Synthesis of (+)-Dehydrobulbispermine Analogs

Abstract

An eight-step synthesis of a (+)-dehydrobulbispermin analog was developed. Starting from optically active 4-alkylidene-tetrahydroisoquinoline, the Eschenmoser–Claisen rearrangement enabled the introduction of the central quaternary center with complete remote stereocontrol. Subsequent iodolactonization, N-BOC group cleavage, and D-ring closure delivered the key quaternary stereotriads as present in (+)-bulbispermine and (+)-hamayne. Then, methyl lithium addition and protection of the resulting OH group allowed completion of the carbon skeleton. OTBS group removal and TEMPO oxidation afforded a ketoaldehyde, which finally underwent an intramolecular aldol condensation, building up the C ring and the α-crinan-11-ol tetracycle derivatives, which will be used as key intermediates in the bulbispermine and 11-hydroxyvittatine-type α-crinane alkaloid total syntheses.

Keywords

4-Alkylidene-tetrahydroisoquinoline - Eschenmoser–Claisen rearrangement - Iodolactonization - Quaternary stereotriad - Methyl lithium addition - Intramolecular aldol condensation - α-Crinan-11-ol derivatives

Publication History

Received: 23 December 2025

Accepted after revision: 14 January 2026

Accepted Manuscript online:
15 January 2026

Article published online:
26 January 2026

• References

• 1 Mabberly DJ. The Plant Book. Cambridge University Press; 1990
• 2a Jin Z, Yao G. Nat Prod Rep 2019; 36: 1462
• 2b Singh A, Desgagne-Penix I. Plant Sci Today 2014; 1: 114
• 3a Jin Z. Nat Prod Rep 2013; 30: 349
• 3b Nair JJ, Bastida J, Viladomat F, van Staden J. Nat Prod Commun 2012; 140: 405
• 3c McNulty J, Nair JJ, Codina C. et al. Phytochemistry 2007; 68: 1068
• 3d McNulty J, Nair JJ, Bastida J, Pandey J, Griffin C. Nat Prod Commun 2009; 4: 483
• 3e Luchetti G, Johnston R, Mathieu V. et al. ChemMedChem 2012; 7: 815
• 3f Havelek R, Seifrtova M, Kravolec K. et al. Phytomedicine 2014; 21: 479
• 3g Khumkhrong K, Piboonprai K, Chaichompoo W. et al. Biomolecules 2019; 9: 494
• 3h Naidoo D, Roy A, Slavetínská LP, Chukwujekwu JC, Gupta S, van Staden J. J Ethnopharmacol 2020; 248: 112305
• 3i Jayawardena TU, Merindol N, Liyanage NS, Desgagné-Penix I. Nat Prod Rep 2024; 41: 721

(+)-α-Crinane [4aS-(4aα,5β,11bβ)]:
• 4a Fales HM, Wildman WC. J Org Chem 1961; 26: 1617
• 4b Fales HM, Wildman WC. J Org Chem 1961; 26: 881
• 4c Fales HM, Wildman WC. J Am Chem Soc 1958; 80: 4395

(−)-β-Crinane [4aR-(4aα,5β,11bβ)]:
• 4d Jeffs PW, Warren FL, Wright WG. J Chem Soc 1960; 1090
• 4e Wildman WC. J Am Chem Soc 1958; 80: 2567
• 4f Wildman WC. J Am Chem Soc 1956; 78: 4180

