The Application of 2-Benzyl-1,4-naphthoquinones as Pronucleophiles in Aminocatalytic Synthesis of Tricyclic Derivatives

Article abstract of DOI:10.1021/acs.joc.8b00170

This study demonstrates an unprecedented reactivity of 2-substituted-1,4-naphthoquinones. By applying the principle of vinylogy, they have been employed as vinylogous pronucleophiles in the organocatalytic cascade reaction for the first time. This novel catalytic activation of 1,4-naphthoquinones enables access to carboannulated naphthalen-1(4H)-one derivatives of biological importance. The site-selectivity and stereoselectivity of a process proved possible to control by the proper choice of reaction conditions.

Full text of DOI:10.1021/acs.joc.8b00170

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The Application of 2-Benzyl-1,4-naphthoquinones as
Pronucleophiles in Aminocatalytic Synthesis of Tricyclic Derivatives
Anna Skrzy#ska, Marta Romaniszyn, Dominika Pomik#o, and Lukasz Albrecht
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00170 • Publication Date (Web): 12 Apr 2018
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The Application of 2-Benzyl-1,4-naphthoquinones
as Pronucleophiles in Aminocatalytic Synthesis of
Tricyclic Derivatives
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Anna Skrzyńska,‡ Marta Romaniszyn,‡ Dominika Pomikło, and Łukasz Albrecht*
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology,
Zeromskiego 116, 90-924 Łódź, Poland
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
SYNOPSIS TOC
KEYWORDS: Asymmetric catalysis; Vinylogy; 1,4-Naphthoquinones; Naphthalen-1(4H)-ones;
Remote functionalization.
ABSTRACT: This study demonstrates an unprecedented reactivity of 2-substituted-1,4-
naphthoquinones. By applying the principle of vinylogy they have been employed as vinylogous
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pronucleophiles in the organocatalytic cascade reaction for the first time. This novel catalytic
activation of 1,4-naphthoquinones enables access to carboannulated naphthalen-1(4H)-one
derivatives of biological importance. The site-selectivity and stereoselectivity of a process
proved possible to control by the proper choice of reaction conditions.
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Introduction
The development of methods for the facile and efficient construction of complex carbocyclic
frameworks constitutes highly relevant goal in the contemporary organic chemistry.1 In
particular, the application of cascade reactivities involving C-C bond-forming event merged with
subsequent reactions for the synthesis of bio-inspired products have received considerable
interest in the past few years.2 Among various privileged carbocyclic structures in organic
chemistry, α-tetralone and naphthalen-1(4H)-one ring systems occupy a prominent position
(Scheme 1, top). Due to the presence of a carbonyl group and a double bond within their
structure they possess high synthetic usefulness correlated with the functionalization potential of
these reactive moieties. Furthermore, such ring systems can be found in nature.3,4 For instance,
Hamigerans are a family of natural products that contains a α-tetralone structural unit merged
with additional five-membered cyclopentane ring (Scheme 1, bottom).4
Scheme 1. The importance of α-tetralone and naphthalen-1(4H)-one derivatives
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1,4-Naphthoquinones and their 2-alkyl-substituted derivatives constitute a useful group of
reactants commonly employed in asymmetric synthesis.5 Due to the presence of a highly
electron-deficient double bond they can act as electrophiles in a Michael-type additions.5b-e
Furthermore, they are employed as electron-poor dienophiles in various cycloaddition
reactions.5f-i Surprisingly, to the best of our knowledge their potential as vinylogous
pronucleophiles in organic synthesis has never before been explored. In the context, it is worth to
note that the vinylogous reactivity of organic compounds constitutes a rapidly developing field in
the contemporary organic chemistry.6,7 Due to the presence of conjugated double bond system in
vinylogous reactants a transfer of electrophilic or nucleophilic character to a remote reaction site
is possible. In the past few years the principle of vinylogy has been successfully implemented in
the field of asymmetric organocatalysis.7,8 In such a manner new reaction pathways have been
identified opening access to a variety of optically active products relevant for life-science
industry.
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Given the importance of carboannulated naphthalen-1(4H)-one derivatives and lack of
literature precedents on nucleophilic reactivity of 2-substituted-1,4-naphthoquinones 1, the task
of development of such a reactivity for the synthesis of carboannulated naphthalen-1(4H)-ones 3
has been undertaken. The novel reactivity concept is based on the application of dienolate A
readily available via deprotonation of 2-substituted-1,4-naphthoquinones 1 at the C-1’ position.
We envisioned that deprotonation of 1 should be possible to realize under relatively mild, basic
conditions due to the efficient stabilization of A through resonance (Scheme 2, middle). It was
anticipated that such a system should be capable of participating in the cascade reaction
involving Michael addition from the C-1’ position of A to the iminium-ion-activated enal 2
followed by the intramolecular aldol condensation to give 3 (Scheme 2, bottom, cascade A).
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However, it should be noted that due to ambident nature of the nucleophile A employed an
alternative reaction scenario is also possible (Scheme 2, bottom, cascade B). It can be initiated
through the Michael addition of A via C-3 nucleophilic position to the iminium-ion-activated
enal 1. Subsequent cyclization via intramolecular Michael addition and re-oxidation should
afford undesired 4.
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Herein, we present our studies on the first application of 2-substituted-1,4-naphthoquinones 1
as vinylogous pronucleophiles in asymmetric organocatalysis. Careful optimization of reaction
conditions enabled to control the site-selectivity of the cascade providing an efficient and
stereoselective access to carboannulated naphthalen-1(4H)-ones 3 (Scheme 2, bottom, cascade
A).
