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
carlos@scripps.edu
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-1,3indandiones (17) in very good yields. We demonstrate for the first time amino acid- and aminecatalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of
conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/
Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine
intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellent
starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and
amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields.
Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retroMichael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5ab in moderate yield
from enone 1a and 1,3-indandione 3.
Introduction
Critical objectives in modern synthetic organic chemistry include the improvement of reaction efficiency, the
avoidance of toxic reagents, the reduction of waste, and
the responsible utilization of our resources. Domino or
tandem reactions, which consist of several bond-forming
reactions, address many of these objectives. Domino
reactions involve two or more bond-forming transformations that take place under the same reaction conditions.
Combinations of reactions involving the same mechanism
are classified as homodomino reactions, whereas a sequence of reactions with different mechanisms are classified as heterodomino reactions.1 One of the ultimate
goals in organic synthesis is the catalytic asymmetric
assembly of simple and readily available precursor
molecules into stereochemically complex products, a
process that ultimately mimics biological synthesis. In
this regard, the development of domino and other multicomponent reaction methodologies can provide expedient access to complex products from simple starting
* To whom correspondence should be addressed. Fax: +1-858-7842583.
(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.
materials.2 Domino reactions have gained wide acceptance because they increase synthetic efficiency by
decreasing the number of laboratory operations required
and the quantities of chemicals and solvents used. Thus,
these reactions can facilitate ecologically and economically favorable syntheses.
Recently organocatalysis has emerged as a promising
synthetic tool for constructing C-C, C-N, and C-O
bonds in aldol,3 Michael,4 Mannich,5 Diels-Alder,6 and
related reactions7 in highly diastereo- and enantioselective processes. In these recently described reactions,
structurally simple and stable chiral organoamines facilitate iminium- and enamine-based transformations
with carbonyl compounds. Often, the organocatalysts can
be used in operationally simple and environmentally
friendly experimental protocols. Because these reactions
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10.1021/jo049581r CCC: $27.50 © 2004 American Chemical Society
5838
J. Org. Chem. 2004, 69, 5838-5849
Published on Web 08/06/2004
Organocatalytic Heterodomino K-DA-E Reactions
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
to create one-pot and domino reaction schemes (assembly
reactions). To date, we have described asymmetric assembly reactions involving aldol-aldol,3c,d Michaelaldol,7d Mannich-cyanation,5d Mannich-allylation,5f amination-aldol,7g and Knoevanagel-Michael4a reactions.
Recently, we reported two interesting domino reactions
founded on Knoevenagel/Diels-Alder reaction sequences.
The first was the direct organocatalytic asymmetric
domino Knoevenagel/Diels-Alder reaction sequence to
accomplish the diastereo- and enantioselective construction of highly substituted spiro[5.5]undecane-1,5,9triones.6a The second was the direct organocatalytic,
hetero-domino, Knoevenagel/Diels-Alder/epimerization
sequence to prepare symmetric prochiral and highly
substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones
(5) in diastereospecific fashion from commercially available 4-substituted 3-buten-2-ones (1), aldehydes (2), and
(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.
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1,3-indandione.6b Herein, we report the first direct organocatalytic asymmetric hetero-domino Knoevenagel/Diels-Alder/epimerization (K-DA-E) reaction sequence to
generate highly substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones (5) in a highly diastereoselective and
modestly enantioselective process from commercially
available 4-substituted-3-buten-2-ones (1a-l), aldehydes
(2a-p), and 1,3-indandione (3) as shown in Scheme 1.
Spirocyclic ketones (5) are attractive intermediates in the
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J. Org. Chem, Vol. 69, No. 18, 2004 5839
Ramachary et al.
CHART 1. Benzoannelated Centropolyquinanes
synthesis of natural products and in material chemistry
and are the excellent starting materials for the synthesis
of fenestranes8 (centrotriindane and centrotetraindanes),
topologically nonplanar hydrocarbon centrohexaindane,
and other frameworks bearing the [5.5.5.5]fenestrane
core as shown in Chart 1. Fenestrindanes with 8-fold
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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,
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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.
5840 J. Org. Chem., Vol. 69, No. 18, 2004
peripheral functionalization could serve as unusual
motifs for liquid crystal engineering and dendrimer
chemistry and for the construction of graphite cuttings
bearing a saddle-like, three-dimensionally distorted core.8
Results and Discussion
We envisioned that amino acids 4a-e and simple
amines 4f-j (Chart 2) would act as organocatalysts of
the Knoevenagel condensation of aldehydes 2a-p with
1,3-indandione 3 to provide arylidene indandiones 17ap. There is ample precedence for amine-catalyzed Knoevenagel reactions.9 2-Arylideneindan-1,3-diones (17) are
attractive compounds in medicinal and material chemistry. For example, substituted 2-arylideneindan-1,3(9) (a) Ishikawa, T.; Uedo, E.; Okada, S.; Saito, S. Synlett 1999, 4,
450. (b) Tanikaga, R.; Konya, N.; Hamamura, K.; Kaji, A. Bull. Chem.
Soc. Jpn. 1988, 61, 3211. (c) Tietze, L. F.; Beifuss, U. The Knoevenagel
reaction. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.11, pp 341392. (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.
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
diones 17 derivatives show antibacterial activites,10
nonlinear optical properties,11 electroluminescent devices,12 and are useful as eye lens clarification agents.13
The arylidene indandiones are very good organic Lewis
acids14 (OLA) with low energy LUMO configurations and
are useful as heterodienes and Michael acceptors in
cycloaddition reactions.15 Here, we have utilized arylidene
indandiones 17 as dienophiles in Diels-Alder chemistry.