Syntheses of (+) and (−)-Crinane
• 4g Das MK, Yadav A, Majumder S, Mondal A, Bisai A. Tetrahedron 2021; 82: 131928
• 5a Chaichompoo W, Rojsitthisak P, Supaweera N. et al. Phytochem 2025; 233: 114383 (IIIb)
• 5b Chaichompoo W, Rojsitthisak P. et al. Phytochem 2023; 205: 113473 (IIa or, preferentially IVa)
• 5c Kempthorne CJ, Borra S, Kumar M, Dokuburra CB, Liscombe D, McNulty J. Nat Prod Res 2023; 37: 4232 (IIb)
• 5d Sancha SAR, Gomes AV, Loureiro JB, Saravia L, Ferreira MJU. Molecules 2022; 27: 05759 (IIb)
• 5e Akinyele ST, Elusijan CA, Omisore NO, Adewunmi CO. J Ethnopharmacol 2022; 296: 115359 (Ib)
• 5f Steyn KH, de Villiers A, van Otterlo WAL, Green IR. South Afr J Bot 2022; 46: 503 (Ia)
• 5g Chaichompoo W, Chokchaisiri R, V A Pabuprapap W, Yompakdee C, Suksamrarn A. Phytochem Lett 2020; 37: 101 (IIc or, preferentially IVc)
• 5h Lan P, Banwell MG, Willis AC. J Org Chem 2019; 84: 3431 (Ia, IIa, IIIa, Va/b)
• 5i Khumkhrong P, Piboonprai K, Chaichompoo W. et al. Biomolecules 2019; 9: 494 (Ib)
• 5j Borra S, Lapinskaite R, Kempthorne C, Liscombe D, McNulty J, Hudlicky T. J Nat Prod 2018; 81: 1451 (IIb)
• 5k Lubbe A, Gude H, Verpoorte R, Choi YH. Phytochem 2013; 88: 43 (IIb)
• 5l Luchetti G, Johnston R, Mathieu V. et al. ChemMedChem 2012; 7: 815 (Ia)
• 5m Tam NT, Chang J, Jung E-J, Cho C-G. J Org Chem 2008; 73: 6258 (Ib, IIIb)
• 5n Bohno M, Sugie K, Imase H, Yusof YB, Oishi T, Chida N. Tetrahedron 2007; 63: 6977 (IIb)
• 5o Forgo P, Hohmann J. J Nat Prod 2005; 68: 1588 (IIa)
• 5p Abdel-Halim OB, Morikawa T, Ando S, Matsuda H, Yoshikawa MJ. Nat Prod 2004; 67: 1119 (Ia, Ic)
• 5q Hohmann J, Forgo P, Molnár J. et al. Planta Med 2002; 68: 454 (IIb)
• 5r Pham LH, Gründemann E, Döpke W. Pharmazie 1997; 52: 160 (IIa)
• 5s Viladomat F, Codina JB, Campbell WE, Mathe S. Phytochem 1994; 35: 809 (Ia, Ib, Ic)
• 5t Baudouin G, Tillequin F, Koch M. Heterocycles 1994; 38: 965 (IIb, albiflomanthine: 4β-OH-IIb)
• 5u Mügge C, Schablinski B, Obst K, Döpke W. Pharmazie 1994; 49: 644 (IIa)
• 5v Likhitwitayawuid K, Angerhofer CK, Chai H, Pezzuto JM, Cordell GA. J Nat Prod 1993; 56: 1331 (Ib)
• 5w Pabuccuoglu V, Richomme P, Götzler T, Kivcak B, Freyer AJ, Shamma MJ. Nat Prod 1989; 52: 785 (IIa, IIb, IVb)
• 5x Evidente A. J Nat Prod 1986; 49: 168 (IIa)
• 5y Kobayashi S, Tokumoto T, Kihara M, Imakura Y, Shingu T, Taira Z. Chem Pharm Bull 1984; 32: 3015 (Ia, Ib, Ic)
• 5z Ali AA, Ramadan MA, Frahm AW. Planta Med 1984; 60: 424 (Ia)
• 5aa Ochi M, Otsuki H, Nagao K. Bull Chem Soc Jpn 1976; 49: 3363 (Ia, Ib)
• 6 Remarks: (1) (+)-bulbispermine (3R, 11R) and (+)-hamayne (3R, 11S) represent C11 diastereomers. However, the naming of these compounds (and derivatives) within literature and databases partly remains inconsistent (“hamayne” is used for “bulbispermine”). (2) within some publications, R/S determination (C-11) and drawing are inconsistent, especially in connection with the data of compound IVa–c
• 7a Endo Y, Suigura Y, Funasaki M, Kagechika H, Ishibashi M. J Nat Med 2019; 73: 648 (VIc)
• 7b Verma P, Chandra A, Pandey G. J Org Chem 2018; 83: 9968 (VIb)
• 7c Gao Y-R, Wang D-Y, Wang Y-Q. Org Lett 2017; 19: 3516 (VIa)
• 7d Guerrieri CG, Pigni NB, de Andrade JP. et al. Arab J Chem 2016; 9: 688 (VIf)
• 7e Chen C-K, Lin F-H, Tseng L-H, Jiang C-L, Lee S-S. J Nat Prod 2011; 74: 411 (VIa, VId. TFA)
• 7f Nair JJ, Machocho AK, Campbell WE. et al. Phytochem 2000; 54: 945 (VIa)
• 7g Pearson WH, Lovering FE. J Org Chem 1998; 63: 3607 (VIb)
• 7h Pham LH, Döpke W, Wagner J, Mügge C. Phytochem 1998; 48: 371 (VIa)
• 7i Viladomat F, Almanza GR, Codina C, Bastida J, Campbell WE, Mathee S. Phytochem 1996; 43: 1379 (VIf)
• 7j Pearson WH, Lovering FE. J Am Chem Soc 1995; 117: 12336 (VIb)
• 7k Ref. 5s (VIe)