Scheme 2. 2-Substituted-1,4-naphthoquinones 1 in asymmetric organocatalysis and the
objectives of our studies
Results and Discussion
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Optimization studies were initiated using 2-benzyl-1,4-naphthoquinone 1a and
cinnamaldehyde 2a as model reagents (Table 1). Initial experiment performed in
dichloromethane in the presence of diphenylprolinol trimethylsilyl ether 5a9 as aminocatalyst
and sodium acetate as basic co-catalyst confirmed the viability of our synthetic hypothesis (Table
1, entry 1). Disappointingly, the conversion to 3a was low and the formation of the side-product
4a arising from the alternative reaction mechanism (Scheme 2, cascade B) was observed. To our
delight, both diastereoselectivity and enantioselectivity of the process were excellent. In order to
improve the conversion and suppress the formation of 4a, the co-catalyst screening was
performed (Table 1, entries 1-5). Among compounds tested the use of amphiprotic additive (4-
(dimethylamino)benzoic acid, DMABA) provided the best conversion and limited the formation
of 3a to the highest extend (Table 1, entry 5). In the course of the further studies the influence of
various aminocatalyst 5 on the reaction outcome was evaluated (Table 1, entries 5-8) indicating
that the alteration of 5 did not improve the results. Similarly, the change of solvent was not
beneficial for the developed cascade (Table 1, compare entries 5, 9-11). Therefore, the influence
of the relative ratio of reactants and temperature on the reaction was tested (Table 1, entries
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o
12,13). The use of 2a as limiting factor and performing the reaction at 5 C for longer time
enabled to increase the conversion with the high chemo- and stereoselectivity of the process
being maintained (Table 1, entry 13). Notably, for the convenience of the project the catalyst
loading was increased to 30 mol% in order to achieve full conversion within shorter timeframe
and similar results were obtained (Table 1, entry 14).
Table 1. 2-Substituted-1,4-naphthoquinones 1 as vinylogous pronucleophiles in asymmetric
organocatalysis – optimization studiesa
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Conv.b
(yield)
Catalyst (additive)
Solvent
3a:4a
drc
erd
1
5a (NaOAc)
5a (Et3N)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CCl4
41
3.3:1
>20:1
3.3:1
n.d.
>20:1
>20:1
>20:1
n.d.
99:1
n.d.
n.d.
n.d.
99:1
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
99:1
99:1
2
18
3
5a (Li2CO3)
5a (K2CO3)
39
4
<5
5
5a (DMABA)
5b (DMABA)
5c (DMABA)
5d (DMABA)
5a (DMABA)
5a (DMABA)
5a (DMABA)
50 (34)
34
11:1
11:1
8:1
>20:1
>20:1
>20:1
n.d.
6
7
33
8
<5
n.d.
9
13
>20:1
>20:1
7:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10
11
12
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
36
12e 5a (DMABA)
13f 5a (DMABA)
61
10:1
12:1
12:1
93 (64)
97 (67)
14g 5a (DMABA)
a
Reactions performed on a 0.1 mmol scale employing 1a (1.0 equiv), 2a (1.2 equiv), catalyst
5a (20 mol%) with additive (20 mol%) in 0.4 mL of the solvent at room temperature (for detailed
reaction conditions and screening results, see Supporting Information).
1
determined by H NMR of a crude reaction mixture. Isolated yield is given in parentheses.
Determined by H NMR of a crude reaction mixture. Determined by chiral stationary phase
HPLC. e Reaction performed using 1a (2 equiv) and 2a (1 equiv). f Reaction performed using 1a
(2 equiv) and 2a (1 equiv) at 5 oC for 6 days. g Reaction performed using 1a (2 equiv) and 2a (1
equiv) at 5 oC using catalyst 5a (30 mol%) for 3 days.
b
Conversion was
c
1
d
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Being successful in accomplishing optimization studies, the scope of developed cascade
reactivity was studied (Scheme 3, Table 2). Initially, the performance of various 2-substituted-
1,4-naphthoquinones 1 as vinylogous pronucleophiles in the developed cascade was tested
(Scheme 3). To our delight, the reaction cascade involving Michael addition followed by the
aldol condensation proved unbiased towards the position of groups on the aromatic substituent in
the benzyl moiety of 1 (Scheme 3, compare 3b-d). Furthermore, their electronic properties had
no significant impact on the cascade outcome (Scheme 3, compare 3b,e,f). Notably, in all of the
cases the excellent enantio- and diastereoselectivity of the process was fully maintained.
Furthermore, chemoselectivity of the cascade was high with the side-reaction initiated through
the Michael addition from the C-3 position of the naphthoquinone ring being supressed to high
extent. It is worth to stress out that when 1,4-naphthoquinone bearing methyl substituent instead
of benzyl group in the 2 position was employed no reaction was observed.
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Scheme 3. 2-Substituted-1,4-naphthoquinones 1 as vinylogous pronucleophiles in asymmetric
organocatalysis - 2-substituted-1,4-naphthoquinone 1 scope
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Subsequently, various α,β-unsaturated aldehydes 2 were evaluated in the developed cascade
(Table 2). It was found that the presence of both electron-withdrawing groups (Table 2, entries 2-
8) as well as electron-donating groups (Table 2, entries 9-11) on the aromatic substituent in 2 did
not affect the cascade providing the target products 3 in a highly enantio- and diastereoselective
fashion. The reaction outcome did also not depend from the location of the substituent on the
aromatic moiety in 2 (Table 2, entries 6-8 vs. 10,11). Notably, the use of aliphatic, linear enals
resulted in sluggish conversion.
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Table 2. 2-Substituted-1,4-naphthoquinones 1 as vinylogous pronucleophiles in asymmetric
organocatalysis – α,β-unsaturated aldehyde 2 scopea
R
Yield [%]
drb
erc
1
2
3
4
5
6
7
8
Ph (3a)
67
54
47
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64
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99:1
4-CF3C6H4 (3g)
4-NO2C6H4 (3h)
2-NO2C6H4 (3i)
4-BrC6H4 (3j)
4-ClC6H4 (3k)
3-ClC6H4 (3l)
2-ClC6H4 (3m)
99:1
99.5:0.5
99.5:0.5
99:1
99:1
99:1
99.5:0.5
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4-MeC6H4 (3n)
4-(MeO)C6H4 (3o)
2-(MeO)C6H4 (3p)
2,4-Cl2C6H3 (3q)
Ph (3a)
61
47
70
62
70
>20:1
>20:1
>20:1
>20:1
>20:1
98.5:1.5
98.5:1.5
>99.5:0.5
99:1
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13d
99:1
a
Reactions realized on a 0.1 mmol scale using 1 (2.0 equiv) and 2a (1.0 equiv) in 0.4 mL of
b
1
c
CH2Cl2 for 2-6 days. Determined by H NMR of a crude reaction mixture. Determined by a
chiral stationary phase HPLC. d The reaction performed on a 1 mmol scale.
Furthermore, disubstituted aromatic rings were well-tolerated as presented in the cascade leading
to the formation of 3q (Table 2 ,entry 12). It is worth to note that the developed cascade was also
performed in a 10-fold larger scale (Table 2, entry 13) providing 3a with comparable results to
those obtained on a 0.1 mmol scale (Table 2, entry 1), thus increasing the attractiveness of our
approach.