As dienophiles, 17a-p undergo [4 + 2] cycloaddition
reactions with 2-amino-1,3-butadienes 18a-l generated
in situ from enones 1a-l and amino acids or amines to
generate substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4triones 5 and 6 in a diastereoselective manner (Figure
1). Epimerization of the minor diastereomer transspirane 6 to the more stable cis-spirane 5 occurred under
the same reaction conditions. This domino Knoevenagel/
Diels-Alder reaction generates a quaternary carbon
center with formation of three new carbon-carbon σ
bonds via organocatalysis.
(10) (a) Salama, M. A.; Yousif, N. M.; Ahmed, F. H.; Hammam, A.
G. Pol. J. Chem. 1998, 62, 243. (b) Afsah, E. M.; Etman, H. A.;
Hamama, W. S.; Sayed-Ahmed, A. F. Boll. Chim. Farm. 1998, 137,
244. (c) El-Ablak, F. Z.; Metwally, M. A. J. Serb. Chem. Soc. 1992, 57,
635. (d) Osman, S. A. M.; Yousif, N. M.; Ahmed, F. H.; Hammam, A.
G. Egypt. J. Chem. 1988, 31, 727. (e) Afsah, E. M.; Hammouda, M.;
Zoorob, H.; Khalifa, M. M.; Zimaity, M. Pharmazie 1990, 45, 255. (f)
Yoakim, C.; Hache, B.; Ogilvie, W. W.; O’Meara, J.; White, P.;
Goudreau, N. PCT Int. Appl. 2002, 121 pp. CODEN: PIXXD2 WO
2002050082 A2 20020627. Patent written in English.
(11) Szymusiak, H.; Zielinski, R.; Domagalska, B. W.; Wilk, K. A.
Comput. Chem. 2000, 24, 369.
(12) Murakami, M.; Fukuyama, M.; Suzuki, M.; Hashimoto, M. Jpn.
Kokai Tokkyo Koho 1996, 13 pp. CODEN: JKXXAF JP 08097465 A2
19960412 Heisei. Patent written in Japanese.
(13) Aziz, A. B. M. S. A.; Mohamed, E. S. Eur. Pat. Appl. 1992, 14
pp. CODEN: EPXXDW EP 489991 A1 19920617. Patent written in
English.
(14) (a) Cammi, R.; Ghio, C.; Tomasi, J. Int. J. Quantum Chem.
1986, 29, 527. (b) Liedl, E.; Wolschann, P. Monatsh. Chem. 1982, 113,
1067. (c) Goerner, H.; Leitich, J.; Polansky, O. E.; Riemer, W.; RitterThomas, U.; Schlamann, B. Monatsh. Chem. 1980, 111, 309. (d)
Haslinger, E.; Wolschann, P. Bull. Soc. Chim. Belg. 1977, 86, 907. (e)
Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1969, 100, 576. (f)
Margaretha, P. Tetrahedron 1972, 28, 83.
(15) (a) Bitter, J.; Leitich, J.; Partale, H.; Polansky, O. E.; Riemer,
W.; Ritter-Thomas, U.; Schlamann, B.; Stilkerieg, B. Chem. Ber. 1980,
113, 1020. (b) Bloxham, J.; Dell, C. P. J. Chem. Soc., Perkin Trans. 1
1993, 24, 3055. (c) Righetti, P. P.; Gamba, A.; Tacconi, G.; Desimoni,
G. Tetrahedron 1981, 37, 1779. (d) Eweiss, N. F. J. Heterocycl. Chem.
1982, 19, 273.
In these three component organocatalytic K-DA-E
reactions, the Knoevenagel condensation generates reactive dienophiles that can be readily isolated from the
reaction mixture. For example, reaction of 4-nitrobenzaldehyde 2a and 1,3-indandione 3 in methanol at
ambient temperature under L-proline or pyrrolidine
catalysis furnished the expected 2-(4-nitro-benzylidene)indan-1,3-dione 17a in almost quantitative yield as
shown in Scheme 2. Under similar reaction conditions
with different aromatic aldehydes, a wide variety of
2-arylideneindan-1,3-dione dienophiles (17) were synthesized in very good yields.
Amino Acid-Catalyzed Direct Asymmetric Hetero-Domino K-DA-E Reactions. We found that the
three-component reaction of trans-4-phenyl-3-buten-2-one
1a, 4-nitrobenzaldehyde 2a, and 1,3-indandione 3 with
a catalytic amount of L-proline (20 mol %) in methanol
at ambient temperature for 24 h furnished the expected
nonsymmetrical Diels-Alder products 5aa and 6aaΨ in
86% yield with thermodynamically stable cis-spirane 5aa
as the major isomer, dr 24:1 (Table 1, entry 1) (ΨIn all
compounds denoted 5xy and 6xy, x is incorporated from
reactant enones 1 and y is incorporated from the reactant
aldehydes 2.) Unfortunately, the enantiomeric excess (ee)
of the major cis-spirane 5aa was only 5%. Interestingly,
the same reaction with an extended reaction time furnished cis-spirane 5aa as a single diastereomer in 96%
yield, however with 3% ee (Table 1, entry 2). The minor
diastereomer, trans-spirane 6aa, was effectively epimerized to the thermodynamically stable cis-spirane 5aa
under prolonged reaction time via proline catalysis. The
stereochemistry of products 5aa and 6aa was established
by NMR analysis.16
In the three-component hetero-domino K-DA-E reaction of enone 1a, 4-nitrobenzaldehyde 2a, and 1,3indandione 3 catalyzed directly by L-proline, we found
that the solvent (dielectric constant) and temperature
had a significant effects on reaction rates, yields, dr’s,
and ee’s (Table 1). The hetero-domino K-DA-E reaction
catalyzed by L-proline at ambient temperature in aprotic/
nonpolar solvents produced products 5aa and 6aa in low
(16) Stereochemistries of the cis- and trans-spiranes were established using COSY experiments and were also based on MOPAC
calculations of the thermodynamic equilibration between the two
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
entry
catalyst
(20 mol %)
aldehyde