Related alkaloids displaying a stereotriad 4a, 10b, 1 are less well known:
• 7l Whitlock Jr HW, Smith GL. J Am Chem Soc 1967; 89: 3600
• 7m Fales HM, Wildman WC. J Org Chem 1961; 26: 881
• 7n Fales HM, Wildman WC. J Org Chem 1961; 26: 181
• 7o Jeffs PW, Warren FL, Wright WG. J Chem Soc 1960; 1097 So far, the data basis connected with these compounds is incomplete

Synthesis of (+)-Amabiline (ent-VIb):
• 8a Findlay AD, Banwell MG. Org Lett 2009; 11: 3160
• 8b Ref. 7h (ent-VIb)
• 9a Cahlíková L, Kawano I, Rezácová M, Blunden G, Hulcová D, Havelek R. Phytochem Rev 2021; 20: 303
• 9b Nair JJ, van Staden J. Fitoterapia 2019; 134: 305
• 9c Cimmino A, Masi M, Evidente M, Superchi S, Evidente A. Chirality 2017; 29: 486
• 9d Henry S, Kidner R. et al. Eur J Med Chem 2016; 120: 313 For reduced bioactivities of the 1,2 dihydroxylated α-crinanes see Ref. 7 and literature cited therein

Apohaemanthamine:
• 10a Cedròn JC, Gutiérrrez D, Flores N, Ravelo ÁG, Estévez-Braun AB. Med Chem 2012; 20: 5464
• 10b Cabezas F, Ramirez A, Viladomat F, Codina C, Bastida J. Chem Pharm Bull 2003; 51: 315
• 10c Campbell WE, Nair JJ, Gammon DW. et al. Phytochem 2000; 53 (04) 587 Ref. 10d, Ref. 5aa

For a comprehensive review see:
• 11a Hu N, White LV, Lan P, Banwell MG. Molecules 2021; 26: 765
• 11b van Otterlo WAL, Green IR. Nat Prod Commun 2018; 13: 255
• 11c Pandey G, Gadre SR. Pure Appl Chem 2012; 84: 1597

