Yuan Huang ·Fanglin Xue ·Hengmao Liu ·Fei Xue ·Xiao-Yu Liu ·Hao Song ·Yong Qin

Abstract An asymmetric total synthesis of (+)-21- epi-eburnamonine has been achieved.Key features of the synthesis include a visiblelight photocatalytic intra-/intramolecular radical cascade reaction to assemble the tetracyclic ABCD ring system, and a highly diastereoselective Johnson-Claisen rearrangement to establish the C20 all-carbon quaternary stereocenter.

Keywords Eburnamine-vincamine alkaloids·Photochemistry·Radical cascade reaction·Johnson-claisen rearrangement

1 Introduction

The eburnamine-vincamine indole alkaloids are a large group of natural products occurring in the plant familyApocynaceae(For selected reviews, see: [1— 8]).Featuring the fused-pentacyclic skeleton with multiple continuous stereocenters, this compound class has played an important role in natural product chemistry owing to their diverse structures (For selected reviews, see: [1— 8]) and medical importance in cell multiplication, cardiovascular system, and brain functions [9,10].During the past few decades, the continuing interests in this family regarding either the synthesis or the pharmacological activities have led to abundant research results.The prominent alkaloids (+)-vincamine (Fig.1,1), (-)-eburnamonine (2) and theircisD/E ring fusion congeners (Fig.1,3-5) exhibit signifi cant cerebral/peripheral vasorelaxation and antihypertensive bioactivities, especially 1 and 2 have been used in the treatment of hypertension [9— 12], making them among the most-studied synthetic targets in eburanamine-vincamine family (For selected examples of racemic total synthesis of 1, see: [13— 20]; For selected examples of asymmetric total synthesis of 1, see: [21— 32]; For selected examples of racemic total synthesis of 2, see: [33— 53]; For selected examples of asymmetric total synthesis of 2, see: [54— 62]).Quite a few synthetic non-natural analogues also exert bioactivities; for instance, (-)-20-epi-vincamine (6) and (-)-20-epi-eburnamonine (7) withtransD/E ring fusion show better peripheral vasodilation than (+)-vincamine (1) and (-)-eburnamonine (2) [63], and (-)-21-epi-vincamine (8) displays higher binding affinity to human serum albumin than 2 [63].However, compared to thecisseries (For selected examples of asymmetric total synthesis of 1, see: [21— 32]; For selected examples of asymmetric total synthesis of 2, see: [54— 62]), the asymmetric synthesis of the above molecules (i.e.,6— 8) withtransD/E ring fusion remains limited [63— 67].Among the numerous strategies developed to access eburanamine-vincamine alkaloids, stereoselective construction of the C20 and C21 stereocenters has always been the most difficult point.Particularly, the establishment of the C20/C21transrelative stereochemistry is challenging [67].

Fig.1 Structures of representative Eburnamine-Vincamine alkaloids and non-natural analogues

Attracted by the fascinating structures and prominent biological activities of eburnamine-vincamine alkaloids, our group has devoted to the development of efficient strategies towards natural products belonging to this category [32,68].In 2017, we reported three types of nitrogen-centered photocatalytic radical cascade reactions.This unifi ed methodology enabled collective synthesis of 33 monoterpenoid indole alkaloids belonging to four families [32].Among them, as outlined in Scheme 1 a, the intra-/intramolecular cascade reaction of propenal 9 under the irradiation of blue LEDs led to the formation of 10 as a pair of separable diastereomers (d.r.= 1:1.5 at C20), of which the A/B/C/D ring of the pentacyclic eburnane skeleton was assembled in one-pot, with the C21(R) stereochemistry established in full control [32].Tetracycle 10b with C20 (R) stereocenter was further elaborated into a series of eburnamine-vincamine family alkaloids, including (+)-eburanamenine (12), (+)-isoeburnamine (4), (-)-eburnamine (3) and (+)-eburnamonine (5).However, the above-mentioned cascade reaction of 9 suff ered from unsatisfactory stereocontrol at C20 (d.r.= 1:1.5), which prompted us to seek new synthetic approaches to eburnamine-vincamine alkaloids in a highly stereoselective fashion.Herein, we report our eff orts in this regard that led to a stereospecifi c total synthesis of (+)-epi-eburnamonine (20S, 21R) (8).