Absolute configuration of the product 3b was unequivocally confirmed by the single crystal X-
ray experiment (Scheme 4).10 The same absolute configuration was assigned by analogy to the
remaining naphthalen-1(4H)-ones 3a,c-q.
Scheme 4. 2-Substituted-1,4-naphthoquinones 1 as vinylogous pronucleophiles in asymmetric
organocatalysis – absolute configuration assignment
Given the stereochemical assignments, a plausible reaction mechanism was proposed (Scheme
5). It is postulated that the reaction cascade is initiated by two parallel processes. Firstly, 2-
substituted-1,4-naphthoquinone 1 is deprotonated to generate the corresponding dienolate A.
Secondly, enal 2 is activated through the iminium ion B formation. Subsequently, the first C-C
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bond-forming event takes place. Enantioselectivity of the Michael addition of 1 to 2 is controlled
by the bulky substituent present at the C-2 of the pyrrolidine moiety in B. Notably, the
diastereoselectivity of the addition is a consequence of dienolate A reacting in its E,Z-
configuration (Scheme 5, TS-1). Dienolate A adopts such a reactive configuration in order to
avoid disfavored interactions (between R2 substituent and the sterically demanding substituent of
the iminium ion B) that are present in the alternative transition state (Scheme 5, TS-2)
proceeding through the E,E-configured dienolate A. The conjugate addition leads to the
formation of enamine 6 that undergoes intramolecular aldol reaction to give iminium ion 7.
Subsequent dehydratation and hydrolytic removal of the catalyst affords target product 3.
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O
Ph
O
O
OTMS
N
R1
O
R2
Ph
E,Z-A
Base
R1
B
TS-1
Favoured
Ph
1
Ph
OTMS
5a
N
H
O
CHO
R2
Ph
R1
OTMS
(-H2O)
Ph
2
O
R2
E,E-A
N
B
TS-2
Disfavoured
O
O
R1
R2
R1
HO
O
N
(-H2O)
R2
TMSO
Ph
N
OTMS
Ph
Ph Ph
7
6
O
O
R1
H2O
R1
(-catalyst)
R2
TMSO
Ph
N
R2
OHC
Ph
3
8
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Scheme 5. 2-Substituted-1,4-naphthoquinones 1 as vinylogous pronucleophiles in asymmetric
organocatalysis – mechanistic considerations
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Conclusions
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In conclusion, we have demonstrated for the first time that 2-substituted-1,4-naphthoquinones
1 can serve as pronucleophiles thus providing new opportunities for organic synthesis. The
reaction between 1 and α,β-unsaturated aldehydes 2 proceeded in a vinylogous fashion providing
carboannulated naphthalen-1(4H)-ones 3 in a sequence of reaction involving Michael addition
followed by the intramolecular aldol condensation. The proper choice of reaction conditions
enabled the control of both the site- and stereo-selectivity of the cascade.
Experimental Section
General Information. Unless otherwise noted, analytical grade solvents and commercially
available reagents were used without further purification. NMR spectra were acquired on a
1
Bruker Ultra Shield 700 instrument, running at 700 MHz for H and 176 MHz for 13C,
respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3:
7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR). Mass spectra were recorded on a spectrometer
using electrospray ionization (ESI+) using TOF mass analyzer (referenced to the mass of the
charged species). Optical rotations were measured on a Perkin-Elmer 241 polarimeter and [α]D
values are given in deg•cm•g-1 •dm-1; concentration c is listed in g•(100 mL)-1. Melting points
were determined in open capillaries and are uncorrected. Analytical thin layer chromatography
(TLC) was performed using pre-coated aluminum-backed plates (Merck Kieselgel 60 F254) and
visualized by ultraviolet irradiation. The enantiomeric ratio (er) of the products was determined
by chiral stationary phase HPLC (Daicel Chiralpak IA, IC and ID column). For flash
chromatography (FC) silica gel (Silica gel 60, 230-400 mesh, Fluka) was used. 2-Substituted-
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1,4-naphthoquinones 1a-f11 and aldehydes 2g-q12 were synthetized from the corresponding
5
6
benzaldehydes according to literature procedures.
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Synthesis of 2- substituted-1,4-naphthoquinone 1 – general procedure. AgNO3 (1 mmol) and
(NH4)2S2O8 (20 mmol) were dissolved in water (40 mL) and a solution of 1,4-naphthoquinone
(10 mmol) and 2-phenylacetic acid (20 mmol) in a 1:1 mixture of acetonitrile/dichloromethane
(40 mL) was quickly added. The biphasic mixture was refluxed (bath temperature ca. 80 °C) for
2 hours, cooled to ambient temperature, and dichloromethane (40 mL) was added. The aqueous
layer was separated and extracted again with dichloromethane (40 mL). The combined organic
layers were dried (anhydrous sodium sulphate) and evaporated. Resulting brown oil was purified
by column chromatography (hexane:EtOAc 100:1). Pure products were obtained as yellow
solids.
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2-Benzyl-1,4-naphthoquinone 1a. Following general procedure, pure product 1a was isolated
by FC on silica (hexane:diethyl ether 100:1) in 71% yield as an yellow solid (mp = 85-86 ˚C). 1H
NMR (700 MHz, CDCl3) δ 8.12–8.10 (m, 1H), 8.06-8.03 (m, 1H), 7.73–7.72 (m, 2H), 7.35-7.33
(m, 2H), 7.27–7.25 (m, 3H), 6.61 (t, J = 1.6 Hz, 1H), 3.90 (d, J = 1.4 Hz, 2H). 13C NMR (176
MHz, CDCl3) δ 185.3, 185.2, 151.0, 136.9, 135.8, 134.0, 133.9, 132.4, 132.2, 129.6 (2C), 129.0
(2C), 127.1, 126.8, 126.3, 35.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H13O2 249.0910;
Found: 249.0913.
2-(4-Chlorobenzyl)-1,4-naphthoquinone 1b. Following general procedure, pure product 1b
was isolated by FC on silica (hexane:diethyl ether 100:1) in 57% yield as an yellow solid (mp =
1
98-100 ˚C). H NMR (700 MHz, CDCl3) δ 8.10 (ddd, J = 4.6, 3.0, 0.5 Hz, 1H), 8.05 (ddd, J =
3.9, 3.0, 0.5 Hz, 1H), 7.75–7.71 (m, 2H), 7.32–7.28 (m, 2H), 7.21–7.17 (m, 2H), 6.62 (t, J = 1.5
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Hz, 1H), 3.87 (d, J = 1.4 Hz, 2H). C NMR (176 MHz, CDCl3) δ 185.1, 185.0, 150.4, 136.0,
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135.4, 134.0, 134.0, 133.1, 132.2, 132.2, 131.0 (2C), 129.1 (2C), 126.8, 126.3, 35.3. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H12ClO2 283.0520; Found: 283.0526.