solvent
(0.5 M)
T (°C)
time (h)
products
yieldb (%)
1
2
3
4
5
6
7
8
9
10e
11e
12e
13
14e
15
16e
17
18
19
20
21
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4d
4e
4a
4a
4a
4a
4a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
MeOH
MeOH
DMSO
THF
CHCl3
C6H6
[bmim]BF4
[bmim]PF6
MeOH
MeOH
THF
THF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
[bmim]BF4
[bmim]PF6
25
25
25
25
25
25
25
25
25
4
25
4
25
4
25
25
25
25
70
25
25
24
96
96
120
120
120
96
96
72
96
96
96
96
96
36
46
24
98
2
24
96
5aa, 6aa
5aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa, 6aa
5aa
5aa, 6aa
5aa
5aa, 6aa
5ab, 6ab
5ab
5ab
5ab, 6ab
5ab, 6ab
86
98
95
54
63
e5
80
45
62
18
e10
e5
68
40
92
19
87
96
96
53
55
drc
(cis/trans)
24:1
g99:1
30:1
2.8:1
1:1
34:1
1.5:1
8.5:1
1.3:1
1:1.4
g99:1
1.6:1
g99:1
1:1
2:1
g99:1
g99:1
1:2
1:2
eed
(cis/trans)
5/3/1/18/15
13/6
1/6/7
17/30/3
42/6
9/17/4
2/14/13
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
1, entries 4-6, 11, and 12). Enantioselectivity improved
in aprotic/nonpolar solvents (Table 1, entries 4-6, 11, and
12). Excellent yields, good diastereoselectivity, and poor
enantioselectivity were observed in protic/polar solvents
(Table 1, entries 1-3). For example, the K-DA-E reaction
in THF furnished spiranes 5aa and 6aa in 54% yield with
dr of 2.8:1 and with ee of 18% for the major cis-spirane
5aa and an ee of 15% for the minor trans-spirane 6aa
(Table 1, entry 4). The same reaction using ionic liquid
[bmim]BF4, a “green solvent”, catalyzed by L-proline at
25 °C furnished the thermodynamically stable product
cis-spirane 5aa as the major diastereomer in 80% yield
with dr of 34:1, albeit with a low ee value of 1% (Table 1,
entry 7). Interestingly, the same reaction under proline
catalysis in ionic liquid [bmim]PF6 at 25 °C furnished
the spiranes 5aa and 6aa in 45% yield with dr of 1.5:1
and with ee of 6% (cis-spirane) and 7% (trans-spirane)
(Table 1, entry 8). In the hetero-domino K-DA-E reaction
under L-proline catalysis, diastereoselectivity was directly
affected by the nature of the solvent (dielectric constant)
as reflected in the epimerization reaction and exo/endo
selectivity. Rates of organocatalytic reactions catalyzed
by amino acids were faster in protic/polar solvents than
in nonprotic/nonpolar solvents presumably due to enhanced stabilization of charged intermediates and more
facile proton-transfer reactions. This is especially true
for the epimerization reaction where the dr’s of the
produces obtained using protic/polar solvents were very
high.
Next we probed the structure and reactivity relationships among a family of amino acids and pyrrolidinebased catalysts by monitoring the reaction yields, dr’s,
and ee values of the hetero-domino K-DA-E reaction and
compared them to the results of the organocatalytic
5842 J. Org. Chem., Vol. 69, No. 18, 2004
asymmetric three-component Diels-Alder (ATCDA) reaction of 1a, 2a, and Meldrum’s acid.6a Among the
catalysts screened in the ATCDA reaction, the 5,5dimethyl thiazolidinium-4-carboxylate (DMTC) proved to
be the most efficient catalyst with respect to yield and
ee. When DMTC was tested in the K-DA-E reaction of
1a, 2a, and 3 in methanol at 25 °C for 72 h, the domino
products 5aa and 6aa were obtained in 62% yield with
dr of 8.5:1 and ee of the major cis-spirane 5aa of 17%
(Table 1, entry 9). The same reaction under DMTC
catalysis at reduced temperature (4 °C) in methanol for
96 h furnished products 5aa and 6aa in 18% yield with
a dr of 1.3:1. Under these conditions, the ee of the major
cis-spirane 5aa was 30% and ee for the minor transspirane 6aa was 3% (Table 1, entry 10). With DMTC
catalysis in THF as solvent at 25 °C, products 5aa and
6aa were obtained in poor yields (e10%) with dr of 1:1.4
and ee for the minor cis-spirane of 42%, while the ee for
the major trans-spirane of 6% (Table 1, entry 11). DMTCcatalyzed K-DA-E reaction in THF at 4 °C for 96 h
furnished the domino products in very poor yields (Table
1, entry 12). An imidazoline-type catalyst, 4-benzyl-1methylimidazolidine-2-carboxylic acid 4c, also catalyzed
the K-DA-E reaction with moderate yield, very good dr,
and low ee at 25 °C and moderate to low yield, and poor
dr with improved ee at 4 °C (Table 1, entries 13 and 14).
trans-3-Hydroxy-L-proline 4d catalyzed the domino KDA-E reaction of 1a, 2a, and 3 with very good yield and
excellent diastereoselectivity, but the ee was poor (Table
1, entry 15). trans-4-Hydroxy-L-proline 4e also catalyzed
the domino K-DA-E reaction of 1a, 2a, and 3 but reaction
yield (19%), dr (1:1), and ee (14 and 13) were poor (Table
1, entry 16). While the Knoevenagel product 17a was
formed and consumed in most of the amino acid-catalyzed
heterodomino K-DA-E reactions, in some reactions (Table
Organocatalytic Heterodomino K-DA-E Reactions
FIGURE 2. Asymmetric solvation in the ionic liquids.
