Direct Organocatalytic Asymmetric Heterodomino Reactions: The

Direct Organocatalytic Asymmetric Heterodomino Reactions: TheKnoevenagel/Diels-Alder/Epimerization Sequence for the HighlyDiastereoselective Synthesis of Symmetrical and Nonsymmetrical

Synthons of Benzoannelated CentropolyquinanesD. 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] 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 highlydiastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensationof 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 ofconversion 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 enamineintermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellentstarting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid andamine 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 yieldfrom enone 1a and 1,3-indandione 3.

Introduction

Critical objectives in modern synthetic organic chem-istry include the improvement of reaction efficiency, theavoidance of toxic reagents, the reduction of waste, andthe responsible utilization of our resources. Domino ortandem reactions, which consist of several bond-formingreactions, address many of these objectives. Dominoreactions involve two or more bond-forming transforma-tions that take place under the same reaction conditions.Combinations of reactions involving the same mechanismare classified as homodomino reactions, whereas a se-quence of reactions with different mechanisms are clas-sified as heterodomino reactions.1 One of the ultimategoals in organic synthesis is the catalytic asymmetricassembly of simple and readily available precursormolecules into stereochemically complex products, aprocess that ultimately mimics biological synthesis. Inthis 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 bydecreasing the number of laboratory operations requiredand the quantities of chemicals and solvents used. Thus,these reactions can facilitate ecologically and economi-cally favorable syntheses.

Recently organocatalysis has emerged as a promisingsynthetic tool for constructing C-C, C-N, and C-Obonds in aldol,3 Michael,4 Mannich,5 Diels-Alder,6 andrelated 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 transformationswith carbonyl compounds. Often, the organocatalysts canbe used in operationally simple and environmentallyfriendly 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, 5838-584910.1021/jo049581r CCC: $27.50 © 2004 American Chemical Society

Published on Web 08/06/2004

share common mechanistic features they may be linkedto create one-pot and domino reaction schemes (assemblyreactions). To date, we have described asymmetric as-sembly reactions involving aldol-aldol,3c,d Michael-aldol,7d Mannich-cyanation,5d Mannich-allylation,5f am-ination-aldol,7g and Knoevanagel-Michael4a reactions.Recently, we reported two interesting domino reactionsfounded on Knoevenagel/Diels-Alder reaction sequences.The first was the direct organocatalytic asymmetricdomino Knoevenagel/Diels-Alder reaction sequence toaccomplish the diastereo- and enantioselective construc-tion of highly substituted spiro[5.5]undecane-1,5,9-triones.6a The second was the direct organocatalytic,hetero-domino, Knoevenagel/Diels-Alder/epimerizationsequence to prepare symmetric prochiral and highlysubstituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones(5) in diastereospecific fashion from commercially avail-able 4-substituted 3-buten-2-ones (1), aldehydes (2), and

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 togenerate highly substituted spiro[cyclohexane-1,2′-in-dan]-1′,3′,4-triones (5) in a highly diastereoselective andmodestly enantioselective process from commerciallyavailable 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. Synlett2002, 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. TetrahedronLett. 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

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synthesis of natural products and in material chemistryand are the excellent starting materials for the synthesisof fenestranes8 (centrotriindane and centrotetraindanes),topologically nonplanar hydrocarbon centrohexaindane,and other frameworks bearing the [5.5.5.5]fenestranecore as shown in Chart 1. Fenestrindanes with 8-fold

peripheral functionalization could serve as unusualmotifs for liquid crystal engineering and dendrimerchemistry and for the construction of graphite cuttingsbearing a saddle-like, three-dimensionally distorted core.8

Results and Discussion

We envisioned that amino acids 4a-e and simpleamines 4f-j (Chart 2) would act as organocatalysts ofthe Knoevenagel condensation of aldehydes 2a-p with1,3-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) areattractive 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., PerkinTrans. 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 Knoevenagelreaction. 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

Ramachary et al.

