Enantioselective and Divergent Syntheses of Alstoscholarisines A, E

Letter Cite This: Org. Lett. 2018, 20, 6202−6205

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Enantioselective and Divergent Syntheses of Alstoscholarisines A, E and Their Enantiomers Lu Hu,†,§ Qi Li,†,§ Licheng Yao,†,§ Bai Xu,‡ Xia Wang,† and Xuebin Liao*,† †

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School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Dis-eases, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China ‡ Institute of Genetics and Development Biology, Chinese Academy of Sciences, Beijing 100084, China S Supporting Information *

ABSTRACT: Concise, enantioselective, and divergent syntheses of alstoscholarisines A and E are presented in 8 and 9 steps, respectively; alstoscholarisine E has never been accessed before. A boron-mediated aldol reaction and Rh-catalyzed cycloisomerization were exploited to access stereoisomers 8 and 9 as key intermediates. The challenging sterically congested alstoscholarisine core was furnished by a reductive transannular cyclization in the final steps. This strategy was also used for the syntheses of enantiomers of alstoscholarisines A and E.

N

eural stem cell (NSC) therapy has opened up new potential for the treatment of neurological diseases, such as Parkinson’s disease, stroke, and Huntington’s disease.1 To date, intensive studies have been focused on this field. Despite these studies, neurological disorders are still difficult to treat. Recently, increasing attention has been focused on identifying new molecules that promote NSC proliferation and differentiation. These molecules could further assist our understanding of the modes of action for neurodegenerative diseases and could also potentially provide useful clinical applications.2 Alstoscholarisines A−E (Figure 1), isolated from Alstonia scholaris, contain five pentacyclic monoterpenoid indole alkaloids.3 Structurally, these alkaloids offer a synthetically challenging 6/5/6/6/6-fused pentacyclic core with five contiguous stereocenters. Biologically, all of them have significant ability to promote NSC proliferation, in which the most potent member (1) exhibited biological activity at a concentration of 0.1 μg/mL in a dosage-dependent manner.3 Because of their high therapeutic potential in neurodegener-

Figure 2. Retrosynthetic analysis of Alstoscholarisines A and E.

ative diseases, the total syntheses of alstoscholarisine alkaloids have attracted much attention from the synthetic chemistry community. In 2016, Bihelovic and Ferjancic reported a racemic synthesis of alstoscholarisine A (1), which was obtained in 13 steps.4 In the same year, Yang accomplished a 10-step enantioselective synthesis of 1.5 Very recently, Mason and Weinreb reported the total synthesis of racemic alstoscholarisines A−E.6 From our point of view, the development of a highly efficient and rapid synthetic strategy Received: August 21, 2018 Published: September 20, 2018

Figure 1. Alstoscholarisines alkaloids. © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b02679 Org. Lett. 2018, 20, 6202−6205

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Organic Letters

Scheme 1. (A) Syntheses of Key Intermediates 13 and 15; (B) Total Synthesis of Alstoscholarisine A; (C) Total Synthesis of Ea

Reagents and conditions: (a) TABF (1.2 equiv), THF, −78 °C, 30 min, then −20 °C, 4 h; (b) n-Bu2BOTf (2 equiv), DIPEA (2.5 equiv), MeCHO (20 equiv, 5.0 M in THF), DCM, −78−0 °C; (c) [RhCl(cod)]2 (5 mol %), [4-F(C6H4)]3P (0.6 equiv), DMF, 85 °C, 24 h; (d) KH (5.0 equiv), THF, −78 °C, 5 h; (e) NIS (1.2 equiv), AgNO3 (0.2 equiv), CH3CN, 80 °C, 1 h; (f) 10 (3.0 equiv), SPhos Pd G2 (5 mol %), K3PO4 (4.0 equiv), Toluene/H2O (5:1), 60 °C; (g) MeSO3H/DCM (1:10), rt, 30 min; (h) Pd(OH)2/C (1.0 equiv), MeOH/EtOAc (1:1), rt, overnight; (i) Bu3SnH (2.4 equiv), Tf2O (2.8 equiv), CH3CN, −40 °C to rt, 4 h; (j) (CH2O)aq, NaBH3CN (5.0 equiv), AcOH (6.5 equiv), MeOH, rt, 1 h; (k) MeSO3H/DCM (1:1), rt, 30 min. DIPEA = N,N-diisopropylethylamine, brsm = based on recovered starting material. Tf2O = Trifluoromethanesulfonic anhydride. a

to access these molecules is critical for exploring their structure−activity relationships (SAR) and assisting our understanding of their biological mechanism at the molecular level. Herein, we reported enantioselective and divergent syntheses of alstoscholarisines A (1) and E (5) in 8 and 9 steps, respectively. The total yield using this divergent route was 18.6%, including 9.7% overall yield for 1 and 8.9% overall yield for 5. To the best of our knowledge, this work represents the first reported enantioselective synthesis of alstoscholarisine E.

