strategically mimics biosynthesis in nature, which allows for structure diversification from a common precursor and the unified total synthesis of deformylcorymine (1), strictamine (2), and calophyline A (3).

achieved by the reductive cleavage of the N4−C14 bond followed by the subsequent N-cyclization to C2. For that purpose, we were inspired by the ability of SmI2 in reducing αamino carbonyls under mild reaction conditions.10 Indeed, the ring migration of 4 to 5 proceeded smoothly in the presence of SmI2 in 59% yield along with the 23% recovery of starting material 4. Thus, the core architecture of deformylcorymine was successfully assembled by the skeletal rearrangement of 4 involving N4 migration from C14 to C2. Mechanistically, 4 was presumably first reduced via single-electron transfer to form ketyl radical B, which was further reduced by SmI2 to furnish anionic intermediate C. Subsequent N4−C14 bond cleavage by elimination followed by N-cyclization to C2 facilitated the observed ring migration. Next, direct reduction of the ketone group in 5 with NaBH4 delivered 12, the C3-epimer of demethyldeformylcorymine. Attempts to reverse the diastereoselectivity of the reduction by using bulkier L-Selectride were unsuccessful. The dominant diastereoselectivity was presumably due to the directive reduction by the NH group or subtle steric effect. To our delight, methylation of 5 via reductive amination followed by the reduction of the ketone with LSelectride furnished natural product defromylcorymine (1) as 5432

DOI: 10.1021/acs.orglett.7b02698 Org. Lett. 2017, 19, 5430−5433

Letter

Organic Letters

■

Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126−9129. (c) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442−6445. (9) Zhang, B.; Wang, X.; Cheng, C.; Sun, D.; Li, C. Angew. Chem., Int. Ed. 2017, 56, 7484−7487. (10) For a review, see: Honda, T. Heterocycles 2011, 83, 1. (11) (a) Schnoes, H. K.; Biemann, K.; Mokrý, J.; Kompis, I.; Chatterjee, A.; Ganguli, G. J. Org. Chem. 1966, 31, 1641−1642. (b) Ahmad, Y.; Fatima, K.; Atta-ur-Rahman; Occolowitz, J. L.; Solheim, B. A.; Clardy, J.; Garnick, R. L.; Le Quesne, P. W. J. Am. Chem. Soc. 1977, 99, 1943−1946. (c) Zhang, L.; Zhang, C.; Zhang, D.; Wen, J.; Zhao, X.; Li, Y.; Gao, K. Tetrahedron Lett. 2014, 55, 1815− 1817. (12) For chemical synthesis of strictamine, see: (a) Moreno, J.; Picazo, E.; Morrill, L. A.; Smith, J. M.; Garg, N. K. J. Am. Chem. Soc. 2016, 138, 1162−1165. (b) Ren, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 3500−3503. (c) Nishiyama, D.; Ohara, A.; Chiba, H.; Kumagai, H.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2016, 18, 1670−1673. (d) Eckermann, R.; Breunig, M.; Gaich, T. Chem. Commun. 2016, 52, 11363−11365. (e) Eckermann, R.; Breunig, M.; Gaich, T. Chem. - Eur. J. 2017, 23, 3938−3949. (f) Smith, M. W.; Zhou, Z.; Gao, A. X.; Shimbayashi, T.; Snyder, S. A. Org. Lett. 2017, 19, 1004−1007. For previous synthetic studies of strictamine, see: (g) Dolby, L. J.; Esfandiari, Z. J. Org. Chem. 1972, 37, 43−46. (h) Dolby, L. J.; Nelson, S. J. J. Org. Chem. 1973, 38, 2882−2887. (i) Bennasar, M.-L.; Zulaica, E.; López, M.; Bosch, J. Tetrahedron Lett. 1988, 29, 2361−2364. (j) Bennasar, M. L.; Zulaica, E.; Ramírez, A.; Bosch, J. J. Org. Chem. 1996, 61, 1239−1251. (k) Koike, T.; Takayama, H.; Sakai, S.-I. Chem. Pharm. Bull. 1991, 39, 1677−1681. (l) Edwankar, R. V.; Edwankar, C. R.; Namjoshi, O. A.; Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2012, 75, 181−188. (m) Komatsu, Y.; Yoshida, K.; Ueda, H.; Tokuyama, H. Tetrahedron Lett. 2013, 54, 377−380. (n) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.; Matsuo, J.-I.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, 906−910. (o) Ren, W.; Tappin, N.; Wang, Q.; Zhu, J. Synlett 2013, 24, 1941−1944. (p) Andreansky, E. S.; Blakey, S. B. Org. Lett. 2016, 18, 6492−6495.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02698. Detailed experimental procedures, characterization data, and 1H and 13C spectra of all products (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Liansuo Zu: 0000-0001-7747-2979 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (21672123) for financial support. REFERENCES