1, entries 10, 11, 12, 14, and 16) unreacted 17a was
isolated in 60-80% yield. Unreacted 17a was the result
of a very slow rate of the formation of the key intermediate 2-amino-1,3-butadiene and subsequent Diels-Alder
reaction under these conditions.
The L-proline-catalyzed three-component hetero-domino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1a
and 1,3-indandione 3 with a different aldehyde, benzaldehyde 2b, furnished products 5ab and 6ab in 87%
yield with dr of 2:1 (Table 1, entry 17). The same reaction,
albeit with an extended reaction time, furnished prochiral
cis-spirane 5ab as a single diastereomer in 96% yield
(Table 1, entry 18). The stereochemistry of products 5ab
and 6ab was established by NMR analysis. The minor
diastereomer, trans-spirane 6ab was effectively epimerized to the thermodynamically stable cis-spirane 5ab
under prolonged reaction time via proline catalysis.
Increasing the reaction temperature to 70 °C facilitated
the epimerization reaction and furnished the expected
domino product 5ab as a single diastereomer in 96% yield
within 2 h. Interestingly the same reaction in the ionic
liquids, [bmim]BF4 and [bmim]PF6, catalyzed by L-proline
at ambient temperature provided the kinetic product
trans-spirane 6ab as the major diastereomer in moderate
yield (Table 1, entries 20 and 21). In these reactions,
enantioselectivity for the minor kinetic product 6ab was
poor. cis-Spirane 5ab has been used as a synthon for the
synthesis of variety of benzoannelated centropolyquinanes
as shown in Chart 1.8
cis-Spirane 5ab is obtained via an endo-transition state
in the classical Diels-Alder route. In ionic liquids,
however, the kinetic product, trans-spirane 6ab, was the
major isomer formed. This is likely due to a unique
organization of the ionic liquid solvent with the 2-amino1,3-butadiene 18a and dienophile 17b in the transition
states as shown in Figure 2. Asymmetric solvation in the
ionic liquids then produces a steric hindrance with the
phenyl group on the dienophile in the endo-transition
state, thereby disfavoring it. In the case of dienophile
17a, the high epimerization rate of trans-spirane 6aa
provides cis-spirane 5aa as the major isomer (Table 1,
entries 7 and 8). Ratio of exo/endo products in ionic
liquids or other solvents mainly depend on four factors,
which are (i) substrate effect (electronic factor), (ii) protic
solvent effect (polarization factor), (iii) steric hindrance
induced by ionic solvation, and (iv) basic nature of organo
catalyst.
Amine-Catalyzed Direct Heterodomino K-DA-E
Reactions. Amines 4f-j can also catalyze the 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-pyrrolidinylmethyl)-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
expected domino products 5aa and 6aa in 71% yield with
dr of 13.5:1, but with poor ee (Table 2, entry 2). Since
enantioselection in these reactions was typically unsatisfactory, we studied the simple achiral amine pyrrolidine
4h and found that it furnished cis-spirane 5ab as a single
diastereomer in 90% yield (Table 2, entry 3). Further we
found that pyrrolidine catalysis was not dramatically
affected with respect to reaction rates, yields, or dr’s by
solvent and temperature modification (Table 2). Under
pyrrolidine catalysis, the heterodomino K-DA-E reaction
worked well in a variety of solvents and the optimal
conditions involved mixing equimolar amounts of enone
1a, aldehyde 2b, and 1,3-diketone 3 in methanol with
heating to 70 °C for 1 h to furnish cis-spirane 5ab as a
single diastereomer in 95% yield (Table 2, entry 9).
Interestingly, the six-membered cyclic amines piperidine
(4i) and morpholine (4j) also catalyzed the heterodomino
K-DA-E reaction. Typically, pyrrolidine-based catalysts
are much more effective than six-membered cyclic amines
as organocatalysts and six-membered cyclic amines are
extremely poor catalysts of aldol reactions.3b The reaction
of enone 1a, aldehyde 2b, and 1,3-diketone 3 under
piperidine 4i catalysis in methanol at 70 °C for 4 h
furnished the expected domino products 5ab and 6ab in
71% yield with dr of 43:1 (Table 2, entry 10). Under the
same conditions, morpholine 4j catalyzed formation of
5ab and 6ab in 46% yield with dr of 18.6:1 (Table 2, entry
11). The pyrrolidine-catalyzed heterodomino K-DA-E
reaction was, however, faster.
Organocatalytic Epimerization of trans-Spirane
6 to cis-Spirane 5. Epimerization of trans-spirane 6 or
the diastereospecific synthesis of cis-spirane 5 in the
heterodomino K-DA-E reaction of enone 1, aldehyde 2,
and 1,3-indandione 3 can be explained as illustrated in
Scheme 3. Amino acid or amine-catalyzed Knoevenagel
condensation9 of aldehyde 2 with 1,3-indandione 3 provides the arylidene-indandione 17 via the in situ generated reactive cationic imine 16. Arylideneindandione 17
then undergoes a concerted [4 + 2] cycloaddition or a
double-Michael reaction with the soft nucleophile, 2-amino1,3-butadiene 18 generated in situ from enone 1 and the
amino acid or amine catalyst, to produce products 5 and
6. The energy difference (∆H) between the two isomers
(17) (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5,
4369. (b) Spencer, T. A.; Neel, H. S.; Ward, D. C.; Williamson, K. L. J.
Org. Chem. 1966, 31, 434. (c) Woodward, R. B. Pure Appl. Chem. 1968,
17, 519. (d) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1612.
(e) Greco, M. N.; Maryanoff, B. E. Tetrahedron Lett. 1992, 33, 5009.