5840 J. Org. Chem., Vol. 69, No. 18, 2004

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 Lewisacids14 (OLA) with low energy LUMO configurations andare useful as heterodienes and Michael acceptors incycloaddition reactions.15 Here, we have utilized arylideneindandiones 17 as dienophiles in Diels-Alder chemistry.As dienophiles, 17a-p undergo [4 + 2] cycloadditionreactions with 2-amino-1,3-butadienes 18a-l generatedin situ from enones 1a-l and amino acids or amines togenerate substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones 5 and 6 in a diastereoselective manner (Figure1). Epimerization of the minor diastereomer trans-spirane 6 to the more stable cis-spirane 5 occurred underthe same reaction conditions. This domino Knoevenagel/Diels-Alder reaction generates a quaternary carboncenter with formation of three new carbon-carbon σbonds via organocatalysis.

In these three component organocatalytic K-DA-Ereactions, the Knoevenagel condensation generates reac-tive dienophiles that can be readily isolated from thereaction mixture. For example, reaction of 4-nitroben-zaldehyde 2a and 1,3-indandione 3 in methanol atambient temperature under L-proline or pyrrolidinecatalysis furnished the expected 2-(4-nitro-benzylidene)-indan-1,3-dione 17a in almost quantitative yield asshown in Scheme 2. Under similar reaction conditionswith different aromatic aldehydes, a wide variety of2-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 thethree-component reaction of trans-4-phenyl-3-buten-2-one1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 witha catalytic amount of L-proline (20 mol %) in methanolat ambient temperature for 24 h furnished the expectednonsymmetrical Diels-Alder products 5aa and 6aaΨ in86% yield with thermodynamically stable cis-spirane 5aaas the major isomer, dr 24:1 (Table 1, entry 1) (ΨIn allcompounds denoted 5xy and 6xy, x is incorporated fromreactant enones 1 and y is incorporated from the reactantaldehydes 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 minordiastereomer, trans-spirane 6aa, was effectively epimer-ized to the thermodynamically stable cis-spirane 5aaunder prolonged reaction time via proline catalysis. Thestereochemistry of products 5aa and 6aa was establishedby 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 foundthat the solvent (dielectric constant) and temperaturehad a significant effects on reaction rates, yields, dr’s,and ee’s (Table 1). The hetero-domino K-DA-E reactioncatalyzed 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 WO2002050082 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 A219960412 Heisei. Patent written in Japanese.

(13) Aziz, A. B. M. S. A.; Mohamed, E. S. Eur. Pat. Appl. 1992, 14pp. CODEN: EPXXDW EP 489991 A1 19920617. Patent written inEnglish.

(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. 11993, 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 MOPACcalculations of the thermodynamic equilibration between the twoisomers (see the Supporting Information).

CHART 2. Screened Organocatalysts for theK-DA-E Reaction

FIGURE 1. Dienes and dienophiles generated under orga-nocatalysis.

SCHEME 2. Organocatalytic KnoevenagelCondensation


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to moderate yields with poor diastereoselectivity (Table1, entries 4-6, 11, and 12). Enantioselectivity improvedin aprotic/nonpolar solvents (Table 1, entries 4-6, 11, and12). Excellent yields, good diastereoselectivity, and poorenantioselectivity were observed in protic/polar solvents(Table 1, entries 1-3). For example, the K-DA-E reactionin THF furnished spiranes 5aa and 6aa in 54% yield withdr of 2.8:1 and with ee of 18% for the major cis-spirane5aa 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 at25 °C furnished the thermodynamically stable productcis-spirane 5aa as the major diastereomer in 80% yieldwith dr of 34:1, albeit with a low ee value of 1% (Table 1,entry 7). Interestingly, the same reaction under prolinecatalysis in ionic liquid [bmim]PF6 at 25 °C furnishedthe spiranes 5aa and 6aa in 45% yield with dr of 1.5:1and with ee of 6% (cis-spirane) and 7% (trans-spirane)(Table 1, entry 8). In the hetero-domino K-DA-E reactionunder L-proline catalysis, diastereoselectivity was directlyaffected by the nature of the solvent (dielectric constant)as reflected in the epimerization reaction and exo/endoselectivity. Rates of organocatalytic reactions catalyzedby amino acids were faster in protic/polar solvents thanin nonprotic/nonpolar solvents presumably due to en-hanced stabilization of charged intermediates and morefacile proton-transfer reactions. This is especially truefor the epimerization reaction where the dr’s of theproduces obtained using protic/polar solvents were veryhigh.