For a review focusing on the generation of the quarternary center see:
• 12a Li C, Ragab SS, Liu G, Tang W. Nat Prod Rep 2020; 37: 276
• 12b For selected syntheses of crinane alkaloids including the C4a, C10b, C11 quarternary stereotriad: Ref. 5h
• 12c Petit L, Banwell MG, Willis AC. Org Lett 2011; 13: 5800
• 12d Ref. 5m
• 12e Ref. 5n
• 12f Nishimata T, Sato Y, Mori M. J Org Chem 1837; 2004: 69

For an N5–C12 ring closure incorporating C6 and C11 carbonyl groups, see:
• 13a Hendrickson JB, Bogard TL, Fisch ME, Grossert S, Yoshimura N. J Am Chem Soc 1974; 96: 7781

For an N5–C12 ring closure incorporating C6 and C11 CH₂ groups, see:
• 13b Ninomiya I, Naito T, Kiguchi T. J Chem Soc, Perkin Trans I 1973; 2261
• 13c Grigg R, Santhakumar V, Sridharan V, Thorton-Pett M, Bridge AW. Tetrahedron 1993; 49: 5177
• 13d Du K, Yang H, Guo P. et al. Chem Sci 2017; 8: 6247

Aldol reactions including the installation of the quaternary C10b center are unknown so far. For a C2–C3 bond formation via an aldol reaction (C11 CH2), see:
• 14 Pandey G, Gupta NR, Gadre SR. Eur J Org Chem 2011; 740
• 15a For crinane alkaloid C-ring formations, see: Refs. 11a and 13
• 15b Bogle KM, Hirst DJ, Dixon DJ. Org Lett 2010; 12: 1252

