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)tocis-spiranes (5). The mechanism of conversion of trans-spiranes (6)tocis-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 materials.2 Domino reactions have gained wide accep- tance because they increase synthetic efficiency by Critical objectives in modern synthetic organic chem- decreasing the number of laboratory operations required istry include the improvement of reaction efficiency, the and the quantities of chemicals and solvents used. Thus, avoidance of toxic reagents, the reduction of waste, and these reactions can facilitate ecologically and economi- the responsible utilization of our resources. Domino or cally favorable syntheses. tandem reactions, which consist of several bond-forming Recently organocatalysis has emerged as a promising reactions, address many of these objectives. Domino synthetic tool for constructing C-C, C-N, and C-O reactions involve two or more bond-forming transforma- bonds in aldol,3 Michael,4 Mannich,5 Diels-Alder,6 and tions that take place under the same reaction conditions. related reactions7 in highly diastereo- and enantioselec- Combinations of reactions involving the same mechanism tive processes. In these recently described reactions, are classified as homodomino reactions, whereas a se- structurally simple and stable chiral organoamines fa- quence of reactions with different mechanisms are clas- cilitate iminium- and enamine-based transformations sified as heterodomino reactions.1 One of the ultimate with carbonyl compounds. Often, the organocatalysts can goals in organic synthesis is the catalytic asymmetric be used in operationally simple and environmentally assembly of simple and readily available precursor friendly experimental protocols. Because these reactions molecules into stereochemically complex products, a process that ultimately mimics biological synthesis. In (2) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. this regard, the development of domino and other mul- 1978, 1759. (b) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Chem. Pharm. ticomponent reaction methodologies can provide expedi- Bull. 1982, 30, 3092. (c) Cane, D. E. Chem. Rev. 1990, 90, 1089. (d) ent access to complex products from simple starting 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. * To whom correspondence should be addressed. Fax: +1-858-784- F.; Modi, A. Med. Res. Rev. 2000, 20, 304. (h) Mayer, S. F.; Kroutil, 2583. W.; Faber, K. Chem. Soc. Rev. 2001, 30, 332. (i) Tietze, L. F.; Evers, T. (1) (a) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, H.; Topken, E. Angew. Chem., Int. Ed. 2001, 40, 903. (j) Tietze, L. F.; 679. (b) Balaure, P. C. F.; Filip, P. I. A. Rev. Roum. Chim. 2001, 46, Evers, H.; Topken, E. Helv. Chim. Acta 2002, 85, 4200. (k) Glueck, S. 809. M.; Mayer, S. F.; Kroutil, W.; Faber, K. Pure Appl. Chem. 2002, 74, 2253.

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

share common mechanistic features they may be linked 1,3-indandione.6b Herein, we report the first direct orga- to create one-pot and domino reaction schemes (assembly nocatalytic asymmetric hetero-domino Knoevenagel/Di- reactions). To date, we have described asymmetric as- els-Alder/epimerization (K-DA-E) reaction sequence to sembly reactions involving aldol-aldol,3c,d Michael- generate highly substituted spiro[cyclohexane-1,2′-in- aldol,7d Mannich-cyanation,5d Mannich-allylation,5f am- dan]-1′,3′,4-triones (5) in a highly diastereoselective and ination-aldol,7g and Knoevanagel-Michael4a reactions. modestly enantioselective process from commercially Recently, we reported two interesting domino reactions available 4-substituted-3-buten-2-ones (1a-l), aldehydes founded on Knoevenagel/Diels-Alder reaction sequences. (2a-p), and 1,3-indandione (3) as shown in Scheme 1. The first was the direct organocatalytic asymmetric Spirocyclic ketones (5) are attractive intermediates in the domino Knoevenagel/Diels-Alder reaction sequence to accomplish the diastereo- and enantioselective construc- (5) (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. tion of highly substituted spiro[5.5]undecane-1,5,9- Tetrahedron Lett. 2001, 42, 199. (b) Cordova, A.; Notz, W.; Zhong, G.; 6a Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. triones. The second was the direct organocatalytic, (c) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. hetero-domino, Knoevenagel/Diels-Alder/epimerization J. Am. Chem. Soc. 2002, 124, 1866. (d) Watanabe, S.; Cordova, A.; sequence to prepare symmetric prochiral and highly 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) substituted spiro[cyclohexane-1,2 -indan]-1 ,3 ,4-triones Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923. (g) (5) in diastereospecific fashion from commercially avail- List, B. J. Am. Chem. Soc. 2000, 122, 9336. (h) Hayashi, Y.; Tsuboi, able 4-substituted 3-buten-2-ones (1), aldehydes (2), and 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.; (3) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208. (k) Notz, 2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; J. Am. Chem. Soc. 2001, 123, 5260. (c) Cordova, A. Notz, W.; Barbas, Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624. C. F., III. J. Org. Chem. 2002, 67, 301. (d) Chowdari, N. S.; Ramachary, (6) (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. D. B.; Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 9591. Chem., Int. Ed. 2003, 42, 4233. (b) Ramachary, D. B.; Chowdari, N. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, S.; Barbas, C. F., III. Synlett 2003, 12, 1909. (c) Ramachary, D. B.; 6798. (f) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Jorgensen, K. Chowdari, N. S.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 6743. A. Chem. Commun. 2002, 620. (g) Nakadai, M.; Saito, S.; Yamamoto, (d) Thayumanavan, R.; Ramachary, D. B.; Sakthivel, K.; Tanaka, F.; H. Tetrahedron 2002, 58, 8167. (h) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817. (e) Northrup, A. X.; Gong, L.-Z.; Qiao, A.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (f) 2003, 125, 5262. (i) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Nakamura, H.; Yamamoto, H. Chem. Commun. 2002, 1648. (g) Juhl, Angew. Chem., Int. Ed. 2003, 42, 2785. (j) Liu, H.; Peng, L.; Zhang, K.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (h) Cavill, T.; Li, Y. New J. Chem. 2003, 27, 1159. (k) Darbre, T.; Machuqueiro, J. L.; Peters, J. U.; Tomkinson, N. C. O. Chem. Commun. 2003, 728. M. Chem. Commun. 2003, 1090. (l) Loh, T.-P.; Feng, L.-C.; Yang, H.- (i) Barluenga, J.; Sobirino, A. S.; Lopez, L. A. Aldrichim. Acta 1999, Y.; Yang, J.-Y. Tetrahedron Lett. 2002, 43, 8741. (m) Kotrusz, P.; 32, 4. (j) Asato, A. E.; Watanabe, C.; Li, X.-Y.; Liu, R. S. H. Tetrahedron Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E. Chem. Commun. Lett. 1992, 33, 3105. (k) Jung, M. E.; Vaccaro, W. D.; Buszek, K. R. 2002, 2510. (n) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, Tetrahedron Lett. 1989, 30, 1893. 573. (o) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (7) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 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CHART 1. Benzoannelated Centropolyquinanes