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2-(3-Chlorobenzyl)-1,4-naphthoquinone 1c. Following general procedure, pure product 1c was
isolated by FC on silica (hexane:diethyl ether 100:1) in 43% yield as an yellow solid (mp = 75-
77 ˚C). 1H NMR (700 MHz, CDCl3) δ 8.11 (ddd, J = 4.8, 2.9, 0.5 Hz, 1H), 8.06 (ddd, J = 4.1,
2.9, 0.5 Hz, 1H), 7.74 (ddd, J = 5.0, 4.5, 3.6 Hz, 2H), 7.29–7.21 (m, 3H), 7.14 (dt, J = 7.2, 1.6
Hz, 1H), 6.63 (t, J = 1.5 Hz, 1H), 3.87 (d, J = 1.3 Hz, 2H). 13C NMR (176 MHz, CDCl3) δ 185.1,
184.9, 150.1, 139.0, 136.0 (2C), 134.8, 134.0, 133.9, 132.2, 130.2, 129.6, 127.7, 127.4, 126.9,
126.3, 35.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H12ClO2 283.0520; Found:
283.0522.
2-(2-Chlorobenzyl)-1,4-naphthoquinone 1d. Following general procedure, pure product 1d
was isolated by FC on silica (hexane:diethyl ether 100:1) in 68% yield as an yellow solid (mp =
1
108-110 ˚C). H NMR (700 MHz, CDCl3) δ 8.16–8.12 (m, 1H), 8.07–8.03 (m, 1H), 7.75–7.73
(m, 2H), 7.42-7.41 (m, 1H), 7.28–7.23 (m, 3H), 6.44 (t, J = 1.7 Hz, 1H), 4.05 (d, J = 1.7 Hz, 2H).
13C NMR (176 MHz, CDCl3) δ 185.1, 185.0, 149.3, 135.7, 134.7, 133.9 (2C), 132.3 (2C), 132.0,
130.1, 128.9, 127.4, 126.8 (2C), 126.3, 33.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H12ClO2 283.0520; Found: 283.0517.
2-(p-Tolyl)-1,4-naphthoquinone 1e. Following general procedure, pure product 1e was isolated
by FC on silica (hexane:diethyl ether 100:1) in 69% yield as an yellow solid (mp = 90-93 ˚C). 1H
NMR (700 MHz, CDCl3) δ 8.15–8.11 (m, 1H), 8.09–8.04 (m, 1H), 7.76–7.72 (m, 2H), 7.20–7.17
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(m, 2H), 6.91–6.88 (m, 2H), 6.62 (t, J = 1.5 Hz, 1H), 3.86 (d, J = 1.5 Hz, 2H), 3.82 (s, 3H). C
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NMR (176 MHz, CDCl3) δ 185.0, 184.9, 150.1, 139.0 (2C), 136.0, 134.8 (2C), 134.0, 133.9,
132.2, 130.2, 129.6, 127.7, 127.4, 126.9, 126.3, 35.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H15O2 263.1067; Found: 263.1062.
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2-(4-Methoxybenzyl)-1,4-naphthoquinone 1f. Following general procedure, pure product 1f
was isolated by FC on silica (hexane:diethyl ether 100:1) in 71% yield as an yellow solid (mp =
1
74-76 ˚C). H NMR (700 MHz, CDCl3) δ 8.10–8.09 (m, 1H), 8.04–8.03 (m, 1H), 7.72–7.71 (m,
2H), 7.17–7.15 (m, 2H), 6.87–6.86 (m, 2H), 6.60 (t, J = 1.5 Hz, 1H), 3.84 (d, J = 1.5 Hz, 2H),
3.79 (s, 3H). 13C NMR (176 MHz, CDCl3) δ 185.3, 185.2, 158.7, 151.4, 135.6, 133.9, 133.8,
132.3, 132.2, 130.6 (2C), 128.7, 126.8, 126.2, 114.4 (2C), 55.4, 35.1. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C18H15O3 279.1016; Found: 279.1022.
General Procedure for the Synthesis of Compounds 3a-q. In an ordinary 4 mL glass vial,
equipped with a magnetic stirring bar and a screw cap, catalyst 5a (0.3 equiv, 0.03 mmol, 9.8
mg) and α,β-unsaturated aldehyde 2 (1.0 equiv, 0.1 mmol) were dissolved in CH2Cl2 (0.2 mL).
Subsequently, the mixture was cooled to 5 °C and a solution of the corresponding 2-alkyl-1,4-
naphthoquinone 1 (2 equiv, 0.2 mmol) and 4-dimethylaminobenzoic acid (0.2 equiv, 0.02 mmol,
3.3 mg) in CH2Cl2 (0.2 mL) was added and stirring was continued for 2-6 days at 5 °C. Crude
product was purified by the flash chromatography on silica gel.
(2R,3R)-5-Oxo-2,3-diphenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-carbaldehyde
3a.
Following general procedure, pure product 3a was isolated after 3 days by FC on silica
(hexane:diethyl ether 4:1) in 67% yield (24 mg, >20:1 dr, 3a:4a 90:10) as an yellow solid (mp =
1
88-90 ˚C). H NMR (700 MHz, CDCl3) δ 10.64 (s, 1H), 8.35–8.31 (m, 1H), 8.29–8.22 (m, 1H),
7.78–7.68 (m, 2H), 7.35–7.28 (m, 5H), 7.27-7.25 (m, 1H), 7.17–7.09 (m, 4H), 6.40 (dd, J = 2.0,
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0.8 Hz, 1H), 4.55 (d, J = 2.7 Hz, 1H), 4.18 (t, J = 2.4 Hz, 1H). C NMR (176 MHz, CDCl3) δ
189.3, 184.6, 166.7, 148.9, 142.1, 141.7, 141.2, 132.5, 131.9, 131.4, 130.2, 129.3 (2C), 129.2
(2C), 128.7, 128.0, 127.8 (2C), 127.7, 127.6, 127.5 (2C), 125.8, 60.5, 57.2. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C26H19O2+H+ 363.1380; Found: 363.1387. The er was determined by
HPLC using a chiral Chiralpack IA [hexane:i-PrOH, 90:10] column; column temperature 30 °C;
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flow rate 1.0 mL/min; tmajor = 10.7 min, tminor = 13.4 min (99:1 er); [α]D = -254.3 (c = 1.0,
CHCl3).