For a Claisen rearrangement to generate an alkaloid quaternary center, see:
• 16a Erhard T, Ehrlich G, Metz P. Angew Chem Int Ed 2011; 50: 3892
• 16b Erhard T, Ehrlich G, Metz P. Angew Chem 2011; 123: 3979
• 16c Mulzer J, Bats JW, List B, Opatz T, Trauner D. Synlett 1997; 441
• 16d Trauner D, Porth S, Opatz T, Bats JW, Giester G, Mulzer J. Synlett 1998; 653
• 16e Chandler M, Parsons PJ. J Chem Soc Chem Commun 1984; 322
• 17 Bernhard S, Kümmerer N, Urgast D. et al. Synthesis 2024; 56: 2537
• 18a Trost BM, Spagnol MD. J Chem Soc, Perkin Trans I 1995; 2083 B
• 18b Laabs S, Scherrmann A, Sudau A, Diederich M, Kierig C, Nubbemeyer U. Synlett 1999; 25
• 18c Laabs S, Münch W, Bats J-W, Nubbemeyer U. Tetrahedron 2002; 58: 1317
• 18d Friedemann NM, Härter A, Brandes S. et al. Eur J Org Synth 2012; 2346
• 19a Nubbemeyer U. J Org Chem 1995; 60: 3773
• 19b Nubbemeyer U. J Org Chem 1996; 61: 3677
• 19c Heescher C, Schollmeyer D, Nubbemeyer U. Eur J Org Chem 2013; 4399
• 19d Donges J, Hofmann S, Brüggemann M, Frank A, Schollmeyer D, Nubbemeyer U. Eur J Org Chem 2021; 3345
• 20 For details see supporting information
• 21a Wick AE, Felix D, Steen K, Eschenmoser A. Helv Chim Acta 1964; 47: 2425
• 21b Bauermeister S, Gouws ID, Strauss HF, Venter EMM. J Chem Soc, Perkin Trans I 1991; 561
• 21c Ref. 8a
• 21d Das MK, De S, Shubhashish, Bisai A. Org Biomol Chem 2015; 13: 3585
• 21e Das MK, De S, Shubhashish, Bisai A. Synthesis 2016; 48: 2093
• 22a Tsang R, Fraser-Reid B. J Am Chem Soc 1986; 108: 2116
• 22b Dickson JK, Tsang R, Liera JM, Fraser-Reid B. J Org Chem 1989; 54: 5350
• 23 Remark in connection with 7b–7c: OH acetylation of amide 7b delivered amide 7c and Zemplén cleavage of the acetate of amide 7c afforded amide 7b, respectively, proving the identity of the quarternary centers
• 24a Smith ABIII, Ott GR. J Am Chem Soc 1996; 118: 13095
• 24b Hayward CM, Yohannes D, Danishefsky SJ. J Am Chem Soc 1993; 115: 9345
• 25a Slabaugh MR, Wildman WC. J Org Chem 1971; 36: 3202
• 25b Zuo X-D, Guo S-M, Yang R, Xie J-H, Zhou Q-L. Org Lett 2017; 19: 5240
• 26 Deposition Number 2490560 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 27a Metz P. Tetrahedron 1993; 49: 6367
• 27b Ref. 19b
• 27c Hungerhoff B, Metz P. J Org Chem 1997; 62: 4442
• 27d Kaluza NM, Schollmeyer D, Nubbemeyer U. Eur J Org Chem 2016; 357
• 27e Ref. 19d
• 27f Chamberlin AR, Dezube M, Dussault P. Tetrahedron Lett 1981; 4611
• 27g Ha H-J, Lee S-Y, Park Y-S. Synth Commun 2000; 30: 3645
• 27h Oberinde MS, Hunter HN, Bremner SW, Organ MG. Eur J Org Chem 2012; 175
• 27i Liu Z, Qu H, Gu X. et al. Tetrahedron Lett 2010; 51: 3518
• 27j Nonaka H, Ogawa N, Maeda N, Wang Y-G, Kobayashi Y. Org Biomol Chem 2010; 8: 5212
• 27k Blot V, Reboul V, Metzner P. Eur J Org Chem 2006; 1934
• 28a Smith EH, Tyrrell ND. J Chem Soc Chem Commun 1983; 285
• 28b Ref. 19d
• 29a Stahl GL, Walter R, Smith CW. J Org Chem 1978; 43: 2285
• 29b Cavelier F, Enjalbal C. Tetrahedron Lett 1996; 37: 5131
• 29c Nudelman A, Bechor Y, Falb E, Fischer B, Wexler BA, Nudelman A. Synth Commun 1998; 28: 471
• 29d Jacobi PA, Murphree S, Ruprecht F, Zheng W. J Org Chem 1996; 61: 2431
• 29e Sakai N, Ohfune Y. J Am Chem Soc 1992; 114: 998
• 30 Thomas KD, Adhikari AV, Chowdhury IH. et al. Eur J Med Chem 2011; 46: 4834
• 31 Deposition Number 2490561 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 32 Zemplén G. Ber Dtsch Chem Ges 1926; 59: 1254
• 33 Cong Z, Zhao B, Wu H. et al. Polymer 2015; 67: 55
• 34a Griffith WP, Ley SV, Whitcombe GP, White AD. J Chem Soc Chem Commun 1987; 1625
• 34b Dess DB, Martin JC. J Org Chem 1983; 48: 4155
• 34c Parikh JR, Doering WVE. J Am Chem Soc 1967; 89: 5505

Side product methyl thiomethyl ether formation
• 34d Urban FJ, Breitenbach R, Murtiashaw CW, Vanderplas B. Tetrahedron Asymmetry 1995; 6: 321
• 34e Akai S, Nemoto H, Egi M. Heterocycles 2008; 76: 1537
• 34f Katritzky AR, Dennis N, Dowlatshahi HAJ. Perkin Trans I 1980; 331 For structures of the side products see supporting information
• 35a Mico A d, Margarita R, Parlanti L, Vescovi A, Piancatelli G. J Org Chem 1997; 62: 6974
• 35b Anelli PL, Biffi C, Montanari F, Quici S. J Org Chem 1987; 52: 2559
• 35c Cella JA, Kelley JA, Kenehan EF. J Org Chem 1975; 40: 1860
• 35d Jurczak J, Gryko D, Kobrzycka E, Gruza H, Prokopowicz P. Tetrahedron 1998; 54: 6051
• 36a Brandt P, Hedberg C, Lawonn K, Pinho P, Andersson PG. Chem Eur J 2001; 7: 1431
• 36b Reetz MT, Steinbach R, Westermann J, Peter R. Angew Chem 1980; 92: 1044
• 36c Reetz MT, Westermann J, Steinbach R. et al. Chem Ber 1985; 118: 1421
• 36d Andrés J, de Elena N, Pedrosa R, Pérez-Encabo A. Tetrahedron 1999; 55: 14137
• 36e Biswas K, Prieto O, Goldsmith PJ, Woodward S. Angew Chem 2005; 117: 2272