As outlined in Figure 2, a divergent strategy enabled rapid access to both alstoscholarisines A (1) and E (5), which are only distinguished from the configuration at C8. A key issue for the syntheses of 1 and 5 was to determine how to assemble the sterically congested ring C. In our analysis, the C ring could be potentially formed through a reductive transannular cyclization reaction from lactam 6 or 7. Although different types of transannular cyclization strategies had been utilized by several groups,6,7 the previous processes did not involve the formation of a sterically congested ring system that is less favorable for the transformation. Our sterically congested lactams 6 and 7 were seemingly more challenging for this strategy. If this 6203

DOI: 10.1021/acs.orglett.8b02679 Org. Lett. 2018, 20, 6202−6205

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of several bases (such as LiHMDS, NaOt-Bu, NaNH2). Notably, these steps could rapidly serve to construct three of the four contiguous stereocenters of alstoscholarisines A and E. With large quantities of 13 in hand, we decided to first complete the synthesis of (−)-alstoscholarisine A (1) (Scheme 1B). An initial attempt to prepare the Suzuki precursor 8 resulted in little success with Danishefsky’s protocol.11 No desired product was obtained, and only decomposition of lactam 13 was observed. The successful iodination was finally realized when 13 was subjected to NIS and AgNO3.12 Treatment of 8 with aqueous conditions and heating at 100 °C resulted in the removal of the Boc group (see Supporting Information (SI)), liberating 16, the stereochemistry of which was confirmed by X-ray crystallography. Next, we attempted to append the indole moiety onto the E ring. Based on the work of Buchwald and colleagues14 on Suzuki cross-coupling, extensive studies on Suzuki cross-coupling were explored and finally the desired assembly of 17 was achieved in high yield (see SI). Buchwald’s precatalyst SPhos palladacycle (SPhos Pd G2) was discovered as the most favorable catalyst for the Suzuki cross-coupling, which converted 8 into 17 in 97% yield. Notably, the boronic acid 10 performed better than its borate ester analogues. Further exposure of indole 17 to methanesulfonic acid resulted in global deprotection of N-Boc. Then, hydrogenation15 with Pearlman’s catalyst afforded compound 6 as a single diastereoisomer (76% yield from 17), setting the stage for N-1/C-2 cyclization. As mentioned before, the most challenging part for the total synthesis was to furnish the C ring. A transannular cyclization of 6 was originally designed to build up this ring system and provide the key intermediate 18, which bears the same skeleton as (−)-1 (Table 1). We speculated that this cyclization process might involve the conversion of amide 6 into a plausible iminium ion 21, which was subsequently trapped by the N-H of the indole moiety through nucleophilic attack. Unfortunately, in an extensive evaluation of the standard reductive methods, such as Schwartz’s reagent,16 DIABL-H,16d,17 and Red-Al,17,18 no satisfysing results were observed (Table 1, entries 1−4). The hurdle was also not overcome with the treatment of POCl3 and NaBH4.19 Inspired by Movassaghi’s transannular cyclization conditions,8 it was found that iminium ion 18 was formed in situ in the presence of trifluoromethanesulfonic anhydride and n-Bu3SnH. After trapping by the N-H of the indole moiety, the desired cyclization product 18 was formed in situ. Then, a one-pot reductive amination20 of 18 produced (−)-1 (76% yield from 6). Then, manipulation of lactam 15 through the same strategy elicited the synthesis of (−)-alstoscholarisine E (5), as shown in Scheme 1C. Notably, a deprotection and hydrogenation sequence provided lactam 7a and stereoisomer 7b in 65% and 30% yields, respectively. The stereochemistry of 7a was unambiguously determined by X-ray crystallography. We postulated steric hindrance between the methyl group at C8 in 22 and Pd(OH)2 enhanced the stereoselectivity (Scheme 2), which, in turn, also illuminated decreased stereoselectivity in the hydrogenation of 23 to give 7a. Then, similar steps were followed and the concise synthesis of (−)-5 was finally accomplished in 9 steps (Scheme 1C). Unsurprisingly, starting from ent-11, the same synthetic sequence in Scheme 1 could also be utilized to provide both (+)-1 and (+)-5 enantiomers. In summary, we have accomplished the enantioselective and divergent syntheses of alstoscholarisines A (1) and E (5) in a

Table 1. Screening Reaction Conditions of Transannular Cyclization

entry

conditions

yield

1 2 3 4 5 6

Cp2ZrCl2, LiAlH(Ot-Bu)3, THF, rt Cp2ZrHCl, THF, 70 °C Red-Al, THF, −78 °C, rt DIBAL-H, THF, −78 °C, 0 °C Tf2O, n-Bu3SnH, CH3CN, −40 °C, −23 °C, rt POCl3, NaBH4, Toluene, reflux; MeOH, rt

tracea 11%b tracea tracea 76%b −a

a

Yield was that of 18 and determined by LC-MS. bYield was that of isolated (−)-1. Cp = cyclopentadienyl.

