FR901483: Synthetic Efficiency Remains a Challenge

Zhuwei Ruan; Cheng Li; Defeng Shen; Sha-Hua Huang; Ran Hong

doi:10.1055/s-0037-1611779

Synthesis, Table of Contents

Synthesis 2019; 51(11): 2237-2251
DOI: 10.1055/s-0037-1611779

review

FR901483: Synthetic Efficiency Remains a Challenge

Zhuwei Ruan

^aKey Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry (CAS), 345 Lingling Road, Shanghai 200032, P. R of China Email: rhong@sioc.ac.cn

^bUniversity of Chinese Academy of Sciences, 19A Yuqiang Road, Beijing 100049, P. R. of China

,

Cheng Li

^cWuXi AppTec, 666 Gaoxin Avenue, Wuhan 430075, P. R. of China

,

Defeng Shen

^aKey Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry (CAS), 345 Lingling Road, Shanghai 200032, P. R of China Email: rhong@sioc.ac.cn

^bUniversity of Chinese Academy of Sciences, 19A Yuqiang Road, Beijing 100049, P. R. of China

,

Sha-Hua Huang*

^aKey Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry (CAS), 345 Lingling Road, Shanghai 200032, P. R of China Email: rhong@sioc.ac.cn

^dSchool of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, P. R. of China Email: shahua@sit.edu.cn

,

Ran Hong*

^aKey Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry (CAS), 345 Lingling Road, Shanghai 200032, P. R of China Email: rhong@sioc.ac.cn

› Author Affiliations

Abstract

All articles of this category

Abstract

FR901483 is a unique alkaloid bearing an aza-tricyclic structure, a phosphate group, and a congested tertiary nitrogen center. This alkaloid was reported to be a potent immunosuppressant with antimetabolite ability. The unprecedented architecture has captured imagination of synthetic chemists since its isolation in 1996. To date, ten total or formal syntheses and several synthetic approaches to access the tricyclic core skeleton have been reported. In this review, we highlight the novel synthetic methods and strategies and discuss the synthetic challenge for meeting the criteria of drug development.

1 Introduction

2 Bioinspired Total Synthesis of FR901483

3 Non-bioinspired Approaches toward FR901483

4 Various Tactics for Accessing the Core Skeleton

5 Challenges for Efficiency

Key words

alkaloids - FR901483 - immunosuppressant - quaternary center - total synthesis

Full Text

References

References
1 Medicines in Development for Autoimmune Diseases 2016 Report. PhRMA; Washington D. C.: 2016

2a Marrack P, Kappler J, Kotzin BL. Nat. Med. 2001; 7: 899
2b Davidson A, Diamond B. N. Engl. J. Med. 2001; 345: 340
2c Goodnow CC. Cell 2007; 130: 25

For recent research process on the mechanism of autoimmune diseases, see:

2d Degn SE, van der Poel CE, Firl DJ, Ayoglu B, Al Qureshah FA, Bajic G, Mesin L, Reynaud CA, Weill JC, Utz PJ, Victora GD, Carroll MC. Cell 2017; 170: 913
2e Hou S, Fölsch H, Ke K, Cook-Mills J, Ramsey-Goldman R, Zhao M. Proc. Natl. Acad. Sci. U.S. A. 2017; 114: 13798
2f Westhorpe CL. V, Norman MU, Hall P, Snelgrove SL, Finsterbusch M, Li A.-Q, Lo C, Tan Z.-H, Li S.-H, Nilsson SK, Kitching AR, Hickey MJ. Nat. Commun. 2018; 9: 747
2g Bloch Y, Bouchareychas L, Merceron R, Skladanowska K, Van den Bossche L, Detry S, Govindarajan S, Elewaut D, Haerynck F, Dullaers M, Adamopoulos IE, Savvides SN. Immunity 2018; 48: 45

3a Suthanthiran M, Morris RE, Strom T. Am. J. Kidney Dis. 1996; 28: 159
3b Halloran PF. N. Engl. J. Med. 2004; 351: 2715

4a Cyclosporine A: Petcher TJ, Weber H.-P, Rüegger A. Helv. Chim. Acta 1976; 59: 1480
4b FK506: Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H. J. Antibiot. 1987; 40: 1249
4c Rapamycin: Sehgal SN, Baker H, Vézina C. J. Antibiot. 1975; 28: 727
4d Mycophenolate mofetil: Sievers M, Rossi SJ, Ghobrial RM, Arriola E, Nishimura P, Kawano M, Holt CD. Pharmacotherapy 1997; 17: 1178

