direct organocatalytic asymmetric heterodomino reactions

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Direct Organocatalytic Asymmetric Heterodomino Reactions: The Knoevenagel/Diels-Alder/Epimerization Sequence for the Highly Diastereoselective Synthesis of Symmetrical and Nonsymmetrical Synthons of Benzoannelated Centropolyquinanes D. B. Ramachary, K. Anebouselvy, Naidu S. Chowdari, and Carlos F. Barbas III* The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 [email protected] Received March 12, 2004 Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/ Diels-Alder/epimerization reactions of readily available various precursor enones (1a-l), aldehydes (2a-p), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted, symmetrical and nonsymmetrical spiro[cyclohexane-1,2-indan]-1,3,4-triones (5) in a highly diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation of arylaldehydes (2a-p) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3- indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine- catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/ Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellent starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields. Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retro- Michael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5ab in moderate yield from enone 1a and 1,3-indandione 3. Introduction Critical objectives in modern synthetic organic chem- istry include the improvement of reaction efficiency, the avoidance of toxic reagents, the reduction of waste, and the responsible utilization of our resources. Domino or tandem reactions, which consist of several bond-forming reactions, address many of these objectives. Domino reactions involve two or more bond-forming transforma- tions that take place under the same reaction conditions. Combinations of reactions involving the same mechanism are classified as homodomino reactions, whereas a se- quence of reactions with different mechanisms are clas- sified as heterodomino reactions. 1 One of the ultimate goals in organic synthesis is the catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products, a process that ultimately mimics biological synthesis. In this regard, the development of domino and other mul- ticomponent reaction methodologies can provide expedi- ent access to complex products from simple starting materials. 2 Domino reactions have gained wide accep- tance because they increase synthetic efficiency by decreasing the number of laboratory operations required and the quantities of chemicals and solvents used. Thus, these reactions can facilitate ecologically and economi- cally favorable syntheses. Recently organocatalysis has emerged as a promising synthetic tool for constructing C-C, C-N, and C-O bonds in aldol, 3 Michael, 4 Mannich, 5 Diels-Alder, 6 and related reactions 7 in highly diastereo- and enantioselec- tive processes. In these recently described reactions, structurally simple and stable chiral organoamines fa- cilitate iminium- and enamine-based transformations with carbonyl compounds. Often, the organocatalysts can be used in operationally simple and environmentally friendly experimental protocols. Because these reactions * To whom correspondence should be addressed. Fax: +1-858-784- 2583. (1) (a) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, 679. (b) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, 809. (2) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 1759. (b) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Chem. Pharm. Bull. 1982, 30, 3092. (c) Cane, D. E. Chem. Rev. 1990, 90, 1089. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (e) Tietze, L. F. Chem. Rev. 1996, 96, 115. (f) Krystyna, B. S.; Malgorzata, K.; Wojciech, K. Wiad. Chem. 1997, 51, 643. (g) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304. (h) Mayer, S. F.; Kroutil, W.; Faber, K. Chem. Soc. Rev. 2001, 30, 332. (i) Tietze, L. F.; Evers, T. H.; Topken, E. Angew. Chem., Int. Ed. 2001, 40, 903. (j) Tietze, L. F.; Evers, H.; Topken, E. Helv. Chim. Acta 2002, 85, 4200. (k) Glueck, S. M.; Mayer, S. F.; Kroutil, W.; Faber, K. Pure Appl. Chem. 2002, 74, 2253. 5838 J. Org. Chem. 2004, 69, 5838-5849 10.1021/jo049581r CCC: $27.50 © 2004 American Chemical Society Published on Web 08/06/2004

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No Job NameSynthons of Benzoannelated Centropolyquinanes D. B. Ramachary, K. Anebouselvy, Naidu S. Chowdari, and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
[email protected] Received March 12, 2004
Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/ Diels-Alder/epimerization reactions of readily available various precursor enones (1a-l), aldehydes (2a-p), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted, symmetrical and nonsymmetrical spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones (5) in a highly diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation of arylaldehydes (2a-p) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3- indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine- catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/ Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellent starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields. Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retro- Michael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5ab in moderate yield from enone 1a and 1,3-indandione 3.
Introduction
Critical objectives in modern synthetic organic chem- istry include the improvement of reaction efficiency, the avoidance of toxic reagents, the reduction of waste, and the responsible utilization of our resources. Domino or tandem reactions, which consist of several bond-forming reactions, address many of these objectives. Domino reactions involve two or more bond-forming transforma- tions that take place under the same reaction conditions. Combinations of reactions involving the same mechanism are classified as homodomino reactions, whereas a se- quence of reactions with different mechanisms are clas- sified as heterodomino reactions.1 One of the ultimate goals in organic synthesis is the catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products, a process that ultimately mimics biological synthesis. In this regard, the development of domino and other mul- ticomponent reaction methodologies can provide expedi- ent access to complex products from simple starting
materials.2 Domino reactions have gained wide accep- tance because they increase synthetic efficiency by decreasing the number of laboratory operations required and the quantities of chemicals and solvents used. Thus, these reactions can facilitate ecologically and economi- cally favorable syntheses.
Recently organocatalysis has emerged as a promising synthetic tool for constructing C-C, C-N, and C-O bonds in aldol,3 Michael,4 Mannich,5 Diels-Alder,6 and related reactions7 in highly diastereo- and enantioselec- tive processes. In these recently described reactions, structurally simple and stable chiral organoamines fa- cilitate iminium- and enamine-based transformations with carbonyl compounds. Often, the organocatalysts can be used in operationally simple and environmentally friendly experimental protocols. Because these reactions
* To whom correspondence should be addressed. Fax: +1-858-784- 2583.
(1) (a) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, 679. (b) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, 809.
(2) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 1759. (b) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Chem. Pharm. Bull. 1982, 30, 3092. (c) Cane, D. E. Chem. Rev. 1990, 90, 1089. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (e) Tietze, L. F. Chem. Rev. 1996, 96, 115. (f) Krystyna, B. S.; Malgorzata, K.; Wojciech, K. Wiad. Chem. 1997, 51, 643. (g) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304. (h) Mayer, S. F.; Kroutil, W.; Faber, K. Chem. Soc. Rev. 2001, 30, 332. (i) Tietze, L. F.; Evers, T. H.; Topken, E. Angew. Chem., Int. Ed. 2001, 40, 903. (j) Tietze, L. F.; Evers, H.; Topken, E. Helv. Chim. Acta 2002, 85, 4200. (k) Glueck, S. M.; Mayer, S. F.; Kroutil, W.; Faber, K. Pure Appl. Chem. 2002, 74, 2253.
5838 J. Org. Chem. 2004, 69, 5838-5849 10.1021/jo049581r CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004
1,3-indandione.6b Herein, we report the first direct orga- nocatalytic asymmetric hetero-domino Knoevenagel/Di- els-Alder/epimerization (K-DA-E) reaction sequence to generate highly substituted spiro[cyclohexane-1,2′-in- dan]-1′,3′,4-triones (5) in a highly diastereoselective and modestly enantioselective process from commercially available 4-substituted-3-buten-2-ones (1a-l), aldehydes (2a-p), and 1,3-indandione (3) as shown in Scheme 1. Spirocyclic ketones (5) are attractive intermediates in the
(3) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (c) Cordova, A. Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301. (d) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 9591. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (f) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Jorgensen, K. A. Chem. Commun. 2002, 620. (g) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167. (h) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Qiao, A.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (i) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (j) Liu, H.; Peng, L.; Zhang, T.; Li, Y. New J. Chem. 2003, 27, 1159. (k) Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090. (l) Loh, T.-P.; Feng, L.-C.; Yang, H.- Y.; Yang, J.-Y. Tetrahedron Lett. 2002, 43, 8741. (m) Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E. Chem. Commun. 2002, 2510. (n) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (o) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(4) (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441. (b) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. (d) Enders, D.; Seki, A. Synlett 2002, 26. (e) Halland, N.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2002, 67, 8331. (f) List, B.; Castello, C. Synlett 2001, 11, 1687. (g) Olivier, A.; Alexandre, A.; Gerald, B. Org. Lett. 2003, 5, 2559. (h) Melchiorre, P.; Jorgensen, K. A. J. Org. Chem. 2003, 68, 4151. (i) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661. (j) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (k) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(5) (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199. (b) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (c) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866. (d) Watanabe, S.; Cordova, A.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2002, 4, 4519. (e) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett 2003, 12, 1905. (f) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923. (g) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (h) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677. (i) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (j) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208. (k) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624.
(6) (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2003, 42, 4233. (b) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Synlett 2003, 12, 1909. (c) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 6743. (d) Thayumanavan, R.; Ramachary, D. B.; Sakthivel, K.; Tanaka, F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (f) Nakamura, H.; Yamamoto, H. Chem. Commun. 2002, 1648. (g) Juhl, K.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (h) Cavill, J. L.; Peters, J. U.; Tomkinson, N. C. O. Chem. Commun. 2003, 728. (i) Barluenga, J.; Sobirino, A. S.; Lopez, L. A. Aldrichim. Acta 1999, 32, 4. (j) Asato, A. E.; Watanabe, C.; Li, X.-Y.; Liu, R. S. H. Tetrahedron Lett. 1992, 33, 3105. (k) Jung, M. E.; Vaccaro, W. D.; Buszek, K. R. Tetrahedron Lett. 1989, 30, 1893.
(7) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Rajagopal, D.; Moni, M. S.; Subramanian, S.; Swaminathan, S. Tetrahedron: Asymmetry 1999, 10, 1631. (d) Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951. (e) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew. Chem., Int. Ed. Engl. 2002, 41, 1790. (f) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (g) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2003, 5, 1685. (h) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (i) Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448. (j) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808. (k) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, ASAP July 10, 2004.
SCHEME 1. Organocatalytic Heterodomino K-DA-E Reaction of 4-Substituted 3-Buten-2-ones 1a-l, Aldehydes 2a-p, and 1,3-Indandione 3
Organocatalytic Heterodomino K-DA-E Reactions
synthesis of natural products and in material chemistry and are the excellent starting materials for the synthesis of fenestranes8 (centrotriindane and centrotetraindanes), topologically nonplanar hydrocarbon centrohexaindane, and other frameworks bearing the [5.5.5.5]fenestrane core as shown in Chart 1. Fenestrindanes with 8-fold
peripheral functionalization could serve as unusual motifs for liquid crystal engineering and dendrimer chemistry and for the construction of graphite cuttings bearing a saddle-like, three-dimensionally distorted core.8
Results and Discussion
We envisioned that amino acids 4a-e and simple amines 4f-j (Chart 2) would act as organocatalysts of the Knoevenagel condensation of aldehydes 2a-p with 1,3-indandione 3 to provide arylidene indandiones 17a- p. There is ample precedence for amine-catalyzed Kno- evenagel reactions.9 2-Arylideneindan-1,3-diones (17) are attractive compounds in medicinal and material chem- istry. For example, substituted 2-arylideneindan-1,3-
(8) (a) Bredenkotter, B.; Florke, U.; Kuck, D. Chem. Eur. J. 2001, 7, 3387. (b) Tellenbroker, J.; Kuck, D. Eur. J. Org. Chem. 2001, 1483. (c) Bredenkotter, B.; Barth, D.; Kuck, D. Chem. Commun. 1999, 847. (d) Thommen, M.; Keese, R. Synlett 1997, 231. (e) Seifert, M.; Kuck, D. Tetrahedron 1996, 52, 13167. (f) Kuck, D. Chem. Ber. 1994, 127, 409. (g) Kuck, D.; Schuster, A.; Krause, R. A. J. Org. Chem. 1991, 56, 3472. (h) Kuck, D.; Bogge, H. J. Am. Chem. Soc. 1986, 108, 8107. (i) Kuck, D. Adv. Theoretically Interesting Molecules 1998, 4, 81. (j) Kuck, D.; Schuster, A.; Paisdor, B.; Gestmann, D. J. Chem. Soc., Perkin Trans. 1 1995, 6, 721. (k) Paisdor, B.; Kuck, D. J. Org. Chem. 1991, 56, 4753. (l) Paisdor, B.; Gruetzmacher, H. F.; Kuck, D. Chem. Ber. 1988, 121, 1307. (m) Kuck, D.; Lindenthal, T.; Schuster, A. Chem. Ber. 1992, 125, 1449. (n) Schuster, A.; Kuck, D. Angew. Chem., Int. Ed. Engl., 1991, 30, 1699. (o) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1980, 45, 2925. (p) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1979, 44, 1508. (q) Shternberg, I. Ya.; Freimanis, Ya. F. Zh. Org. Khim. 1968, 4, 1081. (r) Patai, S.; Weinstein, S.; Rappoport, Z. J. Chem. Soc. 1962, 1741. (s) Popelis, J.; Pestunovich, V. A.; Sternberga, I.; Freimanis, J. Zh. Organ. Khim. 1972, 8, 1860. (t) Sternberga, I.; Freimanis, J. Kimijas Serija 1972, 2, 207.
(9) (a) Ishikawa, T.; Uedo, E.; Okada, S.; Saito, S. Synlett 1999, 4, 450. (b) Tanikaga, R.; Konya, N.; Hamamura, K.; Kaji, A. Bull. Chem. Soc. Jpn. 1988, 61, 3211. (c) Tietze, L. F.; Beifuss, U. The Knoevenagel reaction. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.11, pp 341- 392. (d) List, B.; Castello, C. Synlett 2001, 11, 1687. (e) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Synth. Commun. 2003, 33, 1587.
