Asymmetric Brønsted Acid Catalyzed Nucleophilic Addition to in situ Generated Chiral N-Acyliminium Ions

Abstract

A new enantioselective Brønsted acid catalyzed nucleophilic substitution of γ-hydroxylactams with indole is presented. The reaction proceeds via an intermediary N-acyliminium ion and provides disubstituted γ-lactams in good yields and with high enantioselectivities.

Key words

organocatalysis - nucleophilic substitution - protonation - amino acid - quaternary stereocenter

References and Notes

• 1 For a review on the stereoselective synthesis of γ-amino acids, see: Ordonez M. Cativiela C. Tetrahedron: Asymmetry  2007,  18:  3 
• 2a Rueping M. Nachtsheim BJ. Moreth SA. Bolte M. Angew. Chem. Int. Ed.  2008,  47:  593 
• For further developments of our initial observation, see:
• 2b Enders D. Narine AA. Toulgoat F. Bisschops T. Angew. Chem. Int. Ed.  2008,  47:  5661 
• 2c Shaikh RR. Mazzanti A. Petrini M. Bartoli G. Melchiorre P. Angew. Chem. Int. Ed.  2008,  47:  8707 
• 2d Sun FL. Zeng M. Gu Q. Shu SL. Chem. Eur. J.  2009,  15:  8709 
• 2e Guo QX. Peng YG. Zhang JW. Song L. Feng Z. Gong LZ. Org. Lett.  2009,  11:  4620 
• For reviews on N-acyliminium activation, see:
• 3a Petrini M. Torregiani E. Synthesis  2007,  159 
• 3b Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
• For the synthesis and structure of γ-amino acid oligomers, see:
• 4a Seebach D. Brenner M. Rueping M. Schweizer B. Jaun B. Chem. Commun.  2001,  207 
• 4b Seebach D. Brenner M. Rueping M. Jaun B. Chem. Eur. J.  2002,  8:  573 
• 4c Seebach D. Albert M. Arvidsson PI. Rueping M. Schreiber JV. Chimia  2001,  55:  345 
• Recent examples for organocatalytic N-acyliminium activation:
• 5a Myers EL. de Vries JG. Aggarwal VK. Angew. Chem. Int. Ed.  2007,  46:  1893 
• 5b Raheem IT. Thiara PS. Peterson EA. Jacobsen EN. J. Am. Chem. Soc.  2007,  129:  13404 
• 5c Mergott DJ. Zuend SJ. Jacobsen EN. Org. Lett.  2008,  10:  745 
• 5d Raheem IT. Thiara PS. Jacobsen EN. Org. Lett.  2008,  10:  1577 
• 5e Peterson EA. Jacobsen EN. Angew. Chem. Int. Ed.  2009,  48:  6328 
• 5f Muratore ME. Holloway CA. Pilling AW. Storer RI. Trevitt G. Dixon DJ. J. Am. Chem. Soc.  2009,  131:  10796 
• 5g For a review on organo-catalytic reactions in natural product synthesis, see: De Figueiredo RM. Christmann M. Eur. J. Org. Chem.  2007,  2575 
• N-Triflylphosphoramides were first described by Yamamoto et al. in 2006:
• 6a Nakashima D. Yamamoto H. J. Am. Chem. Soc.  2006,  128:  9626 
• 6b Jiao P. Nakashima D. Yamamoto H. Angew. Chem. Int. Ed.  2008,  47:  2411 
• 6c Kawasaki M. Li P. Yamamoto H. Angew. Chem. Int. Ed.  2008,  47:  3795 
• 7a Rueping M. Ieawsuwan W. Antonchick AP. Nachtsheim BJ. Angew. Chem. Int. Ed.  2007,  46:  2097 
• 7b Rueping M. Theismann T. Kuenkel A. Koenigs RM. Angew. Chem. Int. Ed.  2008,  47:  2097 
• 7c Rueping M. Ieawsuwan W. Adv. Synth. Catal.  2009,  351:  78 
• For reviews on Brønsted acid catalysis, see:
• 8a Akiyama T. Chem. Rev.  2007,  107:  5744 
• 8b Doyle AG. Jacobsen EN. Chem. Rev.  2007,  107:  5713 
• Examples of chiral phosphoric acid catalyzed reactions from our laboratory:
• 9a Rueping M. Azap C. Sugiono E. Theissmann T. Synlett  2005,  2367 
• 9b Rueping M. Sugiono E. Azap C. Theissmann T. Bolte M. Org. Lett.  2005,  7:  3781 
• 9c Rueping M. Antonchick AP. Theissmann T. Angew. Chem. Int. Ed.  2006,  45:  3683 
• 9d Rueping M. Antonchick AP. Theissmann T. Angew. Chem. Int. Ed.  2006,  45:  6751 
• 9e Rueping M. Theissmann T. Antonchick AP. Synlett  2006,  1071 
• 9f Rueping M. Sugiono E. Azap C. Angew. Chem. Int. Ed.  2006,  45:  2617 
• 9g Rueping M. Azap C. Angew. Chem. Int. Ed.  2006,  45:  7832 
• 9h Rueping M. Sugiono E. Theissmann T. Kuenkel A. Köckritz A. Pews-Davtyan A. Nemati N. Beller M. Org. Lett.  2007,  9:  1065 
• 9i Rueping M. Sugiono E. Moreth SA. Adv. Synth. Catal.  2007,  349:  759 
• 9j Rueping M. Sugiono E. Schoepke FR. Synlett  2007,  1441 
• 9k Rueping M. Antonchick AP. Angew. Chem. Int. Ed.  2007,  46:  4562 
• 9l Rueping M. Antonchick AP. Brinkmann C. Angew. Chem. Int. Ed.  2007,  46:  6903 
• 9m Rueping M. Theissmann T. Raja S. Bats JW. Adv. Synth. Catal.  2008,  350:  1001 
• 9n Rueping M. Antonchick AP. Org. Lett.  2008,  10:  1731 
• 9o Rueping M. Antonchick AP. Angew. Chem. Int. Ed.  2008,  47:  5836 
• 9p Rueping M. Antonchick AP. Angew. Chem. Int. Ed.  2008,  47:  10090 
• 9q Rueping M. Antonchick AP. Sugiono E. Grenader K. Angew. Chem. Int. Ed.  2009,  48:  908 