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 andcompared them to the results of the organocatalytic

asymmetric three-component Diels-Alder (ATCDA) re-action of 1a, 2a, and Meldrum’s acid.6a Among thecatalysts screened in the ATCDA reaction, the 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) proved tobe the most efficient catalyst with respect to yield andee. When DMTC was tested in the K-DA-E reaction of1a, 2a, and 3 in methanol at 25 °C for 72 h, the dominoproducts 5aa and 6aa were obtained in 62% yield withdr of 8.5:1 and ee of the major cis-spirane 5aa of 17%(Table 1, entry 9). The same reaction under DMTCcatalysis at reduced temperature (4 °C) in methanol for96 h furnished products 5aa and 6aa in 18% yield witha dr of 1.3:1. Under these conditions, the ee of the majorcis-spirane 5aa was 30% and ee for the minor trans-spirane 6aa was 3% (Table 1, entry 10). With DMTCcatalysis in THF as solvent at 25 °C, products 5aa and6aa were obtained in poor yields (e10%) with dr of 1:1.4and ee for the minor cis-spirane of 42%, while the ee forthe major trans-spirane of 6% (Table 1, entry 11). DMTC-catalyzed K-DA-E reaction in THF at 4 °C for 96 hfurnished the domino products in very poor yields (Table1, entry 12). An imidazoline-type catalyst, 4-benzyl-1-methylimidazolidine-2-carboxylic acid 4c, also catalyzedthe K-DA-E reaction with moderate yield, very good dr,and low ee at 25 °C and moderate to low yield, and poordr 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 andexcellent diastereoselectivity, but the ee was poor (Table1, entry 15). trans-4-Hydroxy-L-proline 4e also catalyzedthe domino K-DA-E reaction of 1a, 2a, and 3 but reactionyield (19%), dr (1:1), and ee (14 and 13) were poor (Table1, entry 16). While the Knoevenagel product 17a wasformed and consumed in most of the amino acid-catalyzedheterodomino 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-EReaction of 1a, 2a, or 2b and 3a

entrycatalyst

(20 mol %) aldehydesolvent(0.5 M) T (°C) time (h) products yieldb (%)

drc

(cis/trans)eed

(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 18/155 4a 2a CHCl3 25 120 5aa, 6aa 63 1:1 13/66 4a 2a C6H6 25 120 5aa, 6aa e57 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 6/79 4b 2a MeOH 25 72 5aa, 6aa 62 8.5:1 17/-

10e 4b 2a MeOH 4 96 5aa, 6aa 18 1.3:1 30/311e 4b 2a THF 25 96 5aa, 6aa e10 1:1.4 42/612e 4b 2a THF 4 96 5aa, 6aa e513 4c 2a MeOH 25 96 5aa 68 g99:1 9/-14e 4c 2a MeOH 4 96 5aa, 6aa 40 1.6:1 17/415 4d 2a MeOH 25 36 5aa 92 g99:1 2/-16e 4e 2a MeOH 25 46 5aa, 6aa 19 1:1 14/1317 4a 2b MeOH 25 24 5ab, 6ab 87 2:118 4a 2b MeOH 25 98 5ab 96 g99:119 4a 2b MeOH 70 2 5ab 96 g99:120 4a 2b [bmim]BF4 25 24 5ab, 6ab 53 1:221 4a 2b [bmim]PF6 25 96 5ab, 6ab 55 1:2a 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 theExperimental Section). b Yield refers to the purified product obtained by column chromatography. c Ratio based on isolated products (1Hand 13C NMR analysis). d Enantiomeric excesses determined by using chiral-phase HPLC. e 60-80% of unreacted Knoevenagel product17a 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 wasisolated in 60-80% yield. Unreacted 17a was the resultof a very slow rate of the formation of the key intermedi-ate 2-amino-1,3-butadiene and subsequent Diels-Alderreaction under these conditions.