Alternative C1 nucleophile
• 36f Corey EJ, Seebach D. Angew Chem 1965; 77: 1134
• 36g Firouzabadi H, Iranpoor N, Hazarkhani H. J Org Chem 2001; 66: 7527
• 37a Sohtome Y, Takemura N, Iguchi T, Hashimoto Y, Nagasawa K. Synlett 2006; 144
• 37b Raju R, Raghunathan R, Arumugam N, Almansour AI, Kumar RS, Soliman SM. Tetrahedron 2021; 84: 132026
• 37c Förster S, Tverskoy O, Helmchen G. Synlett 2008; 18: 2803
• 38a Barluenga J, Mateos C, Aznar F, Valdes C. Org Lett 2002; 4: 1971
• 38b Drouillat B, Wright K, Quinodoz P, Marrot J, Couty F. J Org Chem 2015; 80: 6936
• 38c Petasis NA, Bzowej EI. J Am Chem Soc 1990; 112: 6392
• 38d Payak JF, Hughes DL, Cai D, Cottrell IF, Verhoeven TR. Org Prep Proc Int 1995; 27: 707
• 38e Kerr N, Hegedus L. Org Synth 2002; 79: 19
• 38f Hartley RC, Li J, Main CA, McKiernan GJ. Tetrahedron 2007; 63: 4825
• 38g Hughes DL, Payak JF, Cai D, Verhoeven TR, Reider PJ. Organometallics 1996; 15: 663
• 39a Ohira S. Synth Commun 1989; 19: 56
• 39b Müller S, Liepold B, Roth GJ, Bestmann HJ. Synlett 1996; 521
• 39c Kumar P, Rahman MA, Haque A, Singh Yadav J. Tetrahedron Lett 2021; 68: 152906
• 39d Polindara-Garcia LA, Miranda LD. Synthesis 2012; 44: 1051
• 40a Schwarz S, Weber G, Depner J, Schaumann J, Schick H, Welzel HP. Tetrahedron 1982; 38: 1261
• 40b Schwarz S, Weber G, Meyer M, Schick H, Welzel H-P. J Prakt Chem 1984; 326: 667
• 41a Ref. 38c
• 41b Ref. 38g
• 41c Eglington G, Jones ERH, Whiting MC. J Chem Soc 1952; 2873
• 41d Liang Y, Hnatiuk N, Rowley JM. et al. J Org Chem 2011; 76: 9962
• 41e Nassar Y, Piva O. Org Biomol Chem 2020; 18: 5811
• 42a Panda J, Gosh S, Gosh S. J Chem Soc, Perkin Trans I 2001; 3013
• 42b Bourgeois D, Prunet J, Pancrazi A, Prangé T, Lallemand J-Y. Eur J Org Chem 2000; 4029
• 42c Ref. 41c
• 43a Takeuchi Y, Azuma K, Takakura K. et al. Tetrahedron 2001; 57: 1213
• 43b Takeuchi Y, Hattori M, Abe H, Harayama T. Synthesis 1999; 1814
• 43c Molas P, Díaz Y, Matheu MI, Castillón S. Synlett 2003; 207
• 44a Wee AGH, Fan G-J. Org Lett 2008; 10: 3869
• 44b Thuan LT. Bull Soc Chim Fr 1956; 642
• 45a Naito T, Miyata O, Kida N, Namoto K, Ninomiya I. Chem Pharm Bull 1990; 38: 2419
• 45b Thoai N. Bull Soc Chim Fr 1964; 225
• 46a Saigo K, Morikawa A, Mukaiyama T. Chem Lett 1975; 4: 145
• 46b Narasaka K, Morikawa A, Saigo K, Mukaiyama T. Bull Chim Soc Jpn 1977; 50: 2773