10

Typical Experimental Procedure Indole (0.1 mmol) and Brønsted acid catalyst (0.05 mmol) were dissolved in dry CH₂Cl₂ (1 mL), and the solution was cooled down to -65 ˚C. Hydroxylactam 1b (0.2 mmol) were dissolved in dry CH₂Cl₂ (0.3 mL) and slowly added to the cooled indole solution within 5 min. The reaction was stirred at -65 ˚C for 48 h, and the crude reaction mixture was purified by chromatography (hexane-EtOAc, 1:1) to yield 18 mg (54%) of 2b as a yellow oil which solidified upon standing.
Selected Data2b: ^¹H NMR (250 MHz, CDCl₃): δ = 8.49 (s, 1 H), 7.42-7.31 (m, 2 H), 7.20-7.14 (m, 1 H), 7.05-6.93 (m, 4 H), 6.66-6.60 (m, 2 H), 4.78 (d, J = 14.97 Hz, 1 H), 3.67 (s, 3 H), 3.55 (d, J = 14.90 Hz, 1 H), 2.65-2.42 (m, 3 H), 2.03-1.92 (m, 1 H), 1.39 (s, 3 H). ^¹³C NMR (63 MHz, CDCl₃): δ = 175.1, 158.6, 137.2, 131.1, 129.5, 124.9, 122.4, 122.4, 120.1, 119.8, 119.7, 113.6, 111.6, 63.5, 55.2, 43.4, 34.7, 30.1, 26.4. IR (neat): ν = 3271, 2967, 2930, 1652, 1511, 1436, 1409, 1246, 1030, 743 cm^-¹. MS (EI): m/z (%) = 334.2 (31) [M] ⁺, 157.2 (76) [M - C₁₀H₁₁NO₂] ⁺.
2d: Yellow oil. ^¹H NMR (250 MHz, CDCl₃): δ = 8.29 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.18-6.99 (m, 4 H), 6.88 (d, J = 2.50 Hz, 1 H), 6.83-6.74 (m, 1 H), 6.65 (d, J = 8.2 Hz, 1 H), 4.67 (d, J = 16.1 Hz, 1 H), 3.99 (d, J = 16.1 Hz, 1 H), 3.58 (s, 3 H), 2.67-2.42 (m, 3 H), 2.13-1.98 (m, 1 H), 1.50 (s, 3 H). ^¹³C NMR (63 MHz, CDCl₃):
δ = 175.6, 156.6, 137.2, 128.8, 127.9, 126.5, 124.9, 122.3, 122.1, 120.3, 119.9, 119.8, 111.5, 109.9, 63.7, 55.0, 38.5, 34.8, 30.2, 26.1. IR (neat): ν = 3270 (br), 2967, 1654, 1491, 1460, 1434, 1408, 1240, 1162, 1113, 1021, 749 cm^-¹.
MS (EI): m/z (%) = 334.2 (23) [M] ⁺, 157.1 (61) [M - C₁₀H₁₁NO₂] ⁺.