(2R,3R)-3-(4-Chlorophenyl)-5-oxo-2-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3b. Following general procedure, pure product 3b was isolated after 2 days by FC
on silica (hexane:diethyl ether 4:1) in 72% yield (29 mg, >20:1 dr, 3b:4b 91:9) as a green solid
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(mp = 130-132 ˚C). H NMR (700 MHz, CDCl3) δ 10.63 (s, 1H), 8.36–8.32 (m, 1H), 8.27–8.22
(m, 1H), 7.77–7.69 (m, 2H), 7.34–7.30 (m, 4H), 7.28–7.26 (m, 1H), 7.15–7.12 (m, 2H), 7.07–
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7.04 (m, 2H), 6.37 (d, J = 1.5 Hz, 1H), 4.48 (d, J = 2.8 Hz, 1H), 4.15 (t, J = 2.4 Hz, 1H). C
NMR (176 MHz, CDCl3) δ 189.2, 184.4 , 166.0, 148.6, 142.0, 141.4, 139.6, 133.7, 132.6, 131.8,
131.5, 130.1, 129.5, 129.3, 129.2 (2C), 128.7 (2C), 128.1 (2C), 127.7, 127.4 (2C), 125.8, 60.5,
56.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18ClO2 397.0990; Found: 397.0991. The
er was determined by HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20] column;
column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 17.9 min, tminor = 22.1 min (98.5:1.5
er); [α]D20 = -256.3 (c = 1.0, CHCl3).
(2R,3R)-3-(3-Chlorophenyl)-5-oxo-2-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3c. Following general procedure, pure product 3c was isolated after 2 days by FC
on silica (hexane:diethyl ether 4:1) in 52% yield (21 mg, 18:1 dr, 3c:4c 88:12) as an yellow solid
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(mp = 118-120 ˚C). H NMR (700 MHz, CDCl3) δ 10.63 (s, 1H), 8.36–8.32 (m, 1H), 8.26–8.23
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(m, 1H), 7.76–7.71 (m, 2H), 7.34–7.30 (m, 2H), 7.30–7.27 (m, 3H), 7.16–7.12 (m, 2H), 7.12–
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7.09 (m, 1H), 7.02–6.98 (m, 1H), 6.39 (dd, J = 2.0, 0.6 Hz, 1H), 4.52 (d, J = 2.7 Hz, 1H), 4.16–
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4.10 (m, 1H). C NMR (176 MHz, CDCl3) δ 189.1, 184.4, 165.8, 148.6, 143.2, 141.9, 141.4,
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135.2, 132.6, 131.8, 131.6, 130.6, 130.1, 129.3 (2C), 128.7, 128.1, 128.0, 127.9, 127.7, 127.4
(2C), 126.1, 126.0, 60.3, 56.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18ClO2
397.0990; found: 397.0999. The er was determined by HPLC using a chiral Chiralpack IC
[hexane:i-PrOH, 80:20] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 16.0
min, tminor = 18.6 min (99:1 er); [α]D20 = -258.8 (c = 1.0, CHCl3).
(2R,3S)-3-(2-Chlorophenyl)-5-oxo-2-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3d. Following general procedure, pure product 3d was isolated after 5 days by FC
on silica (hexane:diethyl ether 4:1) in 65% yield (26 mg, >20:1 dr, 3d:4d 98:2) as a green
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.62 (s, 1H), 8.37–8.33 (m, 1H), 8.27–8.23 (m,
1H), 7.75–7.70 (m, 2H), 7.42 (dd, J = 7.9, 1.5 Hz, 1H), 7.31 (dd, J = 10.2, 4.7 Hz, 2H), 7.27–
7.23 (m, 3H), 7.21 (td, J = 7.5, 1.5 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.05 (dd, J = 7.5, 1.5 Hz,
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1H), 6.41 (bs, 1H), 4.66 (bs, 1H), 4.60 (bs, 1H). C NMR (176 MHz, CDCl3) δ 189.2, 184.5,
165.8, 149.0, 141.8, 141.6, 134.2, 132.5, 131.9, 131.4, 130.4, 130.2, 129.1 (2C), 129.0 (3C),
128.7, 128.0, 127.6 (4C), 125.4, 59.1, 58.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C26H18ClO2 397.0990; Found: 397.0983. The er was determined by HPLC using a chiral
Chiralpack IC [hexane:i-PrOH, 80:20] column; column temperature 30 °C; flow rate 1.0
mL/min; tmajor = 14.4 min, tminor = 15.8 min (99:1 er); [α]D20 = -181.1 (c = 1.0, CHCl3).
(2R,3R)-5-Oxo-2-phenyl-3-(p-tolyl)-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3e. Following general procedure, pure product 3e was isolated after 6 days by FC
on silica (hexane:diethyl ether 4:1) in 62% yield (23 mg, >20:1 dr, 3e:4e 88:12) as an yellow
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amorphous solid. H NMR (700 MHz, CDCl3) δ 10.63 (s, 1H), 8.33 (ddd, J = 8.6, 4.1, 3.3 Hz,
1H), 8.26–8.22 (m, 1H), 7.76–7.67 (m, 2H), 7.32–7.29 (m, 2H), 7.28–7.24 (m, 1H), 7.16–7.13
(m, 4H), 7.02–6.99 (m, 2H), 6.39 (dd, J = 2.0, 0.7 Hz, 1H), 4.53 (d, J = 2.7 Hz, 1H), 4.14 (t, J =
2.4 Hz, 1H), 2.34 (s, 3H). 13C NMR (176 MHz, , CDCl3) δ 189.4, 184.6, 166.9, 149.0, 142.0,
141.8, 138.1, 137.4, 132.5, 131.9, 131.4, 130.2, 130.0 (2C), 129.2 (2C), 128.7, 128.0, 127.7 (2C),
127.5, 127.4 (2C), 125.7, 60.5, 56.9, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H21O2
377.1537; Found: 377.1544. The er was determined by HPLC using a chiral Chiralpack IC
[hexane:i-PrOH, 80:20] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 15.5
min, tminor = 18.0 min (99:1 er); [α]D20=-214.2 (c = 1.0, CHCl3).