CHART 1. Benzoannelated Centropolyquinanes
diones 17 derivatives show antibacterial activites,10
nonlinear optical properties,11 electroluminescent de- vices,12 and are useful as eye lens clarification agents.13
The arylidene indandiones are very good organic Lewis acids14 (OLA) with low energy LUMO configurations and are useful as heterodienes and Michael acceptors in cycloaddition reactions.15 Here, we have utilized arylidene indandiones 17 as dienophiles in Diels-Alder chemistry. As dienophiles, 17a-p undergo [4 + 2] cycloaddition reactions with 2-amino-1,3-butadienes 18a-l generated in situ from enones 1a-l and amino acids or amines to generate substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4- triones 5 and 6 in a diastereoselective manner (Figure 1). Epimerization of the minor diastereomer trans- spirane 6 to the more stable cis-spirane 5 occurred under the same reaction conditions. This domino Knoevenagel/ Diels-Alder reaction generates a quaternary carbon center with formation of three new carbon-carbon σ bonds via organocatalysis.
In these three component organocatalytic K-DA-E reactions, the Knoevenagel condensation generates reac- tive dienophiles that can be readily isolated from the reaction mixture. For example, reaction of 4-nitroben- zaldehyde 2a and 1,3-indandione 3 in methanol at ambient temperature under L-proline or pyrrolidine catalysis furnished the expected 2-(4-nitro-benzylidene)- indan-1,3-dione 17a in almost quantitative yield as shown in Scheme 2. Under similar reaction conditions with different aromatic aldehydes, a wide variety of 2-arylideneindan-1,3-dione dienophiles (17) were syn- thesized in very good yields.
Amino Acid-Catalyzed Direct Asymmetric Het- ero-Domino K-DA-E Reactions. We found that the three-component reaction of trans-4-phenyl-3-buten-2-one 1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 with a catalytic amount of L-proline (20 mol %) in methanol at ambient temperature for 24 h furnished the expected nonsymmetrical Diels-Alder products 5aa and 6aaΨ in 86% yield with thermodynamically stable cis-spirane 5aa as the major isomer, dr 24:1 (Table 1, entry 1) (ΨIn all compounds denoted 5xy and 6xy, x is incorporated from reactant enones 1 and y is incorporated from the reactant aldehydes 2.) Unfortunately, the enantiomeric excess (ee) of the major cis-spirane 5aa was only 5%. Interestingly, the same reaction with an extended reaction time fur- nished cis-spirane 5aa as a single diastereomer in 96% yield, however with 3% ee (Table 1, entry 2). The minor diastereomer, trans-spirane 6aa, was effectively epimer- ized to the thermodynamically stable cis-spirane 5aa under prolonged reaction time via proline catalysis. The stereochemistry of products 5aa and 6aa was established by NMR analysis.16
In the three-component hetero-domino K-DA-E reac- tion of enone 1a, 4-nitrobenzaldehyde 2a, and 1,3- indandione 3 catalyzed directly by L-proline, we found that the solvent (dielectric constant) and temperature had a significant effects on reaction rates, yields, dr’s, and ee’s (Table 1). The hetero-domino K-DA-E reaction catalyzed by L-proline at ambient temperature in aprotic/ nonpolar solvents produced products 5aa and 6aa in low
(10) (a) Salama, M. A.; Yousif, N. M.; Ahmed, F. H.; Hammam, A. G. Pol. J. Chem. 1998, 62, 243. (b) Afsah, E. M.; Etman, H. A.; Hamama, W. S.; Sayed-Ahmed, A. F. Boll. Chim. Farm. 1998, 137, 244. (c) El-Ablak, F. Z.; Metwally, M. A. J. Serb. Chem. Soc. 1992, 57, 635. (d) Osman, S. A. M.; Yousif, N. M.; Ahmed, F. H.; Hammam, A. G. Egypt. J. Chem. 1988, 31, 727. (e) Afsah, E. M.; Hammouda, M.; Zoorob, H.; Khalifa, M. M.; Zimaity, M. Pharmazie 1990, 45, 255. (f) Yoakim, C.; Hache, B.; Ogilvie, W. W.; O’Meara, J.; White, P.; Goudreau, N. PCT Int. Appl. 2002, 121 pp. CODEN: PIXXD2 WO 2002050082 A2 20020627. Patent written in English.
(11) Szymusiak, H.; Zielinski, R.; Domagalska, B. W.; Wilk, K. A. Comput. Chem. 2000, 24, 369.
(12) Murakami, M.; Fukuyama, M.; Suzuki, M.; Hashimoto, M. Jpn. Kokai Tokkyo Koho 1996, 13 pp. CODEN: JKXXAF JP 08097465 A2 19960412 Heisei. Patent written in Japanese.
(13) Aziz, A. B. M. S. A.; Mohamed, E. S. Eur. Pat. Appl. 1992, 14 pp. CODEN: EPXXDW EP 489991 A1 19920617. Patent written in English.
(14) (a) Cammi, R.; Ghio, C.; Tomasi, J. Int. J. Quantum Chem. 1986, 29, 527. (b) Liedl, E.; Wolschann, P. Monatsh. Chem. 1982, 113, 1067. (c) Goerner, H.; Leitich, J.; Polansky, O. E.; Riemer, W.; Ritter- Thomas, U.; Schlamann, B. Monatsh. Chem. 1980, 111, 309. (d) Haslinger, E.; Wolschann, P. Bull. Soc. Chim. Belg. 1977, 86, 907. (e) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1969, 100, 576. (f) Margaretha, P. Tetrahedron 1972, 28, 83.
(15) (a) Bitter, J.; Leitich, J.; Partale, H.; Polansky, O. E.; Riemer, W.; Ritter-Thomas, U.; Schlamann, B.; Stilkerieg, B. Chem. Ber. 1980, 113, 1020. (b) Bloxham, J.; Dell, C. P. J. Chem. Soc., Perkin Trans. 1 1993, 24, 3055. (c) Righetti, P. P.; Gamba, A.; Tacconi, G.; Desimoni, G. Tetrahedron 1981, 37, 1779. (d) Eweiss, N. F. J. Heterocycl. Chem. 1982, 19, 273.
(16) Stereochemistries of the cis- and trans-spiranes were estab- lished using COSY experiments and were also based on MOPAC calculations of the thermodynamic equilibration between the two isomers (see the Supporting Information).
CHART 2. Screened Organocatalysts for the K-DA-E Reaction
FIGURE 1. Dienes and dienophiles generated under orga- nocatalysis.
SCHEME 2. Organocatalytic Knoevenagel Condensation
Organocatalytic Heterodomino K-DA-E Reactions
J. Org. Chem, Vol. 69, No. 18, 2004 5841
to moderate yields with poor diastereoselectivity (Table 1, entries 4-6, 11, and 12). Enantioselectivity improved in aprotic/nonpolar solvents (Table 1, entries 4-6, 11, and 12). Excellent yields, good diastereoselectivity, and poor enantioselectivity were observed in protic/polar solvents (Table 1, entries 1-3). For example, the K-DA-E reaction in THF furnished spiranes 5aa and 6aa in 54% yield with dr of 2.8:1 and with ee of 18% for the major cis-spirane 5aa and an ee of 15% for the minor trans-spirane 6aa (Table 1, entry 4). The same reaction using ionic liquid [bmim]BF4, a “green solvent”, catalyzed by L-proline at 25 °C furnished the thermodynamically stable product cis-spirane 5aa as the major diastereomer in 80% yield with dr of 34:1, albeit with a low ee value of 1% (Table 1, entry 7). Interestingly, the same reaction under proline catalysis in ionic liquid [bmim]PF6 at 25 °C furnished the spiranes 5aa and 6aa in 45% yield with dr of 1.5:1 and with ee of 6% (cis-spirane) and 7% (trans-spirane) (Table 1, entry 8). In the hetero-domino K-DA-E reaction under L-proline catalysis, diastereoselectivity was directly affected by the nature of the solvent (dielectric constant) as reflected in the epimerization reaction and exo/endo selectivity. Rates of organocatalytic reactions catalyzed by amino acids were faster in protic/polar solvents than in nonprotic/nonpolar solvents presumably due to en- hanced stabilization of charged intermediates and more facile proton-transfer reactions. This is especially true for the epimerization reaction where the dr’s of the produces obtained using protic/polar solvents were very high.
Next we probed the structure and reactivity relation- ships among a family of amino acids and pyrrolidine- based catalysts by monitoring the reaction yields, dr’s, and ee values of the hetero-domino K-DA-E reaction and compared them to the results of the organocatalytic
asymmetric three-component Diels-Alder (ATCDA) re- action of 1a, 2a, and Meldrum’s acid.6a Among the catalysts screened in the ATCDA reaction, the 5,5- dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the most efficient catalyst with respect to yield and ee. When DMTC was tested in the K-DA-E reaction of 1a, 2a, and 3 in methanol at 25 °C for 72 h, the domino products 5aa and 6aa were obtained in 62% yield with dr of 8.5:1 and ee of the major cis-spirane 5aa of 17% (Table 1, entry 9). The same reaction under DMTC catalysis at reduced temperature (4 °C) in methanol for 96 h furnished products 5aa and 6aa in 18% yield with a dr of 1.3:1. Under these conditions, the ee of the major cis-spirane 5aa was 30% and ee for the minor trans- spirane 6aa was 3% (Table 1, entry 10). With DMTC catalysis in THF as solvent at 25 °C, products 5aa and 6aa were obtained in poor yields (e10%) with dr of 1:1.4 and ee for the minor cis-spirane of 42%, while the ee for the major trans-spirane of 6% (Table 1, entry 11). DMTC- catalyzed K-DA-E reaction in THF at 4 °C for 96 h furnished the domino products in very poor yields (Table 1, entry 12). An imidazoline-type catalyst, 4-benzyl-1- methylimidazolidine-2-carboxylic acid 4c, also catalyzed the K-DA-E reaction with moderate yield, very good dr, and low ee at 25 °C and moderate to low yield, and poor dr with improved ee at 4 °C (Table 1, entries 13 and 14). trans-3-Hydroxy-L-proline 4d catalyzed the domino K- DA-E reaction of 1a, 2a, and 3 with very good yield and excellent diastereoselectivity, but the ee was poor (Table 1, entry 15). trans-4-Hydroxy-L-proline 4e also catalyzed the domino K-DA-E reaction of 1a, 2a, and 3 but reaction yield (19%), dr (1:1), and ee (14 and 13) were poor (Table 1, entry 16). While the Knoevenagel product 17a was formed and consumed in most of the amino acid-catalyzed heterodomino K-DA-E reactions, in some reactions (Table
TABLE 1. Effect of Solvent and Amino Acid on the Direct Amino Acid Catalyzed Asymmetric Heterodomino K-DA-E Reaction of 1a, 2a, or 2b and 3a
entry catalyst
(20 mol %) aldehyde solvent (0.5 M) T (°C) time (h) products yieldb (%)
drc
(cis/trans)
1 4a 2a MeOH 25 24 5aa, 6aa 86 24:1 5/- 2 4a 2a MeOH 25 96 5aa 98 g99:1 3/- 3 4a 2a DMSO 25 96 5aa, 6aa 95 30:1 1/- 4 4a 2a THF 25 120 5aa, 6aa 54 2.8:1 18/15 5 4a 2a CHCl3 25 120 5aa, 6aa 63 1:1 13/6 6 4a 2a C6H6 25 120 5aa, 6aa e5 7 4a 2a [bmim]BF4 25 96 5aa, 6aa 80 34:1 1/- 8 4a 2a [bmim]PF6 25 96 5aa, 6aa 45 1.5:1 6/7 9 4b 2a MeOH 25 72 5aa, 6aa 62 8.5:1 17/-
10e 4b 2a MeOH 4 96 5aa, 6aa 18 1.3:1 30/3 11e 4b 2a THF 25 96 5aa, 6aa e10 1:1.4 42/6 12e 4b 2a THF 4 96 5aa, 6aa e5 13 4c 2a MeOH 25 96 5aa 68 g99:1 9/- 14e 4c 2a MeOH 4 96 5aa, 6aa 40 1.6:1 17/4 15 4d 2a MeOH 25 36 5aa 92 g99:1 2/- 16e 4e 2a MeOH 25 46 5aa, 6aa 19 1:1 14/13 17 4a 2b MeOH 25 24 5ab, 6ab 87 2:1 18 4a 2b MeOH 25 98 5ab 96 g99:1 19 4a 2b MeOH 70 2 5ab 96 g99:1 20 4a 2b [bmim]BF4 25 24 5ab, 6ab 53 1:2 21 4a 2b [bmim]PF6 25 96 5ab, 6ab 55 1:2 a Experimental conditions: amino acid (0.1 mmol), 4-nitrobenzaldehyde 2a or benzaldehyde 2b (0.5 mmol), and 1,3-indandione 3 (0.5
mmol) in solvent (1 mL) were stirred at ambient temperature for 30 min then benzylidene acetone 1a (1 mmol) was added (see the Experimental Section). b Yield refers to the purified product obtained by column chromatography. c Ratio based on isolated products (1H and 13C NMR analysis). d Enantiomeric excesses determined by using chiral-phase HPLC. e 60-80% of unreacted Knoevenagel product 17a was isolated.
