Development of a Chiral N-Alkoxyamide Strategy and Application to the Asymmetric Total Synthesis of Fasicularin

Abstract

The asymmetric total synthesis of fasicularin by a chiral N-alkoxyamide strategy is reported. Incorporation of the chiral alkoxy group onto an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. DFT calculations indicate that pyramidalization of the N-alkoxyamide nitrogen is crucial to produce a cyclic hemiaminal in equilibrium, which undergoes aza-spirocyclization. The chiral alkoxy group is also used as a stereocontrol element to establish two consecutive stereocenters. The iridium-catalyzed reductive Strecker reaction of the N-alkoxylactam provides the aminonitrile with high diastereoselectivity.

Key words

amides - DFT calculations - fasicularin - heteroatom–heteroatom bonds - nucleophilic addition - remote stereocontrol - total synthesis

Publication History

Received: 30 June 2021

Accepted after revision: 29 July 2021

Accepted Manuscript online:
29 July 2021

Article published online:
17 September 2021

• References


The enhanced nucleophilicity of amide nitrogen enables electrophilic cyclization and amide/aldehyde coupling. For selected reviews, see:
• 1a Robin S, Rousseau G. Tetrahedron 1998; 54: 13681
• 1b Maryanoff BE, Zhang H.-C, Cohen JH, Turchi IJ, Maryanoff CA. Chem. Rev. 2004; 104: 1431
• 2 Nahm S, Weinreb SM. Tetrahedron Lett. 1981; 22: 3815

We have reported nucleophilic addition to N-alkoxyamides via five-membered chelated intermediates. For selected examples, see:
• 3a Shirokane K, Kurosaki Y, Sato T, Chida N. Angew. Chem. Int. Ed. 2010; 49: 6369
• 3b Shirokane K, Wada T, Yoritate M, Minamikawa R, Takayama N, Sato T, Chida N. Angew. Chem. Int. Ed. 2014; 53: 512

For selected examples from other groups, see:
• 3c Iida H, Watanabe Y, Kibayashi C. J. Am. Chem. Soc. 1985; 107: 5534
• 3d Vincent G, Guillot R, Kouklovsky C. Angew. Chem. Int. Ed. 2011; 50: 1350
• 3e Jäkel M, Qu J, Schnitzer T, Helmchen G. Chem. Eur. J. 2013; 19: 16746
• 4 For a two-step synthesis of multisubstituted piperidines using the unique reactivities of N-methoxyamides, see: Yoritate M, Meguro T, Matsuo N, Shirokane K, Sato T, Chida N. Chem. Eur. J. 2014; 20: 8210
• 5 Shirokane K, Tanaka Y, Yoritate M, Takayama N, Sato T, Chida N. Bull. Chem. Soc. Jpn. 2015; 88: 522
• 6 Yokoyama T, Fukami Y, Sato T, Chida N. Chem. Asian J. 2016; 11: 470
• 7 Part of this work was published as a preliminary communication; see: Yamamoto S, Komiya Y, Kobayashi A, Minamikawa R, Oishi T, Sato T, Chida N. Org. Lett. 2019; 21: 1868
• 8a Patil AD, Freyer AJ, Reichwein R, Carte B, Killmer LB, Faucette L, Johnson RK, Faulkner DJ. Tetrahedron Lett. 1997; 38: 363
• 8b Dutta S, Abe H, Aoyagi S, Kibayashi C, Gates KS. J. Am. Chem. Soc. 2005; 127: 15004

For reviews on the total synthesis of fasicularin and related alkaloids, see:
• 9a Kibayashi C, Aoyagi S, Abe H. Bull. Chem. Soc. Jpn. 2003; 76: 2059
• 9b Kibayashi C. Chem. Pharm. Bull. 2005; 53: 1375
• 9c Weinreb SM. Chem. Rev. 2006; 106: 2531
• 9d Kaga A, Chiba S. Synthesis 2018; 50: 685