(f) Snider, B. B.; Yang, K. J. Org. Chem. 1990, 55, 4392.
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
entry
catalyst
(20 mol %)
aldehyde
solvent
(0.5 M)
T (°C)
time (h)
products
yieldb
(%)
drc
(cis/trans)
eed
(cis/trans)
1
2
3
4
5
6
7
8
9e
10
11
4f
4g
4h
4h
4h
4h
4h
4h
4h
4i
4j
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
MeOH
DMSO
MeOH
MeOH
THF
CHCl3
DMSO
DMF
MeOH
MeOH
MeOH
25
25
25
70
25
25
24
25
70
70
70
24
39
8
0.75
7
7
70
24
1
4
4
5aa
5aa, 6aa
5ab
5ab
5ab
5ab
5ab
5ab
5ab
5ab, 6ab
5ab, 6ab
79
71
90
90
85
70
75
80
95
71
46
g99:1
13.5:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
43:1
18.6:1
1
3
a Experimental conditions: amines 4f,g (0.1 mmol), 4h-j (0.15 mmol), 4-nitrobenzaldehyde 2a or benzaldehyde 2b (0.5 mmol), and
1,3-inandione 3 (0.5 mmol) in solvent (1 mL) were stirred at ambient temperatures for 30 min, then benzyl acetone 1a (1 mmol) was
added (see the Experimental Section). b Yield refers to the purified product otabined by column chromatography. c Ratio based on isolated
products (1H and 13C NMR analysis). d Enantiomeric excesses determined by using chiral-phase HPLC. e Enone 1a, benzealdehyde 2b
and 1,3-indandione 3 were used in 0.5 mmol scale.
SCHEME 3. Proposed Catalytic Cycle for the
L-Proline (or Amino Acid or Amine) Catalyzed
Heterodomino K-DA-E Reactions
5aa and 6aa is 5.626 kcal/mol based on AM1 and 4.114
kcal/mol based on PM3 calculations. The energy difference (∆H) between the two isomers of 5ab and 6ab is
6.158 kcal/mol based on AM1 and 5.680 kcal/mol based
on PM3 calculations. Minimized structures of 5aa, 6aa,
5ab, and 6ab are depicted in the Supporting Information.
Since the differences in ∆H’s between the two isomers
of 5aa/6aa and 5ab/6ab are greater than 5 kcal/mol, the
minor kinetic isomers 6aa and 6ab are epimerized to the
5844 J. Org. Chem., Vol. 69, No. 18, 2004
SCHEME 4. Proposed Mechanism for the L-Proline
(Amino Acid or Amine) Catalyzed Epimerization of
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 considerations 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 mechanism19 at the epimerization step as shown in Scheme
4.
The rate of the epimerization was also related to the
nucleophilic strength of the amino acid or amine catalyst,
(18) Zalukaev, L. P.; Anokhina, I. K.; Aver’yanova, I. A. Dokl. Akad.
Nauk SSSR 1968, 181, 103.
(19) (a) Shternberg, I. Y.; Freimanis, Ya. F. Zh. Org. Khim. 1970,
6, 48. (b) Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.; Winemiller,
M. D.; Chamberlin, M. J.; Czulada, G.; Johnson, S. D. J. Org. Chem.
1998, 63, 4359.
Organocatalytic Heterodomino K-DA-E Reactions
SCHEME 5. Organocatalytic Epimerization of
trans-Spirane 6 to cis-Spirane 5
reaction temperature, and nature of the solvent. Epimerization rate of trans-spirane 6 to cis-spirane 5 in protic/
polar solvents under amino acid catalysis was faster than
that in aprotic/nonpolar solvents (Table 1). But under
amine catalysis, the nature of the solvent did not have
much effect on the epimerization rate. In protic/polar
solvents, stabilization of the highly reactive ionic species
generated in the reaction media by hydrogen bonding or
dipolar-dipolar interactions enhanced the reaction rate.
As shown in Scheme 4, the amino acid or amine reacts
with cyclohexanone 6 to generate the enamine 19. The
retro-Michael reaction to form the ring-opened imine/
enolate 20 should be accelerated by hydrogen bonding
with protic/polar solvents. Imine/enolate 20 then undergoes Michael reaction to form the enamine of the thermodynamically stable cis-spirane 21, which undergoes
hydrolysis in situ to furnish cis-spirane 5.
Epimerization of trans-spiranes 6aa and 6ab to cisspiranes 5aa and 5ab, respectively, was confirmed in
studies of the L-proline and pyrrolidine-catalyzed reaction
in methanol at ambient temperature (Scheme 5). The
epimerization reaction catalyzed by pyrrolidine was
significantly faster than that catalyzed by proline. No
epimerization was observed in the absence of catalyst.
To further probe the epimerization mechanism we
sought to study the intermediate enamine of cis-spirane
22. A mixture of cis- and trans-spiranes 5aa and 6aa (1.5:
1) was treated with morpholine in the presence of
catalytic amount of p-TSA under reflux in toluene for 30
min to furnish the enamine of the epimerized cis-spirane
22. NMR analysis of the unpurified mixture showed
features of the enamine (Scheme 6). We studied the
morpholine derived enamine because morpholine 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, cisspirane 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
°C for 96 h furnished the expected cis-spiranes in good
yields with high diastereoselectivity as shown in Table
3. None of these nonsymmetrical cis-spiranes were known
in the literature. Various arylaldehydes with different
electron-donating or -withdrawing groups, as well as
heteroaromatic aldehydes furnished the spiranes without
the loss of diastereoselectivity. Interestingly, the heterodomino K-DA-E reaction of enone 1a, 4-methoxybenzaldehyde 2c, and 1,3-indandione 3 furnished the expected
cis-spirane in 6:1 diastereomeric ratio. In this case, the
epimerization rate of trans-spirane 6ac to cis-spirane 5ac
was slower than with other substrates and so the
diastereoselectivity was poor. Reaction of an arylaldehyde
bearing an electron-donating p-hydroxy substitute furnished cis-spirane 5af in very good yield and a surprisingly high dr (Table 3, entry 3). Likewise, arylaldehydes
with electron withdrawing substituents such as o-nitro,
p-chloro, p-cyano, and p-methoxycarbonyl also furnished
the cis-spiranes 5ah, 5ag, 5ai, and 5aj with high diastereoselectivities. The heterodomino K-DA-E reaction
of heteroaromatic aldehydes, 2-furanaldehyde, and
2-thiophenaldehyde furnished spiranes 5al and 5am with
SCHEME 6
J. Org. Chem, Vol. 69, No. 18, 2004 5845
Ramachary et al.