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5842 J. Org. Chem., Vol. 69, No. 18, 2004
1, entries 10, 11, 12, 14, and 16) unreacted 17a was isolated in 60-80% yield. Unreacted 17a was the result of a very slow rate of the formation of the key intermedi- ate 2-amino-1,3-butadiene and subsequent Diels-Alder reaction under these conditions.
The L-proline-catalyzed three-component hetero-dom- ino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1a and 1,3-indandione 3 with a different aldehyde, benz- aldehyde 2b, furnished products 5ab and 6ab in 87% yield with dr of 2:1 (Table 1, entry 17). The same reaction, albeit with an extended reaction time, furnished prochiral cis-spirane 5ab as a single diastereomer in 96% yield (Table 1, entry 18). The stereochemistry of products 5ab and 6ab was established by NMR analysis. The minor diastereomer, trans-spirane 6ab was effectively epimer- ized to the thermodynamically stable cis-spirane 5ab under prolonged reaction time via proline catalysis. Increasing the reaction temperature to 70 °C facilitated the epimerization reaction and furnished the expected domino product 5ab as a single diastereomer in 96% yield within 2 h. Interestingly the same reaction in the ionic liquids, [bmim]BF4 and [bmim]PF6, catalyzed by L-proline at ambient temperature provided the kinetic product trans-spirane 6ab as the major diastereomer in moderate yield (Table 1, entries 20 and 21). In these reactions, enantioselectivity for the minor kinetic product 6ab was poor. cis-Spirane 5ab has been used as a synthon for the synthesis of variety of benzoannelated centropolyquinanes as shown in Chart 1.8
cis-Spirane 5ab is obtained via an endo-transition state in the classical Diels-Alder route. In ionic liquids, however, the kinetic product, trans-spirane 6ab, was the major isomer formed. This is likely due to a unique organization of the ionic liquid solvent with the 2-amino- 1,3-butadiene 18a and dienophile 17b in the transition states as shown in Figure 2. Asymmetric solvation in the ionic liquids then produces a steric hindrance with the phenyl group on the dienophile in the endo-transition state, thereby disfavoring it. In the case of dienophile 17a, the high epimerization rate of trans-spirane 6aa provides cis-spirane 5aa as the major isomer (Table 1, entries 7 and 8). Ratio of exo/endo products in ionic liquids or other solvents mainly depend on four factors, which are (i) substrate effect (electronic factor), (ii) protic solvent effect (polarization factor), (iii) steric hindrance induced by ionic solvation, and (iv) basic nature of organo catalyst.
Amine-Catalyzed Direct Heterodomino K-DA-E Reactions. Amines 4f-j can also catalyze the hetero- domino K-DA-E reaction under different solvent and temperature conditions. The three-component hetero- domino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 with a catalytic amount of chiral diamine, (S)-1-(2-pyrrolidi- nylmethyl)-pyrrolidine 4f, in methanol at ambient tem- perature for 24 h furnished the domino product 5aa as a single diastereomer in 79% yield but with very poor ee (Table 2, entry 1). The bifunctional acid/base catalyst17
4g, the trifluoroacetic acid salt of diamine 4f, also catalyzed the heterodomino K-DA-E reaction of 1a, 2a, and 3 in DMSO at ambient temperature to furnish the expected domino products 5aa and 6aa in 71% yield with dr of 13.5:1, but with poor ee (Table 2, entry 2). Since enantioselection in these reactions was typically unsat- isfactory, we studied the simple achiral amine pyrrolidine 4h and found that it furnished cis-spirane 5ab as a single diastereomer in 90% yield (Table 2, entry 3). Further we found that pyrrolidine catalysis was not dramatically affected with respect to reaction rates, yields, or dr’s by solvent and temperature modification (Table 2). Under pyrrolidine catalysis, the heterodomino K-DA-E reaction worked well in a variety of solvents and the optimal conditions involved mixing equimolar amounts of enone 1a, aldehyde 2b, and 1,3-diketone 3 in methanol with heating to 70 °C for 1 h to furnish cis-spirane 5ab as a single diastereomer in 95% yield (Table 2, entry 9). Interestingly, the six-membered cyclic amines piperidine (4i) and morpholine (4j) also catalyzed the heterodomino K-DA-E reaction. Typically, pyrrolidine-based catalysts are much more effective than six-membered cyclic amines as organocatalysts and six-membered cyclic amines are extremely poor catalysts of aldol reactions.3b The reaction of enone 1a, aldehyde 2b, and 1,3-diketone 3 under piperidine 4i catalysis in methanol at 70 °C for 4 h furnished the expected domino products 5ab and 6ab in 71% yield with dr of 43:1 (Table 2, entry 10). Under the same conditions, morpholine 4j catalyzed formation of 5ab and 6ab in 46% yield with dr of 18.6:1 (Table 2, entry 11). The pyrrolidine-catalyzed heterodomino K-DA-E reaction was, however, faster.
Organocatalytic Epimerization of trans-Spirane 6 to cis-Spirane 5. Epimerization of trans-spirane 6 or the diastereospecific synthesis of cis-spirane 5 in the heterodomino K-DA-E reaction of enone 1, aldehyde 2, and 1,3-indandione 3 can be explained as illustrated in Scheme 3. Amino acid or amine-catalyzed Knoevenagel condensation9 of aldehyde 2 with 1,3-indandione 3 pro- vides the arylidene-indandione 17 via the in situ gener- ated reactive cationic imine 16. Arylideneindandione 17 then undergoes a concerted [4 + 2] cycloaddition or a double-Michael reaction with the soft nucleophile, 2-amino- 1,3-butadiene 18 generated in situ from enone 1 and the amino acid or amine catalyst, to produce products 5 and 6. The energy difference (H) between the two isomers
(17) (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369. (b) Spencer, T. A.; Neel, H. S.; Ward, D. C.; Williamson, K. L. J. Org. Chem. 1966, 31, 434. (c) Woodward, R. B. Pure Appl. Chem. 1968, 17, 519. (d) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1612. (e) Greco, M. N.; Maryanoff, B. E. Tetrahedron Lett. 1992, 33, 5009. (f) Snider, B. B.; Yang, K. J. Org. Chem. 1990, 55, 4392.
FIGURE 2. Asymmetric solvation in the ionic liquids.
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5aa and 6aa is 5.626 kcal/mol based on AM1 and 4.114 kcal/mol based on PM3 calculations. The energy differ- ence (H) between the two isomers of 5ab and 6ab is 6.158 kcal/mol based on AM1 and 5.680 kcal/mol based on PM3 calculations. Minimized structures of 5aa, 6aa, 5ab, and 6ab are depicted in the Supporting Information. Since the differences in H’s between the two isomers of 5aa/6aa and 5ab/6ab are greater than 5 kcal/mol, the minor kinetic isomers 6aa and 6ab are epimerized to the
thermodynamically more stable cis-isomers 5aa and 5ab, respectively, at room temperature under mild organo- catalysis. Epimerization of trans-spiranes 6 to cis-spi- ranes 5 was favored not only by thermodynamic consid- erations but also electronic effects.18 The minor kinetic isomer trans-spirane 6 was epimerized to the thermody- namically stable cis-spirane 5 via deprotonation/repro- tonation or retro-Michael/Michael reactions catalyzed by amino acid or amine. This is in agreement with the previously proposed retro-Michael/Michael reaction mech- anism19 at the epimerization step as shown in Scheme 4.
The rate of the epimerization was also related to the nucleophilic strength of the amino acid or amine catalyst,
(18) Zalukaev, L. P.; Anokhina, I. K.; Aver’yanova, I. A. Dokl. Akad. Nauk SSSR 1968, 181, 103.
(19) (a) Shternberg, I. Y.; Freimanis, Ya. F. Zh. Org. Khim. 1970, 6, 48. (b) Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.; Winemiller, M. D.; Chamberlin, M. J.; Czulada, G.; Johnson, S. D. J. Org. Chem. 1998, 63, 4359.
TABLE 2. Effect of Solvent and Amine on the Direct Amine-Catalyzed Asymmetric Heterodomino K-DA-E Reaction of 1a, 2a or 2b, and 3a
entry catalyst
(20 mol %) aldehyde solvent (0.5 M) T (°C) time (h) products
yieldb
(%) drc
(cis/trans)
1 4f 2a MeOH 25 24 5aa 79 g99:1 1 2 4g 2a DMSO 25 39 5aa, 6aa 71 13.5:1 3 3 4h 2b MeOH 25 8 5ab 90 >99:1 4 4h 2b MeOH 70 0.75 5ab 90 >99:1 5 4h 2b THF 25 7 5ab 85 >99:1 6 4h 2b CHCl3 25 7 5ab 70 >99:1 7 4h 2b DMSO 24 70 5ab 75 >99:1 8 4h 2b DMF 25 24 5ab 80 >99:1 9e 4h 2b MeOH 70 1 5ab 95 >99:1
10 4i 2b MeOH 70 4 5ab, 6ab 71 43:1 11 4j 2b MeOH 70 4 5ab, 6ab 46 18.6:1
a Experimental conditions: amines 4f,g (0.1 mmol), 4h-j (0.15 mmol), 4-nitrobenzaldehyde 2a or benzaldehyde 2b (0.5 mmol), and 1,3-inandione 3 (0.5 mmol) in solvent (1 mL) were stirred at ambient temperatures for 30 min, then benzyl acetone 1a (1 mmol) was added (see the Experimental Section). b Yield refers to the purified product otabined by column chromatography. c Ratio based on isolated products (1H and 13C NMR analysis). d Enantiomeric excesses determined by using chiral-phase HPLC. e Enone 1a, benzealdehyde 2b and 1,3-indandione 3 were used in 0.5 mmol scale.
SCHEME 3. Proposed Catalytic Cycle for the L-Proline (or Amino Acid or Amine) Catalyzed Heterodomino K-DA-E Reactions
SCHEME 4. Proposed Mechanism for the L-Proline (Amino Acid or Amine) Catalyzed Epimerization of trans-Spirane 6 to cis-Spirane 5
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reaction temperature, and nature of the solvent. Epimer- ization rate of trans-spirane 6 to cis-spirane 5 in protic/ polar solvents under amino acid catalysis was faster than that in aprotic/nonpolar solvents (Table 1). But under amine catalysis, the nature of the solvent did not have much effect on the epimerization rate. In protic/polar solvents, stabilization of the highly reactive ionic species generated in the reaction media by hydrogen bonding or dipolar-dipolar interactions enhanced the reaction rate. As shown in Scheme 4, the amino acid or amine reacts with cyclohexanone 6 to generate the enamine 19. The retro-Michael reaction to form the ring-opened imine/ enolate 20 should be accelerated by hydrogen bonding with protic/polar solvents. Imine/enolate 20 then under- goes Michael reaction to form the enamine of the ther- modynamically stable cis-spirane 21, which undergoes hydrolysis in situ to furnish cis-spirane 5.
Epimerization of trans-spiranes 6aa and 6ab to cis- spiranes 5aa and 5ab, respectively, was confirmed in studies of the L-proline and pyrrolidine-catalyzed reaction in methanol at ambient temperature (Scheme 5). The epimerization reaction catalyzed by pyrrolidine was
significantly faster than that catalyzed by proline. No epimerization was observed in the absence of catalyst.
To further probe the epimerization mechanism we sought to study the intermediate enamine of cis-spirane 22. A mixture of cis- and trans-spiranes 5aa and 6aa (1.5: 1) was treated with morpholine in the presence of catalytic amount of p-TSA under reflux in toluene for 30 min to furnish the enamine of the epimerized cis-spirane 22. NMR analysis of the unpurified mixture showed features of the enamine (Scheme 6). We studied the morpholine derived enamine because morpholine en- amine hydrolysis is slower than that of pyrrolidine or L-proline enamines.19 Attempted purification of the enam- ine 22 by flash column chromatography on silica gel resulted in the formation of the hydrolysis product, cis- spirane 5aa, in quantitative yield.