The L-proline-catalyzed three-component hetero-dom-ino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1aand 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 prochiralcis-spirane 5ab as a single diastereomer in 96% yield(Table 1, entry 18). The stereochemistry of products 5aband 6ab was established by NMR analysis. The minordiastereomer, trans-spirane 6ab was effectively epimer-ized to the thermodynamically stable cis-spirane 5abunder prolonged reaction time via proline catalysis.Increasing the reaction temperature to 70 °C facilitatedthe epimerization reaction and furnished the expecteddomino product 5ab as a single diastereomer in 96% yieldwithin 2 h. Interestingly the same reaction in the ionicliquids, [bmim]BF4 and [bmim]PF6, catalyzed by L-prolineat ambient temperature provided the kinetic producttrans-spirane 6ab as the major diastereomer in moderateyield (Table 1, entries 20 and 21). In these reactions,enantioselectivity for the minor kinetic product 6ab waspoor. cis-Spirane 5ab has been used as a synthon for thesynthesis of variety of benzoannelated centropolyquinanesas shown in Chart 1.8

cis-Spirane 5ab is obtained via an endo-transition statein the classical Diels-Alder route. In ionic liquids,however, the kinetic product, trans-spirane 6ab, was themajor isomer formed. This is likely due to a uniqueorganization of the ionic liquid solvent with the 2-amino-1,3-butadiene 18a and dienophile 17b in the transitionstates as shown in Figure 2. Asymmetric solvation in theionic liquids then produces a steric hindrance with thephenyl group on the dienophile in the endo-transitionstate, thereby disfavoring it. In the case of dienophile17a, the high epimerization rate of trans-spirane 6aaprovides cis-spirane 5aa as the major isomer (Table 1,entries 7 and 8). Ratio of exo/endo products in ionicliquids or other solvents mainly depend on four factors,which are (i) substrate effect (electronic factor), (ii) proticsolvent effect (polarization factor), (iii) steric hindranceinduced by ionic solvation, and (iv) basic nature of organocatalyst.

Amine-Catalyzed Direct Heterodomino K-DA-EReactions. Amines 4f-j can also catalyze the hetero-domino K-DA-E reaction under different solvent andtemperature conditions. The three-component hetero-domino K-DA-E reaction of trans-4-phenyl-3-buten-2-one1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 witha 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 asingle 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, alsocatalyzed the heterodomino K-DA-E reaction of 1a, 2a,and 3 in DMSO at ambient temperature to furnish theexpected domino products 5aa and 6aa in 71% yield withdr of 13.5:1, but with poor ee (Table 2, entry 2). Sinceenantioselection in these reactions was typically unsat-isfactory, we studied the simple achiral amine pyrrolidine4h and found that it furnished cis-spirane 5ab as a singlediastereomer in 90% yield (Table 2, entry 3). Further wefound that pyrrolidine catalysis was not dramaticallyaffected with respect to reaction rates, yields, or dr’s bysolvent and temperature modification (Table 2). Underpyrrolidine catalysis, the heterodomino K-DA-E reactionworked well in a variety of solvents and the optimalconditions involved mixing equimolar amounts of enone1a, aldehyde 2b, and 1,3-diketone 3 in methanol withheating to 70 °C for 1 h to furnish cis-spirane 5ab as asingle diastereomer in 95% yield (Table 2, entry 9).Interestingly, the six-membered cyclic amines piperidine(4i) and morpholine (4j) also catalyzed the heterodominoK-DA-E reaction. Typically, pyrrolidine-based catalystsare much more effective than six-membered cyclic aminesas organocatalysts and six-membered cyclic amines areextremely poor catalysts of aldol reactions.3b The reactionof enone 1a, aldehyde 2b, and 1,3-diketone 3 underpiperidine 4i catalysis in methanol at 70 °C for 4 hfurnished the expected domino products 5ab and 6ab in71% yield with dr of 43:1 (Table 2, entry 10). Under thesame conditions, morpholine 4j catalyzed formation of5ab and 6ab in 46% yield with dr of 18.6:1 (Table 2, entry11). The pyrrolidine-catalyzed heterodomino K-DA-Ereaction was, however, faster.