For the total and formal synthesis of fasicularin, see:
• 10a Abe H, Aoyagi S, Kibayashi C. J. Am. Chem. Soc. 2000; 122: 4583
• 10b Maeng J.-H, Funk RL. Org. Lett. 2002; 4: 331
• 10c Fenster MD. B, Dake GR. Org. Lett. 2003; 5: 4313 ; corrigendum: Org. Lett. 2004, 6, 1187
• 10d Abe H, Aoyagi S, Kibayashi C. J. Am. Chem. Soc. 2005; 127: 1473
• 10e Fenster MD. B, Dake GR. Chem. Eur. J. 2005; 11: 639
• 10f Mei S.-L, Zhao G. Eur. J. Org. Chem. 2010; 1660
• 10g In J, Lee S, Kwon Y, Kim S. Chem. Eur. J. 2014; 20: 17433
• 10h Kaga A, Tnay YL, Chiba S. Org. Lett. 2016; 18: 3506
• 10i Burnley J, Wang ZJ, Jackson WR, Robinson AJ. J. Org. Chem. 2017; 82: 8497
• 10j Takashima K, Hayakawa D, Gouda H, Toyooka N. J. Org. Chem. 2019; 84: 5222

For a synthetic study, see:
• 10k Wardrop DJ, Zhang W, Landrie CL. Tetrahedron Lett. 2004; 45: 4229

For reviews and perspectives on nucleophilic addition to amides, see:
• 11a Seebach D. Angew. Chem. Int. Ed. 2011; 50: 96
• 11b Murai T, Mutoh Y. Chem. Lett. 2012; 41: 2
• 11c Pace V, Holzer W. Aust. J. Chem. 2013; 66: 507
• 11d Sato T, Chida N. Org. Biomol. Chem. 2014; 12: 3147
• 11e Pace V, Holzer W, Olofsson B. Adv. Synth. Catal. 2014; 356: 3697
• 11f Volkov A, Tinnis F, Slagbrand T, Trillo P, Adolfsson H. Chem. Soc. Rev. 2016; 45: 6685
• 11g Więcław MM, Stecko S. Eur. J. Org. Chem. 2018; 6601
• 11h Sato T, Yoritate M, Tajima H, Chida N. Org. Biomol. Chem. 2018; 16: 3864
• 11i Kaiser D, Bauer A, Lemmerer M, Maulide N. Chem. Soc. Rev. 2018; 47: 7899
• 11j Huang P.-Q. Huaxue Xuebao 2018; 76: 357
• 11k Matheau-Raven D, Gabriel P, Leitch JA, Almehmadi YA, Yamazaki K, Dixon DJ. ACS Catal. 2020; 10: 8880
• 11l Ong DY, Chen J.-H, Chiba S. Bull. Chem. Soc. Jpn. 2020; 93: 1339

For recent selected examples of nucleophilic addition to amides from other groups, see:
• 12a Xia Q, Ganem B. Org. Lett. 2001; 3: 485
• 12b Murai T, Mutoh Y, Ohta Y, Murakami M. J. Am. Chem. Soc. 2004; 126: 5968
• 12c Murai T, Asai F. J. Am. Chem. Soc. 2007; 129: 780
• 12d Xiao K.-J, Luo J.-M, Ye K.-Y, Wang Y, Huang P.-Q. Angew. Chem. Int. Ed. 2010; 49: 3037
• 12e Bélanger G, O’Brien G, Larouche-Gauthier R. Org. Lett. 2011; 13: 4268
• 12f Xiao K.-J, Wang A.-E, Huang P.-Q. Angew. Chem. Int. Ed. 2012; 51: 8314
• 12g Jakubec P, Hawkins A, Felzmann W, Dixon DJ. J. Am. Chem. Soc. 2012; 134: 17482
• 12h Sato M, Azuma H, Daigaku A, Sato S, Takasu K, Okano K, Tokuyama H. Angew. Chem. Int. Ed. 2017; 56: 1087