Synthesis of Nonsymmetrical cis-Spiranes. We further explored the scope of the L-proline and pyrrolidine catalyzed hetero-domino K-DA-E reactions with various arylaldehydes (2a-p) and 4-substituted-3-buten-2-ones (1a-l). Each of the targeted spirotriones 5 was obtained as single diastereomers in excellent yields. In this case, even though the enantioselectivities are poor, L-proline was used as catalyst as it is available at reasonable cost. The L-proline-catalyzed heterodomino K-DA-E reactions of trans-4-phenyl-3-butene-2-one 1a, various arylalde- hydes (2a-p) and 1,3-indandione 3 in methanol at 25 °C for 96 h furnished the expected cis-spiranes in good yields with high diastereoselectivity as shown in Table 3. None of these nonsymmetrical cis-spiranes were known in the literature. Various arylaldehydes with different electron-donating or -withdrawing groups, as well as heteroaromatic aldehydes furnished the spiranes without the loss of diastereoselectivity. Interestingly, the hetero- domino K-DA-E reaction of enone 1a, 4-methoxybenz- aldehyde 2c, and 1,3-indandione 3 furnished the expected cis-spirane in 6:1 diastereomeric ratio. In this case, the epimerization rate of trans-spirane 6ac to cis-spirane 5ac was slower than with other substrates and so the diastereoselectivity was poor. Reaction of an arylaldehyde bearing an electron-donating p-hydroxy substitute fur- nished cis-spirane 5af in very good yield and a surpris- ingly high dr (Table 3, entry 3). Likewise, arylaldehydes with electron withdrawing substituents such as o-nitro, p-chloro, p-cyano, and p-methoxycarbonyl also furnished the cis-spiranes 5ah, 5ag, 5ai, and 5aj with high di- astereoselectivities. The heterodomino K-DA-E reaction of heteroaromatic aldehydes, 2-furanaldehyde, and 2-thiophenaldehyde furnished spiranes 5al and 5am with
SCHEME 5. Organocatalytic Epimerization of trans-Spirane 6 to cis-Spirane 5
SCHEME 6
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good to moderate yields but with moderate diastereo- selectivities due to slow epimerization rates. Reaction of 1H-pyrrole-2-carboxyaldehyde 2n with 1a and 3 under L-proline catalysis did not furnish the expected domino product, but under pyrrolidine catalysis at 60 °C for 2 h furnished the domino product 5an in 30% yield with high dr. This domino product 5an was accompanied by an unexpected product, cis-spirane 5ab, in 16% yield and unreacted Knoevenagel product 17n in 25% yield. For- mation of unexpected product 5ab in above reaction will be considered in the next section. Reaction of R,â- unsaturated aldehyde, trans-C6H4-CHdCH-CHO 2p with 1a and 3 under L-proline catalysis also furnished the expected domino product 5ao in good yields with high dr.
Synthesis of Prochiral Symmetrical cis-Spiranes. Pyrrolidine catalyzed, hetero-domino K-DA-E reactions of trans-4-aryl-3-butene-2-ones (1a-l), arylaldehydes (2a-p), and 1,3-indandione 3 in methanol at 70 °C for 1-2 h furnished the expected cis-spiranes 5 di-
astereospecifically in very good yields as shown in Table 4. Various trans-4-aryl-3-buten-2-ones and aryl aldehydes with different substituents on the aromatic ring (ranging from the electron-donating groups such as p-methoxy, m,p-methylenedioxy, p-dimethylamino, and p-hydroxy and electron-withdrawing groups such as p-chloro, p- nitro, p-cyano, and p-methoxycarbonyl) and also the heteroaromatic counterparts furnished the expected cis- spiranes (5) in good yields with high diastereospecificity. The chloro-, cyano-, and methoxycarbonyl-substituted cis- spiranes 5gg, 5ii, and 5jj are potentially interesting intermediates for materials chemistry as they can be readily manipulated. Thus, numerous arylaldehydes and various enones are readily reacted under either L-proline or pyrrolidine catalysis to generate a library of highly functionalized cis-spiranes (5) (Tables 3 and 4).
Synthesis of Highly Substituted cis-Spiranes. To prepare highly substituted dispiranes, we used an aryl- dialdehyde instead of a simple arylaldehyde. Thus, the heterodomino K-DA-E reaction of terephthalaldehyde 2p,
TABLE 3. L-Proline-Catalyzed Heterodomino K-DA-E Reactions of trans-4-Phenyl-3-buten-2-one 1a, Various Aldehydes 2a-o, and 1,3-Indandione 3 in Methanol at 25 °C for 96 ha
a Experimental conditions: L-proline (0.1 mmol), aldehyde 2a-o (0.5 mmol), and 1,3-indandione 3 (0.5 mmol) in methanol (1 mL) was stirred at ambient temperature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was added (see the Experimental Section). b 20% of unreacted dienophiles are isolated. c Reaction was performed under pyrrolidine catalysis at 60 °C for 2 h. This product was accompanied by unexpected product cis-sprirane 5ab (16%) and Knoevenagel product 17n (25%) (see the Experimental Section).
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5846 J. Org. Chem., Vol. 69, No. 18, 2004
a dialdehyde, with trans-4-phenyl-3-butene-2-one 1a and indandione 3 catalyzed by L-proline or pyrrolidine fur- nished the cis-spiranealdehyde 23 and the dispirane 24 as well as the unexpected product 5ab as shown in Table 5. When L-proline was used as a catalyst, incubation of the reaction at 25° C for 96 h furnished products 23 and 24 in 16% and 18% yield, respectively (Table 5, entry 1), while the same reaction performed at 25 °C for 24 h and 40 °C for 48 h resulted in the formation of 23 and 24 in 60% and 18% yield, respectively (Table 5, entry 2). Under L-proline catalysis, the unexpected product 5ab did not form. The reaction catalyzed by pyrrolidine at 70 °C for 2 h furnished the dispirane 24 and the unexpected product 5ab in 15% and 45% yield, respectively (Table 5, entry 3). The identity of dispirane 24 was confirmed by proton, 13C NMR, and mass analysis. We had previ- ously observed that the domino product 5ab was also formed unexpectedly in the hetero-domino K-DA-E reac- tion of enone 1a, aldehyde 2n and 1,3-indandione 3 under pyrrolidine catalysis with 16% yield (Table 3, entry 11).
To investigate the formation of the unexpected product 5ab, the reaction was carried out without the aldehyde. Pyrrolidine catalyzed the reaction of trans-4-phenyl-3- buten-2-one 1a with 1,3-indandione 3 in methanol at 70 °C for 5 h to furnish the cis-spirane 5ab and the Knoevenagel product 17b in 28% and 8% yield, respec- tively, as shown in Scheme 7. The mechanism of forma- tion of the unexpected product cis-spirane can be ex- plained as shown in Scheme 7. First, the Michael addition of indandione 3 to trans-4-phenyl-3-buten-2-one 1a takes place to generate the adduct 25, which can then undergo a retro-Michael reaction in one of two ways. The retro- Michael reaction can either regenerate the starting materials 3 and 1a or generate acetone and the Knoev- enagel product 17b. Compound 17b undergoes a Diels- Alder reaction with trans-4-phenyl-3-buten-2-one 1a to furnish the mixture of cis- and trans-spiranes 5ab and 6ab as described earlier. Finally, epimerization of the trans-spirane 6ab takes place to furnish the cis-spirane 5ab. Thus the mechanism of formation of the unexpected
TABLE 4. Pyrrolidine-Catalyzed Heterodomino K-DA-E Reactions of Various trans-4-Aryl-3-buten-2-ones 1a-l, Arylaldehydes 2a-o, and 1,3-Inandione 3 in Methanol at 70 °C for 1-2 ha
a Experimental conditions: pyrrolidine (0.15 mmol), aldehyde 2a-o (0.5 mmol), and 1,3-inandione 3 (0.5 mmol) in methanol (1 mL) was stirred at ambient temperature for 30 min, and then arylidene acetone 1a-l (0.5 mmol) was added (see the Experimental Section). b Reaction conversion is 50% only.
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J. Org. Chem, Vol. 69, No. 18, 2004 5847
product 5ab involves four steps: a Michael reaction, a retro-Michael reaction, a Diels-Alder reaction, and finally an epimerization reaction.
Application of cis-Spiranes 5. Prochiral cis-spiranes 5 are very useful starting materials in the synthesis of benzoannelated centropolyquinanes. Prochiral cis-spirane
5ab and trans-spirane 6ab have served as useful syn- thons in the synthesis of fenestranes.8 Kuck and co- workers have reported the synthesis of a highly strained centrotetracyclic framework of fenestranes starting from cis- and trans-spiranes 5ab and 6ab. In their study, the cis-spirane 5ab was converted to all-cis-[5.5.5.5]fenes-
SCHEME 7. Pyrrolidine-Catalyzed Direct Michael/Retro-Michael/Diels-Alder/Epimerization Reaction of Enone 1a and 1,3-Indandione 3 in Methanol at 70 °C
SCHEME 8. Application of cis-Spiranes 5 in the Synthesis of Benzoannelated Centropolyquinanes
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5848 J. Org. Chem., Vol. 69, No. 18, 2004
trane 7 in nine synthetic steps as depicted in Scheme 8. The dispirane 24 could serve as a suitable synthon for the synthesis of topologically interesting difenestranes 26 and 27. Fenestranes containing reactive functional
groups such as chloro, cyano, and methoxycarbonyl should allow for the development of a rich chemistry by extension of the peripheral functional groups. Thus, dendrimers, liquid crystals and poly-condensed ring systems with saddle-like molecular structures may be synthesized using the synthons described here.
Conclusions
The results presented here demonstrate amino acid or an amine-based organocatalysis of three different reac- tions in a single pot. This astonishingly simple and atom- economic approach can be used to construct highly functionalized symmetric and nonsymmetric spiro[cyclo- hexane-1,2′-indan]-1′,3′,4-triones (5) in a diastereospecific fashion. Selective multistep reactions of this type inspire analogies to biosynthetic pathways and compliment traditional multicomponent synthetic methodologies. Fur- ther improvements with respect to the enantioselectivity of these reactions might be accessible through the screening or design of novel catalysts. As we have suggested previously, the synthesis of polyfunctionalized molecules under organocatalysis provides a unique and under-explored perspective on prebiotic synthesis. A complete understanding of the scope of organocatalysis should not only empower the synthetic chemist but also provide a new perspective on the origin of complex molecular systems.
Acknowledgment. This study was supported in part by the NIH (CA27489) and the Skaggs Institute for Chemical Biology.
Supporting Information Available: Characterization data (1H NMR, 13C NMR, and mass) for all new compounds and details of experimental procedures. Copies of 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
JO049581R
yieldb (%) entry
catalyst (30 mol %) T (°C) time (h) 23 24 5ab
1 4a 25 96 16 18 2 4a 25 f 40 24 f 48 60 18 3 4h 70 2 15 45
a Experimental conditions: L-proline 4a or pyrrolidine 4h (0.15 mmol), terephthalaldehyde 2p (0.5 mmol), and 1,3 indandione 3 (1.0 mmol) in methanol (1 mL) were stirred at ambient temper- ature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was added (see the Experimental Section). b Yield refers to the purified product obtained by column chromatography.
Organocatalytic Heterodomino K-DA-E Reactions
Supporting Information for JO049581R
Diastereoselective Synthesis of Symmetrical and Non-Symmetrical Synthons
of Benzoannelated Centropolyquinanes D. B. Ramachary, K. Anebouselvy, Naidu S. Chowdari and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Department of Chemistry and Molecular Biology
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California-92037, USA
[email protected]
General Methods. The 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100
MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for 1H
NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR. The coupling
constants J are given in Hz. In the 13C NMR spectra, the nature of the carbons (C, CH, CH2 or
CH3) was determined by recording the DEPT-135 experiment, and is given in parentheses. Flash
chromatography (FC) was performed using silica gel Merck 60 (particle size 0.040-0.063 mm).
High-resolution mass spectra were recorded on an IonSpec FTMS mass spectrometer with a
DHB-matrix. Electrospray ionization (ESI) mass spectrometry were performed on an API 100
Perkin-Elmer SCIEX single quadrupole mass spectrometer. The enantiomeric excess (ee) of the
products were determined by HPLC using Daciel chiralcel OD-H or Daciel chiralpak AS or
Daciel chiralpak AD columns with i-PrOH/hexane as eluent. HPLC was carried out using a
Hitachi organizer consisting of a D-2500 Chromato-Integrator, a L-4000 UV-Detector, and a L-
6200A Intelligent Pump. For thin-layer chromatography (TLC), silica gel plates Merck 60 F254
were used and compounds were visualized by irradiation with UV light and/or by treatment with
a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol
(900 mL) followed by heating.
Materials. All solvents and commercially available chemicals were used as received. trans-4-
(4-methoxyphenyl)-but-3-en-2-one 1c, trans-4-(4-nitrophenyl)-but-3-en-2-one 1h, trans-4-
S2
oxo-but-1-enyl)-benzoic acid methyl ester 1j are prepared by using Wittig reaction with 1-
triphenylphosphoranylidene-2-propanone and corresponding aldehydes in C6H6 at 25° C.
General Procedure for the Preparation of Substituted Spiro[cyclohexane-1,2’-indan]-
1’,3’,4-triones by using Amino acid and Amine Catalyzed Hetero-Domino K-DA-E
Reaction: Catalyzed by Amino acids: In an ordinary glass vial equipped with a magnetic
stirring bar, to 0.5 mmol of the aldehyde and 0.5 mmol of 1,3-indandione was added 1.0 mL of
solvent, and then the catalyst amino acid (0.1 mmol) was added and the reaction mixture was
stirred at ambient temperature for 10 to 15 minutes. When the reaction mixture solidified, more
solvent (0.5 mL) was added. To the reaction mixture 1.0 mmol of enone was added and stirred
at ambient temperature for the time indicated in tables 1 & 3. The crude reaction mixture was
treated with saturated aqueous ammonium chloride solution, the layers were separated, and the
organic layer was extracted with dichloromethane (3 x 8 mL), dried with anhydrous Na2SO4,
and evaporated. The pure Domino Diels-Alder products were obtained by flash column
chromatography (silica gel, mixture of hexane/ethyl acetate). Catalyzed by Amines: Method A.