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 diastereoselectivities due to slow epimerization rates. Reaction of
1H-pyrrole-2-carboxyaldehyde 2n with 1a and 3 under
L-proline catalysis did not furnish the expected domino
product, but under pyrrolidine catalysis at 60 °C for 2 h
furnished the domino product 5an in 30% yield with high
dr. This domino product 5an was accompanied by an
unexpected product, cis-spirane 5ab, in 16% yield and
unreacted Knoevenagel product 17n in 25% yield. Formation of unexpected product 5ab in above reaction will
be considered in the next section. Reaction of R,βunsaturated aldehyde, trans-C6H4-CHdCH-CHO 2p
with 1a and 3 under L-proline catalysis also furnished
the expected domino product 5ao in good yields with high
dr.
Synthesis of Prochiral Symmetrical cis-Spiranes.
Pyrrolidine catalyzed, hetero-domino K-DA-E reactions
of trans-4-aryl-3-butene-2-ones (1a-l), arylaldehydes
(2a-p), and 1,3-indandione 3 in methanol at 70 °C for
1-2 h furnished the expected cis-spiranes 5 di5846 J. Org. Chem., Vol. 69, No. 18, 2004
astereospecifically in very good yields as shown in Table
4. Various trans-4-aryl-3-buten-2-ones and aryl aldehydes
with different substituents on the aromatic ring (ranging
from the electron-donating groups such as p-methoxy,
m,p-methylenedioxy, p-dimethylamino, and p-hydroxy
and electron-withdrawing groups such as p-chloro, pnitro, p-cyano, and p-methoxycarbonyl) and also the
heteroaromatic counterparts furnished the expected cisspiranes (5) in good yields with high diastereospecificity.
The chloro-, cyano-, and methoxycarbonyl-substituted cisspiranes 5gg, 5ii, and 5jj are potentially interesting
intermediates for materials chemistry as they can be
readily manipulated. Thus, numerous arylaldehydes and
various enones are readily reacted under either L-proline
or pyrrolidine catalysis to generate a library of highly
functionalized cis-spiranes (5) (Tables 3 and 4).
Synthesis of Highly Substituted cis-Spiranes. To
prepare highly substituted dispiranes, we used an aryldialdehyde instead of a simple arylaldehyde. Thus, the
heterodomino K-DA-E reaction of terephthalaldehyde 2p,
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 1-2 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.
a dialdehyde, with trans-4-phenyl-3-butene-2-one 1a and
indandione 3 catalyzed by L-proline or pyrrolidine furnished the cis-spiranealdehyde 23 and the dispirane 24
as well as the unexpected product 5ab as shown in Table
5. When L-proline was used as a catalyst, incubation of
the reaction at 25° C for 96 h furnished products 23 and
24 in 16% and 18% yield, respectively (Table 5, entry 1),
while the same reaction performed at 25 °C for 24 h and
40 °C for 48 h resulted in the formation of 23 and 24 in
60% and 18% yield, respectively (Table 5, entry 2). Under
L-proline catalysis, the unexpected product 5ab did not
form. The reaction catalyzed by pyrrolidine at 70 °C for
2 h furnished the dispirane 24 and the unexpected
product 5ab in 15% and 45% yield, respectively (Table
5, entry 3). The identity of dispirane 24 was confirmed
by proton, 13C NMR, and mass analysis. We had previously observed that the domino product 5ab was also
formed unexpectedly in the hetero-domino K-DA-E reaction of enone 1a, aldehyde 2n and 1,3-indandione 3 under
pyrrolidine catalysis with 16% yield (Table 3, entry 11).
To investigate the formation of the unexpected product
5ab, the reaction was carried out without the aldehyde.
Pyrrolidine catalyzed the reaction of trans-4-phenyl-3buten-2-one 1a with 1,3-indandione 3 in methanol at 70
°C for 5 h to furnish the cis-spirane 5ab and the
Knoevenagel product 17b in 28% and 8% yield, respectively, as shown in Scheme 7. The mechanism of formation of the unexpected product cis-spirane can be explained as shown in Scheme 7. First, the Michael addition
of indandione 3 to trans-4-phenyl-3-buten-2-one 1a takes
place to generate the adduct 25, which can then undergo
a retro-Michael reaction in one of two ways. The retroMichael reaction can either regenerate the starting
materials 3 and 1a or generate acetone and the Knoevenagel product 17b. Compound 17b undergoes a DielsAlder reaction with trans-4-phenyl-3-buten-2-one 1a to
furnish the mixture of cis- and trans-spiranes 5ab and
6ab as described earlier. Finally, epimerization of the
trans-spirane 6ab takes place to furnish the cis-spirane
5ab. Thus the mechanism of formation of the unexpected
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
retro-Michael reaction, a Diels-Alder reaction, and
finally an epimerization reaction.