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(2R,3S)-3-(4-Methoxyphenyl)-5-oxo-2-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3f. Following general procedure, pure product 3f was isolated after 5 days by FC
on silica (hexane:diethyl ether 4:1) in 55% yield (22 mg, >20:1 dr, 3f:4f 87:13) as an yellow
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.62 (s, 1H), 8.35–8.31 (m, 1H), 8.26–8.23 (m,
1H), 7.74–7.69 (m, 2H), 7.33–7.28 (m, 2H), 7.28–7.23 (m, 1H), 7.16–7.12 (m, 2H), 7.05–7.01
(m, 2H), 6.88–6.83 (m, 2H), 6.38 (dd, J = 2.0, 0.6 Hz, 1H), 4.50 (d, J = 2.8 Hz, 1H), 4.12 (t, J =
2.4 Hz, 1H), 3.80 (s, 3H). 13C NMR (176 MHz, CDCl3) δ 189.4, 184.6, 167.0, 159.2, 148.9,
142.0, 141.8, 133.1, 132.5, 131.9, 131.4, 130.2, 129.2 (2C), 128.9 (2C), 128.7, 128.0, 127.5,
127.4 (2C), 125.6, 114.7 (2C), 60.7, 56.6, 55.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C27H21O3 393.1486; Found: 393.1490. The er was determined by HPLC using a chiral
Chiralpack IC [hexane:i-PrOH, 80:20] column; column temperature 30 °C; flow rate 1.0
mL/min; tmajor = 25.4 min, tminor =28.1 min (99.5:0.5 er); [α]D20 = -256.3 (c = 1.0, CHCl3).
(2R,3R)-5-Oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-
cyclopenta[a]naphthalene-1-carbaldehyde 3g. Following general procedure, pure product 3g
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was isolated after 3 days by FC on silica (hexane:diethyl ether 4:1) in 54% yield (23 mg, >20:1
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dr, 3g:4g 93:7) as an yellow amorphous solid. H NMR (700 MHz, CDCl3) δ 10.71 (s, 1H),
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8.36–8.32 (m, 1H), 8.23–8.18 (m, 1H), 7.78–7.71 (m, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.36–7.32
(m, 2H), 7.31 (m, 1H), 7.27–7.25 (d, J = 8.1 Hz, 2H), 7.12–7.08 (m, 2H), 6.39 (dd, J = 2.1, 0.8
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Hz, 1H), 4.58 (d, J = 3.0 Hz, 1H), 4.13 (dd, J = 3.0, 2.1 Hz, 1H). C NMR (176 MHz, CDCl3)
188.7, 184.4, 166.0, 147.7, 145.9, 143.6, 140.6, 132.6, 131.9, 131.7, 130.0, 129.8 (q, JC-F = 32.6
Hz), 129.5 (2C), 128.7, 128.2, 128.0, 127.8 (2C), 127.7 (2C), 126.2 (q, JC-F = 3.7 Hz, 2C), 126.0,
124.2 (q, JC-F = 273.0 Hz), 59.9, 57.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H18F3O2
431.1253; Found: 431.1255. The er was determined by HPLC using a chiral Chiralpack IC
[hexane:i-PrOH, 90:10] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 19.3
min, tminor = 21.0 min (99:1 er); [α]D20 = -211.6 (c = 1.0, CHCl3).
(2R,3R)-2-(4-Nitrophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3h. Following general procedure, pure product 3h was isolated after 4 days by FC
on silica (hexane:diethyl ether 4:1) in 47% yield (19 mg, >20:1 dr, 3h:4h 88:12) as an yellow
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solid (mp = 123-125 ˚C). H NMR (700 MHz, CDCl3) δ 10.75 (s, 1H), 8.36–8.31 (m, 1H), 8.19
(dd, J = 7.4, 1.6 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.77–7.74 (m, 2H), 7.38–7.32 (m, 3H), 7.31
(d, J = 8.8 Hz, 2H), 7.13–7.08 (m, 2H), 6.38 (dd, J = 2.1, 0.7 Hz, 1H), 4.60 (d, J = 3.3 Hz, 1H),
4.12 (dd, J = 3.3, 2.1 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ 188.5, 184.3, 165.5, 149.4, 148.9,
147.3, 146.8, 143.8, 140.1, 132.7, 131.9 (4C), 129.8, 129.5, 129.2, 128.7, 128.3, 128.2, 127.9,
126.1, 124.5, 124.4, 59.7, 56.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18NO4
408.1230; Found: 408.1237. The er was determined by HPLC using a chiral Chiralpack IC
[hexane:i-PrOH, 80:20] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 18.0
min, tminor = 20.5 min (>99.5:0.5 er); [α]D20 = -383.8 (c = 1.0, CHCl3).
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(2R,3R)-2-(2-Nitrophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3i. Following general procedure, pure product 3i was isolated after 3 days by FC
on silica (hexane:diethyl ether 4:1) in 50% yield (20 mg, >20:1 dr, 3i:4i 82:18) as an yellow
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.68 (s, 1H), 8.37–8.30 (m, 1H), 8.22–8.15 (m,
1H), 7.85 (dd, J = 8.3, 1.4 Hz, 1H), 7.78–7.71 (m, 2H), 7.51 (td, J = 7.4, 1.4 Hz, 1H), 7.40 (ddd,
J = 8.3, 7.4, 1.4 Hz, 1H), 7.36–7.30 (m, 3H), 7.22–7.18 (m, 1H), 7.16–7.11 (m, 2H), 6.38 (d, J =
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1.6 Hz, 1H), 5.24 (bs, 1H), 4.27 (bs, 1H). C NMR (176 MHz, CDCl3) δ 188.4, 184.3, 166.0,
165.5, 149.5, 147.1, 143.3, 140.2, 134.1, 133.3, 132.6, 131.8, 131.7, 129.9, 129.3 (2C), 128.7,
128.3, 128.1, 128.0, 127.9 (2C), 126.1, 125.0, 61.1, 56.7. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C26H18NO4 408.1230; Found: 408.1238. The er was determined by HPLC using a
chiral Chiralpack IC [hexane:i-PrOH, 90:10] column; column temperature 30 °C; flow rate 1.0
mL/min; tmajor = 24.7min, tminor = 28.4 min (>99.5:0.5 er); [α]D20 = -157.6 (c = 1.0, CHCl3).