To a glass vial equipped with a magnetic stirring bar was added aldehyde (0.5 mmol), 1,3-
indandione (0.5 mmol), solvent (1.0 mL) and then the catalyst amine (0.15 mmol) was added
and the reaction mixture was stirred at ambient temperature for 15 to 30 minutes. When the
reaction mixture solidified, more solvent (0.5 mL) was added. Then 0.5 mmol of the enone was
added and the reaction stirred at 70 °C for 1 to 2 h (Tables 2 & 4). The crude reaction mixture
was treated with saturated aqueous ammonium chloride solution, the layers were separated, and
the organic layer was extracted with dichloromethane (3 x 10 mL), dried with anhydrous
Na2SO4, and evaporated. The pure Domino products were obtained by flash column
chromatography (silica gel, mixture of hexane/ethyl acetate). Method B. To a glass vial
equipped with a magnetic stirring bar was added 0.5 mmol of aldehyde, 0.5 mmol of enone, 0.5
mmol of 1,3-indandione and 1.0 mL of solvent, and then the catalyst L-proline (0.1 mmol) or
pyrrolidine (0.15 mmol) was added and the reaction mixture was heated slowly to 70 °C with
stirring for 1 to 2 h. the Domino products were isolated as in Method A. Both methods gave
identical results.
2-(4-Nitro-benzylidene)-indan-1,3-dione (17a).1 Purified by FC
using EtOAc/hexane and isolated as a light yellow color solid. 1H
NMR (399 MHz, CDCl3): δ 8.55 (2H, td, J = 9.2 and 2.4 Hz), 8.34
(2H, td, J = 9.2 and 2.4 Hz), 8.06 (2H, dd, J = 5.6 and 2.8 Hz), 7.90
(1H, br s, olefinic-H), 7.88 (2H, dd, J = 5.6 and 2.8 Hz). 13C NMR
(100 MHz, CDCl3, DEPT): δ 189.1 (C, C=O), 188.5 (C, C=O), 149.4 (C), 142.67 (CH), 142.60
(C), 140.2 (C), 138.4 (C), 136.0 (CH), 135.9 (CH), 134.2 (2 x CH), 132.2 (C), 123.77 (CH),
123.72 (CH), 123.70 (2 x CH).
(2R, 6S)-2-(4-Nitrophenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5aa). Purified by FC using EtOAc/hexane and isolated as a
white solid. The ee was determined by chiral-phase HPLC using a Daicel
Chiralcell OD-H column (hexane/i-PrOH = 85:15, flow rate 1.0 mL/min,
λ = 254 nm), tR = 28.79 min (major), tR = 38.19 min (minor), ee 30%; 1H
NMR (399 MHz, CDCl3): δ 7.90 (2H, td, J = 9.2 and 2.0 Hz), 7.68 (1H,
td, J = 7.2 and 1.2 Hz), 7.53 (1H, dt, J = 6.4 and 1.6 Hz), 7.50 - 7.42 (2H,
m), 7.26 (2H, td, J = 9.2 and 2.0 Hz), 7.05 - 6.90 (5H, m, Ph-H), 3.98 - 3.76 (4H, m), 2.68 (2H,
m). 13C NMR (100 MHz, CDCl3, DEPT): δ 206.8 (C, C=O, C-4), 202.7 (C, C=O, C-1'), 201.1
(C, C=O, C-3'), 147.0 (C), 144.8 (C), 142.3 (C, C-8'), 141.5 (C, C-9'), 136.6 (C), 135.7 (2 x CH,
C-7' and 6'), 129.1 (2 x CH), 128.3 (2 x CH), 127.8 (3 x CH), 123.4 (2 x CH), 122.5 (CH, C-5'),
122.2 (CH, C-4'), 61.5 (C, C-1 or 2'), 49.0 (CH, C-2), 47.7 (CH, C-6),
43.0 (CH2, C-3), 42.7 (CH2, C-5). HRMS (MALDI-FTMS): m/z
426.1328 (M + H+), calcd. for C26H19NO5H+ 426.1336.
(2S, 6S)-2-(4-Nitrophenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (6aa). Purified by FC using EtOAc/hexane and isolated as
a light yellow solid. The ee was determined by chiral-phase HPLC using
a Daicel Chiralcell OD-H column (hexane/i-PrOH = 85:15, flow rate 1.0
mL/min, λ = 254 nm), tR = 52.16 min (major), tR = 79.60 min (minor), ee
7%; 1H NMR (399 MHz, CDCl3): δ 7.94 (2H, td, J = 8.8 and 1.6 Hz), 7.61 (4H, m), 7.17 (2H,
td, J = 8.8 and 1.6 Hz), 7.05 (4H, m, Ph-H), 6.92 (1H, m), 4.11 (1H, dd, J = 13.6 and 3.2 Hz, H-
2), 3.94 (1H, dd, J = 13.2 and 3.6 Hz, H-6), 3.65 (1H, dd, J = 16.4 and 13.6 Hz), 3.58 (1H, dd, J
S4
= 16.8 and 13.2 Hz), 2.81 (2H, ddd, J = 16.8, 4.8 and 3.2 Hz). 13C NMR (100 MHz, CDCl3,
DEPT): δ 208.7 (C, C=O, C-4), 202.4 (C, C=O, C-1'), 202.1 (C, C=O, C-3'), 145.0 (C), 141.8
(C), 141.7 (C), 136.6 (C), 136.0 (CH, C-7'), 135.9 (CH, C-6'), 134.2 (C), 129.4 (2 x CH), 128.34
(2 x CH), 128.32 (2 x CH), 127.7 (CH), 123.4 (2 x CH), 122.76 (CH, C-5'), 122.74 (CH, C-4'),
61.3 (C, C-1), 44.3 (CH, C-2), 42.5 (CH, C-6), 41.5 (CH2), 41.2 (CH2).
(2β, 6β)-2-(4-Methoxyphenyl)-6-phenylspiro[cyclohexane-1,2’-
indan]-1’,3’,4-trione (5ac). Purified by FC using EtOAc/hexane and
isolated as a light yellow color solid. The ee was not determined. This
product was accompanied by unreacted dienophile 17c in 20% yield. 1H
NMR (399 MHz, CDCl3, major isomer): δ 7.64 (1H, dd, J = 7.6 and 0.8
Hz), 7.47 (1H, dt, J = 8.0 and 1.6 Hz), 7.40 (2H, m), 7.08 - 6.90 (5H, m,
Ph-H), 6.95 (2H, td, J = 8.8 and 2.0 Hz), 6.52 (2H, td, J = 8.8 and 1.6
Hz), 3.80 (4H, m), 3.56 (3H, s, OCH3), 2.63 (2H, ddd, J = 10.4, 6.4 and 1.6 Hz). 13C NMR (100
MHz, CDCl3, DEPT, major isomer): δ 208.3 (C, C=O, C-4), 203.5 (C, C=O, C-1'), 201.9 (C,
C=O, C-3'), 158.5 (C), 142.6 (C), 141.9 (C), 137.3 (C), 135.15 (CH, C-7'), 135.13 (CH, C-6'),
129.4 (C), 129.0 (2 x CH), 128.2 (2 x CH), 127.9 (2 x CH), 127.5 (CH), 122.2 (CH, C-5'), 121.9
(CH, C-4'), 113.5 (2 x CH), 62.1 (C, C-1), 54.8 (CH3, OCH3), 48.5 (CH), 47.8 (CH), 43.6 (CH2),
43.2 (CH2).
2-(4-Methoxy-benzylidene)-indan-1,3-dione (17c).2 Purified by FC
using EtOAc/hexane and isolated as a light yellow color solid. 1H
NMR (399 MHz, CDCl3): δ 8.53 (2H, td, J = 9.2 and 2.0 Hz), 7.97
(2H, m), 7.82 (1H, s, olefinic-H), 7.77 (2H, m), 7.00 (2H, td, J = 8.8
and 2.0 Hz), 3.90 (3H, s, OCH3). 13C NMR (100 MHz, CDCl3, DEPT):
δ 190.7 (C, C=O), 189.4 (C, C=O), 163.9 (C), 146.7 (CH), 142.3 (C), 139.8 (C), 137.1 (2 x CH),
135.0 (CH), 134.8 (CH), 126.45 (C), 126.40 (C), 123.0 (CH), 122.9 (CH), 114.3 (2 x CH), 55.5
(CH3, OCH3).
(2β, 6β)-2-(4-Hydroxyphenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-1’,3’,4-trione (5af).
Purified by FC using EtOAc/hexane and isolated as a white solid. The ee was not determined. 1H NMR (399 MHz, CDCl3): δ 7.63 (1H, br d, J = 7.6 Hz), 7.44 (1H, dt, J = 6.8 and 1.6 Hz),
S5
7.40 - 7.33 (2H, m), 7.04 - 6.88 (5H, m, Ph-H), 6.84 (2H, br d, J = 8.8
Hz), 6.48 (2H, br d, J = 8.8 Hz), 3.85 - 3.68 (4H, m), 2.61 (2H, m). 13C
NMR (100 MHz, CDCl3, DEPT): δ 209.8 (C, C=O, C-4), 203.6 (C, C=O,
C-1'), 202.3 (C, C=O, C-3'), 155.3 (C), 142.5 (C), 141.7 (C), 137.0 (C),
135.35 (CH, C-7'), 135.33 (CH, C-6'), 129.1 (2 x CH), 128.7 (C), 128.2
(2 x CH), 127.8 (2 x CH), 127.6 (CH), 122.3 (CH, C-5'), 122.0 (CH, C-
4'), 115.1 (2 x CH), 62.1 (C, C-1 or 2'), 48.4 (CH, C-2), 47.8 (CH, C-6),
43.5 (CH2, C-3), 43.2 (CH2, C-5). HRMS (MALDI-FTMS): m/z 397.1445 (M + H+), calcd. for
C26H20O4H+ 397.1434.
(2β, 6β)-2-(4-Chlorophenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5ag). Purified by FC using EtOAc/hexane and isolated as
a white solid. The ee was not determined. 1H NMR (399 MHz, CDCl3): δ
7.66 (1H, br d, J = 7.6 Hz), 7.49 (1H, m), 7.43 (2H, m), 7.06 - 6.80 (9H,
m), 3.88 - 3.74 (4H, m), 2.65 (2H, m). 13C NMR (100 MHz, CDCl3,
DEPT): δ 207.6 (C, C=O, C-4), 203.1 (C, C=O, C-1'), 201.5 (C, C=O, C-
3'), 142.4 (C), 141.7 (C), 137.0 (C), 135.9 (C), 135.42 (CH, C-7'), 135.40
(CH, C-6'), 133.3 (C), 129.3 (2 x CH), 128.4 (2 x CH), 128.2 (2 x CH), 127.8 (2 x CH), 127.6
(CH), 122.3 (CH, C-5'), 122.0 (CH, C-4'), 61.8 (C, C-1 or 2'), 48.8 (CH, C-2), 47.6 (CH, C-6),
43.2 (CH2, C-3), 43.1 (CH2, C-5). HRMS (MALDI-FTMS): m/z 415.1079 (M + H+), calcd. for
C26H19O3ClH+ 415.1095.
(2β, 6β)-2-(2-Nitrophenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5ah). Purified by FC using EtOAc/hexane and isolated as
a light yellow color solid. The ee was not determined. 1H NMR (399
MHz, CDCl3): δ 7.75 (1H, br d, J = 7.6 Hz), 7.56 (2H, m), 7.51 - 7.34
(3H, m), 7.23 (1H, dt, J = 7.6 and 1.2 Hz), 7.15 (1H, dt, J = 8.0 and 1.6
Hz), 7.02 - 6.89 (5H, m, Ph-H), 4.64 (1H, dd, J = 14.0 and 4.0 Hz), 3.86 -
3.68 (3H, m), 2.85 (1H, ddd, J = 14.8, 4.0 and 1.2 Hz), 2.70 (1H, ABq, J = 14.0 Hz). 13C NMR
(100 MHz, CDCl3, DEPT): δ 206.5 (C, C=O, C-4), 203.5 (C, C=O, C-1'), 200.8 (C, C=O, C-3'),
150.3 (C), 142.5 (C), 141.4 (C, C-8'), 136.5 (C, C-9'), 135.6 (CH), 135.5 (CH), 132.1 (CH),
131.7 (C), 128.3 (CH), 128.2 (2 x CH), 128.1 (CH), 127.8 (CH), 127.7 (2 x CH), 124.6 (CH),
S6
122.6 (CH, C-5'), 122.1 (CH, C-4'), 61.4 (C, C-1 or 2'), 49.2 (CH, C-2), 43.0 (CH2, C-3), 42.7
(CH2, C-5), 40.9 (CH, C-6). HRMS (MALDI-FTMS): m/z 448.1138 (M + Na+), calcd. for
C26H19NO5Na+ 448.1155.