2 Results, Discussion and Conclusion

Outlined in Scheme 1 b is our synthetic plan of (+)-21-epieburnamonine (8).We envisioned that the known compound propynal 15 [32] would be an appropriate precursor for construction the A/B/C/D framework of eburnane skeleton through intra-intramolecular photocatalytic radical cascade reaction.The resultant tetracyclic product 14 bears a propenol functionality at C20, which allows us to forge the C20 all-carbon quaternary stereocenter of 13 via Johnson-Claisen rearrangement [62,69— 72].We supposed that the substrate-controlled stereoselectivity in the rearrangement process could guarantee the desired C20 (S) confi guration.Furthermore,13 could be readily transformed into the target (+)-21-epi-eburnamonine via intramolecular amidation [67] and subsequent reduction of the vinyl group.

Scheme 1 a Synthesis of Eburnamonine-vacamine alkaloids via intra-/intramolecular photocatalytic radical cascade reaction developed by our group; b Synthetic plan of (+)-21- epi-eburnamonine

Our synthesis began with preparation of the radical precursor 15 for the devised intra-intramolecular photocatalytic cascade reaction (Scheme 2).Following our previously reported protocols [32], amide 15 was readily obtained from aldehyde ester 16 over five steps on a decagram scale.Upon exposure to the conditions of Ir(dtbbpy)(ppy)2PF6/KHCO3/THF with blue LED irradiation, the intra-intramolecular photocatalytic cascade reaction of 15 proceeded smoothly, delivering a pair of inseparable 2:1 mixtures ofE/Zisomers 17 in 57—65% yield.It is noteworthy that the above conversion allowed the assembly of the A/B/C/D ring system of eburnane-type scaff old, with stereoselectively construction of C21(R) stereochemistry.Subsequently, reduction of propynal 17 with NaBH 4 aff orded the corresponding allylic alcohol 14 as a pair of inseparable geometrical isomers in 63% yield.With 14 available, the vital Johnson-Claisen rearrangement was investigated.Initially,14 was subjected to CH3C(OMe)3/EtCOOH/1,2-dichlorobenzene at 135 °C.However, the reaction gave a complex mixture, and the desired product was not observed.Attempts to improve the reaction by screening different acids, solvents or temperatures were also unsuccessful.Fortunately, after changing the trialkyl orthoacetate from CH3CH(OMe)3to CH3CH(OEt)3, the expected rearrangement took place in the presence of EtCOOH in 1,2-dichlorobenzene at 135 °C to give ethyl ester 20 in 52% yield as a single isomer, thereby constructing the C20 all-carbon quaternary stereocenter.Due to the fact that the inseparable mixture of 14 was completely consumed and only one rearrangement product was observed, we supposed that both geometrical isomers of 14 yielded the same compound 20.The high stereoselectivity of the above-mentioned reaction could be rationalized by the proposed transitionstate T-18 and T-19.Presumably, the carbon—carbon bond formation of the rearrangement via T-18 was hampered by the severe steric repulsion between the ethoxy group and the hydrogen at C2 for both geometrical isomers of 14, thus the reaction would preferentially occur through transition state T-19, favoring the formation of 20 [12].