synthesis of natural products and in material chemistry peripheral functionalization could serve as unusual and are the excellent starting materials for the synthesis motifs for liquid crystal engineering and dendrimer of fenestranes8 (centrotriindane and centrotetraindanes), chemistry and for the construction of graphite cuttings topologically nonplanar hydrocarbon centrohexaindane, bearing a saddle-like, three-dimensionally distorted core.8 and other frameworks bearing the [5.5.5.5]fenestrane core as shown in Chart 1. Fenestrindanes with 8-fold Results and Discussion - (8) (a) Bredenkotter, B.; Florke, U.; Kuck, D. Chem. Eur. J. 2001, We envisioned that amino acids 4a e and simple 7, 3387. (b) Tellenbroker, J.; Kuck, D. Eur. J. Org. Chem. 2001, 1483. amines 4f-j (Chart 2) would act as organocatalysts of (c) Bredenkotter, B.; Barth, D.; Kuck, D. Chem. Commun. 1999, 847. the Knoevenagel condensation of aldehydes 2a-p with (d) Thommen, M.; Keese, R. Synlett 1997, 231. (e) Seifert, M.; Kuck, D. Tetrahedron 1996, 52, 13167. (f) Kuck, D. Chem. Ber. 1994, 127, 1,3-indandione 3 to provide arylidene indandiones 17a- 409. (g) Kuck, D.; Schuster, A.; Krause, R. A. J. Org. Chem. 1991, 56, p. There is ample precedence for amine-catalyzed Kno- 3472. (h) Kuck, D.; Bogge, H. J. Am. Chem. Soc. 1986, 108, 8107. (i) 9 Kuck, D. Adv. Theoretically Interesting Molecules 1998, 4, 81. (j) Kuck, evenagel reactions. 2-Arylideneindan-1,3-diones (17) are D.; Schuster, A.; Paisdor, B.; Gestmann, D. J. Chem. Soc., Perkin attractive compounds in medicinal and material chem- Trans. 1 1995, 6, 721. (k) Paisdor, B.; Kuck, D. J. Org. Chem. 1991, istry. For example, substituted 2-arylideneindan-1,3- 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. (9) (a) Ishikawa, T.; Uedo, E.; Okada, S.; Saito, S. Synlett 1999,4, Engl., 1991, 30, 1699. (o) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 450. (b) Tanikaga, R.; Konya, N.; Hamamura, K.; Kaji, A. Bull. Chem. 1980, 45, 2925. (p) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1979, 44, Soc. Jpn. 1988, 61, 3211. (c) Tietze, L. F.; Beifuss, U. The Knoevenagel 1508. (q) Shternberg, I. Ya.; Freimanis, Ya. F. Zh. Org. Khim. 1968, reaction. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, 4, 1081. (r) Patai, S.; Weinstein, S.; Rappoport, Z. J. Chem. Soc. 1962, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.11, pp 341- 1741. (s) Popelis, J.; Pestunovich, V. A.; Sternberga, I.; Freimanis, J. 392. (d) List, B.; Castello, C. Synlett 2001, 11, 1687. (e) Cardillo, G.; Zh. Organ. Khim. 1972, 8, 1860. (t) Sternberga, I.; Freimanis, J. Fabbroni, S.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Synth. Commun. Kimijas Serija 1972, 2, 207. 2003, 33, 1587.

5840 J. Org. Chem., Vol. 69, No. 18, 2004 Organocatalytic Heterodomino K-DA-E Reactions

CHART 2. Screened Organocatalysts for the K-DA-E Reaction

FIGURE 1. Dienes and dienophiles generated under organocatalysis.

