Expanding the Scope of Primary Amine Catalysis: Stereoselective Synthesis of Indanedione-Fused 2,6-Disubstituted trans-Spirocyclohexanones

Article abstract of DOI:10.1021/acs.joc.5b02921

A cinchona-alkaloid-derived chiral primary-amine-catalyzed enantioselective method for the synthesis of the thermodynamically less stable indanedione-fused 2,6-trans-disubstituted spirocyclohexanones is demonstrated. Both the enantiomeric forms of the trans isomer are obtained in excellent yields and enantioselectivities. Furthermore, one of the enantiopure trans-spiranes bearing an additional α-substitution on the cyclohexanone ring was then epimerized into its thermodynamically stable cis counterpart, with little loss of enantioselectivity to demonstrate the feasibility of such a transformation. Mechanistic investigations revealed two competing pathways, a concerted Diels-Alder reaction and a stepwise Michael addition, for the formation of corresponding products.

Full text of DOI:10.1021/acs.joc.5b02921

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Article
Expanding the scope of primary amine catalysis: Stereoselective synthesis
of indanedione-fused 2,6-disubstituted trans-spirocyclohexanones
Ganapuram Madhusudhan Reddy, Chi-Ting Ko, Kai-Hong Hsieh, Chia-Jui Lee, Utpal Das, and Wenwei Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02921 • Publication Date (Web): 23 Feb 2016
Downloaded from http://pubs.acs.org on February 29, 2016
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Expanding the scope of primary amine catalysis: Stereoselective
synthesis of indanedione-fused 2,6-disubstituted trans-
spirocyclohexanones
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G. Madhusudhan Reddy,§,† Chi-Ting Ko,§,† Kai-Hong Hsieh,§ Chia-Jui Lee,§ Utpal Das§ and
Wenwei Lin*,§
§Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan, R.O.C.
*Tel.: +886-2-77346131. E-mail: wenweilin@ntnu.edu.tw
ABSTRACT: A cinchona-alkaloid-derived chiral primary amine-catalyzed enantioselective
method for the synthesis of the thermodynamically less stable indanedione-fused 2,6-trans
disubstituted spiro cyclohexanones is demonstrated. Both the enantiomeric forms of the trans
isomer are obtained in excellent yields and enantioselectivities. Furthermore, one of the
enantiopure trans spiranes bearing an additional α-substitution on the cyclohexanone ring was
then epimerized into its thermodynamically stable cis counterpart, with little loss of
enantioselectivity to demonstrate the feasibility of such transformation. Mechanistic
investigations revealed two competing pathways, a concerted Diels-Alder reaction and a step-
wise Michael addition for the formation of corresponding products.
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INTRODUCTION
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Over the years, asymmetric aminocatalysis has been widely used for the functionalization of
carbonyl compounds, which happens to be one of the most classical organic transformations, in
an enantioselective fashion. However, for a substantially long period, the potential of primary
amines1 as chiral inducers for such aminocatalysis has been overshadowed by the chiral cyclic
secondary amines such as L-proline and its derivatives accompanied by phenylalanine-derived
imidazolidinones.2,3 The latter have been considered to be far superior organocatalysts for
aminocatalysis of the sterically non-demanding carbonyl compounds. But the task of asymmetric
induction becomes quite challenging in case of sterically hindered and less reactive substrates,
where neither the classical secondary amine catalysis nor the metal-based approaches could
prove to be successful. In such context, primary amines could prove to be more efficient and
could broaden the scope of the substrates for aminocatalysis to a large extent via their diverse
modes of activation.4a
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Among all the classes of primary amine organocatalysts, those derived from cinchona alkaloids
have attracted much attention of the researchers working on asymmetric aminocatalysis as they
could be easily synthesized and are readily tunable. Moreover, these conformationally unique
catalytic systems could activate both the electrophiles and the nucleophiles simultaneously, and
have the ability to catalyze the reaction either via the base-catalyzed or the enamine/iminium
activation pathway. Melchiorre et. al. have illustrated the potential of cinchona alkaloid derived
primary amines as organocatalysts to replace the conventional cyclic secondary amines for the
activation of α,β-unsaturated ketones to furnish the formal Diels-Alder products with far superior
enantioselectivities, via an alternative double Michael reaction pathway.5,6 Since then,
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considerable efforts have been made towards the development of asymmetric aminocatalysis
using cinchona alkaloid derived primary amines.4,7
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In an attempt to expand the scope of such primary amine catalysis, our group has been recently
evaluating the cases where the results of aminocatalysis with cyclic secondary amines were not
convincing. In such context, we encountered the L-proline-catalyzed domino Knoevenagel/Diels-
Alder/epimerization sequence for the synthesis of indanedione-fused cis-spirocyclohexanones
reported by Barbas et. al.,8 where the chiral secondary amine could not induce any considerable
enantioselectivity. It has been more than a decade, but till date, there have been no substantial
efforts to develop an enantioselective format of this transformation resulting in indanedione-
fused spirocyclohexanones.9-16 However, there have been a few methods reported for the
synthesis of spirocyclohexanones fused to other ring systems.17 So we decided to evaluate the
ability of cinchona alkaloid-derived primary amines to stereoselectively catalyze the reaction
leading to indanedione-fused spirocyclohexanones and then were keen to investigate the
corresponding reaction mechanism (Scheme 1). The resulting adducts represent the potential
leads for the development of anti-cancer agents which have a well-defined activity on apoptosis
and cell differentiation.18
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Scheme 1. Domino reaction for formation of 2,6-disubstituted cyclohexanones from 2-arylidene-1,3-
indanediones and 4-substituted-3-buten-2-ones.
RESULTS AND DISCUSSION
Initially, we carried out the reaction of trans-4-phenyl-3-buten-2-one (2a) with 2-arylidene
indanedione (1c) using 10 mol% each of I and 2-fluoro benzoic acid (3a) (Table 1, entry 1). The
spirocyclohexanone product 4ca was obtained in 80% yield (dr = 1.4:1). From the X-ray
crystallographic analysis of the product 4ca, it was quite unexpected to see the formation of
thermodynamically less stable trans spirane (exo product) in excess as against the earlier results,8
where cis spirane (endo product) was exclusively formed in most cases. This indicated a
competing two-step enamine/iminium activation pathway for the formation of trans-4ca as
against the concerted Diels-Alder mechanism which results in cis-4ca as reported earlier. The ee
of cis and trans diastereomers was found to be 77% and 98% respectively, which was promising
when compared to the same reaction being catalyzed by L-proline (VI) or Jørgensen’s catalyst
VII (entries 6 and 7). From the previous reports, it could be evaluated that the synthesis of
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indanedione-fused trans spirocyclohexanones (cyclohexanone fused to a 5-membered ring) is
difficult to accomplish as compared to the trans isomers of spirocyclohexanones that are fused to
other ring systems.17 Encouraged by this, we initially focused on the stereoselective synthesis of
thermodynamically less stable trans spiranes 4.
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Figure 1. Catalysts screened during optimization.