Next, we turned our attention to the last stage of the synthesis of (+)-21-epi-eburnamonine (9).To this end, conversion of indoline 20 to indole 13 through a deprotection/oxidation sequence was implemented first.Specifi -cally, upon treatment of 20 with Mg/MeOH followed by addition of CH3ONa, theN-Ts group was removed along with the transesterifi cation of the methyl ester group, delivering 21 in 74% yield.Subsequent oxidation of indoline 21 with (PhSeO)2O led to the formation of indole 13 in 80% yield.Furthermore, by employing the reductive conditions of [Rh(H)CO](PPh3)3/PhSiH3, amide 13 was smoothly converted into amine 22.Finally, cyclization of the E ring was realized by subjecting 22 to K2CO3/MeOH under reflux.The delivered pentacycle 23 was then subjected to catalytic hydrogenation in which the vinyl group was reduced to aff ord the target molecule in 89% yield.Notably, the NMR data of 8 had identical NMR data to (-)-20-epi-eburnamonine reported in the literature [66] but opposite optical rotation, which again confi rmed the stereochemistry of C20 established in the Johnson-Claisen rearrangement.

Scheme 2 Total synthesis of (+)-21- epi-eburnamonine (8)

In summary, we have disclosed an efficient approach to the asymmetric total synthesis of (+)-21-epi-eburnamonine withtransD/E ring fusion.From a strategical perspective, the synthesis features a photocatalytic intra-intramolecular radical cascade reaction to assemble the A/B/C/D ring system and a highly diastereoselecive Johnson-Claisen rearrangement to forge the C20 all-carbon quaternary stereocenter.This synthetic strategy provided alternative access towards more derivatives of eburnamine-vincamine alkaloids.

AcknowledgementsWe are grateful for the financial surpport from National Natural Science Foundation of China (21921002 and 21991114) and National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2018ZX09711003-015 and 2018ZX09711001-005-004).

Compliance with Ethical Standards

Conflict of interestThe authors declare no conflict of interest.

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creat iveco mmons.org/licen ses/by/4.0/.

References

1.J.E.Saxton, in The Eburnamine-Vincamine Group, ed.by A.Weiss-berger, E.Taylor.Indoles part IV: The Monoterpene Indole Alkaloids, (Wiley, New York, 1983), p.439—465

2.Atta-ur-Rahman, M.Sultana, Heterocycles 22, 841—858 (1984)

3.M.Lounasmaa, A.Tolvanen, inG.A.Cordell.vol 42.ed.by T.Alkaloids (Academic Press, New York, 1992), pp.1—116

4.J.E.Saxton, Nat.Prod.Rep.11, 493—531 (1994)

5.J.E.Saxton, Nat.Prod.Rep.13, 327—363 (1996)

6.J.E.Saxton, Nat.Prod.Rep.14, 559—590 (1997)

7.J.Leonard, Nat.Prod.Rep.16, 319—338 (1999)

8.M.H.Zenk, M.Juenger, Phytochemistry 68, 2757—2772 (2007)

9.á.Vas, B.Gulyás, Med.Res.Rev.25 , 737—757 (2005)

10.A.Nemes, inAnalogue-Based Drug Discovery II.ed.by J.Fischer, C.R.Ganellin (Wiley, Weinheim, 2010), pp.189—215

11.H.R.Olpe, G.Barrionueno, G.Lynch, Life Sci.31, 1947—1953 (1982)

12.A.H.A.Fayed, Biol.Trace Elem.Res.136, 314—319 (2010)

13.M.E.Kuehne, J.Am.Chem.Soc.86, 2946 (1964)

14.K.H.Gibson, J.E.Saxton, J.Chem.Soc.D 799, 1490 (1969)

15.J.L.Herrmann, R.J.Cregge, J.E.Richman, C.L.Semmelhack, R.H.Schlessinger, J.Am.Chem.Soc.96, 3702—3703 (1974)

16.K.H.Gibson, J.E.Saxton, Tetrahedron 33, 833—836 (1977)

17.J.L.Herrmann, R.J.Cregge, J.E.Richman, G.R.Kieczykowski, S.N.Normandin, M.L.Quesada, C.L.Semmelhack, A.J.Poss, R.H.Schlessinger, J.Am.Chem.Soc.101, 1540—1544 (1979)