Application of cis-Spiranes 5. Prochiral cis-spiranes
5 are very useful starting materials in the synthesis of
benzoannelated centropolyquinanes. Prochiral cis-spirane
5848 J. Org. Chem., Vol. 69, No. 18, 2004
5ab and trans-spirane 6ab have served as useful synthons in the synthesis of fenestranes.8 Kuck and coworkers have reported the synthesis of a highly strained
centrotetracyclic framework of fenestranes starting from
cis- and trans-spiranes 5ab and 6ab. In their study, the
cis-spirane 5ab was converted to all-cis-[5.5.5.5]fenes-
Organocatalytic Heterodomino K-DA-E Reactions
TABLE 5. Synthesis of Highly Substituted
groups such as chloro, cyano, and methoxycarbonyl
should allow for the development of a rich chemistry by
extension of the peripheral functional groups. Thus,
dendrimers, liquid crystals and poly-condensed ring
systems with saddle-like molecular structures may be
synthesized using the synthons described here.
cis-Spriranesa
Conclusions
entry
catalyst
(30 mol %)
T (°C)
time (h)
23
1
2
3
4a
4a
4h
25
25 f 40
70
96
24 f 48
2
16
60
yieldb (%)
24
5ab
18
18
15
45
The results presented here demonstrate amino acid or
an amine-based organocatalysis of three different reactions in a single pot. This astonishingly simple and atomeconomic 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. Further improvements with respect to the enantioselectivity
of these reactions might be accessible through the
screening or design of novel catalysts. As we have
suggested previously, the synthesis of polyfunctionalized
molecules under organocatalysis provides a unique and
under-explored perspective on prebiotic synthesis. A
complete understanding of the scope of organocatalysis
should not only empower the synthetic chemist but also
provide a new perspective on the origin of complex
molecular systems.
a
Experimental conditions: L-proline 4a or pyrrolidine 4h (0.15
mmol), terephthalaldehyde 2p (0.5 mmol), and 1,3 indandione 3
(1.0 mmol) in methanol (1 mL) were stirred at ambient temperature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was
added (see the Experimental Section). b Yield refers to the purified
product obtained by column chromatography.
trane 7 in nine synthetic steps as depicted in Scheme 8.
The dispirane 24 could serve as a suitable synthon for
the synthesis of topologically interesting difenestranes
26 and 27. Fenestranes containing reactive functional
Acknowledgment. This study was supported in
part by the NIH (CA27489) and the Skaggs Institute
for Chemical Biology.
Supporting Information Available: Characterization
data (1H NMR, 13C NMR, and mass) for all new compounds
and details of experimental procedures. Copies of 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO049581R
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
Carlos@scripps.edu
General Methods. The 1H NMR and
13
C 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
13
C 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 L6200A 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-(3oxo-but-1-enyl)-benzoic acid methyl ester 1j are prepared by using Wittig reaction with 1triphenylphosphoranylidene-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), 1,3indandione (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).
13
C 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, H2), 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).
13
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
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.
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, C4'), 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).
13
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, C3'), 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).
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
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 (MALDIFTMS): 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).
13
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, C4'), 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.
1
H 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, C7'), 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 (MALDIFTMS): 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).
13
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 (MALDIFTMS): 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
3.2 Hz, H-3α and 5α). 13C NMR (100 MHz, CDCl3, DEPT): δ 210.0 (C, C=O, C-4), 202.8 (2 x
C, C=O, C-1' and 3'), 142.0 (2 x C, C-8’ and 9’), 137.2 (2 x C), 135.3 (2 x CH, C-7’ and 6’),
128.3 (4 x CH), 128.1 (4 x CH), 127.3 (2 x CH), 122.4 (2 x CH, C-5’ and 4’), 61.5 (C, C-1 or
2’), 43.4 (2 x CH, C-6 and 2), 41.5 (2 x CH2, C-3 and 5). HRMS (MALDI-FTMS): m/z
403.1300 (M + Na+), calcd. for C26H20O3Na+ 403.1305.
(2β,
6β)-2,6-bis-(Napthalen-1-yl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5bk).6 Purified by FC using EtOAc/hexane and isolated
as a white solid and it has a plane of symmetry with chair
conformation. 1H NMR (399 MHz, CDCl3): δ 8.32 (2H, d, J = 8.8 Hz),
7.74 (1H, d, J = 7.6 Hz), 7.56 (4H, m), 7.40 - 7.29 (7H, m), 7.05 (2H, t,
J = 7.6 Hz), 6.97 (1H, dt, J = 7.6 and 0.8 Hz), 6.71 (1H, d, J = 8.0 Hz), 5.01 (2H, dd, J = 14.0
S11
and 4.0 Hz), 4.02 (2H, t, J = 14.0 Hz), 2.76 (2H, dd, J = 14.4 and 3.6 Hz). 13C NMR (100 MHz,
CDCl3, DEPT): δ 208.3 (C, C=O), 204.7 (C, C=O), 200.4 (C, C=O), 143.3 (C, C-8'), 141.3 (C,
C-9'), 135.0 (CH, C-7'), 134.8 (CH, C-6'), 134.3 (2 x C), 133.7 (2 x C), 130.7 (2 x C), 128.3 (2 x
CH), 128.1 (2 x CH), 126.3 (2 x CH), 125.6 (2 x CH), 124.7 (2 x CH), 124.6 (2 x CH), 123.5 (2
x CH), 122.2 (CH, C-5'), 121.8 (CH, C-4'), 61.2 (C, C-1), 45.2 (2 x CH), 42.2 (2 X CH2).
HRMS (MALDI-FTMS): m/z 503.1619 (M + Na+), calcd. for C34H24O3Na+ 503.1618.
(2β, 6β)-2,6-bis-(Thiophen-2-yl)spiro[cyclohexane-1,2’-indan]-1’,3’,4trione (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).
13
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,
ABq, J = 14.8 Hz).