SCHEME 2. Organocatalytic Knoevenagel Condensation

In these three component organocatalytic K-DA-E reactions, the Knoevenagel condensation generates reactive dienophiles that can be readily isolated from the 10 diones 17 derivatives show antibacterial activites, reaction mixture. For example, reaction of 4-nitroben- 11 nonlinear optical properties, electroluminescent de- zaldehyde 2a and 1,3-indandione 3 in methanol at 12 13 vices, and are useful as eye lens clarification agents. ambient temperature under L-proline or pyrrolidine The arylidene indandiones are very good organic Lewis catalysis furnished the expected 2-(4-nitro-benzylidene)- 14 acids (OLA) with low energy LUMO configurations and indan-1,3-dione 17a in almost quantitative yield as are useful as heterodienes and Michael acceptors in shown in Scheme 2. Under similar reaction conditions 15 cycloaddition reactions. Here, we have utilized arylidene with different aromatic aldehydes, a wide variety of - indandiones 17 as dienophiles in Diels Alder chemistry. 2-arylideneindan-1,3-dione dienophiles (17) were syn- - + As dienophiles, 17a p undergo [4 2] cycloaddition thesized in very good yields. - reactions with 2-amino-1,3-butadienes 18a l generated Amino Acid-Catalyzed Direct Asymmetric Het- - in situ from enones 1a l and amino acids or amines to ero-Domino K-DA-E Reactions. We found that the ′ ′ ′ generate substituted spiro[cyclohexane-1,2 -indan]-1 ,3 ,4- three-component reaction of trans-4-phenyl-3-buten-2-one triones 5 and 6 in a diastereoselective manner (Figure 1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 with 1). Epimerization of the minor diastereomer trans- a catalytic amount of L-proline (20 mol %) in methanol spirane 6 to the more stable cis-spirane 5 occurred under at ambient temperature for 24 h furnished the expected the same reaction conditions. This domino Knoevenagel/ nonsymmetrical Diels-Alder products 5aa and 6aaΨ in - Diels Alder reaction generates a quaternary carbon 86% yield with thermodynamically stable cis-spirane 5aa - center with formation of three new carbon carbon σ as the major isomer, dr 24:1 (Table 1, entry 1) (ΨIn all bonds via organocatalysis. compounds denoted 5xy and 6xy, x is incorporated from reactant enones 1 and y is incorporated from the reactant (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.; aldehydes 2.) Unfortunately, the enantiomeric excess (ee) Hamama, W. S.; Sayed-Ahmed, A. F. Boll. Chim. Farm. 1998, 137, of the major cis-spirane 5aa was only 5%. Interestingly, 244. (c) El-Ablak, F. Z.; Metwally, M. A. J. Serb. Chem. Soc. 1992, 57, the same reaction with an extended reaction time fur- 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.; nished cis-spirane 5aa as a single diastereomer in 96% Zoorob, H.; Khalifa, M. M.; Zimaity, M. Pharmazie 1990, 45, 255. (f) yield, however with 3% ee (Table 1, entry 2). The minor Yoakim, C.; Hache, B.; Ogilvie, W. W.; O’Meara, J.; White, P.; Goudreau, N. PCT Int. Appl. 2002, 121 pp. CODEN: PIXXD2 WO diastereomer, trans-spirane 6aa, was effectively epimer- 2002050082 A2 20020627. Patent written in English. ized to the thermodynamically stable cis-spirane 5aa (11) Szymusiak, H.; Zielinski, R.; Domagalska, B. W.; Wilk, K. A. under prolonged reaction time via proline catalysis. The Comput. Chem. 2000, 24, 369. (12) Murakami, M.; Fukuyama, M.; Suzuki, M.; Hashimoto, M. Jpn. stereochemistry of products 5aa and 6aa was established Kokai Tokkyo Koho 1996, 13 pp. CODEN: JKXXAF JP 08097465 A2 by NMR analysis.16 19960412 Heisei. Patent written in Japanese. (13) Aziz, A. B. M. S. A.; Mohamed, E. S. Eur. Pat. Appl. 1992, 14 In the three-component hetero-domino K-DA-E reac- pp. CODEN: EPXXDW EP 489991 A1 19920617. Patent written in tion of enone 1a, 4-nitrobenzaldehyde 2a, and 1,3- English. indandione 3 catalyzed directly by L-proline, we found (14) (a) Cammi, R.; Ghio, C.; Tomasi, J. Int. J. Quantum Chem. 1986, 29, 527. (b) Liedl, E.; Wolschann, P. Monatsh. Chem. 1982, 113, that the solvent (dielectric constant) and temperature 1067. (c) Goerner, H.; Leitich, J.; Polansky, O. E.; Riemer, W.; Ritter- had a significant effects on reaction rates, yields, dr’s, Thomas, U.; Schlamann, B. Monatsh. Chem. 1980, 111, 309. (d) and ee’s (Table 1). The hetero-domino K-DA-E reaction Haslinger, E.; Wolschann, P. Bull. Soc. Chim. Belg. 1977, 86, 907. (e) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1969, 100, 576. (f) catalyzed by L-proline at ambient temperature in aprotic/ Margaretha, P. Tetrahedron 1972, 28, 83. nonpolar solvents produced products 5aa and 6aa in low (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 (16) Stereochemistries of the cis- and trans-spiranes were estab- 1993, 24, 3055. (c) Righetti, P. P.; Gamba, A.; Tacconi, G.; Desimoni, lished using COSY experiments and were also based on MOPAC G. Tetrahedron 1981, 37, 1779. (d) Eweiss, N. F. J. Heterocycl. Chem. calculations of the thermodynamic equilibration between the two 1982, 19, 273. isomers (see the Supporting Information).