18.D.Genin, R.Z.Andriamialisoa, N.Langlois, Y.Langlois, J.Org.Chem.52, 353—356 (1987)

19.Z.Koblicová, J.Holubek, J.Trojánek, Collect.Czech.Chem.Commun.53, 2722—2730 (1988)

20.M.Lounasmaa, A.Tolvanen, J.Org.Chem.55, 4044—4047 (1990)

21.C.Szántay, L.Szabó, G.Kalaus, Tetrahedron Lett.14, 191—192 (1973)

22.P.Pf?ffli, W.Oppolzer, R.Wenger, H.Hauth, Helv.Chim.Acta.58, 1131—1145 (1975)

23.W.Oppolzer, H.Hauth, P.Pf?ffli, R.Wenger, Helv.Chim.Acta.60, 1801—1810 (1977)

24.C.Szántay, L.Szabó, G.Kalaus, Tetrahedron 33, 1803—1808 (1977)

25.G.Rossey, A.Wick, E.Wenkert, J.Org.Chem.47, 4745—4749 (1982)

26.L.Szabó, G.Kalaus, C.Szántay, Arch.Pharm.316, 629—638 (1983)

27.L.Szabó, J.Sápi, G.Kalaus, G.Argay, A.Kálmán, E.Baitz-Gács, J.Tamás, C.Szántay, Tetrahedron 39, 3737—3747 (1983)

28.K.Hakam, M.Thielmann, T.Thielmann, E.Winterfeldt, Tetrahedron 43, 2035—2044 (1987)

29.P.Gmeiner, P.L.Feldman, M.Y.Chu-Moyer, H.Rapoport, J.Org.Chem.55, 3068—3074 (1990)

30.D.Desma?le, K.Mekouar, J.d’Angelo, J.Org.Chem.62, 3890—3901 (1997)

31.T.Nagy, L.Szabó, G.Kalaus, C.Szántay, Heterocycles 45, 2007—2013 (1997)

32.X.Wang, D.Xia, W.Qin, R.Zhou, X.Zhou, Q.Zhou, W.Liu, X.Dai, H.Wang, S.Wang, L.Tan, D.Zhang, H.Song, X.Y.Liu, Y.Qin, Chem 2, 803—816 (2017)

33.M.F.Bartlett, W.I.Taylor, J.Am.Chem.Soc.82, 5941—5946 (1960)

34.E.Wenkert, B.Wickberg, J.Am.Chem.Soc.87, 1580—1589 (1965)

35.J.L.Hermann, G.R.Kieczykowski, S.E.Normandin, R.H.Schlessinger, Tetrahedron Lett.17, 801—804 (1976)

36.F.Klatte, U.Rosentreter, E.Winterfeldt, Angew.Chem.Int.Ed.Engl.16, 878—879 (1977); Angew.Chem.89, 916—917 (1977)

37.E.Wenkert, T.Hudlickv, H.D.H.Showalter, J.Am.Chem.Soc.100, 4893—4894 (1978)

38.A.Buzas, J.P.Jacquet, G.Lavielle, J.Org.Chem.45, 32—34 (1980)

39.E.Wenkert, T.D.J.Halls, L.D.Kwart, G.Magnusson, H.D.H.Showalter, Tetrahedron 37, 4017—4025 (1981)

40.K.Irie, Y.Ban, Heterocycles 15, 201—206 (1981)

41.T.Imanishi, K.Miyashita, A.Nakai, M.Inoue, M.Hanaoka, Chem.Pharm.Bull.30, 1521—1524 (1982)

42.G.Massiot, F.S.Oliveira, J.Lévy, Tetrahedron Lett.23, 177—180 (1982)

43.T.Imanishi, K.Miyashita, A.Nakai, M.Inoue, M.Hanaoka, Chem.Pharm.Bull.31, 1191—1198 (1983)