13
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
5e).
13
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
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),
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
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
13
C 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 (MALDIFTMS): m/z 413.1396 (M + H+), calcd. for C26H20O5H+ 413.1383.
(2β,6β)-4-[2H1]Hydroxy-4-[2H3]methoxy-2,6-bis-(4-[2H1]hydroxyphenyl)spiro[cyclohexane1,2’-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.
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, C4’), 116.0 (4 x CH), 101.5 (C, C-4, DO-C-OCD3), 64.4 (C, C-1 or 2'), 46.2 (2 x CH), 35.4 (2 x
CH2). HRMS (MALDI-FTMS): m/z 413.1396 (M + H+), calcd. for C26H20O5H+ 413.1383.
(2β,
6β)-2,6-bis-(4-Chlorophenyl)spiro[cyclohexane-1,2’-indan]-1’,3’,4-trione
(5gg).5b,d
Purified by FC using EtOAc/hexane and isolated as a white solid and it has a plane of symmetry
with chair conformation. 1H NMR (399 MHz, CDCl3): δ 7.67 (1H, td, J = 7.6 and 1.2 Hz), 7.56
S14
(1H, dt, J = 7.2 and 1.6 Hz), 7.52 - 7.44 (2H, m), 6.97 (8H, dd, J = 12.8
and 9.2 Hz), 3.80 - 3.70 (4H, m), 2.63 (2H, m).
13
C 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
(2H, dd, J = 14.4 and 2.8 Hz).
13
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’,4trione (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, C3'), 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 (MALDIFTMS): m/z 429.1242 (M - H), calcd. for C28H18O3N2-H 429.1245.
(2β,
6β)-2,6-bis-(4-Methoxycarbonyl)spiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (5jj). Purified by FC using EtOAc/hexane and isolated as a
white solid and it has a plane of symmetry with chair conformation. 1H
NMR (399 MHz, CDCl3): δ 7.69 (4H, d, J = 8.4 Hz), 7.67 (1H, m, H-7'),
7.52 (1H, mt, J = 6.8 Hz, H-6'), 7.45 - 7.40 (2H, m, H-5' and 4'), 7.12 (4H,
d, J = 8.4 Hz), 3.98 - 3.86 (4H, m, H-2, 6, 3a, 5a), 3.77 (6H, s, 2 x
CO2CH3), 2.68 (2H, ABq, J = 14.8 Hz, H-3e and 5e). 13C NMR (100 MHz,
CDCl3, DEPT): δ 206.8 (C, C=O, C-4), 202.6 (C, C=O, C-1'), 201.0 (C, C=O, C-3'), 166.1 (2 x
C, O-C=O), 142.2 (C, C-8'), 142.1 (2 x C), 141.4 (C, C-9'), 135.7 (2 x CH, C-7' and 6'), 129.5 (4
x CH), 129.3 (2 x C), 128.0 (4 x CH), 122.4 (CH, C-5'), 122.1 (CH, C-4'), 61.3 (C, C-1), 51.8 (2
x CH3, CO2CH3), 48.4 (2 x CH, C-2 and 6), 42.8 (2 x CH2). HRMS (MALDI-FTMS): m/z
519.1408 (M + Na+), calcd. for C30H24O7Na+ 519.1414.
(2β,
6β)-2-(4-formylphenyl)-6-phenylspiro[cyclohexane-1,2’-indan]-
1’,3’,4-trione (23). Purified by FC using EtOAc/hexane and isolated as a
light yellow color solid. The ee was not determined. 1H NMR (399 MHz,
CDCl3): δ 9.77 (1H, s, CHO), 7.65 (1H, td, J = 7.6 and 0.8 Hz), 7.55 (2H,
td, J = 8.4 and 1.6 Hz), 7.50 (1H, m), 7.43 (1H, dd, J = 2.4 and 0.8 Hz),
7.42 (1H, d, J = 1.2 Hz), 7.23 (2H, br d, J = 8.4 Hz), 7.04 - 6.80 (5H, m,
Ph-H), 3.94 - 3.76 (4H, m), 2.68 (2H, m).
13
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, HC=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 (MALDIFTMS): 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
(2H, br d, J = 12.8 Hz), 2.27 (2H, m).
13
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.
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.
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
13C NMR spectrum of 5aa
X = Solvent (CH3CO2Et)
x
x
x
13C NMR spectrum of 6aa
13C NMR spectrum of 5ac
X = Solvent (CH3CO2Et)
X
X
X
13C NMR spectrum of 5af
13C NMR spectrum of 5ag
13C NMR spectrum of 5ah
X = Solvent (CH3CO2Et)
X
X
X
13C NMR spectrum of 5ai
X = Solvent (CH3CO2Et)
X
X
X
X
13C NMR spectrum of 5aj
X = Solvent (CH3CO2Et)
X
X
X
X
NOESY spectrum of 5ak
ROESY spectrum of 5ak
13C NMR spectrum of 5ak
13C NMR spectrum of 5al
13C NMR spectrum of 5am
13C NMR spectrum of 5an
13C NMR spectrum of 5ao
13C NMR spectrum of 5ab
13C NMR spectrum of 5ab & 6ab
(5ab : 6ab = 1:2)
x = cis-Spirane 5ab
13C NMR spectrum of 5bk
13C NMR spectrum of 5km
13C NMR spectrum of 5ll
13C NMR spectrum of 5cc
13C NMR spectrum of 5dd
1H NMR spectrum of 5ee
1H NMR spectrum of 5ff
in CD3OD
13C NMR spectrum of 5ff
in CD3OD
13C NMR spectrum of 5gg
13C NMR spectrum of 5ha
13C NMR spectrum of 5ii
13C NMR spectrum of 5jj
13C NMR spectrum of 23
13C NMR spectrum of 24