We screened other cinchona alkaloid-derived catalysts II-V (Table 1, entries 2-5) and found that
catalyst IV gave the best results (97% yield, 3.6:1 dr and 99% ee; entry 3). Following this, an
extensive screening of different solvents was carried out using IV (Table 2, entries 1-11). The ee
of trans diastereomer remained unaffected in most cases, while that of cis isomer varied over a
wide range. Although the mixed solvent system of DCM:Toluene (Table 2. entry 11) initially
appeared to give better results in terms of diastereoselectivity, it was found later during the
screening of additives, catalyst loading and reaction temperatures that the use of single solvent
system was beneficial.
Table 1. Optimization of reaction conditions.a
Entry
Cat.
Solvent
T (d)
Yield (%)b
drb
ee (%)c
1
2
3
I
Toluene
Toluene
Toluene
6
1
2
80
95
97
1.4:1
1.6:1
2:1
98/77d
99/70d
98/84
II
III
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IV
V
Toluene
Toluene
Toluene
Toluene
1
10
6
97
Trace
75
3.6:1
--
99/85
--
VI
VII
1:2.6
--
11/13
--
11
0
9
a
b
3a (2-Fluorobenzoic acid, 10 mol%). Yield of 4ca (cis + trans) as
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determined by 1H NMR analysis of the crude reaction mixture using
Ph3CH as an internal standard. c ee of trans/cis products as determined by
d
HPLC analysis on a chiral stationary phase. ee of ent-trans-4ca/ent-cis-
4ca.
Table 2: Solvent screening for the domino double Michael addition of 2a to 1c.a
Entry
Cat.
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
Solvent
DCM
T (d)
1
Yield (%)b
drb
ee (%)c
98/47
90/28
98/36
-/36
1
2
84
47
3.7:1
4.2:1
2.9:1
1:7
THF
8.5
9.5
9.5
10
6
3
EA
66
4
MeOH
CHCl3
44
5
71
1.6:1
1.2:1
1:1.2
1:1.1
2.6:1
1.2:1
4.3:1
98/25
97/82
98/36
96/43
99/59
99/26
98/84
6
Xylenes
Et2O
94
7
1
96
8
1,4-Dioxane
BrPh
2
81
9
1
98
10
11
1,2-DCE
DCM:Toluene
(1:4)
5
>99
>99
1
12d
13d
IV
II
DCM
4
5
1
85
81
96
>20:1
14:1
1:1
98/97
98/97e
98/97
DCM
14f
IV
Toluene
a
b
3a (2-Fluorobenzoic acid, 10 mol%). Yield of 4ca (cis + trans) as
determined by 1H NMR analysis of the crude reaction mixture using
Ph3CH as an internal standard. c ee of trans/cis products as determined by
d
HPLC analysis on a chiral stationary phase. 1c (1.2 equiv), IV or II (5
mol%) and 3d (2-nitrobenzoic acid, 20 mol%) in DCM (0.25 mL) at 10 oC.
e
f
ee of ent-trans-4ca/ent-cis-4ca.
IV (5 mol%) and 3e (2,6-
dihydroxybenzoic acid, 10 mol%) in toluene (0.5mL) at 60 oC (to obtain
cis isomer).
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A rigorous screening of catalyst loadings, additives, temperature and concentrations was then
carried out (see SI for detailed screening of reaction conditions). It is clear that an enhanced
reaction rate resulted in the formation of the kinetically favoured trans spirane, while the
prolonged reaction time increased the formation of thermodynamically more stable cis spirane.
After a careful study of different reaction parameters, the optimal conditions were established as
in table 2, entry 12. Additionally, under these optimized conditions, ent-trans-4ca could also be
obtained in good yields and selectivities using the pseudo-enantioner II (entry 13). To our
surprise, when the additive 3e was used, the thermodynamic endo product (cis-4ca) could also be
acquired with good enantioselectivity under slightly modified reaction conditions (entry 14).
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Table 3. Substrate scope for the domino Michael addition
using different substituted 1 and 2 for the synthesis of trans-4.
Entry R1
R2
T [d] Yield [%]a
drb
ee [%]c
96
1
Ph (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-ClPh (2b)
4-BrPh (2c)
5
75 (4aa)
80(4ba)
85 (4ca)
90 (4da)
96 (4ea)
91 (4fa)
80 (4ga)
71 (4ha)
66 (4ia)
82 (4ja)
74 (4cb)
77 (4cc)
13:1
17:1
>20:1
>20:1
14:1
12:1
10:1
7:1
2
4-ClPh (1b)
4-BrPh (1c)
4-CNPh (1d)
4-NO2Ph (1e)
2-BrPh (1f)
5
98
3
4
98
4
4
98
5
10
3.5
11
10
4
97
6
82
7
4-MePh (1g)
4-OMePh (1h)
2-OMePh (1i)
2-Thienyl (1j)
4-BrPh (1c)
4-BrPh (1c)
97
8
99
9
>20:1
1:1
91
10d
11
12
4
97
5
>20:1
>20:1
98
5
98
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4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-CNPh (2d)
4-NO2Ph (2e)
2-BrPh (2f)
4
89 (4cd)
73 (4ce)
70 (4cf)
76 (4cg)
89 (4ch)
75 (4ci)
15:1
8:1
97
97
98
98
97
98
10
5
18:1
11:1
>20:1
10:1
4-OMePh (2g)
2-OMePh (2h)
2-Thienyl (2i)
4
6
10
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12
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4-BrPh (1c)
8
a
b
Isolated yield of 4. Diastereomeric ratio of trans:cis as determined by 1H NMR analysis
c
of the crude reaction mixture using Ph3CH as an internal standard. ee of trans-4 as
determined by HPLC analysis on a chiral stationary phase. d Reaction temperature: 30 oC.
With the optimal conditions in hand, we then studied the scope of this domino Michael addition
reaction for the synthesis of trans spiranes with varying R1 and R2 substituents. The excellent
results with a wide range of the substrates are presented in table 3. Likewise, using the pseudo-
enantiomer II, we also demonstrated the synthesis of ent-trans-4 and the results are summarized
in table 4. It could be seen that the results with catalyst II followed the similar trend as seen with
catalyst IV, and the excellent outcome of the reaction could be reiterated.
Table 4. Substrate scope for the domino Michael addition using different
substituted 1 and 2 for the synthesis of ent-trans-4.