For selected examples of iridium-catalyzed reductive nucleo­philic addition, see:
• 13a Gregory AW, Chambers A, Hawkins A, Jakubec P, Dixon DJ. Chem. Eur. J. 2015; 21: 111
• 13b Nakajima M, Sato T, Chida N. Org. Lett. 2015; 17: 1696
• 13c Katahara S, Kobayashi S, Fujita K, Matsumoto T, Sato T, Chida N. J. Am. Chem. Soc. 2016; 138: 5246
• 13d Huang P.-Q, Ou W, Han F. Chem. Commun. 2016; 52: 11967
• 13e Tan PW, Seayad J, Dixon DJ. Angew. Chem. Int. Ed. 2016; 55: 13436
• 13f Fuentes de Arriba ÁL, Lenci E, Sonawane M, Formery O, Dixon DJ. Angew. Chem. Int. Ed. 2017; 56: 3655
• 13g Xie L.-G, Dixon DJ. Chem. Sci. 2017; 8: 7492
• 13h Yoritate M, Takahashi Y, Tajima H, Ogihara C, Yokoyama T, Soda Y, Oishi T, Sato T, Chida N. J. Am. Chem. Soc. 2017; 139: 18386
• 13i Xie L.-G, Dixon DJ. Nat. Commun. 2018; 9: 2841
• 13j Ou W, Han F, Hu X.-N, Chen H, Huang P.-Q. Angew. Chem. Int. Ed. 2018; 57: 11354
• 13k Takahashi Y, Yoshii R, Sato T, Chida N. Org. Lett. 2018; 20: 5705
• 13l Takahashi Y, Sato T, Chida N. Chem. Lett. 2019; 48: 1138
• 13m Rogova T, Gabriel P, Zavitsanou S, Leitch JA, Duarte F, Dixon DJ. ACS Cat. 2020; 10: 11438
• 13n Chen D.-H, Sun W.-T, Zhu C.-J, Lu G.-S, Wu D.-P, Wang A.-E, Huang P.-Q. Angew. Chem. Int. Ed. 2021; 60: 8827
• 13o Yamazaki K, Gabriel P, Carmine GD, Pedroni J, Farizyan M, Hamlin TA, Dixon DJ. ACS Cat. 2021; 11: 7489

Tinnis/Adolfsson have reported Mo(CO)₆-catalyzed hydrosilylation; see:
• 13p Tinnis F, Volkov A, Slagbrand T, Adolfsson H. Angew. Chem. Int. Ed. 2016; 55: 4562
• 13q Trillo P, Slagbrand T, Adolfsson H. Angew. Chem. Int. Ed. 2018; 57: 12347
• 14 Kishida A, Nagaoka H. Tetrahedron Lett. 2008; 49: 6393
• 15 Chatterjee AK, Choi T.-L, Sanders DP, Grubbs RH. J. Am. Chem. Soc. 2003; 125: 11360
• 16 Winkler FK, Dunitz JD. J. Mol. Biol. 1971; 59: 169
• 17 Glover SA, Rosser AA. Molecules 2018; 23: 2834
• 18 A detailed computational study on the allylation of 24 is now underway and will be reported separately.
• 19a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
• 19b Morgen M, Bretzke S, Li P, Menche D. Org. Lett. 2010; 12: 4494
• 20 Batory LA, McInnis CE, Njardarson JT. J. Am. Chem. Soc. 2006; 128: 16054
• 21a Wailes PC, Weigold H. J. Organomet. Chem. 1970; 24: 405
• 21b Hart DW, Schwartz J. J. Am. Chem. Soc. 1974; 96: 8115
• 22 For a selected review, see: Corey EJ, Helal CJ. Angew. Chem. Int. Ed. 1998; 37: 1986
• 23a CCDC 1580840 (lactam 40a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

For a racemic structure of compound 40b, see:
• 23b Oishi T, Yamamoto S, Yokoyama T, Kobayashi A, Sato T, Chida N. Acta Crystallogr., Sect. E 2015; 71: 1528
• 24 Unfortunately, the factors controlling the stereoselectivity derived from the chiral alkoxy group are yet to be clarified.
• 25 Tsunoda T, Suzuki M, Noyori R. Tetrahedron Lett. 1980; 21: 1357
• 26 Motoyama Y, Aoki M, Takaoka N, Aoto R, Nagashima H. Chem. Commun. 2009; 1574
• 27 MacroModel . Schrödinger, LLC; New York (NY, USA): 2020
• 28 Gaussian 16, Revision B.01 . Gaussian, Inc; Wallingford (CT, USA): 2016
• 29 Galan BR, Kalbarczyk KP, Szczepankiewicz S, Keister JB, Diver ST. Org. Lett. 2007; 9: 1203