Unactivated Norbornenes in [3+2] Cycloadditions: Remarkably Stereo-controlled Entry into Norbornane-Fused Spirooxindolopyrrolidines, Spiro-1,3-indandionolylpyrrolidines, and Spirooxindolopyrrolizidines

Abstract

1,3-dipolar cycloaddition reactions of azomethine ylides with unactivated norbornene dipolarophiles and a highly diastereoselective synthesis of the novel norbornane-fused spirooxindolo­pyrrolidines, spiroacenaphthylenolylpyrrolidines, spiro-1,3-indan-dionolylpyrrolidines, and spirooxindolopyrrolizidines having an array of stereocenters are reported. The stereoselective synthesis of spirooxindolopyrrolizidines with eight stereocenters was demonstrated. Single-crystal X-ray structural analyses were performed to unambiguously establish the structure and stereochemistry of the key products.

Key words

1,3-dipolar cycloaddition - oxindoles - spiro compounds - stereoselective synthesis - ylides

References and Notes

• 1 Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 
• 2a Harwood LM. Vickers RJ. In Synthetic Applications of 1.3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson WH. Wiley; New York: 2003.  p.169-252  
• 2b Padwa A. 1,3-Dipolar Cycloaddition Chemistry   Wiley; New York: 1984. 
• 2c Coldham I. Hufton R. Chem. Rev.  2005,  105:  2765 
• 2d Pandey G. Banerjee P. Gadre SR. Chem. Rev.  2006,  106:  4484 
• 2e Nájera C. Sansano J. Org. Biomol. Chem.  2009,  7:  4567 
• 2f Chen Q.-A. Wang D.-S. Zhou Y.-G. Chem. Commun.  2010,  46:  4043 
• 2g Bonin B. Chauveau A. Micouin L. Synlett  2006,  2349 
• 2h Adrio J. Carretero JC. Chem. Commun.  2011,  47:  6784 
• 2i Huisgen R. Niklas K. Heterocycles  1984,  22:  21 
• 3a Galliford CV. Scheidt KA. Angew. Chem. Int. Ed.  2007,  46:  8748 
• 3b Krapcho AP. Synthesis  1974,  383 
• 3c Sannigrahi M. Tetrahedron  1999,  55:  9007 
• 3d Padwa A. Bur SK. Tetrahedron  2007,  63:  5341 
• 3e Francke W. Kitching W. Curr. Org. Chem.  2001,  5:  233 
• 3f Rosenberg S. Leino R. Synthesis  2009,  2651 
• 4a Zhou F. Liu Y.-L. Zhou J. Adv. Synth. Catal.  2010,  352:  1381 
• 4b Marti C. Carreira EM. Eur. J. Org. Chem.  2003,  2209 
• 5a Kornet MJ. Thio AP. J. Med. Chem.  1976,  19:  892 
• 5b Okita T. Isobe M. Tetrahedron  1994,  50:  11143 
• 5c Rosenmond P. Hosseini-Merescht M. Bub C. Liebigs Ann. Chem.  1994,  2:  151 
• 5d Abou-Gharbia MA. Doukas PH. Heterocycles  1979,  12:  637 
• 6a Shebahar PR. Williams RM. J. Am. Chem. Soc.  2000,  122:  5666 
• 6b Sebahar PR. Usui T. Williams RM. Tetrahedron  2002,  58:  6311 
• 7a Antonchick AP. Gerding-Reimers C. Catarinella M. Schürmann M. Preut H. Ziegler S. Rauh d. Waldmann H. Nature Chem.  2010,  2:  735 
• 7b Karthikeyan K. Saranya N. Kalaivani A. Perumal PT. Synlett  2010,  2751 
• 7c Karthikeyan K. Sivakumar PM. Doble M. Perumal PT. Eur. J. Med. Chem.  2010,  45:  3446 
• 7d Shanmugam P. Viswambharan B. Selvakumar K. Madhavan S. Tetrahedron Lett.  2008,  49:  2611 
• 7e Hemamalini A. Nagarajan S. Ravinder P. Subramanian V. Das TM. Synthesis  2011,  2495 
• 7f Purushothaman S. Prasanna R. Niranjana P. Raghunathan R. Nagaraj S. Rengusamy R. Bioorg. Med. Chem. Lett.  2010,  20:  7291 
• 7g Kumar RR. Perumal S. Senthilkumar P. Yogeeswari P. Sriram D. J. Med. Chem.  2008,  51:  5731 
• 7h Girgis AS. Eur. J. Med. Chem.  2009,  1257 
• 7i Nair V. Mathai S. Augustine A. Viji S. Radhakrishnan KV. Synthesis  2004,  2617 
• 7j Soret A. Müller C. Guillot R. Blanco L. Deloisy S. Tetrahedron  2011,  67:  698 
• 8a Warrener RN. Butler DN. Aldrichimica Acta  1997,  30:  119 
• 8b

