Catalytic Asymmetric 6π-Electrocyclization: Accessing Highly Substituted Optically Active 2-Pyrazolines via Diastereoselective Alkylations

Abstract

The chiral phosphoric acid catalyzed asymmetric electrocyclization of α,β-unsaturated hydrazones has been studied. This reaction is one of the first catalytic asymmetric 6π-electrocyclizations reported, and enables the synthesis of 2-pyrazolines in high yields and enantiomeric ratios. The obtained products are not only interesting because of their pharmaceutical properties, but can be manipulated in highly diastereoselective fashion, as shown for alkylation reactions. Thus, the combination of catalytic asymmetric 6π-electrocyclization followed by diastereoselective alkylation can provide interesting synthetic building blocks in optically active form.

Key words

electrocyclic reactions - enantioselective organocatalysis - heterocycles - diastereoselectivity - 2-pyrazolines

References

• 1a Kagan HB. Riant O. Chem. Rev.  1992,  92:  1007 
• 1b Gothelf KV. Jørgensen KA. Chem. Rev.  1998,  98:  863 
• 1c Jørgensen KA. Angew. Chem. Int. Ed.  2000,  39:  3558 ; Angew. Chem. 2000, 112, 3702
• 1d Corey EJ. Angew. Chem. Int. Ed.  2002,  41:  1650 ; Angew. Chem. 2002, 114, 1724
• 1e Stanley LM. Sibi MP. Chem. Rev.  2008,  108:  2887 
• 1f Cycloaddition Reactions in Organic Synthesis   Kobayashi S. Jørgensen KA. Wiley-VCH; Weinheim: 2002. 
• For reviews, see:
• 2a The Claisen Rearrangement   Hiersemann M. Nubbemeyer U. Wiley-VCH; Weinheim: 2007. 
• 2b Hiersemann M. Abraham L. Eur. J. Org. Chem.  2002,  1461 
• 2c Nubbemeyer U. Synthesis  2003,  961 
• 2d Martín Castro AM. Chem. Rev.  2004,  104:  2939 
• For selected recent examples, see:
• 2e Abraham L. Czerwonka R. Hiersemann M. Angew. Chem. Int. Ed.  2001,  40:  4700 ; Angew. Chem. 2001, 113, 4835
• 2f Anderson CE. Overman LE. J. Am. Chem. Soc.  2003,  125:  12412 
• 2g Uyeda C. Jacobsen EN. J. Am. Chem. Soc.  2008,  130:  9228 
• 2h Rueping M. Antonchick AP. Angew. Chem. Int. Ed.  2008,  47:  10090 ; Angew. Chem. 2008, 120, 10244
• 3a Liang G. Gradl SN. Trauner D. Org. Lett.  2003,  5:  4931 
• 3b Aggarwal VK. Belfield AJ. Org. Lett.  2003,  5:  5075 
• 3c Liang G. Trauner D. J. Am. Chem. Soc.  2004,  126:  9544 
• 4a Walz I. Togni A. Chem. Commun.  2008,  4315 
• 4b Yaji K. Shindo M. Synlett  2009,  2524 
• For organocatalytic examples, see:
• 4c Rueping M. Ieawsuwan W. Antonchick AP. Nachtsheim BJ. Angew. Chem. Int. Ed.  2007,  46:  2097 ; Angew. Chem. 2007, 119, 2143
• 4d Rueping M. Ieawsuwan W. Adv. Synth. Catal.  2009,  351:  78 
• The development of a catalytic non-asymmetric 6π-electrocyclization was first achieved by Bergman and Trauner, see:
• 5a Bishop LM. Barbarow JE. Bergman RG. Trauner D. Angew. Chem. Int. Ed.  2008,  47:  8100 ; Angew. Chem. 2008, 120, 8220
• This work was highlighted in:
• 5b Tantillo DJ. Angew. Chem. Int. Ed.  2009,  48:  31 ; Angew. Chem. 2009, 121, 33
• 6 Müller S. List B. Angew. Chem. Int. Ed.  2009,  48:  9975 ; Angew. Chem. 2009, 121, 10160
• 7 Maciver EE. Thompson S. Smith MD. Angew. Chem. Int. Ed.  2009,  48:  9979 ; Angew. Chem. 2009, 121, 10164
• 8 Both reactions were highlighted in: Vicario JL. Badia D. ChemCatChem  2010,  2:  375 
• 9 Fischer E. Knoevenagel O. Justus Liebigs Ann. Chem.  1887,  239:  194 
• 10 Huisgen R. Angew. Chem. Int. Ed.  1980,  19:  947 ; Angew. Chem. 1980, 92, 979
• For reviews on chiral phosphoric acid catalysis, see:
• 11a Akiyama T. Chem. Rev.  2007,  107:  5744 
• 11b Terada M. Chem. Commun.  2008,  4097 
• 12a Cuberes R, Berrocal J, Contijoch M, and Frigola J. inventors; WO  99/62884. 
• 12b Calvet C. Cuberes R. Pérez-Maseda C. Frigola J. Electrophoresis  2002,  23:  1702 
• 13 For a review, see: Kumar S. Bawa S. Drabu S. Kumar R. Gupta H. Recent Pat. Anti-Infect. Drug Discovery  2009,  4:  154 
• For selected examples, see:
• 14a 2-Pyrazolines in natural product synthesis, see: Whitlock GA. Carreira EM. J. Org. Chem.  1997,  62:  7916 
• 14b Whitlock GA. Carreira EM. Helv. Chim. Acta  2000,  83:  2007 
• 14c For reduction of activated 2-pyrazolines, see: De los Santos JM. López Y. Aparicio D. Palacios F. J. Org. Chem.  2008,  73:  550 
• 14d For alkylation of 1,3,5-triarylpyrazolines, see: Huang YR. Katzenellenbogen JA. Org. Lett.  2000,  2:  2833 
• 14e For nucleophilic additions to 3-unsubstituted 2-pyrazolines, see: Guerra FM. Mish MR. Carreira EM. Org. Lett.  2000,  2:  4265 
• 15 Nishiyama H. Arai H. Kanai Y. Kawashima H. Itoh K. Tetrahedron Lett.  1986,  27:  361 
• 16a Hearn MJ. Lebold SA. Sinha A. Sy K. J. Org. Chem.  1989,  54:  4188 
• 16b Harej M. Dolenc D. J. Org. Chem.  2007,  72:  7214