Entry
R1
R2
T [d] Yield [%]a
drb ee [%[c
1
2
3
4
5
6
Ph (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
5
73 (4aa)
85 (4ba)
81 (4ca)
99 (4da)
95 (4ea)
78 (4fa)
13:1
97
97
98
98
99
68
4-ClPh (1b)
4-BrPh (1c)
4-CNPh (1d)
4-NO2Ph (1e)
2-BrPh (1f)
5
17:1
14:1
5
4
>20:1
17:1
10
7
10:1
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4-MePh (1g)
4-OMePh (1h)
2-OMePh (1i)
2-Thienyl (1j)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
4-BrPh (1c)
Ph (2a)
11
10
10
4
75 (4ga)
61 (4ha)
62 (4ia)
80 (4ja)
82 (4cb)
70 (4cc)
73 (4cd)
79 (4ce)
65 (4cf)
88 (4cg)
81 (4ch)
70 (4ci)
13:1
9:1
98
93
78
96
97
98
97
97
97
94
97
98
8
Ph (2a)
9
Ph (2a)
>20:1
1:1
10d
11
12
13
14
15
16
17
18
Ph (2a)
4-ClPh (2b)
4-BrPh (2c)
4-CNPh (2d)
4-NO2Ph (2e)
2-BrPh (2f)
4-OMePh (2g)
2-OMePh (2h)
2-Thienyl (2i)
5
>20:1
>20:1
18:1
9:1
10
11
12
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5
4
10
5
>20:1
10:1
>20:1
12:1
4
6
8
a Isolated yield of ent-4. b Diastereomeric ratio of trans:cis as determined by 1H NMR analysis
c
of the crude reaction mixture using Ph3CH as an internal standard. ee of ent-trans-4 as
determined by HPLC analysis on a chiral stationary phase. d Reaction temperature: 30 oC.
We then extended the scope of the reaction using ethyl vinyl ketones and 2-cyclohexenone as
pronucleophiles, which would result in an additional stereocenter in the corresponding products
5 and 6 (Scheme 2). Since the reactivity of the substrates was lower, the reactions had to be
carried out at room temperature resulting in a lower diastereoselectivities while the excellent
enantioselectivities were still retained.
Scheme 2. Asymmetric synthesis of 5 and 6 with an additional stereocenter.
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Later on, we were keen to take the advantage of the fact that R1 and R2 groups in substrates could
be exchanged, that would still result in the same product. This gave us the flexibility to tune the
reactivity of the substrates accordingly. To demonstrate this, we chose the substrates 1j and 2a
which displayed poor reactivity at 10°C (Table 3, entry 10). When the reaction was carried out
with the substrates having R1 and R2 groups exchanged (1a and 2j), both the reactivity and the
selectivity improved drastically (Scheme 3). This result showed that it was possible to synthesize
an array of spiranes with excellent results by interchanging the substituents on the substrates.
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Scheme 3. Scope of the reaction by interchanging the R1 and R2 substituents.
We then attempted the one-pot operation for the synthesis of the trans spiranes starting from 1,3-
indanedione (7), aldehyde 8 and 2 (Scheme 4). The results were equally promising and the
products could be obtained in almost similar yields and stereoselectivities as compared to the
two-step process.
Scheme 4. One-pot reaction for the synthesis of trans-4.
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To establish the viability of this protocol, we also carried out a gram-scale reaction (10 mmol
scale) for the synthesis of trans-4ca from 7, 8 and 2, which furnished the product in 74% yield
(>20:1 dr; 99% ee) under the similar reaction conditions (Scheme 5).
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Scheme 5. Gram-scale reaction for the synthesis of trans-4ca.
The absolute configurations of trans-4ca, trans-5cca, cis-4ca (from its acetal derivative, cis-
15ca) and cis-5aca (from its acetal derivative, cis-16aca) were established by X-ray
crystallography.19 Mechanistically, this reaction could proceed either via the Diels-Alder
pathway or the double Michael addition pathway (Scheme 6).
Scheme 6. Possible reaction pathways.
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One of our vital objectives was to transform the kinetic trans spiranes into the
thermodynamically stable cis congeners so as to demonstrate the generality of this method for
the synthesis of all four stereoisomeric forms of the product. We envisioned that, based on the
retro-Michael/Michael mechanism for epimerization proposed earlier,8,20 when the trans spirane
is treated with an amine in a polar protic solvent, only one of the two stereocenters would be
rearranged and hence the enantioselectivity would be retained by the resulting cis products
(Scheme 7, path A).21 But the results were rather unlike. In all the cases, irrespective of the
catalyst (IV, cyclohexylamine or pyrrolidine) and the solvent used, we could observe complete
conversion of the trans isomer 4ca into cis-4ca, but only as racemic mixture (Scheme 8, eqn.
a).22 We initially attributed this result to the lack of regioselectivity during the formation of the
initial enamine intermediate, which would subsequently result in the formation of both the
enantiomers in almost equal amounts (Scheme 9, case 1).
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In an attempt to confirm this, enantiopure cis-4ca was treated with amine in DCM under similar
conditions (Scheme 8, eqn. b). It was envisioned that regioselectivity during enamine formation
would have no role to play in this case, and both the regioisomeric enamines would go through
the retro-Michael/Michael pathway and result in the regeneration of starting material cis-4ca,
with complete retention of enantioselectivity (Scheme 9, case 2). But, to our surprise, the
enantiopure cis-4ca completely racemized even in this case (eqn. b).23 This clearly indicated that
the epimerization may not be taking place solely via the retro-Michael/Michael pathway as
proposed earlier. We assume that it follows a competing retro-Diels-Alder/Diels-Alder pathway,
where both the stereocenters would be rearranged (Scheme 7, path B), and result in the racemic
products in presence of an achiral amine. However, during the epimerization of trans-4ca, the
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use of acidic additive or performing the reaction at 10°C resulted in cis-4ca with slight ee (23-
25%) (Scheme 8, eqn c).22 This result demonstrates that the retro-Diels-Alder pathway is
decelerated in presence of additive or at lower temperature, thereby allowing the retro-
Michael/Michael pathway to takeover. Moreover, the epimerization of the products by either of
these pathways is slowed down to a large extent when IV was used as the catalyst (Scheme 8,
eqn. a).22
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Scheme 7. Mechanistic possibilities for epimerization.
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Scheme 8. Control experiments to elucidate the mechanism of epimerization
Scheme 9. Retro-Michael/Michael pathway for epimerization of trans-4 would result in rac-cis-4 due to lack
of regioselectivity during enamine formation (CASE-1). Similar transformation of cis-4 would be expected to
result in retention of enantioselectivity (CASE-2, which is not observed during our study, thereby
ascertaining the retro-Diels-Alder/Diels-Alder pathway for epimerization).
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These results also explain the formation of kinetic trans spiranes with excellent diastereo- and
enantioselectivities (Tables 3 and 4), as the reactions are carried out using II or IV at lower
temperatures and in presence of additive which would suppress the subsequent epimerization of
the trans products. Furthermore, it could be ascertained that the formation of cis-4ca in entry 14
of table 2 is indeed taking place via the domino Michael addition pathway and not by the
epimerization of the initially formed trans-4ca, which if took place, would have resulted in the
loss of enantioselectivity of cis-4ca. It has been a general perception that it is very difficult to
ascertain the mechanistic pathway followed by a reaction when it has more than one possibilities
that could result in quite similar transition states or intermediates, thereby yielding similar
products. But in this case, using the enantiopure substrates for epimerization under different
conditions, we were able to understand and ascertain the reaction pathway.