(2R,3R)-2-(4-Bromophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1
carbaldehyde 3j. Following general procedure, pure product 3j was isolated after 2 days by FC
on silica (hexane:diethyl ether 4:1) in 55% yield (24 mg, >20:1 dr, 3j:4j 92:2) as an yellow solid
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(mp = 130-132 ˚C). H NMR (700 MHz, CDCl3) δ 10.67 (s, 1H), 8.33 (m, 1H), 8.21 (m, 1H),
7.76–7.71 (m, 2H), 7.46–7.40 (m, 2H), 7.35–7.32 (m, 2H), 7.32–7.28 (m, 1H), 7.10 (m, 2H),
7.05–6.99 (m, 2H), 6.38 (dd, J = 2.0, 0.6 Hz, 1H), 4.49 (d, J = 2.9 Hz, 1H), 4.11–4.10 (m, 1H).
13C NMR (176 MHz, CDCl3) δ 188.9, 184.4, 166.2, 148.0, 143.0, 140.9, 140.7, 132.6, 132.3
(2C), 131.9, 131.6, 130.0, 129.4 (2C), 129.11 (2C), 128.7, 128.1, 127.9, 127.8 (2C), 125.9,
121.4, 59.7, 57.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18BrO2 441.0485; Found:
441.0477. The er was determined by HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20]
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column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 18.1 min, tminor = 22.8 min
(99:1 er); [α]D20 = -285.9 (c = 1.0, CHCl3).
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(2R,3R)-2-(4-Chlorophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3k. Following general procedure, pure product 3k was isolated after 3 days by FC
on silica (hexane:diethyl ether 4:1) in 52% yield (21 mg, >20:1 dr, 3k:4k 93:7) as an yellow
solid (mp = 118-120 ˚C). 1H NMR (700 MHz, CDCl3) δ 10.67 (s, 1H), 8.34–8.32 (m, 1H), 8.22–
8.20 (m, 1H), 7.76–7.71 (m, 2H), 7.37–7.32 (m, 2H), 7.32–7.27 (m, 3H), 7.09 (m, 4H), 6.38 (dd,
J = 2.0, 0.6 Hz, 1H), 4.50 (d, J = 2.9 Hz, 1H), 4.12–4.10 (m, 1H). 13C NMR (176 MHz, CDCl3) δ
189.7, 184.4, 166.2, 148.1, 142.7, 140.7, 140.3, 133.4, 132.6, 131.9, 131.6, 130.1, 129.4 (2C),
129.3 (2C), 128.8 (2C), 128.7, 128.1, 127.9, 127.8 (2C), 125.9, 59.6, 57.1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C26H18ClO2 397.0990; Found: 397.0988. The er was determined by
HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20] column; column temperature 30 °C;
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flow rate 1.0 mL/min; tmajor = 17.0 min, tminor = 21.3 min (99:1 er); [α]D = -336.8 (c = 1.0,
CHCl3).
(2R,3R)-2-(3-Chlorophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3l. Following general procedure, pure product 3l was isolated after 2 days by FC
on silica (hexane:diethyl ether 4:1) in 56% yield (22 mg, >20:1 dr, 3l:4l 88:12) as a green
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.69 (s, 1H), 8.35–8.33 (m, 1H), 8.23–8.21 (m,
1H), 7.76–7.71 (m, 2H), 7.36–7.33 (m, 2H), 7.32–7.28 (m, 1H), 7.25–7.24 (m, 2H), 7.13–7.10
(m, 3H), 7.06–7.02 (m, 1H), 6.38 (dd, J = 2.0, 0.7 Hz, 1H), 4.50 (d, J = 2.9 Hz, 1H), 4.15–4.13
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(m, 1H). C NMR (176 MHz, CDCl3) δ 188.9, 184.4, 166.1, 147.9, 143.9, 142.8, 140.8, 135.0,
132.6, 131.9, 131.6, 130.4, 130.0, 129.4 (2C), 128.7, 128.1, 127.9, 127.8 (2C), 127.7, 127.3,
126.0, 125.8, 59.8, 56.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18ClO2 397.0990;
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Found: 397.0995. The er was determined by HPLC using a chiral Chiralpack IA [hexane:i-
PrOH, 90:10] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 11.2 min, tminor
= 13.7 min (99:1 er); [α]D20 = -360.3 (c = 1.0, CHCl3).
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(2R,3R)-2-(2-Chlorophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3m. Following general procedure, pure product 3m was isolated after 2 days by
FC on silica (hexane:diethyl ether 4:1) in 64% yield (25 mg, >20:1 dr, 3m:4m 91:9) as an yellow
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solid (mp = 98-100 ˚C). H NMR (700 MHz, CHCl3) δ 10.68 (s, 1H), 8.35–8.31 (m, 1H), 8.25
(m, 1H), 7.78–7.68 (m, 2H), 7.38 (m, 1H), 7.35–7.31 (m, 2H), 7.31–7.27 (m, 1H), 7.27–7.17 (m,
2H), 7.17–7.13 (m, 2H), 7.06–7.03 (m, 1H), 6.37 (d, J = 2.1 Hz, 1H), 5.09 (bs, 1H), 4.19 (bs,
13
1H). C NMR (176 MHz, CHCl3) δ 188.8, 184.5, 166.4, 148.4, 142.6, 140.8, 133.8, 132.5,
131.8, 131.4 (2C), 130.4, 130.1, 129.2 (2C), 128.7 (2C), 128.6, 128.0, 127.9 (2C), 127.7, 127.5,
125.7, 56.4, 56.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H18ClO2 397.0990; Found:
397.0993. The er was determined by HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20]
column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 16.3 min, tminor = 18.0 min
(99.5:0.5 er); [α]D20 = -121.9 (c = 1.0, CHCl3).
(2R,3R)-5-Oxo-3-phenyl-2-(p-tolyl)-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3n. Following general procedure, pure product 3n was isolated after 3 days by FC
on silica (hexane:diethyl ether 4:1) in 61% yield (23 mg, >20:1 dr, 3n:4n 98:2) as a brown
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.61 (s, 1H), 8.35–8.32 (m, 1H), 8.26–8.24 (m,
1H), 7.75–7.69 (m, 2H), 7.35–7.31 (m, 2H), 7.30–7.27 (m, 1H), 7.14–7.10 (m, 4H), 7.04 (d, J =
8.1 Hz, 2H), 6.39 (dd, J = 2.0, 0.6 Hz, 1H), 4.52 (d, J = 2.6 Hz, 1H), 4.16-4.15 (m, 1H), 2.33 (s,
3H). 13C NMR (176 MHz, CDCl3) δ 189.5, 184.6, 166.8, 149.1, 141.8, 141.2, 138.7, 137.3,
132.3, 131.9, 131.4, 130.3, 129.9 (2C), 129.3 (2C), 128.7, 128.0, 127.8 (2C), 127.7, 127.3 (2C),
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125.7, 60.2, 57.3, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H21O2 377.1537; Found:
377.1530. The er was determined by HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20]
column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 15.7 min, tminor = 17.7 min
(98.5:1.5 er); [α]D20 = -199.9 (c = 1.0, CHCl3).
