Synlett 2018; 29(10): 1257-1271
DOI: 10.1055/s-0036-1591579
account
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Bromocyclization of Allylic Amides Mediated by Phosphorus Catalysis

Yuji Kawato
School of Pharmaceutical Sciences, University of Shizuoka, Japan   Email: hamashima@u-shizuoka-ken.ac.jp
,
Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, Japan   Email: hamashima@u-shizuoka-ken.ac.jp
› Author Affiliations
This work was supported by JSPS KAKENHI (Grant Number 16H05077 and 16K18848) and a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from MEXT, Japan, and partially supported by Platform Project for Supporting Drug Discovery and Life Science Research from Japan Agency for Medical Research and Development (AMED).
Further Information

Publication History

Received: 06 March 2018

Accepted after revision: 03 April 2018

Publication Date:
14 May 2018 (online)


Abstract

Halocyclization of alkenes is commonly employed to increase molecular complexity during organic synthesis because it enables double installation of heteroatoms on a carbon–carbon double bond. Moreover, stereodefined halogenated compounds are widely found among naturally occurring compounds and can serve as versatile chiral building blocks. Therefore, the development of asymmetric halocyclization reactions is of great interest and, in recent years, there has been remarkable progress in catalytic asymmetric halogenation reactions. This account summarizes recent progress made by our group on phosphorus-­catalyzed enantioselective bromocyclization of allylic amides. Building on a comprehensive study of the reaction mechanism, we discovered an intriguing catalytic reaction in which P+Br species serves as a fine-tuning element for substrate fixation. We also describe the application of this bromocyclization to asymmetric desymmetrization of 1,4-diene substrates and a concise synthesis of the HIV-protease inhibitor ­nelfinavir using the newly developed desymmetrization reaction as a key step.

1 Introduction

2 Enantioselective Bromocyclization of Allylic Amides with a BINAP Catalyst

2.1 Bromocyclization with a P/P Catalyst

2.2 Bromocyclization with a P/P=O Catalyst

3 Desymmetrization of Bisallylic Amides through Enantioselective Bromocyclization

3.1 Desymmetrization of Bisallylic Amides

3.2 Enantioselective Synthesis of Nelfinavir

4 Summary

 
  • References


    • Halogenated natural products, see:
    • 1a Gribble GW. In Naturally Occurring Organohalogen Compounds–A Comprehensive Update. Springer; Berlin: 2010: 1
    • 1b Gribble GW. J. Nat. Prod. 1992; 55: 1353
    • 1c Vaillancourt FH. Yeh E. Vosburg DA. Garneau-Tsodikova S. Walsh CT. Chem. Rev. 2006; 106: 3364
    • 1d Wagner C. El Omari M. König GM. J. Nat. Prod. 2009; 72: 540
    • 1e Wang B.-G. Gloer JB. Ji N.-Y. Zhao J.-C. Chem. Rev. 2013; 113: 3632
    • 1f Baunach M. Franke J. Hertweck C. Angew. Chem. Int. Ed. 2015; 54: 2604
    • 1g Chung W.-j. Vanderwal CD. Angew. Chem. Int. Ed. 2016; 55: 4396