(2R, 6S)-2-(4-Cyanophenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5ai). Purified by FC using EtOAc/hexane and isolated as a
white solid. The ee was determined by chiral-phase HPLC using a Daicel
Chiralcell OD-H column (hexane/i-PrOH = 85:15, flow rate 1.0 mL/min,
λ = 254 nm), tR = 24.26 min (major), tR = 34.80 min (minor), ee 7.4%. 1H
NMR (399 MHz, CDCl3): δ 7.66 (1H, td, J = 7.6 and 0.8 Hz), 7.55 (1H,
dt, J = 6.8 and 1.2 Hz), 7.48 (1H, dt, J = 7.6 and 1.2 Hz), 7.44 (1H, ddd, J
= 7.6, 1.2 and 0.8 Hz), 7.33 (2H, td, J = 8.8 and 2.0 Hz), 7.17 (2H, td, J = 8.8 and 2.0 Hz), 7.04 -
6.80 (5H, m, Ph-H), 3.81 (4H, m), 2.66 (2H, m). 13C NMR (100 MHz, CDCl3, DEPT): δ 206.7
(C, C=O, C-4), 202.5 (C, C=O, C-1'), 201.0 (C, C=O, C-3'), 142.6 (C), 142.1 (C), 141.4 (C),
136.6 (C), 135.5 (2 x CH, C-7' and 6'), 131.9 (2 x CH), 128.7 (2 x CH), 128.1 (2 x CH), 127.6 (2
x CH), 127.6 (CH), 122.2 (CH, C-5'), 121.9 (CH, C-4'), 117.8 (C), 111.3 (C, CN), 61.4 (C, C-1),
48.7 (CH, C-2), 47.8 (CH, C-6), 42.9 (CH2), 42.4 (CH2). HRMS (MALDI-FTMS): m/z
406.1441 (M + H+), calcd. for C27H19NO3H+ 406.1438.
(2β, 6β)-2-(4-Methoxycarbonylphenyl)-6-phenylspiro[cyclohexane-
1,2’-indan]-1’,3’,4-trione (5aj). Purified by FC using EtOAc/hexane and
isolated as a white solid. The ee was not determined. 1H NMR (399 MHz,
CDCl3): δ 7.69 (2H, br d, J = 8.4 Hz), 7.66 (1H, br d, J = 7.6 Hz), 7.47
(1H, br dt, J = 6.4 and 2.0 Hz), 7.40 (2H, m), 7.14 (2H, br d, J = 8.4 Hz),
7.06 - 6.70 (5H, m, Ph-H), 3.86 (4H, m), 3.74 (3H, s, OCH3), 2.68 (2H,
m). 13C NMR (100 MHz, CDCl3, DEPT): δ 207.3 (C, C=O, C-4), 202.8
(C, C=O, C-1'), 201.2 (C, C=O, C-3'), 166.0 (C, O-C=O), 142.4 (C), 142.3 (C), 141.5 (C), 136.8
(C), 135.3 (2 x CH, C-7' and 6'), 129.3 (2 x CH), 129.1 (C), 128.1 (2 x CH), 128.0 (2 x CH),
127.7 (2 x CH), 127.5 (CH), 122.2 (CH, C-5'), 121.9 (CH, C-4'), 61.5 (C, C-1), 51.7 (CH3,
CO2CH3), 48.6 (CH, C-2), 48.1 (CH, C-6), 43.0 (CH2), 42.8 (CH2). HRMS (MALDI-FTMS):
m/z 461.1358 (M + Na+), calcd. for C28H22O5Na+ 461.1359.
S7
(2β, 6β)-2-(Napthalen-1-yl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5ak). Purified by FC using EtOAc/hexane and isolated as
a white solid. The ee was not determined. 1H NMR (399 MHz, CDCl3):
δ 8.26 (1H, d, J = 8.8 Hz), 7.71 (1H, br d, J = 7.6 Hz), 7.66 (1H, br d, J =
7.6 Hz), 7.59 (1H, dt, J = 6.8 and 1.6 Hz), 7.47 (2H, m), 7.43 (1H, dt, J =
8.0 and 0.8 Hz), 7.30 (2H, m), 7.14 (1H, td, J = 6.8 and 0.8 Hz), 7.10
(1H, d, J = 7.6 Hz), 7.10 - 6.85 (5H, m, Ph-H), 4.82 (1H, dd, J = 14.0 and 4.0 Hz), 3.95 (1H, dd,
J = 17.6 and 14.4 Hz), 3.96 - 3.85 (2H, m), 2.74 (1H, br dd, J = 10.0 and 1.6 Hz), 2.69 (1H, ddd,
J = 14.4, 4.0 and 1.6 Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 208.4 (C, C=O, C-4), 204.1
(C, C=O, C-1'), 201.1 (C, C=O, C-3'), 143.0 (C), 141.7 (C), 137.2 (C), 135.2 (CH, C-7'), 135.1
(CH, C-6'), 134.4 (C), 133.8 (C), 130.7 (C), 128.4 (CH), 128.3 (2 x CH), 128.2 (3 x CH), 127.6
(CH), 126.4 (CH), 125.7 (CH), 124.7 (2 x CH), 123.5 (CH), 122.4 (CH, C-5'), 121.9 (CH, C-4'),
61.7 (C, C-1 or 2'), 49.4 (CH, C-2), 45.1 (CH, C-6), 43.4 (CH2, C-3), 41.7 (CH2, C-5). HRMS
(MALDI-FTMS): m/z 431.1632 (M + H+), calcd. for C30H22O3H+ 431.1642.
(2β, 6β)-2-(Furan-2-yl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5al). Purified by FC using EtOAc/hexane and isolated as a
light yellow color solid. The ee was not determined. 1H NMR (399 MHz,
CDCl3, major isomer): δ 7.71 (1H, br dd, J = 6.4 and 0.4 Hz), 7.59 - 7.48
(3H, m), 7.03 - 6.90 (5H, m, Ph-H), 6.86 (1H, br t, J = 1.6 Hz), 5.94 (2H,
br s), 3.93 (1H, dd, J = 14.0 and 4.4 Hz), 3.86 - 3.62 (3H, m), 2.73 (1H,
ddd, J = 14.8, 4.0 and 0.8 Hz), 2.64 (1H, td, J = 12.4 and 2.0 Hz). 13C NMR (100 MHz, CDCl3,
DEPT, major isomer): δ 207.3 (C, C=O, C-4), 202.1 (C, C=O, C-1'), 201.3 (C, C=O, C-3'),
151.2 (C), 142.1 (C), 141.7 (CH), 141.6 (C), 137.0 (C), 135.16 (CH, C-7'), 135.15 (CH, C-6'),
128.2 (2 x CH), 127.9 (2 x CH), 127.5 (CH), 122.4 (CH, C-5'), 122.1 (CH, C-4'), 109.8 (CH),
107.4 (CH), 60.2 (C, C-1), 47.6 (CH, C-2), 43.0 (CH2), 42.0 (CH, C-6), 41.5 (CH2). HRMS
(MALDI-FTMS): m/z 371.1282 (M + H+), calcd. for C24H18O4H+ 371.1278.
(2α, 6β)-2-(Furan-2-yl)-6-phenylspiro[cyclohexane-1,2’-indan]-1’,3’,4-trione (6al). Purified
by FC using EtOAc/hexane and isolated as a light yellow color solid. The ee was not
determined. 1H NMR (399 MHz, CDCl3, minor isomer): δ 7.76 (1H, m), 7.66 (1H, m), 7.60 -
S8
7.50 (2H, m), 7.11 (1H, m), 7.06 - 6.92 (5H, m, Ph-H), 6.20 (1H, dd,
J = 3.2 and 2.0 Hz), 6.00 (1H, br d, J = 3.6 Hz), 3.97 (1H, dd, J =
14.0 and 4.4 Hz), 3.88 (1H, dd, J = 8.8 and 5.6 Hz), 3.60 (1H, dd, J =
16.0 and 13.2 Hz), 3.14 (2H, m), 2.77 (1H, dd, J = 14.4 and 4.0 Hz). 13C NMR (100 MHz, CDCl3, DEPT, minor isomer): δ 208.7 (C, C=O,
C-4), 202.2 (C, C=O, C-1'), 200.7 (C, C=O, C-3'), 152.1 (C), 142.3
(CH), 141.6 (C), 141.4 (C), 137.3 (C), 135.6 (CH, C-7'), 135.5 (CH, C-6'), 128.4 (2 x CH),
128.2 (2 x CH), 127.4 (CH), 122.9 (CH, C-5'), 122.8 (CH, C-4'), 110.2 (CH), 107.7 (CH), 59.6
(C, C-1), 43.9 (CH, C-2), 42.5 (CH2), 40.6 (CH, C-6), 38.2 (CH2). HRMS (MALDI-FTMS): m/z
371.1282 (M + H+), calcd. for C24H18O4H+ 371.1278.
(2β, 6β)-2-(Thiophen-2-yl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5am). Purified by FC using EtOAc/hexane and isolated as
a light yellow color solid. The ee was not determined. This product was
accompanied by unreacted dienophile 17m in 20% yield. 1H NMR (399
MHz, CDCl3): δ 7.68 (1H, td, J = 7.6 and 1.2 Hz), 7.53 - 7.43 (3H, m),
7.04 - 6.90 (5H, m, Ph-H), 6.86 (1H, dd, J = 4.8 and 0.8 Hz), 6.70 (1H,
ddd, J = 3.6, 1.2 and 0.8 Hz), 6.61 (1H, dd, J = 4.8 and 3.2 Hz), 4.14 (1H, dd, J = 14.4 and 4.4
Hz), 3.83 - 3.70 (3H, m), 2.81 (1H, ddd, J = 14.8, 4.4 and 1.6 Hz), 2.64 (1H, td, J = 12.4 and 1.6
Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 207.4 (C, C=O, C-4), 203.3 (C, C=O, C-1'), 202.1
(C, C=O, C-3'), 143.1 (C), 142.3 (C), 140.6 (C), 137.3 (C), 135.6 (2 x CH, C-7' and 6'), 128.6 (2
x CH), 128.2 (2 x CH), 127.9 (CH), 126.6 (2 x CH), 124.6 (CH), 122.7 (CH, C-5'), 122.4 (CH,
C-4'), 62.3 (C, C-1), 48.5 (CH, C-2), 45.1 (CH2), 44.0 (CH, C-6), 43.4 (CH2). HRMS (MALDI-
FTMS): m/z 387.1057 (M + H+), calcd. for C24H18O3SH+ 387.1049.
2-(Thiophen-2-ylmethylene)-indan-1,3-dione (17m).3 Purified by FC
using EtOAc/hexane and isolated as a light yellow color solid. 1H NMR
(399 MHz, CDCl3): δ 8.04 (1H, br dd, J = 4.0 and 0.8 Hz), 7.99 (1H, s,
olefinic-H), 8.00 - 7.94 (2H, m), 7.85 (1H, td, J = 5.2 and 0.8 Hz), 7.80 -
7.74 (2H, m), 7.23 (1H, dd, J = 4.8 and 3.6 Hz).
S9
(2β, 6β)-2-(1H-Pyrrol-2-yl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5an). Purified by FC using EtOAc/hexane and isolated as
a yellow color solid. This product was accompanied by unreacted
dienophile 17n in 25% yield and unexpected cis-spirane 5ab in 16%
yield. 1H NMR (399 MHz, CDCl3): δ 7.88 (1H, br s, N-H), 7.66 (1H, td,
J = 7.6 and 0.8 Hz), 7.56 - 7.44 (3H, m), 7.04 - 6.90 (5H, m, Ph-H), 6.30
(1H, dt, J = 2.4 and 1.6 Hz), 5.79 (1H, m), 5.75 (1H, br dd, J = 5.6 and 2.4 Hz), 3.87 (1H, dd, J
= 14.4 and 4.4 Hz), 3.80 - 3.66 (3H, m), 2.77 (1H, ddd, J = 14.4, 4.0 and 1.6 Hz), 2.64 (1H, td, J
= 12.0 and 1.6 Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 207.8 (C, C=O, C-4), 203.5 (C,
C=O, C-1'), 203.2 (C, C=O, C-3'), 142.7 (C), 141.8 (C), 137.2 (C), 135.4 (CH, C-7'), 135.2 (CH,
C-6'), 128.4 (2 x CH), 127.9 (C), 127.8 (2 x CH), 127.6 (CH), 122.3 (CH, C-5'), 122.2 (CH, C-
4'), 117.1 (CH), 108.2 (CH), 106.8 (CH), 62.0 (C, C-1), 48.0 (CH, C-2), 43.1 (CH2), 42.9 (CH2),
41.9 (CH, C-6). HRMS (MALDI-FTMS): m/z 370.1452 (M + H+), calcd. for C24H19O3NH+
370.1438.
2-(1H-Pyrrol-2-ylmethylene)-indan-1,3-dione (17n).4 Purified by FC
using EtOAc/hexane and isolated as a light yellow color solid. 1H NMR
(399 MHz, CDCl3): δ 13.09 (1H, br s, N-H or O-H), 7.87 (2H, m), 7.70
(2H, m), 7.66 (1H, br s, olefinic-H), 7.33 (1H, m), 7.02 (1H, m), 6.47
(1H, td, J = 4.8 and 2.4 Hz).