J. Org. Chem, Vol. 69, No. 18, 2004 5841 Ramachary et al.

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 catalyst solvent drc eed entry (20 mol %) aldehyde (0.5 M) T (°C) time (h) products yieldb (%) (cis/trans) (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. to moderate yields with poor diastereoselectivity (Table asymmetric three-component Diels-Alder (ATCDA) re- 1, entries 4-6, 11, and 12). Enantioselectivity improved action of 1a, 2a, and Meldrum’s acid.6a Among the in aprotic/nonpolar solvents (Table 1, entries 4-6, 11, and catalysts screened in the ATCDA reaction, the 5,5- 12). Excellent yields, good diastereoselectivity, and poor dimethyl thiazolidinium-4-carboxylate (DMTC) proved to enantioselectivity were observed in protic/polar solvents be the most efficient catalyst with respect to yield and (Table 1, entries 1-3). For example, the K-DA-E reaction ee. When DMTC was tested in the K-DA-E reaction of in THF furnished spiranes 5aa and 6aa in 54% yield with 1a, 2a, and 3 in methanol at 25 °C for 72 h, the domino dr of 2.8:1 and with ee of 18% for the major cis-spirane products 5aa and 6aa were obtained in 62% yield with 5aa and an ee of 15% for the minor trans-spirane 6aa dr of 8.5:1 and ee of the major cis-spirane 5aa of 17% (Table 1, entry 4). The same reaction using ionic liquid (Table 1, entry 9). The same reaction under DMTC [bmim]BF4, a “green solvent”, catalyzed by L-proline at catalysis at reduced temperature (4 °C) in methanol for 25 °C furnished the thermodynamically stable product 96 h furnished products 5aa and 6aa in 18% yield with cis-spirane 5aa as the major diastereomer in 80% yield a dr of 1.3:1. Under these conditions, the ee of the major with dr of 34:1, albeit with a low ee value of 1% (Table 1, cis-spirane 5aa was 30% and ee for the minor trans- entry 7). Interestingly, the same reaction under proline spirane 6aa was 3% (Table 1, entry 10). With DMTC catalysis in ionic liquid [bmim]PF6 at 25 °C furnished catalysis in THF as solvent at 25 °C, products 5aa and the spiranes 5aa and 6aa in 45% yield with dr of 1.5:1 6aa were obtained in poor yields (e10%) with dr of 1:1.4 and with ee of 6% (cis-spirane) and 7% (trans-spirane) and ee for the minor cis-spirane of 42%, while the ee for (Table 1, entry 8). In the hetero-domino K-DA-E reaction the major trans-spirane of 6% (Table 1, entry 11). DMTC- under L-proline catalysis, diastereoselectivity was directly catalyzed K-DA-E reaction in THF at 4 °C for 96 h affected by the nature of the solvent (dielectric constant) furnished the domino products in very poor yields (Table as reflected in the epimerization reaction and exo/endo 1, entry 12). An imidazoline-type catalyst, 4-benzyl-1- selectivity. Rates of organocatalytic reactions catalyzed methylimidazolidine-2-carboxylic acid 4c, also catalyzed by amino acids were faster in protic/polar solvents than the K-DA-E reaction with moderate yield, very good dr, in nonprotic/nonpolar solvents presumably due to en- and low ee at 25 °C and moderate to low yield, and poor hanced stabilization of charged intermediates and more dr with improved ee at 4 °C (Table 1, entries 13 and 14). facile proton-transfer reactions. This is especially true trans-3-Hydroxy-L-proline 4d catalyzed the domino K- for the epimerization reaction where the dr’s of the DA-E reaction of 1a, 2a, and 3 with very good yield and produces obtained using protic/polar solvents were very excellent diastereoselectivity, but the ee was poor (Table high. 1, entry 15). trans-4-Hydroxy-L-proline 4e also catalyzed Next we probed the structure and reactivity relation- the domino K-DA-E reaction of 1a, 2a, and 3 but reaction ships among a family of amino acids and pyrrolidine- yield (19%), dr (1:1), and ee (14 and 13) were poor (Table based catalysts by monitoring the reaction yields, dr’s, 1, entry 16). While the Knoevenagel product 17a was and ee values of the hetero-domino K-DA-E reaction and formed and consumed in most of the amino acid-catalyzed compared them to the results of the organocatalytic heterodomino K-DA-E reactions, in some reactions (Table 5842 J. Org. Chem., Vol. 69, No. 18, 2004 Organocatalytic Heterodomino K-DA-E Reactions