      For reviews on enantioselective halocyclization, see:
    • 2a Chen G. Ma S. Angew. Chem. Int. Ed. 2010; 49: 8306
    • 2b Tan CK. Zhou L. Yeung Y.-Y. Synlett 2011; 1335
    • 2c Castellanos A. Fletcher SP. Chem. Eur. J. 2011; 17: 5766
    • 2d Denmark SE. Kuester WE. Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
    • 2e Hennecke U. Chem. Asian J. 2012; 7: 456
    • 2f Tan CK. Yeung Y.-Y. Chem. Commun. 2013; 7985
    • 2g Murai K. Fujioka H. Heterocycles 2013; 87: 763
    • 2h Cheng YA. Yu WZ. Yeung Y.-Y. Org. Biomol. Chem. 2014; 12: 2333
    • 3a Genet J.-P. In Modern Reduction Methods . Andersson PG. Munslow IJ. Wiley-VCH; Weinheim: 2008: 1
    • 3b Ohkuma T. Kitamura M. Noyori R. In Catalytic Asymmetric Synthesis, 2nd ed. . Ojima I. Wiley-VCH; Weinheim: 2000: 1
    • 3c Verendel JJ. Pàmies O. Diéguez M. Andersson PG. Chem. Rev. 2014; 114: 2130
    • 3d Margarita C. Andersson PG. J. Am. Chem. Soc. 2017; 139: 1346
    • 4a Katsuki T. In Comprehensive Asymmetric Catalysis II . Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 2001: 621
    • 4b Matsumoto K. Katsuki T. In Catalytic Asymmetric Synthesis 3rd ed. New York, 2010; 839
    • 4c Katsuki T. Martin VS. Org. React. 1996; 48: 1
    • 5a Marko IE. Svendsen JS. In Comprehensive Asymmetric Catalysis II . Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 2001: 713
    • 5b Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev. 1994; 94: 2483
    • 5c Cha JK. Kim N.-S. Chem. Rev. 1995; 95: 1761
    • 6a Brown RS. Nagorski RW. Bennet AJ. McClung RE. D. Aarts GH. M. Klobukowski M. McDonald R. Santarsiero BD. J. Am. Chem. Soc. 1994; 116: 2448
    • 6b Neverov AA. Brown RS. J. Org. Chem. 1996; 61: 962
    • 6c Brown RS. Acc. Chem. Res. 1997; 30: 131
    • 6d Denmark SE. Burk MT. Hoover AJ. J. Am. Chem. Soc. 2010; 132: 1232 ; see, also Ref. 14c

      For selected examples of amine catalysts, see:
    • 7a Haas J. Piguel S. Wirth T. Org. Lett. 2002; 4: 297
    • 7b Whitehead DC. Yousefi R. Jaganathan A. Borhan B. J. Am. Chem. Soc. 2010; 132: 3298
    • 7c Jaganathan A. Garzan A. Whitehead DC. Staples RJ. Borhan B. Angew. Chem. Int. Ed. 2011; 50: 2593
    • 7d Nicolaou KC. Simmons NL. Ying Y. Heretsch PM. Chen JS. J. Am. Chem. Soc. 2011; 133: 8134
    • 7e Chen Z.-M. Zhang Q.-W. Chen Z.-H. Li H. Tu Y.-Q. Zhang F.-M. Tian J.-M. J. Am. Chem. Soc. 2011; 133: 8818
    • 7f Li H. Zhang F.-M. Tu Y.-Q. Zhang Q.-W. Chen Z.-M. Chen Z.-H. Li J. Chem. Sci. 2011; 2: 1839
    • 7g Jaganathan A. Staples RJ. Borhan B. J. Am. Chem. Soc. 2013; 135: 14806
    • 7h Wilking M. Mück-Lichtenfeld C. Daniliuc CG. Hennecke U. J. Am. Chem. Soc. 2013; 135: 8133
    • 7i Zhang Y. Xing H. Xie W. Wan X. Lai Y. Ma D. Adv. Synth. Catal. 2013; 355: 68
    • 7j Zhang W. Liu N. Schienebeck CM. Zhou X. Izhar II. Guzei IA. Tang W. Chem. Sci. 2013; 4: 2652
    • 7k Yin Q. You S.-L. Org. Lett. 2014; 16: 2426
    • 7l Jaganathan A. Borhan B. Org. Lett. 2014; 16: 3616
    • 7m Li L. Su C. Liu X. Tian H. Shi Y. Org. Lett. 2014; 16: 3728
    • 7n Cai Q. Yin Q. You S.-L. Asian J. Org. Chem. 2014; 3: 408

    • As seminal related intermolecular vicinal halofunctionalizations, see:
    • 7o Soltanzadeh B. Jaganathan A. Staples RJ. Borhan B. Angew. Chem. Int. Ed. 2015; 54: 9517
    • 7p Soltanzadeh B. Jaganathan A. Yi Y. Yi H. Staples RJ. Borhan B. J. Am. Chem. Soc. 2017; 139: 2132