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We then carried out the epimerization of substrate trans-5cca which has an additional methyl
substitution that would direct the regioselective formation of less substituted enamine 12
(Scheme 8, eqn. d). This should result in the inversion of R2 stereocenter after ring
opening/closing and lead to the formation of cis-5cca, without any loss of enantioselectivity. As
expected, the trans spirane could be successfully epimerized into its cis counterpart with 95% ee
using 3 eq of pyrrolidine.23 This result substantiated that the retro-Michael/Michael pathway was
predominantly followed during epimerization resulting in retention of enantioselectivity by the
cis products. These results were helpful to prove that the additional substitution on the
cyclohexanone ring of trans spiranes prevented the racemisation by retro-Diels-Alder pathway
and allowed the stereoselective synthesis of corresponding cis products. As a consequence, the
long-standing problem of obtaining both the cis and trans isomers of indanedione-fused spiro
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cyclohexanones with good enantioselectivities was solved. The cis spiranes without the methyl
substitution could be preferably synthesized following the conditions as in Table 2, entry 14,
resulting in the products with excellent enantioselectivity.
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CONCLUSIONS:
In summary, we have developed an efficient cinchona alkaloid-derived primary amine catalysis
for an unprecedented enantioselective syntheis of 1,3-indanedione-fused trans spiro
cyclohexanones. This method happens to be the first one to be reported for the enantioselective
synthesis of the kinetically controlled trans congeners of such spiranes. We then conclusively
demonstrated an alternative retro-Diels-Alder/Diels-Alder pathway for the epimerization of trans
spiranes into the corresponding cis congeners, which could be prevented by incorporating an
additional substitution on the cyclohexanone ring, resulting in the generation of cis spiranes with
good selectivities via retro-Michael/Michael pathway.
EXPERIMENTAL SECTION:
General experimental methods:
All solvents and reagents were used as purchased from commercial suppliers without further
purification. Starting materials and catalysts which were not commercially available were
synthesized by the previously reported methods. Analytical thin layer chromatography (TLC)
was performed on precoated alumina-backed silica gel plates (0.2 mm thickness) which were
developed using UV florescence and iodine. Flash-chromatography was performed on silica gel
(230-400 mesh). Melting points were measured on a standard melting point apparatus and are
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uncorrected. H NMR spectra were recorded on a 400 MHz spectrometer, while 13C NMR
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spectra were recorded on a 100 MHz instrument. Chemical shifts are reported in δ ppm
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referenced to an internal TMS standard for H NMR and chloroform-d (δ = 77.0 ppm) for C
NMR. HRMS spectra were recorded using MALDI (TOF analyzer), ESI (TOF analyzer) and EI
(Magnetic sector analyzer). The X-ray diffraction measurements were carried out at 298 K on a
CCD area detector system equipped with a graphite monochromator and a Mo-Kα fine-focus
sealed tube (k = 0.71073 Å ). Optical rotations were measured in CHCl3 on a polarimeter with a
50 mm cell (c given in g/100mL) operating at λ = 589 nm, corresponding to the sodium D line, at
the indicated temperatures. The enantiomeric excess of compounds whose racemic samples
could not be synthesized was analyzed by comparing the retention times in the HPLC
chromatograms of the corresponding enantiomers.
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a) General procedure A for the synthesis of trans-4 or ent-trans-4 from 1 and 2:
To a glass vial equipped with a magnetic stir bar was charged 2 (0.1 mmol), 1 (1.2 eq), IV (5
mol%), 3d (20 mol%) and DCM (0.25 mL) and stirred at 10 °C for the time specified. Then the
reaction was quenched by the addition of 0.1M HCl (0.25 mL) and the aqueous layer was
extracted with DCM (2 x 0.25 mL). The combined organic layers were concentrated in vacuo
and the crude reaction mass was purified by flash column chromatography over silica gel to give
the pure compound trans-4.
b) General procedure B for the synthesis of trans-4 or ent-trans-4 from 1 and 2:
To a glass vial equipped with a magnetic stir bar was charged 2 (0.1 mmol), 1 (1.2 eq), II (5
mol%), 3d (20 mol%) and DCM (0.25 mL) and stirred at 10 °C for the time specified. Then the
reaction was quenched by the addition of 0.1M HCl (0.25 mL) and the aqueous layer was
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extracted with DCM (2 x 0.25 mL). The combined organic layers were concentrated in vacuo
and the crude reaction mass was purified by flash column chromatography over silica gel to give
the pure compound ent-trans-4.
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c) General procedure C for the one-pot synthesis of trans-4 from 7, 8 and 2:
To a glass vial equipped with a magnetic stir bar was charged 2 (0.1 mmol), 7 (1.2 eq), 8 (1.2 eq),
IV (5 mol%), 3d (20 mol%) and DCM (0.25 mL) and stirred at 10 °C for the time specified.
Then the reaction was quenched by the addition of 0.1M HCl (0.25 mL) and the aqueous layer
was extracted with DCM (2 x 0.25 mL). The combined organic layers were concentrated in
vacuo and the crude reaction mass was purified by flash column chromatography over silica gel
to give the pure compound trans-4.
d) General procedure D for the synthesis of trans-5:
To a glass vial equipped with a magnetic stir bar was charged ethyl vinyl ketone (0.1 mmol), 1
(1.2 eq), IV (5 mol%), 3d (10 mol%) and DCM (0.25 mL) and stirred at 30 °C for the time
specified. Then the reaction was quenched by the addition of 0.1 M HCl (0.25 mL) and the
aqueous layer was extracted with DCM (2 x 0.25 mL). The combined organic layers were
concentrated in vacuo and the crude reaction mass was purified by flash column chromatography
over silica gel to give pure compound trans-5.
e) General procedure E for the synthesis of trans-6:
To a glass vial equipped with a magnetic stir bar was charged 1 (0.1 mmol), 2-cyclohexenone (5
eq), IV (5 mol%), 3d (20 mol%) and Toluene (0.25 mL) and stirred at 30 °C for the time
specified. Then the reaction was quenched by the addition of 0.1 M HCl (0.25 mL) and the
aqueous layer was extracted with DCM (2 x 0.25 mL). The combined organic layers were
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concentrated in vacuo and the crude reaction mass was purified by flash column chromatography
over silica gel to give the pure compound trans-6.
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f) General procedure F for the epimerization of enantiopure trans-4 to cis-4:
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To a glass vial equipped with a magnetic stir bar was charged trans-4 (0.1 mmol), pyrrolidine,
IV, cyclohexylamine or VI (20 mol%) and appropriate solvent (0.25 mL) and stirred at room
temperature. Then the reaction was quenched by the addition of 0.1M HCl (0.25 mL) and the
aqueous layer was extracted with DCM (2 x 0.25 mL). The combined organic layers were
concentrated in vacuo and the crude reaction mass was purified by flash column chromatography
over silica gel to give pure cis-4.
g) General procedure G for the epimerization of enantiopure trans-5 to cis-5:
To a glass vial equipped with a magnetic stir bar was charged trans-5 (0.1 mmol), pyrrolidine (3
eq), 3d (3 eq) and MeOH:DCM (1:2, 0.25 mL) and stirred at 50°C for 7 days. Then the reaction
was quenched by the addition of 0.1M HCl (0.25 mL) and the aqueous layer was extracted with
DCM (2 x 0.25 mL). The combined organic layers were concentrated in vacuo and the crude
reaction mass was purified by flash column chromatography over silica gel to give pure cis-5.
h) General procedure H for the synthesis of cis-15ca and cis-17aca:
To a glass vial equipped with a magnetic stir bar was charged cis-4ca or cis-5aca (0.1 mmol),
ethylene glycol (1.2 eq), p-TSA (10 mol%) and DCM (0.5 mL) and stirred under reflux for 12h.