Organocatalytic Epimerization of trans-Spirane6 to cis-Spirane 5. Epimerization of trans-spirane 6 orthe diastereospecific synthesis of cis-spirane 5 in theheterodomino K-DA-E reaction of enone 1, aldehyde 2,and 1,3-indandione 3 can be explained as illustrated inScheme 3. Amino acid or amine-catalyzed Knoevenagelcondensation9 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 17then undergoes a concerted [4 + 2] cycloaddition or adouble-Michael reaction with the soft nucleophile, 2-amino-1,3-butadiene 18 generated in situ from enone 1 and theamino acid or amine catalyst, to produce products 5 and6. 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 4.114kcal/mol based on PM3 calculations. The energy differ-ence (∆H) between the two isomers of 5ab and 6ab is6.158 kcal/mol based on AM1 and 5.680 kcal/mol basedon 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 isomersof 5aa/6aa and 5ab/6ab are greater than 5 kcal/mol, theminor 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 kineticisomer trans-spirane 6 was epimerized to the thermody-namically stable cis-spirane 5 via deprotonation/repro-tonation or retro-Michael/Michael reactions catalyzed byamino acid or amine. This is in agreement with thepreviously proposed retro-Michael/Michael reaction mech-anism19 at the epimerization step as shown in Scheme4.

The rate of the epimerization was also related to thenucleophilic 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 of1a, 2a or 2b, and 3a

entrycatalyst

(20 mol %) aldehydesolvent(0.5 M) T (°C) time (h) products

yieldb

(%)drc

(cis/trans)eed

(cis/trans)

1 4f 2a MeOH 25 24 5aa 79 g99:1 12 4g 2a DMSO 25 39 5aa, 6aa 71 13.5:1 33 4h 2b MeOH 25 8 5ab 90 >99:14 4h 2b MeOH 70 0.75 5ab 90 >99:15 4h 2b THF 25 7 5ab 85 >99:16 4h 2b CHCl3 25 7 5ab 70 >99:17 4h 2b DMSO 24 70 5ab 75 >99:18 4h 2b DMF 25 24 5ab 80 >99:19e 4h 2b MeOH 70 1 5ab 95 >99:1

10 4i 2b MeOH 70 4 5ab, 6ab 71 43:111 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), and1,3-inandione 3 (0.5 mmol) in solvent (1 mL) were stirred at ambient temperatures for 30 min, then benzyl acetone 1a (1 mmol) wasadded (see the Experimental Section). b Yield refers to the purified product otabined by column chromatography. c Ratio based on isolatedproducts (1H and 13C NMR analysis). d Enantiomeric excesses determined by using chiral-phase HPLC. e Enone 1a, benzealdehyde 2band 1,3-indandione 3 were used in 0.5 mmol scale.