44.G.Kalaus, N.Malkieh, I.Katona, M.Kajtár-Peredy, T.Koritsánszky, A.Kálmán, L.Szabó, C.Szántay, J.Org.Chem.50, 3760—3767 (1985)

45.P.Magnus, P.Pappalardo, I.Southwell, Tetrahedron 42, 3215—3222 (1986)

46.E.Wenkert, T.Hudlicky, J.Org.Chem.53, 1953—1957 (1988)

47.E.Karvinen, M.Lounasmaa, Heterocycles 34, 1773—1782 (1992)

48.M.D.Kaufman, P.A.Grieco, J.Org.Chem.59, 7197—7198 (1994)

49.A.D.S.Goes, C.Ferroud, J.Santamaria, Tetrahedron Lett.36, 2235—2238 (1995)

50.P.A.Grieco, M.D.Kaufman, J.Org.Chem.64, 7586—7593 (1999)

51.A.K.Ghosh, R.Kawahama, J.Org.Chem.65, 5433—5435 (2000)

52.R.Lavilla, O.Coll, J.Bosch, M.Orozco, F.J.Luque, Eur.J.Org.Chem.2001, 3719—3729 (2001)

53.T.L.Ho, C.K.Chen, Helv.Chim.Acta.88, 2764—2770 (2005)

54.L.Novák, J.Rohály, C.Szántay, L.Czibula, Heterocycles 6, 1149—1156 (1977)

55.P.Magnus, P.Brown, J.Chem.Soc.Chem.Commun.4, 184—186 (1985)

56.M.Node, H.Nagasawa, K.Fuji, J.Am.Chem.Soc.109, 7901—7903 (1987)

57.M.Node, H.Nagasawa, K.Fuji, J.Org.Chem.55, 517—521 (1990)

58.A.G.Schultz, L.Pettus, J.Org.Chem.62, 6855—6861 (1997)

59.D.S.Liyanage, C.S.Jungong, A.V.Novikov, Tetrahedron Lett.56, 2269—2271 (2015)

60.K.R.Prasad, J.E.Nidhiry, Synlett 23, 1477—1480 (2012)

61.J.E.Nidhiry, K.R.Prasad, Tetrahedron 69, 5525—5536 (2013)

62.G.Pandey, A.Mishra, J.Khamrai, Org.Lett.19, 3267—3270 (2017)

63.L.Czibula, A.Nemes, G.Visky, M.Farkas, Z.Szombathelyi, E.Kárpáti, P.Sohár, M.Kessel, J.Kreidl, Liebigs Ann.Chem.3, 221—229 (1993)

64.A.G.H.Wee, Q.Yu, Tetrahedron Lett.41, 587—590 (2000)

65.A.G.H.Wee, Q.Yu, J.Org.Chem.66, 8935—8943 (2001)

66.Y.Yasui, H.Takeda, Y.Takemoto, Chem.Pharm.Bull.56, 1567—1574 (2008)

67.W.Zhang, X.T.Chen, Y.An, J.Q.Wang, C.L.Zhuang, P.Tang, F.E.Chen, Chem.Eur.J.26, 10439—10443 (2020)

68.Q.L.Zhou, X.Dai, H.Song, H.He, X.B.Wang, X.-Y.Liu, Y.Qin, Chem.Commun.54, 9510—9512 (2018)

69.R.A.Fernandes, A.K.Chowdhury, P.Kattanguru, Eur.J.Org.Chem.14, 2833—2871 (2014)

70.P.G.Baraldi, A.Barco, S.Benetti, G.P.Pollini, E.Polo, D.Simoni, J.Org.Chem.50, 23—29 (1985)

71.F.W.Ng, H.Lin, S.J.Danishefsky, J.Am.Chem.Soc.124, 9812—9824 (2002)

72.C.Ozturk, V.Aviyente, J.Org.Chem.70, 7028—7034 (2005)