Enantioselective Diels-Alder Reactions: Effect of the Achiral Template on Reactivity and Selectivity

Abstract

Several achiral templates have been evaluated in chiral Lewis acid mediated enantioselective Diels-Alder reactions. Templates such as pyrrolidinones and pyrazolidinones that are capable of forming six-membered chelates with the Lewis acid exhibited the best reactivity and highest selectivity.

Key words

Diels-Alder - achiral template - chiral Lewis acid - chelation

References and Notes

• For comprehensive reviews on enantioselective Diels-Alder reactions, see:
• 1a Corey EJ. Angew. Chem. Int. Ed.  2002,  41:  1650 
• 1b Dias LC. J. Brazilian Chem. Soc.  1997,  8:  289 
• 2 For a recent review on chiral bis(oxazolines), see: Desimoni G. Faita G. Jørgensen KA. Chem. Rev.  2006,  106:  3561 
• 3a Evans DA. Miller SJ. Lectka T. von Matt P. J. Am. Chem. Soc.  1999,  121:  7559 
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• 3c Evans DA. Murry JA. von Matt P. Norcross RD. Miller SJ. Angew. Chem., Int. Ed. Engl.  1995,  34:  798 
• 3d Evans DA. Miller SJ. Lectka T. J. Am. Chem. Soc.  1993,  115:  6460 
• 4 Kanemasa S. Oderaotoshi Y. Sakaguchi S.-i. Yamamoto H. Tanaka J. Wada E. Curran DP. J. Am. Chem. Soc.  1998,  120:  3074 
• 5a Carbone P. Desimoni G. Faita G. Filippone S. Righetti P. Tetrahedron  1998,  54:  6099 
• 5b Desimoni G. Faita G. Righetti P. Sardone N. Tetrahedron  1996,  52:  12019 
• 5c Corey EJ. Ishihara K. Tetrahedron Lett.  1992,  33:  6807 
• 6a

  See ref. 3a.

• 6b Takacs JM. Lawson EC. Reno MJ. Youngman MA. Quincy DA. Tetrahedron: Asymmetry  1997,  8:  3073 
• 6c Evans DA. Kozlowski MC. Tedrow JS. Tetrahedron Lett.  1996,  37:  7481 
• 7 Evans DA. Johnson JS. Burgey CS. Campos KR. Tetrahedron Lett.  1999,  40:  2879 
• 8a Davies IW. Gerena L. Cai D. Larson RD. Verhoeven TR. Reider PJ. Tetrahedron Lett.  1997,  38:  1145 
• 8b Davies IW. Gerena L. Castonguay L. Senanayake CH. Larson RD. Verhoeven TR. Reider PJ. Chem. Commun.  1996,  1753 
• 9a Evans DA. Olhava EJ. Johnson JS. Janey JM. Angew. Chem. Int. Ed.  1998,  37:  3372 
• 9b Ghosh AK. Cho H. Cappiello J. Tetrahedron: Asymmetry  1998,  9:  3687 
• 10 Evans DA. Miller SJ. Lectka T. Tetrahedron Lett.  1993,  34:  7027 
• 11a

  See ref. 3d and 4. For select additional examples, see:

• 11b Sibi MP. Venkatraman L. Liu M. Jasperse CP. J. Am. Chem. Soc.  2001,  123:  8444 
• 11c Jensen KB. Gothelf KV. Hazell RG. Jørgensen KA. J. Org. Chem.  1997,  62:  2471 
• 11d Corey EJ. Houpis IN. Tetrahedron Lett.  1993,  34:  2421 
• 12a

  See ref. 8b. For recent examples from our laboratory, see:

• 12b Sibi MP. Stanley LM. Jasperse CP. J. Am. Chem. Soc.  2005,  127:  8276 
• 12c Sibi MP. Petrovic G. Zimmerman J. J. Am. Chem. Soc.  2005,  127:  2390 
• 12d Sibi MP. Prabagaran N. Ghorpade SG. Jasperse CP. J. Am. Chem. Soc.  2003,  125:  11796 
• Templates 3, 4, 8 and 11-14 are commercially available. Templates 5-7, 9, and 10 were prepared using literature procedures. For compound 5, see:
• 14a Reddy PA. Hsiang BCH. Latifi TN. Hill W. Woodward KE. Rothman SM. Ferrendelli JA. Covey DA. J. Med. Chem.  1996,  39:  1898 
• For compounds 6 and 7, see:
• 14b Bhatia PA. Brooks CDW. Basha A. Ratajczyk JD. Gunn BP. Bouska JB. Lanni C. Young PR. Bell RL. Carter GW. J. Med. Chem.  1996,  39:  3938 
• 14c Basha A. Tetrahedron Lett.  1988,  29:  2525 
• 14d

  For compound 9, see ref. 11b.

• 15 Akiyama T. Horiguchi N. Ida T. Ozaki S. Chem. Lett.  1995,  975 
• 16a Sibi MP. Guerrero MA. Synthesis  2005,  1528 
• 16b Sibi MP. Shay JJ. Liu M. Jasperse CP. J. Am. Chem. Soc.  1998,  120:  6815 
• 16c Sibi MP. Shay JJ. Ji J. Tetrahedron Lett.  1997,  38:  5955 
• 16d

  See ref. 12c.

• 17 Koukcovsky C. Pouilhes A. Langlois Y. J. Am. Chem. Soc.  1990,  112:  6672 
• 18a

  See ref. 3c.