SCHEME 3. Proposed Catalytic Cycle for theL-Proline (or Amino Acid or Amine) CatalyzedHeterodomino K-DA-E Reactions

SCHEME 4. Proposed Mechanism for the L-Proline(Amino Acid or Amine) Catalyzed Epimerization oftrans-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 thanthat in aprotic/nonpolar solvents (Table 1). But underamine catalysis, the nature of the solvent did not havemuch effect on the epimerization rate. In protic/polarsolvents, stabilization of the highly reactive ionic speciesgenerated in the reaction media by hydrogen bonding ordipolar-dipolar interactions enhanced the reaction rate.As shown in Scheme 4, the amino acid or amine reactswith cyclohexanone 6 to generate the enamine 19. Theretro-Michael reaction to form the ring-opened imine/enolate 20 should be accelerated by hydrogen bondingwith protic/polar solvents. Imine/enolate 20 then under-goes Michael reaction to form the enamine of the ther-modynamically stable cis-spirane 21, which undergoeshydrolysis in situ to furnish cis-spirane 5.

Epimerization of trans-spiranes 6aa and 6ab to cis-spiranes 5aa and 5ab, respectively, was confirmed instudies of the L-proline and pyrrolidine-catalyzed reactionin methanol at ambient temperature (Scheme 5). Theepimerization reaction catalyzed by pyrrolidine was

significantly faster than that catalyzed by proline. Noepimerization was observed in the absence of catalyst.

To further probe the epimerization mechanism wesought to study the intermediate enamine of cis-spirane22. A mixture of cis- and trans-spiranes 5aa and 6aa (1.5:1) was treated with morpholine in the presence ofcatalytic amount of p-TSA under reflux in toluene for 30min to furnish the enamine of the epimerized cis-spirane22. NMR analysis of the unpurified mixture showedfeatures of the enamine (Scheme 6). We studied themorpholine derived enamine because morpholine en-amine hydrolysis is slower than that of pyrrolidine orL-proline enamines.19 Attempted purification of the enam-ine 22 by flash column chromatography on silica gelresulted in the formation of the hydrolysis product, cis-spirane 5aa, in quantitative yield.

Synthesis of Nonsymmetrical cis-Spiranes. Wefurther explored the scope of the L-proline and pyrrolidinecatalyzed hetero-domino K-DA-E reactions with variousarylaldehydes (2a-p) and 4-substituted-3-buten-2-ones(1a-l). Each of the targeted spirotriones 5 was obtainedas single diastereomers in excellent yields. In this case,even though the enantioselectivities are poor, L-prolinewas used as catalyst as it is available at reasonable cost.The L-proline-catalyzed heterodomino K-DA-E reactionsof 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 goodyields with high diastereoselectivity as shown in Table3. None of these nonsymmetrical cis-spiranes were knownin the literature. Various arylaldehydes with differentelectron-donating or -withdrawing groups, as well asheteroaromatic aldehydes furnished the spiranes withoutthe 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 expectedcis-spirane in 6:1 diastereomeric ratio. In this case, theepimerization rate of trans-spirane 6ac to cis-spirane 5acwas slower than with other substrates and so thediastereoselectivity was poor. Reaction of an arylaldehydebearing 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, arylaldehydeswith electron withdrawing substituents such as o-nitro,p-chloro, p-cyano, and p-methoxycarbonyl also furnishedthe cis-spiranes 5ah, 5ag, 5ai, and 5aj with high di-astereoselectivities. The heterodomino K-DA-E reactionof heteroaromatic aldehydes, 2-furanaldehyde, and2-thiophenaldehyde furnished spiranes 5al and 5am with

SCHEME 5. Organocatalytic Epimerization oftrans-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 of1H-pyrrole-2-carboxyaldehyde 2n with 1a and 3 underL-proline catalysis did not furnish the expected dominoproduct, but under pyrrolidine catalysis at 60 °C for 2 hfurnished the domino product 5an in 30% yield with highdr. This domino product 5an was accompanied by anunexpected product, cis-spirane 5ab, in 16% yield andunreacted Knoevenagel product 17n in 25% yield. For-mation of unexpected product 5ab in above reaction willbe considered in the next section. Reaction of R,â-unsaturated aldehyde, trans-C6H4-CHdCH-CHO 2pwith 1a and 3 under L-proline catalysis also furnishedthe expected domino product 5ao in good yields with highdr.