      For selected examples of Brønsted acids, see:
    • 8a Huang D. Wang H. Xue F. Guan H. Li L. Peng X. Shi Y. Org. Lett. 2011; 13: 6350
    • 8b Denmark SE. Burk MT. Org. Lett. 2012; 14: 256
    • 8c Dobish MC. Johnston JN. J. Am. Chem. Soc. 2012; 134: 6068
    • 8d Toda Y. Pink M. Johnston JN. J. Am. Chem. Soc. 2014; 136: 14734
    • 8e Jiang H.-J. Liu K. Yu J. Zhang L. Gong L.-Z. Angew. Chem. Int. Ed. 2017; 56: 11931

      For selected examples of hydrogen-bonding catalysts, see:
    • 9a Murai K. Matsushita T. Nakamura A. Fukushima S. Shimura M. Fujioka H. Angew. Chem. Int. Ed. 2010; 49: 9174
    • 9b Murai K. Shimizu N. Fujioka H. Chem. Commun. 2014; 12530
    • 9c Tungen JE. Nolsøe JM. J. Hansen TV. Org. Lett. 2012; 14: 5884

      For selected examples of Lewis acid catalysts, see:
    • 10a Inoue T. Kitagawa O. Saito A. Taguchi T. J. Org. Chem. 1997; 62: 7384
    • 10b Kang SH. Lee SB. Park CM. J. Am. Chem. Soc. 2003; 125: 15748
    • 10c Ning Z. Jin R. Ding J. Gao L. Synlett 2009; 2291
    • 10d Huang D. Liu X. Li L. Cai Y. Liu W. Shi Y. J. Am. Chem. Soc. 2013; 135: 8101
    • 10e Miles DH. Veguillas M. Toste FD. Chem. Sci. 2013; 4: 3427
    • 10f Arai T. Sugiyama N. Masu H. Kado S. Yabe S. Yamanaka M. Chem. Commun. 2014; 8287
    • 10g Huang H. Pan H. Cai Y. Liu M. Tian H. Shi Y. Org. Biomol. Chem. 2015; 13: 3566
    • 10h Liu W. Pan H. Tian H. Shi Y. Org. Lett. 2015; 17: 3956
    • 10i Arai T. Watanabe O. Yabe S. Yamanaka M. Angew. Chem. Int. Ed. 2015; 54: 12767

      For selected examples of phase-transfer catalysts and a related phosphate anion catalyst, see:
    • 11a Rauniyar V. Lackner AD. Hamilton GL. Toste FD. Science 2011; 334: 1681
    • 11b Wang YM. Wu J. Hoong C. Rauniyar V. Toste FD. J. Am. Chem. Soc. 2012; 134: 12928
    • 11c Xie W. Jiang G. Liu H. Hu J. Pan X. Zhang H. Wan X. Lai Y. Ma D. Angew. Chem. Int. Ed. 2013; 52: 12924
    • 11d Liu H. Jiang G. Pan X. Wan X. Lai Y. Ma D. Xie W. Org. Lett. 2014; 16: 1908
    • 11e Hiramatsu K. Honjo T. Rauniyar V. Toste FD. ACS Catal. 2016; 6: 161
    • 11f Hennecke U. Müller CH. Fröhlich R. Org. Lett. 2011; 13: 860

      For single-site Lewis base catalysts, see:
    • 12a Sakakura A. Ukai A. Ishihara K. Nature 2007; 445: 900
    • 12b Chen F. Tan CK. Yeung Y.-Y. J. Am. Chem. Soc. 2013; 135: 1232
    • 12c Ke Z. Tan CK. Chen F. Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
    • 12d Denmark SE. Burk MT. Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 20655
    • 12e Tay DW. Leung GY. C. Yeung Y.-Y. Angew. Chem. Int. Ed. 2014; 53: 5161
    • 12f Nakatsuji H. Sawamura Y. Sakakura A. Ishihara K. Angew. Chem. Int. Ed. 2014; 53: 6974
    • 12g Samanta RC. Yamamoto H. J. Am. Chem. Soc. 2017; 139: 1460