Then the crude reaction mass was directly purified by flash column chromatography over silica
gel to give pure cis-15ca or cis-17aca as a colorless solid.
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6. Characterization data for all compounds:
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(2S, 6S)-2,6-diphenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-4aa): Following the
general procedure A, 4aa was obtained in 75% yield (28.5 mg, trans:cis = 13:1) as a yellow solid
(mp.: 205.1-209.1 °C). HPLC analysis (Chiralpak IB column, Hexane-IPA = 90:10, flow rate =
1.0 mL min-1, λ = 227 nm; TR = 15.97 min (major), 24.09 min (minor)): 96% ee, [α]D30 = −166.1
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(c = 0.5 in CH2Cl2); Rf 0.25 (EA/hexanes: 1/5); H NMR (400 MHz, CDCl3) δ/ppm, 7.59-7.52
(m, 4H), 7.07-6.99 (m, 6H), 6.96-6.93 (m, 4H), 3.98 (dd, J = 13.5, 3.2 Hz, 2H), 3.62 (dd, J =
16.7, 13.5 Hz, 2H), 2.78 (dd, J = 16.8, 3.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ/ppm, 210.0,
202.9, 142.1, 137.3, 135.4, 128.4, 128.2, 127.4, 122.5, 61.7, 43.5, 41.6. IR (KBr): 3036, 2923,
1739, 1593, 1409, 1242, 758, 698 cm-1. HRMS (ESI) for C26H21O3 [M+H]+ (381.1491) found:
381.1492.
(2R, 6R)-2,6-diphenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (ent-trans-4aa):
Following the general procedure B, ent-4aa was obtained in 73% yield (27.7 mg, trans:cis =
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13:1) as a yellow solid (mp.: 205.1-209.1 °C). [α]D = +166.5 (c = 0.5 in CH2Cl2. HPLC
analysis (Chiralpak IB column, Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm; TR =
16.73 min (major), 24.27 min (minor)): 97% ee
(2S,6S)-2-(4-chlorophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(trans-
4ba) : Following the general procedure A, 4ba was obtained in 80% yield (33.2 mg, trans:cis =
17:1) as a white solid (mp.: 177.4-178.2 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA
= 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR = 17.91 min (major), 27.54 min (minor)):
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98% ee, [α]D = −140.2 (c = 0.5 in CH2Cl2); Rf 0.28 (EA/hexanes: 1/5); H NMR (400 MHz,
CDCl3) δ/ppm, 7.64-7.57 (m, 4H), 7.07-7.00 (m, 5H), 6.94-6.90 (m, 4H), 3.95 (td, J = 13.3, 3.2
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Hz, 2H), 3.60 (dd, J = 13.8, 7.1 Hz, 1H), 3.57 (dd, J = 13.2, 6.7 Hz, 1H), 2.81-2.72 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ/ppm, 209.5, 202.8, 202.6, 142.0, 141.9, 137.0, 135.9, 135.63, 135.62,
133.2, 129.7, 128.4, 128.3, 128.2, 127.5, 122.62, 122.56, 61.5, 43.9, 42.5, 41.59, 41.56. IR (KBr):
1794, 1721, 1644, 1610, 1489, 1104, 758 cm-1. HRMS (ESI) for C26H20O3Cl [M+H]+ (415.1101)
found: 415.1109.
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(2R,6R)-2-(4-chlorophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-
trans-4ba) : Following the general procedure B, ent- 4ba was obtained in 85% yield (35.3 mg,
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trans:cis = 17:1) as a white solid (mp.: 177.4-178.2 °C). [α]D = +141.6. HPLC analysis:
Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR = 19.32
min (minor), 31.16 min (major), 97% ee.
(2S,6S)-2-(4-bromophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(trans-
4ca) : Following the general procedure A, 4ca was obtained in 85% yield (39.0 mg) as a white
solid (mp.: 143.0-144.1 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10, flow
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rate = 1.0 mL min-1, λ = 227 nm): TR = 18.53 min (major), 32.43 min (minor)): 98% ee, [α]D
=
−178.5 (c = 0.5 in CH2Cl2); Rf 0.25 (EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3) δ/ppm, 7.64-
7.57 (m, 4H), 7.18 (d, 2H, J = 8.3 Hz), 7.07-7.00 (m, 3H), 6.93-6.91 (m, 2H), 6.87-6.83 (m, 2H),
3.95 (dd, 1H, J = 10.1, 3.3 Hz), 3.92 (dd, 1H, J = 9.9, 3.3 Hz), 3.60 (dd, 1H, J = 13.6, 8.0 Hz),
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3.56 (dd, 1H, J = 13.1, 7.7 Hz), 2.78 (td, 2H, J = 3.4, 15.8 Hz). C NMR (100 MHz, CDCl3)
δ/ppm, 209.4, 202.7, 202.5, 142.0, 141.9, 137.0, 136.5, 135.63, 135.61, 131.4, 130.1, 128.3,
128.2, 127.5, 122.64, 122.57, 121.4, 61.4, 44.0, 42.6, 41.57, 41.56. IR (KBr): 3062, 2957, 2921,
1704, 1594, 1490, 1255, 763, 736, 700 cm-1. HRMS (ESI) for C26H20O3Br [M+H]+ (459.0596)
found: 459.0606.
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(2R,6R)-2-(4-bromophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-
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trans-4ca): Following the general procedure B, ent-4ca was obtained in 81% yield (37.2 mg,
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trans:cis = 14:1) as a white solid (mp.: 143.0-144.1 °C). [α]D = +180.6 (c = 0.5 in CH2Cl2).
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HPLC analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227
nm): TR = 19.61 min (minor), 32.70 min (major), 98% ee.
(2S,6S)-2-(4-bromophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (cis-4ca) :
To a glass vial equipped with a magnetic stir bar was charged 2 (0.1 mmol), 1 (1.2 eq), IV (5
mol%), 3e (10 mol%) and toluene (0.5 mL) and stirred at 60 °C for 24h. Then the reaction was
quenched by the addition of 0.1M HCl (0.25 mL) and the aqueous layer was extracted with DCM
(2 x 0.25 mL). The combined organic layers were concentrated in vacuo and the crude reaction
mass was purified by flash column chromatography over silica gel to give the pure compound
4ca. in 96% yield (44.1 mg, trans:cis = 1:1) as a colorless solid (mp.: 93.2-94.4 °C). HPLC
analysis (Chiralpak AD-H column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm):
TR = 39.13 min (major), 51.80 min (minor)): 97% ee, [α]D29 = +1.8 (c = 0.5 in CH2Cl2); Rf 0.30
(EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.66 (d, J = 7.6 Hz, 1H),7.53 (td, J = 6.7,
1.7 Hz, 1H),7.50-7.41 (m, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.03-6.88 (m, 7H), 3.86-3.70 (m, 4H),
2.71-2.56 (m, 2H). 13C NMR (100 MHz, CDCl3) δ/ppm: 207.8, 203.2, 201.6, 142.6, 141.9, 137.1,
136.6, 135.54, 135.5, 131.5, 129.8, 128.4, 127.9, 127.7, 122.5, 122.1, 131.6, 61.8, 49.0, 47.9,
43.3, 43.27. IR (KBr): 3062, 2957, 2921, 1704, 1594, 1490, 1255, 763, 736, 700 cm-1. HRMS
(ESI) for C26H20O3Br [M+H]+ (459.0596) found: 459.0596.