Amine-Catalyzed Direct Heterodomino K-DA-E Reactions. Amines 4f-j can also catalyze the heterodomino K-DA-E reaction under different solvent and temperature conditions. The three-component heterodomino 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 temperature 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 FIGURE 2. Asymmetric solvation in the ionic liquids. expected domino products 5aa and 6aa in 71% yield with dr of 13.5:1, but with poor ee (Table 2, entry 2). Since 1, entries 10, 11, 12, 14, and 16) unreacted 17a was enantioselection in these reactions was typically unsat- isolated in 60-80% yield. Unreacted 17a was the result isfactory, we studied the simple achiral amine pyrrolidine of a very slow rate of the formation of the key intermedi- 4h and found that it furnished cis-spirane 5ab as a single ate 2-amino-1,3-butadiene and subsequent Diels-Alder diastereomer in 90% yield (Table 2, entry 3). Further we reaction under these conditions. found that pyrrolidine catalysis was not dramatically The L-proline-catalyzed three-component hetero-dom- affected with respect to reaction rates, yields, or dr’s by ino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1a solvent and temperature modification (Table 2). Under and 1,3-indandione 3 with a different aldehyde, benz- pyrrolidine catalysis, the heterodomino K-DA-E reaction aldehyde 2b, furnished products 5ab and 6ab in 87% worked well in a variety of solvents and the optimal yield with dr of 2:1 (Table 1, entry 17). The same reaction, conditions involved mixing equimolar amounts of enone albeit with an extended reaction time, furnished prochiral 1a, aldehyde 2b, and 1,3-diketone 3 in methanol with cis-spirane 5ab as a single diastereomer in 96% yield heating to 70 °C for1htofurnish cis-spirane 5ab as a (Table 1, entry 18). The stereochemistry of products 5ab single diastereomer in 95% yield (Table 2, entry 9). and 6ab was established by NMR analysis. The minor Interestingly, the six-membered cyclic amines piperidine diastereomer, trans-spirane 6ab was effectively epimer- (4i) and morpholine (4j) also catalyzed the heterodomino ized to the thermodynamically stable cis-spirane 5ab K-DA-E reaction. Typically, pyrrolidine-based catalysts under prolonged reaction time via proline catalysis. are much more effective than six-membered cyclic amines Increasing the reaction temperature to 70 °C facilitated as organocatalysts and six-membered cyclic amines are the epimerization reaction and furnished the expected extremely poor catalysts of aldol reactions.3b The reaction domino product 5ab as a single diastereomer in 96% yield of enone 1a, aldehyde 2b, and 1,3-diketone 3 under within 2 h. Interestingly the same reaction in the ionic piperidine 4i catalysis in methanol at 70 °C for 4 h liquids, [bmim]BF4 and [bmim]PF6, catalyzed by L-proline furnished the expected domino products 5ab and 6ab in at ambient temperature provided the kinetic product 71% yield with dr of 43:1 (Table 2, entry 10). Under the trans-spirane 6ab as the major diastereomer in moderate same conditions, morpholine 4j catalyzed formation of yield (Table 1, entries 20 and 21). In these reactions, 5ab and 6ab in 46% yield with dr of 18.6:1 (Table 2, entry enantioselectivity for the minor kinetic product 6ab was 11). The pyrrolidine-catalyzed heterodomino K-DA-E poor. cis-Spirane 5ab has been used as a synthon for the reaction was, however, faster. synthesis of variety of benzoannelated centropolyquinanes Organocatalytic Epimerization of trans-Spirane as shown in Chart 1.8 6tocis-Spirane 5. Epimerization of trans-spirane 6 or cis-Spirane 5ab is obtained via an endo-transition state the diastereospecific synthesis of cis-spirane 5 in the in the classical Diels-Alder route. In ionic liquids, heterodomino K-DA-E reaction of enone 1, aldehyde 2, however, the kinetic product, trans-spirane 6ab, was the and 1,3-indandione 3 can be explained as illustrated in major isomer formed. This is likely due to a unique Scheme 3. Amino acid or amine-catalyzed Knoevenagel organization of the ionic liquid solvent with the 2-amino- condensation9 of aldehyde 2 with 1,3-indandione 3 pro- 1,3-butadiene 18a and dienophile 17b in the transition vides the arylidene-indandione 17 via the in situ gener- states as shown in Figure 2. Asymmetric solvation in the ated reactive cationic imine 16. Arylideneindandione 17 ionic liquids then produces a steric hindrance with the then undergoes a concerted [4 + 2] cycloaddition or a phenyl group on the dienophile in the endo-transition double-Michael reaction with the soft nucleophile, 2-amino- state, thereby disfavoring it. In the case of dienophile 1,3-butadiene 18 generated in situ from enone 1 and the 17a, the high epimerization rate of trans-spirane 6aa amino acid or amine catalyst, to produce products 5 and provides cis-spirane 5aa as the major isomer (Table 1, 6. The energy difference (∆H) between the two isomers entries 7 and 8). Ratio of exo/endo products in ionic liquids or other solvents mainly depend on four factors, (17) (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, which are (i) substrate effect (electronic factor), (ii) protic 4369. (b) Spencer, T. A.; Neel, H. S.; Ward, D. C.; Williamson, K. L. J. solvent effect (polarization factor), (iii) steric hindrance 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. induced by ionic solvation, and (iv) basic nature of organo (e) Greco, M. N.; Maryanoff, B. E. Tetrahedron Lett. 1992, 33, 5009. catalyst. (f) Snider, B. B.; Yang, K. J. Org. Chem. 1990, 55, 4392.