    • For seminal related sulfenylation and selenylation, see:
    • 12h Denmark SE. Kalyani D. Collins WR. J. Am. Chem. Soc. 2010; 132: 15752
    • 12i Denmark SE. Jaune A. J. Am. Chem. Soc. 2013; 135: 6419
    • 12j Denmark SE. Chi HM. J. Am. Chem. Soc. 2014; 136: 3655
    • 12k Denmark SE. Chi HM. J. Am. Chem. Soc. 2014; 136: 8915

      For selected examples of bifunctional catalysts, see:
    • 13a Zhang W. Zheng S. Liu N. Werness JB. Guzei IA. Tang W. J. Am. Chem. Soc. 2010; 132: 3664
    • 13b Veitch GE. Jacobsen EN. Angew. Chem. Int. Ed. 2010; 49: 7332
    • 13c Paull DH. Fang C. Donald JR. Pansick AD. Martin SF. J. Am. Chem. Soc. 2012; 134: 11128
    • 13d Brindle CS. Yeung CS. Jacobsen EN. Chem. Sci. 2013; 4: 2100
    • 13e Tripathi CB. Mukherjee S. Org. Lett. 2014; 16: 3368
    • 13f Guo B. Fu C. Ma S. Chem. Commun. 2014; 4445
    • 13g Zhou L. Tan CK. Jiang X. Chen F. Yeung Y.-Y. J. Am. Chem. Soc. 2010; 132: 15474
    • 13h Zhou L. Chen J. Tan CK. Yeung Y.-Y. J. Am. Chem. Soc. 2011; 133: 9164
    • 13i Jiang X. Tan CK. Zhou L. Yeung Y.-Y. Angew. Chem. Int. Ed. 2012; 51: 7771
    • 13j Sawamura Y. Nakatsuji H. Sakakura A. Ishihara K. Chem. Sci. 2013; 4: 4181
    • 13k Cheng YA. Yu WZ. Yeung Y.-Y. Angew. Chem. Int. Ed. 2015; 54: 12102
    • 13l Sawamura Y. Ogura Y. Nakatsuji H. Sakakura A. Ishihara K. Chem. Commun. 2016; 6068
    • 14a Neverov AA. Brown RS. J. Org. Chem. 1998; 63: 5977
    • 14b Neverov AA. Feng HX. Hamilton K. Brown RS. J. Org. Chem. 2003; 68: 3812
    • 14c As nice examinations on the enantiodetermining step of a Lewis base-catalyzed bromocyclization, see: Böse D. Denmark SE. Synlett 2018; 29: 433

      For our recent studies on halofunctionalization, see:
    • 15a Ikeuchi K. Ido S. Yoshimura S. Asakawa T. Inai M. Hamashima Y. Kan T. Org. Lett. 2012; 14: 6016
    • 15b Ikeuchi K. Hayashi M. Yamamoto T. Inai M. Asakawa T. Hamashima Y. Kan T. Eur. J. Org. Chem. 2013; 6789
    • 15c Egami H. Ide T. Fujita M. Tojo T. Hamashima Y. Sodeoka M. Chem. Eur. J. 2014; 20: 12061
    • 15d Egami H. Ide T. Kawato Y. Hamashima Y. Chem. Commun. 2015; 16675
    • 15e Egami H. Asada J. Sato K. Hashizume D. Kawato Y. Hamashima Y. J. Am. Chem. Soc. 2015; 137: 10132
    • 15f Egami H. Yoneda T. Uku M. Ide T. Kawato Y. Hamashima Y. J. Org. Chem. 2016; 81: 4020
    • 15g Egami H. Masuda S. Kawato Y. Hamashima Y. Org. Lett. 2018; 20: 1367
    • 15h Egami H. Niwa T. Sato H. Hotta R. Rouno D. Kawato Y. Hamashima Y. J. Am. Chem. Soc. 2018; 140: 2785