4-((2S,6S)-1',3',4-trioxo-2-phenyl-1',3'-dihydrospiro[cyclohexane-1,2'-inden]-6-
yl)benzonitrile (trans-4da) : Following the general procedure A, 4da was obtained in 90% yield
(36.5 mg) as a yellow solid (mp.: 158.5-159.2 °C). HPLC analysis (Chiralpak IB column
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(Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR = 48.15 min (major), 68.52 min
(minor)): 98% ee, [α]D30 = −203.5 (c = 0.5 in CH2Cl2); Rf 0.09 (EA/hexanes: 1/5); 1H NMR (400
MHz, CDCl3) δ/ppm: 7.62-7.58 (m, 4H), 7.38 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.05-
7.01 (m, 3H), 6.92-6.90 (m, 2H), 4.04 (dd, J = 13.5, 3.2 Hz, 1H), 3.94 (dd, J = 13.2, 3.2 Hz, 1H),
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3.68-3.54 (m, 2H), 2.82 (dd, J = 10.5, 3.2 Hz, 1H), 2.77 (dd, J = 10.4, 3.3 Hz, 1H). C NMR
(100 MHz, CDCl3) δ/ppm: 208.8, 202.4, 202.2, 143.0, 141.9, 141.8, 136.7, 135.9, 135.9, 132.1,
129.3, 128.3, 127.7, 122.72, 122.70, 118.2, 111.5, 61.4, 44.2, 43.0, 41.6, 41.1. IR (KBr): 3063,
2915, 1702, 1597, 1499, 1254, 163, 735, 699 cm-1. HRMS (ESI) for C27H20NO3 [M+H]+
(406.1443) found: 406.1451.
4-((2R,6R)-1',3',4-trioxo-2-phenyl-1',3'-dihydrospiro[cyclohexane-1,2'-inden]-6-
yl)benzonitrile (ent-trans-4da) : Following the general procedure B, ent-4da was obtained in
99% yield (40.1 mg) as a yellow solid (mp.: 158.5-159.2 °C).[α]D30 = +200.2 (c = 0.5 in CH2Cl2).
HPLC analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227
nm): TR = 55.43 min (minor), 73.71 min (major), 98% ee.
(2S,6S)-2-(4-nitrophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-4ea) :
Following the general procedure A, 4ea was obtained in 96% yield (40.8 mg, trans:cis = 14:1) as
a white solid (mp.: 141.3-141.8 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10,
flow rate = 1.0 mL min-1, λ = 229 nm): TR = 45.65 min (major), 55.84 min (minor)): 97% ee,
[α]D = −182.9 (c = 0.5 in CH2Cl2); Rf 0.13(EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3)
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δ/ppm: 7.94 (d, J = 8.6 Hz, 2H), 7.63-7.59 (m, 4H), 7.17 (d, J = 8.7 Hz, 2H), 7.08-7.03 (m, 3H),
6.93-6.91 (m, 2H), 4.11 (dd, J = 13.5, 3.4 Hz, 1H), 3.94 (dd, J = 13.1, 3.4 Hz, 1H), 3.65 (dd, J =
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16.6, 13.5 Hz, 1H), 3.58 (dd, J = 16.9, 13.1 Hz, 1H), 2.82 (td, J = 16.9, 4.4 Hz, 2H). C NMR
(100 MHz, CDCl3) δ/ppm: 208.6, 202.4, 202.1, 147.1, 145.1, 141.9, 141.8, 136.7, 136.0, 135.9,
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129.5, 128.3, 127.7, 123.4, 122.8, 122.7, 61.3, 44.4, 42.6, 41.6, 41.2. IR (KBr): 3061, 2925, 1702,
1604, 1512, 1255, 761, 736, 701 cm-1. HRMS (ESI) for C26H20NO5 [M+H]+ (426.1341) found:
426.1351.
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(2R,6R)-2-(4-nitrophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (ent-trans-
4ea) : Following the general procedure B, ent-4ea was obtained in 95% yield (40.4 mg, trans:cis
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= 17:1) as a white solid (mp.: 158.5-159.2 °C). [α]D = +200.2 (c = 0.5 in CH2Cl2). HPLC
analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR
= 46.79 min (minor), 54.54 min (major), 99% ee.
(2R,6S)-2-(2-bromophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(trans-
4fa): Following the general procedure A, 4fa was obtained in 91% yield (41.8 mg, trans:cis =
12:1) as a white solid (mp.: 163.6-164.9 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA
= 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR = 14.39 min (major), 42.78 min (minor)):
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82% ee, [α]D = +3.5 (c = 0.5 in CH2Cl2); Rf 0.25 (EA/hexanes: 1/5); 1H NMR (400 MHz,
CDCl3) δ/ppm: 7.84 (d, J = 7.6 Hz, 1H), 7.71-7.59 (m, 3H), 7.41 (dd, J = 0.9, 7.9 Hz, 1H), 7.33
(td, J = 1.3, 7.6 Hz, 1H), 7.28 (dd, J = 1.8, 8.0 Hz, 1H), 7.10 (td, J = 1.7, 7.9 Hz, 1H), 7.06-6.95
(m, 5H), 4.30 (t, J = 6.1 Hz, 1H), 3.94 (dd, J = 3.9, 13.8 Hz, 1H), 3.76 (dd, J = 14.0, 15.9 Hz,
1H), 3.28 (dd, J = 6.3, 16.0 Hz, 1H), 2.98 (dd, J = 6.0, 16.0 Hz, 1H), 2.79 (dd, J = 3.9, 16.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ/ppm: 209.8, 202.5, 199.9, 142.4, 141.0, 138.8, 137.3, 135.7,
135.4, 132.8, 129.8, 129.0, 128.7, 128.2, 127.7, 127.5, 125.9, 123.0, 122.8, 59.4, 43.4, 43.3, 43.1,
42.9. IR (KBr): 2924, 1701, 1595, 1458, 1257, 1024, 758, 701 cm-1. HRMS (ESI) for
C26H20O3Br [M+H]+ (459.0596) found: 459.0604.
(2S,6R)-2-(2-bromophenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-
trans-4fa): Following the general procedure B, ent-4fa was obtained in 78% yield (35.8 mg,
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trans:cis = 10:1) as a white solid. HPLC analysis: Chiralpak IB column (Hexane-IPA = 90:10,
flow rate = 1.0 mL min-1, λ = 227 nm): TR = 14.43 min (minor), 41.42 min (major), 68%.