J. Org. Chem, Vol. 69, No. 18, 2004 5843 Ramachary et al.

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 catalyst solvent yieldb drc eed entry (20 mol %) aldehyde (0.5 M) T (°C) time (h) products (%) (cis/trans) (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 SCHEME 4. Proposed Mechanism for the L-Proline L-Proline (or Amino Acid or Amine) Catalyzed (Amino Acid or Amine) Catalyzed Epimerization of Heterodomino K-DA-E Reactions trans-Spirane 6 to cis-Spirane 5

thermodynamically more stable cis-isomers 5aa and 5ab, respectively, at room temperature under mild organocatalysis. Epimerization of trans-spiranes 6 to cis-spiranes 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 thermodynamically stable cis-spirane 5 via deprotonation/reprotonation 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 5aa and 6aa is 5.626 kcal/mol based on AM1 and 4.114 4. kcal/mol based on PM3 calculations. The energy differ- The rate of the epimerization was also related to the ence (∆H) between the two isomers of 5ab and 6ab is nucleophilic strength of the amino acid or amine catalyst, 6.158 kcal/mol based on AM1 and 5.680 kcal/mol based on PM3 calculations. Minimized structures of 5aa, 6aa, (18) Zalukaev, L. P.; Anokhina, I. K.; Aver’yanova, I. A. Dokl. Akad. 5ab, and 6ab are depicted in the Supporting Information. Nauk SSSR 1968, 181, 103. Since the differences in ∆H’s between the two isomers (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, of 5aa/6aa and 5ab/6ab are greater than 5 kcal/mol, the M. D.; Chamberlin, M. J.; Czulada, G.; Johnson, S. D. J. Org. Chem. minor kinetic isomers 6aa and 6ab are epimerized to the 1998, 63, 4359. 5844 J. Org. Chem., Vol. 69, No. 18, 2004 Organocatalytic Heterodomino K-DA-E Reactions

SCHEME 5. Organocatalytic Epimerization of significantly faster than that catalyzed by proline. No trans-Spirane 6 to cis-Spirane 5 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 enamine hydrolysis is slower than that of pyrrolidine or L-proline enamines.19 Attempted purification of the enamine 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 arylaldehydes (2a-p) and 1,3-indandione 3 in methanol at 25 reaction temperature, and nature of the solvent. Epimer- °C for 96 h furnished the expected cis-spiranes in good ization rate of trans-spirane 6 to cis-spirane 5 in protic/ yields with high diastereoselectivity as shown in Table polar solvents under amino acid catalysis was faster than 3. None of these nonsymmetrical cis-spiranes were known that in aprotic/nonpolar solvents (Table 1). But under in the literature. Various arylaldehydes with different amine catalysis, the nature of the solvent did not have electron-donating or -withdrawing groups, as well as much effect on the epimerization rate. In protic/polar heteroaromatic aldehydes furnished the spiranes without solvents, stabilization of the highly reactive ionic species the loss of diastereoselectivity. Interestingly, the hetero- generated in the reaction media by hydrogen bonding or domino K-DA-E reaction of enone 1a, 4-methoxybenz- dipolar-dipolar interactions enhanced the reaction rate. aldehyde 2c, and 1,3-indandione 3 furnished the expected As shown in Scheme 4, the amino acid or amine reacts cis-spirane in 6:1 diastereomeric ratio. In this case, the with cyclohexanone 6 to generate the enamine 19. The epimerization rate of trans-spirane 6ac to cis-spirane 5ac retro-Michael reaction to form the ring-opened imine/ was slower than with other substrates and so the enolate 20 should be accelerated by hydrogen bonding diastereoselectivity was poor. Reaction of an arylaldehyde with protic/polar solvents. Imine/enolate 20 then under- bearing an electron-donating p-hydroxy substitute fur- goes Michael reaction to form the enamine of the ther- nished cis-spirane 5af in very good yield and a surpris- modynamically stable cis-spirane 21, which undergoes ingly high dr (Table 3, entry 3). Likewise, arylaldehydes hydrolysis in situ to furnish cis-spirane 5. with electron withdrawing substituents such as o-nitro, Epimerization of trans-spiranes 6aa and 6ab to cis- p-chloro, p-cyano, and p-methoxycarbonyl also furnished spiranes 5aa and 5ab, respectively, was confirmed in the cis-spiranes 5ah, 5ag, 5ai, and 5aj with high di- studies of the L-proline and pyrrolidine-catalyzed reaction astereoselectivities. The heterodomino K-DA-E reaction in methanol at ambient temperature (Scheme 5). The of heteroaromatic aldehydes, 2-furanaldehyde, and epimerization reaction catalyzed by pyrrolidine was 2-thiophenaldehyde furnished spiranes 5al and 5am with