Synthesis of Prochiral Symmetrical cis-Spiranes.Pyrrolidine catalyzed, hetero-domino K-DA-E reactionsof trans-4-aryl-3-butene-2-ones (1a-l), arylaldehydes(2a-p), and 1,3-indandione 3 in methanol at 70 °C for1-2 h furnished the expected cis-spiranes 5 di-

astereospecifically in very good yields as shown in Table4. Various trans-4-aryl-3-buten-2-ones and aryl aldehydeswith different substituents on the aromatic ring (rangingfrom the electron-donating groups such as p-methoxy,m,p-methylenedioxy, p-dimethylamino, and p-hydroxyand electron-withdrawing groups such as p-chloro, p-nitro, p-cyano, and p-methoxycarbonyl) and also theheteroaromatic 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 interestingintermediates for materials chemistry as they can bereadily manipulated. Thus, numerous arylaldehydes andvarious enones are readily reacted under either L-prolineor pyrrolidine catalysis to generate a library of highlyfunctionalized cis-spiranes (5) (Tables 3 and 4).

Synthesis of Highly Substituted cis-Spiranes. Toprepare highly substituted dispiranes, we used an aryl-dialdehyde instead of a simple arylaldehyde. Thus, theheterodomino 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 Aldehydes2a-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) wasstirred 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 accompaniedby unexpected product cis-sprirane 5ab (16%) and Knoevenagel product 17n (25%) (see the Experimental Section).

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a dialdehyde, with trans-4-phenyl-3-butene-2-one 1a andindandione 3 catalyzed by L-proline or pyrrolidine fur-nished the cis-spiranealdehyde 23 and the dispirane 24as well as the unexpected product 5ab as shown in Table5. When L-proline was used as a catalyst, incubation ofthe reaction at 25° C for 96 h furnished products 23 and24 in 16% and 18% yield, respectively (Table 5, entry 1),while the same reaction performed at 25 °C for 24 h and40 °C for 48 h resulted in the formation of 23 and 24 in60% and 18% yield, respectively (Table 5, entry 2). UnderL-proline catalysis, the unexpected product 5ab did notform. The reaction catalyzed by pyrrolidine at 70 °C for2 h furnished the dispirane 24 and the unexpectedproduct 5ab in 15% and 45% yield, respectively (Table5, entry 3). The identity of dispirane 24 was confirmedby proton, 13C NMR, and mass analysis. We had previ-ously observed that the domino product 5ab was alsoformed unexpectedly in the hetero-domino K-DA-E reac-tion of enone 1a, aldehyde 2n and 1,3-indandione 3 underpyrrolidine catalysis with 16% yield (Table 3, entry 11).

To investigate the formation of the unexpected product5ab, 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 theKnoevenagel 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 additionof indandione 3 to trans-4-phenyl-3-buten-2-one 1a takesplace to generate the adduct 25, which can then undergoa retro-Michael reaction in one of two ways. The retro-Michael reaction can either regenerate the startingmaterials 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 tofurnish the mixture of cis- and trans-spiranes 5ab and6ab as described earlier. Finally, epimerization of thetrans-spirane 6ab takes place to furnish the cis-spirane5ab. 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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product 5ab involves four steps: a Michael reaction, aretro-Michael reaction, a Diels-Alder reaction, andfinally an epimerization reaction.

Application of cis-Spiranes 5. Prochiral cis-spiranes5 are very useful starting materials in the synthesis ofbenzoannelated 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 strainedcentrotetracyclic framework of fenestranes starting fromcis- and trans-spiranes 5ab and 6ab. In their study, thecis-spirane 5ab was converted to all-cis-[5.5.5.5]fenes-

SCHEME 7. Pyrrolidine-Catalyzed Direct Michael/Retro-Michael/Diels-Alder/Epimerization Reaction ofEnone 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 forthe synthesis of topologically interesting difenestranes26 and 27. Fenestranes containing reactive functional

groups such as chloro, cyano, and methoxycarbonylshould allow for the development of a rich chemistry byextension of the peripheral functional groups. Thus,dendrimers, liquid crystals and poly-condensed ringsystems with saddle-like molecular structures may besynthesized using the synthons described here.