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(trans-
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4ga) : Following the general procedure A, 4ga was obtained in 80% yield (31.6 mg, trans:cis =
10:1) as a yellow solid (mp.: 135.8-136.2 °C). HPLC analysis (Chiralpak IB column (Hexane-
IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226 nm): TR = 13.59 min (major), 20.55 min (minor)):
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97% ee, [α]D = −157.0 (c = 0.5 in CH2Cl2); Rf 0.28 (EA/hexanes: 1/5); 1H NMR (400 MHz,
CDCl3) δ/ppm: 7.60-7.53 (m, 4H), 7.06-6.99 (m, 3H), 6.95-6.93 (m, 2H), 6.87-6.82 (m, 4H),
3.96 (dd, J = 6.1, 3.4 Hz, 1H), 3.93 (dd, J = 6.1, 3.4 Hz, 1H), 3.61 (dd, J = 16.8, 9.6 Hz, 1H),
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3.57 (dd, J = 16.8, 9.4 Hz, 1H), 2.77 (dd, J = 16.8, 3.4 Hz, 2H), 2.14 (s, 3H). C NMR (100
MHz, CDCl3) δ/ppm: 210.2, 203.0, 202.9, 142.2, 142.1, 137.4, 137.0, 135.3, 134.4, 128.9, 128.4,
128.3, 128.2, 127.4, 122.6, 122.5, 61.7, 43.7, 43.1, 41.9, 41.7, 20.9. IR (KBr): 3032, 2920, 1703,
1595, 1254, 761, 699 cm-1. HRMS (ESI) for C27H23O3 [M+H]+ (395.1647) found: 395.1645.
(2R,6R)-2-(4-methylphenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-
trans-4ga) : Following the general procedure B, ent-4ga was obtained in 75% yield (29.6 mg,
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trans:cis = 13:1) as a yellow solid (mp.: 135.8-136.2 °C). [α]D = +156.0 (c = 0.5 in CH2Cl2).
HPLC analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226
nm): TR = 13.79 min (minor), 20.34 min (major), 98% ee.
(2S,6S)-2-(4-methoxyphenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-
4ha) : Following the general procedure A, 4ha was obtained in 71% yield (29.1 mg, trans:cis =
7:1) as a yellow solid (mp.: 120.2-121.0 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA
= 90:10, flow rate = 1.0 mL min-1, λ = 226 nm): TR = 21.64 min (major), 33.58 min (minor)):
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99% ee, [α]D = −155.3 (c = 0.5 in CH2Cl2); Rf 0.16 (EA/hexanes: 1/5); 1H NMR (400 MHz,
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CDCl3) δ/ppm: 7.61-7.54 (m, 4H), 7.07-7.00 (m, 3H), 6.95-6.93 (m, 2H), 6.87 (d, J = 8.7 Hz,
2H), 6.58 (d, J = 8.7, 2H), 3.94 (dt, J = 13.4, 3.7, 2H), 3.64-3.55 (m, 5H), 2.78 (dd, J = 9.2, 3.3
Hz, 1H), 2.73 (dd, J = 9.2, 3.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ/ppm: 210.2, 203.1, 203.0,
158.6, 142.2, 137.4, 135.38, 135.36, 129.5, 129.4, 128.4, 128.2, 127.4, 122.54, 122.49, 113.6,
61.8, 55.0, 43.6, 42.8, 42.0, 41.7. IR (KBr): 3068, 2918, 1702, 1598, 1522, 1348, 1255, 761, 698
cm-1. HRMS (ESI) for C27H23O4 [M+H]+ (411.1596) found: 411.1600.
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(2R,6R)-2-(4-methoxyphenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-
trans-4ha) : Following the general procedure B, ent-4ha was obtained in 61% yield (25.0 mg,
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trans:cis = 9:1) as a yellow solid (mp.: 120.2-121.0 °C). [α]D = +154.2 (c = 0.5 in CH2Cl2).
HPLC analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226
nm): TR = 22.62 min (minor), 32.23 min (major), 93% ee.
(2S,6S)-2-(2-methoxyphenyl)-6-phenylspiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-
4ia) : Following the general procedure A, 4ia was obtained in 66% yield (27.1 mg) as a yellow
solid (mp.: 133.5-134.1 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10, flow
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rate = 1.0 mL min-1, λ = 227 nm): TR = 14.79 min (major), 18.57 min (minor)): 91% ee, [α]D
=
−35.4 (c = 0.5 in CH2Cl2); Rf 0.14 (EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.78
(d, J = 7.6 Hz, 1H), 7.64-7.50 (m, 3H), 7.17-7.13 (m, 2H), 7.00-6.93 (m, 6H), 6.52 (d, J = 8.1 Hz,
1H), 4.14 (dd, J = 8.9, 5.2 Hz, 1H), 3.93 (dd, J = 14.4, 3.0 Hz, 1H), 3.81 (dd, J = 16.4, 14.5 Hz,
1H), 3.27 (s, 3H), 3.22 (dd, J = 16.2, 9.0 Hz, 1H), 3.01 (dd, J = 16.1, 5.2 Hz, 1H), 2.70 (dd, J =
16.4, 3.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ/ppm: 210.6, 202.5, 200.5, 155.9, 141.8, 141.6,
137.7, 135.0, 134.9, 128.7, 128.6, 128.5, 128.1, 127.2, 122.4, 122.1, 120.7, 109.5, 60.0, 53.8,
42.7, 42.2, 41.9, 37.2. IR (KBr): 3063, 2958, 1704, 1597, 1493, 1461, 1249, 755, 700 cm-1.
HRMS (ESI) for C27H23O4 [M+H]+ (411.1596) found: 411.1597.
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(ent-
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trans-4ia) : Following the general procedure B, ent-4ia was obtained in 62% yield (25.4 mg) as a
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yellow solid (mp.: 133.5-134.1 °C). [α]D = +25.8 (c = 0.5 in CH2Cl2); HPLC analysis:
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Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 227 nm): TR = 14.99
min (minor), 17.51 min (major), 78% ee.
(2S,6R)-2-phenyl-6-(thiophen-2-yl)spiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-4ja) :
Following the general procedure A, 4ja was obtained in 82% yield (31.7 mg, trans:cis = 1:1) as a
yellow solid (mp.: 195.8-196.5 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10,
flow rate = 1.0 mL min-1, λ = 226 nm): TR = 18.03 min (major), 20.02 min (minor)): 97% ee,
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[α]D = −134.6 (c = 0.5 in CH2Cl2); Rf 0.23(EA/hexanes: 1/5); H NMR (400 MHz, CDCl3)
δ/ppm: 7.72-7.69 (m, 1H), 7.66-7.60 (m, 3H), 7.09-7.02 (m, 3H), 6.97-6.93 (m, 3H), 6.72 (dd, J
= 3.7, 5.0 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 4.27 (dd, J = 12.8, 3.8 Hz, 1H), 3.93 (dd, J = 12.7,
3.6 Hz, 1H), 3.55 (dd, J = 12.8, 7.9 Hz, 1H), 3.52 (dd, J = 12.7, 7.5 Hz, 1H), 2.96 (dd, J = 16.8,
3.9 Hz, 1H), 2.82 (dd, J = 16.5, 3.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ/ppm: 208.9, 202.3,
202.2, 142.2, 142.1, 140.2, 137.4, 135.5, 128.4, 128.3, 127.5, 126.6, 126.5, 124.5, 122.7, 61.4,
44.1, 43.1, 41.9, 38.9. IR (KBr): 3071, 2956, 2922, 1724, 1701, 1593, 1349, 1254, 765, 705 cm-1.