      For oxazoline and related heterocycle-containing natural products, see:
    • 16a Bergeron RJ. Chem. Rev. 1984; 84: 587
    • 16b Davidson BS. Chem. Rev. 1993; 93: 1771
    • 16c Yeh VS. C. Tetrahedron 2004; 60: 11995
    • 16d You S.-L. Kelly JW. Chem. Eur. J. 2004; 10: 71
    • 16e Prinsep MR. Moore RE. Levine IA. Patterson GM. L. J. Nat. Prod. 1992; 55: 140
    • 16f Li Q. Woods KW. Claiborne A. Gwaltney SL. II. Barr KJ. Liu G. Gehrke L. Credo RB. Hui YH. Lee J. Warner RB. Kovar P. Nukkala MA. Zielinski NA. Tahir SK. Fitzgerald M. Kim KH. Marsh K. Frost D. Ng S.-C. Rosenberg S. Sham HL. Bioorg. Med. Chem. 2002; 12: 465
  • 17 As generally described in other examples, it cannot be ruled out that a carbocation intermediate would be generated in the reaction of 1c to explain the observed low enantioselectivity.
  • 18 Kawato Y. Kubota A. Ono H. Egami H. Hamashima Y. Org. Lett. 2015; 17: 1244

    • For preparation of bisphosphine monoxide compounds, see:
    • 19a Petersson MJ. Loughlin WA. Jenkins ID. Chem. Commun. 2008; 4493
    • 19b Boezio AA. Pytkowicz J. Côté A. Charette AB. J. Am. Chem. Soc. 2003; 125: 14260 ; See, also Ref. 22

      For selected examples on Lewis acid catalysis of phosphonium salts, see:
    • 20a Mukaiyama T. Matsui S. Kashiwagi K. Chem. Lett. 1989; 993
    • 20b Terada M. Kouchi M. Tetrahedron 2006; 62: 401
    • 20c Selva M. Perosa A. Tundo P. Brunelli D. J. Org. Chem. 2006; 71: 5770
    • 20d Hudnall TW. Kim Y.-M. Bebbington MW. P. Bourissou D. Gabbaï FP. J. Am. Chem. Soc. 2008; 130: 10890
    • 20e Tan C. Wang P. Liu H. Zhao X.-L. Lu Y. Liu Y. Chem. Commun. 2015; 10871
  • 21 In Modern Acetylene Chemistry . Trost BM. Li C.-J. Wiley-VCH; Weinheim: 2015
  • 22 For enantioselective bromolactonization of conjugate enynes for the preparation of chiral allenes, see: Zhang W. Liu N. Schienebeck CM. Decloux K. Zheng S. Werness JB. Tang W. Chem. Eur. J. 2012; 18: 7296 ; see, also Ref. 13a
  • 23 Kawato Y. Ono H. Kubota A. Nagao Y. Morita N. Egami H. Hamashima Y. Chem. Eur. J. 2016; 22: 2127

    • For general reviews on desymmetrization, see:
    • 24a García-Urdiales E. Alfonso I. Gotor V. Chem. Rev. 2005; 105: 313
    • 24b Studer A. Schleth F. Synlett 2005; 3033
    • 24c Wennemers H. Chem. Commun. 2011; 12036
    • 24d Díaz-de-Villegas MD. Gálvez JA. Badorrey R. López-Ram-de-Víu MP. Chem. Eur. J. 2012; 18: 13920
    • 24e Fernández-Pérez H. Etayo P. Lao JR. Núñez-Rico JL. Vidal-Ferran A. Chem. Commun. 2013; 10666
    • 24f Manna MS. Mukherjee S. Org. Biomol. Chem. 2015; 13: 18

      For reviews on desymmetrization of symmetric dienes, see:
    • 25a Willis MC. J. Chem. Soc., Perkin Trans. 1 1999; 1765
    • 25b Nakahara K. Fujioka H. Symmetry 2010; 2: 437
    • 25c Maertens G. Ménard M.-A. Canesi S. Synthesis 2014; 46: 1573
    • 25d Wang M. Feng M. Tang B. Jiang X. Tetrahedron Lett. 2014; 55: 7147
    • 25e Hennecke U. Wilking M. Synlett 2014; 25: 1633
    • 25f Petersen KS. Tetrahedron Lett. 2015; 56: 6523
    • 25g Borissov A. Davies TQ. Ellis SR. Fleming TA. Richardson MS. W. Dixon DJ. Chem. Soc. Rev. 2016; 45: 5474