(2β, 6β)-2-Styryl-6-phenylspiro[cyclohexane-1,2’-indan]-1’,3’,4-
trione (5ao). Purified by FC using EtOAc/hexane and isolated as a light
yellow color solid. The ee was not determined. 1H NMR (399 MHz,
CDCl3): δ 7.80 (1H, br d, J = 7.2 Hz), 7.58 (2H, m), 7.50 (1H, m), 7.09
(3H, m), 7.04 - 6.85 (7H, m), 6.38 (1H, d, J = 15.6 Hz), 5.65 (1H, br dd, J
= 16.0 and 8.0 Hz) [olefinic-H]; 3.71 (2H, m), 3.42 (2H, m), 2.60 (2H,
m). 13C NMR (100 MHz, CDCl3, DEPT): δ 207.8 (C, C=O, C-4), 203.0
(C, C=O, C-1'), 201.8 (C, C=O, C-3'), 142.3 (C), 142.0 (C), 137.1 (C), 135.8 (C), 135.5 (CH, C-
7'), 135.4 (CH, C-6'), 133.3 (CH), 128.25 (2 x CH), 128.22 (2 x CH), 127.7 (2 x CH), 127.6
(CH), 127.5 (CH), 126.1 (2 x CH), 125.7 (CH), 122.5 (CH, C-5'), 122.2 (CH, C-4'), 60.9 (C, C-1
S10
or 2'), 48.1 (CH, C-2), 46.4 (CH, C-6), 43.0 (CH2, C-3), 42.9 (CH2, C-5). HRMS (MALDI-
FTMS): m/z 407.1641 (M + H+), calcd. for C28H22O3H+ 407.1642.
(2β, 6β)-2,6-Diphenylspiro[cyclohexane-1,2’-indan]-1’,3’,4-trione
(5ab).5a Purified by FC using EtOAc/hexane and isolated as a white solid
and it has a plane of symmetry with chair conformation. 1H NMR (399
MHz, CDCl3): δ 7.64 (1 H, td, J = 7.6 and 1.2 Hz), 7.48 (1 H, m), 7.41 (2
H, m), 7.08-6.90 (10 H, m, 2 x Ph-H), 3.81 (4 H, m), 2.66 (2 H, ABq, J =
17.1 Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 208.4 (C, C=O, C-4),
203.4 (C, C=O, C-1'), 201.8 (C, C=O, C-3'), 142.7 (C, C-8’), 141.9 (C, C-9’), 137.3 (2 x C),
135.2 (2 x CH, C-7' and 6'), 128.3 (4 x CH), 128.0 (4 x CH), 127.6 (2 x CH), 122.4 (CH, C-5'),
122.0 (CH, C-4'), 62.0 (C, C-1 or C-2’), 48.7 (2 x CH), 43.4 (2 x CH2). HRMS (MALDI-
FTMS): m/z 381.1492 (M + H+), calcd. for C26H20O3H+ 381.1485.
(2α, 6β)-2,6-Diphenylspiro[cyclohexane-1,2’-indan]-1’,3’,4-trione
(6ab).5a Purified by FC using EtOAc/hexane and isolated as a light
yellow color solid and it has C2 symmetry with stable twist conformation. 1H NMR (399 MHz, CDCl3): δ 7.57 (2 H, m), 7.52 (2 H, m), 7.08-6.90
(10 H, m, 2 x Ph-H), 3.99 (2 H, dd, J = 13.5 and 3.2 Hz, H-2 and 6), 3.62
(2 H, dd, J = 16.3 and 13.5 Hz, H-3β and 5β), 2.78 (2 H, dd, J = 16.7 and
3.2 Hz, H-3α and 5α). 13C NMR (100 MHz, CDCl3, DEPT): δ 210.0 (C, C=O, C-4), 202.8 (2 x
C, C=O, C-1' and 3'), 142.0 (2 x C, C-8’ and 9’), 137.2 (2 x C), 135.3 (2 x CH, C-7’ and 6’),
128.3 (4 x CH), 128.1 (4 x CH), 127.3 (2 x CH), 122.4 (2 x CH, C-5’ and 4’), 61.5 (C, C-1 or
2’), 43.4 (2 x CH, C-6 and 2), 41.5 (2 x CH2, C-3 and 5). HRMS (MALDI-FTMS): m/z
403.1300 (M + Na+), calcd. for C26H20O3Na+ 403.1305.
(2β, 6β)-2,6-bis-(Napthalen-1-yl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5bk).6 Purified by FC using EtOAc/hexane and isolated
as a white solid and it has a plane of symmetry with chair
conformation. 1H NMR (399 MHz, CDCl3): δ 8.32 (2H, d, J = 8.8 Hz),
7.74 (1H, d, J = 7.6 Hz), 7.56 (4H, m), 7.40 - 7.29 (7H, m), 7.05 (2H, t,
J = 7.6 Hz), 6.97 (1H, dt, J = 7.6 and 0.8 Hz), 6.71 (1H, d, J = 8.0 Hz), 5.01 (2H, dd, J = 14.0
S11
and 4.0 Hz), 4.02 (2H, t, J = 14.0 Hz), 2.76 (2H, dd, J = 14.4 and 3.6 Hz). 13C NMR (100 MHz,
CDCl3, DEPT): δ 208.3 (C, C=O), 204.7 (C, C=O), 200.4 (C, C=O), 143.3 (C, C-8'), 141.3 (C,
C-9'), 135.0 (CH, C-7'), 134.8 (CH, C-6'), 134.3 (2 x C), 133.7 (2 x C), 130.7 (2 x C), 128.3 (2 x
CH), 128.1 (2 x CH), 126.3 (2 x CH), 125.6 (2 x CH), 124.7 (2 x CH), 124.6 (2 x CH), 123.5 (2
x CH), 122.2 (CH, C-5'), 121.8 (CH, C-4'), 61.2 (C, C-1), 45.2 (2 x CH), 42.2 (2 X CH2).
HRMS (MALDI-FTMS): m/z 503.1619 (M + Na+), calcd. for C34H24O3Na+ 503.1618.
(2β, 6β)-2,6-bis-(Thiophen-2-yl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-
trione (5km). Purified by FC using EtOAc/hexane and isolated as a
white solid and it has a plane of symmetry with chair conformation. 1H
NMR (399 MHz, CDCl3): δ 7.72 (1H, td, J = 6.8 and 1.2 Hz), 7.62 - 7.60
(1H, m), 7.57 (2H, dt, J = 7.2 and 2.0 Hz), 6.87 (2H, dd, J = 5.2 and 1.2
Hz), 6.69 (2H, br d, J = 4.0 Hz), 6.61 (2H, dd, J = 5.2 and 3.6 Hz), 4.08
(2H, dd, J = 14.4 and 4.4 Hz), 3.70 (2H, t, J = 14.4 Hz), 2.80 (2H, ddd, J = 14.4, 4.0 and 0.8
Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 205.9 (C, C=O), 202.6 (C, C=O), 202.0 (C, C=O),
143.0 (C, C-8'), 142.2 (C, C-9'), 140.1 (2 x C), 135.4 (CH, C-7'), 135.37 (CH, C-6'), 126.4 (4 x
CH), 124.5 (2 x CH), 122.6 (CH, C-5'), 122.4 (CH, C-4'), 62.2 (C, C-1), 44.6 (2 x CH, C-2 and
6), 43.3 (2 x CH2, C-3 and 5). HRMS (MALDI-FTMS): m/z 393.0618 (M + H+), calcd. for
C22H16O3S2H+ 393.0614.
(2β, 6β)-2,6-bis-(Furan-2-yl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-
trione (5ll). Purified by FC using EtOAc/hexane and isolated as a light
yellow color solid and it has a plane of symmetry with chair
conformation. 1H NMR (399 MHz, CDCl3): δ 7.80 - 7.74 (2H, m, H-7'
and 6'), 7.67 - 7.63 (2H, m, H-5' and 4'), 6.89 (2H, br d, J = 1.2 Hz), 5.95
(2H, dd, J = 3.2 and 2.0 Hz), 5.93 (2H, br d, J = 3.6 Hz), 3.86 (2H, dd, J
= 14.0 and 3.6 Hz, H-2 and 6), 3.64 (2H, t, J = 14.4 Hz, H-3a and 5a), 2.70 (2H, dd, J = 15.2 and
4.0 Hz, H-3e and 5e). 13C NMR (100 MHz, CDCl3, DEPT): δ 206.6 (C, C=O, C-4), 201.2 (C,
C=O, C-1'), 201.1 (C, C=O, C-3'), 151.1 (C), 141.9 (2 x CH), 141.5 (C), 135.2 (CH), 135.2
(CH), 122.6 (CH), 122.5 (CH), 109.9 (2 x CH), 109.8 (2 x C), 107.7 (2 x CH), 58.8 (C, C-1),
41.4 (2 x CH), 41.2 (2 x CH2). HRMS (MALDI-FTMS): m/z 361.1069 (M + H+), calcd. for
C22H16O5H+ 361.107.
(2β, 6β)-2,6-bis-(4-Methoxyphenyl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5cc).5a,b,d Purified by FC using EtOAc/hexane and isolated
as a white solid and it has a plane of symmetry with chair conformation. 1H NMR (399 MHz, CDCl3): δ 7.64 (1H, br dd, J = 7.6 and 1.2 Hz), 7.45
- 7.34 (3H, m), 6.94 (4H, br d, J = 9.2 Hz), 6.51 (4H, dd, J = 8.8 and 2.4
Hz), 3.76 (4H, m), 3.54 (3H, s, OCH3), 3.53 (3H, s, OCH3), 2.61 (2H,
ABq, J = 14.8 Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 208.3 (C,
C=O, C-4), 203.6 (C, C=O, C-1’), 202.1 (C, C=O, C-3’), 158.4 (2 x C),
142.6 (C, C-8'), 141.9 (C, C-9'), 135.12 (CH, C-7'), 135.1 (CH, C-6'), 129.4 (2 x C), 128.9 (4 x
CH), 122.2 (CH, C-5'), 121.8 (CH, C-4'), 113.4 (4 x CH), 62.2 (C, C-1), 54.7 (2 x CH3, OCH3),
47.7 (2 x CH), 43.5 (2 x CH2). HRMS (MALDI-FTMS): m/z 441.1682 (M + H+), calcd. for
C28H24O5H+ 441.1696.
(2β, 6β)-2,6-bis-(Benzo[1,3]dioxol-5-yl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5dd). Purified by FC using EtOAc/hexane and isolated as
a white solid and it has a plane of symmetry with chair conformation. 1H
NMR (399 MHz, CDCl3): δ 7.71 (1H, td, J = 7.6 and 0.8 Hz), 7.58 - 7.46
(3H, m), 6.50 - 6.42 (6H, m), 5.73 (4H, dd, J = 7.6 and 1.6 Hz, OCH2O),
3.69 (4H, m, H-2,6,3a and 5a), 2.59 (2H, ABq, J = 14.8 Hz, H-3e and
5e). 13C NMR (100 MHz, CDCl3, DEPT): δ 207.9 (C, C=O), 203.4 (C,
C=O), 201.8 (C, C=O), 147.2 (2 x C), 146.6 (2 x C), 142.7 (C, C-8'),
141.9 (C, C-9'), 135.3 (CH, C-7'), 135.28 (CH, C-6'), 131.1 (2 x C), 122.4 (CH, C-5'), 122.1
(CH, C-4'), 121.6 (2 x CH), 108.1 (2 x CH), 107.9 (2 x CH), 100.8 (2 x CH2, OCH2O), 62.1 (C,
C-1 or 2'), 48.2 (2 x CH), 43.6 (2 x CH2). HRMS (MALDI-FTMS): m/z
491.1107 (M + Na+), calcd. for C28H20O7Na+ 491.1101.
(2β, 6β)-2,6-bis-(4-N,N-Dimethylaminophenyl)spiro[cyclohexane-1,2’-
indan]-1’,3’,4-trione (5ee). Purified by FC using EtOAc/hexane and
isolated as a light yellow color solid and it has a plane of symmetry with
chair conformation. 1H NMR (399 MHz, CDCl3): δ 7.65 (1H, m, H-7'), 7.45
(2H, m), 7.39 (1H, m), 6.86 (4H, d, J = 9.2 Hz), 6.34 (4H, d, J = 8.8 Hz),
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3.80 - 3.63 (4H, m, H-2, 6, 3a and 5a), 2.72 (12H, s, 2 x N(CH3)2), 2.58 (2H, dd, J = 14.0 and
3.2 Hz, H-3e and 5e). 13C NMR (100 MHz, CDCl3, DEPT): δ 209.4 (C, C=O), 204.3 (C, C=O),
202.7 (C, C=O), 149.5 (2 x C), 143.0 (C), 142.3 (C), 134.96 (CH), 134.87 (CH), 128.6 (4 x CH),
125.3 (2 x C), 122.3 (CH), 121.9 (CH), 112.1 (4 x CH), 62.7 (C, C-1), 47.9 (2 x CH), 43.9 (2 x
CH2), 40.2 (4 x CH3). HRMS (MALDI-FTMS): m/z 467.2313 (M + H+), calcd. for
C30H30O3N2H+ 467.2329.
(2β, 6β)-2,6-bis-(4-Hydroxyphenyl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-trione (5ff).
Purified by FC using EtOAc/hexane and isolated as a white solid and it has
a plane of symmetry with chair conformation. This compound yeilded poor
resolution 1H and 13C NMR in CDCl3 even at 60° C. 1H NMR (399 MHz,
CDCl3): δ 7.64 (1H, br d, J = 7.6 Hz), 7.50 (1H, m), 7.43 (2H, m), 6.84 (4H,
td, J = 8.4 and 2.0 Hz), 6.45 (4H, td, J = 8.8 and 2.0 Hz), 5.78 (2H, s, 2 x
Ph-OH), 3.71 (4H, m), 2.59 (2H, ABq, J = 14.8 Hz). HRMS (MALDI-
FTMS): m/z 413.1396 (M + H+), calcd. for C26H20O5H+ 413.1383.