(1) For selected accounts and reviews of akuammiline alkaloids, see: (a) Ramirez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 1891− 1915. (b) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447− 457. (c) Eckermann, R.; Gaich, T. Synthesis 2013, 45, 2813−2823. (d) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. Angew. Chem., Int. Ed. 2015, 54, 400−412. (e) Zi, W.; Zuo, Z.; Ma, D. Acc. Chem. Res. 2015, 48, 702−711. (f) Susick, R. B.; Morrill, L. A.; Picazo, E.; Garg, N. K. Synlett 2017, 28, 1−11. (2) For representative chemical synthesis of akuammiline alkaloids, see the following. Aspidophylline A: (a) Zu, L.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877−8879. (b) Li, Q.; Li, G.; Ma, S.; Feng, P.; Shi, Y. Org. Lett. 2013, 15, 2601−2603. (c) Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814−1817. (d) Ren, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 1818−1821. (e) Jiang, S.; Zeng, X.; Liang, X.; Lei, T.; Wei, K.; Yang, Y. Angew. Chem., Int. Ed. 2016, 55, 4044−4048. (f) Wang, T.; Duan, X.; Zhao, H.; Zhai, S.; Tao, C.; Wang, H.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2017, 19, 1650−1653. Scholarisine A: (g) Adams, G. L.; Carroll, P. J.; Smith, A. B., III. J. Am. Chem. Soc. 2012, 134, 4037−4040. (h) Adams, G. L.; Carroll, P. J.; Smith, A. B., III. J. Am. Chem. Soc. 2013, 135, 519− 528. (i) Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135, 12964−12967. Picrinine: (j) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 4504−4507. (k) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. J. Org. Chem. 2015, 80, 8954− 8967. Aspidodasycarpine and lonicerine: (l) Li, Y.; Zhu, S.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982−3985. Scholarisine K and alstolactine A: (m) Wang, D.; Hou, M.; Ji, Y.; Gao, S. Org. Lett. 2017, 19, 1922− 1925. (3) Hudson, B. M.; Harrison, J. G.; Tantillo, D. J. Tetrahedron Lett. 2013, 54, 2952−2955. (4) Li, G.; Xie, X.; Zu, L. Angew. Chem., Int. Ed. 2016, 55, 10483− 10486. (5) (a) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am. Chem. Soc. 1994, 116, 12133−12134. (b) For an elegant example of nickel-promoted Heck-type cyclization in total synthesis, see: Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017−11018. (6) Li, L.; Yang, T.; Liu, Y.; Liu, J.; Li, M.; Wang, Y.; Yang, S.; Zou, Q.; Li, G. Org. Lett. 2012, 14, 3450−3453. (7) Subhadhirasakul, S.; Takayama, H.; Miyabe, Y.; Aimi, N.; Ponglux, D.; Sakai, S. Chem. Pharm. Bull. 1994, 42, 2645−2646. (8) For total synthesis of vincorine, see: (a) Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013−6020. (b) Zi, W.; 5433

DOI: 10.1021/acs.orglett.7b02698 Org. Lett. 2017, 19, 5430−5433