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(2R,3R)-2-(4-Methoxyphenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3o. Following general procedure, pure product 3o was isolated after 2 days by FC
on silica (hexane:diethyl ether 4:1) in 47% yield (18 mg, >20:1 dr, 3o:4o 93:7) as an yellow solid
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(mp = 100-102 ˚C). H NMR (700 MHz, CDCl3) δ 10.60 (s, 1H), 8.35–8.32 (m, 1H), 8.27–8.24
(m, 1H), 7.75–7.69 (m, 2H), 7.34–7.31 (m, 2H), 7.30–7.27 (m, 1H), 7.13–7.09 (m, 2H), 7.09–
7.05 (m, 2H), 6.87–6.82 (m, 2H), 6.39 (dd, J = 2.0, 0.6 Hz, 1H), 4.50 (d, J = 2.7 Hz, 1H), 4.15 (t,
13
J = 2.4 Hz, 1H), 3.79 (s, 3H). C NMR (176 MHz, CDCl3) δ 189.5, 184.6, 166.7, 159.1, 149.1,
141.6, 141.2, 133.7, 132.5, 131.9, 131.4, 130.3, 129.3 (2C), 128.7, 128.5 (2C), 128.0, 127.8 (2C),
127.7, 125.7, 114.6 (2C), 59.9, 57.4, 55.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H21O3
393.1486; Found: 393.1488. The er was determined by HPLC using a chiral Chiralpack IA
[hexane:i-PrOH, 90:10] column; column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 14.3
min, tminor = 21.5 min (98.5:1.5 er); [α]D20 = -193.7 (c = 1.0, CHCl3).
(2R,3R)-2-(2-Methoxyphenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3p. Following general procedure, pure product 3p was isolated after 4 days by FC
on silica (hexane:diethyl ether 4:1) in 70% yield (27 mg, >20:1 dr, 3p:4p 89:11) as an yellow
solid (mp = 158-160 ˚C). 1H NMR (700 MHz, CDCl3) δ 10.59 (s, 1H), 8.34–8.32 (m, 1H), 8.28–
8.26 (m, 1H), 7.74–7.68 (m, 2H), 7.33–7.30 (m, 2H), 7.28–7.26 (m, 1H), 7.26–7.23 (m, 1H),
7.15–7.13 (m, 2H), 7.00–6.98 (m, 1H), 6.90–6.87 (m, 2H), 6.36 (dd, J = 2.0, 0.8 Hz, 1H), 4.82
(d, J = 2.8 Hz, 1H), 4.22–4.18 (m, 1H), 3.66 (s, 3H). 13C NMR (176 MHz, CDCl3) δ 189.5,
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184.8, 167.2, 157.1, 150.0, 141.6, 141.2, 132.4, 131.8, 131.1, 130.4, 129.3, 129.1, 129.0 (2C),
128.8, 128.6, 128.0 (2C), 127.9, 127.4, 125.1, 121.1, 111.4, 56.2, 55.7, 55.5. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C27H21O3 393.1486; Found: 393.1481. The er was determined by HPLC
using a chiral Chiralpack ID [hexane:i-PrOH, 90:10] column; column temperature 30 °C; flow
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rate 1.0 mL/min; tmajor = 24.1 min, tminor = 25.3 min (>99.5:0.5 er); [α]D = -199.9 (c = 1.0,
CHCl3).
(2S,3R)-2-(2,4-Dichlorophenyl)-5-oxo-3-phenyl-3,5-dihydro-2H-cyclopenta[a]naphthalene-1-
carbaldehyde 3q. Following general procedure, pure product 3q was isolated after 3 days by FC
on silica (hexane:diethyl ether 4:1) in 62% yield (27 mg, >20:1 dr, 3q:4q 99:1) as an yellow
amorphous solid. 1H NMR (700 MHz, CDCl3) δ 10.71 (s, 1H), 8.42–8.30 (m, 1H), 8.26–8.15 (m,
1H), 7.76-7.72 (m, 2H), 7.40 (m,1H), 7.35–7.28 (m, 3H), 7.18 (dd, J = 8.3, 2.2 Hz, 1H), 7.15–
7.12 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.40–6.33 (m, 1H), 5.00 (bs, 1H), 4.14 (bs, 1H). 13C
NMR (176 MHz, CDCl3) δ 188.5, 184.4, 165.9, 159.5, 147.9, 143.0, 140.5, 133.8, 132.6, 131.8,
131.6, 130.2, 130.0, 129.5, 129.3 (2C), 128.6, 128.1, 127.9 (2C), 127.9, 127.8, 127.0, 125.9,
62.0, 54.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H17Cl2O2 431.0600; Found: 431.0609.
The er was determined by HPLC using a chiral Chiralpack IC [hexane:i-PrOH, 80:20] column;
column temperature 30 °C; flow rate 1.0 mL/min; tmajor = 15.1 min, tminor = 17.7 min (99:1 er);
[α]D20 = -147.7 (c = 1.0, CHCl3).
1
Supporting Information. Full account of screening results, X-ray structure, copies of H and
13C NMR spectra, HPLC traces (PDF).
AUTHOR INFORMATION
Corresponding Author
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e-mail: lukasz.albrecht@p.lodz.pl, www.a-teamlab.p.lodz.pl
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Author Contributions
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All authors have given approval to the final version of the manuscript. ‡ These authors
contributed equally.
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Funding Sources
National Science Centre, Poland, Sonata Bis programme (grant number: 2015/18/E/ST5/00309)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This project was realized within the Sonata Bis programme (grant number:
2015/18/E/ST5/00309) from the National Science Centre, Poland. Thanks are expressed to Dr.
Jakub Wojciechowski (Faculty of Chemistry, Lodz University of Technology) for performing X-
ray analysis.
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