• 18b

  General Procedure for the Enantioselective Diels-Alder Reactions.
  A mixture of 1 (20 mg, 0.055 mmol) and Cu(OTf)₂ (18 mg, 0.05 mmol) in CH₂Cl₂ (2 mL) was stirred at r.t. for 1 h to give a clear green solution. A solution of dienophile (0.5 mmol) in CH₂Cl₂ (2 mL) was added at the temperature given in the tables, followed by freshly distilled cyclopentadiene (165 mg, 2.5 mmol). The reaction was monitored by TLC. After completion of the reaction, H₂O (2 mL) was added and the mixture was extracted with CH₂Cl₂, washed with brine and dried. The solvent was evaporated and the residue was purified by chromatography to give pure product. The endo/exo ratio was evaluated on the basis of ¹H NMR spectrum and the enantiomeric purity was determined by HPLC.
  DA Adduct from Compound 4. [α]_D ²⁵ -176.3 (c 2.2, CHCl₃); 97% ee estimated on the basis of HPLC using a chiral column [Daicel Chiralcel AD with hexane-2-PrOH, 97:3 v/v, 0.5 mL/min, t _R (S-isomer) = 34.5 min, t _R (R-isomer) = 30.4 min].
  ¹H NMR (400 MHz, CDCl₃): δ = 1.30-1.50 (m, 3 H), 1.82-1.90 (m, 1 H), 1.93-2.02 (m, 2 H), 2.57 (t, J = 8.0 Hz, 2 H), 2.86 (s, 1 H), 3.20 (s, 1 H), 3.64-3.76 (m, 2 H), 3.90-3.97 (m, 1 H), 5.80 (dd, J = 5.6, 2.7 Hz, 1 H), 6.17 (dd, J = 5.6, 3.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.3, 29.4, 34.1, 42.9, 44.7, 46.0, 46.2, 50.2, 131.8, 137.9, 175.1, 175.6.
  DA Adduct from Compound 5. [α]_D ²⁵ -164.76 (c 2.1, CHCl₃); 99% ee estimated on the basis of HPLC using a chiral column [Daicel Chiralcel OD with hexane-2-PrOH, 99:1 v/v, 0.6 mL/min, t _R (S-isomer) = 18.8 min, t _R (R-isomer) = 22.9 min].
  ¹H NMR (400 MHz, CDCl₃): δ = 1.16 (s, 3 H), 1.20 (s, 3 H), 1.32-1.47 (m, 3 H), 1.78-1.91 (m, 3 H), 2.87 (s, 1 H), 3.20 (s, 1 H), 3.56-3.66 (m, 2 H), 3.92-3.98 (m, 1 H), 5.81 (dd, J = 5.6, 3.0 Hz, 1 H), 6.18 (dd, J = 5.6, 3.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.4, 24.5, 29.4, 32.4, 42.1, 42.9, 43.2, 44.7, 46.2, 50.1, 131.8, 138.0, 176.0, 180.1.
  DA Adduct from Compound 9. [α]_D ²⁵ -129.3 (c 1.0, CHCl₃); 98% ee estimated on the basis of HPLC using a chiral column [Daicel Chiralcel OD-H with hexane-2-PrOH, 98:2 v/v, 1.0 mL/min, t _R (S-isomer) = 22.6 min, t _R (R-isomer) = 24.3 min].
  ¹H NMR (400 MHz, CDCl₃): δ = 1.18 (s, 6 H), 1.31-1.46 (m, 3 H), 1.83 (ddd, J = 11.6, 9.2, 3.6 Hz, 1 H), 2.52 (d, J = 17.2 Hz, 1 H), 2.58 (d, J = 17.2 Hz, 1 H), 2.87 (s, 1 H), 3.19 (s, 1 H), 3.79 (dt, J = 7.6, 4.0 Hz, 1 H), 3.98 (d, J = 14.0 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 5.76 (dd, J = 5.6, 3.2 Hz, 1 H), 6.17 (dd, J = 5.6, 3.2 Hz, 1 H), 7.18-7.22 (m, 1 H), 7.24-7.28 (m, 2 H), 7.42-7.45 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.3, 26.5, 29.5, 43.0, 44.1, 44.5, 46.3, 50.2, 57.0, 60.7, 127.4, 128.4, 129.0, 131.7, 138.1, 138.3, 171.7, 174.3.
  DA Adduct from Compound 17. [α]_D ²⁵ -155.9 (c 1.2, CHCl₃); 98% ee estimated on the basis of HPLC using a chiral column after conversion to the known benzyl ester [Daicel Chiralcel OJ with hexane-EtOH-i-PrOH, 100:0.5:0.4, 0.25 mL/min, t _R (S-isomer) = 47.4 min, t _R (R-isomer) = 50.6 min].
  ¹H NMR (500 MHz, CDCl₃): δ = 1.12 (d, J = 7.3 Hz, 3 H), 1.23 (s, 3 H), 1.25 (s, 3 H), 1.44-1.46 (m, 1 H), 1.69 (d, J = 8.3 Hz, 1 H), 2.11-2.13 (m, 1 H), 2.52 (s, 1 H), 2.62 (s, 2 H), 3.20 (s, 1 H), 3.40 (dd, J = 3.9, 3.4 Hz, 1 H), 4.03 (AB q, J = 17.6, 14.2 Hz, 2 H), 5.73 (dd, J = 5.9, 2.9 Hz, 1 H), 6.36 (dd, J = 5.9, 2.9 Hz, 1 H), 7.25-7.34 (m, 3 H), 7.48-7.50 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 20.7, 26.4, 26.6, 36.5, 44.3, 47.2, 47.3, 49.7, 52.8, 57.1, 60.8, 127.6, 128.6, 129.1, 131.1, 138.4, 140.0, 171.6, 174.6.

13

All new compounds showed analytical and spectral characteristics consistent with their structure. An experimental procedure and spectral data for select cycloadducts are provided.