5a Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. N. Engl. J. Med. 2003; 349: 931
5b Jardine AG, Fellström B, Logan JO, Cole E, Nyberg G, Grönhagen-Riska C, Madsen S, Neumayer HH, Maes B, Ambühl P, Olsson AG, Pedersen T, Holdaas H. Am. J. Kidney Dis. 2005; 46: 529

For reviews of immunosuppressants derived from natural products, see:

6a Mann J. Nat. Prod. Rep. 2001; 18: 417
6b Newman DJ, Cragg GM. J. Nat. Prod. 2012; 75: 311

For a review of natural products and their derivatives undergoing clinical trials in immunological diseases, see:

6c Butler M, Robertson AA. B, Cooper MA. Nat. Prod. Rep. 2014; 31: 1612

7 Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi HB, Doherty PC, Thomas PG, McGargill MA. Nat. Immunol. 2013; 14: 1266
8 For a review, see: Blagosklonny MV. Oncoimmunology 2013; 2: 26961 ; and references cited therein
9 Sakamoto K, Tsujii E, Abe F, Nakanishi T, Yamashitat M, Shigematsu N, Izumi S, Okuhara M. J. Antibiot. 1996; 49: 37
10 Snider BB, Lin H. J. Am. Chem. Soc. 1999; 121: 7778
11 Bonjoch J, Diaba F, Puigbó G, Solé D, Segarra V, Santamaría L, Beleta J, Ryder H, Palacios JM. Bioorg. Med. Chem. 1999; 7: 2891
12 For previous review on the total syntheses and construction of the core structure of FR90483, see: Bonjoch J, Diaba F. Synthesis of Immunosuppressant FR901483 and Biogenetically Related TAN1251 Alkaloids. In Studies in Natural Products Chemistry, Vol. 32, Part L. Atta-ur-Rahman, Elsevier; London: 2005. 3–60

Selected recent examples:

13a Schimid M, Trauner D. Angew. Chem. Int. Ed. 2017; 56: 12332
13b Newton CG, Tran DN, Wodrich MD, Cramer N. Angew. Chem. Int. Ed. 2017; 56: 13776

14 Snider BB, Lin H, Foxman BM. J. Org. Chem. 1998; 63: 6442
15 Shirafuji H, Tsubotani S, Ishimaru T, Harada S. WO 9113887, 1999
16 A focused review on the biomimetic approach toward FR901483, see: Liang H, Ciufolini MA. Biomimetic Synthesis of Alkaloids Derived from Tyrosine: The Case of FR-901483 and TAN-1251 Compounds. In Biomimetic Organic Synthesis, Vol. 1. Poupon E, Nay B. Wiley-VCH; Weinheim: 2011. Chap. 2, 61-89
17 Grundke G, Keese W, Rimpler M. Synthesis 1987; 1115
18 García-Urdiales E, Alfonso I, Gotor V. Chem. Rev. 2005; Enzymatic aldol-type desymmetrization for other substrates was known and applied in the syntheses of chiral intermediates as well as natural products, see: 105: 313
19 A recent review summarizes several oxidative cyclization strategies in biosynthesis, see: Tang M.-C, Zou Y, Watanabe K, Walsh CT, Tang Y. Chem. Rev. 2017; 117: 5226
20 Scheffler G, Seike H, Sorensen EJ. Angew. Chem. Int. Ed. 2000; 39: 4593

21a Braun NA, Ousmer M, Bray JD, Bouchu D, Peters K, Peters E.-M, Ciufolini MA. J. Org. Chem. 2000; 65: 4397

For pioneering work in oxidative dearomatization of phenolic amides with hypervalent-iodine oxidants, see:

21b Tamura Y, Yakura T, Haruta JI, Kita Y. J. Org. Chem. 1987; 52: 3927
21c Kita Y, Yakura T, Tohma H, Kikuchi K, Tamura Y. Tetrahedron Lett. 1989; 30: 1119
21d Kita Y, Tohma H, Kikuchi K, Inagaki M, Yakura T. J. Org. Chem. 1991; 56: 435

22a Ousmer M, Braun NA, Ciufolini MA. Org. Lett. 2001; 3: 765
22b Ousmer M, Braun NA, Bavoux C, Perrin M, Ciufolini MA. J. Am. Chem. Soc. 2001; 123: 7534

23 Maeng JH, Funk RL. Org. Lett. 2001; 3: 1125

24a Funk RL, Bolton GL. J. Am. Chem. Soc. 1988; 110: 1290
24b Funk RL, Bolton GL. Tetrahedron Lett. 1988; 29: 1111
24c Yost KJ, Funk RL. J. Org. Chem. 1996; 61: 2598