Conclusions

The results presented here demonstrate amino acid oran amine-based organocatalysis of three different reac-tions in a single pot. This astonishingly simple and atom-economic approach can be used to construct highlyfunctionalized symmetric and nonsymmetric spiro[cyclo-hexane-1,2′-indan]-1′,3′,4-triones (5) in a diastereospecificfashion. Selective multistep reactions of this type inspireanalogies to biosynthetic pathways and complimenttraditional multicomponent synthetic methodologies. Fur-ther improvements with respect to the enantioselectivityof these reactions might be accessible through thescreening or design of novel catalysts. As we havesuggested previously, the synthesis of polyfunctionalizedmolecules under organocatalysis provides a unique andunder-explored perspective on prebiotic synthesis. Acomplete understanding of the scope of organocatalysisshould not only empower the synthetic chemist but alsoprovide a new perspective on the origin of complexmolecular systems.

Acknowledgment. This study was supported inpart by the NIH (CA27489) and the Skaggs Institutefor Chemical Biology.

Supporting Information Available: Characterizationdata (1H NMR, 13C NMR, and mass) for all new compoundsand details of experimental procedures. Copies of 13C NMRspectra of all new compounds. This material is available freeof charge via the Internet at http://pubs.acs.org.

JO049581R

TABLE 5. Synthesis of Highly Substitutedcis-Spriranesa

yieldb (%)entry

catalyst(30 mol %) T (°C) time (h) 23 24 5ab

1 4a 25 96 16 182 4a 25 f 40 24 f 48 60 183 4h 70 2 15 45

a Experimental conditions: L-proline 4a or pyrrolidine 4h (0.15mmol), 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) wasadded (see the Experimental Section). b Yield refers to the purifiedproduct obtained by column chromatography.


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

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-

(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,

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

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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-


(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

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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.

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(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


(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-


(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

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(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


(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)

≡

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(2)

≡

(3)

≡

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(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.

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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13C NMR spectrum of 5aa X = Solvent (CH3CO2Et)

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13C NMR spectrum of 6aa

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13C NMR spectrum of 5ac X = Solvent (CH3CO2Et)

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13C NMR spectrum of 5af

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13C NMR spectrum of 5ag

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13C NMR spectrum of 5ah X = Solvent (CH3CO2Et)

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13C NMR spectrum of 5ai X = Solvent (CH3CO2Et)

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13C NMR spectrum of 5aj X = Solvent (CH3CO2Et)

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NOESY spectrum of 5ak

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ROESY spectrum of 5ak

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13C NMR spectrum of 5ak

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13C NMR spectrum of 5al

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13C NMR spectrum of 5am

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13C NMR spectrum of 5an

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13C NMR spectrum of 5ao

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13C NMR spectrum of 5ab

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13C NMR spectrum of 5ab & 6ab (5ab : 6ab = 1:2) x = cis-Spirane 5ab

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13C NMR spectrum of 5bk

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13C NMR spectrum of 5km

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13C NMR spectrum of 5ll

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13C NMR spectrum of 5cc

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13C NMR spectrum of 5dd

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1H NMR spectrum of 5ee

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1H NMR spectrum of 5ff in CD3OD

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13C NMR spectrum of 5ff in CD3OD

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13C NMR spectrum of 5gg

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13C NMR spectrum of 5ha

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13C NMR spectrum of 5ii

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13C NMR spectrum of 5jj

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13C NMR spectrum of 23

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13C NMR spectrum of 24

Documents

Direct Organocatalytic Asymmetric Heterodomino Reactions: The