SCHEME 6

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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). good to moderate yields but with moderate diastereo- astereospecifically in very good yields as shown in Table selectivities due to slow epimerization rates. Reaction of 4. Various trans-4-aryl-3-buten-2-ones and aryl aldehydes 1H-pyrrole-2-carboxyaldehyde 2n with 1a and 3 under with different substituents on the aromatic ring (ranging L-proline catalysis did not furnish the expected domino from the electron-donating groups such as p-methoxy, product, but under pyrrolidine catalysis at 60 °C for 2 h m,p-methylenedioxy, p-dimethylamino, and p-hydroxy furnished the domino product 5an in 30% yield with high and electron-withdrawing groups such as p-chloro, p- dr. This domino product 5an was accompanied by an nitro, p-cyano, and p-methoxycarbonyl) and also the unexpected product, cis-spirane 5ab, in 16% yield and heteroaromatic counterparts furnished the expected cis- unreacted Knoevenagel product 17n in 25% yield. For- spiranes (5) in good yields with high diastereospecificity. mation of unexpected product 5ab in above reaction will The chloro-, cyano-, and methoxycarbonyl-substituted cis- be considered in the next section. Reaction of R,â- spiranes 5gg, 5ii, and 5jj are potentially interesting unsaturated aldehyde, trans-C6H4-CHdCH-CHO 2p intermediates for materials chemistry as they can be with 1a and 3 under L-proline catalysis also furnished readily manipulated. Thus, numerous arylaldehydes and the expected domino product 5ao in good yields with high various enones are readily reacted under either L-proline dr. or pyrrolidine catalysis to generate a library of highly Synthesis of Prochiral Symmetrical cis-Spiranes. functionalized cis-spiranes (5) (Tables 3 and 4). Pyrrolidine catalyzed, hetero-domino K-DA-E reactions Synthesis of Highly Substituted cis-Spiranes. To of trans-4-aryl-3-butene-2-ones (1a-l), arylaldehydes prepare highly substituted dispiranes, we used an aryl- (2a-p), and 1,3-indandione 3 in methanol at 70 °C for dialdehyde instead of a simple arylaldehyde. Thus, the 1-2 h furnished the expected cis-spiranes 5 di- heterodomino K-DA-E reaction of terephthalaldehyde 2p, 5846 J. Org. Chem., Vol. 69, No. 18, 2004 Organocatalytic Heterodomino K-DA-E Reactions

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 1-2ha

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. a dialdehyde, with trans-4-phenyl-3-butene-2-one 1a and To investigate the formation of the unexpected product indandione 3 catalyzed by L-proline or pyrrolidine fur- 5ab, the reaction was carried out without the aldehyde. nished the cis-spiranealdehyde 23 and the dispirane 24 Pyrrolidine catalyzed the reaction of trans-4-phenyl-3- as well as the unexpected product 5ab as shown in Table buten-2-one 1a with 1,3-indandione 3 in methanol at 70 5. When L-proline was used as a catalyst, incubation of °Cfor5htofurnish the cis-spirane 5ab and the the reaction at 25° C for 96 h furnished products 23 and Knoevenagel product 17b in 28% and 8% yield, respec- 24 in 16% and 18% yield, respectively (Table 5, entry 1), tively, as shown in Scheme 7. The mechanism of forma- while the same reaction performed at 25 °C for 24 h and tion of the unexpected product cis-spirane can be ex- 40 °C for 48 h resulted in the formation of 23 and 24 in plained as shown in Scheme 7. First, the Michael addition 60% and 18% yield, respectively (Table 5, entry 2). Under of indandione 3 to trans-4-phenyl-3-buten-2-one 1a takes L-proline catalysis, the unexpected product 5ab did not place to generate the adduct 25, which can then undergo form. The reaction catalyzed by pyrrolidine at 70 °C for a retro-Michael reaction in one of two ways. The retro- 2 h furnished the dispirane 24 and the unexpected Michael reaction can either regenerate the starting product 5ab in 15% and 45% yield, respectively (Table materials 3 and 1a or generate acetone and the Knoev- 5, entry 3). The identity of dispirane 24 was confirmed enagel product 17b. Compound 17b undergoes a Diels- by proton, 13C NMR, and mass analysis. We had previ- Alder reaction with trans-4-phenyl-3-buten-2-one 1a to ously observed that the domino product 5ab was also furnish the mixture of cis- and trans-spiranes 5ab and formed unexpectedly in the hetero-domino K-DA-E reac- 6ab as described earlier. Finally, epimerization of the tion of enone 1a, aldehyde 2n and 1,3-indandione 3 under trans-spirane 6ab takes place to furnish the cis-spirane pyrrolidine catalysis with 16% yield (Table 3, entry 11). 5ab. Thus the mechanism of formation of the unexpected

J. Org. Chem, Vol. 69, No. 18, 2004 5847 Ramachary et al.

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

product 5ab involves four steps: a Michael reaction, a 5ab and trans-spirane 6ab have served as useful syn- retro-Michael reaction, a Diels-Alder reaction, and thons in the synthesis of fenestranes.8 Kuck and co- finally an epimerization reaction. workers have reported the synthesis of a highly strained Application of cis-Spiranes 5. Prochiral cis-spiranes centrotetracyclic framework of fenestranes starting from 5 are very useful starting materials in the synthesis of cis- and trans-spiranes 5ab and 6ab. In their study, the benzoannelated centropolyquinanes. Prochiral cis-spirane cis-spirane 5ab was converted to all-cis-[5.5.5.5]fenes- 5848 J. Org. Chem., Vol. 69, No. 18, 2004 Organocatalytic Heterodomino K-DA-E Reactions