25 To deliver the requisite stereoisomer in the reduction step, here we coined as ‘stereoconfined reduction’ to differentiate from other terms like ‘stereoselective’ which does not refer a confined stereochemistry. See a recent discussion: Zheng K, Hong R. Nat. Prod. Rep. 2019; 36: in press; DOI: 10.1039/c8np00094h
26 Kan T, Fujimoto T, Ieda S, Asoh Y, Kitaoka H, Fukuyama T. Org. Lett. 2004; 6: 2729
27 Ieda S, Asoh Y, Fujimoto T, Kitaoka H, Kan T, Fukuyama T. Heterocycles 2009; 79: 721
28 Dahlén A, Hilmersson G. Eur. J. Inorg. Chem. 2004; 3393

29a Ieda S, Kan T, Fukuyama T. Tetrahedron Lett. 2010; 51: 4027
29b Ieda S, Masuda A, Kariyama M, Wakimoto T, Asakawa T, Fukuyama T, Kan T. Heterocycles 2012; 86: 1071

30a Lu JL, Brummond KM. Org. Lett. 2001; 3: 1347
30b Hong S, Brummond KM. J. Org. Chem. 2005; 70: 907

31a Overman LE, Ricca DJ. The Intramolecular Mannich and Related Reactions. In Comprehensive Organic Synthesis, Vol. 2. Trost BM, Fleming I. Pergamon; Oxford: 1991. Chap. 4.4, 1007
31b Overman LE. Acc. Chem. Res. 1992; 25: 352
31c Overman LE, Kakimoto M.-a, Okazaki ME, Meier GP. J. Am. Chem. Soc. 1983; 105: 6622

For a comprehensive review of this topic, see:

31d Overman LE, Humphreys PG, Wellmaker GS. The Aza-Cope/Mannich Reaction. In Organic Reactions, Vol. 75. Wiley; Hoboken: 2011. Chap. 4, 747-820

32 Carson CA, Kerr MA. Org. Lett. 2009; 11: 777

33a Cain CM, Cousins RP. C, Coumbarides G, Simpkins NS. Tetrahedron 1990; 46: 523

For a comprehensive review on asymmetric deprotonation with lithium amides including desymmetrization, see:

33b Simpkins NS, Weller MD. Org. React. 2012; 79: 1

34a Young IS, Williams JL, Kerr MA. Org. Lett. 2005; 7: 953
34b Carson CA, Kerr MA. J. Org. Chem. 2005; 70: 8242
34c Jackson SK, Karadeolian A, Driega AB, Kerr MA. J. Am. Chem. Soc. 2008; 130: 4196
34d Kang Y.-B, Tang Y, Sun X.-L. Org. Biomol. Chem. 2006; 4: 299

For a recent review, see:

34e Kerr MA. Isr. J. Chem. 2016; 56: 476

35a Krapcho AP, Glynn GA, Grenon BJ. Tetrahedron Lett. 1967; 8: 215

For a comprehensive review, see:

35b Krapcho AP, Ciganek E. Org. React. 2013; 81: 1

36 Ma A.-J, Tu Y.-Q, Peng J.-B, Dou Q.-Y, Hou S.-H, Zhang F.-M, Wang S.-H. Org. Lett. 2012; 14: 3604
37 Goddard-Borger ED, Stick RV. Org. Lett. 2007; 9: 3797
38 Trost BM, Scudder PH. J. Am. Chem. Soc. 1977; 99: 7601

For applications of semipinacol rearrangement in natural product total synthesis, see:

39a Wang B.-M, Tu Y.-Q. Acc. Chem. Res. 2011; 44: 1207
39b Song Z.-L, Fan C.-A, Tu Y.-Q. Chem. Rev. 2011; 111: 7523
39c Zhang X.-M, Tu Y.-Q, Zhang F.-M, Chen Z.-H, Wang S.-H. Chem. Soc. Rev. 2017; 46: 2272

40 Wrobleski A, Coombs TC, Huh CW, Li S.-W, Aubé J. Org. React. 2011; 78: 1

41a Huo H.-H, Zhang H.-K, Xia X.-E, Huang P.-Q. Org. Lett. 2012; 14: 4834
41b Huo H.-H, Xia X.-E, Zhang H.-K, Huang P.-Q. J. Org. Chem. 2013; 78: 455

For precious examples, see:

42a Fu R, Du Y, Li Z.-Y, Xu W.-X, Huang P.-Q. Tetrahedron 2009; 65: 9765
42b Fu R, Ye J.-L, Dai X.-J, Ruan Y.-P, Huang P.-Q. J. Org. Chem. 2010; 75: 4230
42c Yang R.-F, Huang P.-Q. Chem.–Eur. J. 2010; 16: 10319
42d Tuo S.-C, Ye J.-L, Wang A.-E, Huang S.-Y, Huang P.-Q. Org. Lett. 2011; 13: 5270
42e Zhang H.-K, Li X, Huang H, Huang P.-Q. Sci. China Chem. 2011; 54: 737

43a Xiao K.-J, Luo J.-M, Ye K.-Y, Wang Y, Huang P.-Q. Angew. Chem. Int. Ed. 2010; 49: 3037

For a recent elegant highlight on this topic, see:

43b Huang P.-Q. Acta Chim. Sin. 2018; 76: 357

44 Wardrop DJ, Zhang WM. Org. Lett. 2001; 3: 2053

45a Bonjoch J, Diaba F, Puigbo G, Peidro E, Sole D. Tetrahedron Lett. 2003; 44: 8387
45b Diaba F, Ricou E, Solé D, Teixidó E, Valls N, Bonjoch J. ARKIVOC 2007; (iv): 320

46 Asari A, Angelow P, Auty JM, Hayes CJ. Tetrahedron Lett. 2007; 48: 2631
47 Diaba F, Martínez-Laporta A, Bonjoch J. J. Org. Chem 2014; 79: 9365

48a Simila ST. M, Reichelt A, Martin SF. Tetrahedron Lett. 2006; 47: 2933
48b Simila ST. M, Martin SF. J. Org. Chem. 2007; 72: 5342

49 Seike H, Sorensen EJ. Synlett 2008; 695
50 Li B.-L, Gao W.-Y, Li H, Zhang S.-Q, Han X.-Q, Lu J, Liang R.-X, Hong X, Jia Y.-X. Chin. J. Chem. 2019; 37: 63

51a Yamazaki N, Suzuki H, Kibayashi C. J. Org. Chem. 1997; 62: 8280

For a discussion on the anti-Bredt rule in natural products, see:

51b Mak JY. W, Pouwer RH, Williams CM. Angew. Chem. Int. Ed. 2014; 53: 13664

52 Suzuki H, Yamazaki N, Kibayashi C. Tetrahedron Lett. 2001; 42: 3013
53 Kropf JE, Meigh IC, Bebbington MW. P, Weinreb SM. J. Org. Chem. 2006; 71: 2046
54 Kaden S, Reissig HU. Org. Lett. 2006; 8: 4763
55 Perreault S, Rovis T. Synthesis 2013; 45: 719

56a Friedman RK, Rovis T. J. Am. Chem. Soc. 2009; 131: 10775
56b Oinen ME, Yu RT, Rovis T. Org. Lett. 2009; 11: 4934
56c Dalton DM, Rovis T. Org. Lett. 2013; 15: 2346

For reviews, see:

56d Perreault S, Rovis T. Chem. Soc. Rev. 2009; 38: 3149
56e Keller-Friedman R, Oberg KM, Dalton DM, Rovis T. Pure Appl. Chem. 2010; 82: 1353

57 Efficiency in Natural Product Total Synthesis. Huang P.-Q, Yao Z.-J, Hsung RP. Wiley-VCH; Weinheim: 2018
58 Kuttruff CA, Eastgate MD, Baran PS. Nat. Prod. Rep. 2014; 31: 419
59 Bauer A, Brönstrup M. Nat. Prod. Rep. 2014; 31: 35

60a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
60b Over B, Wetzel S, Grütter C, Nakai Y, Renner S, Rauh D, Waldmann H. Nat. Chem. 2013; 5: 21
60c Lawson AD. G, MacCoss M, Heer JP. J. Med. Chem. 2018; 61: 4283

A very recent viewpoint on natural product-derived scaffolds in drug discovery, see:

60d Davison EK, Brimble MA. Curr. Opin. Chem. Biol. 2019; 52: 1

61 Other case likes peduncularine, receiving no medicinal studies even though the total synthesis has been accessed many times in the past two decades. See a recent review: Zhang Y, Tian X, Zhang Y, Huang S.-H, Hong R. Chin. J. Org. Chem. 2019; 39: 47

62a Stockdale TP, Williams CM. Chem. Soc. Rev. 2015; 44: 7737

A recent interesting case is worthy of mention, see:

62b Degorce SL, Bodnarchuk MS, Cumming IA, Scott JS. J. Med. Chem. 2018; 61: 8934

63a Schultz C. Bioorg. Med. Chem. 2003; 11: 885
63b Zawilska JB, Wojcieszak J, Olejniczak AB. Pharmacol. Rep. 2013; 65: 1