Initial attempts employing a Weinreb amide formation and a subsequent methyl Grignard reagent addition to synthesize ketone 26a failed. For data of the Weinreb amid see supporting information:
• 47a Nahm S, Weinreb SM. Tetrahedron Lett 1981; 22: 3815
• 47b Albarghouti G, Kotikalapudi R, Lankri D, Valerio V, Tsvelikhovsky D. Chem Commun 2016; 52: 3095
• 47c Williams JM, Jobson RB, Yasuda N, Marchesini G, Dolling H-U, Grabowski EJJ. Tetrahedron Lett 1995; 36: 5461
• 48a Chilot J-J, Doutheau A, Gore J. Bull Soc Chim Fr 1984; 2: 307
• 48b Yates P, Kaldas M. Can J Chem 1992; 70: 1492
• 48c Imanishi T, Yamashita M, Matsui M, Tanaka T, Miyashita K, Iwata C. Chem Pharm Bull 1992; 40: 2691
• 48d Tnay YL, Chiba S. Chem Asian J 2015; 10: 873
• 49 Alessandrini L, Casati S, Ciuffreda P, Ottria R, Santaniello E. J Carbohydr Chem 2008; 27: 332 In analogy, the hydroxy group of keton 26a selectively underwent esterification, no mixed ketal acetates from hemiketals 26b/c were found

Remark: Initial investigations attempting C-ring closure focused on intramolecular enolate alkylation. In this connection, the OH group of enol ether 24 was activated as mesylate (standard conditions). However, all runs pointing on intramolecular enolate alkylation to generate a cyclohexanone C ring failed. For data of the mesylate see supporting information. Furthermore, substitution of the mesylates with thiophenolate and subsequent sulfoxide generation would have introduced a substitution pattern ready for a Pummerer rearrangement:
• 50 Wojaczynska E, Skarzewski J. Tetrahedron Asymmetry 2008; 19: 2252 Again, this sequence proved not successful

Starting from endo enolether 24 most (electrophilic) oxidation reagents primarily addressed the enol ether function and the OH function served as a nucleophile leading to ketals 23 and 25, respectively:
• 51a Laxmi YRS, Bäckvall J-E. Chem Commun 2000; 611
• 51b Chowdhury RL, Bäckvall J-E. J Chem Commun, Chem Commun 1991; 1063
• 51c Ref. 34c
• 51d Ref. 46
• 51e Mello R, Martinez F, Jaime, Gonzalez-Nunez ME. J Org Chem 2007; 72: 9376 (Oppenauer)
• 51f Ref. 35
• 52a Ref. 34b For selected variants see:
• 52b Vimal Varghese V, Hudlicky T. Synlett 2013; 24: 369
• 52c Lin Q-X, Ho T-L. Tetrahedron 2013; 69: 2996
• 52d Barrett SD, Holt MC, Kramer JB. et al. J Med Chem 2019; 62: 4731
• 53a Kalaitzakis D, Sofiadis M, Tsopanakis V, Montagnon T, Vassilikogiannakis G. Org Biomol Chem 2020; 18: 2817
• 53b Umekubo N, Iwata R, Hayashi Y. Chem Lett 2020; 49: 867
• 54a Tang H, Chen Q-F, Liu X-Y, Zhang H, Chen D-L, Wang F-P. Tetrahedron 2016; 72: 1357