      For recent examples of organocatalytic desymmetrization of electron-deficient dienes, see:
    • 26a Takizawa S. Nguyen TM.-N. Grossmann A. Enders D. Sasai H. Angew. Chem. Int. Ed. 2012; 51: 5423
    • 26b Rubush DM. Morges MA. Rose BJ. Thamm DH. Rovis T. J. Am. Chem. Soc. 2012; 134: 13554
    • 26c Corbett MT. Johnson JS. Chem. Sci. 2013; 4: 2828
    • 26d Wu W. Li X. Huang H. Yuan X. Lu J. Zhu K. Ye J. Angew. Chem. Int. Ed. 2013; 52: 1743
    • 26e Pantaine L. Coeffard V. Moreau X. Greck C. Org. Lett. 2015; 17: 3674
    • 26f Lin Q. Li Y. Das DK. Zhang G. Zhao Z. Yang S. Fang X. Chem. Commun. 2016; 6459

      For selected examples of transition-metal-catalyzed desymmetrization of unactivated dienes, see:
    • 27a Schreiber SL. Schreiber TS. Smith DB. J. Am. Chem. Soc. 1987; 109: 1525
    • 27b La DS. Alexander JB. Cefalo DR. Graf DD. Hoveyda AH. Schrock RR. J. Am. Chem. Soc. 1998; 120: 9720
    • 27c Sato Y. Sodeoka M. Shibasaki M. J. Org. Chem. 1989; 54: 4738
    • 27d Tamao K. Tohma T. Inui N. Nakayama O. Ito Y. Tetra­hedron Lett. 1990; 31: 7333
    • 28a Reactions of Alkenes . In Asymmetric Brønsted Acid Catalysis . Rueping M. Parmar D. Sugiono E. Wiley-VCH; Weinheim: 2016: 161
    • 28b Shapiro ND. Rauniyar V. Hamilton GL. Wu J. Toste FD. Nature 2011; 470: 245
    • 28c Sakakura A. Sakuma M. Ishihara K. Org. Lett. 2011; 13: 3130
    • 28d Sakuma M. Sakakura A. Ishihara K. Org. Lett. 2013; 15: 2838
    • 29a Inoue T. Kitagawa O. Saito A. Taguchi T. J. Org. Chem. 1997; 62: 7384
    • 29b As a seminal related kinetic resolution, see: Jaganathan A. Staples RJ. Borhan B. J. Am. Chem. Soc. 2013; 135: 14806 ; see, also 12e
  • 30 For a related one-pot protocol, see: Dai C. Genovino J. Bechle BM. Corbett MS. Huh CW. Rose CR. Sun J. Warmus JS. Blakemore DC. Org. Lett. 2017; 19: 1064
  • 31 Ito J. Nishiyama H. Synlett 2012; 23: 509
    • 32a Gaumont A.-C. Gulea M. Levillain J. Chem. Rev. 2009; 109: 1371
    • 32b Xavier J.-B. Fernando A. Mercedes A. Curr. Top. Med. Chem. 2014; 12: 1244
  • 33 Nagao Y. Hisanaga H. Egami H. Kawato Y. Hamashima Y. Chem. Eur. J. 2017; 23: 16758
    • 34a Patani GA. LaVoie EJ. Chem. Rev. 1996; 96: 3147
    • 34b Bursavich MG. Rich DH. J. Med. Chem. 2002; 45: 541
    • 34c Mason JD. Future Med. Chem. 2010; 12: 1813
    • 34d Meanwell NA. J. Med. Chem. 2011; 54: 2529
  • 35 For the first synthesis of Nelfinavir, see: Kaldor SW. Kalish VJ. Davies JF. II. Shetty BV. Fritz JE. Appelt K. Burgess JA. Campanale KM. Chirgadze NY. Clawson DK. Dressman BA. Hatch SD. Khalil DA. Kosa MB. Lubbehusen PP. Muesing MA. Patick AK. Reich SH. Su KS. Tatlock JH. J. Med. Chem. 1997; 40: 3979