TABLE 5. Synthesis of Highly Substituted groups such as chloro, cyano, and methoxycarbonyl cis-Spriranesa 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 reactions in a single pot. This astonishingly simple and atom- economic approach can be used to construct highly functionalized symmetric and nonsymmetric spiro[cyclohexane-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 b catalyst yield (%) under-explored perspective on prebiotic synthesis. A entry (30 mol %) T (°C) time (h) 23 24 5ab complete understanding of the scope of organocatalysis 1 4a 25 96 16 18 should not only empower the synthetic chemist but also 2 4a 25 f 40 24 f 48 60 18 provide a new perspective on the origin of complex 3 4h 70 2 15 45 molecular systems. a Experimental conditions: L-proline 4a or pyrrolidine 4h (0.15 mmol), terephthalaldehyde 2p (0.5 mmol), and 1,3 indandione 3 Acknowledgment. This study was supported in (1.0 mmol) in methanol (1 mL) were stirred at ambient temper- part by the NIH (CA27489) and the Skaggs Institute ature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was for Chemical Biology. added (see the Experimental Section). b Yield refers to the purified product obtained by column chromatography. Supporting Information Available: Characterization data (1H NMR, 13C NMR, and mass) for all new compounds trane 7 in nine synthetic steps as depicted in Scheme 8. and details of experimental procedures. Copies of 13C NMR The dispirane 24 could serve as a suitable synthon for spectra of all new compounds. This material is available free the synthesis of topologically interesting difenestranes of charge via the Internet at http://pubs.acs.org. 26 and 27. Fenestranes containing reactive functional JO049581R

J. Org. Chem, Vol. 69, No. 18, 2004 5849 Supporting Information for JO049581R

CONTENTS Page No.

1. General Methods S2

2. General Procedure S3

3. Spectral Data S4-S17

4. Minimized Structures S17-S19

5. References S19-S20

6. NMR Spectrums S21-S51

S1 Direct Organocatalytic Asymmetric Hetero-Domino Reactions: The Knoevenagel/Diels-Alder/Epimerization (K-DA-E) Sequence for the Highly 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 13 NMR and relative to the central CDCl3 resonance (δ = 77.0) for C NMR. The coupling 13 constants J are given in Hz. In the C 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- (napthalen-1-yl)-but-3-en-2-one 1b are prepared by using standard aldol condensation from

S2 acetone and corresponding aldehydes. trans-4-(3-oxo-but-1-enyl)-benzonitrile 1i and trans-4-(3- 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.

S3 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, 1 λ = 254 nm), tR = 28.79 min (major), tR = 38.19 min (minor), ee 30%; H

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, 13 m). C 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 1 7%; H 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 13 = 16.8 and 13.2 Hz), 2.81 (2H, ddd, J = 16.8, 4.8 and 3.2 Hz). C 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 13 Hz), 3.80 (4H, m), 3.56 (3H, s, OCH3), 2.63 (2H, ddd, J = 10.4, 6.4 and 1.6 Hz). C 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 13 and 2.0 Hz), 3.90 (3H, s, OCH3). C 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. 1 H 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 1 a white solid. The ee was not determined. H 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, 13 m), 3.88 - 3.74 (4H, m), 2.65 (2H, m). C 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, 1 λ = 254 nm), tR = 24.26 min (major), tR = 34.80 min (minor), ee 7.4%. H

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 - 13 6.80 (5H, m, Ph-H), 3.81 (4H, m), 2.66 (2H, m). C 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, 13 m). C 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 1 a white solid. The ee was not determined. H 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, 13 J = 14.4, 4.0 and 1.6 Hz). C 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, 13 ddd, J = 14.8, 4.0 and 0.8 Hz), 2.64 (1H, td, J = 12.4 and 2.0 Hz). C 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 1 determined. H 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). 13 C 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 13 Hz). C 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% 1 yield. H 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 13 = 12.0 and 1.6 Hz). C 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, 13 m). C 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 = 13 17.1 Hz). C 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. 1 H 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 13 3.2 Hz, H-3α and 5α). C 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 1 conformation. H 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 13 Hz). C 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 1 conformation. H 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 13 4.0 Hz, H-3e and 5e). C 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. S12 (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. 1 H 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, 13 ABq, J = 14.8 Hz). C 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 13 5e). C 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 1 chair conformation. H 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),

S13 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 13 3.2 Hz, H-3e and 5e). C 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 1 13 1 resolution H and C NMR in CDCl3 even at 60° C. H 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. 2 2 2 (2β,6β)-4-[ H1]Hydroxy-4-[ H3]methoxy-2,6-bis-(4-[ H1]hydroxyphenyl)spiro[cyclohexane- 7 1,2’-indan]-1’,3’-dione. Dihydroxy cis-spirane 5ff in CD3OD furnished the deuterated hemiacetal in good conversion after storage at 4° C in an NMR tube. 1 H 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 1 with chair conformation. H 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. 1 H 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 13 (2H, dd, J = 14.4 and 2.8 Hz). C 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-

S15 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 13 CO2CH3), 2.68 (2H, ABq, J = 14.8 Hz, H-3e and 5e). C 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, 13 Ph-H), 3.94 - 3.76 (4H, m), 2.68 (2H, m). C 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

S16 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 13 (2H, br d, J = 12.8 Hz), 2.27 (2H, m). C 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)

≡

S17 (2)

≡

(3)

≡

S18 (4)

≡

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. 1 7. When the H 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.

S19 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.

S20