For data of the mesylate see supporting information. Intramolecular enolate alkylation:
• 54b Chang N-C, Chang C-K. J Org Chem 1996; 61: 4967
• 54c Liu D, Hong S, Corey EJ. J Am Chem Soc 2006; 128: 8160
• 54d Stork G, Brizzolara A, Landesman H, Szmuszkovicz J, Terrell R. J Am Chem Soc 1963; 85: 207

A first attempt running a one pot Ru-catalyzed HAT/intramolecular Aldol condensation following a procedure of Cho and Shim. failed:
• 55 Cho CS, Kim BT, Kim T-J, Shim SC. J Org Chem 2001; 66: 9020
• 56a Baldwin SW, Debenham JS. Org Lett 2000; 2: 99
• 56b Jhuo D-H, Hong B-C, Chang C-W, Lee G-H. Org Lett 2014; 16: 2724
• 56c Srikrishna A, Beeraiah B. Tetrahedron Asymmetry 2007; 18: 2587
• 56d Dalko PI, Moisan L. Angew Chem 2004; 116: 5248
• 56e Markert M, Mulzer J, Schetter B, Mahrwald R. J Am Chem Soc 2007; 129: 7258
• 56f Whitesell JK, Whitesell MA. Synthesis 1983; 517
• 56g Sakthivel K, Notz W, Bui T, Barbas CF. J Am Chem Soc 2001; 123: 5260
• 56h List B. Tetrahedron 2002; 58: 5573
• 57a Orsini F, Pelizzoni F, Forte M, Destro R, Gariboldi P. Tetrahedron 1988; 44: 519
• 57b Firouzabadi H, Iranpoor N, Ghaderi A, Ghavami M. Tetrahedron Lett 2012; 53: 5515
• 57c Pavan Kumar CS, Harsha KB, Mantelingu K, Rangappa KS. RSC Adv 2015; 5: 61664
• 58a Nagumo S, Matoba A, Ishii Y. et al. Tetrahedron 2002; 58: 9871
• 58b Diaba F, Ricou E, Bonjoch J. Tetrahedron Asymmetry 2006; 17: 1437 Condensation only:
• 58c Duhamel P, Kotera M, Monteil T, Marabout B, Davoust D. J Org Chem 1989; 54: 4419
• 58d Auty JMA, Churcher I, Hayes CJ. Synlett 2004; 1443
• 58e Whipp CJ, de Turiso FG-L. Tetrahedron Lett 2008; 49: 5508
• 59a Yamada YMA, Shibasaki M. Tetrahedron Lett 1998; 39: 5561
• 59b Saito S, Kobayashi S. J Am Chem Soc 2006; 128: 8704
• 60 Remark: Treatment of ketal hemiacetals 30a/b with DBU or NaH in THF and KOH in MeOH, respectively, caused degradation of the material only
• 61 Tan D-X, Zhou J, Liu C-Y. Angew Chem 2020; 132: 3862
• 62 Remark: Reaction of ketal hemiacetals 30a/b with KOH applying these PTC conditions delivered a mixture of the Aldol products 33 and 34, too
• 63a Hu J, Bian M, Ding H. Tetrahedron Lett 2016; 57: 5519
• 63b Nising CF, Bräse S. Chem Soc Rev 2008; 37: 1218
• 64 Furthermore, a minor oxidation product was isolated with about 1% yield. The compound displayed an ether bridge related to Apohaemanthamine (Ref. 10). For structure and details concerning NOEDS analyses see supporting information
• 65 Deposition Number 2490562 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures For an established related sequence see
• 66 Zhang Q, Zhang F-M, Zhang C-S. et al. J Org Chem 2019; 84: 12664
• 67 The successful total syntheses of all target alkaloid series I–IV (Fig. 1) should enable the correction of all inconsistent data series published within these compounds so far and the adequate revision of the data bases (hits in Reaxys, SciFinder-N)