HRMS (ESI) for C24H19O3S [M+H]+ (387.1055) found: 387.1055.
(2R,6S)-2-phenyl-6-(thiophen-2-yl)spiro[cyclohexane-1,2'-indene]-1',3',4-trione (ent-trans-
4ja) : Following the general procedure B, ent-4ja was obtained in 80% yield (30.9 mg, trans:cis
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= 1:1) as a yellow solid (mp.: 195.3-196.3 °C). [α]D = +135.5 (c = 0.5 in CH2Cl2). HPLC
analysis: Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226 nm): TR
= 18.24 min (minor), 19.90 min (major), 96% ee.
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(2S,6S)-2-(4-bromophenyl)-6-(4-chlorophenyl)spiro[cyclohexane-1,2'-indene]-1',3',4-trione
(trans-4cb) : Following the general procedure A, 4cb was obtained in 74% yield (36.5 mg) as a
yellow solid (mp.: 193.7-194.8 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10,
flow rate = 1.0 mL min-1, λ = 226 nm): TR = 19.32 min (major), 30.19 min (minor)): 98% ee,
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[α]D = −152.4 (c = 0.5 in CH2Cl2); Rf 0.29 (EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3)
δ/ppm: 7.62 (s, 4H), 7.18 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H),
6.83 (d, J = 8.5 Hz, 2H), 3.92 (dt, J = 13.3, 3.5 Hz, 2H), 3.55 (dd, J = 16.8, 13.4 Hz, 2H), 2.75
(dd, J = 16.6, 3.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ/ppm: 208.8, 202.3, 141.8, 136.2,
135.8, 135.7, 133.3, 131.3, 130.0, 129.7, 128.4, 122.7, 121.5, 61.1, 42.93, 42.90, 41.51, 41.4. IR
(KBr): 3065, 2920, 1703, 1593, 1490, 1253, 824, 735, 700 cm-1. HRMS (EI) for C26H18O3ClBr
[M]+ (492.0128) found: 492.0125.
(2R,6R)-2-(4-bromophenyl)-6-(4-chlorophenyl)spiro[cyclohexane-1,2'-indene]-1',3',4-trione
(ent-trans-4cb) : Following the general procedure B, ent-4cb was obtained in 82% yield (40.4
mg) as a yellow solid (mp.: 193.7-194.8 °C). [α]D30 = +151.6 (c = 0.5 in CH2Cl2). HPLC analysis:
Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226 nm): TR = 19.62
min (minor), 29.98 min (major), 97% ee.
(2S,6S)-2,6-bis(4-bromophenyl)spiro[cyclohexane-1,2'-indene]-1',3',4-trione (trans-4cc) :
Following the general procedure A, 4cc was obtained in 77% yield (41.4 mg) as a yellow solid
(mp.: 203.9-204.5 °C). HPLC analysis (Chiralpak IB column (Hexane-IPA = 90:10, flow rate =
1.0 mL min-1, λ = 226 nm): TR = 20.50 min (major), 34.79 min (minor)): 98% ee, [α]D30 = −157.2
(c = 0.5 in CH2Cl2); Rf 0.29 (EA/hexanes: 1/5); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.62 (s, 4H),
7.18 (d, J = 8.5 Hz, 4H), 6.83 (d, J = 8.5 Hz, 4H), 3.91 (dd, J = 13.2, 3.3 Hz, 2H), 3.54 (dd, J =
16.7, 13.3 Hz, 2H), 2.75 (dd, J = 16.7, 3.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ/ppm: 208.8,
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202.3, 141.8, 136.2, 135.9, 131.4, 130.0, 122.7, 121.5, 61.1, 43.0, 41.5. IR (KBr): 3062, 2919,
1703, 1593, 1488, 1254, 822, 735, 698 cm-1. HRMS (MALDI) for C26H18O3Br2Na [M+Na]+
(558.9515) found: 558.9535.
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(ent-trans-
4cc) : Following the general procedure B, ent-4cc was obtained in 70% yield (37.7 mg) as a
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yellow solid (mp.: 203.9-204.5 °C). [α]D = +157.8 (c = 0.5 in CH2Cl2). HPLC analysis:
Chiralpak IB column (Hexane-IPA = 90:10, flow rate = 1.0 mL min-1, λ = 226 nm): TR = 20.75
min (minor), 34.48 min (major), 98% ee.
(2S,6S)-4-(2-(4-bromophenyl)-1',3',4-trioxo-1',3'-dihydrospiro[cyclohexane-1,2'-inden]-6-
yl)benzonitrile (trans-4cd) : Following the general procedure A, 4cd was obtained in 89% yield
(43.1 mg, trans:cis = 15:1) as a yellow solid (mp.: 189.8-190.3 °C). HPLC analysis (Chiralpak
IB column (Hexane-IPA = 85:15, flow rate = 1.0 mL min-1, λ = 226 nm): TR = 36.58 min (major),
30
48.26 min (minor)): 97% ee, [α]D = −180.7 (c = 0.5 in CH2Cl2); Rf 0.09 (EA/hexanes: 1/5); 1H
NMR (400 MHz, CDCl3) δ/ppm: 7.67-7.60 (m, 4H), 7.37 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.6 Hz,
2H), 7.08 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 3.99 (dd, J = 13.2, 3.4 Hz, 1H), 3.91 (dd,
J = 13.3, 3.4 Hz, 1H), 3.58 (dd, J = 16.7, 8.8 Hz, 1H), 3.54 (dd, J = 13.3, 9.0 Hz, 1H), 2.80 (dd, J
13
= 4.5, 3.8 Hz, 1H), 2.76 (dd, J = 4.7, 3.7 Hz, 1H). C NMR (100 MHz, CDCl3) δ/ppm: 208.2,
202.1, 202.0, 142.7, 141.75, 141.66, 136.21, 136.19, 135.9, 132.1, 131.5, 130.0, 129.2, 122.9,
122.8, 121.8, 118.2, 111.6, 61.0, 43.4, 43.2, 41.5, 41.1. IR (KBr): 2922, 1702, 1598, 1489, 1412,
1255, 735, 700 cm-1. HRMS (ESI) for C27H19NO3Br [M+H]+ (484.0548) found: 484.0553.
(2R,6R)-4-(2-(4-bromophenyl)-1',3',4-trioxo-1',3'-dihydrospiro[cyclohexane-1,2'-inden]-6-
yl)benzonitrile (ent-trans-4cd) : Following the general procedure B, ent-4cd was obtained in
73% yield (35.3 mg, trans:cis = 18:1) as a yellow solid (mp.: 189.8-190.3 °C). [α]D30 = +181.7 (c
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