(2β,6β)-4-[2H1]Hydroxy-4-[2H3]methoxy-2,6-bis-(4-[2H1]hydroxyphenyl)spiro[cyclohexane-
1,2’-indan]-1’,3’-dione.7 Dihydroxy cis-spirane 5ff in CD3OD furnished the deuterated
hemiacetal in good conversion after storage at 4° C in an NMR tube. 1H NMR (399 MHz, CD3OD, major product): δ 7.53 (1H, td, J = 7.2
and 1.2 Hz), 7.46 (1H, m), 7.42 (2H, m), 6.78 (4H, td, J = 8.8 and 2.0
Hz), 6.36 (4H, td, J = 8.8 and 2.0 Hz), 3.46 (2H, dd, J = 13.6 and 3.2
Hz), 2.76 (2H, t, J = 13.6 Hz), 2.10 (2H, dd, J = 13.6 and 1.6 Hz). 13C
NMR (100 MHz, CD3OD, DEPT): δ 205.7 (C, C=O, C-1’), 205.5 (C,
C=O, C-3’), 157.4 (2 x C), 144.3 (C, C-8’), 143.5 (C, C-9’), 136.6
(CH, C-7’), 136.4 (CH, C-6’), 131.4 (2 x C), 130.6 (4 x CH), 123.1 (CH, C-5’), 123.0 (CH, C-
4’), 116.0 (4 x CH), 101.5 (C, C-4, DO-C-OCD3), 64.4 (C, C-1 or 2'), 46.2 (2 x CH), 35.4 (2 x
CH2). HRMS (MALDI-FTMS): m/z 413.1396 (M + H+), calcd. for C26H20O5H+ 413.1383.
(2β, 6β)-2,6-bis-(4-Chlorophenyl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-trione (5gg).5b,d
Purified by FC using EtOAc/hexane and isolated as a white solid and it has a plane of symmetry
with chair conformation. 1H NMR (399 MHz, CDCl3): δ 7.67 (1H, td, J = 7.6 and 1.2 Hz), 7.56
S14
(1H, dt, J = 7.2 and 1.6 Hz), 7.52 - 7.44 (2H, m), 6.97 (8H, dd, J = 12.8
and 9.2 Hz), 3.80 - 3.70 (4H, m), 2.63 (2H, m). 13C NMR (100 MHz,
CDCl3, DEPT): δ 207.2 (C, C=O, C-4), 203.0 (C, C=O, C-1’), 201.4 (C,
C=O, C-3’), 142.4 (C, C-8'), 141.7 (C, C-9'), 135.8 (CH, C-7'), 135.75
(CH, C-6'), 135.71 (2 x C), 133.4 (2 x C), 129.3 (4 x CH), 128.5 (4 x CH),
122.5 (CH, C-5'), 122.1 (CH, C-4'), 61.6 (C, C-1), 47.9 (2 x CH), 43.1 (2 x
CH2). HRMS (MALDI-FTMS): m/z 449.0728 (M + H+), calcd. for
C26H18O3Cl2H+ 449.0706.
(2β, 6β)-2,6-bis-(4-Nitrophenyl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-
trione (5ha). Purified by FC using EtOAc/hexane and isolated as a light
yellow color solid and it has a plane of symmetry with chair conformation. 1H NMR (399 MHz, CDCl3): δ 7.90 (4H, td, J = 9.2 and 2.0 Hz), 7.71 (1H,
td, J = 7.6 and 0.8 Hz), 7.61 (1H, dt, J = 7.2 and 1.2 Hz), 7.54 (1H, dt, J =
7.6 and 0.8 Hz), 7.48 (1H, td, J = 7.6 and 0.8 Hz), 7.24 (4H, td, J = 8.8 and
2.0 Hz), 3.96 (2H, dd, J = 14.0 and 3.6 Hz), 3.84 (2H, t, J = 14.4 Hz), 2.71
(2H, dd, J = 14.4 and 2.8 Hz). 13C NMR (100 MHz, CDCl3, DEPT): δ 205.5 (C, C=O, C-4),
202.1 (C, C=O, C-1’), 200.5 (C, C=O, C-3’), 147.2 (2 x C), 144.1 (2 x C), 141.9 (C, C-8'), 141.2
(C, C-9'), 136.4 (2 x CH, C-7’ & 6’), 129.0 (4 x CH), 123.5 (4 x CH), 122.7 (CH, C-5'), 122.4
(CH, C-4'), 61.0 (C, C-1), 48.1 (2 x CH), 42.5 (2 x CH2).
(2β, 6β)-2,6-bis-(4-Cyanophenyl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-
trione (5ii). Purified by FC using EtOAc/hexane and isolated as a white
solid and it has a plane of symmetry with chair conformation. 1H NMR (399
MHz, CDCl3): δ 7.69 (1H, br d, J = 7.6 Hz, H-7'), 7.62 (1H, dt, J = 7.2 and
1.2 Hz, H-6'), 7.56 (1H, dt, J = 7.2 and 1.2 Hz, H-5'), 7.47 (1H, br d, J = 7.6
Hz, H-4'), 7.35 (4H, d, J = 8.4 Hz), 7.16 (4H, d, J = 8.4 Hz) [-C6H4-CN],
3.85-3.75 (4H, m, H-2, 6, 3a, 5a), 2.67 (2 H, dd, J = 13.2 and 2.4 Hz, H-3e and 5e). 13C NMR
(100 MHz, CDCl3, DEPT): δ 205.8 (C, C=O, C-4), 202.08 (C, C=O, C-1'), 200.6 (C, C=O, C-
3'), 142.0 (2 x C), 141.9 (C, C-8'), 141.1 (C, C-9'), 136.2 (CH, C-7'), 136.2 (CH, C-6'), 132.1 (4
x CH), 128.7 (4 x CH), 122.5 (CH, C-5'), 122.2 (CH, C-4'), 117.8 (2 x C), 111.7 (2 x C, C6H4-
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CN), 61.0 (C, C-1 or 2'), 48.2 (2 x CH, C-2 and 6), 42.3 (2 x CH2, C-3 and 5). HRMS (MALDI-
FTMS): m/z 429.1242 (M - H), calcd. for C28H18O3N2-H 429.1245.
(2β, 6β)-2,6-bis-(4-Methoxycarbonyl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5jj). Purified by FC using EtOAc/hexane and isolated as a
white solid and it has a plane of symmetry with chair conformation. 1H
NMR (399 MHz, CDCl3): δ 7.69 (4H, d, J = 8.4 Hz), 7.67 (1H, m, H-7'),
7.52 (1H, mt, J = 6.8 Hz, H-6'), 7.45 - 7.40 (2H, m, H-5' and 4'), 7.12 (4H,
d, J = 8.4 Hz), 3.98 - 3.86 (4H, m, H-2, 6, 3a, 5a), 3.77 (6H, s, 2 x
CO2CH3), 2.68 (2H, ABq, J = 14.8 Hz, H-3e and 5e). 13C NMR (100 MHz,
CDCl3, DEPT): δ 206.8 (C, C=O, C-4), 202.6 (C, C=O, C-1'), 201.0 (C, C=O, C-3'), 166.1 (2 x
C, O-C=O), 142.2 (C, C-8'), 142.1 (2 x C), 141.4 (C, C-9'), 135.7 (2 x CH, C-7' and 6'), 129.5 (4
x CH), 129.3 (2 x C), 128.0 (4 x CH), 122.4 (CH, C-5'), 122.1 (CH, C-4'), 61.3 (C, C-1), 51.8 (2
x CH3, CO2CH3), 48.4 (2 x CH, C-2 and 6), 42.8 (2 x CH2). HRMS (MALDI-FTMS): m/z
519.1408 (M + Na+), calcd. for C30H24O7Na+ 519.1414.
(2β, 6β)-2-(4-formylphenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (23). Purified by FC using EtOAc/hexane and isolated as a
light yellow color solid. The ee was not determined. 1H NMR (399 MHz,
CDCl3): δ 9.77 (1H, s, CHO), 7.65 (1H, td, J = 7.6 and 0.8 Hz), 7.55 (2H,
td, J = 8.4 and 1.6 Hz), 7.50 (1H, m), 7.43 (1H, dd, J = 2.4 and 0.8 Hz),
7.42 (1H, d, J = 1.2 Hz), 7.23 (2H, br d, J = 8.4 Hz), 7.04 - 6.80 (5H, m,
Ph-H), 3.94 - 3.76 (4H, m), 2.68 (2H, m). 13C NMR (100 MHz, CDCl3,
DEPT): δ 207.4 (C, C=O, C-4), 202.9 (C, C=O, C-1'), 201.3 (C, C=O, C-3'), 191.4 (CH, H-
C=O), 144.2 (C), 142.4 (C), 141.6 (C), 136.8 (C), 135.5 (2 x CH, C-7’ & 6’), 135.4 (C), 129.6
(2 x CH), 128.8 (2 x CH), 128.3 (2 x CH), 127.9 (2 x CH), 127.7 (CH), 122.4 (CH, C-5’), 122.1
(CH, C-4’), 61.6 (C, C-1 or 2'), 48.9 (CH), 48.3 (CH), 43.1 (CH2), 42.8 (CH2). HRMS (MALDI-
FTMS): m/z 407.1282 (M - H+), calcd. for C27H20O4-H+ 407.1289.
1-{(2β, 6β)-6-phenylspiro[cyclohexane-1,2'-indan]-1',3',4-trione-2-yl}-4-{(2''β, 6''α)-6''-
phenylspiro[cyclohexane-1'',2'''-indan]-1''',3''',4''-trione-2''-yl}-benzene (24). Purified by
FC using EtOAc/hexane and isolated as a yellow color solid. The ee was not determined. 1H
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NMR (399 MHz, CDCl3): δ 7.56 (1H, br d, J = 7.6 Hz), 7.53 (1H, br d,
J = 7.6 Hz), 7.45 (1H, dt, J = 6.8 and 0.8 Hz), 7.43 (1H, dt, J = 6.8 and
0.8 Hz), 7.36 (2H, m), 7.30 (1H, m), 7.27 (1H, br t, J = 8.0 Hz), 7.02 -
6.88 (10H, m, 2 x Ph-H), 6.68 (4H, s, -C6H4-), 3.80 - 3.46 (8H, m), 2.56
(2H, br d, J = 12.8 Hz), 2.27 (2H, m). 13C NMR (100 MHz, CDCl3,
DEPT): δ 208.14 (C, C=O, C-4), 208.11 (C, C=O, C-4''), 203.08 (C,
C=O, C-1'), 203.06 (C, C=O, C-1'''), 201.48 (C, C=O, C-3'), 201.45 (C,
C=O, C-3'''), 142.4 (2 x C), 141.7 (2 x C), 137.07 (C), 137.05 (C),
136.9 (2 x C), 135.2 (2 x CH), 135.15 (CH), 135.1 (CH), 128.3 (4 x
CH), 128.1 (4 x CH), 127.9 (4 x CH), 127.6 (2 x CH), 122.23 (CH), 122.20 (CH), 122.0 (CH),
121.9 (CH), 61.7 (2 x C, C-1 and 1’’), 48.78 (CH), 48.72 (CH), 47.94 (CH), 47.92 (CH), 43.2 (4
x CH2). HRMS (MALDI-FTMS): m/z 705.2228 (M + Na+), calcd. for C46H34O6Na+ 705.2247.
Minimized structures of spiranes 5aa, 6aa, 5ab and 6ab based on MOPAC calculations.8
(1)
References
1. Bloxham, J.; Dell, C. P. Tetrahedron Lett. 1991, 32, 4051.
2. Matsushima, R.; Tatemura, M.; Okamoto, N. Journal of Materials Chemistry, 1992, 2,
507.
3. Franz, C.; Heinisch, G.; Holzer, W.; Mereiter, K.; Strobl, B.; Zheng, C. Heterocycles
1995, 41, 2527.
4. Dumpis, T.; Vanags, O. Kimijas Serija 1961, 2, 241.
5. (a) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1979, 44, 1508. (b) Shternberg, I. Ya.;
Freimanis, Ya. F. Zh. Organ. Khim., 1968, 4, 1081. (c) Patai, S.; Weinstein, S.;
Rappoport, Z. J. Chem. Soc., 1962, 1741. (d) Popelis, J.; Pestunovich, V. A.; Sternberga,
I.; Freimanis, J. Zh. Organ. Khim., 1972, 8, 1860. (e) Sternberga, I.; Freimanis, J.
Kimijas Serija 1972, 2, 207.
6. Seifert, M.; Kuck, D. Tetrahedron 1996, 52, 13167.
7. When the 1H NMR of the compound 5ff was recorded immediately after adding CD3OD,
it showed a mixture of three deuterated compounds with the hemiacetal as the minor, but
when the 1H NMR was recorded after storage at 4o C for 4-5 days, the hemiacetal was
the major product.
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8. Heat of formations (H) of spiranes 5aa, 6aa, 5ab and 6ab are calculated based on PM3
(MOPAC) calculations in CS Chem3D Ultra using wave function as closed shell
(restricted) and minimize energy to minimum RMS Gradient of 0.100.
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