  The stereochemistry of the major isomer of 31a was confirmed from the X-ray crystal structure analysis.

• 8c For 1,3-indandiones derivatives and their biological activities, see: Kabat HJ. Pharmacology  1994,  80:  160 
• 8d

  The stereochemistry of 33 and 34 was confirmed from the X-ray crystal structure analysis.

• 8e

  Based on the X-ray structure analyses of 36 and 37 (Figure  [³] ), and 46b the stereochemistry of other products in Schemes  [5] and  [6] was assigned.

9

Crystallographic data of all X-ray crystal structures reported in this work have been deposited with the Cambridge Crystallographic Data Centre under the following deposition numbers: CCDC 847073 (13), CCDC 847074 (14), CCDC 847075 (22), CCDC 847076 (30a), CCDC 847077 (31a), CCDC 847078 (33), CCDC 847079 (34), CCDC 847080 (36), CCDC 847081 (37), CCDC 847082 (43), and CCDC 847083 (46b).
Typical Experimental Procedure A dry flask containing N-methylisatin (5a, 161 mg, 1 mmol), sarcosine (6, 98 mg, 1.1 mmol), and the norbornene dipolarophile 7a (213 mg, 1 mmol) in EtOH (3 mL) was heated at 80 ˚C for 20 h under an inert atmosphere. After completion of the reaction (TLC monitoring), the flask containing the reaction mixture was cooled to r.t., and the solvent was evaporated under vacuum. Purification of the resulting crude reaction mixture by column chromatography on neutral alumina (EtOAc-hexanes = 60:40) gave the product 13 (220 mg, 55%).
Spectral Data for Compound 13
Colorless solid; mp 223-225 ˚C (MeOH-hexanes = 1:1). IR (KBr): 2948, 2906, 1750, 1717, 1606, 1467, 1437 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.56 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 7.11 (t, 1 H, J = 7.6 Hz), 6.85 (d, 1 H, J = 7.6 Hz), 4.88 (s, 1 H), 4.56 (s, 1 H), 3.68 (s, 3 H), 3.60 (s, 3 H), 3.47 (t, 1 H, J = 8.2 Hz), 3.20 (s, 3 H), 3.08 (d, 1 H, J = 9.6 Hz), 3.01-2.98 (m, 1 H), 2.87 (d, 1 H, J = 9.6 Hz), 2.89-2.85 (m, 1 H), 2.65 (d, 1 H, J = 8.2 Hz), 1.96 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 178.2, 171.1, 144.0, 129.4, 127.8, 126.1, 122.7, 108.3, 82.1, 80.4, 74.2, 58.4, 55.8, 52.2, 52.1, 51.5, 50.7, 47.5, 35.1, 26.3. MS (CI): m/z (%) = 402 (100) [M + 2]⁺, 401 (30) [M + 1]⁺ 195 (8), 175 (7), 111 (30), 79 (15). ESI-HRMS: m/z calcd for C₂₁H₂₄N₂O₆Na [M + Na]⁺: 423.1532; found: 423.1532 [M + Na]⁺.