    • For other synthetic routes to Nelfinavir and related molecules, see:
    • 36a Rieger DL. J. Org. Chem. 1997; 62: 8546
    • 36b Inaba T. Birchler AG. Yamada Y. Sagawa S. Yokota K. Ando K. Uchida I. J. Org. Chem. 1998; 63: 7582
    • 36c Inaba T. Yamada Y. Abe H. Sagawa S. Cho H. J. Org. Chem. 2000; 65: 1623
    • 36d Zook SE. Busse JK. Borer BC. Tetrahedron Lett. 2000; 41: 7017
    • 36e Albizati KF. Babu S. Birchler A. Busse JK. Fugett M. Grubbs A. Haddach A. Pagan M. Potts B. Remarchuk T. Rieger D. Rodriguez R. Shanley J. Szendroi R. Tibbetts T. Whitten K. Borer BC. Tetrahedron Lett. 2001; 42: 6481
    • 36f Kim BM. Bae SJ. So SM. Yoo HT. Chang SK. Lee JH. Kang J. Org. Lett. 2001; 3: 2349
    • 36g Ma D. Zou B. Zhu W. Xu H. Tetrahedron Lett. 2002; 43: 8511
    • 36h Ikunaka M. Matsumoto J. Fujima Y. Hirayama Y. Org. Process Res. Dev. 2002; 6: 49
    • 36i Sadagopan Raghavan S. Krishnaiah V. Sridhar B. J. Org. Chem. 2010; 75: 498
  • 37 For a review of the syntheses of the central carbon framework of HIV-protease inhibitors, see: Izawa K. Onishi T. Chem. Rev. 2006; 106: 2811

    • For recent reviews of Nelfinavir and other HIV-protease inhibitors for the treatment of cancer, see:
    • 38a Gantta S. Casper C. Ambinder RF. Curr. Opin. Oncol. 2013; 25: 495
    • 38b Maksimovic-Ivanic D. Fagone P. McCubrey J. Bendtzen K. Mijatovic S. Nicoletti F. Int. J. Cancer 2017; 140: 1713

      For selected examples of anticancer activities of Nelfinavir, see:
    • 39a Jiang W. Mikochik PJ. Ra JH. Lei H. Flaherty KT. Winkler JD. Spitz FR. Cancer Res. 2007; 67: 1221
    • 39b Brüning A. Burger P. Vogel M. Rahmeh M. Gingelmaier A. Friese K. Lenhard M. Burges A. Cancer Biol. Ther. 2009; 8: 226
    • 39c Zeng J. See AP. Aziz K. Thiyagarajan S. Salih T. Gajula RP. Armour M. Phallen J. Terezakis S. Kleinberg L. Redmond K. Hales RK. Salvatori R. Quinones-Hinojosa A. Tran PT. Lim M. Cancer Biol. Ther. 2011; 12: 657
    • 39d Guan M. Fousek K. Chow WA. FEBS J. 2012; 279: 2399
    • 39e Ismail WI. W. King JA. Anwar K. Pillay TS. J. Cell. Biochem. 2013; 114: 1729
    • 39f Xiang T. Du L. Pham P. Zhu B. Jiang S. Cancer. Lett. 2015; 364: 79
  • 40 Berthod M. Favre-Réguillon A. Mohamad J. Mignani G. Docherty G. Lemaire M. Synlett 2007; 1545

    • For the synthesis of 34, see:
    • 41a Houpis IN. Molina A. Reamer RA. Lynch JE. Volante RP. Reider PJ. Tetrahedron Lett. 1993; 34: 2593
    • 41b Gohring W. Gokhale S. Hilpert H. Roessler F. Schlageter M. Vogt P. Chimia 1996; 50: 532

      Selected examples for ozonolysis of tert-amine-containing substrates in the presence of acid additives, see:
    • 42a Ledoux S. Marchalant E. Célérier J.-P. Lhommet G. Tetrahedron Lett. 2001; 42: 5397
    • 42b Dieter RK. Watson R. Tetrahedron Lett. 2002; 43: 7725
    • 42c Brambilla M. Davies SG. Fletcher AM. Roberts PM. Thomson JE. Zimmer D. Tetrahedron 2016; 72: 7417
  • 43 Nagao Y. Hisanaga H. Utsumi T. Egami H. Kawato Y. Hamashima Y. J. Org. Chem. 2018; DOI 10.1021/acs.joc.8b00039