Scheme 2. Stereochemical Model of Hydrogenation

pivotal cyclization proceeded smoothly, the core structure of 1 and 5 could be then formed. Suzuki−Miyaura cross-coupling and subsequent hydrogenation were anticipated to construct lactam 6 or 7 from alkenyl iodide 8 or 9, which could be prepared from the simple building blocks of lactam 11 and acetaldehyde. It was noteworthy that lactam 11 could be readily prepared relying on Hayashi’s elegant work on asymmetric conjugate addition of the alkyne moiety to the cyclic α, β-unsaturated lactam (Figure 2b).8 Thus, our syntheses feature the first application of this method in total synthesis. Analysis of the structures between 8 and 9 demonstrated that the key challenge to be overcome in this route is to build the three desired contiguous stereocenters. A stepwise approach via a diastereoselective aldol reaction and subsequent Rh-catalyzed cycloisomerization was designed at an early stage to generate two isomers of C8. Our synthesis started with the preparation of 13 and 15 using lactam 118 as the starting material (Scheme 1A). Treatment of 11 with TBAF afforded alkyne 12 in 97% yield. Boron-mediated aldol reaction9 followed by Trost’s cycloisomerization10 was carried out to provide alcohol 14 and 13 at a ratio of 2.4:1 (75% yield from 12). Preparation of the two isomers was critical for our divergent syntheses. To our delight, undesired 14 could be epimerized to key intermediate 15 in the presence of KH in 61% yield (70% brsm) after a screening 6204

DOI: 10.1021/acs.orglett.8b02679 Org. Lett. 2018, 20, 6202−6205

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(8) Dou, X.; Huang, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2016, 55, 1133. (9) (a) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 5, 559. (b) Ito, H.; Momose, T.; Konishi, M.; Yamada, E.; Watanabe, K.; Iguchi, K. Tetrahedron 2006, 62, 10425. (c) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321. (d) Van Horn, D. E.; Masamune, S. Tetrahedron Lett. 1979, 20, 2229. (e) Vintonyak, V. V.; Maier, M. E. Org. Lett. 2007, 9, 655. (10) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482. (b) Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K. J. Am. Chem. Soc. 2009, 131, 17087. (c) Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. W. J. Am. Chem. Soc. 2012, 134, 1930. (11) Chemler, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001, 3, 2949. (12) (a) Dharuman, S.; Vankar, Y. D. Org. Lett. 2014, 16, 1172. (b) Jana, S.; Rainier, J. D. Org. Lett. 2013, 15, 4426. (13) Wang, J.; Liang, Y.-L.; Qu, J. Chem. Commun. 2009, 5144. (14) (a) Düfert, M. A.; Billingsley, K. L.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 12877. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073. (15) (a) Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913. (b) Johnson, C. D.; Lane, S. J. Org. Chem. 1988, 53, 5130. (c) Kou, K. G. M.; Kulyk, S.; Marth, C. J.; Lee, J. C.; Doering, N. C.; Li, B. X.; Gallego, G. M.; Lebold, T. P.; Sarpong, R. J. Am. Chem. Soc. 2017, 139, 13882. (16) (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408. (b) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem. 1996, 61, 4115. (c) Shirokane, K.; Wada, T.; Yoritate, M.; Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2014, 53, 512. (d) Feldman, K. S.; Folda, T. M. J. Org. Chem. 2016, 81, 4566. (17) Forns, P.; Diez, A.; Rubiralta, M. Tetrahedron 1996, 52, 3563. (18) Cannon, J. G.; Walker, K. A.; Montanari, A.; Long, J. P.; Flynn, J. R. J. Med. Chem. 1990, 33, 2000. (19) (a) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157. (b) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1991, 462, 462. (20) Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2009, 48, 7616. (b) Lewin, G.; Bernadat, G.; Aubert, G.; Cresteil, T. Tetrahedron 2013, 69, 1622.

concise fashion. The synthetic sequence we developed is the first asymmetric total synthesis of 5. A Boron-mediated aldol reaction rendered two useful isomers, which could both be utilized for divergent synthesis. The reductive transannular cyclization was the pivotal maneuver for the construction of the 6/5/6/6/6-fused pentacyclic core. Further application of our strategy to access alstoscholarisines B, C, and D along with related biological research is underway and will be reported in due course.

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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.8b02679. Experimental procedures and analytical data for new compounds (PDF) Accession Codes

CCDC 1857109 and 1857116 contain 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xuebin Liao: 0000-0002-0290-894X Author Contributions §

L.H., Q.L., and L.Y. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua-Peking Centre for Life Sciences and the“1000 Talents Recruitment Program”.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02679 Org. Lett. 2018, 20, 6202−6205